SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia.

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

Biotransformation of beta-ketosulfides to produce chiral beta-hydroxysulfoxides.

The biotransformations of a series of substituted phenylthio-2-propanone and benzylthio-2-propanone were carried out using Helminthosporium sp. NRRL 4671, Mortierella isabellina ATCC 42613, or Rhodococcus erythropolis IGTS8. Several products gave microbial oxidation of sulfide to sulfoxide and reduction of carbonyl to secondary alcohol, producing beta-hydroxysulfoxides in medium to high enantiomeric and diastereomeric purities. Fungal biotransformations using Helminthosporium sp. and M. isabellina resulted in the opposite sulfoxide configurations of various beta-hydroxysulfoxide products.

Oxynitrilases for asymmetric C-C bond formation.

Oxynitrilases for the preparation of (R)- or (S)-cyanohydrins are now readily available. The research efforts of a number of groups have established these enzymes as catalysts with significant potential for application to asymmetric synthesis. Advances made in molecular cloning and genetics have delivered information on the oxynitrilase mechanism of action and sufficient quantities of enzyme to satisfy industrial requirements.

Immobilized horse liver alcohol dehydrogenase as an on-line high-performance liquid chromatographic enzyme reactor for stereoselective synthesis.

Horse liver alcohol dehydrogenase (HLADH) has been non-covalently immobilized on an immobilized artificial membrane (IAM) high-performance liquid chromatography (HPLC) stationary phase. The resulting IAM-HLADH retained the reductive activity of native HLADH as well as the enzyme's enantioselectivity and enantiospecificity. HLADH was also immobilized in an IAM HPLC stationary phase prepacked in a 13 x 4.1 mm ID column to create an immobilized enzyme reactor (HLADH-IMER). The reactor was connected through a switching valve to a column containing a chiral stationary phase (CSP) based upon p-methylphenylcarbamate derivatized cellulose (Chiralcel OJR-CSP). The results from the combined HLADH-IMER/CSP and chromatographic system demonstrate that the enzyme retained its activity and stereoselectivity after immobilization in the column and that the substrate and products from the enzymatic reduction could be transferred to a second column for analytical or preparative separation. The combined HLADH-IMER/CSP system is a prototype for the preparative on-line use of cofactor-dependent enzymes in large-scale chiral syntheses.

An administrative perspective on emergency medicine.

Administrators expect that their emergency room will meet the expectations of all the patients they serve. To do so requires leadership, planning, and cooperation. To not do so is a contradiction of the term emergency, and a misrepresentation of purpose, intent, and capability.

Lengthening of an above-knee amputation by transposition of the ipsilateral tibia.

In a case of above-knee amputation, the transposition of the ipsilateral tibia, in order to preserve sufficient length to facilitate fitting of an artificial limb, is described. Satisfactory vascular supply and lack of neurovascular injury are noted.