David F. Hardwick

Pathogenesis of methionine-induced toxicity☆

Abstract L-methionine 10 mMole/Kg. per day administered orally to guinea pigs leads to a state characterized early by fatty liver, hypoglycemia and aminoacidemia and later by hypothermia, profound hypoglycemia and death within 60 hours. Paralleling the development of this state is a progressive fall in hepatic ATP probably caused by binding of available hepatic ATP to methionine, thus forming increasing and substantial amounts of hepatocellular S-adenosylmethionine and S-adenosylhomocysteine. In support of the concept that the biochemical changes induced by methionine intoxication are mediated through an hepatic ATP insufficiency is the finding that adenine, administered to intoxicated animals completely reverses the hypoglycemic effects of methionine. The possibility that a similar mechanism of intoxication occurs in human methionine ingestion and hypermethioninemic states is discussed.

Cystathioninuria in Two Healthy Siblings

Abstract Tests in two siblings with cystathioninuria indicated that the disorder is congenital and not secondary. Yet both children enjoy good physical and mental health. Their parents excrete subs...

Creatinine excretion in children and the usefulness of creatinine equivalents in amino acid chromatography

Abstract The daily output of urinary creatinine and α-amino nitrogen was estimated using samples from 228 children aged between one month and five years. The data demonstrate the marked variability from child to child in the output of both of these substances. The data also indicate deficiencies in the practice of using creatinine equivalents as a basis for quantitative examination of urinary amino acids in children.

Sodium Tolerance in Experimental Hypertension

A sodium tolerance test was applied to rats subjected to three diverse procedures for the production of experimental renal and hormonal hypertension. Sodium tolerance was impaired in all three types of hypertension to the extent that an accelerated excretion of the imposed sodium load occurred, although there was no change in the plasma sodium level. The disturbance was proportional to the height of the blood pressure but occurred even in those treated rats which remained normotensive.

Clinical laboratory—Past, present, and future: An opinion*

In this review we have tried to identify some of the management issues affecting laboratories in the past, present, and future. In particular, we have focused on the increases in utilization and cost and have attempted to demonstrate some of the factors affecting the supply and demand sides of these issues. In the absence of a price mechanism to allocate resources, alternative strategies to evaluate and regulate laboratory use were discussed. Although promise is held out by some of these approaches, they are not, in our view, fully workable at this stage. We suggest that, in the interim, sound medical direction and management of the laboratory as a production function can be of benefit in inhibiting, if not actually controlling, cost increases. In particular, we recommend concentration on the management of technology because of its crucial role in laboratory costs and utilization. Emerging trends in clinical laboratory and monitoring technologies suggest that issues relating to decentralization, quality control, and funding will have to be addressed in the near future. The prime motivation for clinical laboratory use, i.e., the generation of answers to clinical questions, seems destined to continue and expand. The challenge for practitioners, researchers, and policy-makers is to harness, evaluate, and manage the technologies that can best contribute to both medical practice and health.

Clinical laboratory management: a critical evaluation.

The clinical laboratory is described as a system with an enquiry component or demand side, where control of test utilization is the mandate of the clinical physician or surgeon, and a production component or supply side, where answers to clinical questions are generated and control of test data production is the mandate of the laboratory physician. Supply side unit costs are maintained by increased production effectiveness brought about by the judicious manipulation of supply costs; labor costs; and capital expenditures for automated equipment, robots, and information technologies. The pathologists prime role as controller of the supply side is outlined, as are the clinical physicians prime role and pathologists subsidiary role in control of test use on the demand side.

The Effect of Pitressin on Sodium Tolerance in Experimental Hypertension

Rats subjected to diverse hypertension-inducing procedures develop an abnormal sodium tolerance characterized by an accelerated rate of excretion of an administered load. Pitressin reverses this abnormality in sodium tolerance during the period corresponding to the delayed depressor phase of the response to the extract.

On being a pathologist-a logic for life.

Pathology has encouraged, stimulated, permitted, enabled, and provided me with a conceptual basis for understanding numerous ideas and opportunities that I have encountered in life. At the age of 16 years, as a student at the University of British Columbia (UBC), I first encountered the study of interrelationships of institutions offered by a brilliant sociologist in his last years of teaching, Prof C. W. Topping. His elaboration of the interaction of institutions closely paralleled my next academic insights, the Medical School Pathology course with Prof William Boyd and Harold Taylor. Understanding process, including the importance of prior conditions such as drinking water contaminated by bacteria or inhaling carcinogens on the ensuing pathogenetic process, was a wonderful experience. Then followed the revelation that virtually all medical practitioners implemented tactical interventions dependent on the pathogenetic stages of disease. The parallel with social/political situations requiring clarification of process and use of tactical interventions was immediately obvious to me. As I proceeded to residency training, the Dean at UBC, Dr Jack McCreary, a senior pediatrician, invited me to study pediatrics, which I did for a year but then returned to pathology the following years, first to study pediatric pathology at the Childrens Hospital in Los Angeles and, later, general pathology in Vancouver. When I finished my residency training, I wrote and passed the Canadian and American specialty examinations and began the practice of pediatric pathology and teaching undergraduate medical school students. I had to administer the hospital division of pediatric pathology, perform neonatal and pediatric autopsies, review surgicals, oversee the pediatric clinical