Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor induce adhesion and chemotaxis of human eosinophils via p38 mitogen-activated protein kinase and nuclear factor kappaB

Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kappaB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-kappaB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), alpha6, beta2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-kappaB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

ANEURYSM OF SINUS OF VALSALVA DISSECTING INTO THE INTERVENTRICULAR SEPTUM – ECHOCARDIOGRAPHIC DIAGNOSIS (A Case Report)

Aneurysm of sinus of Valsalva dissecting into interventricular septum is a rare entity. We report one such case who was incidentally diagnosed by echocardiography to have this abnormality during evaluation of a clinically suspected isolated aortic regurgitation.KEY WORDS: Aneurysm – dissecting – sinus of Valsalva, Echocardiography     

EFFICACY OF SUCRALFATE IN PREVENTING GASTROINTESTINAL SIDE EFFECTS OF NSAIDs

To find out the efficacy of sucralfate in preventing gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs) a prospective, randomised single blind study was conducted from 1989 to 1992. Patients with osteoarthritis, rheumatoid arthritis and other long standing painful conditions, who were expected to receive NSAIDs for over three months, were recruited into the study. All medicines were discontinued for a period of 10–15 days prior to initial endoscopic assessment. NSAID therapy was started and the patients were randomised to receive either placebo (group A) or sucralfate (group B) in addition. Patient were reassessed clinically every week and an endoscopic examination was repeated after 6–8 weeks of follow-up. A total of 176 patients were studied in group A (n=91) and group B (n=85). At the end of 8 weeks gastrointestinal symptoms were present in 30.6% and 26.4% patients of group A and B respectively. Endoscopic assessment showed superficial lesions in 36.5% and 18.7% while endoscopic ulcer in 2.4% and 1.1% patients of groups A and B respectively. Thus in patients receiving chronic NSAID therapy, simultaneous administration of sucralfate reduces the incidence of superficial gastric lesions but has no significant effect on symptoms or ulcer formation.KEY WORDS: Gastropathy, Sucralfate, Nonsteroidal anti-inflammatory drugs     

The Pulmonary Absorption of Aerosolized and Intratracheally Instilled rhG-CSF and monoPEGylated rhG-CSF

Purpose. The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. Methods. Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss Aerosonic nebulizer containing 5 ml of protein solution at 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be 13 µl after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (PI2) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 µl. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. Results. The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The C _max values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 ± 135 (ng/ml) rhG-CSF; 182 ± 14 P12 v. IT: 105 ± 12 rhG-CSF; 65.9 ± 5 P12). Similarly, T_max was reached much earlier after aerosol administration (Aerosol: 21.7 ± 4.8 (min) rhG-CSF; 168 ± 31 P12 v. IT: 100 ± 17 rhG-CSF; 310 ± 121 P12). Estimated bioavailabilities (F_lung %) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 ± 14 rhG-CSF; 12.3 ± 1.9 P12 v. IT: 11.9 ± 1.5 rhG-CSF; 1.6 ± 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. Conclusions. Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.     

THE ROLE OF RAPID SLIDE CULTURE IN THE DIAGNOSIS AND MANAGEMENT OF PULMONARY TUBERCULOSIS

Rapid slide culture method using human blood medium was utilized for the primary culture of Mycobacterium tuberculosis and the results obtained were compared with results of smear examination of sputum specimens from fresh cases of pulmonary tuberculosis. Smear and rapid slide culture results of a total of 320 patients were analyzed. Slide culture was positive in 104 cases whereas smears were positive in 90 cases. Early culture confirmation in 7 days coupled with positivity better than smear examination, makes rapid slide culture a better method for diagnosis.KEY WORDS: Mycobacterium tuberculosis, Rapid slide culture, Bacteriological techniques, Colony count microbial     

温血心停跳液与冷晶体心停跳液对狗心率变异性的影响

为探讨体外循环（ＣＰＢ）导致心脏植物神经系统（ＣＡＳ）损伤的机理,了解温血心停跳液能否防止ＣＰＢ后心率变异性（ＨＲＶ）的降低,采用对照方法观察了温血心停跳液与冷晶体心停跳液对狗ＨＲＶ的影响。结果显示：ＣＰＢ后温血心停跳液组（ＷＢ组）和冷晶体心停跳液组（ＣＣ组）的全频谱（ＴＰ）、低频（ＬＦ）和高频（ＨＦ）均较术前明显降低（Ｐ＜０．０５）,而且ＣＣ组比ＷＢ组降低更明显（Ｐ＜０．０５）,但ＬＦ／ＨＦ在组内及组间均无明显变化（Ｐ＞０．０５）。ＣＰＢ后２４小时平均心率（ＭＨＲ）明显增加（Ｐ＜０．０５）,且ＣＣ组高于ＷＢ组（Ｐ＜０．０５）。本研究表明：采用温血心停跳液或冷晶体心停跳液的ＣＰＢ不会干扰ＣＡＳ平衡,但均能使ＨＲＶ降低,温血心停跳液不能防止ＨＲＶ损害。