Archives of Internal Medicine

Barron, Bruce A.;Bukantz, Samuel C.

doi: 10.1001/archinte.1967.00290240069001pmid: N/A

Abstract In THIS paper the current Food and Drug Administration (FDA) regulations pertaining to the testing of new drugs are reviewed, and a basic statistical issue of the design of a clinical trial is discussed. The regulatory procedures that are described are applicable to any sponsor of a clinical trial—whether that sponsor is a pharmaceutical corporation, a department of pharmacology within a medical school, or an individual. The validity of any conclusion concerning the effects of a new drug—both beneficial and adverse—is dependent upon the experimental design of the trial. The statistical principle discussed here provides a ruler with which to measure the sensitivity of the design of a clinical trial. Kefauver-Harris Amendments Prior to the passage of the 1938 Food, Drug, and Cosmetic Act, drugs could be marketed before "clearance" by the Federal Government. The clearance procedures established by the 1938 act were limited to tests for safety. The 1962 References 1. Hill, A. Bradford: Controlled Clinical Trials , Oxford: Blackwell Scientific Publications, 1960. 2. Armitage, Peter: Sequential Medical Trials , Oxford: Blackwell Scientific Publications, 1960. 3. Anscombe, F.J.: Sequential Medical Trials , J Amer Stat Assoc 58:365, 1963.Crossref

Blount, Robert E.

doi: 10.1001/archinte.1967.00290240079002pmid: N/A

Abstract OVER a billion people live in tropical and subtropical areas where malaria is still a serious threat.1,2 The global eradication program has so far succeeded mostly in temperate zones. Resourceful mosquito vectors, through either physiological or behavioral resistance to residual insecticides, together with serious administrative problems, threaten the success of the eradication program.3 The appearance of chloroquine-resistant strains of falciparum malaria in South America and in Southeast Asia compounds the situation.4-9 Studies in volunteers in the United States, with strict controls, provide confirmation of drug resistance.8 Most of these strains are refractory not only to chloroquine, but to other synthetic antimalarials such as quinacrine (Atabrine), chlorguanide, and pyrimethamine.10 In late 1965, outbreaks of falciparum malaria appeared in American, Australian, and Korean troops in South Vietnam. Cases occurred almost exclusively among members of rifle companies who had engaged the Viet Cong in intense combat in the central high-land jungles. Clinical References 1. Tropical Health , National Academy of Science, National Research Council, 1962. 2. World Health Organization document A-16-P and B-3, (March 13,) 1963. 3. Bruce-Chwatt, L.J.: Malaria Research for Malaria Eradication , Trans Roy Soc Trop Med Hyg 59:105-137 ( (Jan) ) 1965.Crossref 4. Young, M.D., and Moore, D.V.: Chloroquine Resistant in Plasmodium Falciparum , Amer J Trop Med Hyg 10:317-320 ( (May) ) 1961. 5. Young, M.D., et al: Drug Resistant P falciparum From Thailand , Amer J Trop Med Hyg 12:305-314 ( (May) ) 1963. 6. Sandosham, A.A.; Eyles, D.E.; and Montgomery, R.: Drug Resistance in Falciparum Malaria in SE Asia, Proceedings of the Seventh International Congress on Tropical Medicine and Malaria, September 1963. 7. Eyles, D.E., et al: P Falciparum Resistant to Chloroquine in Cambodia , Amer J Trop Med Hyg 12:840-843 ( (Nov) ) 1963. 8. Powell, R.D., et al: Studies on a Strain of Chloroquine-Resistant Plasmodium falciparum From Vietnam , Bull WHO 31:379-392, 1964. 9. Blount, R.E.: Malaria: An Unsolved Military Medical Problem , Amer J Med Sci 247:407-411 ( (April) ) 1964.Crossref 10. Tigerft, W.D.: Present and Future Malaria Problems , Milit Med 131( (suppl) ):853-856 (Sept) 1966. 11. Blount, R.E.: Malaria in Vietnam, Special Report to the Surgeon General, Jan 29, 1966. 12. Dennis, L.H.; Eichelberger, J.W., Jr.; and Conrad, M.E.: Coagulation Factors in Drug Resistant Plasmodium falciparum Malaria , Clin Res 14:338 ( (April) ) 1966. 13. Dennis, L.G., et al: A Coagulation Defect and Its Treatment With Heparin in Plasmodium knowlesi Malaria in Rhesus Monkeys , Milit Med 131 ( (suppl) ):1107-1110 (Sept) 1966. 14. Hardaway, R.M.: Syndromes of Disseminated Intravascular Coagulation , Springfield, Ill: Charles C Thomas, Publishers, 1966. 15. McKay, D.G.: Disseminated Intravascular Coagulation , New York: Paul B. Hoeber, Inc., 1965. 16. Devakul, D.; Harinsuta, T.; and Reid, H.A.: 125I-Labelled Fibrinogen in Cerebral Malaria , Lancet 2:886-888, ( (Oct 22) ) 1966.Crossref 17. Brooks, M.H., et al: General Pathophysiology of Chloroquine-Resistant P falciparum Malaria , Amer J Med to be published. 18. McCabe, M.E.: Malaria—A Military Medical Problem Yet With Us , Med Serv J Canada 22:313-332 ( (May) ) 1966. 19. Barry, K.G., and Malloy, J.P.: Oliguric Renal Failure: Evaluation and Therapy by Intravenous Infusion of Mannitol , JAMA 179:510-513 ( (Feb 17) ) 1962.Crossref 20. Segal, A.: The Clinical Use of Dextran Solutions , New York: Grune & Stratton, Inc., 1964. 21. Faris, A.A.; Hardin, C.A.; and Poser, C.M.: Pathogenesis of Hemorrhagic Infarction of the Brain , Arch Neurol 9:468-476 ( (Nov) ) 1963.Crossref 22. McFarland, W.; Galbraith, R.G.; and Miale, A.J.: Heparin Therapy in Auto-immune Hemolytic Anemia , Blood 15:741-747 ( (May) ) 1960. 23. Young, M.D.: " Malaria " in Hunter, G.W., III; Frye, W.W.; and Swartzwelder, J. (eds.): A Manual of Tropical Medicine , ed 4, Philadelphia: W. B. Saunders Company, 1966. 24. Blohm, R.W., Jr.: Notes on Malaria—Past, Present and Future , USARV Medical Newsletter 1:45-47 ( (Aug-Sept) ) 1966. 25. Powell, R.D.: The Chemotherapy of Malaria , Clin Pharmacol Ther 7:48-76 ( (Jan-Feb) ) 1966.

Sheehy, Thomas W.;Reba, Richard C.;Neff, Thomas A.;Gaintner, J. Richard;Tigertt, William D.

doi: 10.1001/archinte.1967.00290240083003pmid: N/A

Abstract Shortly SHORTLY after the antimalarial activity of the parent sulfone dapsone was discovered, the drug was discarded as too toxic for human use.1-4 This occurred at the time when it was assumed that the amount of sulfone necessary for treatment was similar to that used with the sulfa drugs, ie, 1 to 2 gm daily. As a result, total doses of 36 and 16 gm of dapsone were administered over periods as short as nine days in the first human trials of dapsone as an antimalarial agent.5,6 In both clinical trials, dapsone was effective against Plasmodium falciparum, but later reports of its toxicity1-4 and the successful introduction of the 4-aminoquinoline drugs led to abandonment of dapsone as an antimalarial drug. In 1949, dapsone was introduced for the treatment of leprosy,7 and soon after small daily doses of dapsone were found to be therapeutically effective and relatively non-toxic (ie, 100 mg or References 1. Buttle, G.A.H., et al: Treatment of Streptococcal Infections in Mice With 4:4′diaminodiphenylsulfone , Lancet 1:1331-1334, 1937.Crossref 2. Foeneau, E., et al: Action Antistreptococcique des P-aminophenylalcoysulfonas et de Quelques Derives Sulfures Voiains , C R Soc Biol 127:393-397, 1938. 3. Long, P.H.: Early Experiences With DDS in Man , Int J Leprosy 18:247, 1950. 4. Coggeshall, L.T.; Maier, J.; and Best, C.A.: The Effectiveness of Two New Types of Chemotherapeutic Agents in Malaria , JAMA 117:1077-1081, 1941.Crossref 5. Patrono, V.: Sull'attivita Antimalarica del 4-4′diaminodifenilsulfone , G Med Milit 417:427-437, 1943. 6. Tarabini, G., and Secreto, E.: I1 Didestrosio Diaminodifenilsulfone Nella Eura Della Malaria , Boll Soc Medicochir Modena 1:19-31, 1945. 7. Cochrane, R.G., et al: Two and One Half Years' Experimental Work on Sulfone Group of Drugs , Leprosy Rev 20:4-64, 1949. 8. Garrett, A.S., and Corcos, M.G.: Dapsone Treatment of Leprosy , Leprosy Rev 23:106-108, 1952. 9. Garrett, A.S.: Five Years of Mass Dapsone (DDS) Treatment , Leprosy Rev 27:54-60, 1956. 10. Lecker, D.L: Note on Sulfone Activity in Malaria Infection , Leprosy Rev 27:66-69, 1956. 11. Archibald, H.M., and Ross, C.M.: A Preliminary Report on the Effect of Diamino-diphenylsulphone on Malaria in Northern Nigeria , J Trop Med Hyg 63:25-27, 1960. 12. Costa, F.C.: A Accao Antipaludica das Sulfonas , Ann Inst Med Trop 17:737-753, 1960. 13. Basu, P.C.; Mondal, M.M.; and Chakrabarti, S.C.: Treatment of Human Malaria by Diaminodiphenyl-sulphone (DDS), Singly and in Combination With Pyrimethamine , Indian J Malar 16:157-175, 1962. 14. Ramakrishnan, S.P., et al: A Study on the Joint Action of Diaminodiphenylsulfone (DDS) and Pyrimethamine in the Sporogony Cycle of Plasmodium Galinacium , Indian J Malar 17:141-148, 1963. 15. DeGowin, R.L., et al: The Effects of Diaminodiphenylsulfone (DDS) Against Chloroquine Resistant Plasmodium falciparum , Bull WHO 34:671-681, 1966. 16. Sheehy, T.W., and Bartelloni, P.J.: Combined Therapy for Acute Chloroquine-Resistant Falciparum Malaria , JAMA 199:141-172, 1967. 17. Skeggs, L.T.: An Automatic Method for Colorimetric Analysis , Amer J Clin Path 28:311-322, 1957. 18. Malloy, H.T., and Evelyn, K.A.: Determination of Bilirubin With a Photoelectric Colorimeter , J Biol Chem 119:481-490, 1937. 19. Karmen, A.; Wroblewski, F.; and LaDue, J.S.: Transaminase Activity in Human Blood , J Clin Invest 34:136-133, 1955. 20. Strumia, M.M.; Sample, A.B.; and Hart, E.D.: An Improved Microhematocrit Method , Amer J Clin Path 24:1016-1024, 1954. 21. Russell, P.F., et al: Practical Malariology , (ed 2), London: Oxford University Press, Inc, 1963. 22. Naylor, R.F., and Hanks, J.H.: The Influence of 4:4′diaminodiphenylsulfone (DDS) on the Respiration, Reproduction and Mutation of Mycobacteria , Int J Leprosy 29:56-64, 1961. 23. Levaditi, C., and Pèrault, R.: Mècanisme d'action des Sulfamides, des Sulfones et Dessulfoxydes. Phènomène de Woods , C R Soc Biol 135:1043-1046, 1941. 24. Grob, D.: Proteolytic Enzymes , J Gen Physiol 29:219-247, 1946.Crossref 25. Brownlee, G.: correspondence , Int J Leprosy 18:247, 1950. 26. Ramanujam, K., and Smith, M.: Hemolytic Anemia During Treatment of Leprosy With Diaminodiphenylsulfone by Mouth , Lancet 1:21-22, 1951.Crossref 27. Smith, R.S., and Alexander, S.: Heinz-Body Anemia Due to Dapsone , Brit Med J 1:625-627, 1959.Crossref 28. Garrett, A.S., and Corcus, M.G.: Dapsone Treatment of Leprosy , Leprosy Rev 23:106-108, 1952. 29. McNamara, J.V., et al: The Effect of Paraaminobenzoic Acid on the Hemolytic Effects of 4,4′diaminodiphenylsulfone , Milit Med 131:1057-1060, 1966. 30. Pengally, C.D.R.: Dapsone Induced Haemolysis , Brit Med J 2:662-664, 1963.Crossref 31. Nahas, L.; Rzeppa, H.; and Sousa-Lima, L.D.E.: Blood Picture in Sulphone Treatment of Leprosy , Int J Leprosy 22:22-30, 1954. 32. Floch, H.; Lecuiller, A.; and Destombes, P.: Est-il Indifférent d'administrer le Diaminodiphényl/sulfona par la Voie Buccale ou par la Voie Intramusculaire? Bull Soc Path Exot 44:461-466, 1951. 33. Montoya, R., and Pesce, H.: Symptoms of Psychosis Caused by Sulphone Treatment of Leprosy , Rev Brasil Lepr 29:141-155, 1952. 34. Peddar, R.K., and Chatterjee, K.R.: Autoradiographic Detection of Sulfone in the Affected Tissues of Leprosy Patients , Nature 180:854-855, 1957.Crossref 35. Browne, S.G.: Desensitization for Dapsone Dermatitis , Brit Med J 2:664-666, 1963.Crossref

Sun, David C. H.;Albacete, Rene A.;Chen, Jeanne K.

doi: 10.1001/archinte.1967.00290240089004pmid: N/A

Abstract The PRESENCE of a malabsorption syndrome in patients with cirrhosis has long been suspected. Mulnutrition,1,2 portal hypertension,3 lack of secretion of bile acids,4-6 pancreatic disease7-10 and mucosal changes of small intestine3 have been listed as possible causes for malabsorption in patients with cirrhosis. A comprehensive evaluation of each of these aspects in the same patient is indeed wanting. The aim of this study is to detect the incidence of malabsorption in patients with Laennec's cirrhosis, and the possible cause of this defect. Materials and Methods Twenty patients with cirrhosis of the liver were studied. The diagnosis of Laennec's cirrhosis was established by needle biopsy of the liver. The clinical features of each patient were carefully recorded; presence of muscle wasting, ascites, portal hypertension, precoma and other signs of physical stigmata were noted. A complete liver function profile was done at fortnightly intervals. This included the determination of serum bilirubin, cephalin-cholesterol References 1. Nelson, R.A., and Code, C.F.: Effect of Niacin Deficiency on the Absorption of Water and Sodium from the Small Bowel , Physiologist 2:89, 1959. 2. Jackson, S.P.U., and Linder, G.C.: The Influence of Malnutrition on the Pancreas , Metabolism 2:562-567, 1953. 3. Astaldi, G., and Strosselli, E.: Peroral Biopsy of the Intestinal Mucosa in Hepatic Cirrhosis , Amer J Dig Dis 5:603-612, 1960.Crossref 4. Gross, J.B., et al: Total Solids, Fat and Nitrogen in the Feces: A study of Patients With Primary Parenchymatous Hepatic Disease , Gastroenterology 16:140-150, 1950. 5. Atkinson, M.; Nordin, B.E.C.; and Sherlock, S.: Malabsorption and Bone Disease in Prolonged Obstructive Jaundice. Quart J Med 25:299-312, 1956. 6. Fast, B.B., et al: Fat Absorption in Alcoholics With Cirrhosis , Gastroenterology 37:321-324, 1959. 7. Kirshbaum, J.D., and Shure, N.: Alcoholic Cirrhosis of the Liver , J Lab Clin Med 28:721-731, 1943. 8. Albacete, R.A., and Sun, D.C.H.: Absorptive Function in Liver Disease, abstracted , Gastroenterology 44:813, 1963. 9. Van Goidsenhoven, G.E., et al: Pancreatic Function in Cirrhosis of the Liver , Amer J Dig Dis 8:160-173, 1963.Crossref 10. Sobel, H.J., and Wayne, J.D.: Pancreatic Changes in Various Types of Cirrhosis in Alcoholics , Gastroenterology 45:341-344, 1963. 11. Van de Kamer, J.H.; ten Bokkel Huinink, H.; and Weyers, H.A.: Rapid Method for the Determination of Fat in Feces , J Biol Chem 177:347-355, 1949. 12. Sun, D.C.H., and Shay, H.: Pancreozymin-Secretin Test: The Combined Study of Serum Enzymes and Duodenal Contents in the Diagnosis of Pancreatic Disease , Gastroenterology 38:570-581, 1960. 13. Sun, D.C.H.: Normal Values for Pancreozymin-Secretin Test , Gastroenterology 44:602-606, 1963. 14. Sun, D.C.H.: The Use of Pancreozymin-Secretin Test in the Diagnosis of Pancreatitis and Tu- mors of the Pancreas, Gastroenterology 45:203-208, 1963. 15. Somogyi, M.: Micromethods for the Estimation of Diastase , J Biol Chem 125:399-414, 1938. 16. Teller, J.D.: Measurement of Amylase Activity , J Biol Chem 185:701-704, 1950. 17. Maclay, E.A.: A Suitable Substrate for the Determination of Pancreatic Lipase in Serum and Other Body Fluids , Amer J Med Tech 14:197-201, 1948. 18. Santini, R., Jr.; Sheehy, T.W.; and Martinez, de Jesus J.: The Xylose Tolerance Test With a Five Gram Dose , Gastroenterology 40:772-774, 1961. 19. Roe, J.H., and Rice, E.W.: Photometric Method for Determination of Free Pentoses in Animal Tissues , J Biol Chem 173:507-512, 1948. 20. Baraona, E., et al: Absorptive Function of the Small Intestine in Liver Cirrhosis , Amer J Dig Dis 7:318-330, 1962.Crossref 21. Gross, J.B., et al: Study of Fecal Excretion of Fat and Nitrogen and External Pancreatic Function in Cases of Primary Parenchymatous Hepatic Disease , Mayo Clin Proc 26:9-13, 1951. 22. Summerskill, W.H.J., and Moertel, C.G.: Malabsorption Syndrome Associated With Anicteric Liver Disease , Gastroenterology 42:380-392, 1962. 23. Dawson, A.M., and Isselbacher, K.J.: Studies on Lipid Metabolism in the Small Intestine With Observations on the Role of Bile Salts , J Clin Invest 39:730-740, 1960.Crossref 24. Fowler, D., and Cooke, W.T.: Diagnostic Significance of D-xylose Excretion Test ; Gut 1:67-70, 1960.Crossref 25. Dreiling, D.A., and Hollander, F.: Studies in Pancreatic Function: I. Preliminary Series of Clinical Studies With the Secretin Test , Gastroenterology 11:714-729, 1948. 26. Herfort, K.: A Secretin Pancréatique au Cours de Certaines Affections Hépato-bilaires , Gastroenterologia 72:51-59, 1947.Crossref 27. Burton, P., et al: A Test of Pancreatic Function in Man Based on the Analysis of Duodenal Contents After Administration of Secretin and Pancreozymin , Gut 1:111-124, 1960.Crossref

Raffensperger, E. C.;D'Agostino, Frank;Manfredo, Hector;Ramirez, Manuel;Brooks, Frank P.;O'Neill, Frances

doi: 10.1001/archinte.1967.00290240095005pmid: N/A

Abstract THE QUANTITATIVE fecal fat determination is an important laboratory procedure in studying intestinal malabsorption. It establishes the presence and measures the degree of malabsorption of fat, and it may be used to evaluate the efficacy of treatment. Methods The survey covers 149 patients who were studied as inpatients or outpatients at the Gastrointestinal Clinic of the Hospital of the University of Pennsylvania from 1962 to 1966. All had ingested standard diets containing 90 to 100 gm of fat per day. More than 90% of the determinations were done on a 72 hour or longer stool collection. More than one fecal fat determination was frequently done on each patient, but for this report, only the first determination was used. The method of Van de Kamer et al1 was employed for quantitative fecal fat determination. More than 5 gm of fecal fat and more than 200 gm net weight of stool References 1. Van de Kamer, J.H.; Huinink, H.T.B.; and Weyers, H.A.: A rapid Method for the Determination of Fat in the Feces , J Biol Chem 177:347-355 ( (Jan) ) 1949. 2. Lewis, G.T., and Partin, H.C.: Fecal Fat on an Essentially Fat Free Diet , J Lab Clin Med 44:91-93 ( (July) ) 1954. 3. Norcia, L.N., and Lyndberg, W.O.: Fat Excretion: The Influence of Dietary Fat on Fecal Fat Excretion , J Nutr 54:491-508 ( (Dec) ) 1954. 4. Wollaeger, E.E., et al: The Total Solids, Fat and Nitrogen in the Feces: 1. A Study of Normal Persons and of Patients With Duodenal Ulcer on a Test Diet Containing Large Amounts of Fat , Gastroenterology 6:83-92 ( (Feb) ) 1946. 5. Annegers, J.H.; Boutwell, J.H.; and Ivy, A.C.: The Effect of Dietary Fat on Fecal Fat Excretion and Subjective Symptoms in Man , Gastroenterology 10:486-495 ( (March) ) 1948. 6. Annegers, J.H.: Function of Pancreatic Juice and of Bile in Assimilation of Dietary Triglycerides , Arch Intern Med 93:9-22 ( (Jan) ) 1954.Crossref

Spector, Israel;Corn, Milton

doi: 10.1001/archinte.1967.00290240099006pmid: N/A

Abstract In PATIENTS with liver disease one or more abnormalities of hemostasis can frequently be demonstrated in the laboratory.1 Although it is generally believed that these abnormalities predispose to hemorrhage, it has not been clearly established that hemostatic defects are more common or more severe in bleeding than in nonbleeding patients with liver diesase. The many comprehensive reports of hemostasis in liver disease2-7 have not systematically related laboratory tests to clinical hemorrhage. Similarly, previous studies of hemostatic defects in patients with bleeding8-11 do not present comparable data on nonbleeding cirrhotics. Correlation between laboratory tests and clinical bleeding is further complicated by the difficulty in classifying minor degrees of hemorrhage. In the present report hemostatic studies were performed on a consecutive series of patients with cirrhosis admitted to a medical ward and were correlated with the incidence of major hemorrhage, defined as bleeding sufficiently severe to require transfusion. Materials References 1. Ratnoff, O.D.: Hemostatic Mechanisms in Liver Disease , Med Clin N Amer 47:721-736, 1963. 2. Harrington, W.J., et al: Bleeding Tendency in Hepatocellular and Obstructive Jaundice , Bull New Eng Med Center 12:121-128, 1950. 3. Rapaport, S.I., et al: Plasma Clotting Factors in Chronic Hepatocellular Disease , New Eng J Med 263:278-282, 1960.Crossref 4. Weaver, W.T.; Anlyan, W.G.; and Postlethwait, R.W.: Blood Coagulation Factors in Liver Disease , Surgery 50:207-212, 1961. 5. Hedenberg, L., and Korsan-Bengtsen, K.: Clotting Tests and Other Tests of the Hemostatic Mechanism in Cirrhosis of the Liver and Their Diagnostic Significance , Acta Med Scand 172:229-235, 1962.Crossref 6. Hallen, A., and Nilsson, I.M.: Coagulation Studies in Liver Disease , Thrombos Diathes Haemorrh 11:51-56, 1964. 7. Deutsch, E.: "Blood Coagulation Changes in Liver Disease" in Poppen, H. and Schaffner, F. (eds.) : Progress in Liver Disease , New York: Grune & Stratton, Inc., 1965, pp 69-83, vol 2. 8. Stefanini, M., and Petrillo E.: The Relative Importance of Plasmatic and Vascular Factors of Hemostasis in the Pathogenesis of Hemorrhagic Disease of Liver Dysfunction , Acta Med Scand 134:139-145, 1949.Crossref 9. Cowling, D.C.: Coagulation Defects in Liver Disease , J Clin Path 9:347-350, 1956.Crossref 10. Mandel, E.E., and Lazerson, J.: Thrombasthenia in Liver Disease , New Eng J Med 265: 56-61, 1961.Crossref 11. Grossi, C.E.; Rousselot, L.M.; and Panke, W.F.: Coagulation Defects in Patients With Cirrhosis of the Liver Undergoing Portasystemic Shunts , Amer J Surg 104:512-526, 1962.Crossref 12. Spector, I.; Corn, M.; and Ticktin, H.E.: Effect of Plasma Transfusions on the Prothrombin Time and Clotting Factors in Liver Disease , New Eng J Med 275:1032-1037, 1966.Crossref 13. Chalmers, T.C.; Bigelow, F.S.; and Desforges, J.F.: The Effects of Massive Gastrointestinal Hemorrhage on Hemostasis: II. Coagulation Factors , J Lab Clin Med 43:511-517, 1954. 14. Welch, C.S., et al: Treatment of Bleeding From Portal Hypertension in Patients With Cirrhosis of the Liver , New Eng J Med 24:493-502, 1956.Crossref 15. Finkbiner, K.B., et al: Coagulation Defects in Liver Disease and Response to Transfusion During Surgery , Amer J Med 26:199-213, 1957.Crossref 16. Kupfer, H., et al: Statistical Correlation of Liver Function Tests With Coagulation Factor Deficiencies in Laennec's Cirrhosis , Thrombos Diathes Haemorrh 10:317-331, 1964. 17. Davidson, C.S.: Management of Emergencies: III. Is Life Worth Living? It Depends on the Liver , New Eng J Med 274:894-896, 1966.Crossref

Lindsay, Philip G.

doi: 10.1001/archinte.1967.00290240105007pmid: N/A

Abstract That temperamental dignotions, and conjecture of prevalent humours, may be collected from spots in our nails, we are not averse to concede. —Sir Thomas Browne IT HAS long been appreciated that systemic disease can produce changes in the nails. Hippocrates, in his classic description of the clubbing phenomenon in empyema, first directed attention to the systemic onychopathies. A relative spate of descriptive reports in more recent times was begun by J. C. Reil's 1792 notation on white transverse bands and sulci following febrile diseases.1 Gradually, such entities as Beau's lines,2 Mees' lines,3 splinter hemorrhages,4 koilonychia,5 pigmented nails,6 onycholysis,7 Terry nails,8 Muehrcke's striae,9 azure lunulae,10 rubra lunulae,11 platonychia,12 the nail-patella syndrome,13 and the yellownail syndrome,14 came to be recognized as nail signs of diagnostic significance. There are now more than 40 described onychopathies due to systemic illnesses and three monographs focusing on the nails in disease.1517 That certain nail References 1. Reil, J.C.: Unguium Vitia in Convalescentibus a Febre Maligna Observata, Memorabilum Clinicorum , Halae: Litteris trampianis , 2:206-207, 1792. 2. Beau, J.H.S.: Certain Caracteres de Semeiologie Retrospective, Presentes par les Ongles , Arch Gen Med 9:447, 1846. 3. Mees, R.A.: Een Verschijnsel bij Polyneuritis Arsenicosa , Nederl T Geneesk 1:391, 1919. 4. Horder, T.: Discussion on Clinical Significance and Course of Subacute Bacterial Endocarditis , Brit Med J 2:301-311 ( (Aug 28) ) 1920.Crossref 5. Jalili, M.A., and Al-Kassab, S.: Koilonychia and Cysteine Content of Nails , Lancet 2:108-110 ( (Aug 15) ) 1959.Crossref 6. Valero, A., and Sherf, K.: Pigmented Nails in Peutz-Jeghers Syndrome , Amer J Gastroent 43:56-58 ( (Jan) ) 1965. 7. Luria, M.N., and Asper, S.P., Jr.: Onycholysis in Hyperthyroidism , Ann Intern Med 49:102-108 ( (July) ) 1958.Crossref 8. Terry, R.: White Nails in Hepatic Cirrhosis , Lancet 1:757-759 ( (April 10) ) 1954.Crossref 9. Muehrcke, R.C.: The Finger Nails in Chronic Hypoalbuminemia , Brit Med J 1:1327-1328 ( (June 9) ) 1956.Crossref 10. Bearn, A.G., and McKusick, V.A.: Azure Lunulae: An Unusual Change in the Fingernails in Two Patients With Hepato-Lenticular Degeneration (Wilson's Disease) , JAMA 166:904-906 ( (Feb 22) ) 1958.Crossref 11. Terry, R.: Red Half-Moons in Cardiac Failure , Lancet 2:842-844 ( (Oct 23) ) 1954.Crossref 12. Kleeberg, J.: Flat Finger-Nails in Cirrhosis of the Liver , Lancet 2:248-249 ( (Aug 11) ) 1951.Crossref 13. Brixey, A.M., Jr., and Burke, R.M.: Arthro-Onycho Dysplasia: Hereditary Syndrome Involving Deformity of Head of Radius, Absence of Patellas, Posterior Iliac Spurs, Dystrophy of Finger Nails , Amer J Med 8:738-744 ( (June) ) 1950.Crossref 14. Samman, P.D., and White, W.F.: The "Yellow Nail" Syndrome , Brit J Derm 76:153-157 ( (April) ) 1964.Crossref 15. Samman, P.D.: The Nails in Disease , Springfield, Ill: Charles C Thomas, Publisher, 1965. 16. Berry, T.J.: The Hand as a Mirror of Systemic Disease , Philadelphia: F. A Davis Company, 1963. 17. Pardo-Costello, V., and Pardo, O.A.: Disease of the Nails , ed 3, Springfield, Ill: Charles C Thomas, Publisher, 1960. 18. Hudson, J.B., and Dennis, A.J.: Transverse White Lines in the Fingernails After Acute and Chronic Renal Failure , Arch Intern Med 117:276-279 ( (Feb) ) 1966.Crossref 19. Bean, W.B.: A Discourse on Nail Growth and Unusual Fingernails , Trans Amer Clin Climat Assoc 74:152-167, 1963. 20. Lindsay, P.G.: The Half and Half Nail , J Lab Clin Med 66:892 ( (Nov) ) 1965. 21. Terry, R.: The Onychodermal Band in Health and Disease , Lancet 1:179-181 ( (Jan 22) ) 1955.Crossref 22. Morey, D.A.J., and Burke, J.O.: Distinctive Nail Changes in Advanced Hepatic Cirrhosis , Gastroenterology 29:258-261 ( (Aug) ) 1955.

Schacht, Richard A.;Conway, James;Stewart, Bruce H.

doi: 10.1001/archinte.1967.00290240110008pmid: N/A

Abstract Following the observation of split renal function studies by White in 1950,1 later modified as a diagnostic test for renovascular hypertension by Howard et al in 1954,2 it seemed possible that split renal function studies might be relied upon to provide a basis for the identification of patients with hypertension resulting from a diminished blood flow to one kidney. In 1957, Conner and associates3 reported that in cases of unilateral renovascular disease the blood pressure improved after surgery only when the preoperative test had shown a diminished urine flow and sodium concentration on the involved side. A number of methods have subsequently been used to improve the performance or interpretation of split renal function tests, namely those of Rapoport in 1960,4 Stamey in 1961,5 and Birchall et al in 1962.6 It is apparent from the number of tests which have been introduced as well as from published reports,7-10 that no References 1. White, H.L.: " The Excretion of Sodium in Relation to Glomerular Filtration ," in Bradley, S. E. (ed.): Renal Function: Transactions of the Second Conference , New York: Josiah Macy, Jr. Foundation, 1950, p 127. 2. Howard, J.E., et al: Hypertension Resulting From Unilateral Renal Vascular Disease and Its Relief by Nephrectomy , Bull Hopkins Hosp 94:51-85 ( (Feb) ) 1954. 3. Connor, T.B., et al: Hypertension Due to Unilateral Renal Disease: With a Report on a Functional Test Helpful in Diagnosis , Bull Hopkins Hosp 100:241-276 ( (June) ) 1957. 4. Rapoport, A.: Modification of the "Howard Test" for the Detection of Renal Artery Obstruction , New Eng J Med 263:1159-1165 ( (Dec) ) 1960.Crossref 5. Stamey, T.A.: The Diagnosis of Curable Unilateral Renal Hypertension by Ureteral Catheterization , Postgrad Med 29:496-504 ( (May) ) 1961. 6. Birchall, R.; Batson, J.D., Jr.; and Brennan, W.: Contribution of Differential Renal Function Studies to the Diagnosis of Renal Artery Hypertension , Amer J Med 32:164-170 ( (Feb) ) 1962.Crossref 7. Revell, S.T.R., et al: An Appraisal of Certain Tests for the Detection of Hypertension of Unilateral Renal Origin , Ann Intern Med 53:970-991 ( (Nov) ) 1960.Crossref 8. Baker, G.P., Jr.; Page, L.B.; and Leadbetter, G.W., Jr.: Hypertension and Renovascular Disease: A Follow-Up Study of 23 Patients With an Analysis of Factors Influencing the Results of Surgery , New Eng J Med 267:1325-1334 ( (Dec) ) 1962.Crossref 9. Scott, F.B.; Selzman, H.M.; and Feste, J.R.: Diagnostic Approach to Renal Vascular Hypertension , J Urol 86:31-35 ( (July) ) 1961. 10. Stewart, B.H., et al: Renal Hypertension: An Appraisal of Diagnostic Studies and of Direct Operative Treatment , Arch Surg 85:617-636 ( (Oct) ) 1962.Crossref 11. Correa, R.J., Jr., et al: Renal Vascular Disease as a Cause of Hypertension: Selection of Patients for Arteriographic Studies , J Mich Med Soc 61:1361-1363 ( (Nov) ) 1962. 12. Stewart, B.H., et al: Differential Function Studies in Hypertension: Indications and Techniques , J Urol 94:7-14 ( (July) ) 1965. 13. Smith, H.W.: The Kidney: Structure and Function in Health and Disease , New York: Oxford University Press, 1951. 14. Poutasse, E.F., and Dustan, H.P.: Arteriosclerosis and Renal Hypertension: Indications for Aortography in Hypertensive Patients and Results of Surgical Treatment of Obstructive Lesions of the Renal Artery , JAMA 165:1521-1525 ( (Nov) ) 1957.Crossref 15. Richardson, J.R., Jr., et al: The Function of Individual Kidneys in Hypertension of Renal Vascular Origin , J Lab Clin Med 65:49-63 ( (Jan) ) 1965. 16. Stamey, T.A.: in Gross, F. (ed.): Antihypertensive Therapy , Berlin: Springer-Verlag, 1966.

Carvajal, Jorge A.;Anderson, W. Robert;Weiss, Leo;Grismer, Jerome;Berman, Reuben

doi: 10.1001/archinte.1967.00290240115009pmid: N/A

Abstract THE CLINICAL significance of atheroembolism from aortic and arterial atheromatous plaques to various organs and tissues has not been appreciated until fairly recently. Embolization of atheromatous material has been seen with increasing frequency, and it is now recognized that impaction of this material within small arteries and arterioles may be manifested by (1) paroxismal ischemic changes of the feet and legs with pain, livedo reticularis, and gangrene despite adequate arterial pulses1-3; (2) hypertension and impaired renal function4-6; (3) abdominal pain, gastrointestinal hemorrhage, and pancreatitis7,8; and (4) occasionally neurological symptoms and retinal emboli.9-12 The purpose of this paper is to describe the clinical and pathologic findings in five patients with most of these manifestations and in whom the diagnosis of atheroemboli was made. The use of diagnostic muscle biopsies and the clinical significance of embolization to the renal and gastrointestinal systems are emphasized. Report of Cases Case 1 (MSH 68147). —A References 1. Richards, A.M., et al: Cholesterol Embolism: A Multiple System Disease Masquerading as Polyarteritis Nodosa , Amer J Cardiol 15:696-707, 1965.Crossref 2. Anderson, W.R.: Necrotizng Angiitis Associated With Embolization of Cholesterol: Case Report With Emphasis on the Use of Muscle Biopsy as a Diagnostic Aid , Amer J Clin Path 43:65-71, 1965. 3. Richards, A.M., and Anderson, W.R.: Clinical and Experimental Cholesterol Embolism, abstracted , Proc Centr Soc Clin Res 38:66, 1965. 4. Flory, C.M.: Arterial Occlusion Produced by Emboli From Eroded Aortic Atheromatous Plaques , Amer J Path 21:549-565, 1945. 5. Handler, F.P.: Clinical and Pathologic Significance of Atheromatous Embolization, With Emphasis on Etiology of Renal Hypertension , Amer J Med 20:366-373, 1956.Crossref 6. Thurlbeck, W.M., and Castleman, B.: Atheromatous Emboli to the Kidneys After Aortic Surgery , New Eng J Med 257:442-447, 1957.Crossref 7. Probstein, J.G.; Joshi, R.A.; and Blumenthal, H.T.: Atheromatous Embolization: An Etiology of Acute Pancreatitis , Arch Surg 75:566-572, 1957.Crossref 8. Gore, I., and Collins, D.P.: Spontaneous Atheromatous Embolization: Review of the Literature and Report of 16 Additional Cases , Amer J Clin Path 33:416-426, 1960. 9. Winter, W.J., Jr.: Atheromatous Emboli: A Cause of Cerebral Infarction , Arch Path 64:137-142, 1957. 10. Witmer, R., and Schmid, A.: Cholesterinkrystall als Retinaler Arterieller Embolus , Ophthalmologica 135:432-433, 1958.Crossref 11. McBrien, D.J.; Bradley, R.D.; and Ashton, N.: The Nature of Retinal Emboli in Stenosis of the Internal Carotid Artery , Lancet 1:697-699, 1963.Crossref 12. David, N.J., et al: Fatal Atheromatous Cerebral Embolism Associated With Bright Plaques in the Retinal Arterioles: Report of a Case , Neurology 13:708-713, 1963.Crossref 13. Panum, P.L.: Experimentelle Beitrage zur Lehre von der Embolie , Virchow Arch Path Anat 25:308-310, 1862.Crossref 14. Meyer, W.W.: Cholesterinkristallembolie Kleiner Organarterien und ihre Folgen , Virchow Arch Path Anat 314:616-638, 1947.Crossref 15. Williams, C.M., and Goodman, H.: Livedo Reticularis , JAMA 85:955-958, 1925.Crossref 16. McCombs, R.P.; Patterson, J.F.; and MacMahon, H.E.: Syndromes Associated With Allergic Vasculitis , New Eng J Med 255:251-261, 1956.Crossref 17. Ingram, J.T., and Sutherland, T.W.: Multiple Skin Necrosis (Arteriolar) , Arch Derm 75:820-825, 1957.Crossref 18. Edwards, E.A.: Remittent Necrotizing Acrocyanosis , JAMA 161:1530-1534, 1956.Crossref 19. Hoye, S.J., et al: Atheromatous Embolization: A Factor in Peripheral Gangrene , New Eng J Med 261:128-131, 1959.Crossref 20. Edwards, J.E.: An Atlas of Acquired Diseases of the Heart and Great Vessels , Philadelphia: W. B. Saunders Company, 1961, vol 1, p 308 21. vol 2, p 492 22. vol 3, pp 988, 1004. 23. Snider, H.E., and Shapiro, J.L.: A Correlative Study of Atheromatous Embolism in Human Beings and Experimental Animals , Surgery 49:195-204, 1961. 24. Eliot, R.S.; Kunjuh, V.I.; and Edwards, J.E.: Atheromatous Embolism , Circulation 30:611-618, 1964.Crossref 25. Anderson, W.R.; Richards, A.M.; and Weiss, L.: Hemorrhage and Necrosis of the Stomach and Bowel Due to Atheroemboli: A Correlative Study of Atheromatous Emboli to the Gastrointestinal Tract in Humans and Experimental Animals , Amer J Clin Path , to be published. 26. Porter, W.B., and Vaughan, E.W.: Coronary Embolism: A Complication of Syphilitic Aortitis: Report of 3 Cases , Amer J Med Sci 200:184-191, 1940.Crossref 27. Wenger, N.K., and Bauer, S.: Coronary Embolism: Review of the Literature and Presentation of 15 Cases , Amer J Med 25:549-557, 1958.Crossref 28. Sayre, G.P., and Campbell, D.C.: Multiple Peripheral Emboli in Atherosclerosis of the Aorta , Arch Intern Med 103:799-806, 1959.Crossref

Seaman, Arthur J.;Lutcher, C. Lawrence;Moffat, Charlotte A.;Hueber, Bonita E.

doi: 10.1001/archinte.1967.00290240122010pmid: N/A

Abstract OUR EXPERIMENTAL preparation, "The Living Extracorporeal Eye,"1,2 permits us to examine thromboembolic phenomena intravascularly under microscopic magnification in the microcirculation of a living organ. Additionally, the composition of the oxygenated arterial blood supply is under our control and not altered by feedback mechanisms triggered by neurogenic or blood-borne signals. In this paper we describe some of our initial attempts to define the sequence and components of thromboembolic phenomena obstructing the microcirculation. These include induced platelet aggregation, thrombin evolution produced by several techniques, and venous erythrothrombosis induced by intravascular hemagglutination. We have studied the influence of sodium heparin, sodium warfarin, and clinical dextran on these events. These phenomena are then related to the events observed when silicone-handled human blood without added anticoagulant is perfused intravascularly until clotting evolves spontaneously. Methods and Materials The living extracorporeal eye is a bovine eye enucleated immediately after slaughter. The ciliary artery is catheterized forthwith References 1. Seaman, A.J. et al: The Living Extracorporeal Eye , Scand J Clin Lab Invert 17( (suppl 84) ):101, 1965. 2. Lutcher, C.L.; Moffat, C.; and Seaman, A.J.: A New Technique for Studying the Microcirculation, abstracted , Clin Res 14:162, 1966. 3. Swank, R.L.: Alteration of Blood on Storage: Measurement of Adhesiveness of "Aging" Platelets and Leukocytes and Their Removal by Filtration ; New Eng J Med 265:728, 1961.Crossref 4. Hellem, A.J.: Demonstration of a Substance in Red cells Affecting the Adhesiveness of Blood Platelets , Proc VII Cong Intern Soc Hemat 2:791, 1958. 5. Gaarder, A., et al: Adenosine Diphosphate in Red Cells as a Factor in the Adhesiveness of Human Blood Platelets , Nature 192:531, 1961.Crossref 6. O'Brien, J.R.: Platelet Aggregation: I: Some Effects of the Adenosine Phosphates, Thrombin and Cocaine Upon Platelet Adhesiveness , J Clin Path 15:446, 1962.Crossref 7. Honour, A.J., and Mitchell, J.R.A.: Platelet Clumping in Injured Vessels , Brit J Exp Path 45:75, 1964. 8. Born, G.V.R., and Cross, M.J. The Aggregation of Blood Platelets , J Physiol 168:178, 1963. 9. Kaser-Glanzmann, R., and Luscher, E.F.: The Mechanism of Platelet Aggregation in Relation to Hemostasis , Thromb Diath Haemorrh 7:480, 1962. 10. Pickering, G.: Symposium on Cardiovascular Disease; Section of Neurology , Proc Roy Soc Med 52:540, 1959. 11. Pickering, G.: Pathogenesis of Myocardial and Cerebral Infarction: Nodular Arteriosclerosis , Brit Med J 1:517, 1964.Crossref 12. McBrien, D.J.; Bradley, R.D.; and Ashton, M.: The Nature of Retinal Emboli in Stenosis of the Internal Carotid Artery , Lancet 1:697, 1963.Crossref 13. Russel, R.W.R.: Observations on the Retinal Blood-Vessels in Monocular Blindness , Lancet 2:1422, 1961.Crossref 14. Mustard, J.R., et al: ADP Platelet Thrombosis, abstracted , J Clin Invest 43:1305, 1964. 15. Grette, K.: Studies on the Mechanism of Thrombin-Catalyzed Hemostatic Reactions in Blood Platelets , Acta Physiol Scand 56 ( (suppl 195) ): 1962. 16. Conner, W.E.; Hoak, J.C.; and Warner, E.D.: Massive Thrombosis Produced by Fatty Acid Infusion , J Clin Invest 42:860, 1963.Crossref 17. Botti, R.E., and Ratnoff, O.D.: The Clot-Promoting Effect of Soaps of Long-Chain Saturated Fatty Acids , J Clin Invest 42:1569, 1963.Crossref 18. Davie, E.W., and Ratnoff, O.D.: Waterfall Sequence for Intrinsic Blood Clotting , Science 145:1310, 1964.Crossref 19. MacFarlane, R.G.: An Enzyme Cascade in the Blood Clotting Mechanism, and Its Function as a Biochemical Amplifier , Nature 202:497, 1964.Crossref 20. Seaman, A.J.; Lutcher, C.L.; and Moffat, C.: First Observations of Intravascular Blood Transfusion Reactions Studied With the Living Extracorporeal Eye, abstracted , Blood 26:882, 1965. 21. Seaman, A.J.; Lutcher, C.L.; and Moffat, C.: Intravascular Hemagglutination Observed in the Living Extracorporeal Eye , Blood , to be published. 22. Richardson, J.H.; Alderfer, H.H.; and Reid, J.D.: Response of Eye and Brain to Micro-emboli , Ann Intern Med 57:1013, 1962.Crossref 23. Ellis, C.J., et al: Medical Investigation of Retinal Vascular Occlusion , Brit Med J 2:1093, 1964.Crossref