A gene for a low density lipoprotein receptor-related protein in the nematode Caenorhabditis elegans.

A >23-kb gene that encodes a large integral membrane protein with a predicted structure similar to that of the low density lipoprotein (LDL) receptor-related protein (LRP) of mammals has been isolated and sequenced from the free-living nematode Caenorhabditis elegans. The 4753-amino acid predicted C. elegans product shares a nearly identical number and arrangement of amino acid sequence motifs with human LRP, and several exons of the C. elegans LRP gene correspond to exons of related parts of the human LDL receptor gene. The existence of an apparent homolog of LRP in C. elegans offers the possibility of genetic analysis of the in vivo roles of LRP and of the relationship between protein structure and function in a simple model organism.     

Control of congenital infection with Toxoplasma gondii by neonatal screening based on detection of specific immunoglobulin M antibodies eluted from phenylketonuria filter-paper blood-spot samples

Two ongoing neonatal screening programmes for congenital infection with Toxoplasma gondii are presented. The New England Newborn Screening Programme has included congenital toxoplasmosis since 1986. The test is based on detection of Toxoplasma-speci fi c immunoglobulin M (IgM) antibodies eluted from the phenylketonuria (PKU) card. The seroprevalence of Toxoplasma IgG antibodies is at present about 13% and the birth prevalence of congenital toxoplasmosis approximately 1 per 10000 liveborn children. The Danish national neonatal screening programme was expanded to include congenital toxoplasmosis from 1 January 1999. The test is also based on detection of Toxoplasma-speci fi c IgM antibodies eluted from PKU cards. The seroprevalence of Toxoplasma IgG antibodies in pregnant women is around 25% and the birth prevalence about 1 per 3000 liveborn children. The birth prevalence of congenital Toxoplasma infection is within the range of other congenital disorders included in different screening programmes. Neonatal screening is feasible in areas with a low risk of congenital infection where prenatal screening will not be applicable.     

Adenovirus-mediated gene therapy of osteoblasts in vitro and in vivo.

Modulation of biological pathways governing osteogenesis may accelerate osseous regeneration and reduce the incidence of complications associated with fracture healing. Transforming growth factor beta1 (TGF-beta1) is a potent growth factor implicated in the regulation of osteogenesis and fracture repair. The use of recombinant proteins, however, has significant disadvantages and has limited the clinical utility of these molecules. Targeted gene therapy using adenovirus vectors is a technique that may circumvent difficulties associated with growth factor delivery. In this study, we investigate the efficacy of replication-deficient adenoviruses containing the human TGF-beta1 and the bacterial lacZ genes in transfecting osteoblasts in vitro and osseous tissues in vivo. We demonstrate that adenovirus-mediated gene therapy efficiently transfects osteoblasts in vitro with the TGF-beta1 virus causing a marked up-regulation in TGF-beta1 mRNA expression even 7 days after transfection. Increased TGF-beta1 mRNA expression was efficiently translated into protein production and resulted in approximately a 46-fold increase in TGF-beta1 synthesis as compared with control cells (vehicle- or B-galactosidase-transfected). Moreover, virally produced TGF-beta1 was functionally active and regulated the expression of collagen IalphaI (5-fold increase) and the vascular endothelial growth factor (2.5-fold increase). Using an adenovirus vector encoding the Escherichia coli LacZ gene, we demonstrated that adenovirus-mediated gene transfer efficiently transfects osteoblasts and osteocytes in vivo and that transfection can be performed by a simple percutaneous injection. Finally, we show that delivery of the hTGF-beta1 gene to osseous tissues in vivo results in significant changes in the epiphyseal plate primarily as a result of increased thickness of the provisional calcification zone.     

Drug delivery of anticancer agents: water soluble 4-poly (ethylene glycol) derivatives of the lignan, podophyllotoxin.

This paper reports on the synthesis and in vivo oncolytic activity of a series of water-soluble acyl derivatives of polyethylene glycol (PEG) conjugated podophyllotoxin. Some analogs of the polymer conjugate showed significantly better activity in a murine leukemia model than native podophyllotoxin suspended in an intralipid emulsion. Additionally, when tested intravenously against a solid lung tumor (A549) model, some conjugated analogs were equivalent to the podophyllotoxin/intralipid emulsion, while those compounds demonstrating slower rates of plasma hydrolysis (in vitro) appeared to cause greater toxicity. There appeared to be an overall correlation between the in vivo antitumor activity of the conjugate and its rate of hydrolysis in vitro, with those showing faster release possessing greater antitumor activity. In conclusion, the solubilization and predictable release of podophyllotoxin from a PEG carrier was achieved and resulted in some derivatives demonstrating, at a minimum, equivalency with podophyllotoxin when administered on an equal molar basis. Further studies may be warranted to assess the PEG-conjugates pharmacokinetics and therapeutic indices in leukemic models.     

The development of CD4+ T effector cells during the type 2 immune response

Multiple pathways may be involved in the development of interleukin 4 (IL-4) producing T helper (Th) cells and the associated type 2 immune response. Increasing evidence suggests that the strength of signals delivered to the T cell may favor the development of the type 2 response. In contrast, antigen-presenting cell- (APC) derived stimuli produced following pattern recognition receptor binding during the innate response promotes the development of interferon-gamma (IFN-gamma) producing cells and the associated type 1 immune response. In many cases, the balance between increased signaling strength and the innate response may determine whether the type 2 response develops. T cell receptor (TCR), CD4, and costimulatory molecule interactions may all contribute to signal strength, but the type 2 immune response may be particularly dependent on the availability of coreceptor and costimulatory molecule interactions. B7 ligand interactions are required for the development of the type 2 immune response and interaction of CD28 with either B7-1 or B7-2 can provide sufficient signals for its initiation. In B7-2-deficient mice, the initial type 2 immune response is intact, but the response is not sustained, suggesting that B7-2 is important at later stages of the type 2 immune response. The roles of CD28 and CTLA-4 during the type 2 response remain unclear. The type 2 response to infectious pathogens is pronounced in CD28-/- mice, suggesting that other costimulatory molecule interactions can substitute for CD28 for the development of IL-4 producing T cells and the associated type 2 immune response.     

Esophagopericardial Fistula Arising From Barrett's Esophagus

Esophagopericardial fistula is a rare complication of numerous benign, malignant, and traumatic conditions of the esophagus. Approximately 100 cases of fistulae between the esophagus and heart have been reported. We describe the second reported case of an esophagopericardial fistula secondary to a benign esophageal ulcer within Barrett's mucosa without prior surgery. The radiologic, endoscopic, and surgical management of this case are discussed.     

Intravenous gamma globulin therapy in systemic juvenile rheumatoid arthritis

Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.     

β-淀粉样蛋白在老年痴呆症发生发展中的作用及其机制

0 引言 阿尔茨海默病(Alzheimers disease, AD)亦称老年性痴呆症,是一种常见的中枢神经系统退行性疾病,主要临床表现为进行性记忆力减退、认知功能障碍以及人格改变等症状. 现在许多国家包括我国的人均预期寿命达到70岁. 由于老年痴呆与增龄有密切关系,随着人类寿命的普遍延长,老年痴呆的发病率也大大增加. 因此,对于AD发病机理和防治的研究近些年来已经成为国内外关注的热点. AD的主要病理特征有,在大脑皮层和海马出现β-淀粉样蛋白(amyloid-β protein, Aβ)聚集形成的老年斑(SP),Tau蛋白异常聚集形成的神经纤维缠结(NFT)以及脑皮层和海马区神经细胞减少. 随着研究的逐渐深入,越来越多的证据表明Aβ在AD的发生、发展中起到主导的作用. Aβ的神经毒性涉及到复杂的分子机制主要包括破坏细胞内的Ca2 稳态,促进自由基的形成,降低K 通道的功能,增强致炎细胞因子引起的炎症反应等. 因此,把现阶段对Aβ的研究成果进行综合分析和概述将对今后AD的防治有很大帮助.