Jillian J. Kril

Neuropathology of thiamine deficiency disorders

The Wernicke-Korsakoff syndrome (WKS) is the most frequently encountered manifestation of thiamine deficiency in Western society. It is commonly seen in alcoholic patients, but may also occur in patients with impaired nutrition from other causes, such as those with gastrointestinal disease or AIDS. The pathology is restricted to the central nervous system and is characterised by neuronal loss, gliosis and vascular damage in regions surrounding the third and fourth ventricles and the cerebral aqueduct. In addition to WKS, thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and it has been implicated in the pathogenesis of cerebellar degeneration and peripheral neuropathy. Thus thiamine deficiency results in significant nervous system pathology and vigilance should be maintained in the diagnosis and treatment of this readily preventable cause of disease.

Amino-Acid Neurotransmitter Receptor Changes in Cerebral-Cortex in Alcoholism - Effect of Cirrhosis of the Liver

Abstract: γ‐Aminobutyric acidA/benzodiazepine receptor binding sites and the N‐methyl‐D‐aspartate subclass of glutamate receptor sites were assessed in synaptic plasma membrane homogenates of cerebral cortex tissue obtained at autopsy from cirrhotic and noncirrhotic alcoholic patients and matched control subjects. The alcoholic patients consumed an average of >80 g of ethanol/day, the control subjects <20 g/day. Postmortem delays up to ∼ 100 h caused no significant loss of any of the binding sites; the patient and subject groups were closely matched for age. The affinities (KD) of the receptor sites did not differ between the patient and subject groups, nor between cortical regions. Using three different radioligands ([3H]muscimol, [3H]flunitrazepam, and [3H]diazepam), the γ‐aminobutyric acidA/benzodiazepine receptor complex was found to have greater density (Bmax) in superior frontal gyrus in alcoholic patients (which selectively shows morphological change in alcoholic patients), but was unchanged in motor cortex. Alcoholic patients with cirrhosis had much less pronounced changes. The density of the N‐methyl‐D‐aspartate subclass of glutamate receptors, assessed with [3H]MK‐801. did not vary across patient and subject groups.

Progression of neurological disease in thiamin-deficient rats is enhanced by ethanol

The clinical and neuropathological consequences of either ethanol consumption or thiamin deficiency or both were examined in Wistar rats aged nine weeks divided into five groups and fed one of the following diets: a thiamin-replete (control) diet (A): a thiamin-fortified diet with water (B) or 15% ethanol (C); or a thiamin-deficient diet with water (D) or 15% ethanol (E). Rats fed diets A, B or C for 35 weeks showed no clinical signs of neurological disease at any stage and no significant brain pathology when harvested. Rats fed diets D and E progressed through a common sequence of clinical signs of neurological disease typical of acute thiamin deficiency, viz loss of coat condition, ataxia, opisthotonus and ultimately death within 10-23 weeks. The onset and progression of these stages of neurological disease were significantly earlier and faster (p less than 0.001 for proportion of opisthotonic and ataxic animals at weeks 10 and 15) in the thiamin-deficient rats that received ethanol than in those that did not. At death, the brain pathology in these two groups was limited and similar.

The contribution of alcohol, thiamine deficiency and cirrhosis of the liver to cerebral cortical damage in alcoholics.

The relative roles of alcohol toxicity, thiamine deficiency and cirrhosis of the liver in the pathogenesis of alcohol-related brain damage are unclear. Brain shrinkage and neuronal loss from four regions of the cortex was determined in 22 alcoholics with the Wernicke-Korsakoff Syndrome (WKS), cirrhosis of the liver or neither of these complications and compared to 22 age-matched non-alcoholic controls. Brain shrinkage was most marked in those alcoholics with WKS. Neuronal loss occurred only from the superior cortex and was of equal magnitude in all alcoholic subgroups. In an animal model of alcohol abuse and thiamine deficiency, neuronal loss from the cerebral cortex occurred in a time-dependent manner. Furthermore, those cells which contained the calcium-binding protein parvalbumin appeared to be preferentially damaged in this model.

Method of melanin bleaching in MIB1-Ki67 immunostaining of pigmented lesions: A quantitative evaluation in malignant melanomas.

The effect of melanin bleaching on the immunoreactivity of the MIB1-Ki67 antigen in pigmented melanocytic lesions was investigated. Eight paired non-pigmented and heavily pigmented malignant melanomas (6 primary melanomas and 2 secondary melanomas) were selected. Avidin–biotin immunoperoxidase complex (ABC) and microwave antigen retrieval were used in immunostaining. Sections were incubated with 10% H2O2 for 24u2009h before immunostaining with primary antibody MIB1, or after the completion of immunostaining. Non-bleached controls were obtained by conducting the identical staining but omitting the bleaching procedure. In all heavily pigmented lesions bleached by 10% H2O2 before or after immunostaining, the melanin was bleached effectively and MIB1-positively stained cells were clearly seen. Cell counting in the non-pigmented group found that there were no significant differences in the percentage of MIB1-positive melanoma cells (%MIB1) between non-bleached controls and those sections which had been bleached by 10% H2O2 either before or after the immunostaining. The results suggest that hydrogen peroxide can effectively bleach melanin in pigmented melanocytic lesions without significantly affecting MIB1-Ki67 immunolabelling.

Concentrations of transferrin and carbohydrate‐deficient transferrin in postmortem human brain from alcoholics

Transferrin (T f) and its carbohydrate‐deficient isoform (CDT) were measured by radioimmunoassay in phosphate‐buffered saline extracts of two informative areas of cerebral cortex tissue obtained at autopsy from alcoholics without other associated disease (n = 4); alcoholics with cirrhosis of the liver (n = 4) and agematched controls (n = 4). Total T f was also measured in two informative cortical areas from five dementia cases. All cases were male. Total immunoreactive T f was assayed directly in the extract, CDT immunoreactivity in the concentrated eluate after the sialylated form was removed by passing through DEAE‐Sephacel at pH 5.65. Brain CDT averaged 10% of total T f overall. Although replicate extractions of individual samples gave consistent assays for both substances, there was wide variation both between different cortical areas from a given case and between cases within groups. There were no significant differences between total T f levels in uncomplicated alcoholics, dementia cases and controls, but cirrhotic alcoholics gave significantly higher values. The CDT: T f ratio was not increased in the brains of either group of alcoholics compared to controls. Whereas the serum CDT: T f ratio is an excellent marker of recent alcohol consumption, brain T f and CDT concentrations do not mark alcoholism nor dementia, and their biological variability diminishes their usefulness as disease indices. However, brain T f may be a marker of cirrhosis‐induced changes.