The efficacy of the neurotrophic peptide ORG 2766 in diabetic patients with polyneuropathy was evaluated in a double-blind, placebo-controlled, multicentre trial. One hundred and twenty four patients were randomised in five groups to receive 0.1, 0.4, 2 or 5 mg ORG 2766 or placebo, once daily, administered subcutaneously 52 weeks. Thermal discrimination thresholds (TDT) and vibration perception thresholds (VPT), motor and sensory nerve conduction velocity, Hoffmann reflex, heart rate variation during deep breathing and heart rate response after standing up, neurological examination score and neuropathic symptom score were determined at baseline and after 17, 34 and 52 weeks of treatment. Of the nerve function indices studied, at week 52 the TDTwarmth of the hand in the ORG 2766 0.1, 0.4 and 5 mg groups and the TDTcold of the foot in the ORG 2766 0.1 and 0.4 mg groups significantly improved compared with placebo. Further significant improvement as compared with placebo was observed in the paraesthesia score at week 34 and week 52 in the ORG 2766 2 mg group. Only at week 34 had both the heartbeat variation during deep breathing and the VPT of the foot in the ORG 2766 0.1 mg group improved significantly, compared with placebo. No further statistically significant differences were observed at time for the other measures. No adverse reactions were observed. The only recorded drug-induced side effect was pain at the injection site. Taking all measures of efficacy into account, the statistically significant results observed did not show consistency within each measure. Therefore, it is concluded that ORG 2766, in contrast to earlier reports, is not effective in treating diabetic polyneuropathy. 相似文献
Chromaffin cells of the adrenal medulla and their tumor counterparts, the pheochromocytoma (PC12) cells, are well-established
model systems in neurobiology. The development of sympathoadrenal progenitor cells to chromaffin cells can be studied with
regard to developmental signals which trigger the differentiation. With regard to potential treatments of neurological disorders
like Parkinson’s disease chromaffin cell grafting can be used as one therapeutical approach. The beneficial effect of chromaffin
cell grafts is possibly not only related to the release of dopamine but may also be linked to the release of growth factors.
One of the growth factors that is synthesized by chromaffin and PC12 cells is basic fibroblast growth factor (FGF-2). The
experimental data available so far, are in agreement with different functional roles of FGF-2. This article summarizes the
putative physiological functions of FGF-2 in the adrenal medulla. Three differential functional roles of FGF-2 are discussed:
(1) as a differentiation factor for sympathoadrenal progenitor cells; (2) as a target-derived neurotrophic factor for preganglionic
sympathetic neurons which innervate adrenal medullary cells; (3) as an auto-/paracrine factor in the adrenal medulla.
Accepted: 21 August 1996 相似文献
Glial-derived neurotrophic factor (GDNF), neurturin (NRTN), persephin (PSPN), and artemin (ARTN) are a group of proteins belonging
to the GDNF family ligands (GFLs). GDNF, NRTN, and ARTN support the survival of central, peripheral, and autonomic neuron
populations, while PSPN supports the survival of only several central neuron populations. A common receptor, RET, modulates
the action of this family and a co-receptor, GFRα, determines RET ligand specificity. GDNF and NRTN appear to be essential
for enteric nervous system (ENS) development in mammals, zebrafish, and other teleostean species. GFLs are also essential
for the maintenance and plasticity of adult mammalian ENS. In this study, the distribution pattern of GFLs in the intestine
of five adult fish (bass, gilt-head, scorpionfish, trout, and zebrafish) was evaluated by immunochemical and immunocytochemical
analysis. The results demonstrated the presence of GDNF, NRTN, and ARTN in the gut of all species studied. They appeared to
be spread in the ENS and/or endocrine cells of the intestine. These findings suggest that the presence of GFLs in fish gut
is not only limited to developmental period, but could be also involved in the enteric physiology of adult species. 相似文献
Besides intrinsic determinants of cell growth, epigenetic signals have been proposed to regulate development and maintenance of neurons. Here we provide evidence that cerebral astrocytes contribute significantly to the set of environmental influences that are required for long-term survival of neurons derived from the mammalian central nervous system. Cerebral astrocytes in serum-free culture express diffusible and non-diffusible neuron-supporting signals, including cell-adhesive neurite growth-promoting glycoproteins, diffusible neurotrophic factors as well as membrane-bound molecules that mediate cell contact interactions. The combination and synergistic interaction of these environmental signals markedly enhance the survival of brain neurons. While astroglia-derived cell-adhesive substrates that include a high molecular weight complex consisting of laminin β-chains and proteoglycan (Matthiessen et al., 1989) stimulate neurite outgrowth, they fail to enhance long-term neuronal survival when additional neurotrophic and cell-contact interactions are lacking. Astrocytes release a diffusible neurotrophic activity that, when permanently applied, maintains long-term survival of central neurons in culture. The soluble neurotrophic activity seems to interact synergistically with cell-bound signals which are also required for long-term survival and which are expressed by astrocytes and neurons, but not by fibroblasts. Among neurons from different brain areas, such as hippocampus, cerebral cortex and septum, regional differences in their responsiveness to the astroglial neurotrophic activity have been observed. 相似文献
The human immunodeficiency virus (HIV) induces neuronal death, presumably by apoptosis. This effect may be triggered by the glycoprotein 120 (HIVgp120) released by HIV when infecting a cell, and mediated by tumor necrosis factor alpha (TNF), a pro-inflammatory cytokine. Both molecules, HIVgp120 and TNF, increase sleep when administered acutely in the brain. On the other hand, sleep deprivation increases the levels of several growth factors. In this context, we challenged rats with HIVgp120 or TNF simultaneously with sleep deprivation. Our results indicate that both HIVgp120 and TNF increase neuronal death in the rat cerebral cortex, but not hippocampus, and that this effect is completely prevented by total deprivation of sleep. These results suggest that acute total deprivation of sleep protects against the HIVgp120 and TNF deleterious effects. 相似文献
Purpose: To describe a case series of ocular complications associated with upper respiratory tract infections.
Methods: Four patients aged 21–61 years (three females, one male) had confirmed ocular complications connected with a general upper respiratory tract infection with myalgia and fever. Ophthalmological examination, including a visual acuity test, a slit-lamp exam, intraocular pressure measurements, fluorescein and indocyanine green angiography, optical coherence tomography (OCT), and diagnostic tests for influenza were performed in the patients (RT-PCR, HAI).
Results: Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was diagnosed in three patients and serous macular detachment (SME) in one. Influenza virus infection was confirmed by molecular biological methods (RT-PCR) or the hemagglutination inhibition test (HAI) in two patients. All patients were treated with systemic prednisone.
Conclusion: A coincidence between APMPPE and SME epitheliopathy and influenza virus infection was observed in different months of a given epidemic season. 相似文献
Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors. 相似文献