Aluminum induced encephalopathy in the rat

Aluminum tartrate (AlT) but not sodium tartrate (NaT) produces a progressive encephalopathy when injected intracerebroventricularly in the rat. This syndrome, lethal within 30-35 days, is characterized by progressively deranged behavior. An early startle reaction (day 14), later joined by locomotor discoordination (day 19) is followed by locomotor and electrocorticographic (ECoG) seizures (day 21) in chronically instrumented AlT rats. There is early dissociation between ECoG and locomotor aspects. When tested in the shuttlebox for estimation of learning and memory function 7-8 days after AlT injection, marked impairment of both active and passive avoidance was observed. Glucose uptake capacity of synaptosomes from brain areas of AlT and NaT animals was indexed by the 2-deoxy-D-glucose method. Striatal and cortical synaptosomes showed reduced uptake activity 7 days following AlT injection. By day 14, hypothalamic areas also became affected, striatal uptake was further inhibited, and cortical uptake was reduced to 57% of control. The ECoG background rhythm remained unchanged until days 20-23, when the mean peak frequency was reduced. The model may be useful in the study of central aluminum toxicity and may have predictive validity in the testing of procedures to counter aluminum-associated encephalopathies in man.     

Acute cholecystitis and thiazides.

Drugs purchased by a random sample (17 000) of the population of Jämtland county, Sweden, are continuously monitored. Patients who had been admitted to the county''s only hospital with acute cholecystitis and who were part of this sample were studied, and controls matched for age and sex were drawn from the sample. The purchase of thiazides and other drugs prescribed to the patients with acute cholecystitis was compared with that of the controls. The estimated relative risk of developing acute cholecystitis in patients who had purchased thiazides in the year before admission to hospital, as compared with those who had not, was 2.1 (95% confidence limit 1.1-3.9). As it has been reliably reported that the use of thiazides is not itself associated with cholelithiasis, the association found between thiazides and cholecystitis suggests that thiazides may increase the risk of acute cholecystitis developing in a patient with gall stones.     

Familial ADH-responsive diabetes insipidus: response to thiazides and chlorpropamide

Twenty cases of familial ADH-responsive diabetes insipidus were identified within five generations, and eight patients were studied by one of two established dehydration protocols. In each case there was partial to total failure of response to the initial administration of ADH which was slowly corrected by continued administration. This initial failure can lead to misinterpretation of the dehydration test unless the medullary solute washout effect is taken into account in chronically polyuric patients.Treatment consisted of thiazides and/or chlorpropamide. All cases responded well.The response to chlorpropamide suggests that the failure of ADH production is not complete in these patients, and that the major defect is a failure of ADH release in response to normal stimuli. Chlorpropamide may act by either facilitating ADH release or by synergistically interacting with available ADH at the tubular level.     

Phospholipid and cholesterol alterations accompany structural disarray in myelin membrane of rats with hepatic encephalopathy induced by thioacetamide

Fulminant hepatic failure is often associated with a wide range of neurological symptoms which are collectively referred to as hepatic encephalopathy. Fulminant hepatic failure with associated hepatic encephalopathy has a poor prognosis with the currently available sure treatment being only liver transplantation. This is largely owing to the lack of understanding of critical factors involved in the etiology of the condition. Lipid changes have been implicated in cerebral derangements characteristic of hepatic encephalopathy. About 79% of the brain lipid is concentrated in the myelin fraction where they play an important role in ion balance and conduction of nerve impulses. Hence, in the present study we aimed to investigate changes in myelin lipid composition and structure. Myelin was isolated by sucrose density gradient centrifugation from cerebral cortex of male Wistar rats (250-300 g body weight) treated with 300 mg/kg body weight thioacetamide administered twice at 24h interval to induce hepatic encephalopathy. Significant decrease was observed in the cholesterol and phospholipids content of myelin from treated rats. Sphingomyelin, phosphatidylserine and phosphatidylethanolamine content also decreased significantly following 18 h of thioacetamide administration. However, phosphatidylcholine levels remained unaltered. Transmission electron microscopic observation of myelin membrane from cerebral cortex sections showed considerable disorganization in myelin structure. Increase in malondialdehyde levels precede lipid changes leading to the speculation that oxidative damage may be the critical factor leading to decrease in the anionic phospholipids. Changes in myelin were evident only in later stages of hepatic encephalopathy indicating that myelin alteration may not play a role in early stages of hepatic encephalopathy. Nevertheless, myelin alteration may have a crucial role to play in various psycho-motor alterations during later stages of hepatic encephalopathy.     

Comparison of thiazides and amiloride in treatment of moderate hypertension.

The biochemical disturbance produced by thiazide diuretics and by amiloride during treatment of moderate hypertension were compared. Two parallel studies were initiated. In one 40 patients with newly diagnosed hypertension were treated with metoprolol and a diuretic, either hydrochlorothiazide or amiloride. In a second study 38 patients receiving longstanding treatment with hypotensives and thiazides either continued the treatment or replaced the thiazide with amiloride. Initial biochemical assessments were compared with those after two years in the study. In previously untreated patients, thiazide produced a significant fall in plasma potassium and hyperuricaemia that did not occur with amiloride (p less than 0.001). Those patients receiving long term treatment for their hypertension who continued to take thiazides had persistent hypokalaemia and hyperuricaemia. Substitution with amiloride corrected the hypokalaemia and serum uric acid returned toward normal ranges, but this change was not statistically significant. Patients receiving long term treatment also had impaired glucose tolerance, this remained unchanged in those receiving thiazide but was corrected in those receiving amiloride. Compared with amiloride thiazides produced undesirable but reversible biochemical changes. As control of hypertension was equally effective with both preparations, we suggest that a combination of amiloride with a beta blocker in treatment of moderate hypertension in preferred.     

Disparate regions of envelope protein regulate syncytium formation versus spongiform encephalopathy in neurological disease induced by murine leukemia virus TR

The murine leukemia virus (MLV) TR1.3 provides an excellent model to study the wide range of retrovirus-induced central nervous system (CNS) pathology and disease. TR1.3 rapidly induces thrombotic events in brain microvessels and causes cell-specific syncytium formation of brain capillary endothelial cells (BCEC). A single amino acid substitution, W102G, in the MLV envelope protein (Env) regulates the pathogenic effects. The role of Env in determining this disease phenotype compared to the induction of spongiform encephalomyelitis with a longer latency, as seen in several other MLV and in human retroviruses, was determined by studying in vitro-attenuated TR1.3. Virus cloned from this selection, termed TRM, induced progressive neurological disease characterized by ataxia and paralysis and the appearance of spongiform neurodegeneration throughout the brain stem and spinal cord. This disease was associated with virus replication in both BCEC and highly ramified glial cells. TRM did not induce syncytium formation, either in vivo or in vitro. Sequence and mutational analyses demonstrated that TRM contained a reversion of Env G102W but that neurological disease mapped to the single amino acid substitution Env S159P. The results demonstrate that single nucleotide changes within disparate regions of Env control dramatically different CNS disease patterns.     

Hydrogen sulphide ameliorates dopamine‐induced astrocytic inflammation and neurodegeneration in minimal hepatic encephalopathy

It has been demonstrated that the action of dopamine (DA) could enhance the production of tumour necrosis factor‐α (TNF‐α) by astrocytes and potentiate neuronal apoptosis in minimal hepatic encephalopathy (MHE). Recently, sodium hydrosulfide (NaHS) has been found to have neuroprotective properties. Our study addressed whether NaHS could rescue DA‐challenged inflammation and apoptosis in neurons to ameliorate memory impairment in MHE rats and in the neuron and astrocyte coculture system. We found that NaHS suppressed DA‐induced p65 acetylation, resulting in reduced TNF‐α production in astrocytes both in vitro and in vivo. Furthermore, decreased apoptosis was observed in neurons exposed to conditioned medium from DA + NaHS‐challenged astrocytes, which was similar to the results obtained in the neurons exposed to TNF‐α + NaHS, suggesting a therapeutic effect of NaHS on the suppression of neuronal apoptosis via the reduction of TNF‐α level. DA triggered the inactivation of p70 S6 ribosomal kinase (S6K1) and dephosphorylation of Bad, resulting in the disaggregation of Bclxl and Bak and the release of cytochrome c (Cyt. c), and this process could be reversed by NaHS administration. Our work demonstrated that NaHS attenuated DA‐induced astrocytic TNF‐α release and ameliorated inflammation‐induced neuronal apoptosis in MHE. Further research into this approach may uncover future potential therapeutic strategies for MHE.     

Differences in clinical manifestations of influenza-associated encephalopathy by age

Data from patients in Japan was analyzed to examine the age distribution and differences by age in the clinical manifestations of influenza-associated encephalopathy. Between 1998 and 2002, 472 cases of influenza-associated encephalopathy in patients aged 15 years or younger were reported to the Collaborative Study Group on Influenza-Associated Encephalopathy. These cases were divided into two groups by age: 0–5 and 6–15 years. The differences between the groups were estimated based on the data for those aged 0–5 years, and the odds ratios and 95% confidence intervals calculated. Distribution was inversely correlated with age, with a peak at 1–2 years old. In comparison with patients aged 0–5, those aged 6–15 years had a significantly greater incidence of type B infection, lower frequency of convulsions, higher frequency of loss of consciousness and altered consciousness as the initial neurological symptom, lower serum transaminase levels, lower frequency of low-density area for brain CT upon admission, and lower incidence of sequelae. Our analysis indicates that the clinical course, laboratory data, and brain imaging findings of influenza-associated encephalopathy exhibits patterns that vary with age.     

Solvent encephalopathy.

Nineteen children aged 8-14 years were admitted over a six-year period with an acute encephalopathy due to toluene intoxication. Seven had a history of euphoria and hallucinations. The remainder presented with coma (4), ataxia (3), convulsions (3), and behaviour disturbance with diplopia (2), A history of glue sniffing was elicited in 14, but in the remainder toluene assay confirmed the diagnosis. Thirteen children recovered completely; five still had psychological impairment and personality change on discharge from hospital but were lost to follow-up, and one has a persistent cerebellar ataxia one year after the acute episode, despite absence of further exposure. Toluene inhalation is an important cause of encephalopathy in children and may lead to permanent neurological damage. Diagnosis is most important if further damage due to continued abuse is to be prevented, and toluene assay is a valuable aid to diagnosis.