Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of the p38 and p42/44 mitogen-activated protein kinases

IL-10 is an anti-inflammatory cytokine with potent immunomodulatory effects, including inhibition of cytokine production. However, regulation of monocyte IL-10 production is poorly understood. In this report we have investigated the mechanisms of LPS-induced IL-10 production by human peripheral blood monocytes and demonstrate that IL-10 synthesis is uniquely dependent on the endogenous proinflammatory cytokines IL-1 and/or TNF-alpha. LPS signal transduction in monocytes has been shown to involve activation of the p38 and p42 mitogen-activated protein kinase (MAPK) cascades. The results in this paper indicate that inhibition of p38 MAPK potently inhibited the production of IL-10, IL-1beta, and TNF-alpha, whereas blockade of the p42/44 MAPK pathway, while partially inhibiting TNF-alpha and IL-1beta production, had no effect on monocyte secretion of IL-10. Furthermore, neither the inhibition of monocyte TNF-alpha induced by IL-10 nor the stimulation of soluble TNF receptor production was affected by inhibition of the p42/44 MAPK pathway, suggesting that this signaling event is not involved in either monocyte production of or anti-inflammatory responses to IL-10. These data raise the interesting possibility that proinflammatory TNF-alpha-mediated effects may be selectively blocked without modulating the induction or the response to IL-10, whereas the signaling events associated with the anti-inflammatory events induced by IL-10 remain to be elucidated.     

The low-affinity dihydropyridine receptor and Na+/Ca2+ exchanger are associated in adrenal medullary mitochondria

The effect of Ca2+ channel-acting drugs on bovine adrenal mitochondria Ca2+ movements was investigated. Mitochondrial Ca2+ uptake is performed by an energy-driven Ca2+ uniporter with a Km of 20.9 +/- 3.2 microM and Vmax of 148.1 +/- 7.2 nmol 45Ca2+ min-1 mg-1. Ca2+ release is performed through an Na+/Ca2+ antiporter with a Km for Na+ of 4.2 +/- 0.5 mM, a Vmax of 7.5 +/- 0.4 nmol 45Ca2+ min-1 mg-1, and a Hill coefficient of 1.4 +/- 0.2 Ca2+ efflux through the mitochondrial Na+/Ca2+ exchanger was inhibited by several dihydropyridines (nitrendipine, felodipine, nimodipine, (+)isradipine) and by the benzothiazepine diltiazem with similar potencies. In contrast, neither CGP 28392, Bay-K-8644, amlodipine, nor verapamil had any effect on Ca2+ efflux. Nitrendipine at 20 microM modified neither the Km nor the Hill coefficient for Na+, whereas the Vmax was reduced to 2.9 nmol 45Ca2+ min-1 mg-1, thus demonstrating noncompetitive modulation of the Na+/Ca2+ exchanger. None of the Ca2+ channel-acting drugs assayed at 100 microM affected Ca2+ influx through the uniporter. Ca2+ channel blockers inhibited the Na+/Ca2+ antiporter and displaced the specific binding of [3H]nitrendipine to intact mitochondria with Ki values similar to the IC50s obtained for the inhibition of the Ca2+ efflux. Ca2+ channel-acting drugs that did not inhibit the Na+/Ca2+ exchanger (amlodipine, CGP 28392, Bay-K-9644, and verapamil, at concentrations of 100 microM or higher) had no effect on [3H]nitrendipine binding. These results suggest that the adrenomedullary mitochondrial dihydropyridine receptor is associated with the Na+/Ca2+ exchanger.     

Canine bronchial sustained contraction in Ca2+-free medium: role of intracellular Ca2+

We evaluated whether cartilage was a source of Ca2+ and the possible role of Ca2+ recycling in the sustained bronchial contraction (SBC) induced by carbachol (Cch) in Ca2+-free medium. Canine first-order bronchi were studied with cartilage and epithelium (+CAR + EPI) and without these structures individually (-CAR + EPI and +CAR - EPI) or together (-CAR - EPI). After cartilage removal (-CAR - EPI or -CAR + EPI) Cch produced a transient contraction in Ca2+-free medium. Removal of the epithelium alone had minor effects on the magnitude of the SBC but increased the effect of removal of cartilage to diminish the SBC. Bronchial strips with cartilage were able to respond to Cch with lower Ca2+ concentrations (10-100 microM) than could dissected preparations. Preincubation with BAY K 8644 (30-1000 nM) or 60 mM KCl or -CAR - EPI tissues converted the transient contractions to Cch in Ca2+-free medium to sustained contractions. In microelectrode studies, 50 nM Cch induced membrane oscillations in solutions with 2.5 mM Ca2+ in bronchial preparations, plus or minus cartilage, and in undissected tissues in Ca2+-free medium but not in -CAR - EPI tissues. Preincubation with 1 microM BAY K 8644 in Ca(2+)-free medium restored these oscillations in -CAR - EPI tissues. The release of 45Ca2+ from cartilage was too rapid to provide a reservoir of Ca2+ to support multiple SBCs in Ca2+-free medium. Moreover, in the Ca2+-free medium (with 10 nM Ca2+ after tissue +CAR + EPI incubation) excitatory junction potentials rapidly disappeared. Addition of 1 microM nifedipine or 1 mM EGTA during the SBC of +CAR + EPI tissues produced complete relaxation. A transient contraction to Cch occurred with prior addition of nifedipine. Inhibition of the sarcoplasmic reticulum Ca2+ pump by tissue incubation with cyclopiazonic acid (CPA; 10 microM), or briefly with 1 mM EGTA significantly diminished the SBC induced by Cch in Ca2+-free medium. CPA and EGTA together abolished the Cch-induced SBC. Thus, cartilage plays a more complex role than as a Ca2+ reservoir to support the SBC induced by Cch in Ca2+-free solution; its removal affects the process supporting SBCs involving intracellular Ca2+ storage and Ca2+ entrance through voltage-dependent channels.     

Thoracoscopic-assisted pulmonary resection in lung cancer

BACKGROUND: Thoracoscopic-assisted pulmonary resection for lung cancer is controversial. The appropriateness of this approach has to be compared with the golden standard of an open resection. METHODS: This study consists of 66 patients with a clinical stage 1 disease. A thoracoscopic exploration was executed in 41 patients. Only in 16 cases was a thoracoscopic resection finally possible. The clinical and pathological TNM classification, the histological types and the surgical procedure are reported. The reasons for conversion are documented. RESULTS: To investigate the appropriateness of the thoracoscopic approach we evaluated only the pathologically proven stage 1 disease in both groups. Postoperative complications, hospital stay and survival are compared. CONCLUSION: Until now we can conclude that there is no adverse effect on survival because of the thoracoscopic approach.     

Rural and urban differences in physician resource use for low-risk obstetrics

OBJECTIVE: To explore the hypothesis that rural obstetricians (OBs) and family physicians (FPs) utilized fewer resources during the care of the low-risk women who initially booked with them than did their urban counterparts of the same specialties. DATA SOURCES/STUDY DESIGN: A stratified random sample of Washington state rural and urban OBs and FPs was selected during 1989. A participation rate of 89 percent yielded 209 participating physicians. The prenatal and intrapartum medical records of a random sample of the low-risk patients who initiated care with the sampled providers during a one-year period were abstracted in detail and analyzed with the physician as the unit of analysis. Complete data for 1,683 patients were collected. Resource use elements (e.g., urine culture) were combined by standardizing them with average charge data so that aggregate resource use could be analyzed. Intraspecialty comparisons for resource use by category and overall were performed. FINDINGS/CONCLUSIONS: Results show that rural physicians use fewer overall resources in caring for nonreferred low-risk-booking obstetric patients than do their urban colleagues. Resource use unit expenditures showed the hypothesized pattern for both specialties for total, intrapartum, and prenatal care with the exception of FPs for prenatal care. Approximately 80 percent of the resource units used by each physician type were related to hospital care. No differences were shown in patterns of care for most clinically important aspects of care (e.g., cesarean delivery rates), and no evidence suggested that outcomes differed. The overall differences were due to specific components of care (e.g., fewer intrapartum hospital days and less epidural anesthesia).     

Delayed childbearing--are there any risks?

OBJECTIVE: To determine whether women delivering their first child at age 35 years or older are at increased risk of adverse (non-genetic) pregnancy outcomes. DESIGN AND SETTING: A cross-sectional analytic study of singleton deliveries in Northern Sydney Area Health Service (NSAHS) hospitals. PARTICIPANTS: All women aged > or = 20 years delivering their first child between 1 January 1990 and 31 December 1991. MAIN OUTCOME MEASURES: Obstetric complications and procedures, type of delivery and neonatal outcomes. RESULTS: Compared with women aged 20-29 years, women delivering their first child at > or = 35 years were at increased risk of pre-existing maternal hypertension (adjusted odds ratio [OR], 3.5; 95% confidence interval [CI], 1.7-7.0), antepartum haemorrhage (adjusted OR, 2.4; 95% CI, 1.6-3.7), preterm delivery (33-36 weeks) (adjusted OR, 2.0; 95% CI, 1.5-2.8) and breech presentation (adjusted OR, 1.8; 95% CI, 1.3-2.4). Women aged > or = 35 years were also substantially more likely to have an operative delivery, induced labour and/or epidural anaesthesia. Neither these women nor their infants were at increased risk of pregnancy-induced hypertension, gestational diabetes, threatened premature labour, postpartum haemorrhage, very preterm delivery (< or = 32 weeks), perinatal death, low Apgar scores or the need for neonatal resuscitation. CONCLUSIONS: Women who delay the birth of their first child face some increased risks, but these risks, for the most part, are manageable in the context of modern obstetric care.     

Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil

A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation.