Highs and Lows in Lipoprotein Cholesterol Hypercholesterolemia has long loomed large amidst the various risk factors for coronary disease. A vast amount of effort and expense has gone into the study of its cause, mechanism, epidemiology, and possible correction by diet and drugs. Even now, despite recent doubts, the plasma cholesterol level is believed by many to be a reliable atherogenic index. With increasing understanding of the metabolism and transport of cholesterol, this simplistic index gave way to a sophisticated schema in which the low-density \g=b\-lipoprotein cholesterol level, rather than the total plasma cholesterol level became a key to atherogenesis. However, the lipoprotein story did not end there. A new contender, high-density \g=a\-lipoproteincholesterol, entered the atherogenic arena. A number of investigators recently reexamined the effect of this lipoprotein on atherogenesis\p=m-\aneffect observed by Barr et al1 in 1951 but ignored since that time. In contrast with the atherogenic \g=b\-lipoprotein, the high-density \g=a\\x=req-\ lipoprotein appears to protect persons from atherosclerosis, possibly by transporting cholesterol out of the vessel wall.2 A low rather than a high plasma level of high-density lipoprotein constitutes a coronary risk factor. (The highs and the lows become confusing when one forgets that they apply to levels as well as to densities.) The importance of this factor has been underscored by two recent studies from parts of the world as distant from each other as Norway and New Zealand. Miller et al' report a follow-up study of 6,595 men aged 20 to 49 years living in the municipality of Tromsö, Norway. Discriminant functional analysis of their data showed the risk for coronary disease to be related directly to low-density and inversely to high-density lipoprotein cholesterol levels. The latter relationship proved to be three times more predictive of coronary heart disease than the former. Stanhope and Sampson" conducted an epidemiologic study to find metabolic correlates to the higher incidence of ischémie heart disease among New Zealand Maoris, especially females, than among whites. Their data from plasma lipid analyses in 715 adolescents attending a large school showed that plasma high-density lipoprotein cholesterol levels were lower in Maoris than in non-Maoris and were also lower in girls than in boys. Low-density lipoprotein levels did not show sex or race difference. The
yet
to
practical implications of these and similar studies have fully explored. It is becoming increasingly apparent,
be
Address editorial communications to the
Editor,
Requirements for Authors.—Congress recently passed The Copyright Revision Act of 1976 which affects JAMA's procedure for acceptance of manuscripts. Please New
refer to the "Instructions for Authors" page for details.
however, that widely accepted coronary risk factors and dietary
regimens
for their correction may be due for
reassessment.
Samuel Vaisrub, MD 1. Barr BP, Russ EM, Eder HA: Protein-lipid relationships in human plasma: II. In atherosclerosis and related conditions. Am J Med 11:480-493, 1951. 2. Miller GJ, Miller NE: Plasma\p=m-\highdensity lipoprotein concentration and development of ischemic heart disease. Lancet 1:16-19, 1975. 3. Miller NE, F\l=o/\rde OH, Thelle DS, et al: The Troms\l=o/\Heart Study: High density lipoprotein and coronary heart-disease: A prospective case-control study. Lancet 1:965-967, 1977. 4. Stanhope JM, Sampson VM: High-density-lipoprotein cholesterol and other serum lipids in a New Zealand biracial adolescent sample: The Wairoa College Survey. Lancet 1:968-970, 1977.
Antiviral Drugs A few among us may recall the excitement and astonishment that we experienced when first having access to penicillin to treat serious or life-threatening infections. With the discovery of this antibiotic, a new class of therapeutic agents was founded, and there opened before us therapeutic vistas beyond anything we had dreamed of. The second major antibiotic to be introduced was streptomycin for the treatment of tuberculosis. For the first time, we witnessed recoveries from tuberculous meningitis, a disease that had resulted in 100% mortality. The privilege of using these miracle drugs shortly after their discovery was, for some of us, the most exciting experience of our lifetime. In the years that have followed, we grew accustomed to the discovery of powerful new therapeutic agents, accepted their introduction into medicine with little or no fanfare, and lost the excitement and admiration they should have invoked in us. However, the development of antiviral agents has regenerated the excitement that follows a major breakthrough, especially one that may lead to the development of a totally new class of drugs, new areas for research, and perhaps cure of diseases for which we presently have no treatment.1 Two antiviral drugs now show great promise—amantadine hydrochloride for the treatment of influenza2 and vidarabine for
535 N Dearborn St, Chicago 60610
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/31/2015
the treatment of herpes simplex infections.3 The entrance of both of these drugs onto the therapeutic scene has been more gradual and less dramatic than was the introduction of peni¬ cillin and streptomycin, but their ultimate impact on medical practice may be just as great or even greater. Fortunately, we have more than 30 years of experience with the antibacterial drugs on which we can draw in planning for future experiments with antiviral agents, and enough parallelism is now apparent between the antivirals and antibacterials that we can avoid some of the pitfalls that might otherwise await us. The antiviral agents appear to be most effective when the infecting viral load is small. Therefore, early treatment produces more dramatic improvement than starting therapy late in the course of the disease. Some viruses, like some bacteria, eg, the tubercle bacillus, have long periods of latency during which they are not susceptible to attack by chemotherapeutic agents. Therefore, one may treat the acute manifestations of an infection but not eradicate the infecting agent from the body. If host resistance does not reach and remain at an adequate level, the disease can recur after chemotherapy has been stopped. When antiviral agents are effective, a satisfactory clinical response occurs. If they are ineffective, increasing the dosage of drug beyond the acceptable therapeutic range does not cure the infection, results in a toxic reaction to the drug, and may harm the patient. Vidarabine is metabolized to arabinosyl hypoxanthine, which also has antiviral properties, but the parent drug and its metabolite are excreted in the urine. Therefore, dosage must be governed by kidney function and be appropriately reduced when kidney failure supervenes. Finally virus diseases like bacterial diseases are better prevented than cured, and the availability of antiviral agents should not diminish our efforts to achieve satisfactory levels of immunity against virus infections by vaccinations. One can only speculate about the future, but amantadine and vidarabine have shown that agents can be found that selectively damage virus particles without injury to mammalian cells. If we should enjoy the same success in developing additional antivi¬ ral agents in the future as we have in developing antibacterial agents in the past, then we will have conquered most of the diseases that shorten the normal life span. What will be left are those diseases that man inflicts on himself through carelessness, greed, laziness, and stupidity. For these traits in man, there are no cures as yet in sight. William R. Barclay, MD
Antivirals with clinical potential: A symposium at Stanford University. J Infect Dis 133(suppl), 1976. 2. Chanin A: Influenza: Vaccines or amantadine? JAMA 237:1445, 1977. 3. Whitley RJ, Soong S, Dolin R, et al: Adenine arabinoside therapy of biopsy-proven herpes simplex. N Engl J Med 297:289-294, 1977. 4. Taber LH, Greenberg SB, Perez FI, et al: Herpes simplex encephalitis treated with vidarabine (adenine arabinoside). Arch Neural 34:608-610, 1977. 5. Check W: Herpes simplex successfully treated. JAMA 238:1121-1126, 1977. 6. Aronson MD, Phillips CF, Gump DW, et al: Vidarabine therapy for severe herpesvirus infections: An unusual syndrome of chronic varicella and transient 1.
Lost in Metrication Old-times who trained before the metric era caught up with medicine remember well how difficult it was to adapt to the early inroads of the metric system. With drams, ounces, minims, and grains ingrained in the mind, it was a struggle to engram into it grams, milligrams, and cubic centimeters. Conversions were a chore. But the metric system was the wave of the future, and to resist its onward surge was patently futile. It was equally futile to resist its lateral motion when milliequivalents began to replace milligrams percent. This too was taken in stride as a necessary step in the march of progress. In grappling with the metric system, the physician could not count on sympathy from the layman to whom the old English units of prescribed drugs meant little. The patient about to receive a hypodermic injection of morphine could not care less whether the dose was 1/4 of a grain or 15 mg. The physician's perplexities were not his concern. Currently, however, the all encompassing expansion of the metric system is involving the laymen as much as the physician. Everyone must adjust to kilograms, kilometers, and centimeters, as pounds, miles, and inches fade away into the distance. Everyone must adapt to the unfamiliar ranges of the Celsius scale, which is replacing the Fahrenheit. And no longer will anyone dream of owning green acres of land, when deeds refer only to hectares. There is little doubt that all will eventually adjust to the metric system just as physicians did in the past. They will do so out of concern for posterity. Future generations should be of the mensurational dichotomies. spared misery But will future generations be spared the embarrassments of ignorance when they encounter the mention of old measure¬ ment units in old proverbs? How, for instance, will "an ounce of prevention is worth a pound of cure" be understood by one who never heard of ounces or pounds? Will the needed information be provided in parentheses, footnotes, and addenda, or will the proverb itself be transcribed into "28.3495 grams of prevention is worth 0.3732 kilograms of cure"? More importantly, how will literary quotations containing references to archaic measurement units be explained to the future reader? If transcription is the answer, then Shakespeare may yet turn in his grave on hearing Shylock insist on the "0.4563 kg of flesh" and King Lear exclaim: "Ay, every 2.54 cm a King." And there is no telling what the ghost of Robert Frost will do when miles are converted into kilometers in his memorable "But I have promises to keep,/ And miles to go before I sleep." Having previously defined poetry as "what is lost in translation," will he now in his incorporeal state redefine it as "what is lost in metrication"? There will indeed be a sense of loss. Haunting memories will remain of a vanished golden age when authors could get a great deal of mileage from a single study, and readers could take it with a grain of salt.
immunologic deficiency. JAMA 235:1339-1342, 1976.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/31/2015
Samuel Vaisrub, MD
yet
to
practical implications of these and similar studies have fully explored. It is becoming increasingly apparent,
be
Address editorial communications to the
Editor,
Requirements for Authors.—Congress recently passed The Copyright Revision Act of 1976 which affects JAMA's procedure for acceptance of manuscripts. Please New
refer to the "Instructions for Authors" page for details.
however, that widely accepted coronary risk factors and dietary
regimens
for their correction may be due for
reassessment.
Samuel Vaisrub, MD 1. Barr BP, Russ EM, Eder HA: Protein-lipid relationships in human plasma: II. In atherosclerosis and related conditions. Am J Med 11:480-493, 1951. 2. Miller GJ, Miller NE: Plasma\p=m-\highdensity lipoprotein concentration and development of ischemic heart disease. Lancet 1:16-19, 1975. 3. Miller NE, F\l=o/\rde OH, Thelle DS, et al: The Troms\l=o/\Heart Study: High density lipoprotein and coronary heart-disease: A prospective case-control study. Lancet 1:965-967, 1977. 4. Stanhope JM, Sampson VM: High-density-lipoprotein cholesterol and other serum lipids in a New Zealand biracial adolescent sample: The Wairoa College Survey. Lancet 1:968-970, 1977.
Antiviral Drugs A few among us may recall the excitement and astonishment that we experienced when first having access to penicillin to treat serious or life-threatening infections. With the discovery of this antibiotic, a new class of therapeutic agents was founded, and there opened before us therapeutic vistas beyond anything we had dreamed of. The second major antibiotic to be introduced was streptomycin for the treatment of tuberculosis. For the first time, we witnessed recoveries from tuberculous meningitis, a disease that had resulted in 100% mortality. The privilege of using these miracle drugs shortly after their discovery was, for some of us, the most exciting experience of our lifetime. In the years that have followed, we grew accustomed to the discovery of powerful new therapeutic agents, accepted their introduction into medicine with little or no fanfare, and lost the excitement and admiration they should have invoked in us. However, the development of antiviral agents has regenerated the excitement that follows a major breakthrough, especially one that may lead to the development of a totally new class of drugs, new areas for research, and perhaps cure of diseases for which we presently have no treatment.1 Two antiviral drugs now show great promise—amantadine hydrochloride for the treatment of influenza2 and vidarabine for
535 N Dearborn St, Chicago 60610
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/31/2015
the treatment of herpes simplex infections.3 The entrance of both of these drugs onto the therapeutic scene has been more gradual and less dramatic than was the introduction of peni¬ cillin and streptomycin, but their ultimate impact on medical practice may be just as great or even greater. Fortunately, we have more than 30 years of experience with the antibacterial drugs on which we can draw in planning for future experiments with antiviral agents, and enough parallelism is now apparent between the antivirals and antibacterials that we can avoid some of the pitfalls that might otherwise await us. The antiviral agents appear to be most effective when the infecting viral load is small. Therefore, early treatment produces more dramatic improvement than starting therapy late in the course of the disease. Some viruses, like some bacteria, eg, the tubercle bacillus, have long periods of latency during which they are not susceptible to attack by chemotherapeutic agents. Therefore, one may treat the acute manifestations of an infection but not eradicate the infecting agent from the body. If host resistance does not reach and remain at an adequate level, the disease can recur after chemotherapy has been stopped. When antiviral agents are effective, a satisfactory clinical response occurs. If they are ineffective, increasing the dosage of drug beyond the acceptable therapeutic range does not cure the infection, results in a toxic reaction to the drug, and may harm the patient. Vidarabine is metabolized to arabinosyl hypoxanthine, which also has antiviral properties, but the parent drug and its metabolite are excreted in the urine. Therefore, dosage must be governed by kidney function and be appropriately reduced when kidney failure supervenes. Finally virus diseases like bacterial diseases are better prevented than cured, and the availability of antiviral agents should not diminish our efforts to achieve satisfactory levels of immunity against virus infections by vaccinations. One can only speculate about the future, but amantadine and vidarabine have shown that agents can be found that selectively damage virus particles without injury to mammalian cells. If we should enjoy the same success in developing additional antivi¬ ral agents in the future as we have in developing antibacterial agents in the past, then we will have conquered most of the diseases that shorten the normal life span. What will be left are those diseases that man inflicts on himself through carelessness, greed, laziness, and stupidity. For these traits in man, there are no cures as yet in sight. William R. Barclay, MD
Antivirals with clinical potential: A symposium at Stanford University. J Infect Dis 133(suppl), 1976. 2. Chanin A: Influenza: Vaccines or amantadine? JAMA 237:1445, 1977. 3. Whitley RJ, Soong S, Dolin R, et al: Adenine arabinoside therapy of biopsy-proven herpes simplex. N Engl J Med 297:289-294, 1977. 4. Taber LH, Greenberg SB, Perez FI, et al: Herpes simplex encephalitis treated with vidarabine (adenine arabinoside). Arch Neural 34:608-610, 1977. 5. Check W: Herpes simplex successfully treated. JAMA 238:1121-1126, 1977. 6. Aronson MD, Phillips CF, Gump DW, et al: Vidarabine therapy for severe herpesvirus infections: An unusual syndrome of chronic varicella and transient 1.
Lost in Metrication Old-times who trained before the metric era caught up with medicine remember well how difficult it was to adapt to the early inroads of the metric system. With drams, ounces, minims, and grains ingrained in the mind, it was a struggle to engram into it grams, milligrams, and cubic centimeters. Conversions were a chore. But the metric system was the wave of the future, and to resist its onward surge was patently futile. It was equally futile to resist its lateral motion when milliequivalents began to replace milligrams percent. This too was taken in stride as a necessary step in the march of progress. In grappling with the metric system, the physician could not count on sympathy from the layman to whom the old English units of prescribed drugs meant little. The patient about to receive a hypodermic injection of morphine could not care less whether the dose was 1/4 of a grain or 15 mg. The physician's perplexities were not his concern. Currently, however, the all encompassing expansion of the metric system is involving the laymen as much as the physician. Everyone must adjust to kilograms, kilometers, and centimeters, as pounds, miles, and inches fade away into the distance. Everyone must adapt to the unfamiliar ranges of the Celsius scale, which is replacing the Fahrenheit. And no longer will anyone dream of owning green acres of land, when deeds refer only to hectares. There is little doubt that all will eventually adjust to the metric system just as physicians did in the past. They will do so out of concern for posterity. Future generations should be of the mensurational dichotomies. spared misery But will future generations be spared the embarrassments of ignorance when they encounter the mention of old measure¬ ment units in old proverbs? How, for instance, will "an ounce of prevention is worth a pound of cure" be understood by one who never heard of ounces or pounds? Will the needed information be provided in parentheses, footnotes, and addenda, or will the proverb itself be transcribed into "28.3495 grams of prevention is worth 0.3732 kilograms of cure"? More importantly, how will literary quotations containing references to archaic measurement units be explained to the future reader? If transcription is the answer, then Shakespeare may yet turn in his grave on hearing Shylock insist on the "0.4563 kg of flesh" and King Lear exclaim: "Ay, every 2.54 cm a King." And there is no telling what the ghost of Robert Frost will do when miles are converted into kilometers in his memorable "But I have promises to keep,/ And miles to go before I sleep." Having previously defined poetry as "what is lost in translation," will he now in his incorporeal state redefine it as "what is lost in metrication"? There will indeed be a sense of loss. Haunting memories will remain of a vanished golden age when authors could get a great deal of mileage from a single study, and readers could take it with a grain of salt.
immunologic deficiency. JAMA 235:1339-1342, 1976.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/31/2015
Samuel Vaisrub, MD
