Inclusion formation by ataxins -1, -2, -3, and -7

The authors studied inclusion formation in vitro using transiently transfected PC12 cells, with epitope-tagged and untagged full-length and truncated wild-type and expanded ataxins -1, -2, -3, and -7. At 72 hours, no inclusions were seen with wild-type full-length or truncated ataxins -2, -3, or -7, and only one with ataxin-1. Truncation abolished nuclear localization of ataxins -1 and -7, and allowed nuclear entry of ataxin-2. Of the expanded ataxins, only -1 and -2 formed inclusions, and those of ataxin-2 were rare and exclusively cytoplasmic. Truncation resulted in inclusion formation by ataxins -3 and -7, increased ataxin-1 inclusions, and enabled formation of nuclear ataxin-2 inclusions. There was no recruitment of wild-type ataxin-1 to expanded ataxin-1 inclusions.     

INCLUSION FORMATION BY ATAXINS -1, -2, -3, AND -7

The authors studied inclusion formation in vitro using transiently transfected PC12 cells, with epitope-tagged and untagged full-length and truncated wild-type and expanded ataxins -1, -2, -3, and -7. At 72 hours, no inclusions were seen with wild-type full-length or truncated ataxins -2, -3, or -7, and only one with ataxin-1. Truncation abolished nuclear localization of ataxins -1 and -7, and allowed nuclear entry of ataxin-2. Of the expanded ataxins, only -1 and -2 formed inclusions, and those of ataxin-2 were rare and exclusively cytoplasmic. Truncation resulted in inclusion formation by ataxins -3 and -7, increased ataxin-1 inclusions, and enabled formation of nuclear ataxin-2 inclusions. There was no recruitment of wild-type ataxin-1 to expanded ataxin-1 inclusions.     

Elevated 14-3-3 protein and axonal loss in immunoglobulin-responsive,idiopathic acute transverse myelitis

OBJECTIVES: To report the elevation of the 14-3-3 protein and the complete denervation of hand muscles in idiopathic acute transverse myelitis (IATM) of the cervical cord. CASE DESCRIPTION: In a 29-year-old woman with a 2-week history of neck pain and repeated attenuated flus, subacute quadriplegia, hypaesthesia of both arms, a T3 sensory level, and urinary dysfunction occurred. Based upon the clinical findings, the cervical MRIs, and an elevated 14-3-3 protein in the CSF, IATM C4-C7 was diagnosed. Ten, 17, 28 and 61 days after onset, nerve conduction studies revealed complete denervation of the right abductor pollicis brevis and abductor digiti minimi muscles but gradual improvement of the compound muscle action potential of the left abductor pollicis brevis muscle. F-waves of the right median nerve were absent. Tibial somatosensory evoked potentials showed a prolonged central conduction time. Transcranial magnetic stimulation evoked a response in the left but not the right abductor digiti minimi muscle. CONCLUSION: IATM may cause elevation of the 14-3-3 protein and loss of motor axons originating from affected anterior horn cells.     

Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 are increased in POEMS syndrome

The authors quantitatively measured levels of matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP), and vascular endothelial growth factor (VEGF) in blood samples of POEMS syndrome. Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 were more increased in patients with POEMS syndrome than in patients with other neurologic disorders or in healthy controls. Serum levels of VEGF and TIMP-1 were strongly correlated with each other. Increased circulating levels of MMP-1, -2, -3, -9, and TIMP-1 may lead to a better understanding the pathogenesis of POEMS syndrome.     

HIV-1 and methamphetamine alter galectins -1, -3, and -9 in human monocyte-derived macrophages

Journal of NeuroVirology - Macrophages are key elements of the innate immune system. Their HIV-1 infection is a complex process that involves multiple interacting factors and various steps and is...     

14—3—3蛋白与肿瘤

一、14—3—3蛋白慨述 14-3-3蛋白是一种酸性可溶性蛋白,于1967年由Moor和Perez从牛的脑组织中分离,并因其经二乙氨乙基纤维素层析中的组分分布数量和在淀粉-凝胶电泳中的迁移位置而得名。由于14—3—3蛋白在脑组织中的含量最高,约占脑可溶性蛋白的1％,因而在很长一段时间内,它被认为是脑特异性蛋白,并且是动物所特有的、对维持脑神经功能具有独一无二作用的蛋白质。     

Normalization of 14-3-3 in CJD

We report on a 47-year-old woman with autopsy proven Creutzfeldt-Jakob disease (CJD), who had a positive initial 14-3-3 test but a subsequent negative test under pharmacologic suppression of the periodic epileptiform discharges on EEG. Multiple factors associated with a subsequent 14-3-3 test becoming negative are known. However none of these circumstances were applicable to our patient. This case history suggests sedative therapy in CJD may induce false negative 14-3-3 testing. This appears to be a relevant finding, since the differential diagnosis between non-convulsive status epilepticus and CJD is not always evident in the initial stage of the disease and some patients with CJD present with seizures.     

δ-, but not μ- and κ-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury

Recent observations from our laboratory have led us to hypothesize that δ-opioid receptors may play a role in neuronal protection against hypoxic/ischemic or glutamate excitotocity. To test our hypothesis in this work, we used two independent methods, i.e., “same field quantification” of morphologic criteria and a biochemical assay of lactate dehydrogenase (LDH) release (an index of cellular injury). We used neuronal cultures from rat neocortex and studied whether (1) glutamate induces neuronal injury as a function of age and (2) activation of opioid receptors (δ, μ and κ subtypes) protects neurons from glutamate-induced injury. Our results show that glutamate induced neuronal injury and cell death and this was dependent on glutamate concentration, exposure period and days in culture. At 4 days, glutamate (up to 10 mM, 4 h-exposure) did not cause apparent injury. After 8–10 days in culture, neurons exposed to a much lower dose of glutamate (100 μM, 4 h) showed substantial neuronal injury as assessed by morphologic criteria (>65%, n=23, P<0.01) and LDH release (n=16, P<0.001). Activation of δ-opioid receptors with 10 μM DADLE reduced glutamate-induced injury by almost half as assessed by the same criteria (morphologic criteria, n=21, P<0.01; LDH release, n=16, P<0.01). Naltrindole (10 μM), a δ-opioid receptor antagonist, completely blocked the DADLE protective effect. Administration of μ- and κ-opioid receptor agonists (DAMGO and U50488H respectively, 5–10 μM) did not induce appreciable neuroprotection. Also, μ- or κ-opioid receptor antagonists had no appreciable effect on the glutamate-induced injury. This study demonstrates that activation of neuronal δ-opioid receptors, but not μ- and κ-opioid receptors, protect neocortical neurons from glutamate excitotoxicity.     

School-based interventions for anxious children: 3-, 6-, and 12-month follow-ups

ObjectiveTo follow 61 participants (7–11 years old) from a study that compared three school-based interventions for anxious children: group cognitive-behavioral therapy (CBT) for children, group CBT for children plus parent training, and no-treatment control to determine whether posttreatment benefits are sustained longitudinally.MethodParent, child, and clinician report measures of child anxiety were completed at 3,6, and 12 months posttreatment. Semistructured diagnostic interviews were administered at 6- and 12-month follow-ups. For initial analyses, the group CBT and group CBT plus parent training conditions were collapsed into one group and compared to control. When significant results were found, each active treatment group was compared to control.ResultsAcross several measures, the collapsed CBT group sustained significant improvement in anxiety severity and impairment across a 12-month period compared to control. There were no significant differences between the three groups on remission of baseline anxiety disorders or incidence of new anxiety disorders during the follow-up. Several parent-report measures at 3 and 6 months posttreatment suggested that group CBT for children plus parent training provided additional benefit over the group CBT for children when each was compared to the control group.ConclusionsSchool-based CBT appears effective in decreasing anxiety symptoms up to 12 months posttreatment for anxious children. J. Am. Acad. Child Adolesc. Psychiatry, 2008; 47(9): 1039–1047.     

μ-, but not δ-, opioid receptor-mediated antinociception in mice is attenuated by γ-irradiation

Mice were exposed to whole-body irradiation (500 rads) from a ¹³⁷Cs γ-source and tested 2 h later for antinociception (tail-flick test) produced by intracerebroventricular administration of morphine or the more δ-selective opioid peptide, [ -Pen², -Pen⁵]enkephalin (DPLPE). Irradiation significantly attenuated the antinociception produced by morphine, but not by DPLPE. These results demonstrate a differential sensitivity of μ- and δ-opioid receptors to γ-irradiation and, in addition, may be of clinical relevance for cancer patients receiving concurrent radiation therapy and opioid analgesics.     

14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

We explored simultaneously 14-3-3 protein, neuron-specific enolase (NSE), and one astroglial protein, S-100, recently proposed as Creutzfeld-Jakob disease (CJD) markers, in the cerebrospinal fluid (CSF) of 129 patients with suspected CJD. Cutoff values for NSE and S-100 were established at 25 and 2.5 ng/ml, respectively. The highest sensitivity was observed for S-100 (94.2%) followed by 14-3-3 (89.8%) and NSE (79.7%), while the highest specificity in CJD diagnosis was obtained with 14-3-3 protein (100%) as compared with NSE (91.5%) and S-100 (85.4%). No influence of sex, genotype at codon 129 of the prion protein gene, time between sampling, and death or disease duration has been found. Based on 90 cases initially referred as 'probable' or 'possible' CJD, with 14-3-3, NSE, or S-100 we could correctly discriminate between 'CJD' or 'non-CJD' categories in 94.4, 86.5, and 90% of the cases, respectively. When limited to 'possible CJD' cases, diagnosis based on one of the three CSF proteins was accurate in 98, 90.7 and 87.3%, respectively. In view of the fact that the CSF 14-3-3 protein test alone has the highest specificity and good sensitivity, it appears that there is no additional advantage at the moment to include NSE and/or S-100 protein in the exploration of clinically suspected CJD cases.     

14-3-3 Proteins,particularly of the epsilon isoform,are detectable in cerebrospinal fluids of cerebellar diseases in children

Background: Detection of 14-3-3 proteins in cerebrospinal fluid (CSF) is a powerful tool for elucidating the mechanisms of neurological disorders. There have been useful studies on 14-3-3 CSF protein detection in Creutzfeldt–Jakob disease and other neurological disorders, but none on cerebellar diseases. Objective: To elucidate whether 14-3-3 CSF proteins are a sensitive biomarker of cerebellar disruption in children. Materials and Methods: We examined 14-3-3 CSF proteins by immunoblotting in seven patients with cerebellar disorders: two with acute cerebellitis, two with acute cerebellar ataxia, and three with cerebellar atrophy. We also investigated 14-3-3 CSF proteins in four cases of febrile seizure and three of influenza-related encephalopathy. Isoforms of 14-3-3 proteins were also identified using isoform-specific antibodies. Results: 14-3-3 proteins were detected in CSF of six patients with cerebellar disorders, the exception being one with acute cerebellar ataxia caused by viral infection. Interestingly, only the 14-3-3 ε isoform was detected in two tested patients with cerebellar involvement. Moreover, longitudinal analysis of 14-3-3 CSF proteins in one patient with infantile neuroaxonal dystrophy showed that the 14-3-3 band density proportionally decreased when the cerebellar atrophy gradually progressed. Another CSF derived from a case of febrile seizure showed no 14-3-3 proteins, whereas all those derived from influenza-related encephalopathy demonstrated 14-3-3 CSF proteins with six isoforms. Conclusions: This is the first report on 14-3-3 CSF proteins as a significant biomarker of cerebellar disruption, as well as other brain diseases. Since 14-3-3 ε is localized in the molecular layer of cerebellum, the unique detection of 14-3-3 ε may indicate cerebellar involvement in the brain.     

国人Creutzfeldt-Jakob病临床、病理、免疫组化、PrP基因、14-3-3蛋白及动物传递的研究

目的 探讨国人Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病（ＣＪＤ）的临床、病理及免疫组化、ＰｒＰ基因、１４－３－３蛋白及实验鼠传递结果。方法 统计２４例ＣＪＤ患者的临床资料,进行脑组织病理检查。其中１０例脑切片作ＰｒＰ免疫组化染色,１０例进行ＰｒＰ基因表达,５例脑脊液行１４－３－３蛋白检测,７例进行实验鼠传递。结果 （１）２４例ＣＪＤ中散发１９例,可能为医源性３例,家族性１例,与Ａｌｚｈｅｉｍｅｒ病并存１例;（２）国人ＣＪＤ急性、亚急性发病高达９６％,急性发病者病程短,脑萎缩不明显;（３）脑组织石蜡切片以ＰｒＰ抗血清为第一抗体免疫组化染色,均呈突触型阳性;（４）１４－３－３蛋白表达对ＣＪＤ的临床诊断有特异性;（５）活检脑组织对实验鼠传递成功。结论 国人ＣＪＤ发病过程和临床表现有若干特殊性,通过１４－３－３蛋白表达,可