NMDA receptor dysfunction in Alzheimer's disease

The inherent neurotoxic potential ofthe endogenous excitatory amino acid glutamate, may be causally related to the pathogenesis ofAD neurodegeneration disorders. Neuronal excitotoxicity is conceivably mediated by the N-methyl-D-aspartate-(NMDA)-Ca2+- ionotropic receptor. NMDA receptors exist as multimeric complexes comprising proteins from two families – NR1 and NR2(A-D). The polyamines, spermine and spermidine bind to, and modulate NMDA receptor efficacy via interaction with exon 5, an alternatively-spliced, 21 amino acid, N-terminal cassette. ADassociated cognitive impairment may therefore occur via subunitspecific NMDA receptor dysfunction effecting regional selectivity ofneuronal degradation. Total RNA was prepared from pathologically spared and susceptible regions from AD cases and matched controls. Quantitation was performed using standard curve methodology in which a known amount ofa synthetic ribonucleic acid competitor deletion construct was co-amplified against total RNA. Expression profile analysis oftwo NR1 mRNA subsets has revealed significant differences in NR11XX mRNA levels in cingulate gyrus, P.

Relationship between the microcirculation and the pathological changes in the spradic and variant forms of Creutzfeldt-Jakob Disease (CJD)

This chapter is concerned with the influence of the brain microcirculation on the development of the pathological changes in Creutzfeldt-Jakob disease (CJD). Hence, the spatial correlations between the vacuolation, prion protein (PrP) deposits, and the blood vessel profiles were studied in immunolabelled sections of the cerebral cortex, hippocampus, and cerebellum in two subtypes of CJD, viz., sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). In sCJD, both the vacuolation and the ‘synaptic-type’ PrP deposits were spatially correlated with the blood vessels; the PrP deposits being the more strongly correlated than the vacuoles. In vCJD, there were no significant spatial correlations between either the vacuolation or the diffuse-type of PrP deposit and the microvessels. By contrast, a consistent pattern of spatial correlation was observed in gyri of the cerebral cortex between the florid PrP deposits and blood vessels. In both sCJD and vCJD, the frequency of positive spatial correlations was similar in the different gyri of the cerebral cortex and in the upper compared with the lower laminae. In conclusion, the microcirculation appears to be more significantly involved in determining the pathological changes in sCJD than in vCJD. The spatial correlations of the florid PrP deposits in vCJD and the synaptic deposits in sCJD and the blood vessels may be attributable to factors associated with the microcirculation which enhance the aggregation of PrP molecules rather than representing a possible haematogenous spread of the disease.

Ocular and systemic vascular function in human ageing

The importance of vascular risk factors in various age-related pathologies has been extensively researched. Nevertheless, the haemodynamic disturbance occurring in various ocular and systemic vascular beds to impact upon ocular function remained largely unknown. The purpose of the following studies was to explore the presence and impact of both ocular and systemic vascular dysregulation as well as biochemical vascular risk factors in healthy elderly individuals and patients with age-related macular degeneration. Furthermore, the possible role was played by circulatory oxidative stress and its relationship with endothelial dysfunction at both ocular and systemic levels has also been investigated. There were four principal sections to the present work: 1. To assess the relationship between ocular and systemic anti-oxidative defence in healthy individuals The principal findings of this work were: -It has been shown that MPOD significantly and positively related with circulatory GSH levels. 2. To investigate macro- and microcirculation and oxidative stress in early AMD patients without overt systemic disease The principal findings of this work were: -AMD patients exhibit abnormal macrocirculation compared to the controls. -Blood GSSG level was significantly higher in early AMD patients than controls. -AMD patients showed abnormal microcirculation at retinal level compared. -In early AMD patients, retinal venous RT positively correlated with blood GSSG levels. 3. To assess the relationship between ocular vascular function and circulatory markers of endothelial dysfunction and CVD risk The principal findings of this work were: -Age had a positive effect on ET-1, vWF and slope of retinal arterial constriction in otherwise healthy individuals. -Even in otherwise healthy individuals, retinal arterial vascular function showed a significant correlation with circulatory markers of endothelial dysfunction and CVD risk. 4. To assess age-related changes in ANS and vascular function, and their relationship to retinal vascular function parameters The principal findings of this work were: -Elderly individuals demonstrated abnormal circadian changes of PSNS activity compared to middle-aged group. -Elderly groups showed higher ET-1 and vWF level as well as C-IMT and AIx, and also impaired retinal vascular function compared to the middle-aged group. -In the elderly group, impaired retinal vascular function significantly correlated with the dysregulation of PSNS activity.

Autonomic dysfunction in unselected and untreated primary open angle glaucoma patients:A pilot study

Purpose: To investigate the presence of silent cardiac ischaemic episodes and the status of autonomic function in consecutive, newly diagnosed and untreated primary open-angle glaucoma patients. Methods: Twenty-four consecutively diagnosed glaucoma patients and 22 age-matched controls were subjected to ambulatory 24-h blood pressure (BP) and electrocardiogram (ECG) monitoring by using Cardiotens-01 (Meditech Ltd). Based on the ECG recordings, heart rate variability (HRV) frequency domain parameters [low-frequency (LF), high-frequency (HF) and LF/HF ratio] were calculated and analysed in the two study groups. Results: Glaucoma patients demonstrated higher LF and LF/HF values than normal subjects for both the active period (p = 0.020 and 0.029) and the passive period (p = 0.044 and 0.049 respectively). HRV parameters were similar in patients and controls suffering from silent cardiac ischaemia (p > 0.05); however, glaucoma patients with normal ECG demonstrated higher LF and LF/HF values during the active period of the 24-h measurement period than control subjects characterized by the same cardiac activity (p = 0.010 and 0.021 respectively). Conclusion: Independent of a history and/or clinical signs of cardiovascular disease, glaucoma patients exhibit abnormal autonomic function. © 2007 The Authors.

Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly:a community-based cross-sectional survey

Context: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. Objective: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. Design, Setting, and Participants: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. Exclusions: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. Outcome Measure: Tests of thyroid function (TSH concentration and free T 4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. Explanatory Variables: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004) Analysis: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction Results: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. Conclusions: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population. Copyright © 2006 by The Endocrine Society.

Neurophysiology of CSWS-associated cognitive dysfunction

The phenomenon of continuous spikes and waves during slow-wave sleep (CSWS) is associated with a number of epileptic syndromes, which share a behavioral phenotype characterized by deterioration of cognitive, behavioral, or sensorimotor functions. Available evidence seems to suggest that spike-wave activity is a result of a complex interaction between cortical and subcortical inhibitory networks and can "per se" produce a transient loss of underlying cortical functions. Syndromes like Landau-Kleffner syndrome, CSWS, and phenomena such as negative myoclonus could share in common--at least at the neurophysiological level--some similarities. Differences in behavioral phenotypes could be explained in term of maturational and genetic differences, as well as by the functional specificity of the involved areas.

Postcesarean pelvic floor dysfunction contributes to undisclosed psychosocial morbidity

OBJECTIVE: To estimate the prevalence and severity of postcesarean pelvic dysfunction. STUDY DESIGN: Using biopsychosocial interviewing at home, 184 postcesarean primiparas were compared to 100 vaginally delivered women regarding symptoms of stress incontinence, anal incontinence and dyspareunia. Delivery details were confirmed from medical records. RESULTS: Comparison of postcesarean vs. vaginally delivered women revealed stress incontinence in 33% vs. 54% and dyspareunia in 27% vs. 46%, both differences reaching statistical significance, unlike anal incontinence, which was manifest in 51% vs. 44%. When compared to emergency cesarean the relative risk of stress incontinence following an elective cesarean was 0.99 (0.71, 1.39), of dyspareunia 1.02 and of anal incontinence 1.05, indicating no statistically significant difference. Thirty (22%) stress incontinent and 4 (3%) fecally incontinent mothers used pads continuously, suggesting severe physical morbidity. Severe dysphoria (depression) was expressed by 41 (35%) stress incontinent mothers, 38 (30%) with dyspareunia and 34 (26%) with anal incontinence; the association of severe dysphoria with dyspareunia was statistically significant (OR = 2.504 [1.362, 4.602]). Few women came forward to seek help. CONCLUSION: Pelvic dysfunction was similar after elective or emergency cesarean. Compared to vaginal delivery, postcesarean stress incontinence and dyspareunia were less frequent but biopsychosocial morbidity could be severe.