Proliferative ischaemic retinopathy in a case of systemic lupus erythematosus and antiphospholipidic syndrome

PURPOSE/METHODS: We report a 34-year-old woman with sytemic lupus erythematosus (S.L.E.) and antiphospholipidic syndrome which presented severe ischaemic retinopathy and neovascular proliferation. RESULTS/CONCLUSIONS: We achieved no progression of the disease and stabilization of visual acuity with panphotocoagulation. We recommend periodic ophtalmologic exams because of the scarce symptomatology.     

A rat brain slice preserving synaptic connections between neurons of the suprachiasmatic nucleus,organum vasculosum lamina terminalis and supraoptic nucleus

The organum vasculosum lamina terminalis (OVLT), the suprachiasmatic nucleus (SCN) and the supraoptic nucleus (SON) are three hypothalamic structures involved in the osmotic and circadian control of neurohypophysial secretion. Recent experiments have suggested that interactions between osmotic and circadian factors may be important for homeostasis. The existence of an in vitro slice preparation retaining these nuclei and their interconnections would therefore be useful for the analysis of synaptic interactions. In the rat, the OVLT, SCN and SON are found at increasingly ventral and lateral positions along the rostro-caudal axis, such that conventional 400 microm slices taken in the pure coronal or horizontal planes do not retain all three nuclei. Here we show that horizontal slices cut at angles of 38-42 degrees relative to the dorsal surface of the cortex retain large fractions of the three nuclei. Intracellular recordings revealed membrane properties consistent with those previously published for OVLT, SCN and SON neurons. Moreover, antidromic and synaptic responses evoked by electrical stimulation revealed that extensive axonal projections are retained between these nuclei. Finally, chemical and osmotic stimulation of the OVLT exerted powerful influences on the rate of spontaneous synaptic events in SON neurons. We therefore conclude that angled horizontal hypothalamic slices represent a useful preparation for the analysis of physiological interactions between the OVLT, SCN and SON.     

Nitric oxide-induced genotoxicity,mitochondrial damage,and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53

Nitric oxide (NO(*)) is mutagenic and, under appropriate conditions of exposure, also induces apoptosis in many in vitro and in vivo experimental models. Biochemical and cellular mechanisms through which NO(*) induces apoptosis are incompletely understood, but involve p53/mitochondria-dependent signaling pathways. In this study, we exposed human lymphoblastoid cells harboring either wild-type (TK6 cells) or mutant p53 (WTK-1 cells) to NO(*), delivered by diffusion through Silastic tubing. Cells were exposed for 2 h at constant rates of 100-533 nM/s, similar to levels estimated to occur in vivo in inflamed tissues. DNA double-strand breaks and fragmentation detected 8-48 h after NO(*) treatment were more extensive in TK6 cells than in WTK-1 cells, whereas NO(*)-induced mutant fractions in both HPRT and TK1 genes were significantly lower in TK6 cells than in WTK-1 cells (P < 0.01-0.05). Treatment of TK6 cells with NO(*) caused extensive apoptosis, but this response was delayed and greatly reduced in magnitude in WTK-1 cells. Mitochondrial membrane depolarization and cytochrome c release were induced in both cell types. However, elevation of apoptotic protease-activating factor-1 (Apaf-1) protein and reduction of X-chromosome-linked inhibitor of apoptosis (XIAP) protein were observed only in TK6 cells. These results indicate that p53 status is an important modulator of NO(*)-induced mutagenesis and apoptosis, and suggest that levels of the Apaf-1 and XIAP proteins, but not mitochondrial depolarization and cytochrome c release, are regulated by p53 in these human lymphoblastoid cells. Thus, Apaf-1 and XIAP may play important roles in the regulation of p53-mediated apoptotic responses.     

流感病毒A／越南/1194/2004H5N1毒株灭活裂解疫苗的安全性和免疫原性

背景:在亚洲、非洲和欧洲,致病性H5N1流感病毒引起禽流感在家禽和候鸟中爆发流行,还导致了人类发病和死亡。虽然目前H5N1毒株引起人与人之间的传染不太可能,但它仍可能是未来流感大范围流行的潜在威胁因素。本试验的目的就是评价针对H5N1病毒株的裂解病毒疫苗的安全性和免疫原性。方法:对300名志愿者(年龄为18岁～40岁)进行随机、开放标签的、无对照的Ⅰ期试验。300名志愿者被分为6组:7.5mg血凝素加佐剂组(n=50)、7.5mg血凝素不加佐剂组(n=49)、15mg血凝素加佐剂组(n=50)、15mg血凝素不加佐剂组(n=50)、30mg血凝素加佐剂组(n=51)、30mg血…     

CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice.

PURPOSE: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model. EXPERIMENTAL DESIGN: We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model. RESULTS: Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival. CONCLUSIONS: Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.     

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study

Background  

To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients.     

Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.      

Parents and children in art

It is an honour to have been asked to contribute to this volume that commemorates the life and work of Spyros Doxiadis. Spyros was, and is still, a vital and stimulating influence on those of us who were fortunate enough to have been his colleague in all phases of his life. My period of closeness to him was when he was working in Sheffield with Ronald Illingworth. At that time (now over 40 years ago) he and Katherine were having their children and my wife and I was having ours. Then words like "bonding" had not become commonplace as today, but the functional patterns of family relationships were something about which we were intensely aware. I particularly remember a summer when we were holidaying on a tidal estuary between Anglesey and Holy Island and recall a moment when Spyros and I were sitting on a grass topped sandbank watching our children and wives at the water's edge "messing around" with a boat. We watched and discussed the beauty of the postures and poses of our womenfolk with the children and the children with each other. It was the memory of that conversation that stimulated me to propose the topic of this essay in Spyros' memory.