Reproductive toxicity studies with oxybutynin hydrochloride

Oxybutynin hydrochloride, an anti-cholinergic/anti-spasmodic agent, was examined for its effect on fertility and peri-post natal development in the rat and its embryotoxic potential in the rat and rabbit. In the rat effects on reproductive performance included a slight increase in the incidence of foetal malformations, extended gestation period and impaired post natal performance of offspring. These findings occurred at dosages clearly associated with maternal toxicity. Oxybutynin hydrochloride did not exert an effect on reproductive processes in the rat at lower dosages or on embryonic and foetal development in the rabbit.     

Multiattribute utility assessment of outcomes of treatment for head and neck cancer.

Good clinical practice is dependent on continuous audit. Most audits of head and neck cancer treatment planning have been subjective, with only 5-year survival rates being considered objectively. Improvements in clinical care require not only measurable goals that relate to patients'' perspectives, but also a means of assessing to what extent those goals have been met. In this context, 5-year survival rates are too crude to be useful, although they remain important for other reasons. Because a simple clinical objective measure of outcome applicable to head and neck cancer is not available, multiattribute assessment techniques were used to develop a clinically based scale for outcomes following treatment for head and neck cancer, with domains centred on social function, pain, physical appearance, eating and speech problems, nausea, donor site problems and shoulder function. Domains were weighted relative to each other; pain (mean weight 85) and social function (89) were considered most important followed by physical appearance (76), eating (76) and speech problems (74) A series of graded statements was constructed within each domain and scaled relative to each other. These components were also combined into an overall scale that will enable objective outcome assessment in this important area of medical care.     

Brevetoxins bind to multiple classes of sites in rat brain synaptosomes.

The brevetoxins (PbTx series), neurotoxins produced by the marine dinoflagellate Ptychodiscus brevis, cause dose-dependent activation of the voltage-sensitive sodium channel (VSSC). Saturation binding studies employing adult rat brain synaptosomes suggest the existence of a high affinity/low capacity (HA/LC) and a second, lower affinity/higher capacity (LA/HC) class of binding site. LIGAND analysis of saxitoxin and brevetoxin saturation binding data yields a statistically identical Bmax for the brevetoxin high affinity/low capacity (HA/LC) site (1.9 +/- 0.98 pmol/mg protein) and for saxitoxin (1.72 +/- 0.78 pmol/mg protein; P less than 0.001). The stoichiometry of HA/LC brevetoxin binding and saxitoxin binding approaches 1:1. Covalent modification of synaptosomes with a brevetoxin photoaffinity probe preferentially blocks the HA/LC binding site. Hill plots of saturation binding data yield a coefficient of 1.0 +/- 0.02, demonstrating a lack of cooperativity between brevetoxin binding site classes. Kd and Bmax for toxin binding are independent of membrane polarity, intimating that the observed low affinity/high capacity (LA/HC) binding characteristics are not due to modification of the HA/LC site, and strongly argue for the presence of multiple brevetoxin binding site classes. Half-maximal binding at the LA/HC site, and strongly argue for the presence of multiple brevetoxin binding site classes. Half-maximal binding at the LA/HC site occurs at concentration ranges for which the brevetoxins allosterically modulate binding of other natural toxins to their specific sites.     

The relationship between genetic and physical distances in the cloned a1-sh2 interval of the Zea mays L. genome.

A 470-kb segment from the long arm of chromosome 3 of Zea mays (inbred LH82), encompassing the a1-sh2 interval, was cloned as a yeast artificial chromosome. Comparison of the sizes of the restriction fragments generated from the cloned DNA fragment and from the DNA isolated from the maize inbred line LH82 established the colinearity of the a1-sh2 interval in these DNAs. By utilizing a chromosome fragmentation technique, a yeast artificial chromosome encompassing the a1-sh2 interval was separately fragmented at the a1 and sh2 loci. Comparison of the sizes of these fragmentation products established the physical distance between the a1 and sh2 loci to be 140 kb. Furthermore, these fragmentation experiments established the physical orientation of the a1 and sh2 genes relative to the maize centromere. The molecular cloning of the contiguous region between the a1 and sh2 loci made it possible to define the relationship between physical and genetic distances over a relatively large segment of the maize genome. In this interval, the relationship between physical and genetic distances is 1560 kb/centimorgan, which compares with 1460 kb/centimorgan for the entire maize genome, and 217 kb/centimorgan for a 1-kb segment within the a1 locus. Therefore, these findings are consistent with the hypothesis that genes per se are preferred sites for meiotic recombination rather than the hypothesis that genes reside in large recombinationally active segments of the genome.     

Recombinations defining centromeric and telomeric borders for the hereditary haemochromatosis locus.

Hereditary haemochromatosis (HFE) is a common inherited disorder, affecting approximately five per thousand white people of northern European descent. Genetic linkage and linkage disequilibrium studies indicate that the disease locus is tightly linked to HLA-A and D6S105. Recombination between HFE and HLA class I loci is known to be rare. We report here two pedigrees in which recombinations telomeric of HLA-A occurred. These recombinant events define new centromeric and telomeric borders for the HFE locus.     

Electrocardiographic findings in children with Lyme disease.

The incidence of cardiac involvement in Lyme disease (LD) has been estimated to be 4 to 10% in adults, with conduction and rhythm disturbances noted most frequently. To assess the frequency of electrocardiographic abnormalities in children with LD, we prospectively performed 12-lead electrocardiograms in 32 randomly selected children presenting with LD between May and September 1989. No patient had symptoms of cardiac involvement. Using defined diagnostic criteria, combining symptoms, signs, serology, and residence in or travel to an endemic area, 14 patients were classified as having definite LD and 10 were categorized as probable. The incidence of electrocardiographic abnormalities in the definite group was 29% (4/14), including two patients with 1 degree atrioventricular block, one with left axis deviation, and one with ventricular ectopy. Thirty percent (3/10) of the probable group had abnormal ECGs, including one with ST-T wave abnormalities, one with prominent sinus arrhythmia, sinus bradycardia, and wandering atrial pacemaker, and one with ectopic atrial bradycardia. No patient required cardiac therapy. The incidence of abnormal ECG findings in this group of children with either probable or definite LD was thus 29%, with 1 degree atrioventricular block noted most frequently. When the diagnosis of LD is highly suspected, an electrocardiogram may be a useful screening test for cardiac involvement.     

Oxygen consumption following trauma: a reappraisal in severely injured patients requiring mechanical ventilation

Oxygen consumption (VO2) immediately following major injury in man has been said to be reduced. The evidence for this is poor. We have therefore measured VO2 soon after major injury in 16 patients. VO2 was reduced in only two patients, within the normal range in four and increased in ten. VO2 was maintained by increased oxygen extraction in six patients leading to low levels of mixed venous oxygen saturation. There is no evidence for an 'ebb phase' response in man.