JoHn PèRez - Academia.edu (original) (raw)
Papers by JoHn PèRez
Toxicon, 1999
Snake venoms are complex mixtures of many toxins and enzymes which effectively immobilize prey wi... more Snake venoms are complex mixtures of many toxins and enzymes which effectively immobilize prey without a struggle and assist in digestion. Certain animals have a remarkable resistance to envenomation of snakes. Naturally occurring factors that neutralize snake venoms have been found in the sera of most snakes and a few warm-blooded animals. These antihemorrhagic and antineurotoxic factors have been purified from snake and mammalian sera. The antihemorrhagins are not immunoglobulins since they have different physical and chemical characteristics. The natural immunity to hemorrhagins is the result of tissue inhibitors of metalloproteinases (TIMP) found in animal sera of resistant animals. Most animals have matrix metalloproteinases (MMP) and TIMP that are implicated in a wide variety of normal physiological processes and pathological conditions. MMP in animals have many biological functions in embryogenesis, morphogenesis and tissue remodeling. MMP activities are precisely regulated by endogenous TIMP. Disruption of the balance between MMP and TIMP causes various diseases such as arthritis, periodontal diseases, diabetes, ophthalmologic conditions, neoplasia, metabolic bone disease, atherosclerosis and orthopedic conditions. Resistant animals that have a high titer of TIMP would have a survival advantage when bitten by poisonous snakes. Snake venoms are abundant and stable sources of MMP which are medically important. The venom MMP which cause unregulated destruction of tissue have sequences which have some degree of homology with mammalian MMP which control normal biological processes. Resistant animals are important sources of TIMP which can be used to study metalloproteinase related diseases. For these reasons the MMP in snakes and TIMP in resistant animal are excellent candidates for developing new drug therapies.
Toxicon, 2003
Mortality due to snake envenomation is not a major problem in the United States with approximatel... more Mortality due to snake envenomation is not a major problem in the United States with approximately 8 -12 deaths per year, but envenomation is a serious problem that can result in functional disability, loss of extremities, and a costly recovery. Physicians encounter different clinical situations with each new snakebite victim because of the geographical variations in snake venoms. The best and most acceptable form of treatment is the use of antivenom; however, it must be administered as soon as possible since it is not so effective at reducing local signs of envenomation such as necrosis. The antivenom in the United States is in short supply, expensive and may not even be the most effective for neutralizing all North American snake venoms. In this study, we tested two antivenoms. The first was a Crotalidae Polyvalent Fab fragment with Ovine origin (FabO) manufactured in London, and the second was Antivipmyn, a Mexican manufactured antivenom that is F(ab 0 ) 2 fragment produced in horse (Fab 2 H). The efficacy of the two antivenoms was tested with 15 different snake venoms found in North America. Three different assays were used to test the efficacy of the antivenoms, the in vivo serum protection test (ED 50 ), antihemorrhagic and anticoagulant. The Fab 2 H antivenom was most effective in neutralizing the hemorrhagic activity of 78% of the hemorrhagic venoms used in this study. In the ED 50 assay, the Fab 2 H antivenom was effective in neutralizing all venoms used in this study, while FabO neutralized all but C. m. molossus venom. However, in most cases, FabO required less antivenom than Fab 2 H antivenom to neutralize three LD 50 .
Toxicon, 2003
Mortality due to snake envenomation is not a major problem in the United States with approximatel... more Mortality due to snake envenomation is not a major problem in the United States with approximately 8–12 deaths per year, but envenomation is a serious problem that can result in functional disability, loss of extremities, and a costly recovery. Physicians encounter different clinical situations with each new snakebite victim because of the geographical variations in snake venoms. The best and most acceptable form of treatment is the use of antivenom; however, it must be administered as soon as possible since it is not so effective at reducing local signs of envenomation such as necrosis. The antivenom in the United States is in short supply, expensive and may not even be the most effective for neutralizing all North American snake venoms. In this study, we tested two antivenoms. The first was a Crotalidae Polyvalent Fab fragment with Ovine origin (FabO) manufactured in London, and the second was Antivipmyn, a Mexican manufactured antivenom that is F(ab′)2 fragment produced in horse (Fab2H). The efficacy of the two antivenoms was tested with 15 different snake venoms found in North America. Three different assays were used to test the efficacy of the antivenoms, the in vivo serum protection test (ED50), antihemorrhagic and anticoagulant. The Fab2H antivenom was most effective in neutralizing the hemorrhagic activity of 78% of the hemorrhagic venoms used in this study. In the ED50 assay, the Fab2H antivenom was effective in neutralizing all venoms used in this study, while FabO neutralized all but C. m. molossus venom. However, in most cases, FabO required less antivenom than Fab2H antivenom to neutralize three LD50.
Toxicon, 2007
Crotalus durissus cumanensis snake venoms from different Venezuelan regions, showed biochemical a... more Crotalus durissus cumanensis snake venoms from different Venezuelan regions, showed biochemical and hemostatic variations. Fibrino(geno)lytic, hemorrhagic and procoagulant activities and gel-filtration chromatography and SDS-PAGE profiles were analyzed. Differences were observed in fibrinolytic activity: kallikrein-like amidolytic activity was highest in venoms of Santa Teresa, and Margarita. Lagunetica and Carrizales venoms showed the maximum fibrin lysis. The highest hemorrhagic activity was seen in Lagunetica venom. Margarita had the lowest LD50 of 0.18. Lagunetica, Carrizales and Anzoátegui induced a rapid degradation of fibrinogen α chains and slower degradation on β chains, which could possibly due to a higher content of α fibrinogenases in these venoms. This fibrinogenolytic activity is decreased by metalloprotease inhibitors. All venoms, except Carrizales, presented thrombin-like activity. Anzoátegui, Carrizales and Lagunetica, in which fibrinolytic activity was present, showed the largest concentration of high molecular mass components. These results represent a new finding, not previously described, of fibrinolytic activity in South American C. durissus venoms. Santa Teresa and Margarita had fibrinolytic activity, and lack of hemorrhagic activity, representing an important finding in Venezuelan venoms since the description of a fibrinolytic molecule without hemorrhagic activity can have valuable potential in thrombolytic therapy.
Current Drug Targets - Cardiovascular & Hematological Disorders, 2004
The existence of disintegrins, non-enzymatic, small molecular weight proteins from viper venom, h... more The existence of disintegrins, non-enzymatic, small molecular weight proteins from viper venom, has been known for 2 decades, and their impact on cellular research has been substantial and far-reaching. Disintegrins have been the molecular scaffold used in the design of therapeutics for the prevention of thrombosis and cancer. Their sequencing has provided insights into the evolution of proteins over millennia. Production of recombinant disintegrin mutants and fusion proteins has allowed investigations into molecular mechanisms at work in cell-extracellular matrix interactions. Structural homologies with non-snake proteins have shown disintegrin-like molecules in species ranging from slime mold to humans. Intracellular signaling events have been elucidated through the use of venom disintegrins, including events related to programmed cell death, motility, cell proliferation and viral pathogenesis. Disintegrin sequences (protein or genes) have been placed in microbubbles and liposomes and been found to target neovascular endothelium and metastatic tumors in two mouse models. The purpose of this review is to highlight the members of this disintegrin family discovered since 1998 as well as the increased understanding of their usefulness in therapeutics and technical assays.
Nature, 2010
Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generat... more Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generate a 'thermal image' of predators or prey. Infrared signals are initially received by the pit organ, a highly specialized facial structure that is innervated by nerve fibers of the somatosensory system. How this organ detects and transduces infrared signals into nerve impulses is not known. Here we use an unbiased transcriptional profiling approach to identify TRPA1 channels as infrared receptors on sensory nerve fibers that innervate the pit organ. TRPA1 orthologues from pit bearing snakes (vipers, pythons, and boas) are the most heat sensitive vertebrate ion channels thus far identified, consistent with their role as primary transducers of infrared stimuli. Thus, snakes detect infrared signals through a mechanism involving radiant heating of the pit organ, rather than photochemical transduction. These findings illustrate the broad evolutionary tuning of TRP channels as thermosensors in the vertebrate nervous system. Venomous pit vipers detect warm-blooded prey through their ability to sense infrared (750 nm -1 mm wavelength) radiation. Superimposition of thermal and visual images within the snake's brain enables it to track animals with great precision and speed. Biophysical studies suggest that this system is exquisitely sensitive, such that vipers can detect prey at distances Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Infectious Diseases in Clinical Practice, 2001
New England Journal of Medicine, 1996
Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of ... more Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of the left ventricular outflow tract, in patients with hypertrophic obstructive cardiomyopathy. We assessed the hemodynamic effects of the ingestion of ethanol, in an amount commonly consumed socially, in patients with hypertrophic cardiomyopathy. We performed echocardiography in 36 patients before and several times after the ingestion of either 50 ml of 40 percent ethanol or an isocaloric placebo with the aroma of rum. Each patient received both ethanol and placebo, on different days. The patients, but not the physicians, were blinded to the content of the drink. We measured the sizes of the left atrium and left ventricle, the left-ventricular-wall thickness, blood pressure, heart rate, the degree of systolic anterior motion of the mitral valve, and the pressure gradient across the left ventricular outflow tract. The ingestion of ethanol regulated in a significant drop in the mean (+/- SD) systolic blood pressure (from 130.5 +/- 18.6 to 122.5 +/- 20.3 mm Hg, P<0.001), a significant increase in systolic anterior motion of the mitral valve (from a grade of 2.1 to a grade of 2.5, P<0.001), and a 63 percent increase in the mean gradient across the left ventricular outflow tract (from 38.1 +/- 26.5 to 62.2 +/- 42.4 mm Hg, P<0.001). These changes, which were not associated with symptoms, did not occur after the ingestion of placebo. The ingestion of a small amount of ethanol caused an increase in the gradient across the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy, which could have and adverse clinical effect.
Clinical Infectious Diseases, 2003
Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell reco... more Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell recovery when receiving highly active antiretroviral therapy (HAART), there are few data on mortality. Mortality rates were studied for 253 individuals aged у50 years and a younger group of 535 people in a retrospective cohort; for untreated persons in each age group, the proportions surviving at 3 years were 83% and 70% ( ), P ! .01 respectively. No significant difference in the survival rate was found between the older (83%) and younger (89%) patients who received HAART ( ). The hazard ratio for death in the older untreated group was P p .29 2.4 (95% confidence interval [CI], 1.4-3.9) when exposed to HAART. However, compared with older untreated patients, the hazard ratio for death decreased to 0.28 (95% CI, 0.15-0.52) for treated older adults. The effect of HAART substantially improves the survival rate for older individuals and supports the importance of treatment in this group.
The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impa... more The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impaired left ventricular function. Such dysfunction in aortic stenosis may be reversible if caused by afterload mismatch, but not if it is caused by superimposed myocardial infarction. From our echocardiography database, 55 patients with severe aortic stenosis (valve area < or =0.75 cm2) and ejection fractions of 30% or lower who subsequently underwent aortic valve replacement were included. The operative mortality and clinical follow-up were detailed. There were 10 perioperative deaths (operative mortality, 18%). Twenty (36%) of the 55 patients had a prior myocardial infarction. In the 35 patients without prior myocardial infarction, there was only 1 death (3%). In contrast, 9 of 20 patients with prior myocardial infarction died (mortality rate, 45%; P< or =.001). The factors significantly associated with perioperative death on univariate analysis (functional class, mean aortic gradient, and prior myocardial infarction) were entered into a model for stepwise logistic regression. This multivariate analysis showed that only prior myocardial infarction was independently associated with perioperative death (odds ratio, 14.9; 95% confidence interval, 2.4-92.1; P = .004). The risk of aortic valve replacement in patients with severe aortic stenosis and severely reduced left ventricular systolic function is extremely high if the patients have had a prior myocardial infarction. This information should be factored into the risk-benefit analysis that is done preoperatively for these patients, and it may preclude operation for some.
American Heart Journal, 1995
Protruding aortic arch atheromas are associated with otherwise unexplained strokes and transient ... more Protruding aortic arch atheromas are associated with otherwise unexplained strokes and transient ischemic attacks. Therefore aortic atheromas also may be important in patients with carotid artery disease. Forty-five patients with ≥50% carotid stenosis and stroke or transient ischemic attack within 6 weeks underwent transesophageal echocardiographic examination (TEE). They were matched for age, sex, and hypertension with 45 control subjects who had also had a recent cerebral event but in whom significant carotid stenosis was absent. Protruding aortic arch atheromas were present in 17 (38%) of 45 patients with carotid disease and only 7 (16%) of 45 of control subjects (p = 0.02). Mobile atheromas (with the greatest embolic potential) were present almost exclusively in case patients, 6 (13%) of 45, versus 1 (2%) of 45 control subjects (p = 0.05). Case patients with mobile atheromas had the most severe carotid stenosis (≥80%). Cerebral symptoms were discordant with the side of the carotid stenosis in 10 case patients, and 4 had atheromas. In conclusion, protruding atheromas of the aortic arch are present in significant numbers of symptomatic patients with carotid artery disease. These atheromas may represent an additional cause of symptoms in patients with carotid stenosis. TEE to look for protruding aortic atheromas may be considered in patients with neurologic events despite the presence of significant carotid stenosis, especially if the symptoms are discordant with the side of carotid stenosis.
Journal of The American College of Cardiology, 1991
Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data wer... more Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data were compared in adult patients with isolated or combined aortic and mitral valve disease. A clinical decision to operate, not operate or remain uncertain was made by experienced cardiologists given either Doppler echocardiographic or cardiac catheterization data. A prospective evaluation was performed on 189 consecutive patients (mean age 67 years) with valvular heart disease who were being considered for surgical treatment on the basis of clinical information. All patients underwent cardiac catheterization and detailed Doppler echocardiographic examination.Three sets of two cardiologist decision makers who did not know patient identity were given clinical information in combination with either Doppler echocardiographic or cardiac catheterization data. The combination of Doppler echocardiographic and clinical data was considered inadequate for clinical decision making in 21% of patients with aortic and 5% of patients with mitral valve disease. The combination of cardiac catheterization and clinical data was considered inadequate in 2% of patients with aortic and 2% of patients with mitral valve disease. Among the remaining patients, the cardiologists using echocardiographic or angiographic data were in agreement on the decision to operate or not operate in 113 (76% overall).When the data were analyzed by specific valve lesion, decisions based on Doppler echocardiography or catheterization were in agreement in 92%, 90%, 83% and 69%, respectively, of patients with aortic regurgitation, mitral stenosis, aortic stenosis and mitral regurgitation. Differences in cardiac output determination, estimation of valvular regurgitation and information concerning coronary anatomy were the main reasons for different clinical management decisions. These results suggest that for most adult patients with aortic or mitral valve disease, alone or in combination, Doppler echocardiographic data enable the clinician to make the same decision reached with catheterization data.
Journal of The American College of Cardiology, 1995
We attempted to determine the prevalence of strands on native and prosthetic valves, as detected ... more We attempted to determine the prevalence of strands on native and prosthetic valves, as detected by transesophageal echocardiography, and to assess the relative risk for systemic emboli associated with these strands.Fine threadlike strands, seen on native and prosthetic valves by transesophageal echocardiography, have been implicated in systemic embolization.During a 2-year period, 1,559 patients underwent transesophageal echocardiography at our center. Of these, 41 patients had strands and no other identifiable source of systemic emboli. They were matched for age, gender, history of hypertension and history of smoking with a control group of 41 patients without strands who also had no identifiable source of emboli. The risk of embolization in the two groups was compared.Of 1,559 patients studied by transesophageal echocardiography, 86 (5.5%) had strands. Strands were far more common on mitral valves than on aortic valves. Of the patients with strands, 38% had had an event consistent with a systemic embolus, whereas 62% had not. Of 597 patients with an embolic event, 63 (10.6%) had strands, whereas only 23 (2.3%) of 962 patients without emboli had strands. In the case-control study, 33 (83%) of the 41 patients with strands without another source of embolism had emboli compared with only 12 (29%) of the 41 control patients without another source (odds ratio 10.0, 95% confidence interval 3.6 to 27.8, p = 0.00001).Valvular strands visualized by transesophageal echocardiography are associated with systemic embolization.
Journal of The American College of Cardiology, 1994
Objectives. The purpose of this study was to prospectively evaluate the risk of vascular events i... more Objectives. The purpose of this study was to prospectively evaluate the risk of vascular events in patients with protruding aortic atheromas.Background. Protruding atheromas of the thoracic aorta have been shown to be associated with embolic disease in previous retrospective studies.Methods. During a 1-year period, 521 patients had transesophageal echocardiography. Of these, 42 patients had protruding atheromas and no other source of emboli. They were followed up for up to 2 years (mean follow-up 14 months) and compared with a control group without atheromas, matched for age, gender and hypertension.Results. Of 42 patients with atheromas, 14 (33%) had 19 vascular events during follow-up (5 brain, 2 eye, 4 kidney, 1 bowel, 7 lower extremity). Of 42 control patients, 3 (7%) had vascular events (2 brain, 1 eye). Univariate analysis identified only protruding atheromas as significantly correlating with events (p = 0.003). There was no positive correlation of events with age, gender, hypertension, smoking, family history, atrial fibrillation, valve replacement, antithrombotic drug use, diabetes or coronary disease. Multivariate analysis showed that only protruding atheromas independently predicted events (p = 0.005, odds ratio 4.3, 95% confidence interval 1.2 to 15.0). Nine patients died in the atheroma group versus six in the control group, but this was not statistically significant (p = 0.39).Conclusions. Protruding atheromas seen on transesophageal echocardiography predict future vascular events.
Arthritis and Rheumatism, 2006
ObjectiveTo compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX mono... more ObjectiveTo compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.MethodsThis was a 2-year, multicenter, double-blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.This was a 2-year, multicenter, double-blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.ResultsCombination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.ConclusionIn this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.
American Heart Journal, 1997
Plasma homocyst(e)ine [H(e)] levels correlate with the prevalence of arterial occlusive diseases.... more Plasma homocyst(e)ine [H(e)] levels correlate with the prevalence of arterial occlusive diseases. Recently, transesophageal echocardiography (TEE) has been used to evaluate patients with atherosclerotic plaques in the thoracic aorta. The purpose of this study was to determine whether H(e) levels correlate with the degree of atherosclerotic plaque in the thoracic aorta (ATH) as seen on TEE. Maximum plaque areas for three locations in the thoracic aorta (arch, proximal descending, and distal descending) were measured with TEE in 156 patients. Maximum plaque areas for these locations were added to yield an estimate of ATH. ATH and H(e) levels, and levels of folic acid, vitamin B 12 , and pyridoxal 5`-phosphate were measured in a double-blind manner. Univariate analysis demonstrated a significant correlation of H(e) with ATH ( r = 0.3, p < 0.001). On multivariate analysis, H(e) was independently predictive of ATH ( r for the model including H(e) was 0.63, p < 0.0001). Plasma H(e) levels are therefore significantly and independently correlated with the degree of atherosclerosis in the thoracic aorta. (Am Heart J 1997;133:534-40.)
Infectious Diseases in Clinical Practice, 2001
New England Journal of Medicine, 1996
Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of ... more Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of the left ventricular outflow tract, in patients with hypertrophic obstructive cardiomyopathy. We assessed the hemodynamic effects of the ingestion of ethanol, in an amount commonly consumed socially, in patients with hypertrophic cardiomyopathy. We performed echocardiography in 36 patients before and several times after the ingestion of either 50 ml of 40 percent ethanol or an isocaloric placebo with the aroma of rum. Each patient received both ethanol and placebo, on different days. The patients, but not the physicians, were blinded to the content of the drink. We measured the sizes of the left atrium and left ventricle, the left-ventricular-wall thickness, blood pressure, heart rate, the degree of systolic anterior motion of the mitral valve, and the pressure gradient across the left ventricular outflow tract. The ingestion of ethanol regulated in a significant drop in the mean (+/- SD) systolic blood pressure (from 130.5 +/- 18.6 to 122.5 +/- 20.3 mm Hg, P<0.001), a significant increase in systolic anterior motion of the mitral valve (from a grade of 2.1 to a grade of 2.5, P<0.001), and a 63 percent increase in the mean gradient across the left ventricular outflow tract (from 38.1 +/- 26.5 to 62.2 +/- 42.4 mm Hg, P<0.001). These changes, which were not associated with symptoms, did not occur after the ingestion of placebo. The ingestion of a small amount of ethanol caused an increase in the gradient across the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy, which could have and adverse clinical effect.
Clinical Infectious Diseases, 2003
Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell reco... more Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell recovery when receiving highly active antiretroviral therapy (HAART), there are few data on mortality. Mortality rates were studied for 253 individuals aged у50 years and a younger group of 535 people in a retrospective cohort; for untreated persons in each age group, the proportions surviving at 3 years were 83% and 70% ( ), P ! .01 respectively. No significant difference in the survival rate was found between the older (83%) and younger (89%) patients who received HAART ( ). The hazard ratio for death in the older untreated group was P p .29 2.4 (95% confidence interval [CI], 1.4-3.9) when exposed to HAART. However, compared with older untreated patients, the hazard ratio for death decreased to 0.28 (95% CI, 0.15-0.52) for treated older adults. The effect of HAART substantially improves the survival rate for older individuals and supports the importance of treatment in this group.
The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impa... more The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impaired left ventricular function. Such dysfunction in aortic stenosis may be reversible if caused by afterload mismatch, but not if it is caused by superimposed myocardial infarction. From our echocardiography database, 55 patients with severe aortic stenosis (valve area < or =0.75 cm2) and ejection fractions of 30% or lower who subsequently underwent aortic valve replacement were included. The operative mortality and clinical follow-up were detailed. There were 10 perioperative deaths (operative mortality, 18%). Twenty (36%) of the 55 patients had a prior myocardial infarction. In the 35 patients without prior myocardial infarction, there was only 1 death (3%). In contrast, 9 of 20 patients with prior myocardial infarction died (mortality rate, 45%; P< or =.001). The factors significantly associated with perioperative death on univariate analysis (functional class, mean aortic gradient, and prior myocardial infarction) were entered into a model for stepwise logistic regression. This multivariate analysis showed that only prior myocardial infarction was independently associated with perioperative death (odds ratio, 14.9; 95% confidence interval, 2.4-92.1; P = .004). The risk of aortic valve replacement in patients with severe aortic stenosis and severely reduced left ventricular systolic function is extremely high if the patients have had a prior myocardial infarction. This information should be factored into the risk-benefit analysis that is done preoperatively for these patients, and it may preclude operation for some.
Toxicon, 1999
Snake venoms are complex mixtures of many toxins and enzymes which effectively immobilize prey wi... more Snake venoms are complex mixtures of many toxins and enzymes which effectively immobilize prey without a struggle and assist in digestion. Certain animals have a remarkable resistance to envenomation of snakes. Naturally occurring factors that neutralize snake venoms have been found in the sera of most snakes and a few warm-blooded animals. These antihemorrhagic and antineurotoxic factors have been purified from snake and mammalian sera. The antihemorrhagins are not immunoglobulins since they have different physical and chemical characteristics. The natural immunity to hemorrhagins is the result of tissue inhibitors of metalloproteinases (TIMP) found in animal sera of resistant animals. Most animals have matrix metalloproteinases (MMP) and TIMP that are implicated in a wide variety of normal physiological processes and pathological conditions. MMP in animals have many biological functions in embryogenesis, morphogenesis and tissue remodeling. MMP activities are precisely regulated by endogenous TIMP. Disruption of the balance between MMP and TIMP causes various diseases such as arthritis, periodontal diseases, diabetes, ophthalmologic conditions, neoplasia, metabolic bone disease, atherosclerosis and orthopedic conditions. Resistant animals that have a high titer of TIMP would have a survival advantage when bitten by poisonous snakes. Snake venoms are abundant and stable sources of MMP which are medically important. The venom MMP which cause unregulated destruction of tissue have sequences which have some degree of homology with mammalian MMP which control normal biological processes. Resistant animals are important sources of TIMP which can be used to study metalloproteinase related diseases. For these reasons the MMP in snakes and TIMP in resistant animal are excellent candidates for developing new drug therapies.
Toxicon, 2003
Mortality due to snake envenomation is not a major problem in the United States with approximatel... more Mortality due to snake envenomation is not a major problem in the United States with approximately 8 -12 deaths per year, but envenomation is a serious problem that can result in functional disability, loss of extremities, and a costly recovery. Physicians encounter different clinical situations with each new snakebite victim because of the geographical variations in snake venoms. The best and most acceptable form of treatment is the use of antivenom; however, it must be administered as soon as possible since it is not so effective at reducing local signs of envenomation such as necrosis. The antivenom in the United States is in short supply, expensive and may not even be the most effective for neutralizing all North American snake venoms. In this study, we tested two antivenoms. The first was a Crotalidae Polyvalent Fab fragment with Ovine origin (FabO) manufactured in London, and the second was Antivipmyn, a Mexican manufactured antivenom that is F(ab 0 ) 2 fragment produced in horse (Fab 2 H). The efficacy of the two antivenoms was tested with 15 different snake venoms found in North America. Three different assays were used to test the efficacy of the antivenoms, the in vivo serum protection test (ED 50 ), antihemorrhagic and anticoagulant. The Fab 2 H antivenom was most effective in neutralizing the hemorrhagic activity of 78% of the hemorrhagic venoms used in this study. In the ED 50 assay, the Fab 2 H antivenom was effective in neutralizing all venoms used in this study, while FabO neutralized all but C. m. molossus venom. However, in most cases, FabO required less antivenom than Fab 2 H antivenom to neutralize three LD 50 .
Toxicon, 2003
Mortality due to snake envenomation is not a major problem in the United States with approximatel... more Mortality due to snake envenomation is not a major problem in the United States with approximately 8–12 deaths per year, but envenomation is a serious problem that can result in functional disability, loss of extremities, and a costly recovery. Physicians encounter different clinical situations with each new snakebite victim because of the geographical variations in snake venoms. The best and most acceptable form of treatment is the use of antivenom; however, it must be administered as soon as possible since it is not so effective at reducing local signs of envenomation such as necrosis. The antivenom in the United States is in short supply, expensive and may not even be the most effective for neutralizing all North American snake venoms. In this study, we tested two antivenoms. The first was a Crotalidae Polyvalent Fab fragment with Ovine origin (FabO) manufactured in London, and the second was Antivipmyn, a Mexican manufactured antivenom that is F(ab′)2 fragment produced in horse (Fab2H). The efficacy of the two antivenoms was tested with 15 different snake venoms found in North America. Three different assays were used to test the efficacy of the antivenoms, the in vivo serum protection test (ED50), antihemorrhagic and anticoagulant. The Fab2H antivenom was most effective in neutralizing the hemorrhagic activity of 78% of the hemorrhagic venoms used in this study. In the ED50 assay, the Fab2H antivenom was effective in neutralizing all venoms used in this study, while FabO neutralized all but C. m. molossus venom. However, in most cases, FabO required less antivenom than Fab2H antivenom to neutralize three LD50.
Toxicon, 2007
Crotalus durissus cumanensis snake venoms from different Venezuelan regions, showed biochemical a... more Crotalus durissus cumanensis snake venoms from different Venezuelan regions, showed biochemical and hemostatic variations. Fibrino(geno)lytic, hemorrhagic and procoagulant activities and gel-filtration chromatography and SDS-PAGE profiles were analyzed. Differences were observed in fibrinolytic activity: kallikrein-like amidolytic activity was highest in venoms of Santa Teresa, and Margarita. Lagunetica and Carrizales venoms showed the maximum fibrin lysis. The highest hemorrhagic activity was seen in Lagunetica venom. Margarita had the lowest LD50 of 0.18. Lagunetica, Carrizales and Anzoátegui induced a rapid degradation of fibrinogen α chains and slower degradation on β chains, which could possibly due to a higher content of α fibrinogenases in these venoms. This fibrinogenolytic activity is decreased by metalloprotease inhibitors. All venoms, except Carrizales, presented thrombin-like activity. Anzoátegui, Carrizales and Lagunetica, in which fibrinolytic activity was present, showed the largest concentration of high molecular mass components. These results represent a new finding, not previously described, of fibrinolytic activity in South American C. durissus venoms. Santa Teresa and Margarita had fibrinolytic activity, and lack of hemorrhagic activity, representing an important finding in Venezuelan venoms since the description of a fibrinolytic molecule without hemorrhagic activity can have valuable potential in thrombolytic therapy.
Current Drug Targets - Cardiovascular & Hematological Disorders, 2004
The existence of disintegrins, non-enzymatic, small molecular weight proteins from viper venom, h... more The existence of disintegrins, non-enzymatic, small molecular weight proteins from viper venom, has been known for 2 decades, and their impact on cellular research has been substantial and far-reaching. Disintegrins have been the molecular scaffold used in the design of therapeutics for the prevention of thrombosis and cancer. Their sequencing has provided insights into the evolution of proteins over millennia. Production of recombinant disintegrin mutants and fusion proteins has allowed investigations into molecular mechanisms at work in cell-extracellular matrix interactions. Structural homologies with non-snake proteins have shown disintegrin-like molecules in species ranging from slime mold to humans. Intracellular signaling events have been elucidated through the use of venom disintegrins, including events related to programmed cell death, motility, cell proliferation and viral pathogenesis. Disintegrin sequences (protein or genes) have been placed in microbubbles and liposomes and been found to target neovascular endothelium and metastatic tumors in two mouse models. The purpose of this review is to highlight the members of this disintegrin family discovered since 1998 as well as the increased understanding of their usefulness in therapeutics and technical assays.
Nature, 2010
Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generat... more Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generate a 'thermal image' of predators or prey. Infrared signals are initially received by the pit organ, a highly specialized facial structure that is innervated by nerve fibers of the somatosensory system. How this organ detects and transduces infrared signals into nerve impulses is not known. Here we use an unbiased transcriptional profiling approach to identify TRPA1 channels as infrared receptors on sensory nerve fibers that innervate the pit organ. TRPA1 orthologues from pit bearing snakes (vipers, pythons, and boas) are the most heat sensitive vertebrate ion channels thus far identified, consistent with their role as primary transducers of infrared stimuli. Thus, snakes detect infrared signals through a mechanism involving radiant heating of the pit organ, rather than photochemical transduction. These findings illustrate the broad evolutionary tuning of TRP channels as thermosensors in the vertebrate nervous system. Venomous pit vipers detect warm-blooded prey through their ability to sense infrared (750 nm -1 mm wavelength) radiation. Superimposition of thermal and visual images within the snake's brain enables it to track animals with great precision and speed. Biophysical studies suggest that this system is exquisitely sensitive, such that vipers can detect prey at distances Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Infectious Diseases in Clinical Practice, 2001
New England Journal of Medicine, 1996
Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of ... more Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of the left ventricular outflow tract, in patients with hypertrophic obstructive cardiomyopathy. We assessed the hemodynamic effects of the ingestion of ethanol, in an amount commonly consumed socially, in patients with hypertrophic cardiomyopathy. We performed echocardiography in 36 patients before and several times after the ingestion of either 50 ml of 40 percent ethanol or an isocaloric placebo with the aroma of rum. Each patient received both ethanol and placebo, on different days. The patients, but not the physicians, were blinded to the content of the drink. We measured the sizes of the left atrium and left ventricle, the left-ventricular-wall thickness, blood pressure, heart rate, the degree of systolic anterior motion of the mitral valve, and the pressure gradient across the left ventricular outflow tract. The ingestion of ethanol regulated in a significant drop in the mean (+/- SD) systolic blood pressure (from 130.5 +/- 18.6 to 122.5 +/- 20.3 mm Hg, P<0.001), a significant increase in systolic anterior motion of the mitral valve (from a grade of 2.1 to a grade of 2.5, P<0.001), and a 63 percent increase in the mean gradient across the left ventricular outflow tract (from 38.1 +/- 26.5 to 62.2 +/- 42.4 mm Hg, P<0.001). These changes, which were not associated with symptoms, did not occur after the ingestion of placebo. The ingestion of a small amount of ethanol caused an increase in the gradient across the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy, which could have and adverse clinical effect.
Clinical Infectious Diseases, 2003
Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell reco... more Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell recovery when receiving highly active antiretroviral therapy (HAART), there are few data on mortality. Mortality rates were studied for 253 individuals aged у50 years and a younger group of 535 people in a retrospective cohort; for untreated persons in each age group, the proportions surviving at 3 years were 83% and 70% ( ), P ! .01 respectively. No significant difference in the survival rate was found between the older (83%) and younger (89%) patients who received HAART ( ). The hazard ratio for death in the older untreated group was P p .29 2.4 (95% confidence interval [CI], 1.4-3.9) when exposed to HAART. However, compared with older untreated patients, the hazard ratio for death decreased to 0.28 (95% CI, 0.15-0.52) for treated older adults. The effect of HAART substantially improves the survival rate for older individuals and supports the importance of treatment in this group.
The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impa... more The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impaired left ventricular function. Such dysfunction in aortic stenosis may be reversible if caused by afterload mismatch, but not if it is caused by superimposed myocardial infarction. From our echocardiography database, 55 patients with severe aortic stenosis (valve area < or =0.75 cm2) and ejection fractions of 30% or lower who subsequently underwent aortic valve replacement were included. The operative mortality and clinical follow-up were detailed. There were 10 perioperative deaths (operative mortality, 18%). Twenty (36%) of the 55 patients had a prior myocardial infarction. In the 35 patients without prior myocardial infarction, there was only 1 death (3%). In contrast, 9 of 20 patients with prior myocardial infarction died (mortality rate, 45%; P< or =.001). The factors significantly associated with perioperative death on univariate analysis (functional class, mean aortic gradient, and prior myocardial infarction) were entered into a model for stepwise logistic regression. This multivariate analysis showed that only prior myocardial infarction was independently associated with perioperative death (odds ratio, 14.9; 95% confidence interval, 2.4-92.1; P = .004). The risk of aortic valve replacement in patients with severe aortic stenosis and severely reduced left ventricular systolic function is extremely high if the patients have had a prior myocardial infarction. This information should be factored into the risk-benefit analysis that is done preoperatively for these patients, and it may preclude operation for some.
American Heart Journal, 1995
Protruding aortic arch atheromas are associated with otherwise unexplained strokes and transient ... more Protruding aortic arch atheromas are associated with otherwise unexplained strokes and transient ischemic attacks. Therefore aortic atheromas also may be important in patients with carotid artery disease. Forty-five patients with ≥50% carotid stenosis and stroke or transient ischemic attack within 6 weeks underwent transesophageal echocardiographic examination (TEE). They were matched for age, sex, and hypertension with 45 control subjects who had also had a recent cerebral event but in whom significant carotid stenosis was absent. Protruding aortic arch atheromas were present in 17 (38%) of 45 patients with carotid disease and only 7 (16%) of 45 of control subjects (p = 0.02). Mobile atheromas (with the greatest embolic potential) were present almost exclusively in case patients, 6 (13%) of 45, versus 1 (2%) of 45 control subjects (p = 0.05). Case patients with mobile atheromas had the most severe carotid stenosis (≥80%). Cerebral symptoms were discordant with the side of the carotid stenosis in 10 case patients, and 4 had atheromas. In conclusion, protruding atheromas of the aortic arch are present in significant numbers of symptomatic patients with carotid artery disease. These atheromas may represent an additional cause of symptoms in patients with carotid stenosis. TEE to look for protruding aortic atheromas may be considered in patients with neurologic events despite the presence of significant carotid stenosis, especially if the symptoms are discordant with the side of carotid stenosis.
Journal of The American College of Cardiology, 1991
Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data wer... more Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data were compared in adult patients with isolated or combined aortic and mitral valve disease. A clinical decision to operate, not operate or remain uncertain was made by experienced cardiologists given either Doppler echocardiographic or cardiac catheterization data. A prospective evaluation was performed on 189 consecutive patients (mean age 67 years) with valvular heart disease who were being considered for surgical treatment on the basis of clinical information. All patients underwent cardiac catheterization and detailed Doppler echocardiographic examination.Three sets of two cardiologist decision makers who did not know patient identity were given clinical information in combination with either Doppler echocardiographic or cardiac catheterization data. The combination of Doppler echocardiographic and clinical data was considered inadequate for clinical decision making in 21% of patients with aortic and 5% of patients with mitral valve disease. The combination of cardiac catheterization and clinical data was considered inadequate in 2% of patients with aortic and 2% of patients with mitral valve disease. Among the remaining patients, the cardiologists using echocardiographic or angiographic data were in agreement on the decision to operate or not operate in 113 (76% overall).When the data were analyzed by specific valve lesion, decisions based on Doppler echocardiography or catheterization were in agreement in 92%, 90%, 83% and 69%, respectively, of patients with aortic regurgitation, mitral stenosis, aortic stenosis and mitral regurgitation. Differences in cardiac output determination, estimation of valvular regurgitation and information concerning coronary anatomy were the main reasons for different clinical management decisions. These results suggest that for most adult patients with aortic or mitral valve disease, alone or in combination, Doppler echocardiographic data enable the clinician to make the same decision reached with catheterization data.
Journal of The American College of Cardiology, 1995
We attempted to determine the prevalence of strands on native and prosthetic valves, as detected ... more We attempted to determine the prevalence of strands on native and prosthetic valves, as detected by transesophageal echocardiography, and to assess the relative risk for systemic emboli associated with these strands.Fine threadlike strands, seen on native and prosthetic valves by transesophageal echocardiography, have been implicated in systemic embolization.During a 2-year period, 1,559 patients underwent transesophageal echocardiography at our center. Of these, 41 patients had strands and no other identifiable source of systemic emboli. They were matched for age, gender, history of hypertension and history of smoking with a control group of 41 patients without strands who also had no identifiable source of emboli. The risk of embolization in the two groups was compared.Of 1,559 patients studied by transesophageal echocardiography, 86 (5.5%) had strands. Strands were far more common on mitral valves than on aortic valves. Of the patients with strands, 38% had had an event consistent with a systemic embolus, whereas 62% had not. Of 597 patients with an embolic event, 63 (10.6%) had strands, whereas only 23 (2.3%) of 962 patients without emboli had strands. In the case-control study, 33 (83%) of the 41 patients with strands without another source of embolism had emboli compared with only 12 (29%) of the 41 control patients without another source (odds ratio 10.0, 95% confidence interval 3.6 to 27.8, p = 0.00001).Valvular strands visualized by transesophageal echocardiography are associated with systemic embolization.
Journal of The American College of Cardiology, 1994
Objectives. The purpose of this study was to prospectively evaluate the risk of vascular events i... more Objectives. The purpose of this study was to prospectively evaluate the risk of vascular events in patients with protruding aortic atheromas.Background. Protruding atheromas of the thoracic aorta have been shown to be associated with embolic disease in previous retrospective studies.Methods. During a 1-year period, 521 patients had transesophageal echocardiography. Of these, 42 patients had protruding atheromas and no other source of emboli. They were followed up for up to 2 years (mean follow-up 14 months) and compared with a control group without atheromas, matched for age, gender and hypertension.Results. Of 42 patients with atheromas, 14 (33%) had 19 vascular events during follow-up (5 brain, 2 eye, 4 kidney, 1 bowel, 7 lower extremity). Of 42 control patients, 3 (7%) had vascular events (2 brain, 1 eye). Univariate analysis identified only protruding atheromas as significantly correlating with events (p = 0.003). There was no positive correlation of events with age, gender, hypertension, smoking, family history, atrial fibrillation, valve replacement, antithrombotic drug use, diabetes or coronary disease. Multivariate analysis showed that only protruding atheromas independently predicted events (p = 0.005, odds ratio 4.3, 95% confidence interval 1.2 to 15.0). Nine patients died in the atheroma group versus six in the control group, but this was not statistically significant (p = 0.39).Conclusions. Protruding atheromas seen on transesophageal echocardiography predict future vascular events.
Arthritis and Rheumatism, 2006
ObjectiveTo compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX mono... more ObjectiveTo compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.MethodsThis was a 2-year, multicenter, double-blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.This was a 2-year, multicenter, double-blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.ResultsCombination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.ConclusionIn this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.
American Heart Journal, 1997
Plasma homocyst(e)ine [H(e)] levels correlate with the prevalence of arterial occlusive diseases.... more Plasma homocyst(e)ine [H(e)] levels correlate with the prevalence of arterial occlusive diseases. Recently, transesophageal echocardiography (TEE) has been used to evaluate patients with atherosclerotic plaques in the thoracic aorta. The purpose of this study was to determine whether H(e) levels correlate with the degree of atherosclerotic plaque in the thoracic aorta (ATH) as seen on TEE. Maximum plaque areas for three locations in the thoracic aorta (arch, proximal descending, and distal descending) were measured with TEE in 156 patients. Maximum plaque areas for these locations were added to yield an estimate of ATH. ATH and H(e) levels, and levels of folic acid, vitamin B 12 , and pyridoxal 5`-phosphate were measured in a double-blind manner. Univariate analysis demonstrated a significant correlation of H(e) with ATH ( r = 0.3, p < 0.001). On multivariate analysis, H(e) was independently predictive of ATH ( r for the model including H(e) was 0.63, p < 0.0001). Plasma H(e) levels are therefore significantly and independently correlated with the degree of atherosclerosis in the thoracic aorta. (Am Heart J 1997;133:534-40.)
Infectious Diseases in Clinical Practice, 2001
New England Journal of Medicine, 1996
Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of ... more Ethanol causes vasodilation, which might have an adverse effect, due to increased obstruction of the left ventricular outflow tract, in patients with hypertrophic obstructive cardiomyopathy. We assessed the hemodynamic effects of the ingestion of ethanol, in an amount commonly consumed socially, in patients with hypertrophic cardiomyopathy. We performed echocardiography in 36 patients before and several times after the ingestion of either 50 ml of 40 percent ethanol or an isocaloric placebo with the aroma of rum. Each patient received both ethanol and placebo, on different days. The patients, but not the physicians, were blinded to the content of the drink. We measured the sizes of the left atrium and left ventricle, the left-ventricular-wall thickness, blood pressure, heart rate, the degree of systolic anterior motion of the mitral valve, and the pressure gradient across the left ventricular outflow tract. The ingestion of ethanol regulated in a significant drop in the mean (+/- SD) systolic blood pressure (from 130.5 +/- 18.6 to 122.5 +/- 20.3 mm Hg, P<0.001), a significant increase in systolic anterior motion of the mitral valve (from a grade of 2.1 to a grade of 2.5, P<0.001), and a 63 percent increase in the mean gradient across the left ventricular outflow tract (from 38.1 +/- 26.5 to 62.2 +/- 42.4 mm Hg, P<0.001). These changes, which were not associated with symptoms, did not occur after the ingestion of placebo. The ingestion of a small amount of ethanol caused an increase in the gradient across the left ventricular outflow tract in patients with hypertrophic obstructive cardiomyopathy, which could have and adverse clinical effect.
Clinical Infectious Diseases, 2003
Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell reco... more Although human immunodeficiency virus-infected people aged у50 years have a blunted CD4 cell recovery when receiving highly active antiretroviral therapy (HAART), there are few data on mortality. Mortality rates were studied for 253 individuals aged у50 years and a younger group of 535 people in a retrospective cohort; for untreated persons in each age group, the proportions surviving at 3 years were 83% and 70% ( ), P ! .01 respectively. No significant difference in the survival rate was found between the older (83%) and younger (89%) patients who received HAART ( ). The hazard ratio for death in the older untreated group was P p .29 2.4 (95% confidence interval [CI], 1.4-3.9) when exposed to HAART. However, compared with older untreated patients, the hazard ratio for death decreased to 0.28 (95% CI, 0.15-0.52) for treated older adults. The effect of HAART substantially improves the survival rate for older individuals and supports the importance of treatment in this group.
The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impa... more The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impaired left ventricular function. Such dysfunction in aortic stenosis may be reversible if caused by afterload mismatch, but not if it is caused by superimposed myocardial infarction. From our echocardiography database, 55 patients with severe aortic stenosis (valve area < or =0.75 cm2) and ejection fractions of 30% or lower who subsequently underwent aortic valve replacement were included. The operative mortality and clinical follow-up were detailed. There were 10 perioperative deaths (operative mortality, 18%). Twenty (36%) of the 55 patients had a prior myocardial infarction. In the 35 patients without prior myocardial infarction, there was only 1 death (3%). In contrast, 9 of 20 patients with prior myocardial infarction died (mortality rate, 45%; P< or =.001). The factors significantly associated with perioperative death on univariate analysis (functional class, mean aortic gradient, and prior myocardial infarction) were entered into a model for stepwise logistic regression. This multivariate analysis showed that only prior myocardial infarction was independently associated with perioperative death (odds ratio, 14.9; 95% confidence interval, 2.4-92.1; P = .004). The risk of aortic valve replacement in patients with severe aortic stenosis and severely reduced left ventricular systolic function is extremely high if the patients have had a prior myocardial infarction. This information should be factored into the risk-benefit analysis that is done preoperatively for these patients, and it may preclude operation for some.