Functional amyloids: interrelationship with other amyloids and therapeutic assessment to treat neurodegenerative diseases.

Misfolded ß-sheet structures of proteins leading to neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are in the spotlight since long. However, not much was known about the functional amyloids till the last decade. Researchers have become increasingly more concerned with the degree of involvement of these functional amyloids in human physiology. Interestingly, it has been found that the human body is exposed to a tremendous systemic amyloid burden, especially, during aging. Although many findings regarding these functional amyloids come up every day, some questions still remain unanswered like do these functional amyloids directly involve in the fibrillization of amyloid beta (Aß) 42 peptide or enhance the Aß42 aggregation rate; whether functional bacterial amyloids (FuBA) co-localize with the senile plaques of AD or not. A detailed review of the latest status regarding the interrelationship between functional amyloids, pathogenic amyloids and misfolded prions and therapeutic assessment of functional amyloids for the treatment of neurodegenerative diseases can help identify an alternative medication for neurodegeneration. A unique mathematical model is proposed here for alteration of Aß42 aggregation kinetics in AD to carve out the future direction of therapeutic consideration.

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Comparative assessment of phototherapy protocols for reduction of oxidative stress in partially transected spinal cord slices undergoing secondary degeneration.

BACKGROUND: Red/near-infrared light therapy (R/NIR-LT) has been developed as a treatment for a range of conditions, including injury to the central nervous system (CNS). However, clinical trials have reported variable or sub-optimal outcomes, possibly because there are few optimized treatment protocols for the different target tissues. Moreover, the low absolute, and wavelength dependent, transmission of light by tissues overlying the target site make accurate dosing problematic. RESULTS: In order to optimize light therapy treatment parameters, we adapted a mouse spinal cord organotypic culture model to the rat, and characterized myelination and oxidative stress following a partial transection injury. The ex vivo model allows a more accurate assessment of the relative effect of different illumination wavelengths (adjusted for equal quantal intensity) on the target tissue. Using this model, we assessed oxidative stress following treatment with four different wavelengths of light: 450 nm (blue); 510 nm (green); 660 nm (red) or 860 nm (infrared) at three different intensities: 1.93 × 10(16) (low); 3.85 × 10(16) (intermediate) and 7.70 × 10(16) (high) photons/cm(2)/s. We demonstrate that the most effective of the tested wavelengths to reduce immunoreactivity of the oxidative stress indicator 3-nitrotyrosine (3NT) was 660 nm. 860 nm also provided beneficial effects at all tested intensities, significantly reducing oxidative stress levels relative to control (p ≤ 0.05). CONCLUSIONS: Our results indicate that R/NIR-LT is an effective antioxidant therapy, and indicate that effective wavelengths and ranges of intensities of treatment can be adapted for a variety of CNS injuries and conditions, depending upon the transmission properties of the tissue to be treated.

Rotarod motor performance and advanced spinal cord lesion image analysis refine assessment of neurodegeneration in experimental autoimmune encephalomyelitis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is a commonly used experimental model for multiple sclerosis (MS). Experience with this model mainly comes from the field of immunology, while data on its use in studying the neurodegenerative aspects of MS is scarce. NEW METHOD: The aim of this study is to improve and refine methods to assess neurodegeneration and function in EAE. Using the rotarod, a tool used in neuroscience to monitor motor performance, we evaluated the correlation between motor performance, disease severity as measured using a clinical scale and area covered by inflammatory lesions. RESULTS: The included parameters are highly correlated in a non-linear manner, with motor performance rapidly decreasing in the intermediate values of the clinical scale. The relation between motor performance and histopathological damage is exclusively determined by lesions in the ventral and lateral columns, based on a new method of analysis of the entire spinal cord. Using a set of definitions for distinct disease milestones, we quantified disease duration as well as severity. COMPARISON WITH EXISTING METHODS: The rotarod measures motor performance in a more objective and quantitative manner compared to using a clinical score. The outcome shows a strong correlation to the surface area of inflammatory lesions in the motor systems of the spinal cord. CONCLUSIONS: These results provide an improved workflow for interpreting the outcome of EAE from a neurological point of view, with the eventual goal of dissecting neurodegeneration and evaluating neuroprotective drugs in EAE for application in MS.

Clinical, methodological and theoretical issues in the assessment of cognition after anaesthesia and surgery: a review.

As people live longer, the burden of cognitive impairment to elderly patients, their families and society becomes increasingly common and important. The loss of independence, a reduction in the quality of life and increased mortality are possible correlates to the mental disintegration. Cognitive dysfunction following major surgery on the elderly is a significant problem which adds to other cognitive impairments caused by neurodegeneration, cerebrovascular impairments and other causes. There are challenges in reviewing the literature because of many methodological concerns. There is no standard definition; the diagnosis is made only by the results of neuropsychological tests which are not standardised for this purpose; test results are analysed by different statistical methods (some of them inappropriate); controls are often absent or poorly matched; and pre-existing mild cognitive impairment, which affects 10 to 20% of people older than 65 years and is similar to the subtle cognitive impairment following surgery, is not sought for and recognised. Reviews of the subject have varied from descriptions such as 'a well recognised and significant problem' to 'a hypothetical phenomenon for which there is no International Statistical Classification of Disease (ICD-9) code, and no Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) code'. This article examines both sides of the spectrum in a detailed review which explains the necessary psychological 'jargon', discusses the methods used and points to areas of future research.

[Dynamic assessment of corpus callosum and corticospinal tracts structure using diffusion-tensor MRI in diffuse axonal injury].

BACKGROUND: Diffuse axonal injury (DAI) causes neurodegenerative processes in brain which can last weeks and months after traumatic brain injury. Aim of this study was to assess structural changes of corpus callosum and corticospinal tracts in dynamics using diffusion-tensor magnetic resonance imaging (DT-MRI) in severe DAI. MATERIALS AND METHODS: 14 patients with severe DAI (GCS < or = 8 in acute period) were examined using DT-MRI. In 12 cases 1.5 Tesla device was used, in 2-3 Tesla tomography was applied. Initial studies were performed on 3rd-17th days after injury and control studies were done between 3 weeks and 33 months after injury. Outcomes were assessed using GOS 6 months after injury and later. RESULTS: MR-tractography demonstrated almost absolutely absent visualization of ascending fibers of corpus callosum 3-20 weeks after brain injury in 5 patients with poor outcomes (severe disability and persistent vegetative state). Raized asymmetry of corticospinal tracts was associated with hemiparesis or quadriparesis in the same patients. In 6 patients with severe disability partial loss and thinning of corpus callosum fibers were observed. In 2 patients with good recovery and moderate disability repeated studies showed no severe changes in structure of corpus callosum. CONCLUSION: DT-MRI presents new data about structural changes of white matter tracts in traumatic brain injury.

Setting prudent public health policy for electromagnetic field exposures.

Electromagnetic fields (EMF) permeate our environment, coming both from such natural sources as the sun and from manmade sources like electricity, communication technologies and medical devices. Although life on earth would not be possible without sunlight, increasing evidence indicates that exposures to the magnetic fields associated with electricity and to communication frequencies associated with radio, television, WiFi technology, and mobile cellular phones pose significant hazards to human health. The evidence is strongest for leukemia from electricity-frequency fields and for brain tumors from communication-frequency fields, yet evidence is emerging for an association with other diseases as well, including neurodegenerative diseases. Some uncertainty remains as to the mechanism(s) responsible for these biological effects, and as to which components of the fields are of greatest importance. Nevertheless, regardless of whether the associations are causal, the strengths of the associations are sufficiently strong that in the opinion of the authors, taking action to reduce exposures is imperative, especially for the fetus and children. Inaction is not compatible with the Precautionary Principle, as enunciated by the Rio Declaration. Because of ubiquitous exposure, the rapidly expanding development of new EMF technologies and the long latency for the development of such serious diseases as brain cancers, the failure to take immediate action risks epidemics of potentially fatal diseases in the future.

Characteristics and trends in required home care by GPs in Austria: diseases and functional status of patients.

BACKGROUND: Almost all societies carry responsibility towards patients who require continuous medical care at home. In many health systems the general practitioner cooperates with community based services of home care and coordinates all medical and non medical activities. In Austria the general practitioner together and in cooperation with relatives of the patient and professional organisations usually takes on this task by visiting his patients. This study was carried out to identify diseases that need home care and to describe the functional profile of home care patients in eastern Austria. METHODS: Cross sectional observational study with 17 GP practices participating during 2 study periods in 1997 and in 2004 in eastern Austria. Each GP identified patients requiring home care and assessed their underlying diseases and functional status by filling in a questionnaire personally after an encounter. Patients in nursing homes were excluded. Statistical tests used were t-tests, contingency tables, nonparametric Wilcoxon signed rank sum test and Fisher-combination test. RESULTS: Patients with degenerative diseases of the central nervous system (65%) caused by Alzheimer's disease and cerebrovascular occlusive disease and patients with degenerative diseases of the skeletal system (53%) were the largest groups among the 198 (1997) and 261 (2004) home care cases of the 11 (1997) and 13 (2004) practices. Malignant diseases in a terminal state constituted only 5% of the cases. More than two thirds of all cases were female with an average age of 80 years. Slightly more than 70% of the patients were at least partially mobile. CONCLUSION: Home care and home visits for patients with degenerative diseases of the central nervous and skeletal system are important elements of GP's work. Further research should therefore focus on effective methods of training and rehabilitation to better the mental and physical status of patients living in their private homes.

Assessment of subjective health and health-related quality of life in persons with acquired or degenerative brain injury.

PURPOSE OF REVIEW: Health-related quality of life is a new outcome variable in neurology. Several generic measures aim at assessing this variable in adults with neurological diseases. Disease-specific measures are still rare; however, individuals with neurological diseases frequently suffer from cognitive impairment, yet are often excluded from health-related quality of life investigations. When included in such studies, cognitive functioning is not monitored via neuropsychological evaluation, possibly leading to methodological problems. Papers from May 2004 until July 2005 are reviewed with respect to psychometric quality and information about persons after traumatic brain injury, stroke, Parkinson's disease or dementia. RECENT FINDINGS: Several new cross-sectional and longitudinal outcome studies are reviewed. The Medical Outcome Study Short Form with 36 items, the Sickness Impact Profile and the Nottingham Health Profile were identified as the most frequently used measures in neurology. For traumatic brain injury, two new generic instrument validations (Life Satisfaction Index-A, Subjective Quality of Life Profile) and one internationally validated disease-specific development (Quality of Life after Brain Injury) were found; for stroke, one disease-specific tool (Burden of Stroke Scale) was identified. In Parkinson's disease, the disease-specific health-related quality of life measure Parkinson's Disease Questionnaire-39 is well validated. In dementia, three dementia-specific instruments (Quality of Life for Dementia, Quality of Life in Late-Stage Dementia Scale and Quality of Life in Alzheimer's Disease Scale) seem to be valid. SUMMARY: In neurology, only a few measures have been developed and validated for respondents with cognitive impairment, often showing poorer validity results than studies involving healthy persons. Health-related quality of life assessment should therefore be validated in the specific diseases and, if necessary, combined with a neuropsychological evaluation and a disease-specific health-related quality of life measure.

EMF and health.

Electric and magnetic fields are ubiquitous in the modern society, and concerns have been expressed regarding possible adverse effects of these exposures. This review covers epidemiologic research on health effects of exposures to static, extremely low-frequency (ELF), and radio frequency (RF) fields. Research on ELF fields has been performed for more than two decades, and the methodology and quality of studies have improved over time. Studies have consistently shown increased risk for childhood leukemia associated with ELF magnetic fields, whereas ELF fields most likely are not a risk factor for breast cancer and cardiovascular disease. There are still inadequate data for other outcomes. More recently, focus has shifted toward RF exposures from mobile telephony. There are no persuasive data suggesting a health risk, but this research field is still immature with regard to the quantity and quality of available data. This technology is constantly changing and there is a need for continued research on this issue. Almost no epidemiologic data are available for static fields.

Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia.

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

Importance of neurological assessment before bone marrow transplantation for osteopetrosis.

Neurological complications of malignant infantile osteopetrosis are well recognised; successful bone marrow transplantation, when performed early in life, can prevent or halt some of them. In a subgroup of infants osteopetrosis is associated with primary retinal degeneration and/or generalised neurodegeneration. Bone marrow transplantation, in spite of being successful in correcting the osseous and haematological abnormalities, does not influence the progressive course of the neurodegenerative disorder. Thus, the recognition of this subgroup of infants with a very poor prognosis is essential before deciding on bone marrow transplantation.