Neuropathology of ALS: Spheroids

I briefly review spheroids observed in the anterior horns of the spinal cord in amyotrophic lateral sclerosis (ALS). Spheroids are argentophilic bodies more than 20 μm in diameter. Recently, some connections between the proximal axonal swellings including spheroids and the perikarya have been reported in some ALS patients with a short clinical course or mild depletion of anterior horn neurons. Most of the cell bodies directly connected with the axonal swellings appear normal, and spheroids are considered to be one of the hallmarks of the early histological changes in this disorder. Spheroids are strongly positive with anti-phosphorylated neurofilament antibody, and are also positive with calcitonin gene-related peptide and anti-peripherin antibody. Some spheroids are immunostained with anti-synaptophysin antibody and anti-ubiquitin antibody. Spheroids are not immunostained with anti-phosphorylated tau antibody, or high molecular weight microtubule associated proteins. Electron microscopically, spheroids are usually composed of densely packed accumulation of 10 nm neurofilaments with a variety of orientations, plus vesicles, dense bodies and mitochondria. When the swellings of the initial segment is relatively pronounced, the undercoating is obscured and the neurofilaments become interwoven in some parts. In the first internode of the myelinated axons, as the swellings become larger, the neurofilaments lose their parallel orientation and become intermingled. Large accumulation of neurofilaments resembling spheroids in the perikarya of large anterior horn cells suggests that spheroids could be derived not only from the axon including the proximal portion, but also from the perikarya. Structures apparently identical to axonal spheroids are observed at the light and electron microscopic levels in the proximal portion of axons of anterior horn cells in animal models intoxicated with β, β'-iminodipropionitrile (IDPN), or with aluminum, in hereditary canine spinal muscular atrophy (HCSMA). The pathogenetic mechanism is probably associated with an impairment in slow axonal transport which particularly affects the neurofilaments in IDPN and aluminum intoxication. Impairment of slow axonal transport of neurofilaments also plays an important role in the pathogenesis of ALS. The average diameter of even normalappearing initial segment is larger in ALS than in the controls. The perikarya connected with the swollen proximal axons and their dendrites almost always appear normal. These findings suggest that the slow axonal transport of neurofilaments is probably impaired in this portion of the axon at an early stage in ALS as well as animal models for human ALS. However, techniques to analyze slow axonal transport in humans still remain tobe developed. Recently, overexpression of neurofilament subunits in transgenic mice produces a condition resembling ALS. The transgenic model may offer an interesting perspective not only for testing therapeutic strategies but also for investigating in a systematic way the various genetic and environment factors controlling the onset and progression of the disease and might yield new insights on the etiology of ALS.     

Laser induced autofluorescence studies of animal skin used in modeling of human cutaneous tissue spectroscopic measurements

BACKGROUND/PURPOSE: Laser-induced autofluorescence spectroscopy provides excellent possibilities for medical diagnostics of different tissue pathologies including cancer. However, to create the whole picture of pathological changes, investigators collect spectral information from patients in vivo or they study different tumor models to obtain objective information for fluorescent properties of every kind of healthy and diseased tissue. Therefore, it is very important to find the most appropriate, and close to the human skin, animal samples from the fluorescence point of view, which will allow the extrapolation of the animal data to human spectroscopic diagnostics. METHODS: In the present work, we examined the autofluorescence properties of different animal skin tissues, which are considered as the most common skin models. A nitrogen laser was used as an excitation source. Samples of healthy mouse, chicken and pig skin in vivo and/or ex vivo were studied and were compared with results obtained from investigations of healthy human skin in vivo. RESULTS AND CONCLUSION: Specific features of the recorded spectra are discussed and the possible origin of the obtained fluorescence signals is proposed. Quantitative evaluation of data extrapolation for each skin type is also depicted.     

Transactional models of early education effectiveness - What is the message for policy?

There is now a substantial body of American research evidence demonstrating that early education programmes can have major long term effects right through into adult life. Cost-benefit analysis has enabled the data to be transformed into a compelling case for public financial investment. But insufficient attention has been paid to explaining how a short term preschool programme could have such enduring effects. The effects are best understood by applying a transactional model which shows how processes in the school and community transformed and amplified short term effects into long term outcomes. Adopting a transactional model modifies the messages for policy. The results of evaluations carried out in one society may not apply in another. In some school systems there may be more effective strategies than early education for improving educational prospects.     

Effect of temperature in focal ischemia of rat brain studied by 31P and 1H spectroscopic imaging

³¹P, ¹H and lactate spectroscopic imaging was used to evaluate the effects of hypothermia on focal cerebral ischemia produced by middle cerebral artery occlusion. The effects on high energy phosphate metabolism, pH, lactate and NAA were investigated in 24 spontaneously hypertensive rats subjected to either permanent or transient ischemia. Under either normothermic (37.5°C) or hypothermic (32°C) conditions, with permanent 6-h occlusion, there was little difference between groups in either the NMR measurements or the volume of infarction. In animals that underwent 3 h of ischemia followed by 12 h of reperfusion, the ischemic changes in lactate, pH, NAA, and high-energy phosphate returned toward control values, and there was a protective effect of hypothermia (infarct volume of 211 ± 26 and 40 ± 14 mm³ in normothermic and hypothermic groups, respectively). Thus, hypothermia did not ameliorate the changes in lactate, pH, NAA, or high energy phosphate levels occurring during ischemia, however, during reperfusion there was an improvement in both the recovery of these metabolites and pathological outcome in hypothermic compared with normothermic animals.     

Improved intracranial lesion characterization by tissue segmentation based on a 3D feature map

Our aim was to develop an accurate multispectral tissue segmentation method based on 3D feature maps. We utilized proton density (PD), T₂-weighted fast spin-echo (FSE), and T₁-weighted spin-echo images as inputs for segmentation. Phantom constructs, cadaver brains, an animal brain tumor model and both normal human brains and those from patients with either multiple sclerosis (MS) or primary brain tumors were analyzed with this technique. Initially, misregistration, RF inhomogeneity and image noise problems were addressed. Next, a qualified observer identified samples representing the tissues of interest. Finally, k-nearest neighbor algorithm (k-NN) was utilized to create a stack of color-coded segmented images. The inclusion of T₁ based images, as a third input, produced significant improvement in the delineation of tissues. In MS, our 3D technique was found to be far superior to that based on any combination of 2D feature maps (P < 0.001). We identified at least two distinctly different classes of lesions within the same MS plaque, representing different stages of the disease process. Further, we obtained the regional distribution of MS lesion burden and followed its changes over time. Neuropsychological aberrations were the clinical counterpart of the structural changes detected in segmentation. We could also delineate the margins of benign brain tumors. In malignant tumors, up to four abnormal tissues were identified: 1) a solid tumor core, 2) a cystic component, 3) edema in the white matter, and 4) areas of necrosis and hemorrhage. Subsequent neurosurgical exploration confirmed the distribution of tissues as predicted by this analysis.     

Establishment and characterization of a chronic infectious mononucleosislike syndrome in common marmosets

Epstein-Barr virus (EBV) was inoculated into two species of marmosets. Successful infection was established in the majority of the animals of one species, Callithrix jacchus, as evidenced by the development of high, persistent levels of antibody against virus-specific capsid and early nonstructural proteins. Antibodies also were produced against the major membrane antigen and, in some animals, against EBV nuclear antigen (EBNA) 2 but not against EBNA 1. This is the antibody profile normally noted in individuals with chronic infectious mononucleosis (IM). EBV-induced lymphoproliferation was not seen, and EBV-specific proteins were not detected in the peripheral blood lymphocytes of infected animals. Hence, EBV infection in C. jacchus apparently does not generally include extensive B-cell involvement. However, the marmosets clearly are useful as a model for EBV primary infection and also possibly for chronic IM.     

Animal study on the role of serotonin in depression

1. In our series of experiments the role of serotonin in human depression was studied by using animal models of depression.

2. The results of these studies support the hypothesis that some types of human depression may be primarily due to an excessive transmission of serotonin at the synapse.     

Stochastic models for geriatric in-patient behaviour

Departments of geriatric medicine engage in two distinct formsof clinical activity: acute/rehabilitative and long-stay care.These are organizationally distinct and have very differentresource needs. Current hospital planning models, however, assumethat patients all move through the system at the same rate,thereby ignoring this effect of inherent heterogeneity in patientbehaviour. The present paper describes the movement of patientsthrough geriatric hospitals by a two-stage continuous-time Markovmodel, where the stages represent acute/rehabilitative and long-staypatients respectively. Patients are initially admitted to thefirst stage, from which they may depart from the system, bydeath or discharge, or move into the second stage, from whichthey eventually depart by death or discharge (unlikely). Admissionsare modelled in two ways: either as replacements for departuresor as a Poisson stream. Expressions for the distribution andmovement of numbers of patients are derived and evaluated fordata from a number of hospitals. Such an approach has the advantage,over previous crude models, of taking into account differenttypes of patients and introducing variability, thus making itpossible to extract variances as well as means of numbers ofgeriatric patients requiring hospital care.     

Diabetes prevalence in England, 2001--estimates from an epidemiological model.

AIMS: To estimate the total prevalence of diabetes mellitus (diagnosed and undiagnosed) at national, regional and local level in England to support health-care planning and delivery. METHODS: An epidemiological model was constructed by applying age-sex-ethnic-specific reference prevalence rates from epidemiological studies to resident populations (2001 census) of England at national, regional, and local authority/Primary Care Trust levels. RESULTS: Estimated prevalence of total diabetes for all persons in England was 4.41% in 2001, equating to 2 168 000 persons. Type 2 diabetes was estimated to affect 2 002 000 persons (92.3%) and Type 1 diabetes 166 000 persons (7.7%). Diabetes prevalence was estimated to be higher in women (5.17%) than men (3.61%). People from ethnic minority groups had higher crude prevalence than White Europeans (4.29, 5.69, 6.63 and 2.13% among White Europeans, Black African/Caribbeans, South Asians and 'other' groups, respectively). Prevalence increased sharply with age (0.33, 3.37 and 13.92%, respectively, in those aged 0-29, 30-59 and 60+ years). The model allows use of user-defined population denominator estimates to derive numbers and prevalence of people with diabetes for a given local population group, such as at ward or general practice level. CONCLUSIONS: Self-reported diabetes prevalence estimates from community surveys underestimate the true burden of diabetes. The model can be used to derive the expected total prevalence of diabetes in health areas that lack reliable data to facilitate the implementation of the National Service Framework for diabetes. It will also allow estimates of future diabetes prevalence to be derived, and can potentially be used for prevalence estimates in all of the UK.