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Biomedical subjects

E Sim

Publications and source records attributed to E Sim.

At least 73 records · Page 4Linked to original sources
PubMed1996

Fatal transdental posterior rotary subluxation of the cervical spine. A case report.

STUDY DESIGN: The cervical spine of an 86-year-old man known to have a fracture of the odontoid process was removed at autopsy and dissected. OBJECTIVES: To establish the cause of death, which was not apparent. SUMMARY OF BACKGROUND DATA: Ruptures of the vertebral arteries in patients with fractures of the odontoid process are rare. Only a few reports are published in the literature. Those that address postmortem findings in patients with fractures of the odontoid process do not make any reference to associated capsular and ligamentous injuries and the resultant instabilities. METHODS: Because of legal constraints, the cervical spine was removed en bloc 1 week after the patient's death and carefully dissected. RESULTS: In addition to the known bony injury, rupture of the left vertebral artery, epidural hematoma, disruption of the posterior atlantoaxial ligaments, hemorrhage into the anterior ligamentous structures, rupture of the capsule of the right atlantoaxial joint, and stretching of the capsule of the left joint were found to be present. Displacement of the spinal cord by an epidural hematoma secondary to rupture of the left vertebral artery was recorded as the apparent cause of death. The rupture had obviously been caused by the abnormal rotation of the atlas on the axis in a clockwise direction. CONCLUSIONS: Both the fatal outcome and the pathologic examination showed that established management concepts, particularly screw fixation of a fractured odontoid process, should be reconsidered in light of the potential occurrence of transdental posterior rotary subluxation. Because the incidence of capsular, ligamentous, and vascular injuries associated with fractures of the odontoid process is still poorly understood, more autopsies would be needed. The case also raises the question of whether, in an elderly patient like ours, a fracture of the odontoid process should prompt immediate surgical stabilization.

Aged↗
PubMed1996

Long-time quantum simulation of the primary charge separation in bacterial photosynthesis.

Accurate quantum mechanical simulations of the primary charge transfer in photosynthetic reaction centers are reported. The process is modeled by three coupled electronic states corresponding to the photoexcited chlorophyll special pair (donor), the reduced bacteriopheophytin (acceptor), and the reduced accessory chlorophyll (bridge) that interact with a dissipative medium of protein and solvent degrees of freedom. The time evolution of the excited special pair is followed over 17 ps by using a fully quantum mechanical path integral scheme. We find that a free energy of the reduced accessory chlorophyll state approximately equal to 400 cm(-1) lower than that of the excited special pair state yields state populations in agreement with experimental results on wild-type and modified reaction centers. For this energetic configuration electron transfer is a two-step process.

Bacteriochlorophylls↗
PubMed1996

Augmentation of pulmonary blood flow with an axillary arteriovenous fistula after a cavopulmonary shunt.

Of 320 children with cyanotic congenital heart malformations who had previously undergone cavopulmonary shunt operations, 11 had increasing cyanosis and exercise intolerance and were considered unsuitable for definitive repair, a Fontan procedure, or other palliation. Eight had a previous Glenn shunt and three had a previous bidirectional cavopulmonary connection. To augment pulmonary blood flow, 10 patients underwent creation of an ipsilateral axillary arteriovenous fistula. Mean oxygen saturations were 80% +/- 2% before operation, 85% +/- 2% immediately after operation, and 84% +/- 3% at a mean follow-up interval of 7.4 years (range 0.1 to 15.5 years). Mean hemoglobin values were 202 +/- 10 gm/L before operation, 177 +/- 10 gm/L after operation, and 191 +/- 14 gm/L at latest review. The only complication was mild swelling of the arm distal to the fistula in one patient. All patients reported improvement in exercise tolerance. Eight patients have continued evidence of fistula patency. Development of ipsilateral pulmonary arteriovenous fistulas has not been observed in any patient. Creation of an axillary arteriovenous fistula to augment pulmonary blood flow after a cavopulmonary shunt provides useful palliation for complex cyanotic heart disease when other options are limited. Such additional sources of pulmonary blood flow may influence the development of pulmonary arteriovenous fistulas.

Arteriovenous Shunt, Surgical↗
PubMed1996

Arylamine N-acetyltransferase in erythrocytes of cystic fibrosis patients.

Sulphamethoxazole, a substrate of human arylamine N-acetyltransferase, is used in the treatment of cystic fibrosis patients, who metabolise the drug rapidly. Increased metabolic clearance of sulphamethoxazole has been suggested to account for this rapid metabolism. Arylamine N-acetyltransferase type 1 is expressed in erythrocytes and leucocytes and the activity in erythrocytes is shown to contribute approximately 99% of the activity of arylamine N-acetyltransferase type 1 in blood cells. Arylamine N-acetyltransferase type 1 activity in erythrocytes from 16 adult cystic fibrosis patients and 19 age-matched controls were compared. Although there is a variation in erythrocyte arylamine N-acetyltransferase type 1 activity within each group, no difference was found when the two groups were compared. All individuals from the cystic fibrosis and control groups were investigated for certain allelic variants of the arylamine N-acetyltransferase type 1 gene (NAT1). Only one copy of a mutant NAT1 allele (NAT1*11) was found. The heterozygous NAT1 individual is a cystic fibrosis patient with a low level of erythrocyte arylamine N-acetyltransferase type 1 activity. A second distinct arylamine N-acetyltransferase isozyme, arylamine N-acetyltransferase type 2, is encoded at the multi-allelic NAT2 locus. There was no correlation between erythrocyte arylamine N-acetyltransferase-1 activity and NAT2 alleles present in either the cystic fibrosis or control groups. The distribution of NAT2 alleles was very similar in the two groups. The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N-acetyltransferase type 1 activity or to inheritance of alleles at either the NAT1 or NAT2 loci.

Adolescent↗
PubMed1996

Immunochemical detection of arylamine N-acetyltransferase in normal and neoplastic bladder.

The N-acetyltransferase (NAT) phenotype is an important determinant of individual susceptibility to occupational bladder cancer. N-Acetyltransferases arc known to metabolize aromatic amine bladder carcinogens, but the functional significance of NAT expression in the target organ is unclear. To resolve this issue, polygonal antisera against purified recombinant enzymes and C-terminal peptides of human NAT Type 1 (NAT1) and Type 2 (NAT2) were generated. Western blot analysis of exfoliated cells from human urine, pig bladder homogenate, and human bladder tumor-derived cell lines showed that NAT1 was expressed in all three systems, whereas NAT2 did not appear to be expressed in the bladder. Immunohistochemical analysis of human bladder tumor sections indicated that well-differentiated tumor cells expressed NAT1, with the highest level of expression being found in the umbrella cells that line the bladder lumen. Poorly differentiated tumor regions appeared to express NAT1 at lower levels than did well-differentiated areas. These findings support the hypothesis that aromatic amines are metabolized in the bladder epithelium by NAT1.

Amino Acid Sequence↗
PubMed1995

Enzyme kinetic properties of human recombinant arylamine N-acetyltransferase 2 allotypic variants expressed in Escherichia coli.

Arylamine N-acetyltransferase (NAT2) catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-Acetylation is subject to polymorphism, and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate certain arylamine substrates in vivo. Genetic variants at the polymorphic NAT2 locus have been described. We expressed five of the most common NAT2 variants (NAT2 4, NAT2 5A, NAT2 5B, NAT2 6A and NAT2 7B) in Escherichia coli as a convenient source of the human variants. The apparent Km values (at 100 microM acetyl CoA as co-substrate) of the different NAT2 variants for sulphamethazine, dapsone, p-anisidine, 2-aminofluorene, procainamide and isoniazid were determined. Data show that the apparent Km of the slow variant NAT2 7B for the arylamine sulphamethazine was 10-fold lower than all the other allotypes. The apparent Km for the structurally related sulphone antibiotic dapsone was 5-fold lower for the slow variant NAT2 7B when compared with the wild-type NAT2 4. These results indicate that the NAT2 7B specific amino acid substitution, Gly286-Glu, is important in promoting the binding of sulphamethazine and dapsone to the active site.

Arylamine N-Acetyltransferase↗
PubMed1995

Purification of recombinant human N-acetyltransferase type 1 (NAT1) expressed in E. coli and characterization of its potential role in folate metabolism.

Human arylamine N-acetyltransferase type 1 (NAT1) has been cloned from human genomic DNA, into the vector pET(5a) and expressed in Escherichia coli. The recombinant protein has been purified to apparent homogeneity using anion exchange chromatography. The arylamine acceptor specificity, and the effect of potential NAT1 inhibitors has been investigated using purified recombinant protein. The Km of the recombinant NAT1 protein for the substrates para-aminobenzoate (p-aba) and 4-aminosalicylate are 14.3 and 11.8 microM, respectively. Folate and amethopterin were found to be potent competitive inhibitors of p-aba acetylation, with Ki values of 13.3 and 9.5 microM, respectively. The pteroate moiety of folate, in contrast is a poor inhibitor, with 100 microM pteroate inhibiting only 40% of NAT1 activity. A catabolite of folate para-aminobenzoly-L-glutamate has also been shown to be a NAT1 substrate with a Km value of 263 microM.

Arylamine N-Acetyltransferase↗
PubMed1995

Finite element analysis of the stress distributions in the proximal end of the femur after stabilization of a pertrochanteric model fracture: a comparison of two implants.

The study investigated the influence of two different implants--the dynamic hip screw (AOR) 135 degrees with 2-hole-plate and the 135 degrees gamma-nail (HowmedicaR)--on the resulting stress and strain distributions in the proximal femur after stabilization of an idealized trochanteric fracture under typical physiological loading conditions. Data recorded for the uninjured femur were used for comparison. Two-dimensional plane stress finite element models of the femur and the implants were used for the calculations. The three-dimensional nature of this problem was approximated by an appropriate distribution of element thickness according to the real geometry in combination with an overlay technique, superimposing special finite element layers for each constituent of the bone-implant system (i.e. steel, cortical and cancellous bone). Three variations of the idealized fracture were introduced, i.e. free, with callous and bony bridging, the screw being modelled in a movable ('dynamic') as well as in a locked state. As far as the resulting stress distributions are concerned, neither of the two implants proved to be significantly superior to the other for stabilization of the idealized fracture selected.

Bone Nails↗
PubMed1995

Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease.

The effect of the apolipoprotein E genotype on the development of late onset Alzheimer's disease is still debated. Neuropathological studies of Alzheimer's disease have found a great extent of amyloid deposition in cortex and blood vessel walls in association with the apolipoprotein E epsilon 4 genotype [Rebeck G. W. et al. (1993) Neuron 11, 575-580; Schmechel et al. (1993) Proc. natn. Acad. Sci. U.S.A. 90, 9649-9653]. In contrast, the relationship of apolipoprotein E genotype to neurofibrillary pathology in Alzheimer's disease has been less clear. In this study we present evidence on the influence of the apolipoprotein E genotype on Alzheimer's disease related pathology in a series of 76 autopsy cases that had pathology that fulfilled the CERAD criteria for Alzheimer's disease. We found that the presence of the apolipoprotein E epsilon 4 allele is correlated with increased amounts of both amyloid and neuritic pathology in the neocortex as determined using an image analysis system. Comparison of plaque and tangle densities with the allele doses of epsilon 2 and epsilon 4 revealed a striking parallelism, suggesting that the alleles exert their effects very early in the pathological process before deposition of plaques and tangles. Although the apolipoprotein E epsilon 2 allele had a protective effect against both amyloid deposition and neurofibrillary tangle formation, in the presence of the epsilon 4 allele this protective effect against neuritic pathology was less marked than against amyloid deposition. This differential effect on amyloid deposition and the accumulation of neuritic pathology suggests that different molecular mechanisms are involved in the effect of apolipoprotein E on amyloid deposition and on tau phosphorylation.

Aged↗
PubMed1995

Xenogenetics in multifactorial disease susceptibility.

Susceptibility to multifactorial disease includes both genetic and environmental components. These two aspects of susceptibility are interlinked through genetic control of an individual's response to the environment. As a first step in identifying disease susceptibility genes that influence the response of an individual to foreign compounds (xenobiotics), it is necessary to study disorders in which there is an identified environmental trigger. Establishing a DNA resource from individuals with known environmental exposure ('a xenogenetic register') for diseases with an established environmental aetiology is an essential step in beginning to understand how environmental factors contribute to the susceptibility to polygenic diseases. A complementary approach to identification of environmental factors is suggested using a comparison of genetically homogeneous subdivisions of individuals with polygenic diseases where there is no clue to the environmental trigger.

Animals↗
PubMed1995

Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer.

Bladder cancer is a common multifactorial disease and is known to be associated with occupational exposure to arylamines. Smoking is also a recognised contributory environmental cause. Occupational bladder cancer has previously been associated with slow acetylation by N-acetyltransferase (NAT) in humans in phenotyping studies, but more recently there has been some controversy regarding this issue. NAT is an enzymic activity involved in the metabolism of arylamines, and its 'classical' polymorphism is due to multiple alleles at the NAT2 locus. A genotyping approach has been used to investigate NAT2 type in a population of 189 Caucasian bladder cancer patients attending a clinic at a hospital in Birmingham. Genomic DNA was prepared from a blood sample donated by each of the patients and was used in the polymerase chain reaction with primers specific for all NAT2 alleles. Restriction fragment length polymorphism analysis was used to determine which alleles were present. Results have been compared to those from an age-matched non-malignant Caucasian control population (59 individuals) from the same region. Occupational and smoking history was determined by questionnaire and a significant excess of genotypic slow acetylators is found in those groups of bladder cancer patients exposed to arylamines as a result of their occupation or who are cigarette smokers. A higher proportion of slow acetylators is also found in those bladder cancer patients without identified exposure to arylamines when compared to the non-malignant controls. Slow NAT genotype is therefore a contributory risk factor in bladder carcinogenesis which acts through influencing individual response to environmental carcinogens.

Acetylation↗
PubMed1995

Vertical facet splitting: a special variant of rotary dislocations of the cervical spine.

A special variant of rotary displacement of the cervical spine with vertical splitting of an inferior articular process by its articulating partner is reviewed. Eighteen patients with unilaterally locked facet joints confirmed by computerized tomography were seen between 1986 and 1991. Five patients presented with vertical split fractures of an inferior articular process by impaction of the superior process of the subjacent vertebra. This specific fracture pattern is not accounted for in current classifications. Four males and one female with a mean age of 31 years (range 16 to 49 years) were affected. Three of the patients showed no neurological deficits. One patient presented with cerebral contusion and paresis of the right upper extremity, and in one patient the posterior funiculus was involved. Three of the injuries had been sustained recently; the other two were of longer duration. Surgical treatment was chosen in the three cases of recent injury. In two cases surgery was prompted by neurological deficits; in the third case impaction was felt to be of inadequate depth. Surgery consisted in fracture reduction and interbody fusion using plates. The two cases of long-term fractures were treated conservatively, and ankylosis of the facet joints eventually provided adequate stability. If radicular or spinal symptoms are absent, this special variant of locked facet joints can successfully be treated conservatively leaving the rotary displacement uncorrected, provided impaction is adequately deep. The author's experience has shown that indications for surgical management are relative rather than absolute in this fracture variant and that use of computerized tomography is essential to establish the fracture pattern.

Adolescent↗
PubMed1995

Dapsone acetylation by human liver arylamine N-acetyltransferases and interaction with antiopportunistic infection drugs.

Dapsone is used in the treatment of Pneumocystis carinii pneumonia, an opportunistic infection that afflicts acquired immunodeficiency syndrome (AIDS) patients. Inhibition of N-acetyltransferase (NAT)-dependent acetylation of dapsone could increase peak plasma concentrations of dapsone and shift the biotransformation pathway to the P450-mediated formation of a toxic metabolite of dapsone, the hydroxylamine. Therefore, we have determined using human liver cytosol and bacterially expressed NATs, the NAT isoform responsible for acetylating dapsone and the potential for antiopportunistic infection drugs to inhibit this metabolic pathway. Formation of monoacetyldiaminodiphenylsulfone (MADDS) was quantitated by HPLC/UV detection at 270 nm after incubation of dapsone with 100 microM acetyl coenzyme A regenerating system and human liver cytosol. The mean +/- SD apparent KM for the formation of MADDS in three different human livers predicted to be fast acetylators based on genotyping was 98 +/- 17.6 microM, and the Vmax was 190 +/- 20 pmol/min/mg cytosol protein. Eadie-Hofstee transformation of the substrate velocity data was linear, indicating acetylation by a kinetically single enzyme. Sulfamethazine (250 microM) inhibited dapsone acetylation by 100% and 80%, respectively, at dapsone concentrations of 3 and 100 microM, in both fast- and slow-acetylating liver cytosol preparations, whereas para-amino-benzoic acid (100 microM) did not inhibit MADDS formation at either of these dapsone concentrations. Lineweaver-Burk plots of dapsone acetylation in the presence of 0, 25, and 50 microM sulfamethazine showed an increase in the apparent KM, with increase in sulfamethazine concentration with no change in the Vmax, indicating competitive inhibition of dapsone acetylation by sulfamethazine. The apparent KM of dapsone acetylation by bacterially expressed NAT1 and NAT2 enzymes was 687 and 136 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1995

Repair of complete acromioclavicular separations using the acromioclavicular-hook plate.

Complete Tossy III acromioclavicular separations in 21 male patients (according to the Rockwood classification: 7 Type III and 14 Type V lesions) with a mean age of 31 years were treated by surgical repair with the acromicroclavicular-hook plate within a period of 6 years. The population consisted of 18 patients with acute injuries and 3 with old injuries. Six patients experienced infections and delayed wound healing; osteitis did not occur. In 1 case, delayed wound healing was combined with dislocation of the hook. Bending of the implant occurred in another patient. Sixteen patients underwent clinical and radiographic followup at a mean of 38 months. Four patients who had no complications and free mobility of the shoulder joint at the end of treatment after removal of the implant did not appear for followup. One patient died of a malignant brain tumor. According to a modified evaluation system by Poigenfürst et al, clinical and radiographic findings showed 8 excellent, 7 good, and 1 poor result. A secondary widening of the hook hole in the acromion was seen in 13 patients; this was related to the large range of motion of the acromioclavicular joint. Calcifications and ossifications in the coracoclavicular ligaments, diastases in the acromioclavicular joint, and redislocations were not significantly different when this method was compared with other surgical techniques as reported in the literature. Use of the acromioclavicular-hook plate permits retention in the transverse plane without impairing the joint itself, but the technique is challenging.

Acromioclavicular Joint↗
PubMed1995

Metabolic polymorphisms and cancer susceptibility.

The vast majority of cancers arise as a consequence of exposure to environmental agents that are toxic or mutagenic. In response to this, all higher organisms have evolved complex mechanisms by which they can protect themselves from environmental challenge. In many cases, this involves an adaptive response in which the levels of expression of enzymes active in the metabolism and detoxification of the foreign chemical are induced. The best characterized of these enzyme systems are the cytochrome P450s, the GSTs and the NATs. An unfortunate consequence of many of these reactions, however, is the creation of a toxic or mutagenic reaction product from chemicals that require metabolic activation before realizing their full carcinogenic potential. Altered expression of one or more of these drug metabolizing enzymes can therefore be predicted to have profound toxicological consequences. Genetic polymorphisms with well defined associated phenotypes have now been characterized in P450, GST and NAT genes. Indeed, many of these polymorphisms have been associated with decreased or increased metabolism of many tumour promoters and chemical carcinogens and hence offer protection against or increased susceptibility to many distinct tumour types.

Animals↗
PubMed1994

Arylamine N-acetyltransferase in Balb/c mice: identification of a novel mouse isoenzyme by cloning and expression in vitro.

Three genes encoding arylamine N-acetyltransferase were identified in Balb/c mice. All three genes were cloned from genomic DNA, sequenced and expressed in a bacterial expression system. Two of the genes corresponded to Nat-1 and Nat-2 which have been previously identified in A/J and C57B1/6 strains of mice (Martell et al., 1991). The new gene, designated Nat-3, can be distinguished from the other mouse Nat genes both by specific amplification using PCR and by restriction-endonuclease digestion. The products of all three genes are demonstrated to catalyse acetylation of aminofluorene and anisidine following expression in Escherichia coli.

Acetylation↗