Early onset renal cell carcinoma in an adolescent girl with germline <Emphasis Type="Italic">FLCN</Emphasis> exon 5 deletion

Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30–45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.     

Role of hybrid tRNA-binding states in ribosomal translocation

During translation, tRNAs must move rapidly to their adjacent sites in the ribosome while maintaining precise pairing with mRNA. This movement (translocation) occurs in a stepwise manner with hybrid-state intermediates, but it is unclear how these hybrid states relate to kinetically defined events of translocation. Here we analyze mutations at position 2394 of 23S rRNA in a pre-steady-state kinetic analysis of translocation. These mutations target the 50S E site and are predicted to inhibit P/E state formation. Each mutation decreases growth rate, the maximal rate of translocation (k(trans)), and the apparent affinity of EF-G for the pretranslocation complex (i.e., increases K(1/2)). The magnitude of these defects follows the trend A > G > U. Because the C2394A mutation did not decrease the rate of single-turnover GTP hydrolysis, the >20-fold increase in K(1/2) conferred by C2394A can be attributed to neither the initial binding of EF-G nor the subsequent GTP hydrolysis step. We propose that C2394A inhibits a later step, P/E state formation, to confer its effects on translocation. Replacement of the peptidyl group with an aminoacyl group, which is predicted to inhibit A/P state formation, decreases k(trans) without increasing K(1/2). These data suggest that movements of tRNA into the P/E and A/P sites are separable events. This mutational study allows tRNA movements with respect to both subunits to be integrated into a kinetic model for translocation.     

Formula for use of mannitol in patients with intracerebral haemorrhage and high intracranial pressure

BACKGROUND AND OBJECTIVE: Although mannitol has been widely used in hospitals to treat patients with high intracranial pressure (ICP) secondary to intracerebral haemorrhage (ICH), no universal agreement has been reached regarding the optimal dosage of this agent for achieving appropriate intracranial decompression. The aim of this study was to investigate the effects of different mannitol dosages on ICP and the effects of other factors, such as sex, age, haemorrhage location and haematoma volume, on the ICP-lowering effect of mannitol. The data obtained were then used to construct a formula for estimating the total dosage of mannitol required to reduce ICP in individual patients with ICH. PATIENTS AND METHODS: A total of 72 patients with ICH and elevated ICP monitored in our intensive care unit were included in this study. Patients with ICH who had hypoxaemia (arterial oxygen saturation <90%), severe functional disturbances of the liver or kidney, acidosis or pathological changes in the visual conducting pathway were not included in this study. Each patient received 20% intravenous mannitol 125 mL every 4, 6 or 8 hours per day to treat elevated ICP, with ICP levels being measured before administration of mannitol and at least three times per day during administration of the drug. When the ICP reached a fixed level, the dosage of mannitol was gradually reduced. The total dosage of mannitol used to reduce the ICP from the highest value to the fixed value was calculated. Data on the patients' sex, age, haemorrhage location and haematoma volume were also obtained. Multivariate regression analysis of the results enabled development of a formula for use of mannitol in patients with ICH and elevated ICP. RESULTS: Use of mannitol significantly decreased ICP in all patients. The effect of mannitol on ICP reduction was dose-dependent during the period of ICP reduction (p < 0.05) but not after the ICP had reached a fixed level; this limited effectiveness of mannitol when its dosage reaches a certain level was termed 'mannitol saturation dosage'. The reduction in ICP with mannitol was not statistically significantly affected by the patient's sex or age, but was significantly correlated with both haemorrhage location and haematoma volume (p < 0.05). The reduction in ICP with mannitol was greater in patients with supratentorial ICH compared with those with infratentorial ICH (p < 0.0001). CONCLUSION: The total mannitol dosage required for individual patients with ICH and elevated ICP can be calculated by considering the location of the haemorrhage, the volume of the haematoma and the pretreated ICP reading. To this end, the following formula was derived in the study: Total dosage of mannitol (mL of 20% mannitol) = (x + 31.17900 x y - 3.39853 x z - 244.47590)/0.00752, where x = the pretreated ICP (mmH(2)O), y = the haemorrhage location (supratentorial ICH: y = 0, infratentorial ICH: y = 1) and z = the volume of haematoma (mL). Use of this formula in the clinical setting should help reduce the possibility of adverse effects resulting from administration of excessive dosages of mannitol.     

Gx‐50 reduces β‐amyloid‐induced TNF‐α, IL‐1β, NO,and PGE2 expression and inhibits NF‐κB signaling in a mouse model of Alzheimer's disease

Chronic inflammation, which is regulated by overactivated microglia in the brain, accelerates the occurrence and development of Alzheimer's disease (AD). Gx‐50 has been investigated as a novel drug for the treatment of AD in our previous studies. Here, we investigated whether gx‐50 possesses anti‐inflammatory effects in primary rat microglia and a mouse model of AD, amyloid precursor protein (APP) Tg mice. The expression of TNF‐α, IL‐1β, NO, prostaglandin E2, and the expression of iNOS and COX2 were inhibited by gx‐50 in amyloid β (Aβ) treated rat microglia; additionally, microglial activation and the expression of IL‐1β, iNOS, and COX2 were also significantly suppressed by gx‐50 in APP⁺ transgenic mice. Furthermore, gx‐50 inhibited the activation of NF‐κB and MAPK cascades in vitro and in vivo in APP‐Tg mice. Moreover, the expression of TLR4 and its downstream signaling proteins MyD88 and tumor necrosis factor receptor associated factor 6 (TRAF6) was reduced by gx‐50 in vitro and in vivo. Interestingly, silencing of TLR4 reduced Aβ‐induced upregulation of IL‐1β and TRAF6 to levels similar to gx‐50 inhibition; moreover, overexpression of TLR4 increased the expression of MyD88 and TRAF6, which was significantly reduced by gx‐50. These findings provide strong evidence that gx‐50 has anti‐inflammatory effects against Aβ‐triggered microglial overactivation via a mechanism that involves the TLR4‐mediated NF‐κBB/MAPK signaling cascade.     

不同程度非增殖性糖尿病视网膜病变的OCTA表现

目的:利用光学相干断层扫描血管成像(OCTA)探讨不同程度非增殖性糖尿病视网膜病变(NPDR)的表现差异。方法:横断面研究。纳入糖尿病患者77例77眼,分为非DR组(NDR,23眼)和NPDR组(54眼),其中轻度NPDR(20眼)、中度NPDR(20眼)和重度NPDR(14眼)。NDR组与NPDR组的黄斑区中央凹无血管区(FAZ)面积、浅层和深层毛细血管密度(SSP和DSP)、视力(LogMAR)进行比较,不同程度NPDR的视力、FAZ面积、SSP和DSP水平进行比较,FAZ面积、视力、SSP和DSP与病情严重程度进行相关性分析。结果:与NDR组相比,NPDR组的视力值(LogMAR)、黄斑区FAZ面积增大,SSP和DSP降低(P<0.05);不同程度NPDR的视力、FAZ面积、SSP和DSP水平差异显著(P<0.05)。视力(LogMAR)、FAZ面积与病情严重程度呈正相关,SSP和DSP与病情严重程度呈负相关。结论:随着NPDR病情的进展,视力(LogMAR)、FAZ面积增大,SSP和DSP降低。     

278例药物诱发癫癇分析

目的 :探讨药物诱发癫的发病因素及可能诱发癫的药物。方法 :收集国内 12 4篇医学期刊上有关药物诱发癫的文献 ,对其临床资料进行综合统计分析。结果 :涉及药品 68种 ,抗精神病药物发病率最高 ,抗生素次之。诱发癫与药物剂量、给药途径、患者年龄、癫病史及家族史等有关。结论 :有易感因素患者选用所述药物时要慎重或尽量选用发作危险性小的药物     

超声内镜诊治合并假性囊肿的沟槽状胰腺炎1例

沟槽状胰腺炎是一种特殊类型的胰腺炎,临床报道较少。本文报道了1例以间断性上腹痛为主要临床表现、合并假性囊肿的沟槽状胰腺炎病例的超声内镜诊治过程,旨在为该类疾病的临床诊疗提供参考。