Abstract

The incidence of severe adverse cutaneous reactions is low, but may potentially affect any individual taking medication. Occasionally severe adverse cutaneous reactions can be lethal. Optimal management of such cutaneous reactions requires: 1. rapid diagnosis and differentiation from non-drug-induced similar syndromes and interruption of the causal drug; this raises the question of the clinico-pathological distinction between erythema multiforme and Stevens-Johnson's syndrome (SJS), the criteria of which have been recently defined. 2. a precise evaluation of severity within the clinical spectrum ranging from SJS to toxic epidermal necrolysis (TEN) as this is to some extent predictive of the final outcome; and 3. the initiation of a specific treatment based on recent discoveries concerning the pathogenesis of toxic epidermal necrolysis. Thus our group has recently identified the mechanism of epidermal necrolysis that occurs in both SJS and TEN. It involves the apoptosis inducing pathway Fas receptor-Fas ligand. Human immunoglobulins were found to block the process in vitro through anti Fas ligand activity, and to have therapeutic effect in vivo in patients with TEN. (Presented at the 1201st Meeting, April 3, 2001.)

Noninvasive positive pressure ventilation is gaining increasing popularity in the treatment of patients with acute respiratory failure due to both acute episodes such as cardiogenic and noncardiogenic pulmonary edema or pneumonia and acute exacerbation of chronic obstructive pulmonary diseases such as COPD and asthma. This success is the consequence of several clinical trials demonstrating that early application of NPPV can: i) reduce the rate of intubation, ii) reduce the length of ICU and hospital stay, and iii) reduce mortality. Inspiratory pressure support (PSV: pressure support ventilation) is by far the most widely used mode of NPPV. Its implementation is easy and levels between 15-25 cmH₂O are compatible with patient's comfort in almost any condition. Since NPPV is implemented in awake patients, the patient's cooperation is one of the key factor for success. PSV is a flxible technique and the appropriate level of assistance can be tailored on an individual patient's basis. In both acute and acute on chronic respiratory failure, some positive end-expiratory pressure (PEEP) is set by the ventilator, though with different purposes. In the acute patients, the aim of PEEP is to improve oxygenation. In the patients with exacerbation of airflow limitation, PEEP has the aim to counterbalance the Intrinsic PEEP to unload the inspiratory muscles and to improve the patient-ventilator interaction. Finally, proportional assist ventilation (PAV) has been introduced in the last ten years to pursue an almost perfect adaptation of the ventilator to the patient's ventilatory drive and pattern. Both the theoretic background and short-term experimental results in clinical studies are extremely promising. However, there is no evidence that PAV is somehow superior to well set PSV in the clinical settings. Further research is on-going in this field. (Presented at the 1202nd Meeting, April 6, 2001.)

Primary B-cell lymphomas of the skin are not as rare as is generally believed. They are dešned as malignant B-cell proliferations presenting with cutaneous involvement alone and no evidence of extracutaneous manifestations over a period of at least six months when complete staging has been performed. The major subtypes are follicle center-cell lymphoma, marginal zone lymphoma/immunocytoma and large B-cell lymphoma of the leg (EORTC classification 1997). Primary B-cell lymphomas of the skin differ significantly from nodal lymphomas. Awareness of their special clinical behavior should prevent unnecessarily aggressive treatment. Pseudolymphomas of the skin are inflammatory diseases that simulate malignant lymphomas either clinically, histopathologically, or both. Particular pseudolymphomas may mimic cutaneous B-cell lymphomas. The most important examples are: lymphomatoid drug reaction, lymphocytoma (Borrelia burgdorferi as causative agent), arthropod reactions, small papular pseudolymphoma (acral pseudolymphomatous angiokeratoma), pseudolymphomas associated with vaccinations or tattoos and inflammatory pseudotumor. In recent years, new immunohistological and molecular techniques have added important criteria for the differentiation of cutaneous lymphomas from pseudolymphomas. (Presented at the 1203rd Meeting, April 10, 2001.)

The skin is a well-known reflection of internal disease states. It provides the astute clinician with clues that lead to the diagnosis of systemic illness. While skin disease is rarely life-threatening, serious morbidity and mortality may be avoided by early recognition of subtle cutaneous signs signaling internal problems. The recent literature was reviewed to glean new findings that either added new associations to older syndromes or described completely new diseases. While entire books are written regarding the "Skin Signs of Internal Disease", my paper will focus only on the newest of such findings. ( Presented at the 1203rd Meeting, April 10, 2001.)

Autism is a developmental disorder characterized by stereotypical behaviors, disturbances of social interactions, as well as difficulties in communications. Genetic factors are important among idiopathic autistic individuals. Several linkage studies suggested that multiple interacting loci are involved in the inheritance of autism. In addition, individuals with a diagnosis of autism probably comprise a heterogeneous group. It would be ideal to select a homogeneous group of autistic individuals in each genetic study, although it is very difficult due to no established biological markers specific to autism. Positron emission tomography (PET) is a noninvasive functional imaging tool which measures regional uptake and affinity of ligands and metabolic substrates in the brain and other organs. Using PET, our group has demonstrated altered brain serotonin synthesis in autism. In addition, our group has reported that idiopathic autistic individuals with severe stereotypical behavior and social impairment had relative decrease of serotonin synthesis in the cerebellum compared to the cerebrum, whereas those with minor stereotypical behavior and social impairment had relative increase of serotonin synthesis in the cerebellum. Our study of symptomatic autism associated with tuberous sclerosis complex showed that dysfunction in the temporal neocortex may be related to communication delays, while functional imbalance in the subcortical circuits may be related to stereotypical behavior and impaired social interaction. Since previous neuroimaging studies suggested that different locations of brain abnormality are associated with different clinical phenotypes in autism, there may be different causative genes responsible for different clinical symptoms in autism. Our group has recently investigated the vasoactive intestinal peptide receptor type 2 (VIPR2) gene as a candidate gene for autism. Our preliminary data suggested that some of the polymorphism in the upstream region of VIPR2 may be related to gastrointestinal symptoms and stereotypical behaviors in autism. In addition, we are currently investigating the relationship between polymorphisms in several serotonin-related genes and brain serotonin synthesis on PET. We believe that neuroimaging findings will be useful biological markers in order to obtain more homogeneous groups of individuals with autism for genetic analyses in the future. (Presented at the 1205th Meeting, April 26, 2001.)

Myocardial fibrosis is known to occur in human with left ventricular hypertrophy (LVH) associated with arterial hypertension¹ and contributes critically to the overall risk associated with LVH². This fibrosis consists of an increase in the interstitial and perivascular content of fibrillar collagen type I and type III³. Anumber of previous experimental findings suggest that direct fibroblast stimulation by angiotensin II may be involved in myocardial fibrosis associated with arterial hypertension.^1,4 Furthermore, we have shown recently that AT₁ blockade with losartan at doses that do not normalize blood pressure reversed myocardial fibrosis in rats with spontaneous hypertension.^5,6 Thus, in a recent study⁷ we have investigated whether chronic blockade of AT₁ receptors reverses myocardial fibrosis in patients with essential hypertension beyond the hemodynamic effect. The study was performed in 35 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical work-up. Nineteen patients were treated with losartan 50 mg/day (group L) and 16 patients received the calcium channel blocker amlodipine (2.5-10 mg/d) (group A) as treatment. At baseline and after 12 months, right septal endomyocardial biopsies were performed to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red-stained sections using an automated image analysis system. The serum concentration of carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis and depostion at the myocardial level,⁸ was measured by specific RIA. Time-course changes in blood pressure and final values of blood pressure were similar in the two groups of patients. In patients treated with L, CVF decreased from 5.65±0.47 to 3.96±0.34% (M±SEM, P <0.01) and PIP from 127±7 to 99±6 μg/L (P <0.01). Neither CVF nor PIP changed significantly in group A patients. A direct correlation was found between CVF and serum PIP (r=0.44, P <0.001) in all hypertensives before and after treatment. Losartan-treated patients, but not amlodip9inetreated patients exhibited an amelioration of Doppler parameters assessing end-diastolic left ventricular distensibility. These findings suggest that chronic AT₁ blockade reverses myocardial fibrosis in hypertensives beyond its hemodynamic effects. In addition, our results suggest that losartan-induced reparation of myocardial fibrosis may improve diastolic function in hypertensive patients.

After four decades of declining heart disease and stroke rates, there are signs that the diseases may be returning. Both the prevalence of obesity and the prevalence of Type II diabetes mellitus have increased markedly. In response to this threat, the Mayo Clinic Division of Cardiovascular Diseases has organized CardioVision 2020 for Olmsted County, Minnesota. CardioVision 2020 promotes, for the entire community, a tobacco-free environment; the availability of low fat foods; and, opportunities for physical activity for all children and adults. Suggested personal goals for Olmsted County residents are: 1) Tobacco-free and zero exposure to environmental tobacco smoke; 2) Five servings of fruits and vegetables per day, only low fat meats and 1% or skim dairy products; 3) total serum cholesterol less than 200 mg/dl (low density lipoprotein less than 100 mg/dl for individuals with coronary heart disease); 4) blood pressure less than 130 mm Hg systolic and less than 85 mm Hg diastolic; and 5) 30 minutes of physical activity on most, if not all, days of the week. To achieve these goals, CardioVision 2020 will provide leadership and facilitate communication to optimize lifestyle choices, risk factors levels and clinical event rates. The lay and medical communities will be provided with information about progress towards the CardioVision 2020 goals, opportunities that might be taken to speed that progress, and encouragement to adopt lifestyles that minimize the risk of cardiovascular disease. (Presented at the 1210th Meeting, June 2, 2001.)

Active treatment of acute ischemic stroke can only be successful as long as tissue in the area of ischemic compromise is still viable. Therefore, the identification of the area of irreversible damage, and its distinction from the penumbral zone, i.e., tissue with impaired function but preserved morphology, may improve the estimation of the potential efficacy of various therapeutic strategies. This can be achieved by multi-tracer positron emission tomography (PET) and perfusion-weighted (PW) and diffusion-weighted (DW) magnetic resonance imaging in experimental models. Neuroimaging modalities applied in patients with acute ische-mic stroke cannot reliably identify penumbra tissue and detect irreversible damage in the first hours after stroke, when treatment must be initiated to have the potential for success: Multitracer studies for the assessment of flow and irreversible metabolic damage usually are limited in the clinical setting, and arterial blood sampling necessary for quantitative determinations is prohibited under certain circumstances, e.g., when thrombolysis is planned. CT and MRI do not reliably detect irreversible damage in the first hours after stroke, and even DW-MRI may be misleading in some cases; determination of perfusion by PW-MRI yields a poor estimate of the state of tissue. The range of the penumbra can be assessed by combining determinations of flow and benzodiazepine receptor binding by PET of H₂¹⁵O and ¹¹ C-flumazenil (FMZ) and relating flow values and FMZ binding to the final state of the tissue. By this approach, cumulative probability curves can be computed to predict eventual infarction or noninfarction and to define the penumbral range. The computed values are in good agreement with results from other studies proving the validity of the concept of the penumbra which was also demonstrated in several therapeutic studies in which thrombolytic treatment reversed critical ischemia and decreased the volume of the final infarcts. Such neuroimaging findings might serve as surrogate targets in the selection of other therapeutic strategies for large clinical trials. (Presented at the 1211st Meeting, June 6, 2001.)

It is just over 10 years since we introduced the technique of modified ultrafiltration to paediatric cardiac surgery. This represents a very good time to look back on the work done, to consider the position of modified ultrafiltration in the practice of cardiac surgery and to imagine the work that needs to be done in the future. Ultrafiltration began as a response to the observation of an accumulation of total body water associated with open heart surgery. This accumulation of total body water was first studied in detail by Tadaki Maehara from Tokyo working with us after pioneering work by Ivan Novak from Prague. Cardiopulmonary bypass with hypothermia and haemodilution is associated with a dramatic accumulation of water in the body and with tissue oedema. This tissue oedema causes organ dysfunction and it was our hypothesis in the later 80s and early 90s, that removal of water from the body towards the end of cardiopulmonary bypass would result in improved organ function and perhaps better outcomes. In that early era a series of experiments were carried out in which we were able to demonstrate that ultrafiltration performed during bypass (conventional ultrafiltration) was less consistent a technique than modified ultrafiltration (performed just after bypass) in the removal of total body water. In a subsequent prospective randomised trial performed by Suren Naik, we confirmed these changes in total body water and concomitantly demonstrated dramatically improved systolic blood pressure and elevation in haematocrit during ultrafiltration. Further investigation of the elevation of blood pressure by Suren Naik and later by Mike Davis using microsonometric crystals and pre-load recruitable/work index demonstrated that the improved blood pressure was due to improved myocardial contractility and cardiac index and not to elevation of systemic vascular resistance. A serendipitous finding was a fall in pulmonary vascular resistance. Subsequently modified ultrašltration has spread rapidly as a technique throughout the world. In a recent review of American centres presented at the World Congress in Toronto, 65% of American paediatric units were using modified ultrafiltration to support their cardiac practice. As a consequence of the technique spreading there has been a massive expansion in the number of publications and over the last two years, two hundred publications have been added to the bibliography. It is always gratifying as a researcher to see one's research work and hypotheses confirmed by others. I have been glad to see that with almost no exceptions our original findings have been replicated in other centres even to those involving myocardial contractility, some of the most difficult experiments that we have had to do. In addition to the haemodynamic consequences there has been considerable interest in the use of ultrafiltration to modulate the inflammatory response to cardiopulmonary bypass and I shall touch on both the importance of this and the results of the experiments performed during this talk. Recently and in my view completely appropriately modified ultrafiltration has been applied in adults and many workers have replicated the findings that we observed in children in adults. Some of those workers include my old co-workers, particularly Dr Onoe from Osaka. His work and that of others opens the door to many fascinating experiments to be performed in adults undergoing cardiac surgery and I look forward to the results of those experiments with interest. As one might expect with any widely used technique there has been an explosion in variations on the original technique. I shall consider some of those variations and also outline the rules which should be employed for further research. I shall conclude by outlining our current policy which is to use a higher haematocrit during bypass with moderate hypothermia at full flow where ever possible using conventional ultrafiltration during re-warming to increase oxygen delivery as the tissue's oxygen demands rise and to use modified ultrafiltration after cardiopulmonary bypass both to optimise haemodynamics and to modulate the inflammatory response. We must remember, however, that ultrafiltration only treats components of the injury caused by the technique of haemodilution and hypothermic cardiopulmonary bypass. The challenge to all of us is to avoid the original injury and clearly the best way would be to develop techniques which avoid cardiopulmonary bypass altogether. This may not be possible yet for a number of conditions. We should never forget that prevention is better than cure and ultrafiltration is only part of a treatment. (Presented at the 1215th Meeting on June 25, 2001.)

The discovery of the hormone dependence of prostate cancer in the 1940s raised great hopes for the treatment of this cancer. Unfortunately, hormone resistance, which inevitably occurs after a variable interval of time, considerably tempered the initial enthusiasm raised by this treatment modality. Application of the basic principles of cancer therapy to prostate cancer, using the three classical modalities, surgery, radiotherapy and chemotherapy, also rapidly encountered major obstacles. In this organ, situated deeply within the urogenital junction, the efficacy/complication ratio of surgery and radiotherapy was relatively unfavourable to the patient and chemotherapy was found to be virtually ineffective. In the past, prostate cancer was usually diagnosed at the stage of disseminated disease, excluding any chance of cure for the patient. Little progress was made between the 1940s and the 1980s. Considerable progress has improved this situation over the last two decades. Prostate cancer can now be diagnosed at an increasingly earlier stage by means of PSA assay. The efficacy of the various treatment modalities has increased, while their adverse effects have decreased. Surgery has become more refined and can now even be performed laparoscopically. Radiotherapy is more effective, while ensuring better preservation of healthy tissues. Endocrine therapy, formerly limited to surgical castration or oestrogens, has been enriched by LHRH analogues and, more recently, LHRH antagonists and antiandrogens. Chemotherapy is starting to give promising results with the arrival of new molecules. New technologies such as HIFU are opening the way to minimally invasive treatments. From another angle, the genetic revolution is already attacking the citadel of prostate cancer and trials of candidate vaccines are currently underway. If progress in the treatment of prostatic cancer does not yet constitute a revolution, all of these aspects are certainly preparing for a revolution in the very near future. (Presented at the 1220th Meeting on July 13, 2001.)

The stem cells in the small intestine of the mouse are located near the base of the crypts 3-4 cell positions above the functional Paneth cells in an annulus of about 16 cells. They are responsible for all cell replacement (4 lineages) in the mucosa in the animal's life. They undergo about 1000 divisions in the life of a laboratory mouse. Until recently the only marker identifying these crucial cells has been their precise position along the crypt axis. However, they can now be labelled using DNA precursors and also an antibody to Musashi-1, an RNA binding protein. There are about 4-6 lineage ancestor stem cells per crypt and about 3-4.5×10⁶ in total, producing about 2-25×10¹¹ cells per life span. In spite of the large numbers of cells and their extensive cell divisions there are only minor changes with age and a very low cancer incidence, indicating very effective genome protective mechanisms. The crypt and the stem cells specifically are protected by 3 effective mechanisms. DNA replication is a hazardous process and replication-induced errors are prevented by the selective retention in the stem cells of all the template strands of DNA, with the newly synthesised strands passing to the daughter cell destined for loss. Errors induced in the template strands, by genotoxins are prevented by an altruistic cell suicide (apoptosis) in any stem cell incurring such error. Repeated or higher doses of genotoxins could result in the death of all stem cells. This is prevented by the presence of other potential, more resistant stem cells (an hierarchical stem cell organisation). (Presented at the 1221st Meeting on July 13, 2001.)

Considerable progress has been made in developing uniform definitions for acute lung injury and the acute respiratory distress syndrome. These definitions facilitated the conduct of several clinical trials to evaluate new treatment strategies. In addition, clinical research, combined with clinically relevant animal models of acute lung injury, have provided remarkable new insights into the pathogenesis and pathophysiology of acute lung injury. Definitions: Acute lung injury is defined as a PAO₂/FiO₂ <300 with bilateral opacities on the chest radiograph that need not be symmetrical or extensive in the presence of a pulmonary arterial wedge pressure <18 mmHg or the absence of clinical evidence of left atrial hypertension. The acute respiratory distress syndrome is defined by the same criteria except the PAO₂/FiO₂ ratio is <200. Pathogenesis/Pathophysiology: It is clear that there are several neutrophil dependent and independent mechanisms that can precipitate acute lung injury. Injury to the lung endothelial barrier is a prerequisite for the development of protein rich, increased permeability pulmonary edema. There is new experimental evidence that transforming growth factor-Β may be an important mediator of the early increase in lung endothelial and epithelial permeability. In addition, it is also clear that structural and functional injury to the alveolar epithelial barrier is associated with a more prolonged clinical course, longer duration of mechanical ventilation, and higher mortality. Classic morphologic studies in 1977 demonstrated that patients who died with ARDS had extensive injury to the alveolar epithelium. Recent clinical studies have also demonstrated that the inability to remove edema fluid from the airspaces of the lung early in the clinical course of acute lung injury is associated with a more prolonged clinical course and a higher mortality. There are several mechanisms that may be responsible for injury to the alveolar epithelial barrier including mechanical injury from overdistension, oxidant mediated injury, neutrophil dependent injury, as well as direct injury from bacteria or viruses. Treatment: Although several experimental studies and some clinical trials have evaluated a variety of anti-inflammatory therapies, none of these approaches has been proven unequivocally to reduce mortality. However, interestingly, a lung protective ventilatory strategy with 6 ml/kg ideal body weight and a plateau pressure limit of 30 cmH₂O has proven to be efficacious in reducing mortality in a large randomized clinical trial of 861 patients. This clinical trial provided the first evidence that mortality can be substantially reduced with any intervention. The trial demonstrated that absolute mortality was reduced from 39 to 31% with a relative reduction of mortality of 22%. Interestingly, there is also evidence that this clinical trial was associated with a reduction in interleukin-6 levels in the plasma, suggesting that part of the mechanism for the beneficial effect was related to reduced inflammation of the lung. Also, there was evidence of reduced non-pulmonary organ failure in the patients treated with the low tidal volume strategy. A new trial is currently underway in the United States to evaluate the potential benefit of a higher level of positive end-expiratory pressure in patients treated with the low tidal volume, plateau pressure limited strategy. This trial has enrolled 400 patients to date and is scheduled to enroll a maximum 750 patients. The results of this trial will provide new information regarding the potential value of elevated levels of positive end-expiratory pressure in treating patients with acute lung injury and the acute respiratory distress syndrome. Other strategies that are being evaluated currently include the potential value of prone positioning, high frequency ven-tilation, high dose glucocorticoids for persistent late onset ARDS, as well as the value of the pulmonary rterial catheter versus the central venous catheter in administering specific intravascular volume fluid strategies. (Presented at the 1223rd Meeting, August 1, 2001.)

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