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PubMed1999

What is wrong with aluminium? The J.D. Birchall Memorial Lecture.

Aluminium chemistry has features in common with two other groups of elements: (1) divalent magnesium and calcium, and (2) trivalent chromium and iron. The essential differences between the first group and aluminium are explored and it is shown that the much higher acidity of aluminium makes it such a powerful competitor for oxygen-donor ligands, opposite functions of both magnesium and calcium, in cells that its presence is damaging. By way of contrast aluminium is a weaker acid than ferric ions but it is more available. It was necessary for iron to be utilised in the presence of aluminium so special methods had to be devised to distinguish between them. In essence aluminium has always, throughout evolution, been a threat to the biological chemistry of all these three elements. We shall examine this chemistry and then explore the relationship of calcium and aluminium under acid rain conditions.

Aluminum↗
PubMed1996

The TiPS/TINS Lecture. Catecholamines: from gene regulation to neuropsychiatric disorders.

In addition to their ability to change the electrical properties of neurons, evidence suggests that neurotransmitters are able to alter the cell's metabolism. Transmitter phenotype is labile and expression might be regulated, during development, by the cellular environment of neurons. The study of a key enzyme in the synthesis of catecholamines, tyrosine hydroxylase (TH), has provided clues about these adaptive responses. This enzyme has a large molecular diversity, resulting from the differential splicing of its mRNA, which is tissue-specific and might result in long-term changes in activity of the enzyme and, therefore, in the availability of neurotransmitter at various synapses. The presence of different DNA sequences at the TH locus confers susceptibility to various disorders of the brain, including manic-depressive illness and schizophrenia. Indeed, an association between a rare variant allele of the gene encoding TH and the occurrence of schizophrenia has been found in several populations. New techniques being developed to treat diseases such as Parkinson's disease involve various gene therapies, including a method of transferring genes directly into nerve cells using an adenovirus-based system.

Animals↗
PubMed1999

The TINS Lecture. Understanding the roles of Otx1 and Otx2 in the control of brain morphogenesis.

The murine homologs of the orthodenticle (otd) gene of Drosophila, Otx1 and Otx2, have an important role in brain morphogenesis. Analysis of Otx1 and Otx2 null mice reveals that Otx1 is required primarily for corticogenesis and sense-organ development,while Otx2 is necessary for specification and maintenance of anterior neural plate as well as for proper gastrulation. Cross-phylum recoveries of Otx1 abnormalities by Drosophila otd, and vice versa, indicate that genetic functions required in mammalian-brain development evolved in a primitive ancestor of flies and mice. Knock-in mouse models in which Otx2 was replaced with Otx1, and vice versa, provide evidence that the existence of Otx1-/- and Otx2-/- divergent phenotypes largely reflects differences in expression patterns rather than in the biochemical activity of OTX1 and OTX2. In evolutionary terms, some of these findings lead us to hypothesize a fascinating and crucial role for Otx genes that contributes to the genetic program required for the specification of the development of the vertebrate head.

Animals↗
PubMed2001

Curie medal lecture 2000. The optimization of delivered dose in radiotherapy: is it related to low dose rate?

From the beginning of the 20th century with Pierre and Marie Curie, it was found that the preparation of radium into needles and tubes results in a continuous low dose rate radiation in which the total time to give an optimal dose of 60 Gy is reduced to 5 or 6 days. Clinical results quickly followed, showing that tumour sterilization was better ensured by low dose rate radiation over several days than by fractionated high dose rate radiation over several weeks. In the light of my experience of very good results with modern 192 Ir endocurietherapy at an optimal dose rate of 0.6 Gy per h for very bulky tumours, I finally became convinced of the need to study low dose rate in teletherapy using telecobalt with low activity sources (1 Gy per h to achieve long duration sessions of 7-8 h per day over a short total duration of 5 or 7 days).I started in January 1970, at the Institut Gustave Roussy and, after my appointment, at the Henri Mondor Hospital in Creteil, a variety of cancer sites were treated but mostly advanced head and neck cancers. Finally I decided to do a trial of classical fractionated high dose rate radiation vs. subcontinuous low dose rate radiation of advanced breast cancers (T3). The results at 3 months were conclusive: 20% of the cancers treated by 45 Gy fractionated irradiation at high dose rate were sterilized while the proportion sterilized at low dose rate was 70% whether the patients received 45 or 35 Gy. This work opened the way to further study but my retirement loomed and I was not able to pursue it.

Breast Neoplasms↗
PubMed2002

ESTRO Breur Gold Medal Award Lecture 2001: irradiation accidents-- lessons for oncology?

Considering the number of radioactive sources in use all over the world (both in industry and medicine) irradiation accidents are exceedingly rare, as demonstrated by the main databases registering such cases: UNSCEAR, IAEA, REAC/TS (Oak Ridge, USA), the German group in Ulm and the Paris Institut Curie. The precise causes of most accidents have been openly analyzed, allowing to reduce the risk of subsequent identical accidental exposures. In addition, a rapid retrospective overview shows that positive lessons could be drawn from such accidents: 1)Lessons for patient management: one should keep in mind that the first ever allogeneic bone marrow transplantations were performed in 1958, on scientists from Yugoslavia who had been severely irradiated in a nuclear Research laboratory. Apart from what was learned from such accidents for the management of severe aplasia, the treatment of superficial accidental exposures has also benefited radiotherapy patients in certain specific situations. 2) Lessons for technology: the efforts to improve safety in nuclear plants are well known; the (successful) efforts to reduce the once-elevated risks when changing the therapeutic Cobalt 60 sources are less well known. Today, most irradiation accidents (by far) are related to misuse or loss of radioactive sources from industrial radiography sets. However, here again, various technological improvements significantly reduced the risks. 3) Lessons for radiobiology: the need for more and more sophisticated biological dosimetry has led to studies allowing better understanding of the short- and long-term effects of radiation on human cells. Analyses of samples taken in areas which were heavily accidentally irradiated also helped to identify, in particular, the cardinal role of TGF beta and TNF alpha in the development of fibrosis and necrosis after irradiation. 4) Lessons for prevention of accidents in radiotherapy: only three large-scale accidents involving external radiotherapy have been registered in the last decade, but deciphering the cause(s) of such problems clearly participated in the setting of demanding Quality Assurance programmes and strict national and international recommendations. Such open circulation of the information about these (fortunately rare) accidents appears to be one of the ways to improve Quality Assurance in Radiotherapy.

Humans↗
PubMed2000

[Cardiovascular trials in diabetes: past and present. Invited lecture of the XXXVth National Congress of the Spanish Society of Cardiology].

The risk of coronary heart disease in subjects with Type2 diabetes is 2-4 times higher than in non-diabetic subjects of the same age. About 20% of patients with clinically established coronary heart disease have diabetes and the prognosis is much worse in diabetic than in non-diabetic patients. Trial evidence suggests that good blood glucose control reduces the risk of myocardial infarction in diabetic patients and improves prognosis after it. Trial evidence indicates that the benefit from antihypertensive treatment is at least as good in diabetic than in non-diabetic patients, and that diabetic patients with coronary heart disease or other form of atherosclerotic vascular disease should be treated with lipid-lowering drugs (usually with statins), if their LDL cholesterol levels on diet remain> 3.0 mmol/l (115 mg/dl). Trial evidence supports the use of aspirin in middle-aged or elderly diabetic patients. All diabetic patients should be advised to stop smoking.

Animals↗
PubMed2001

From translational research to improved local control and survival: the Gilbert Fletcher Award Lecture, Lugano, March 2000.

Recent clinical trials have shown us that it is possible to improve local control and survival by the concomitant use of radiotherapy and chemotherapy in a large variety of solid tumors, such as head and neck, lung, cervical, and anal cancer. The selection of drugs for this combined treatment, however, has been based on a rather empiric approach. Further research combining the clinical and laboratory expertise now offers the possibility of predicting and improving treatment efficacy for radiotherapy and systemic treatment, given alone or in combination. New methods, such as chromosome and gene expression profiling of individual tumors, are now becoming available with the comparative genomic hybridization assay and microchip DNA arrays. These assays will hopefully be of help in selecting patients for their optimal treatment regimen in the near future. Detailed knowledge of the mechanisms of action of these two treatment modalities will also lead to the development of new and more effective drugs, to be used concomitantly. It is the challenge of translational research to implement its opportunities into daily clinical practice. In analogy to the results obtained with concomitant radiotherapy and chemotherapy, this will lead to improved local control and survival rates in cancer patients.

Antineoplastic Agents, Hormonal↗
PubMed2002

The Gerhard Zbinden memorial lecture: application of biochemical and genetic approaches to understanding pathways of chemical toxicity.

All cells have evolved a complex number of pathways, which allow them to survive in a chemically hostile environment. In multicellular organisms, these pathways are catalysed by a number of key enzymes, which inhibit the absorption of toxins or facilitate their elimination so that they do not accumulate to toxic levels within the cell. These cytoprotective pathways are also critical determinants of the effectiveness of drug therapy and are thought to have evolved from a limited number of biochemical pathways, such as those which allow cells to utilise molecular oxygen in respiration without suffering deleterious effects. The study of both simple and multicellular organisms has shown that many stress response pathways previously considered as distinct adaptive mechanisms in mammalian systems are interrelated coordinated responses to toxic challenge. Understanding the functions and mechanisms of regulation of the genes involved in these pathways has many applications in medical science-in evaluating the role of environmental factors in the pathogenesis of human disease, in chemoprevention, in drug development and in the application of drug therapy. The use of genetic approaches, coupled with new chip-based profiling technologies, will play a key role in the development of studies in this research area.

Adaptation, Physiological↗
PubMed2000

The Gerhard Zbinden memorial lecture. Are environmental chemicals affecting the integrity or expression of the human genome?

Toxicology is entering a new phase wherein powerful model systems will become available to predict toxicity and to study mechanisms of action. For these new techniques to achieve their potential it will be necessary for toxicologists to pose precise questions, and to design experiments to answer those questions unequivocally. These needs are illustrated by recent examples from the study of endocrine disruption in mammals and the validation of accelerated (transgenic) rodent cancer bioassays.

Animals↗
PubMed1997

Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996.

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.

Animals↗
PubMedDate not supplied

David R. Boyd Lecture in Trauma Care and Emergency Medical Systems: upper extremity injuries--past, present, and future.

Since its recognition as a subspeciality soon after World War I, hand surgery has evolved into a highly specialized and sophisticated field of medicine. Enormous advances have been made in the diagnosis and treatment of disorders of the upper limb; primary tenorrhaphy and the application of microsurgical techniques for revascularization, replantation, and free tissue transfer are among the most important innovations. This article reviews the history of flexor tendon surgery and reconstructive microsurgery up to the present time, and makes some predictions for the future direction of these, and other, areas of hand surgery.

Forecasting↗
PubMedDate not supplied

David R. Boyd lecture in trauma care and emergency medical systems: "The surgical complications of toxins.".

Toxins have had major roles in our societies for thousands of years. Interactions between surgeons, both generalists and subspecialists, and those caring for poisoned patients have been extensive throughout history. The advancement of the science of toxicology, the development of regional poison control centers, the development of emergency medicine, and the development of the subspecialty of medical toxicology have led to more appropriate and creative interactions between medical toxicologists, emergency physicians, and surgeons. This article will review the diverse interfaces between the medical toxicologist and the surgeon.

Emergency Medical Services↗