Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disturbed glucose brain metabolism after brain trauma is reflected by changes in extracellular glucose levels. The authors hypothesized that posttraumatic reductions in extracellular glucose levels are not due to ischemia and are associated with poor outcome. Intracerebral microdialysis, electroencephalography, and measurements of brain tissue oxygen levels and jugular venous oxygen saturation were performed in 30 patients with traumatic brain injury. Levels of glucose, lactate, pyruvate, glutamate, and urea were analyzed hourly. The 6-month Glasgow Outcome Scale extended (GOSe6) score was assessed for each patient. In regions of increased glucose utilization defined by positron emission tomography, the extracellular glucose concentration was less than 0.2 mmol/l. Extracellular glucose values were less than 0.2 mmol during postinjury days 0 to 7 in 19% to 30% of hourly samples on each day. Transient decreases in glucose levels occurred with electrographic seizures and nonischemic reductions in cerebral perfusion pressure and jugular venous oxygen saturation. Glutamate levels were elevated in the majority of low-glucose samples, but the lactate/pyruvate ratio did not indicate focal ischemia. Terminal herniation resulted in reductions in glucose with increases in the lactate/pyruvate ratio but not in lactate concentration alone. GOSe6 scores correlated with persistently low glucose levels, combined early low glucose levels and low lactate/glucose ratio, and with the overall lactate/glucose ratio. These results suggest that the level of extracellular glucose is typically reduced after traumatic brain injury and associated with poor outcome, but is not associated with ischemia.
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PMID:Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. 1284 90

Inadequate treatment of severe hyponatremia (<120 mEq/L) can be associated with severe neurological damage. In acute (<48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (>48-72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline.
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PMID:Treatment of symptomatic hyponatremia. 1286 Nov 22

Arginase deficiency is a rare, autosomal recessive, disorder of the urea cycle characterized by mild hyperammonaemia, hyperargininaemia, dibasic aminoaciduria and orotic aciduria, associated with progressive spastic tetraplegia, seizures, psychomotor retardation, and growth failure. We report a family who presented with their daughter at 4 years 11 months of age with an acute encephalopathy. Initial laboratory results revealed hyperammonaemia (160 micromol/L; normal 0-34), hyperargininaemia (512 micromol/L; normal 23-86) and orotic aciduria. A diagnosis of arginase deficiency was confirmed by enzyme assay, and treatment with a modified protein-restricted diet along with sodium benzoate therapy was initiated. Over time, intellectual development has been normal, but the child developed spasticity in her lower extremities. Subsequently, the mother presented at 6 weeks of pregnancy seeking prenatal diagnosis. Prenatal testing for arginase deficiency has only been reported in one other case. Arginase is not expressed in cultured amniotic fluid cells or chorionic villus samples. Testing for arginase activity assay in red blood cells, isolated by cordocentesis, was performed and predicted an unaffected fetus. The result was confirmed by postnatal enzyme analysis of red cells from the newborn. On the basis of our experience, prenatal diagnosis of arginase deficiency by cord red blood cell arginase activity assay appears possible.
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PMID:Prenatal diagnosis for arginase deficiency: a case study. 1460 7

Acute renal failure is a common occurrence in sepsis, but is rarely reported in meningococcemia. We present a young child diagnosed with fulminant meningococcemia who had several poor prognostic factors, including hypotension, thrombocytopenia, purpura fulminans, seizures, the absence of meningitis with meningococcemia, and acute renal failure, which was successfully treated with peritoneal dialysis. Peritoneal dialysis was started on the 5th day because the patient had been anuric for 48 h. At that time, analysis showed that the child was both hypokalemic and hypophosphatemic. His serum blood urea nitrogen was 61 mg/dl, creatinine 2.75 mg/dl, potassium 2.8 mEq/l, and phosphorus 0.7 mg/dl. Urine output began on the 12th day post admission and normalization of serum creatinine was achieved on the 26th day. In conclusion, renal failure is an important complication of meningococcemia and, to be effective, sometimes long-term peritoneal dialysis is required. Profound metabolic abnormalities, such as hypokalemia and hypophosphatemia, may occur paradoxically in the presence of oliguria.
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PMID:Fulminant meningococcemia and acute renal failure in a 3-year-old boy. 1549 Feb 48

OBJECTIVE: To drive pediatrician's attention to a urea cycle enzyme deficiency. The prognosis is directly related to the early diagnosis and treatment. METHODS: We describe a newborn patient who present lethargy, vomitus and seizures 48 hours afther birth. We investigated this patient and the diagnosis of ornithine transcarbamylase deficiency was made. Treatment was started immediately. RESULTS: We followed the patient until he was 1 year old, when he had liver transplant with a good outcome of the disease. CONCLUSION: The ornithine transcarbamylase deficiency is a rare and very serious disease. Any newborn whose evolution is similar to that of a septic patient without any infection must be investigated for this disease. The prognosis is directly related to the early diagnosis and treatment.
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PMID:[Ornithine transcarbamylase deficiency: neonatal diagnostic] 1468 53

In conclusion, we have discussed a reverse genetics approach to studying seizure disorders in mice (Fig. 1), employing a targeted mutagenesis method to exploit the genetic defects identified in human epilepsy families. After detailed characterization of the nature of the human mutation and the mouse counterpart gene, a targeting vector containing the human disease allele is created. The endogenous mouse gene is replaced by the human disease allele through homologous recombination in ES cells, leading to the generation of chimeric animals. Mice carrying one copy or both copies of the human mutation can be bred to study the phenotypic effect of heterozygous and homozygous mutations. At this stage, one may want to split the newly created mice into two groups. One group will go through seizure phenotyping tests, while the other group will be used to generate disease allele-carrying mice on a different genetic background. Phenotypic characterization of mice on different inbred strains includes behavioral monitoring and EEG analysis looking for the occurrence of spontaneous seizures, as well as routine cage examination looking for handling-provoked seizure and ECT- and PTZ- induced seizure paradigms looking for sensitivity to these stimuli. A complete evaluation of the seizure phenotype at the whole-animal level establishes the relevance of the mouse model to the human condition. Further investigation including imaging, electrophysiology and AED response in these mouse models will shed light on the mechanistic basis of the convulsive disorder. Current epilepsy research in mouse genetics offers promise for understanding the molecular mechanisms that underlie epileptogenesis in humans. A large-scale forward genetic effort to create novel mouse mutants with seizure phenotypes by in vivo chemical mutagenesis with ethyl-nitroso urea (ENU) is underway at the Jackson Laboratory (http://www.jax.org/nmf/). Genetic mapping and isolation of the affected genes in these seizure-prone models will provide additional molecular pathways involved in seizures. The mutant mice generated through both forward and reverse genetic approaches will be a valuable resource for the biomedical community to study epilepsy at the molecular level and to characterize the pathological consequences of seizures in the whole organism.
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PMID:Genetic approaches to studying mouse models of human seizure disorders. 1525 May 82

A series of 3-chloro-2-methylphenyl substituted semicarbazones (3-33) was synthesized and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice or rats, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous strychnine (scSTY)-induced seizure and neurotoxicity screens. The aryl urea (1) and the semicarbazide (2) showed anticonvulsant activity in the MES and scPTZ screens with acute neurotoxicity, whereas the semicarbazone derivatives showed good anticonvulsant potency in the scSTY screen with moderate activity against MES and scPTZ screens. Compound 21 exhibited anticonvulsant potency against all the three screens with lesser neurotoxicity. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to phenytoin or carbamazepine as was evident from the CNS studies.
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PMID:3-Chloro-2-methylphenyl-substituted semicarbazones: synthesis and anticonvulsant activity. 1527 6

The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by point mutations in the neuroserpin gene. We have shown a correlation between the predicted effect of the mutation and the number of intracerebral inclusions, and an inverse relationship with the age of onset of disease. Our previous work has shown that the intraneuronal inclusions in FENIB result from the sequential interaction between the reactive centre loop of one neuroserpin molecule with beta-sheet A of the next. We show here that neuroserpin Portland (Ser52Arg), which causes a severe form of FENIB, also forms loop-sheet polymers but at a faster rate, in keeping with the more severe clinical phenotype. The Portland mutant has a normal unfolding transition in urea and a normal melting temperature but is inactive as a proteinase inhibitor. This results in part from the reactive loop being in a less accessible conformation to bind to the target enzyme, tissue plasminogen activator. These results, with those of the CD analysis, are in keeping with the reactive centre loop of neuroserpin Portland being partially inserted into beta-sheet A to adopt a conformation similar to an intermediate on the polymerization pathway. Our data provide an explanation for the number of inclusions and the severity of dementia in FENIB associated with neuroserpin Portland. Moreover the inactivity of the mutant may result in uncontrolled activity of tissue plasminogen activator, and so explain the epileptic seizures seen in individuals with more severe forms of the disease.
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PMID:Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB. 1615 19

Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.
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PMID:Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives. 1529 3

Over the past 20 years children have benefited from major improvements in both technology and clinical management of dialysis. Morbidity during dialysis sessions has decreased with seizures being exceptional and hypotensive episodes rare. Pain and discomfort have been reduced with the use of chronic internal jugular venous catheters and anesthetic creams for fistula puncture. Non-invasive technologies to assess patient target dry weight and access flow can significantly reduce patient morbidity and health care costs. The development of urea kinetic modeling enables calculation of the dialysis dose delivery, Kt/V, and an indirect assessment of the intake. Nutritional assessment and support are of major importance for the growing child. Even if the validity of these "urea only" data is questioned, their analysis provides information useful for follow-up. Newer machines provide more precise control of ultrafiltration by volumetric assessment and continuous blood volume monitoring during dialysis sessions. Buffered bicarbonate solutions are now standard and more biocompatible synthetic membranes and specific small size material dialyzers and tubing have been developed for young infants. More recently, the concept of "ultrapure" dialysate, i.e. free from microbiological contamination and endotoxins, has developed. This will enable the use of hemodiafiltration, especially with the on-line option, which has many theoretical advantages and should be considered in the case of maximum/optimum dialysis need. Although the optimum dialysis dose requirement for children remains uncertain, reports of longer duration and/or daily dialysis show they are more effective for phosphate control than conventional hemodialysis and should be considered at least for some high-risk patients with cardiovascular impairment. In children hemodialysis has to be individualized and viewed as an "integrated therapy" considering their long-term exposure to chronic renal failure treatment. Dialysis is seen only as a temporary measure for children compared with renal transplantation because this enables the best chance of rehabilitation in terms of educational and psychosocial functioning. In long term chronic dialysis, however, the highest standards should be applied to these children to preserve their future "cardiovascular life" which might include more dialysis time and on-line hemodiafiltration with synthetic high flux membranes if we are able to improve on the rather restricted concept of small-solute urea dialysis clearance.
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PMID:Hemodialysis in children: general practical guidelines. 1594 92


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