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Tumour necrosis factor as growth factor for B-cell malignancies
Notes
146
the fetal brain. Treatment included the administration of antibiotics to all mothers with confirmed acute infection during pregnancy, with more intensive antibiotic treatment of those who had infected fetuses and who chose to continue the pregnancy. We report a prospective study of 746 documented cases of maternal toxoplasma infection, in which the infants were followed for at least three months. Infeo tion was diagnosed antenatally in 39 of 42 fetuses. 24 of the 39 pregnancies were terminated, and 15 were continued. All the mothers were treated with spiramytin throughout pregnancy; if fetal infection was demonstrated, pyrimethamine and either sulfadoxine or sulfadiaxine were added to the regimen. Of the 15 fetuses with congenital toxoplasmosis who were carried to term, all but 2, who had chorioretinitis, remained clinically well during follow-up. We conclude that prenatal diagnosis of congenital toxoplasmosis is practical and that prenatal therapy in women who wish to continue their pregnancies reduces the severity of the manifestations of the disease. F. Daffos(1) !nstitut de Pudriculture de Paris, 75014 Paris, France
CARDIOLOGY A rsutdamized, amtrolled qyocardial infarction
trial in patients witb acute
At the University of Michigan, we conducted a randomixed, controlled trial in 507 patients who presented during a 15 month period of time with acute myocardial infarction. Of these patients, 179 were classified as uncomplicated, that referring to the absence of heart failure, angina or significant arrhythmias at 72 hours from the point of hospital admission. Of particular note, 303 (60%) of the patients had received reperfusion therapy, consisting of intravenous thrombolytic therapy, or coronary angioplasty, or both of these interventions at the time of diagnosis of evolving myocardial infarction. The most important predictor of uncomplicated status for the overall group of more than 500 patients was successful reperfusion, and more than a third of these patients met the criteria for randomization. Randomization to early discharge could only be performed if the patient was not only uncomplicated but also had a negative exercise test which was performed with accompanying Thallium scientigraphy. Of the 80 patients who consented to random assignment, 40 were discharged at 3 days and the remaining 40 were discharged at conventional time (8 days). The patients discharged early had a very favora-(1) N. Engl. J. Med. (1988) 318, 271.
ble long term follow-up, now extending out to one year, with no increase in hospital readmissions and no mortality, reinfraction, or increased rate of angina. Of particular note, there was a 20 % savings in cumulative hospital and professional charges. This study demonstrates several key advances in our understanding of patients in the new era of myocardial reperfusion therapy. First, reperfunion therapy to a large population will undoubtedly yield a higher proportion of uncomplicated patients who may indeed be tit for consideration for early hospital discharge. Since the common denominator of favorable outcome was indeed successful reperfusion, all efforts should be made to achieve this important end point. Second, patients may be considered for early discharge and appear to be quite well suited for this new strategy, with an earlier return to work and an improved long term follow-up compared with conventional discharge timing. Third, if widely adopted, this new posture towards patients who are especially uncomplicated after infarction would have a substantial favorable economic impact for patients with acute myocardial infarction. E.J. Top01 (2) The University of Michigan Medical Center, Ann Arbor, Michigan 48109-0022, USA
HEMATOLOGY Tumour necrosisfactor as growth factor for Bcell malignancies
Tumour necrosis factor induces the lysis of tumour cells in vitro and regression of some tumours in vivo. More recently it has also become clear that TNF can act as a growth factor for certain normal cells, including B and T lymphocytes and fibroblasts. We have now shown that TNF can also act as a growth factor for malignancies derived from at least one of these cell types. Thus, addition of tumour necrosis factor to B chronic lymphocytic leukaemia or hairy cell lsukaemia cells prolongs their survival in vitro and induces them to become activated and proliferate. Activation is autocrine in nature since culture with TNF protein induces mRNA for TNF and secretion of fresh protein. Alpha interferon is an effective treatment for patients with hairy cell leukaemia (HCL) and co-culture of HCL cells with alpha interferon blocks TNF mediated survival and proliferation. This effect is mediated by interruption of the TNF generated autocrine loop rather than by any effect on receptor expression. Our observations have two implications. First, other agents that behave like alpha interferon and interrupt TNF autocrine loops may be therapeutically effective and, secondly, that TI:F may act as a growth factor for other (2) N. Engl. J. Med. (‘1988) 318, 1083.
Notes malignancies derived from normal cells that proliferate in response to the cytokine. M.K. Brenner (1) Royal Free Hospital, Hampstead, London NW3
2 QG, UK
147 drug, e.g. a bile acid sequestrant, can produce a marked reduction in cholesterol levels. Other disorders where reductase inhibitors may be effective therapy are familial dysbetalipoproteinemia and the dyslipidemias of diabetes, nephrotic syndrome and familial combined hyperlipidemia. However, if patients with these disorders are treated with HMG-CoA reductase, they should be monitored carefully for side effects. SM. Grundy (2) University of Texas SouthWestern Medical Center, Dallas TX 752359052, USA
NUTRITION Treatment of hypercholesterolemia Although cholesterol lowering drugs are used in only a fraction of hypercholesterolemic patients at present, the results of several large clinical trials provide a rationale for their use in prevention of coronary heart disease (CHD). Recent trials have demonstrated a reduction in morbidity due to CHD, and a retardation and even regression of coronary artery plaques in some patients. The hypolipidemic agents most commonly employed are the fibric acids (clofibrate, gemfibrozil, fenofibrate, bezofibrate). These drugs are generally well tolerated, but they reduce total cholesterol levels only moderately (IO-20%). Another widely used and well tolerated drug is probucol which lowers total cholesterol to about the same extent as fibric acids. Probucol has been recently shown to retard development of atherosclerosis in rabbits with genetic hypercholesterolemia, an important observation which is being further investigated. Because of their eflicacy and proved safety, bile acid sequestrants (cholestyramine and colestipol) and niacin are the drugs of first choice for treatment of hypercholesterolemia. These drugs lower total cholesterol levels by 15-30 %. Unfortunately, they are not always well tolerated by all patients. Finally, the various available drugs can be used in combination to produce a greater plasma cholesterol reduction; for example the combination of a bile acid sequestrant and niacin can reduce cholesterol levels by 30-40 %. The HMG-CoA reductase inhibitors represent a new class of cholesterol-lowering drugs. They act primarily by increasing the expression of LDL receptors, causing a reduction in LDL cholesterol levels. One such agent, lovastatin (Mevacor, Merck & Co.) was approved by the United States Food and Drug Administration in 1987. This potent drug, effective in small doses, has been shown to lower total cholesterol by 30 to 40%. With the exception of rhabdomyolysis, which is rare occurrence, the drug seems to be free from serious side effects. However, until the safety of this class of drugs has been proven, it is prudent to restrict their usage to patients with severe hypercholesteroiemia or to patients with moderate hypercholesterolemia who have other risk factor for coronary heart disease. in persons who do not respond adequately to lovastatin alone, a second
(1) Lancer
(1988) I, 969
INFECTIOUS DISEASES Vaseuler proliferation of infectious origin in HIV-infected patients The vascular proliferation, Kaposi’s sarcoma, has been considered a hallmark of infection with the human immunodeticiency virus (HIV). In this paper, we reported a second type of vascular proliferition in HIVinfected patients, one that may be unique to that setting, and which seems clearly to be of infectious origin. We studied cutaneous vascular proliferations from seven patients with AIDS, whose lesions clinically resembled those of Kaposi’s sarcoma, but on histologic examination had findings that were clearly distinct from those of KS. Unlike the case in KS, the lesions in our patients were composed of epithelioid or cuboida1 endothelial cells, resembling the benign condition called epithelioid hemangioma. An infectious etiology of these unusual vascular lesions was established by the finding of clusters of bacteria within the lesions. The bacteria did not stain with the usual histochemical methods, but did stain with the Warthin-Starry silver stain, similar in this respect to the recently identified agent of cat scratch disease. Two of the patients who were still alive at the time of this study gave histories of being scratched by cats. In all of the lesions treated with antibiotics, complete resolution was seen. Because of the similarity of the bacteria to those of cat scratch disease, we stained sections with an antibody raised against the cat scratch disease bacillus, and positive staining was noted in all cases. These findings highlight the need for biopsy rather than clinical diagnosis of Kaposi’s sarcoma, and establish a seemingly new entity in patients with HIV infection. Ph. E. L.&oh (3) University of San Francisco, San Francisco, CA 94143, USA (2) N. Engl. J. Med. (1988) 319, 24. (3) Lancet (1988) I. 960.
146
the fetal brain. Treatment included the administration of antibiotics to all mothers with confirmed acute infection during pregnancy, with more intensive antibiotic treatment of those who had infected fetuses and who chose to continue the pregnancy. We report a prospective study of 746 documented cases of maternal toxoplasma infection, in which the infants were followed for at least three months. Infeo tion was diagnosed antenatally in 39 of 42 fetuses. 24 of the 39 pregnancies were terminated, and 15 were continued. All the mothers were treated with spiramytin throughout pregnancy; if fetal infection was demonstrated, pyrimethamine and either sulfadoxine or sulfadiaxine were added to the regimen. Of the 15 fetuses with congenital toxoplasmosis who were carried to term, all but 2, who had chorioretinitis, remained clinically well during follow-up. We conclude that prenatal diagnosis of congenital toxoplasmosis is practical and that prenatal therapy in women who wish to continue their pregnancies reduces the severity of the manifestations of the disease. F. Daffos(1) !nstitut de Pudriculture de Paris, 75014 Paris, France
CARDIOLOGY A rsutdamized, amtrolled qyocardial infarction
trial in patients witb acute
At the University of Michigan, we conducted a randomixed, controlled trial in 507 patients who presented during a 15 month period of time with acute myocardial infarction. Of these patients, 179 were classified as uncomplicated, that referring to the absence of heart failure, angina or significant arrhythmias at 72 hours from the point of hospital admission. Of particular note, 303 (60%) of the patients had received reperfusion therapy, consisting of intravenous thrombolytic therapy, or coronary angioplasty, or both of these interventions at the time of diagnosis of evolving myocardial infarction. The most important predictor of uncomplicated status for the overall group of more than 500 patients was successful reperfusion, and more than a third of these patients met the criteria for randomization. Randomization to early discharge could only be performed if the patient was not only uncomplicated but also had a negative exercise test which was performed with accompanying Thallium scientigraphy. Of the 80 patients who consented to random assignment, 40 were discharged at 3 days and the remaining 40 were discharged at conventional time (8 days). The patients discharged early had a very favora-(1) N. Engl. J. Med. (1988) 318, 271.
ble long term follow-up, now extending out to one year, with no increase in hospital readmissions and no mortality, reinfraction, or increased rate of angina. Of particular note, there was a 20 % savings in cumulative hospital and professional charges. This study demonstrates several key advances in our understanding of patients in the new era of myocardial reperfusion therapy. First, reperfunion therapy to a large population will undoubtedly yield a higher proportion of uncomplicated patients who may indeed be tit for consideration for early hospital discharge. Since the common denominator of favorable outcome was indeed successful reperfusion, all efforts should be made to achieve this important end point. Second, patients may be considered for early discharge and appear to be quite well suited for this new strategy, with an earlier return to work and an improved long term follow-up compared with conventional discharge timing. Third, if widely adopted, this new posture towards patients who are especially uncomplicated after infarction would have a substantial favorable economic impact for patients with acute myocardial infarction. E.J. Top01 (2) The University of Michigan Medical Center, Ann Arbor, Michigan 48109-0022, USA
HEMATOLOGY Tumour necrosisfactor as growth factor for Bcell malignancies
Tumour necrosis factor induces the lysis of tumour cells in vitro and regression of some tumours in vivo. More recently it has also become clear that TNF can act as a growth factor for certain normal cells, including B and T lymphocytes and fibroblasts. We have now shown that TNF can also act as a growth factor for malignancies derived from at least one of these cell types. Thus, addition of tumour necrosis factor to B chronic lymphocytic leukaemia or hairy cell lsukaemia cells prolongs their survival in vitro and induces them to become activated and proliferate. Activation is autocrine in nature since culture with TNF protein induces mRNA for TNF and secretion of fresh protein. Alpha interferon is an effective treatment for patients with hairy cell leukaemia (HCL) and co-culture of HCL cells with alpha interferon blocks TNF mediated survival and proliferation. This effect is mediated by interruption of the TNF generated autocrine loop rather than by any effect on receptor expression. Our observations have two implications. First, other agents that behave like alpha interferon and interrupt TNF autocrine loops may be therapeutically effective and, secondly, that TI:F may act as a growth factor for other (2) N. Engl. J. Med. (‘1988) 318, 1083.
Notes malignancies derived from normal cells that proliferate in response to the cytokine. M.K. Brenner (1) Royal Free Hospital, Hampstead, London NW3
2 QG, UK
147 drug, e.g. a bile acid sequestrant, can produce a marked reduction in cholesterol levels. Other disorders where reductase inhibitors may be effective therapy are familial dysbetalipoproteinemia and the dyslipidemias of diabetes, nephrotic syndrome and familial combined hyperlipidemia. However, if patients with these disorders are treated with HMG-CoA reductase, they should be monitored carefully for side effects. SM. Grundy (2) University of Texas SouthWestern Medical Center, Dallas TX 752359052, USA
NUTRITION Treatment of hypercholesterolemia Although cholesterol lowering drugs are used in only a fraction of hypercholesterolemic patients at present, the results of several large clinical trials provide a rationale for their use in prevention of coronary heart disease (CHD). Recent trials have demonstrated a reduction in morbidity due to CHD, and a retardation and even regression of coronary artery plaques in some patients. The hypolipidemic agents most commonly employed are the fibric acids (clofibrate, gemfibrozil, fenofibrate, bezofibrate). These drugs are generally well tolerated, but they reduce total cholesterol levels only moderately (IO-20%). Another widely used and well tolerated drug is probucol which lowers total cholesterol to about the same extent as fibric acids. Probucol has been recently shown to retard development of atherosclerosis in rabbits with genetic hypercholesterolemia, an important observation which is being further investigated. Because of their eflicacy and proved safety, bile acid sequestrants (cholestyramine and colestipol) and niacin are the drugs of first choice for treatment of hypercholesterolemia. These drugs lower total cholesterol levels by 15-30 %. Unfortunately, they are not always well tolerated by all patients. Finally, the various available drugs can be used in combination to produce a greater plasma cholesterol reduction; for example the combination of a bile acid sequestrant and niacin can reduce cholesterol levels by 30-40 %. The HMG-CoA reductase inhibitors represent a new class of cholesterol-lowering drugs. They act primarily by increasing the expression of LDL receptors, causing a reduction in LDL cholesterol levels. One such agent, lovastatin (Mevacor, Merck & Co.) was approved by the United States Food and Drug Administration in 1987. This potent drug, effective in small doses, has been shown to lower total cholesterol by 30 to 40%. With the exception of rhabdomyolysis, which is rare occurrence, the drug seems to be free from serious side effects. However, until the safety of this class of drugs has been proven, it is prudent to restrict their usage to patients with severe hypercholesteroiemia or to patients with moderate hypercholesterolemia who have other risk factor for coronary heart disease. in persons who do not respond adequately to lovastatin alone, a second
(1) Lancer
(1988) I, 969
INFECTIOUS DISEASES Vaseuler proliferation of infectious origin in HIV-infected patients The vascular proliferation, Kaposi’s sarcoma, has been considered a hallmark of infection with the human immunodeticiency virus (HIV). In this paper, we reported a second type of vascular proliferition in HIVinfected patients, one that may be unique to that setting, and which seems clearly to be of infectious origin. We studied cutaneous vascular proliferations from seven patients with AIDS, whose lesions clinically resembled those of Kaposi’s sarcoma, but on histologic examination had findings that were clearly distinct from those of KS. Unlike the case in KS, the lesions in our patients were composed of epithelioid or cuboida1 endothelial cells, resembling the benign condition called epithelioid hemangioma. An infectious etiology of these unusual vascular lesions was established by the finding of clusters of bacteria within the lesions. The bacteria did not stain with the usual histochemical methods, but did stain with the Warthin-Starry silver stain, similar in this respect to the recently identified agent of cat scratch disease. Two of the patients who were still alive at the time of this study gave histories of being scratched by cats. In all of the lesions treated with antibiotics, complete resolution was seen. Because of the similarity of the bacteria to those of cat scratch disease, we stained sections with an antibody raised against the cat scratch disease bacillus, and positive staining was noted in all cases. These findings highlight the need for biopsy rather than clinical diagnosis of Kaposi’s sarcoma, and establish a seemingly new entity in patients with HIV infection. Ph. E. L.&oh (3) University of San Francisco, San Francisco, CA 94143, USA (2) N. Engl. J. Med. (1988) 319, 24. (3) Lancet (1988) I. 960.