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.     

Acute heart failure and acute renal failure in Kawasaki disease

Acute renal failure and acute heart failure are rare in Kawasaki disease. We experienced two patients with Kawasaki disease who presented acute renal failure and acute heart failure. These two patients gave us an important insight into the understanding of water balance and fluid therapy in Kawasaki disease. One patient showed acute prerenal failure due to fluid exudation from the intravascular to the extravascular space, and subsequent acute heart failure. The other patient showed acute heart failure caused by fluid infusion for the treatment of dehydration. It is suggested that acute renal failure could be caused by a fluid shift from the intravascular to the extravascular space in Kawasaki disease. It is also demonstrated that the reserve of cardiac function could be decreased in patients with Kawasaki disease due to myocarditis even with normal echocardiography and chest X-rays.     

Evaluation of neural fold fusion and coincident initiation of spinal cord occlusion in the chick embryo.

Although it is known that rapid expansion of the vertebrate brain begins near the time that the spinal neurocoel is occluded, it still remains unknown when occlusion occurs in relation to neurulation. Since both morphogenetic events are critical for normal brain growth, it is important to decipher the temporal relationship between the two processes. This study assessed the temporal relationship of the two events with the rationale that if it could be demonstrated that occlusion occurs coincident with the completion of neurulation, then it could be argued that factors shown to direct neurulation could also initiate occlusion. Nearly 600 chick embryos (stages 9- through 12+) were cultured atop egg-agar, the caudal extent of neurulation determined, the cranial five pairs of somites removed and the neurocoels assessed for occlusion. In stage 9- through 10- chicks, neurulation of the spinal cord is incomplete. Stages 10 through 12+ exhibit neurulation and occlusion from the 8th to 19th somites. When lateral tissues were removed in embryos 8 through 10-, the neural folds became dysraphic whereas in embryos stage 10 and older, the folds remained fused dorsomedially and occluded. The only surgical manipulation that was found to prevent occlusion was elimination of the lateral tissues responsible for elevation and closure of the neural folds. Analysis of particular components of the lateral tissues essential for convergence, by treating embryos (n = 75) with chemicals known to degrade tissue-tissue bonds or specific components of the perineural matrix, indicated that more than 75% of the embryos treated with EDTA, EDTA plus Ca2+, trypsin, collagenase, or hyaluronidase exhibited little or no effect on convergence, dorsomedial fusion, and concomitant occlusion.     

Inflammatory mediators and the destruction of bone

Bone is remodelled by the coordinated actions of osteoclasts and osteoblasts. Cellular remodelling occurs in discrete packets of bone, and is regulated by local cytokines produced in the environment of the remodelling cells. These cytokines are secreted by immune cells and by bone cells. In addition, some growth regulatory factors are incorporated into the noncollagenous bone matrix and are released in an active form when bone is stimulated to resorb. Complex interactions between these cytokines and their target cells are responsible for the normal delicate balance between bone resorption and bone formation, and disorders of bone loss are due to imbalances between the rates of resorption and formation.     

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.     

Isthmotectal axons make ectopic synapses in monocular regions of the tectum in developing Xenopus laevis frogs.

During the development of binocular maps in the tectum of Xenopus laevis, axons that relay input from the ipsilateral eye via the nucleus isthmi undergo a prolonged period of shifting connections. This shifting accompanies the dramatic change in eye position that takes place as the laterally placed eyes of the tadpole move dorsofrontally. There is a concomitant expansion of the proportion of tectum that receives contralateral retinotectal input corresponding to the binocular portion of the visual field. Electrophysiological recording demonstrates that ipsilateral units are present in those rostral tectal zones, and anatomical methods show that the isthmotectal axons arborize densely in the rostral region but also extend sparser branches into the caudal zone, which is occupied by contralateral inputs with receptive fields in the monocular zone of the visual field. A mechanism that aligns the ipsilateral and contralateral maps is activity-dependent stabilization of isthmotectal axons that exhibit firing patterns correlated with those of nearby retinotectal axons. In order for activity patterns to function in stabilizing correct connections and promoting the withdrawal of incorrect connections, synaptic communication of some sort is hypothesized to be essential. We have investigated whether isthmotectal axons make morphologically identifiable synapses during development and where such synapses are located. We find evidence for morphologically identifiable synapses in all regions of the tectum, along with many growth cones and structures that are probably immature synapses. As in the adult, the synapses contain round, clear vesicles, have asymmetric specializations, and terminate on structures that appear to be dendrites. In both adult and tadpole, the rarity of serial synapses involving isthmotectal terminals suggests that the interactions between retinotectal and isthmotectal inputs are mediated by postsynaptic dendrites.     

新型血管吻合用支架对血管内膜的影响

目的：研制一种可溶性血管内支架辅助血管断端吻合，并检测该支架在血管吻合的过程中对血管内膜的影响。方法：选用高纯度低分子量明胶为主要原料制备血管吻合用支架，利用该支架进行血管吻合操作，观察支架对血管内膜的作用，并从超微结构方面进行研究。结果：明胶类可容性血管内支架表面光滑，在血管吻合的过程中不会对血管壁造成损伤；与同类支架相比具有明显的优势。结论：明胶类可溶性血管内支架具有光滑的外表面，适合于进行血管吻合操作。     

Therapeutic effects of liposomal adriamycin in combination with tumor necrosis factor-alpha.

Liposomes as drug carriers in cancer chemotherapy have attracted considerable interest. To enhance the therapeutic effect of Adriamycin entrapped in liposomes (Lip-ADM) on human solid tumors, we investigated the therapeutic effects of Lip-ADM in combination with recombinant human tumor necrosis factor-alpha (rTNF-alpha), which is known to have specific effects on tumor vasculature. rTNF-alpha or saline solution was injected intravenously into nude mice bearing a human colon cancer strain, HC-1, at 1 hour before intravenous administration of Lip-ADM. The significant therapeutic effect of Lip-ADM in combination with rTNF-alpha was demonstrated by the evaluation with tumor growth curve and the actual tumor weights, in comparison with groups of mice treated with saline solution, rTNF-alpha alone, or with a Lip-ADM after saline. Levels of Adriamycin in tumor tissue in the Lip-ADM in combination with rTNF-alpha-treated group were higher than those in Lip-ADM with saline solution-treated group.