Vascular cell adhesion molecule-1 modulation by tumor necrosis factor in experimental allergic encephalomyelitis

Anti-tumor necrosis factor (TNF) antibodies inhibit passively transferred experimental allergic encephalomyelitis (EAE) in SJL mice. The possibility that this occurs through interference in TNF's upregulation of endothelial cell adhesion molecules was investigated. Expression of both vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on spinal cord vessels increased during EAE. The upregulation of VCAM-1 was markedly reduced or prevented by anti-TNF treatment. Leukocytic infiltration was 15-fold lower in anti-TNF-treated than diseased animals. Spinal cord endothelial expression of VCAM-1, though not ICAM-1 or fibronectin, positively correlated with the extent of T cell, B cell or monocyte infiltration in each animal.     

Lymphoid tissues induce NGF-dependent and NGF-independent neurite outgrowth from rat superior cervical ganglia explants in culture

Induction of neurite outgrowth from superior cervical ganglia (SCG) by rat lymphoid tissues was studied using a tissue culture model. Neonatal rat SCG were cultured with 6–12-week-old rat thymus, spleen, or mesenteric lymph node (MLN) explants in a Martrigel layer, in defined culture medium without exogenous nerve growth factor (NGF). SCG were also co-cultured with neonatal rat heart (as positive control) or spinal cord (SC; as negative control). To determine whether inflammation affects the ability of lymphoid tissues to induce neurite outgrowth, we also examined MLN at various times after infecting rats with Nippostrongylus brasiliensis (Nb-MLN). In one series of experiments, a single lymphoid tissue explant was surrounded by four SCG at a distance of 1 mm. The extent of neurite outgrowth was determinded by counting the number of neurites 0.5 mm away from each ganglion at several time points. Adult thymus and, to a lesser extent, spleen had strong stimulatory effects on neurite outgrowth from SCG after 12 hr or more in culture. For thymus tissue, this was similar to the positive control heart explants. MLN from normal rats had minimal effect on neurite outgrowth; however, Nb-MLN showed a time-dependent enhancement of the neurite outgrowth, maximal at 3 weeks after infection. The relative efficacy of neurite outgrowth induction (heart ≥ thymus ≥ Nb-MLN ≥ spleen ≥ MLN ≥ SC) was confirmed in a second series of experiments where one SCG was surrounded by three different tissue explants. We then examined the role of 2.5S NGF, a well-known trophic factor for sympathetic nerves, in the lymphoid tissue-induced neurite outgrowth. Anti-NGF treatment of co-cultures of SCG and heart almost completely blocked the neurite outgrowth. Anti-NGF also significantly inhibited thymus- and spleen-induced neurite outgrowth, but not as effectively as heart-induced neuritogenesis (93,80, and 77% inhibition at 24 hr; 86,70, and 68% inhibition at 48 hr for heart, thymus, and spleen, respectively). On the other hand, anti-NGF inhibited only 8% of neurite outgrowth induced by 3-week post-infection Nb-MLN at 24 hr, and 41% at 48 hr. These data show that several adult rat lymphoid tissues exert neurotrophic/tropic effects. The predominant growth factor in thymus and spleen is NGF, while Nb-MLN produces factor(s) which is (are) immunologically distinguishable from NGF. These neurotrophic/tropic factors are produced during the reactive lymphoid hyperplasia that forms part of the inflammatory response against the nematode, N. brasiliensis. This suggests the possibility that cytokines produced by lymphocytes or other inflammatory cells may stimulate sympathetic neurite outgrowth in vivo. © 1994 Wiley-Liss, Inc.     

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.     

Oral tuberculosis associated with a treatment with anti-rheumatic drugs

BACKGROUND: The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is one of the traditional disease-modifying antirheumatic drugs. Adalimumab [a human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody] represent an important advance in the treatment of RA and has been recently come in use. TNF-alpha plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation. Infections occur at a high rate among those who use one or the combination of the two medications. METHOD: We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula, complaining of mild dysphagia. The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared. RESULTS: The histopathological examination of a specimen of the oral lesion, taken by biopsy, showed a chronic inflammation characterized by tuberculous granulomas. Polymerase chain reaction test and culture of a new specimen was positive for M. tuberculosis. CONCLUSIONS: The therapeutic use of MTX or/and adalimumab for the treatment of RA or few others diseases, can cause oral tuberculosis.     

Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors?*

When excluding haemophilia and von Willebrand disease, coagulation factors deficiencies constitute rare autosomal recessive disorders (<1 in 500,000) of less precisely defined epidemiology. We have reported herein the distribution of these entities in the French Basque Country, a genetic isolate of very old individualization with peculiar biological specificities. The prevalence of these disorders was markedly high, especially, as already shown, factor XI deficiency. This unusual profile needs to be discussed in the view of population genetics.     

常温与低温体外循环心脏直视手术对细胞因子及补体的影响

目的探讨常温及低温体外循环心脏直视手术对细胞因子及补体的影响。方法选择先天性和风湿性心脏病患者40例,随机分为常温组及低温组各20例,分别于术晨、体外循环结束时及术后1、4、7、14 d抽取患者静脉血标本,测定血浆TNF、IL-2、C3、C4值。结果两组术前各项检查指标无显著差异。(1)两组术后1~4 d的IL-2水平较术前显著下降,至术后7 d恢复正常。体外循环结束至术后4 d,低温组IL-2显著低于常温组。(2)体外循环结束时以及术后1、4、7 d,常温组TNF水平显著低于低温组。两组体外循环结束时及术后1、4 d均高于术前,常温组至术后7 d、低温组术后14 d恢复正常。(3)体外循环结束时及术后1、7 d,常温组C3水平高于低温组,术后4 d两组无差别;常温组及低温组于体外循环结束时、术后1、4 d均低于术前,至术后7 d常温组恢复正常,低温组至术后14 d恢复至术前水平。(4)两组体外循环结束时及术后1、4 d C4水平均低于术前。体外循环结束时、术后1 d,常温组C4水平高于低温组。结论常温体外循环心脏直视手术对细胞因子及补体的影响显著轻于低温组,因而对术后机体的恢复优于低温方法。     

环氧合酶-2和血管内皮生长因子共表达与肝细胞癌血管形成的关系

目的　探讨环氧合酶 (COX) 2与肝细胞癌血管形成的关系。方法　利用免疫组织化学、Westernblot方法检测 48例肝癌组织中COX 2和血管内皮生长因子 (VEGF)蛋白及逆转录 聚合酶链反应法 (RT PCR)检测COX 2和VEGFmRNA的共表达 ,对共表达COX 2和VEGF蛋白和mRNA的肝癌组织进行微血管记数。结果　免疫组织化学检测中 ,48例肝癌组织 3 6例共表达COX 2和VEGF蛋白。类似结果见于蛋白电泳分析。RT PCR显示 ,48例肝癌组织 3 6例共表达COX 2mRNA和VEGFmRNA。两者之间的表达明显相关 (γ =0 .845 )。共表达COX 2和VEGF蛋白和mRNA的肝癌组织中 ,平均微血管数 (5 6.8± 17.5 )个 ,明显高于阴性表达组。结论　COX 2可能与肝细胞癌的血管形成有关 ,且其作用之一可能是通过上调VEGF通道来发挥的     

重组2型腺相关病毒-转化生长因子β3对实验性肝纤维化大鼠肝脏组织病理学和Ⅰ型胶原表达的影响

Objective To investgate the effects of TGF β 3 on rat hepatic fibrosis. Methods The TGF β 3 cDNA was cloned into rAAV2 vector. Rats were randomly divided into four groups: normal control group, model group, negative control group and TGF β 3 group. Hepatic fibrosis was induced by hypodermic injection of 40% CCI4. Recombinant AAV2-TGF β 3 viral particles were injected via the vena caudalis one week before CCh treatment. Rats were executed 8 weeks after CCI4 treatment, global histological change was observed after HE staining, the distribution of the collagen fibers was observed after masson staining, his-tochemistry was done to observe the expression of collagen Ⅰ; The positive area rate of the collagen fibers and the average optical rate of collagen Ⅰ were quantified. Results HE staining indicated that collagen fibers were reduced in the TGF β 3 group. Masson staining shown that the collagen fibers were distributed around the blood vessel, in the portal area and disse space. Compared to the model group (13.2%±2.2%) and negative control group (12.3%±1.5%), the collagen fibers in liver tissues of TGF β3 group (7.7% ± 1.5%) were significantly decreased (q = 9.456, P < 0.01; q = 8.217, P < 0.01). Histochemistry indicated that the collagen fibers of liver tissues of TGF 15 3 group (0.185±0.033) were significantly higher than those in the model group (0.252±0.042) and the negative control group (0.230±0.029), (q = 6.228, P < 0.01; q = 4.346, P < 0.01). Conclusion TGF β 3 alleviates the damage to hepatic cell and the level offibrosis in CCI4 treated rats and inhibits the expression of collagen Ⅰ.     

Accelerating effects of epidermal growth factor on skin lesions of pemphigus vulgaris: a double-blind, randomized, controlled trial

BACKGROUND: Pemphigus vulgaris (PV) is a severe blistering disease involving the skin and mucous membranes. The most common causes of death in these patients are adverse effects of drugs, and infection. Skin lesions are one of the important sources of infection. Thus, any local treatment that could reduce healing time of lesions and consequently reduce the total dosage of drugs needed to treat is favourable. OBJECTIVE: To evaluate the efficacy of epidermal growth factor (EGF) in reducing healing time of lesions in patients with pemphigus vulgaris. METHODS: In this randomized, double-blind, within-patient, left/right, controlled trial, 20 hospitalized patients with pathologial and immunohistologial (direct and indirect immunoflourecence) proven pemphigus vulgaris (PV) were chosen. In addition, all patients had at least one appropriate pemphigus lesion on each side of the body that had not healed after 2-week systemic therapy and sterile saline washing. EGF (10 microg/g) in 0.1% silver sulfadiazine cream vs. 0.1% silver sulfadiazine cream alone was applied randomly on one side of the body. RESULTS: Kaplan-Meier survival analysis suggested that median time to heal with application of EGF plus silver sulfadiazine cream was 9 days, in comparison with 15 days for silver sulfadiazine cream alone (log-rank test, P=0.0003). No intervention-related adverse effect was observed during the study. CONCLUSIONS: EGF can significantly reduce healing time of skin lesions in patients with pemphigus vulgaris, at least when this cream base is applied (Cochrane skin group identifier: CSG20).     

The plasma kallikrein–kinin system and risk of cardiovascular disease in men

BACKGROUND: The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. OBJECTIVE: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). METHODS AND RESULTS: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. CONCLUSIONS: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.