Linkage disequilibrium studies in multiple endocrine neoplasia type 1 (MEN1)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene has been localised to a 2-Mb region of chromosome 11q13 by meiotic mapping studies in MEN1 families. Such studies may have a limited resolution of approximately 1 cM (i.e. 1 Mb) and we have therefore investigated 96 MEN1 families (40 British, 17 French, 12 Finnish, 7 Swedish, 7 Dutch, 7 North American, 2 Australian, 1 New Zealand, 1 German, 1 Spanish and 1 Danish) for linkage disequilibrium, in order to facilitate a finer mapping resolution. We have utilised five microsatellite DNA sequence polymorphisms from the candidate region and have accurately determined their allele sizes, which ranged from 161 bp to 272 bp. The heterozygosity and number of alleles (given in brackets), respectively, at the loci were: D11S1883 (76%, 11), D11S457 (55%, 5), PYGM (94%, 18), D11S1783 (10%, 4) and D11S449 (87%, 16). Allelic association was assessed by Chi-square 2 ×n contingency tables, by Fisher exact 2 ×n contingency tables and by a likelihood-based approach. The results of haplotype analysis revealed 91 different affected haplotypes in the 96 families, an identical affected haplotype being observed in no more than two families. These results indicate the absence of an ancestral affected haplotype. Significant linkage disequilibrium (P < 0.005) could be established amongst the microsatellite loci but not between the loci and MEN1 in either the total population or in any of the geographical sub-populations. The absence of linkage disequilibrium between MEN1 and the polymorphic loci is probably the result of the occurrence of multiple different disease-causing mutations in MEN1. Received: 1 April 1997 / Accepted: 25 June 1997     

Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100.

Haplotype analysis was conducted on the mutant allele of 14 unrelated subjects heterozygous for a mutation in the codon for amino acid 3500 of human apolipoprotein B100. This mutation is associated with defective binding of low-density lipoprotein to the low-density lipoprotein receptor and with moderate hypercholesterolemia. Ten markers were used for haplotyping: eight diallelic markers within the structural gene and two hypervariable loci flanking the gene. Seven of eight unequivocally deduced haplotypes were identical, and one revealed only a minor difference at one of the hypervariable loci. The genotypes of the six other affected subjects were consistent with this same assigned haplotype. These data are consistent with a common ancestral chromosome and provide no evidence for a recurrent mutation at this potentially hypermutable CG dinucleotide, despite the fact that this mutation is not rare.     

Individuals Maintain Similar Rates of Protein Synthesis over Time on the Same Plane of Nutrition under Controlled Environmental Conditions

Consistent individual differences in animal performance drive individual fitness under variable environmental conditions and provide the framework through which natural selection can operate. Underlying this concept is the assumption that individuals will display consistent levels of performance in fitness-related traits and interest has focused on individual variation and broad sense repeatability in a range of behavioural and physiological traits. Despite playing a central role in maintenance and growth, and with considerable inter-individual variation documented, broad sense repeatability in rates of protein synthesis has not been assessed. In this study we show for the first time that juvenile flounder Platichthys flesus reared under controlled environmental conditions on the same plane of nutrition for 46 days maintain consistent whole-animal absolute rates of protein synthesis (A_s). By feeding meals containing ¹⁵N-labelled protein and using a stochastic end-point model, two non-terminal measures of protein synthesis were made 32 days apart (d₁₄ and d₄₆). A_s values (mass-corrected to a standard mass of 12 g) showed 2- to 3-fold variation between individuals on d₁₄ and d₄₆ but individuals showed similar A_s values on both days with a broad sense repeatability estimate of 0.684 indicating significant consistency in physiological performance under controlled experimental conditions. The use of non-terminal methodologies in studies of animal ecophysiology to make repeat measures of physiological performance enables known individuals to be tracked across changing conditions. Adopting this approach, repeat measures of protein synthesis under controlled conditions will allow individual ontogenetic changes in protein metabolism to be assessed to better understand the ageing process and to determine individual physiological adaptive capacity, and associated energetic costs of adaptation, to global environmental change.     

Taxonomic and serologic studies on Micropolyspora faeni and Micropolyspora strains from soil bearing the specific epithet rectivirgula.

The results of serological studies on six strains of Micropolyspora faeni from hay, sputum and plant debris, and five strains of Mip. rectivirgula from soil indicated no significant differences between the two species. Antisera raised in rabbits against purified antigens of the type strains were used to compare the 11 strains by immunoelectrophoresis. The detailed antigenic composition of the type strains was also determined by two-dimensional immunoelectrophoresis against specific rabbit antisera and pooled serum samples from patients suffering from farmer's lung. Cross-reacting antigens were identified by intermediate gel immunoelectrophoresis. The close similarity of the two species was confirmed by the results of 60 morphological physiological and biochemical tests applied to the 11 strains. We consider that the strains belong to a single species and propose that the specific epithet faeni be conserved for the taxon.     

Some blood parameters of the rainbow trout (Salmo gairdneri Richardson)

Fifty rainbow trout of the Kamloops strain were examined for 12 haematological parameters: erythrocyte sedimentation rate, haemoglobin, packed cell volume, erythrocyte count, erythrocyte diameters, mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration, leukocyte count, differential leukocyte count, plasma total protein and plasma glucose concentration. The fish had been held under known environmental and dietetic conditions, and at the time of sampling were 14 months old. The majority of results for erythrocyte sedimentation rate, haemoglobin, packed cell volume, erythrocyte count, erythrocyte diameters, total protein and differential leukocyte count fell within narrow ranges. The total leukocyte counts and glucose levels were more widely spread. The results are discussed and compared with those already published for Idaho and Shasta strains. It is impossible to say whether the differences that were observed between Kamloops and these other varieties were due to strain alone, since other variables were present. Some problems associated with establishing normal ranges for these parameters in fish are discussed.     

1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles: novel synthesis via cyclization of N-acyl-S-methylisothioureas with alkylhydrazines and their potent corticotropin-releasing factor-1 (CRF(1)) receptor antagonist activities.

Cyclizations of alkylhydrazines with N-acyl-S-methylisothioureas, readily synthesized from acyl chlorides, sodium thioisocyanate, dialkylamines then methyl iodide in a one-pot reaction, gave 1-alkyl-3-dialkylamino-5-phenyltriazoles 7 as major products. The regioisomers were assigned through the use of NOE NMR experiments. While bearing a N-bis(cyclopropyl)methyl-N-propylamino group, this series of compounds shows very good binding affinity on the human CRF₁ receptor. Among them, 1-methyl-3-[N-bis(cyclopropyl)methyl-N-propylamino]-5-(2,4-dichlorophenyl)-1H-[1,2,4]triazole 7a had the best binding affinity for the CRF₁ receptor (K_i=9 nM).     

Cytochemical localization of Na+-K+-ATPase in rat type II pneumocytes

The distribution of sodium-potassium-activated adenosinetriphosphatase (Na+-K+-ATPase) in the alveolar portion of rat lungs was examined by indirect immunofluorescence with the use of a mouse monoclonal anti-rat Na+-K+-ATPase and by ultrastructural cytochemistry using p-nitrophenylphosphate as substrate. The reaction was inhibitable by 10 mM ouabain or by the omission of K+ from the reaction mixture. Cysteine or levamisole was used to inhibit alkaline phosphatase activity. By immunofluorescence, staining was confined to cuboidal cells in alveolar spaces. These were tentatively identified as type II pneumocytes. By ultrastructural cytochemistry reaction product was present on the cytoplasmic side of the basolateral membranes of type II pneumocytes. No reaction product was observed in type I pneumocytes or in endothelium. These results indicate that type II pneumocytes contain more Na+-K+-ATPase, an enzyme important in vectorial electrolyte transport, than type I pneumocytes or endothelial cells. More sensitive methods, however, are required to determine the amounts and distribution of this enzyme in type I pneumocytes and pulmonary vascular endothelial cells.     

Three-dimensional computer-assisted design of craniofacial surgical procedures: optimization and interaction with cephalometric and CT-based models

A computer program is described which aids the clinician in planning craniofacial surgical procedures. It operates on a three-dimensional landmark data base derived by combining posteroanterior and lateral cephalograms from the patient and from the Bolton normative standards. A three-dimensional surgical simulation program based on computerized tomographic (CT) data is also described which can be linked to the cephalometrically based program. After the clinician has selected the number and type of osteotomies to be performed on the patient, an automated optimization program computes the postoperative positions of these fragments which best fit the appropriate normal cephalometric form. The clinician then interactively modifies the design to account for such variables as bone-graft resorption, relapse tendency, occlusal disparities, and the condition of the overlying soft-tissue matrix. Osteotomy movement specifications are easily transferred between the CT-based and the cephalometrically based surgical simulation programs. This allows the automated positioning step to be performed on the cephalometrically based model while the interactive step is performed using the superior image provided by the CT-based model.     

A study of gustatory and olfactory function in patients with craniofacial anomalies.

Olfactory and gustatory function can be reiably studied in patients with craniofacial anomalies over the age of 7 years. In our unoperated patients with orbital hypertelorism or craniofacial dysostosis, preoperative evaluation of the olfactory and gustatory functions showed normal values. The same techniques were employed to study any changes in these modalities following reconstructive craniofacial surgery, and the results are presented.