Investigating the effects of targeting nitric oxide pathways in a kainic acid mouse model of epileptogenesis

Epilepsy is one of the most common chronic neurological disorders, and the symptomatic form is characterised by the occurrence of spontaneous recurrent seizures following a neurological insult. One third of epilepsy patients are resistant to antiepileptic drugs (AEDs), therefore the development of novel treatments is required. Glutamate is implicated in epilepsy however, only a few glutamate receptor antagonists have been successful in epilepsy trials. An indirect means of modifying glutamate-mediated excitation, such as targeting nitric oxide (NO), might be a reasonable alternative approach. Selectively targeting NO signalling pathway by two drug interventions was investigated in this thesis. Post-synaptic density 95 blocking peptide (PSD95BP) is a protein that uncouples GluN2 subunits of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor from neuronal NO synthase to prevent downstream neurotoxic signalling of NO. In contrast, 1400W is a highly specific inducible NO synthase inhibitor that binds to the guanidine recognition site of the enzyme, competing with L-arginine and preventing neurotoxic production of NO. These compounds are effective in animal models of stroke and were tested here in a C57BL/6J mouse model of epileptogenesis. Kainic acid (KA) is widely used to induce status epilepticus (SE) in animals and the resulting neuropathology mimics that seen in humans with temporal lobe epilepsy. Repeated low dose administration of KA via intraperitoneal injection every 30 minutes consistently induced generalised seizures but was associated with inter-animal variability in KA sensitivity, acute seizure severity and mortality rate. Extra-dural telemetry electrodes were implanted in mice for electroencephalography (EEG) recordings. Two algorithms, measuring spike frequency and EEG coastline respectively, were used to quantify epileptiform activity. Mice that received drug interventions following KA-induced SE had significantly lower mean spike frequency and fewer extended coastline epochs per day than the control group at both 7 and 14 days after the initial insult. Label-free proteomics quantification showed significant changes to the hippocampal protein profile as a result of both PSD95BP and 1400W administration following KA-induced seizures. Drug treatment, singly or in combination, also reversed the effects of KA on the expression of both transforming growth factor β1 and inwardly rectifying potassium channel 4.1 in the hippocampus. Surgical implantation of extra-dural electrodes significantly lowered the seizure threshold to KA and was associated with an increase in brain expression of pro-inflammatory cytokines, suggesting that careful consideration is required in studies involving intracranial surgery to assess epileptogenesis or AED effects. Current research investigating novel therapeutic agents is focusing on non-NMDA glutamate receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors, as potential AED targets. There are no compounds targeting the NO signalling pathway currently being investigated for the treatment of epilepsy. The data reported in this thesis give cause for optimism but further studies are needed to fully investigate the antiepileptic and possible antiepileptogenic properties of PSD95BP and 1400W and true efficacy will ultimately require clinical evaluation

Intelligibility and acceptability in Cantonese-speaking children with cleft palate: test development

Also available in print.Thesis (B.Sc)--University of Hong Kong, 2005.A dissertation submitted in partial fulfilment of the requirements for the Bachelor of Science (Speech and Hearing Sciences), The University of Hong Kong, June 30, 2005.published_or_final_versionSpeech and Hearing SciencesBachelorBachelor of Science in Speech and Hearing Science

Conservation and Land Use Planning: Linking Municipal Capacity and Biodiversity Outcomes

CaRDI Research & Policy Brief Issue 7

Current Trends in Cancer Support Within the Religious Community

Living with cancer is associated with significant psychological strain. The prevalence and severity of this distress varies according to the time, type, and stage of cancer, as well as other variables including treatment regimen, side effects, and prognosis. More often than not, these struggles are neglected as part of the traditional cancer care plan. Yet, if left unaddressed, emotional strain can add to the suffering caused by cancer by negatively affecting treatment compliance. Faith communities, such as churches, provide an ideal atmosphere to serve and support individuals battling cancer. However, research indicates that spiritual care is often a neglected component in cancer care. Therefore, the purpose of this investigation was to describe felt needs of current cancer patients, availability of psychological services within religious settings, and the capacity of pastors to provide emotional support to cancer patients. Our investigation showed that the majority of church leaders recognize this need and desire training in this particular area. Therefore, a need for an effective church-equipping program is evident and should be a priority of cancer care providers

The impact of postsynaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis

Antiepileptogenic agents that prevent the development of epilepsy following a brain insult remain the holy grail of epilepsy therapeutics. We have employed a label‐free proteomic approach that allows quantification of large numbers of brain‐expressed proteins in a single analysis in the mouse (male C57BL/6J) kainate (KA) model of epileptogenesis. In addition, we have incorporated two putative antiepileptogenic drugs, postsynaptic density protein‐95 blocking peptide (PSD95BP or Tat‐NR2B9c) and a highly selective inducible nitric oxide synthase inhibitor, 1400W, to give an insight into how such agents might ameliorate epileptogenesis. The test drugs were administered after the induction of status epilepticus (SE) and the animals were euthanized at 7 days, their hippocampi removed, and subjected to LC‐MS/MS analysis. A total of 2,579 proteins were identified; their normalized abundance was compared between treatment groups using ANOVA, with correction for multiple testing by false discovery rate. Significantly altered proteins were subjected to gene ontology and KEGG pathway enrichment analyses. KA‐induced SE was most robustly associated with an alteration in the abundance of proteins involved in neuroinflammation, including heat shock protein beta‐1 (HSP27), glial fibrillary acidic protein, and CD44 antigen. Treatment with PSD95BP or 1400W moderated the abundance of several of these proteins plus that of secretogranin and Src substrate cortactin. Pathway analysis identified the glutamatergic synapse as a key target for both drugs. Our observations require validation in a larger‐scale investigation, with candidate proteins explored in more detail. Nevertheless, this study has identified several mechanisms by which epilepsy might develop and several targets for novel drug development

Altered myocardial response in patients with diabetic retinopathy: an exercise echocardiography study

Additional file 1. Multivariable analysis for individual echocardiography parameters

Incidence and Predictors of Post-thrombotic Syndrome in Patients With Proximal Dvt in a Real-world Setting: Findings From the GARFIELD-VTE Registry

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient\u27s self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician\u27s evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection was performed using stepwise algorithm, and predictors of severe PTS were incorporated into a multivariable risk model. The optimistic adjusted c-index was calculated using bootstrapping techniques. Over 36-months, 27.8% of patients developed incident PTS (mild in 18.7%, moderate in 5.7%, severe in 3.4%). Patients with incident PTS were older, had a lower prevalence of transient risk factors of DVT and a higher prevalence of persistent risk factors of DVT. Self-assessment of overall PTS at 24 months showed an agreement of 63.4% with respect to physician\u27s evaluations at 36 months. The severe PTS multivariable model provided an optimistic adjusted c-index of 0.68 (95% CI 0.59-0.77). Approximately a quarter of DVT patients experienced PTS over 36 months after VTE diagnosis. Patient\u27s self-assessment after 24 months provided added value for estimating incident PTS over 36 months. Multivariable risk analysis allowed good discrimination for severe PTS

Association Between Raised Blood Pressure and Dysglycemia in Hong Kong Chinese

OBJECTIVE—To investigate the association between raised blood pressure and dysglycemia

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies