LYSOSOMAL IRON ACCUMULATION AND TUBULAR DAMAGE IN RAT PUROMYCIN NEPHROSIS AND AGEING

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11–12 days rats treated with puromycin (10 mg/100g, i.v.i.) had greater proteinuria (211.6 ± 35.7 mg/day, mean ± s.e.m.) and urinary iron excretion (15.4 ± 2.2 μg/day) than salinetreated controls (14.5 ± 1.4 mg/day and 1.1 ± 0.2 μg/day, respectively, both P<0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 ± 64.5 vs 11.9 ± 8.6 mg%, P<0.001), and proximal tubular cell damage assessed semi-quantitively (1.17 ± 0.10 vs 0.62 ± 0.10, P<0.001) were higher and creatinine clearance (0.15 ± 0.01 vs 0.29 ± 0.02 mL/min perg kidney weight, P<0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.     

神经节细胞胶质瘤恶变及其差异表达基因分析

目的探讨神经节细胞胶质瘤恶性进展的分子变化,为进一步研究分子病因奠定基础。方法取同一患者不断恶化的3次手术标本,行cDNA微阵列检测,分析在不同阶段持续存在的差异表达基因。结果初发(WHO II级)、复发(WHO III级)和再发(WHO IV级)的标本与正常脑组织相比,差异表达基因共19条,其中下调者16条,上调者3条。在下调的基因中,功能明确者有抑制RAF1/MEK/ERKs激酶通路激活的磷酸酰乙醇胺结合蛋白,抑制肿瘤血管增生、侵袭,调控细胞凋亡的碳酰还原酶;抑制c-myc基因表达的肺库否样因子;参与人DNA切除修复的多聚酶ε。结论神经节细胞胶质瘤恶变过程中持续存在的分子变化,以抑制肿瘤增殖基因表达下调为主,其中RAF激酶抑制蛋白、DNA多聚酶ε和碳酰还原酶是参与细胞信号传导和DNA损伤修复等具重要功能的基因,值得进一步研究。     

Clinical characteristics of rapidly progressive leuko-araiosis

Introduction – 38 patients found to have either pure leuko-araiosis (LA) or LA combined with infarction(s) on computer tomography (CT) in 1989 were re-examined in 1992 in order to evaluate the progression of LA. The follow-up period averaged 3.2 years. Material and methods - The clinical and radiological data on patients in 1989 were collected from hospital records and re-evaluated. The patients were re-examined clinically (including 24 hour ambulatory blood pressure measurement), and neuroradiologically (CT) in 1992 for this study. Results – 11 (29%) patients were found to have significant (rapid) progression of the extent of LA on CT during the follow-up. At baseline, there was no significant difference in the mean number of brain infarctions between the groups with progressing (prLA) and non-progressing LA (nprLA) or between the number of cortical and central infarctions within these groups. At follow-up, the total number of infarctions had increased significantly in both groups, but it was mostly because of the increase in cortical infarctions in the prLA group (p = 0.043) and, conversely, the central ones in the nprLA group (p = 0.011). prLA was found to be related to heart failure (82% vs 37%, p = 0.029) and atrial fibrillation (55% vs 19%, p = 0.047), whereas nprLA was strongly associated with a sudden onset of symptoms (78% vs prLA 18%, p = 0.001) like a-true brain infarction. Other clinical factors, including mean blood pressure and heart rate, did not clearly differentiate between the groups. Conclusion - The results suggest that there are different subgroups of patients with LA associated with various vascular factors. The occurrence of LA is not related to the distribution of infarctions. The progression of LA is not related to the number of brain infarctions or to the simultaneous increase of infarctions on CT.     

Non-immune therapy of IgA glomerulonephritis

Summary: The involvement of the IgA immune system and complement components in IgA glomerulonephritis (IgAGN) has prompted the use of immunosuppressive drugs in therapy, but none has so far been shown to alter the natural course of the disease. Because most patients with IgAGN present during the chronic phase of their illness, at the time when the initiating immune events may no longer be active, nonimmune therapy which targets the common pathway of progressive renal injury is likely to be more useful. There is increasing evidence that angiotensin-converting enzyme inhibitors (ACEI) reduce proteinuria and renal injury in patients with IgAGN, and this effect may be observed in both normotensive and hypertensive patients. Yet to be determined is whether this effect is specific for ACEI and whatever other effective antihypertensive drugs may achieve a similar result. Fish oil has recently been shown to retard the progression of renal failure in patients with aggressive IgAGN, but a narrow therapeutic window appears to exist for this form of treatment. Antiplatelet agents on their own appear to be ineffective but in combination with anticoagulation (low dose warfarin) have been shown to have an antiproteinuric effect and may preserve renal function in patients with progressive disease. Future directions of non-immune therapy of IgAGN include evaluation of the renoprotective effect of angiotensin II receptor antagonists, free-radical scavengers and antilipid drugs. More work should also be done to identify factors which put the patients at risk of developing progressive disease and which predict therapeutic response, as has been done recently with the identification of the deletion polymorphism of the angiotensin-converting enzyme gene as a marker of progressive disease and therapeutic response to ACEI in patients with IgAGN.     

低剂量甲基汞在小鼠体内分布及其对细胞周期进程的影响

连续９０天饮用含甲基汞浓度为１／１０００ＬＤ５０、１／１００ＬＤ５０、１／５０ＬＤ５０和１／１０ＬＤ５０的自来水的雄性昆明小鼠，各脏器中总汞含量均高于对照组（Ｐ＜０．０５～０．００５），并且随着染毒剂量增加，脏器中总汞含量也随之增高。同时采用ＦＡＣＳｃａｎ流式细胞仪和“ＣｅｌｌＦＩＴ”软件分析脾细胞周期进程，发现除１／１０００ＬＤ５０剂量组外，其余各剂量组从Ｇｏ／Ｇ１时相进入Ｓ时相的脾细胞百分数均明显高于对照组（Ｐ＜０．０５），与染毒剂量呈明显正相关。表明连续经口摄入低剂量甲基汞小鼠脾细胞周期进程加快，细胞ＤＮＡ复制增强。     

Alpha-SM actin expression as prognostic indicator in IgA nephropathy (Berger's disease)

Recent studies have demonstrated that α-Smooth Muscle actin expression in glomerular and tubulointerstitial compartments of renal tissue could represent a prognostic marker in several renal diseases. Our objective was to identify the prognostic value of α-SM actin actin expression on the evolution of renal damage in Primary IgA nephropathy (Berger’s Disease). 43 patients followed up from 1988 to 1999 at the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil, was studied. Clinical-laboratory data were obtained from the medical records of the patients using a protocol containing name, race, gender, origin, profession, age at clinical presentation of the disease and personal and family history. The parameters assessed in the approach to IgA nephropathy were serum creatinine, creatinine clearance, serum albumin, total serum protein, 24 hours proteinuria, glycaemia, serum sodium, potassium, calcium and phosphorus ions, analysis of urinary sediment, serum complement profile, blood count, and renal biopsy. Morphological evaluation was performed by renal biopsy using common light and immunofluorescence microscopy. Immunohistochemical studies were performed using a murine monoclonal antibody to α-SM actin. Our data showed that α-SM actin expression in the glomerular and tubulointerstitial compartments are not correlated with unfavorable clinical course of primary IgA nephropathy.     

Functional variation of HIV-1 Rev Response Element in a longitudinally studied cohort

We showed previously that HIV-1 Rev Response Element (RRE) contains a certain degree of structural variation, and in a set of limited samples, RRE from HIV-1 natural isolates were found to have functional variability. The significance of the RRE heterogeneity is addressed further by analyzing the functional variation of RREs in a longitudinal cohort. While the RRE activity at early time points was not a good predictor of disease outcome, the RRE activity at late time points was correlated with rates of CD4+ count decline. These data suggest that RRE heterogeneity may be important in viral pathogenesis and disease progression.