Common variants in mismatch repair genes and risk of colorectal cancer.

BACKGROUND AND AIMS: The mismatch repair (MMR) genes are in charge of maintaining genomic integrity. Mutations in the MMR genes are at the origin of a familial form of colorectal cancer (CRC). This syndrome accounts for only a small proportion of the excess familial risk of CRC. The characteristics of the alleles that account for the remainder of cases are unknown. To assess the putative associations between common variants in MMR genes and CRC, we performed a genetic case-control study using a single-nucleotide polymorphism (SNP) tagging approach. PATIENTS AND METHODS: A total of 2299 cases and 2284 unrelated controls were genotyped for 68 tagging SNPs in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were measured in cases and controls and analysed using univariate analysis. Haplotypes were constructed and analysed using logistic regression. We also carried out a two-locus interaction analysis and a global test analysis. RESULTS: Genotype frequencies were found to be marginally different in cases and controls for MSH3 rs26279 with a rare homozygote OR = 1.31 [95% confidence interval (CI) 1.05 to 1.62], p(trend) = 0.04. We found a rare MLH1 (frequency <5%) haplotype, increasing the risk of colorectal cancer: (OR = 9.76; 95% CI, 1.25 to 76.29; p = 0.03). The two-locus interaction analysis has exhibited signs of interaction between SNPs located in genes MSH6 and MSH2. Global testing has showed no evidence of interaction. CONCLUSION: It is unlikely that common variants in MMR genes contribute significantly to colorectal cancer.

Using wire shaping techniques and holographic optics to optimize deposition characteristics in wire-based laser cladding.

In laser cladding, the potential benefits of wire feeding are considerable. Typical problems with the use of powder, such as gas entrapment, sub-100% material density and low deposition rate are all avoided with the use of wire. However, the use of a powder-based source material is the industry standard, with wire-based deposition generally regarded as an academic curiosity. This is because, although wire-based methods have been shown to be capable of superior quality results, the wire-based process is more difficult to control. In this work, the potential for wire shaping techniques, combined with existing holographic optical element knowledge, is investigated in order to further improve the processing characteristics. Experiments with pre-placed wire showed the ability of shaped wire to provide uniformity of wire melting compared with standard round wire, giving reduced power density requirements and superior control of clad track dilution. When feeding with flat wire, the resulting clad tracks showed a greater level of quality consistency and became less sensitive to alterations in processing conditions. In addition, a 22% increase in deposition rate was achieved. Stacking of multiple layers demonstrated the ability to create fully dense, three-dimensional structures, with directional metallurgical grain growth and uniform chemical structure.

The role of light in measuring ocular biomechanics.

The cornea is a highly specialised tissue with a unique set of biomechanical properties determined by its complex structure. The maintenance of these mechanical properties is fundamental to maintain clear vision as the cornea provides the majority of the focussing power of the eye. Changes to the biomechanics of the cornea can occur during ageing, disease, and trauma, or as a result of surgery. Recently there has been increased interest in the mechanical properties of the cornea as knowledge of these properties has significant implications for the improvement of current ocular treatments including PRK and LASIK, and for the diagnosis and tracking of corneal diseases and therapy such as keratoconus and crosslinking. Biomechanics are also important for the development of artificial corneal replacements. This paper describes the use of a novel, non-destructive lateral electronic speckle pattern shearing interferometer (ESPSI). The data generated via this technique give a full-field view of the mechanical response of the cornea under simulated physiological loading conditions, and enables strain and displacement to be determined in three planes. The technique allows corneal stiffness to be quantified and enables changes and non-homogeneities that occur due to surgery or disease to be detected.

Plasma protein binding of carbamazepine.

The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.

Plasma anticonvulsant concentrations during pregnancy.

Plasma anticonvulsant levels were followed during pregnancy in 11 epileptic women taking phenytoin and/or phenobarbital or a drug metabolized in the body to phenobarbital. As judged from the relationship between plasma level and drug dose, phenytoin requirement increased in all 10 women taking this drug during pregnancy. The requirement fell again in the puerperium. Plasma phenobarbital levels decreased during pregnancy in all five women taking a constant daily dose of phenobarbital or a congener. These findings should be borne in mind if epileptics are to be protected against seizures during pregnancy and against anticonvulsant overdosage during the puerperium.

Plasma drug level monitoring in pregnancy.

During pregnancy a number of continuously changing circumstances exist which might be expected to modify the relation between plasma drug levels and drug dosage. Alimentary tract motility may be decreased, the distribution of many drugs may be altered, glomerular filtration rate is greater and biotransformation capacity may be changed as pregnancy advances. However, relatively little has been published on the monitoring of plasma drug levels during pregnancy. It has been established that, in the presence of constant drug doses, plasma levels of phenytoin, phenobarbitone and certain other anticonvulsants tend to fall during pregnancy and rise again during the puerperium. Plasma lithium and possibly digoxin levels also fall relative to drug dose as pregnancy progress, and rise again in the puerperium. While the changes in lithium and digoxin levels are probably chiefly due to increased rate of glomerular filtration during pregnancy, the altered anticonvulsant requirement is more likely to depend mainly on an increased rate of biotransformation. Anticonvulsant plasma levels should be monitored regularly from the outset of pregnancy and more frequently after birth.

Factors influencing plasma concentrations of ethosuximide.

The relation between steady-state plasma ethosuximide level and drug dose was studied in 46 patients. In this population, plasma drug levels were proportional to drug dose, expressed on a body weight basis. Age did not alter this relationship, but plasma levels increased more rapidly, relative to dose, in females than in males. Intake of methylphenobarbitone, but not intake of certain other anticonvulsants (phenytoin, phenobarbitone, primidone and carbamazepine) altered the relationship between plasma ethosuximide level and ethosuximide dose. In individual patients, successive dose increments of equal size produced progressively greater increases in steady-state plasma ethosuximide levels. This phenomenon has obvious therapeutic implications.

Hereditary motor peripheral neuropathy predominantly affecting the arms.

A kinship is described in which there was slowly progressive wasting and weakness of the muscles of the upper and occasionally of the lower limbs. Some members had hyperreflexia. There were no sensory abnormalities. Electrophysiological study suggested the presence of motor peripheral polyneuropathy. The condition appeared to be inherited as an autosomal dominant. The disorder does not appear typical of any of the known hereditary polyneuropathies and it is possible that it may represent a unique hereditary, dominantly motor, polyneuropathy. The significance of the hyperreflexia is uncertain, but raises the possibility of minor central involvement as well as peripheral neuropathy.

Quantitative oxidative enzyme histochemistry of the spinal cord. Part 2. Relation of cell size and enzyme activity to vulnerability to ischaemia.

Cytophotometric measurements of the activities of 5 enzymes (succinate, malate, and NAD+-linked isocitrate dehydrogenases from the tricarboxylic cycle, lactate dehydrogenase from the Embden-Meyerhof pathway, and NADH dehydrogenase) were correlated with cell volume for neurones in the anterior horn of rabbit lumbar and cervical spinal cord. The data for succinate and isocitrate dehydrogenases indicated that these enzymes were at higher concentrations in the smaller neurones, which consist largely of interneurones. No preferential localization to particular sizes of cell could be assigned to the other enzymes studied. The relationship between enzyme distribution patterns and their possible role in contributing toward susceptibility to ischaemia of particular sizes of neurones is discussed.

Quantitative oxidative enzyme histochemistry of the spinal cord. Part 1. Distribution of enzyme activity in anterior horn cells.

Cytophotometric measurements of the activities of 5 oxidative enzymes (succinate, malate, lactate, NAD+-linked isocitrate and NADH dehydrogensases) have been made in anterior horn cells of the lumbar and cervical spinal cord of the rabbit. The thickness of tissue sections was measured by an interference microscope and various optical and chemical precautions were taken to diminish the possible errors that might be involved in cytophotometry. The findings of the study indicated a unimodal distribution of the activities of all of the enzymes studied in anterior horn cells, though there was a wide range of enzyme concentration among different cells. Thus the findings in the rabbit are consistent with the "constant proportion" hypothesis of the activity of certain oxidative enzymes, and are contrary to a previous finding that there may be two populations of succinate dehydrogenase-containing anterior horn cell.

Smallholder dairy farming in the Chikwaka communal land, Zimbabwe: birth, death and demographic trends.

A study of mortality, morbidity and productivity of cattle on smallholder dairy farms was conducted in Chikwaka communal land, Zimbabwe. We estimated the frequency and determinants of mortality in DDP cattle and explored demographic trends. Using Cox proportional-hazards modelling (with the farm as a random effect), the animal-level variables associated with mortality were age, sex and breed. Calf mortality was 35% of calves within the first year of life. This was nearly five-times higher than adult mortality (relative risk (RR) 4.73, 95% CI 2.12, 10.6). Females had lower mortality than males (RR=0.25, 95% CI 0.11, 0.56). After adjusting for the confounding effects of age, Jersey breeding was associated with higher mortality (RR=2.89, 95% CI 1.16, 7.22) whereas Red Dane breeding was associated with lower mortality (RR=0.27, 95% CI 0.11, 0.69). Farms with a higher ratio of non-DDP:DDP cattle had higher mortality in their DDP cattle. Leslie-matrix models simulated population growth and showed that (at the current levels of mortality and fertility) the population would double in approximately 10 years.

Interactions between genes involved in the antioxidant defence system and breast cancer risk.

The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene-gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant.