Rab GTPases as regulators of endocytosis,targets of disease and therapeutic opportunities

Agola JO, Jim PA, Ward HH, BasuRay S, Wandinger‐Ness A. Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities. Rab GTPases are well‐recognized targets in human disease, although are underexplored therapeutically. Elucidation of how mutant or dysregulated Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up‐ or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab‐regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, viability, growth and differentiation. In this review, we focus on Rab GTPase roles in endocytosis to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab GTPase cascades alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential therapeutic modulation of GTPase activity through small molecule interventions are provided.     

Histomorphometric evaluation of delayed changes in masseter muscle after lengthening the rabbit mandible by distraction osteogenesis

Objective:  The aim of the study was to evaluate the delayed responses and changes of gradually lengthened masseter muscles of rabbit mandibles.
Study Design:  Unilateral lengthening of rabbit mandibles was performed in 18 New Zealand rabbits for 7 days at the rate of 1 mm day⁻¹. Mandibles of animals were removed at months 3, 4, and 6 after distraction. Biopsy samples of distracted and contralateral side masseter muscles were histopathologically evaluated and mean area of muscle fibers (MAF) was evaluated with histomorphometric methods. Results were statistically analyzed.
Results:  Mild to moderate atrophy of the fibers, and necrosis and myophagocytosis in some areas were the leading features at month 3 and which were decreased at month 4 in distracted side-muscle specimens, with no statistically significant differences when compared with non-distracted side muscles at the same periods. Almost completely, normal fibers were detected in distracted muscle specimens at month 6. Evidence of myopathic changes was found to disappear at month 6 and no significant difference was found in the MAF of distracted side muscles.
Conclusion:  This study showed that the masseter muscle could adapt to gradual lengthening of the mandible within 6 months. Regenerative features and some degree of atrophic changes that could be observed at months 3 and 4 disappeared at month 6, with adaptation of the fibers.     

中国肝癌肝移植的现状与展望

肝癌行肝移植治疗的指征、效果和相关问题一直存在争论,国际上已经有数个通用的肝癌肝移植标准,如Milan标准、Pittsburgh标准、UCSF标准等等,中国的移植学家们也在纷纷探讨适合中国的肝癌肝移植标准.本文收集并分析近年来国内外的文献,结合本移植中心460例肝移植的病例,对肝癌的分期标准、晚期肝癌行肝移植的指征进行了探讨,笔者认为影响我国肝癌肝移植的主要因素有:供肝的来源、术后乙肝及肿瘤的复发及相关社会因素等.     

Greater hypertrophy in right than left ventricles is associated with pulmonary vasculopathy in sinoaortic-denervated Wistar-Kyoto rats

1. Biventricular hypertrophy has been described in a high blood pressure variability (BPV) model of sinoaortic-denervated (SAD) rats without systemic hypertension. To explore the possible involvement of the lung in SAD-induced right ventricular hypertrophy (RVH), we examined lung morphology, in addition to systemic haemodynamics and ventricle morphology, in Wistar-Kyoto rats 32 weeks after SAD. 2. In Wistar-Kyoto rats 32 weeks after SAD, there existed a substantial elevation in BPV, with no change in the average level of arterial pressure. Biventricular hypertrophy following SAD was characterized by a greater hypertrophy in right than left ventricles; both absolute and normalized right ventricular weights were significantly increased by 22 and 27％, respectively, and only normalized left ventricular weight was significantly increased by 12％. No infarcts were found in any ventricles examined. 3. In the lung, the most prominent change following SAD was pulmonary vasculopathy, including wall thickening, perivascular fibrosis and cell infiltration. In pulmonary arteries with an internal diameter of 70-130 microm, the external diameter, wall thickness and wall thickness to internal diameter ratio were increased in SAD compared with control rats. 4. There was no correlation between right and left ventricular weights. In contrast with BPV-correlated left ventricular weight, right ventricular weight was correlated with the wall thickness of the pulmonary artery, but not with BPV. 5. These findings suggest that greater RVH following SAD is associated with pulmonary vasculopathy, but is not secondary to the left ventricular problems or high BPV.     

Interleukin-6 expression after renal transplantation

BACKGROUND: Interleukin-6 (IL-6) is an inflammatory cytokine that plays a role in transplant rejection. We tested the hypothesis that IL-6 levels in serum or urine could be of value in predicting acute and chronic allograft rejection. Furthermore, we examined whether or not such levels reflected IL-6 expression in the kidney. METHODS: We measured IL-6 and IL-6 soluble receptor (IL-6sR) in serum and urine of 145 transplant patients and 20 normal controls. In parallel, we studied 108 renal biopsies. IL-6 was measured with a bioassay system using an IL-6 dependent cell line. IL-6sR was measured with enzyme-linked immunosorbent assay. The biopsies were examined for IL-6 and IL-6 receptor (IL-6R) expression with immunohistochemistry. RESULTS: Rejection episodes occurring within 2 months of transplantation were accompanied by elevated IL-6 concentrations in serum (17 +/- 4.8 pg/ml, P < 0.05) and urine (114 +/- 27 pg/ml, P < 0.005), compared to controls. These values returned towards baseline (0-5 pg/ml) after successful rejection treatment. The sensitivity of urine measurements was much higher (93%) than serum (54%). The specificity in serum (70%) and urine (60%) was reduced by infection, acute tubular necrosis, and antithymocyte globulin treatment. Serum and urine IL-6sR values did not correlate with rejection. In biopsy tissue, IL-6 and IL-6R were both elevated during rejection. Especially, mononuclear cells within the interstitial infiltrate stained positive. However, the amount of IL-6 positive cells did not correlate with peripheral IL-6 concentrations. CONCLUSIONS: Urine but not serum IL-6 values are sensitive indicators of rejection; however, they are confounded by infection, acute tubular necrosis, and certain antirejection treatments. These features limit their usefulness.      

Prevalence of asthma in Danish children aged 8–10 years

The aim of the study was to estimate the point prevalence of asthma in schoolchildren aged 8–10 y in the County of Copenhagen, Denmark. In all, 1040 schoolchildren were randomly chosen for the study and a total of 774 completed the study. The suspicion of asthma was based on a questionnaire about respiratory symptoms and on daily registration of respiratory symptoms and peak expiratory flow rate (PEF) for 4 weeks. The conclusive diagnosis was based on interview, clinical examination, spirometry and an exercise test. The prevalence of children with asthma diagnosed by their GPs was 3/774 (4. 0%). A further 20/774 (2. 6%) were diagnosed as having asthma. There is evidence to suggest that asthma is less frequent in Denmark than in Great Britain, New Zealand and Australia.     

A molecular basis for hemoglobin-H disease in American blacks

We have applied gene counting and restriction endonuclease mapping techniques to the study of two American black families in which there were one or more cases of HbH disease. We found deletions of three of the four normal alpha-globin genes in individuals with HbH disease. In two of these individuals, the chromosome containing the single alpha gene could have originated by crossing over between mispaired alpha genes, resulting in a deletion of about 4.2 kilobases (kb).     

Videodensitometric quantitation of stenosis: in vitro and in vivo validation

Percentage of stenosis of a vascular lumen was quantitated using a digital subtraction angiography system with videodensitometric analysis. To validate the algorithm and methods, we used precisely drilled Lucite rods of three inner diameters and various reduced diameters to give known luminal reduction. Both in vitro and in vivo results of stenosis measurements resulted in an excellent correlation between actual and measured values (correlation coefficient greater than 0.9 for all trials). Consistent underestimation of stenosis of about 5% was attributed to the various image degradations inherent with the imaging procedure and equipment. Errors were greatest with midrange stenoses and less at the extremes of the lesion values. An insufficient signal-to-noise ratio was caused by low photon flux and/or low contrast material concentration and overlying vasculature filled with contrast material. Overall, the videodensitometric technique is accurate, easy to implement, objective, and relatively free of errors associated with the geometric/edge detection method.