Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection

Long-term display of exogenous proteins on the cell surface may have important research and therapeutic implications. We report a novel method for the cell-surface display of proteins that involves generation of a chimeric protein with core streptavidin, biotinylation of cells, and "decoration" with the protein. A chimeric protein with the extracellular portions of FasL (SA-FasL) was efficiently displayed on the cell surface within 2 hr without detectable cellular toxicity. Biotin and SA-FasL persisted on the cell surface for weeks in vitro and in vivo. Immunomodulation with SA-FasL-decorated splenocytes effectively blocked alloreactive responses in naive and presensitized rodents and prevented the rejection of allogeneic pancreatic islets. This approach may serve as an alternative to gene transfer-based expression with broad research and therapeutic applications.     

Molecular mechanisms of age-related hearing loss

Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with aging and is the most common cause of adult auditory deficiency in the United States. Presbyacusis is defined as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. This condition affects approximately 23% of the population between 65 and 75 years of age and 40% of the population older than 75 years of age. In 1980, it was estimated that 11% of the population was 76 years or older and this number is expected to nearly double by the year 2030 [, Otolaryngol. Head Neck Surg. 100, 262]. When coupled with the fact that the population over 65 years of age is experiencing the most rapid progression of hearing loss, the potential socioeconomic ramifications are staggering. Interestingly, presbyacusis varies in its frequency across differing societies. This discrepancy has been attributed to many factors such as genetics, diet, socioeconomic factors, and environmental variables [, Otolaryngol. Head Neck Surg. 100, 266;. Scand. Audiol. 26 (1997) 133]. The purpose of this discussion is to illuminate the various molecular mechanisms underlying this age-related hearing loss and to offer insights into potential ways to mitigate the effects of aging on hearing impairment.     

Kotz and Ganz osteotomies in the treatment of adult acetabular dysplasia

In hips with acetabular dysplasia, we performed Kotz osteotomy (group 1) in 22 hips (20 patients; mean age 24.3 years) and Ganz osteotomy (group 2) in 23 hips (22 patients; mean age 23.1 years). Group 1 was followed 83.3 (56-112) months and group 2 40.9 (24-66) months. In group 1, Harris hip score improved from average 74.9 to 86.9, mean center edge (CE) angle from -4.5 degrees to 30.3 degrees, and mean vertical center edge (VCE) angle from 5.3 degrees to 36.2 degrees. In group 2, Harris hip score improved from average 76.6 to 91.1, mean CE angle from -5.9 degrees to 32.0 degrees, and mean VCE angle from 5.0 degrees to 41.3 degrees. Using Pauwels criteria, regression was observed in 12 hips in group 1 and one progressed. In group 2, 15 hips showed regression and three progressed. In patients treated with Ganz osteotomy, the complication rate was higher and the complications more serious than in patients treated with Kotz osteotomy. Most complications were, however, seen among the first ten patients treated with Ganz osteotomy. Although we detected no significant difference between the two groups in terms of clinical and radiological findings, we believe the outcome to be slightly better after a properly performed Ganz osteotomy.     

Neuroprotective strategies in Parkinson's disease : an update on progress

In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors. Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3-5% every decade, while in Parkinson's disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70-75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson's disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurodegeneration and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson's disease. Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.     

The expression of DCC protein in female breast cancer

Background. The deleted in colorectal cancer (DCC) gene has been shown to be frequently deleted or its expression reduced or absent in glioblastomas, colorectal, gastro-intestinal, pancreatic and prostatic tumors. In the present study, we investigated the expression of DCC in surgical specimen from 75 patients with primary breast cancer. Methods. The expression of the DCC, estrogen receptors (ER), and progesterone receptors (PR) was studied in 75 surgical specimens of primary breast cancer using an immunohistochemical method. To evaluate the outcomes of the breast cancer patients, we followed up the patients during minimum of 10 years. Results. Reduced or loss of expression of DCC was identified in 45 out of 75 samples. There were significant differences between cases without metastasis or local recurrences versus these with metastasis or local recurrences (p = 0.006), and between patients alive with no evidence of malignancy versus those with recurrence or dead of disease (p = 0.005). There were no significant differences between the DCC status and age, sex, tumor location, stage, grade, or proportion of patients who received adjuvant therapy. Conclusions. These findings suggest that a decrease in DCC expression may influence the prognosis of breast carcinoma patients.     

Production of the novel mesangial autocrine growth factors GDNF and IL-10 is regulated by the immunomodulator AS101

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.     

The relationship between accessory navicular and medial longitudinal arch: evaluation with a plantar pressure distribution measurement system

This study included 92 patients with an accessory navicular (AN) noted on an anteroposterior roentgenography. This group was selected from 860 patients admitted to the authors' gait analysis laboratory. The medial longitudinal arch was evaluated by using an "arch index" calculated from the pressure picture obtained from a pressure distribution measurement system. The average arch index was 0.15 and there was no significant correlation between AN types and arch index. The study concluded that the presence and type of AN are not correlated with the height of the medial longitudinal arch of the foot and that AN is not associated with pes planus.     

皮质类固醇治疗外伤性视神经病变的四天关键时期(英文)

目的:评估静脉注射甲基强的松龙(IVMP)对外伤性视神经病变患者的疗效。方法:回顾性分析2000-01至2007-06我院收治的16例外伤性视神经病变(TON)患者的临床资料。1g甲基强的松龙分3d静脉应用,然后口服泼尼松龙11d,并逐渐减量。记录从损伤开始到治疗开始的时间。视力变化是本研究结果的主要功能评价指标。在入院时,治疗后1,2,3d;1wk和1mo时,分别记录最佳矫正视力(BCVA)。结果:共有16例患者纳入本研究,平均年龄为30岁,其中男性14例、女性2例。引起TON的主要原因有摩托车事故(占69%),打架斗殴(占19%)和体育运动(占12%)。所有患者都表现有相对传入性瞳孔障碍。在损伤后4d内开始静脉注射甲基强的松龙,采用Snellen视力表检查视力,绝大部分(56%)患者视力提高超过3行或大于等于0.5(6/12)。在损伤后5d以上才开始用类固醇治疗,视力则没有任何进步。结论:治疗TON,静脉注射中等到大剂量甲基强的松龙仍将起到重要作用。静脉注射甲基强的松龙治疗TON可能存在伤后4d的关键时期,超过了这个时期,该治疗可能就毫无效果。但还需要有更多的研究来为我们提供有明显统计学意义的数据。     

Transthoracic approach in surgical management of Morgagni hernia.

OBJECTIVE: Morgagni hernia is an uncommon type of diaphragmatic hernias. Numerous approaches have been described and, particularly the significance of laparatomy has been emphasized as an operative technique. We present our experience on patients with Morgagni hernia operated on via transthoracic approach in our department. MATERIALS AND METHODS: Between January 1986 and March 2000, 16 patients with Morgagni hernia were operated in our department. Their ages ranged from 16 to 68 years (mean 51.5). Five (31.25%) patients were male, and 11 (68.75%) patients were female. Chest roentgenograms, thorax CT, barium enema roentgenographic studies were used as diagnostic utilities. Right posterolateral thoracotomy was performed in all patients. RESULTS: Hernia sac was present in all cases. Exploration revealed omentum in hernia sac in eight patients (50%), colon and omentum in seven patients (44%), only colon in one patient (%6). Postoperative course was uneventful. The mean follow-up was 5.7 years. There was no recurrence or symptoms related to the operation. CONCLUSIONS: We advocate transthoracic approach for surgical exposure as it provides wide exposure and easy repair of the hernia sac in Morgagni hernia.