Pathological prion protein in the tongues of sheep infected with naturally occurring scrapie

Tongue involvement by prion spreading was shown to be a common outcome after oral or intracranial experimental challenge with scrapie and transmissible mink encephalopathy sources in rodent models. It is also known that bovine spongiform encephalopathy, which is pathogenic for humans, is experimentally transmissible to sheep and can lead to a disease indistinguishable from scrapie. A recent European Food Safety Authority opinion recommended research into PrPsc accumulation in the tongues of ruminants. We report on the detection of PrPsc in the tongues of seven scrapie-infected sheep by immunohistochemistry and Western blotting.     

Lead Intoxication in Children in Birmingham

Of 38 children investigated between 1966 and 1971 who had a blood lead concentration greater than 37 μg/100 ml eight had encephalopathy and one died; all these eight had a blood lead concentration of 99 μg/100 ml or above. Blood lead levels are related to haemoglobin concentrations and anaemia is common in children with blood lead concentrations of 37-60 μg/100 ml, levels previously accepted as harmless.Children with blood lead concentrations greater than 60 μg/100 ml show radiological evidence of lead intoxication, and treatment for this should be considered when blood lead concentration exceeds 37 μg/100 ml. Children presenting with unexplained encephalopathy should be radiographed for evidence of lead intoxication.     

Lead poisoning in zoo-dwelling primates

Lead intoxication was diagnosed in 42 primates at the National Zoological Park. Diagnoses were made clinically by the observation of signs of encephalopathy and the finding of 200 μg lead or more/100 ml blood, or postmortem by the presence of renal acid-fast intranuclear inclusion bodies and excess lead in liver specimens. Twenty-five of the primates had signs or lesions of lead encephalopathy. Lead poisoning was most common in the Cercopithecidae, and in the summer months. Lead encephalopathy was most frequent in juveniles. Leaded paint on the monkey cages was determined to be the source of poisoning. Blood studies revealed slight hypochromic anemia and immature and stippled erythrocytes. Postmortem lesions included acid-fast intranuclear inclusions in renal tubular and other epithelial cells; metaphyseal bone changes (lead lines); necrosis of striated muscle fibers; and other lesions. Treatment of one monkey for encephalopathy was attempted and proved successful.     

支链氨基酸在肝性脑病中应用的研究进展

肝性脑病作为肝脏疾病终末期常见的并发症之一,严重降低病人的生活质量,影响疾病预后.不合理的营养摄人是肝性脑病的诱因之一.支链氨基酸的应用不仅可预防肝病病人发生肝性脑病,还可以降低肝性脑病病人的意识障碍.本文简述肝性脑病的发生机制,并从理论基础、临床研究叙述支链氨基酸的治疗作用机制,且对常见支链氨基酸药物及已报道的不良反...     

Hashimoto encephalopathy: a case study

The impact of thyroid hormones upon the proper function of central nervous system has been known for many years. The neurological symptoms and psychiatric disturbances may occur both in case of hypo- as well as hyperthyreosis. The encephalopathy Hashimoto (EH) described in this paper is a rare illness which occurs in case of patients suffering from the autoimmunological thyroid disease and increased level of antibodies in serum without any connections to the thyroid function. It is characterised by a variety of neurological symptoms and psychotic disturbances, acute state, high re-occurrence and good reaction to glicocorticosteroid treatment. Although we face encephalopathy Hashimoto extremely rarely in the clinical practice one should remember about it during the diagnostic process because when it is a long lasting untreated illness it may lead to the irreversible changes in the central nervous system.     

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.     

Protection of neurons from high glucose‐induced injury by deletion of MAD2B

Diabetic encephalopathy may lead to cognitive deficits in diabetic patients and diminish quality of life. It has been shown that protracted hyperglycaemia is directly associated with neuronal apoptosis, which is involved in diabetic encephalopathy. The anaphase‐promoting complex (APC) is essential for the survival of post‐mitotic neurons. In our previous study, we found that the mitotic arrest deficient protein MAD2B, one of APC inhibitors, was expressed in neurons in central nervous system. However, whether MAD2B is involved in hyperglycaemia‐induced apoptosis and thus takes part in diabetic encephalopathy is still unknown. To address this issue, we first explored the expression of MAD2B and cyclin B1 detected by immunofluorescence and Western blot. It was found that hyperglycaemia remarkably increased the expression of MAD2B and accumulation of cyclin B1 in cortices of diabetes mellitus rat model and in cultured primary neurons. To further explore the role of MAD2B in hyperglycaemia‐induced neuronal injury, we depleted MAD2B expression by a specifically targeted shRNA against MAD2B. We observed that MAD2B deficiency alleviated cyclin B1 expression and apoptotic neuronal death. These results demonstrate that MAD2B expression is the main culprit for accumulation of cyclin B1 and apoptosis in neurons under high glucose. Moreover, inhibition of the expression of MAD2B prevented neurons from entering an aberrant S phase that led differentiated neurons into apoptotic cell death. These results suggest that hyperglycaemia induced neuronal apoptosis through inducing expression of MAD2B, which represents a novel mechanism of diabetic encephalopathy.     

Wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity.

Thiamine deficiency is known to lead to certain neurological sequelae including Wernicke- Korsakoff encephalopathy. Signs attributable to this condition include ataxia, ophthalmoplegia, nystagmus, and mental confusion. Recognised predisposing conditions include alcoholism gastric carcinoma, pyloric obstruction, hyperemesis gravidarum, and prolonged intravenous feeding. We have recently encountered two cases of Wernicke''s encephalopathy after vertical banded gastroplasty for morbid obesity . Other neurological sequelae are recognised after vertical banded gastroplasty, including Guillain-Barre syndrome, psychosis, and pseudoathetosis, but the causes are multifactorial.     

Copper-dependent functions for the prion protein

Prion diseases such as bovine spongiform encephalopathy and Creutzfeldt-Jakob disease are fatal neurodegenerative diseases. These diseases are characterized by the conversion of a normal cellular protein, the prion protein, to an abnormal isoform that is thought to be responsible for both pathogenesis in the disease and the infectious nature of the disease agent. Understanding the biology and metabolism of the normal prion protein is therefore important for understanding the nature of these diseases. This review presents evidence for the normal function of the cellular prion protein, which appears to depend on its ability to bind copper (Cu). There is now considerable evidence that the prion protein is an antioxidant. Once the prion protein binds Cu, it may have an activity like that of a superoxide dismutase. Conversion of the prion protein to an abnormal isoform might lead to a loss of antioxidant protection that could be responsible for neurodegeneration in the disease.     

Nitric oxide in hepatic encephalopathy and hyperammonemia

Chronic alcoholism, viral hepatitis or hepatotoxic drug overdose result in liver dysfunction which may lead to a neuropsychiatric disorder termed hepatic encephalopathy (HE). Although, the exact molecular mechanisms underlying the pathophysiology of HE are not known, excitatory/inhibitory neurotransmitter imbalance leading to dysfunction of the glutamate-nitric oxide (NO) system is thought to play a major role. Activation of the NMDA subtype of glutamate receptors leads to increase in intracellular calcium, which initiates several calcium-dependent processes including NO formation. NO is a gaseous, highly reactive, freely diffusible molecule with a short half-life. Recent studies demonstrate increased expression of the neuronal isoform of NO synthase (NOS) and the uptake of L-arginine (the obligate precursor of NO) in both chronic and acute HE. Hyperammonemia associated with liver dysfunction results in increased NO, which may lead to learning and memory impairments and cerebral edema commonly seen, particularly in acute hyperammonemia.     

Molecular advances in understanding inherited prion diseases

The prion diseases are neurodegenerative disorders that have attracted great interest because of the possible link between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CTD) in humans. Possible transmission of these diseases has been linked to a single protein termed the prion protein. This protein is an abnormal isoform of a normal synaptic glycoprotein. The majority of prion diseases does not appear to be caused by transmission of an infectious agent but occur spontaneously with no known cause. The strongest supporting evidence that the prion protein is the causative agent in prion disease comes from specific inheritable forms of prion disease which are linked to single point mutations in the prion protein gene. Paradoxically, these point mutations, although autosomal dominant with 100% penetrance do not lead to disease until late in life. Molecular techniques are now being used extensively to determine how these point-mutations alter the prion protein’s normal structure and activity. This review deals with the latest insights into how inherited mutations in the prion protein gene lead to neurodegenerative disease.     

eIF2B-related disorders: antenatal onset and involvement of multiple organs

Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.     

Paludification and Forest Retreat in Northern Oceanic Environments

Examination of temperature variations over the past centuryfor Europe and the Arctic from northern Norway to Siberia suggeststhat variations in the North Atlantic Oscillation are associatedwith an increase in oceanicity in certain maritime regions.A southward depression of the treeline in favour of wet heaths,bogs and wetland tundra communities is also observed in northernoceanic environments. The physiological basis for this changein ecological succession from forest to bog is discussed inrelation to the long-term effects of flooding on tree survival.The heightened values currently detected in the North AtlanticOscillation Index, together with rising winter temperatures,and increased rainfall in many areas in northern Europe, presentsan increasing risk of paludification with adverse consequencesfor forest regeneration, particularly in areas with oceanicclimates. Climatic warming in oceanic areas may increase thearea covered by bogs and, contrary to general expectations,lead to a retreat rather than an advance in the northern limitof the boreal forest. High water-table levels are not automaticallydetrimental to forest survival as can be seen in swamp, bottomlandand mangrove forests. Consequently, the inhibitory effects offlooding on tree survival and regeneration in northern regionsshould not be uncritically accepted as merely due to high waterlevels. Evidence is discussed which suggests that physiologicaland ecological factors may interact to inhibit forest regenerationin habitats where there is a risk of prolonged winter-floodingcombined with warmer winters and cool moist summers.     

Stem cells and neonatal brain injury

Recent advances in regenerative medicine and in our understanding of neurogenesis may lead to new ways of recovering neuronal function lost or damaged during the perinatal period; such injuries are not amenable to conventional therapies. We review recent experimental studies based on immature rodental models of neonatal brain injury, especially hypoxic-ischemic encephalopathy. The developing brain is revealed to have considerable potential with respect to proliferation and migration to the injured site. However, the generation of fully differentiated neurons is extremely limited after brain injuries. Aggressive efforts to adjust the environment of the damaged brain in which tissue regeneration is occurring or more cautious stem cell transplantation will be required for the successful treatment of developmental brain injury. This work was supported by a Research Grant for Cardiovascular Diseases (18C-1) from the Ministry of Health, Labour and Welfare.     

Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families

Intellectual disability and developmental encephalopathies are mostly linked with infant epilepsy. Epileptic encephalopathy is a term that is used to define association between developmental delay and epilepsy. Mutations in the STXBP1 (Syntaxin-binding protein 1) gene have been previously reported in association with multiple severe early epileptic encephalopathies along with many neurodevelopmental disorders. Among the disorders produced due to any mutations in the STXBP1 gene is developmental and epileptic encephalopathy 4 (OMIM: 612164), is an autosomal dominant neurologic disorder categorized by the onset of tonic seizures in early infancy (usually in the first months of life). In this article, we report two Saudi families one with de novo heterozygous stop-gain mutation c.364C > T and a novel missense c. 305C > A p.Ala102Glu in exon 5 of the STXBP1 gene (OMIM: 602926) lead to development of epileptic encephalopathy 4. The variants identified in the current study broadened the genetic spectrum of STXBP1 gene related with diseases, which will help to add in the literature and benefit to the studies addressing this disease in the future.     

Interference of Pb with essential brain tissue Cu, Fe, and Zn as main determinant in experimental tetraethyllead encephalopathy

After exposure of rabbits to tetraethyllead, each analyzed brain area (frontal cortex, cerebellum, hippocampus) contained approximately 33 μg of lead per gram dry weight. At the same time, there was a statistically significant loss in the same brain areas of the essential elements, copper, iron, and zinc. While the molar ratio between gain of lead and decrease of copper revealed an approximate proportionality of 1:1, the ratio between lead and iron was approximately 1:2. The decrease of zinc levels varied in these brain areas and was lowest in the inferior hippocampus. The potentiality of an interference of lead with essential trace metals of the brain, preferentially with the metal group of metalloenzymes, as the primary and dominant mechanism of the toxic action of lead in lead encephalopathy, is discussed.     

Formation and Development of Pseudothecia of Venturia nashicola

Conidia are believed to be the main source of primary inoculum for pear scab, caused by Venturia nashicola, in northern China. Experiments were conducted to investigate the development and potential role of V. nashicola ascospores in northern China. Leaves with pear scab lesions were collected from commercial orchards in November 2003 and 2004 to monitor pseudothecia formation under various environments. Pseudothecium production was shown to occur readily in northern China. The key requirement for pseudothecium production is the occurrence of rain during the winter and early spring, although the exact timing of these rain events appeared not to affect their development. Excess water may lead to the accelerated leaf decay and hence lead to production of fewer pseudothecia. More than 80% scabbed leaves, placed in a pear orchard, produced pseudothecia. Leaves with only non‐sporulating scab lesions in autumn were also able to produce a large number of pseudothecia. Both airborne ascospores and conidia of V. nashicola were caught in a pear orchard. Most ascospores were released by late‐May, a month after pear blossom. These results suggest that ascospores may play an important role in the early stage of pear scab epidemics in spring in northern China.     

Detecting Minimal Hepatic Encephalopathy in an Endemic Country for Hepatitis B: The Role of Psychometrics and Serum IL-6

Background & Aims

It remains unknown what the prevalence of minimal hepatic encephalopathy is in Taiwan, a highly endemic country for chronic viral hepatitis infection. It is also unclear whether abnormal serum cytokine levels can be indicative of the presence of minimal hepatic encephalopathy. We aimed to standardize the tests of psychometric hepatic encephalopathy score and predictive value of proinflammatory cytokines in minimal hepatic encephalopathy in Taiwan.

Methods

180 healthy subjects and 94 cirrhotic patients without a history of overt hepatic encephalopathy from a tertiary center were invited to participate in this cross-sectional study. Blood sampling for determination of serum levels of interleukin 6 and 18 and tumor necrosis factor-α was performed. Based on the normogram of psychometric hepatic encephalopathy score from healthy volunteers, patients with minimal hepatic encephalopathy were identified from the cirrhotic patients using the criterion of a psychometric hepatic encephalopathy score less than −4.

Results

In the healthy subjects, age and education were predictors of subtests of psychometric hepatic encephalopathy score. Minimal hepatic encephalopathy was identified in 27 (29%) cirrhotic patients. Serum interleukin 6 level (OR = 6.50, 95% CI = 1.64–25.76, P = 0.008) was predictive of the presence of minimal hepatic encephalopathy after multivariate analysis.

Conclusions

The psychometric hepatic encephalopathy score can be a useful tool for detecting patients with minimal hepatic encephalopathy in Taiwan and around one third of cirrhotic outpatients fulfill this diagnosis. A high serum interleukin 6 level is predictive of the presence of minimal hepatic encephalopathy.     

Attenuation of Congenital Portosystemic Shunt Reduces Inflammation in Dogs

Liver disease is a major cause of morbidity and mortality. One of the most significant complications in patients with liver disease is the development of neurological disturbances, termed hepatic encephalopathy. The pathogenesis of hepatic encephalopathy is incompletely understood, which has resulted in the development of a wide range of experimental models. Congenital portosystemic shunt is one of the most common congenital disorders diagnosed in client owned dogs. Our recent studies have demonstrated that the pathophysiology of canine hepatic encephalopathy is very similar to human hepatic encephalopathy, which provides strong support for the use of dogs with a congenital portosystemic shunt as a naturally occurring model of human hepatic encephalopathy. Specifically, we have demonstrated an important role for ammonia and inflammation in the development of hepatic encephalopathy in dogs with a congenital portosystemic shunt. Despite the apparent importance of inflammation in driving hepatic encephalopathy in dogs, it is unclear whether inflammation resolves following the successful treatment of liver disease. We hypothesized that haematological and biochemical evidence of inflammation, as gauged by neutrophil, lymphocyte and monocyte concentrations together with C-reactive protein concentrations, would decrease following successful treatment of congenital portosystemic shunts in dogs. One hundred and forty dogs with a congenital portosystemic shunt were enrolled into the study. We found that the proportion of dogs with a monocyte concentration above the reference range was significantly greater in dogs with hepatic encephalopathy at time of initial diagnosis. Importantly, neutrophil and monocyte concentrations significantly decreased following surgical congenital portosystemic shunt attenuation. We also found a significant decrease in C-reactive protein concentrations following surgical attenuation of congenital portosystemic shunts. Our study demonstrates that haematological and biochemical indices of inflammation reduce following successful treatment of the underlying liver disorder.     

Wernicke-Korsakoff syndrome in the course of thyrotoxicosis - a case report

Wernicke-Korsakoff syndrome (also called Wernicke's encephalopathy) is a potentially fatal, neuropsychiatric syndrome caused most frequently by thiamine deficiency. The three classic symptoms found together are confusion, ataxia and eyeball manifestations. Memory disturbances can also be symptoms. Wernicke's encephalopathy mainly results from alcohol abuse, but also from malnutrition, cancer, chronic dialysis, thyrotoxicosis and, in well-founded cases, encephalopathy associated with autoimmune thyroid disease (EAATD). The coexistence of many factors makes a proper diagnosis difficult, delays appropriate treatment and consequently reduces the chance of complete recovery. We present the case of a 53 year-old female with Wernicke's encephalopathy caused by chronic malnutrition, surgical operation, as well as thyrotoxicosis. She received treatment with intravenous thiamine administration and also anti-thyroid treatment which caused satisfactory regression of her neurological symptoms.