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PubMed2000

The Fourth DeWitt S. Goodman lecture. Novel approaches to the prevention of colon cancer by nutritional manipulation and chemoprevention.

Large bowel cancer is one of the most common human malignancies in Western countries including North America. This report details the preventive strategies aimed at reducing the incidence and mortality of large bowel cancer by nutritional manipulation and chemopreventive agents. During recent decades, multidisciplinary research in epidemiology and laboratory animal model studies have contributed much to our understanding of the etiology of this cancer; more importantly, it has enabled us to approach cancer prevention. An impressive body of data thus far accumulated has provided important concepts about dietary factors such as fat and fiber as key modulators of large bowel cancer. Compelling experimental evidence indicates that certain dietary lipids and fibers influence tumorigenesis in the colon. Data obtained in metabolic epidemiological and laboratory animal model studies are sufficiently convincing in showing the enhancement of colon cancer by certain types of fat and protection against it by certain dietary fibers. Our approach to the primary prevention of large bowel cancer is to translate the findings from clinical epidemiological and laboratory studies into sound advice for patients and for the public at large to reduce fat intake and increase fiber intake, specifically cereals and grains. Preclinical efficacy studies have provided scientifically sound evidence as to how several phytochemicals and their synthetic analogues act to retard, block, or reverse carcinogenesis. Equally exciting are opportunities for effective chemoprevention with nonsteroidal anti-inflammatory agents, both synthetic and naturally occurring, or selective cyclooxygenase-2 inhibitors. Our exploration of the multistep process of carcinogenesis has provided substantial insights into the mechanisms by which chemopreventive agents modulate these events. Growing knowledge in this area has brought about an innovative combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. There is growing optimism for the view that realization of preventive concepts in large bowel cancer will also serve as a model for preventing malignancies such as cancer of the prostate and breast.

Cell Transformation, Neoplastic↗
PubMed2000

The sixth Carlos E. Rubio Memorial Lecture. Prevention and treatment of variceal hemorrhage.

The medical treatment of portal hypertension has experienced a marked progress in the past decade due to the introduction of effective portal hypotensive therapy. This has been possible because of the better understanding of the pathophysiological mechanisms leading to portal hypertension. A major step forward was the introduction of beta-blockers for the prevention of bleeding and rebleeding from gastroesophageal varices. Effective therapy requires the reduction of the hepatic venous pressure gradient (HVPG) to 12 mmHg or below, or at least by 20% of baseline values. Unfortunately, this is only achieved in 1/3 to 1/2 of patients. Combination therapy, associating isosorbide-5-mononitrate and propranolol or nadolol administration enhances the reduction in portal pressure and increases the number of patients in whom HVPG decreases by more than 20% of baseline values and below 12 mmHg. Randomized clinical trials (RCT's) do support the concept that combination therapy is more effective than propranolol or nadolol alone, significantly better than sclerotherapy, and probably than endoscopic banding ligation. Therapy may be complemented by the association of spironolactone. The main inconvenience of pharmacological therapy is that there is no non-invasive method available to detect non-responders to treatment. Failures of drug therapy should be managed endoscopically. Failures of endoscopic treatment require 'rescue' by means of TIPS or shunt surgery. Patients with advanced liver failure should be considered for orthotopic liver transplantation, and put into a waiting list if eligible. In the treatment of acute variceal bleeding pharmacological therapy offer the unique advantage of allowing to provide specific therapy immediately after arrival to hospital, or even during transferral to hospital by ambulance, since it does not require sophisticated equipment and highly qualified medical staff. Vasopressin has been abandoned because of its toxicity, although this can be reduced by the combined administration of transdermal nitroglycerin. Terlipressin has longer effects and is more effective and safer than vasopressin alone or in combination with nitroglycerin. It has proved to be effective and to decrease mortality from bleeding in double-blind studies. RCT's have shown that this drug is as effective and safer than emergency sclerotherapy. Therapy should be maintained for five days to prevent early rebleeding. Somatostatin is probably as effective as terlipressin. Octreotide is probably useful after endoscopic therapy but can not be recommended as first line treatment. Endoscopic injection sclerotherapy and endoscopic banding ligation are very effective, but require well trained medical staff. There is an increasing trend for initiating therapy with a pharmacological agent, followed by semi-emergency endoscopic therapy as soon as a well trained endoscopist is available (within 12-24 hours), while maintaining drug therapy for 5 days. Failures of medical therapy may be treated by a second session of endoscopic treatment, but if this fails TIPS of emergency surgery should be done. In high-risk situations, such as bleeding from gastric varices or in patients with advanced liver failure, the decision for TIPS or surgery should be done earlier, after failure of the initial treatment.

Adrenergic beta-Antagonists↗
PubMed2000

Dissociated vertical deviation: etiology, mechanism, and associated phenomena. Costenbader Lecture.

PURPOSE: The etiology and mechanism of dissociated vertical deviation (DVD) are explored. METHODS: In 6 young adults with DVD, the simultaneous horizontal, vertical, and torsional eye movements for both eyes were recorded by using dual-coil scleral search coils. Analysis of the simultaneous vertical and torsional movements that occurred during the DVD response identified the primary muscles acting in the vergences and versions involved. RESULTS: Typically, both horizontal and cyclovertical latent nystagmus developed upon occlusion of either eye. A cycloversion/vertical vergence then occurred, with the fixing eye intorting and tending to depress and the covered eye extorting and elevating. Simultaneously, upward versions occurred for the maintenance of fixation, consisting of various saccades and smooth eye movements, and this led to further elevation of the eye behind the cover. The cyclovertical component of the latent nystagmus became partially damped as the DVD developed. CONCLUSIONS: In patients with an early onset defect of binocular function, the occlusion of one eye, or even concentration on fixing with one eye, produces unbalanced input to the vestibular system. This results in latent nystagmus with a cyclovertical component, sometimes only seen with magnification. A normal, oblique-muscle-produced, cycloversion/vertical vergence then comes into play, occurring in an exaggerated form in the absence of binocular vision, probably as a learned response. This cycloversion/vertical vergence helps damp the cyclovertical nystagmus (a cyclovertical "nystagmus blockage" phenomenon), aiding vision in the fixing eye. But this mechanism also produces unavoidable and undesirable elevation and extorsion of the fellow eye, which we call DVD.

Adolescent↗