Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release.

Degranulating mast cells are increased in the airway smooth muscle (ASM) of asthmatics, where they may influence ASM function. The aim of the present study was to determine whether histamine and tryptase modulate ASM cell granulocyte-macrophage colony-stimulating factor (GM-CSF) and RANTES (regulated on activation, normal T-cell expressed and secreted) release and also to examine which receptors are involved in this release. Confluent, quiescent ASM cells from asthmatic and nonasthmatic donors were treated with histamine (1 microM-100 microM) with and without histamine receptor antagonist pre-treatment, or the protease-activated receptor (PAR)-2 agonists tryptase (0.5-5 nM) and SLIGKV (100 and 400 microM). The cells were then stimulated with interleukin (IL)-1beta and/or tumour necrosis factor (TNF)-alpha (10 ng.mL(-1)) or left unstimulated for 24 h. Release of GM-CSF and RANTES was determined by ELISA and prostaglandin (PG)E(2) measured by enzyme immunoassay. Neither histamine nor tryptase induced ASM GM-CSF or RANTES secretion. However, histamine increased IL-1beta-induced GM-CSF release and markedly reduced TNF-alpha-induced RANTES release by both asthmatic and nonasthmatic cells to a similar extent, but did not modulate PGE(2) release. All changes involved activation of the histamine H1 receptor as they were partially or fully blocked by chlorpheniramine, but not ranitidine. Tryptase, via its proteolytic activity, also potentiated GM-CSF, but not RANTES, release from asthmatic and nonasthmatic ASM cells induced by both cytokines. PAR-2 involvement in the tryptase potentiation was unlikely because SLIGKV had no effect. In conclusion, mast cells, through histamine and tryptase, may locally modulate airway smooth muscle-induced inflammation in asthma.     

<Emphasis Type="Italic">Bcl11b</Emphasis>mutations identified in murine lymphomas increase the proliferation rate of hematopoietic progenitor cells

Background  

The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The Bcl11b gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether Bcl11b is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis.     

The surgical risk of colectomy in patients with cirrhosis

The records of 54 patients with documented cirrhosis who underwent colectomy between January 1970 and January 1984 were studied to assess the operative risk and to determine the preoperative predictive risk factors. In-hospital mortality was 24 percent (13 patients), and postoperative complications occurred in 48 percent (26 patients). The risk of surgical intervention was significantly increased if encephalopathy, ascites, anemia, or hypoalbuminemia was present before operation. A simple operative risk index involving the presence of encephalopathy and ascites and the levels of hemoglobin and albumin is proposed to help distinguish a low-risk subgroup in whom postoperative mortality was 12.8 percent from a high-risk subgroup in whom postoperative mortality was 53.3 percent.     

The effect of concomitant disorders in childhood depression on predicting treatment response

Children with pure depression or depression plus an anxiety-related disorder (n = 14) had a higher drug response rate (57%) and a lower placebo response rate (20%) when compared to children with depression plus a concomitant conduct or oppositional disorder (n = 17) (33% drug response rate and 67% placebo response rate). These findings could explain why studies of prepubertal-onset depression found no differences between drug and placebo treatment assuming that a large percentage of the studies' subjects had concomitant conduct or oppositional disorders. The children with pure depression or depression plus an anxiety-related disorder had different symptom clusters from those with depression plus a concomitant conduct or oppositional disorder. The former had more severe CDRS ratings on sleep, appetite disturbance, depressed feelings, and psychomotor retardation. In contrast, those with a concomitant conduct or oppositional disorder had shorter attention spans and were more likely to disturb other children (based on Conners scale scores).     

The Effect of Flurbiprofen on Steady-State Plasma Lithium Levels

Study Objective . To evaluate the effects of flurbiprofen therapy on the pharmacokinetics of lithium. Design . Placebo-controlled, single-blind, crossover study. Setting . University-affiliated hospital. Patients . Eleven healthy women with bipolar disorder. Interventions . The subjects received therapeutic doses of lithium administered as an immediate-release capsule every 12 hours. In addition, they received one placebo tablet every 12 hours during phase I and flurbiprofen 100 mg every 12 hours during phase II of the study. Measurements and Main Results . Steady-state pharmacokinetic parameters were measured for each phase. Lithium trough plasma concentration (C_min) and area under the curve were statistically significantly increased (p<0.05) when patients received flurbiprofen. Flurbiprofen also caused decreases in lithium clearance and 24-hour lithium urine excretion, although the changes did not reach statistical significance. Clinically significant increases in C_min appeared to be associated with a greater than 1000-μg/24 hour decrease in urinary excretion of prostaglandin E₂. Conclusion . Patients with clinically normal renal function may experience an increase in lithium levels with the initiation of flurbiprofen therapy.