Neuronal damage - recent issues and implications for therapy

The spectrum of structural damage in the brain associated with HIV is now more fully understood. Such changes include inflammatory disorders (such as HIV encephalitis, leukoencephalopathy, and diffuse poliodystrophy), dendritic and synaptic damage, and neuronal loss. However, the relationship between neuronal damage and loss and clinical variables is still not clear. In my laboratory my research group has been addressing three separate areas, which will be the subject of this presentation. (1) The relationship of neuronal damage and loss to various clinical features such as cognitive symptoms, and risk group. (2) The cellular site of production of neurotoxic factors in the HIV-infected brain. (3) Assessing potential neuroprotective strategies using appropriate in-vitro models.     

Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G- CSF-mediated activation of signaling complexes of the p21ras route

Granulocyte colony-stimulating factor (G-CSF) induces rapid phosphorylation of JAK kinases as well as activation of the p21ras route through interaction with its specific receptor (G-CSF-R). The cytoplasmic membrane-proximal region of G-CSF-R (amino acids 631 to 684) is necessary for proliferation induction and activation of JAK2. In contrast, activation of Shc and Syp, signaling molecules implicated in the p21ras signaling route, depends on the phosphorylation of tyrosine residues located in the membrane-distal region (amino acids 685 to 813) of G-CSF-R. We investigated whether G-CSF-induced activation of signaling complexes of the p21ras route depends on the function of the membrane-proximal cytoplasmic region of G-CSF-R. A G- CSF-R mutant was constructed in which tryptophan 650 was replaced by arginine and expressed in BAF3 cells (BAF/W650R). In contrast to BAF3 cell transfectants expressing wild-type G-CSF-R, BAF/W650-R cells did not proliferate and did not show activation of JAK2, STAT1, or STAT3 in response to G-CSF. Immunoprecipitations with anti-Shc and anti-Grb2 antisera showed that mutant W650R also failed to activate Syp and Shc. These data indicate that the membrane-proximal cytoplasmic domain of G- CSF-R is not only crucial for proliferative signaling and activation of JAK2 and STATs, but is also required for activation of the p21ras route, which occurs via the membrane-distal region of G-CSF-R.     

The spatial relationship between neurons and astrocytes in HIV-associated dementia

Specific neuronal spatial distributional patterns have previously been correlated with increasing severity of HIV-associated dementia (HAD). As astrocytes are also a putative site of neurotoxicity, we investigated the spatial relationships of astrocytes with pyramidal and interneurons in the superior frontal gyrus from 29 patients who died from acquired immunodeficiency syndrome. Frontal cortical brain tissue was taken from diseased HIV patients who had been assessed for the presence and severity of HAD using the Memorial Sloan-Kettering Scale. No correlation was found between neuronal density and severity of dementia. However, the pattern of astrocytes became more clustered as dementia progressed. Bivariate spatial pattern analysis of neuronal populations with astrocytes revealed that, with increasing dementia severity, astrocytes and large pyramidal neurons increasingly “repelled” each other, while astrocytes and interneurons evidenced increasing “attraction.” This implies that astrocytes may be more likely to be situated in the vicinity of surviving interneurons but less likely to be situated near surviving large pyramidal neurons in the setting of progressing HAD.     

Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness

European Archives of Psychiatry and Clinical Neuroscience - Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory...     

Intraperitoneal chemotherapy for patients with advanced ovarian cancer: a review of the evidence and standards for the delivery of care

OBJECTIVES: To evaluate the role of intraperitoneal (IP) chemotherapy as part of primary treatment in patients with advanced ovarian cancer and to develop standards of care within the context of current clinical practice. METHODS: A multidisciplinary expert panel, convened to develop standards on the use of IP chemotherapy, searched the MEDLINE, EMBASE, and Cochrane Library databases up to December 2006 for randomized trials or published standards on the efficacy and/or delivery of IP chemotherapy. RESULTS: Eight randomized trials comparing IP chemotherapy versus intravenous (IV) chemotherapy were identified. Three trials reported statistically significant improvements in median survival of 8.0, 11.0, and 15.9 months with cisplatin-based IP chemotherapy. In one trial, the 15.9-month improvement in median overall survival (RR=0.75, 95% CI=0.58-0.97) represented a 25% reduction in the risk of death with IP chemotherapy. Severe adverse events and catheter-related complications were often dose limiting with IP chemotherapy. Using a consensus-based approach with a nationally representative panel, multidisciplinary care standards were developed to review medical and surgical criteria, the practice setting, volume requirements, and the institutional criteria required to safely deliver IP chemotherapy. CONCLUSION: The survival benefits with cisplatin-based IP chemotherapy may represent a significant improvement in the outlook for select patients with advanced ovarian cancer. The delivery of IP chemotherapy is more challenging than the IV route; however, severe adverse events and catheter-related complications may be offset through research defining the optimum treatment regimen, and the standardization of care. System-wide standards for the delivery of IP chemotherapy in Canada for patients with optimally debulked stage III ovarian cancer are offered.     

p38 MAPK对嗜酸性粒细胞和支气管上皮细胞共培养时细胞因子释放的调控作用

目的 了解嗜酸性粒细胞和支气管上皮细胞相互作用诱导细胞因子释放的p38 MAPK信号转导通路.方法 用CD16磁珠抗体分离外周血中嗜酸性粒细胞,以嗜酸性粒细胞和支气管上皮细胞(BEAS-2B)接触共培养为实验模型,观察SB 203580对细胞培养上清液中细胞因子浓度的影响.细胞因子浓度采用ELISA和流式细胞微珠方法测定.结果 SB 203580能够有效抑制BEAS-2B细胞释放IL-6、IL-8(P＜0.05)和嗜酸性粒细胞释放IL-8(P＜0.01).SB 203580对嗜酸性粒细胞与BEAS-2B细胞接触共培养诱导的IL-6、IL-8和IP-10释放具有显著抑制作用(P＜0.001).结论 嗜酸性粒细胞、BEAS-2B细胞单独或相互作用时均通过p38 MAPK信号转导通路释放细胞因子.     

Density and distribution of white matter neurons in schizophrenia,bipolar disorder and major depressive disorder: no evidence for abnormalities of neuronal migration

The neurodevelopmental hypothesis of schizophrenia suggests that this disorder may result from a disruption of normal brain development. While widely cited, neuropathological evidence for this is far from conclusive. Alterations in the density and position of white matter neurons have been previously described in the frontal and temporal lobes and have led to suggestions that abnormal neuronal migration may play a role in the aetiology of schizophrenia. However, these findings have not been replicated. Furthermore, developmental abnormalities may not be specific to schizophrenia. The aim of this study was to examine the density and spatial pattern distribution of white matter neurons in psychiatric and control subjects using sophisticated computerised image analysis techniques. White matter neurons immunoreactive for microtubule associated protein-2 were quantified in the frontal lobe in schizophrenia, bipolar disorder, major depressive disorder and matched controls (each group n = 15). Analysis showed that the density and spatial distribution of white matter neurons did not differ significantly between the control and psychiatric groups. This study cannot replicate the earlier findings of white matter abnormalities in schizophrenia and finds no evidence for abnormal brain development in any of the disorders studied.