- Email: [email protected]
BLOOD PRESSURE AND CORRELATIONS
1110 THROMBOPLASTIN
SIR,-In his review of Anticoagulants and Myocardial Infarction (March 2, p 492), Dr Poller states that his British system "is widely regarded as the model for other countries". May I point out that animal thromboplastin is used in more than 95% of laboratories worldwide. Also, the batch of British comparative thromboplastin recently accepted by WHO and other thromboplastins have been calibrated against the primary international reference preparation coded 6740, a mixture of human brain thromboplastin and absorbed ox plasma. The international calibration of commercial thromboplastin has now been approved by WHO and all the international professional bodies concerned. Do we still need to use thromboplastin prepared from human brain as a routine bench reagent? In the words of Professor Sen,l "It is time for the British to
fall in line with the rest of the world and abandon the use of an of human brain".
extract
Diagnostic Reagents Ltd, Thame,
Fig 1-ARF in an unselected series of patients. 23 responses
were
excluded for sexual disorder
not
K. W. E. DENSON
Oxon OX9 3NY
related
to
impotence.
*p<0-05;**p<0-01.
1. Sen NN. Standardisation of oral
anticoagulant treatment Br Med J 1984; 288: 1693.
BLOOD PRESSURE AND CORRELATIONS
Fig 2-Distribution of potent and impotent men by number of ARF.
*p
**p
in the hypogastrico cavernous axis2and to the nocturnal penile tumescence test (NPT) and intracavernous injection of papaverine test.3Moreover, we excluded patients referred for intermittent claudication who were already impotent. We have established that the PBPI limits for non-arteriogenic impotence are
changes
0-91 ±0-07. We agree that a PBPI below 0-65 means severe arteriogenic impotence. Nevertheless several patients have values in the range 0-65-0-91 yet have arteriographic changes in their penile arteries.2Not all may be impotent but impotence may develop in the presence of some other factor (endocrine, neurological, or venous, or performance anxiety)-just as in coronary heart disease, where lesions of the arterial tree do not necessarily imply a myocardial infarction. Isolated impotence, previously thought to be mainly psychogenic, is a complex multifactorial disease where the arterial component should be considered, with a view to avoidance of ARF. Reversal of impotence by giving up smoking has been reported in one short series.4 We agree with Dr Khosla and Dr West in hoping that this kind of study will lead to enlarged smoking prevention
SiR,—Dr Gill and colleagues (March 9, p 568), discussing the relation between initial blood pressure (BPI) and its fall with treatment (ABP), draw attention to the problem of overinterpretation of data based on statistical correlations. We support their view that pathophysiological conclusions derived from such analyses are inappropriate but wish to make some additional comments. Gill et al state that, if pre-treatment and post-treatment values have equal variance and are not correlated, then the expected correlation coefficient between ABP and BPI would be around 0-71. They illustrate this by using the first two columns ofa random numbers table as the initial and achieved blood pressures (BPI and BP2). However, they do not stress sufficiently clearly that, in practice, pre-treatment and post-treatment blood pressures will be highly correlated. If the coefficient of correlation between BPI and BP2 is p, the correlation coefficient between ABP and BPI is the square root of (I-Q)/2; this will be zero if there is a perfect correlation between BPI and BP 2 (Q = I). An observed correlation between ABP and BPI might therefore reflect the poor quality of data pairing (ie, before and after on the same person). By application of Oldham’s transformation Gill et al proceed to suggest that such correlations between ABP and PBPI are almost always spurious. This suggestion is itself misleading. We have examined four data sets obtained from thirty-three studies on antihypertensive drugs in hypertensives and normotensives done in this department. From the maximum changes in supine systolic BP during a single dose we have calculated the correlation coefficients of ABP vs BPI and of ABP
vs (BP 1 + BP2)/2 (see table). Although the correlation coefficients are all reduced after the Oldham transformation, they remain positive and three are significant. This suggests that there is a real,, albeit weak, relation
CORRELATION COEFFICIENTS
nrosrammes.
Centre d’Etude et de Recherches de 18 rue Boissière, 75116 Paris, France 1. 2. 3.
4.
l’Impuissance,
R. VIRAG P. BOUILLY D. FRYDMAN
Bouilly P, Virag R. The epidemiology of impotence. In: Proceedings of 1st World Meeting on Impotence. Paris: Ceri Edition (in press). Virag R. L’exploration Doppler de l’impuissance. Angeiologie 1980; 32: 117-23. Virag R, Frydman D, Legman M, Floresco J, Bouilly P. Hemodynamic evaluation of arterial and venous lesions as a cause of impotence. Int Angiol 1984; 3: 241-45 Forsberg L, Olson C. Impotence, smoking and &bgr; blocking drugs. Fertil Steril 1979; 31: 589-91
*p<0’05;
j-p<0.001.
1111 between the degree of hypertension and the fall in BP. This relation is clearly not peculiar to calcium channel blockers. As pointed out by Gill et al, it is unlikely that several pharmacologically different antihypertensive drugs and placebo all affect the fundamental mechanism of raised BP in a similar manner. However, all the active agents shown in the table have their major action in reducing arteriolar tone and peripheral resistance; and even a placebo may have its effect by withdrawal of increased
vascular tone. Other effects which may be common to all agents could produce a relation between the change in BP and the degree of hypertension (for example, regression to the mean). Clearly, an antihypertensive agent which produces a fall of 60 mm Hg in a subject with a systolic pressure of 200 mm Hg would be most unlikely to have the same effect in a subject with a systolic pressure of only 100 mm Hg. If we wish to predict for an individual antihypertensive agent the likely lowering of BP, given the initial pressure, it is the relation between BPI and ABP that is important, even though the apparent correlation between the variables merely reflects inversely the correlation between measurements in the same individual. Department of Clinical Physics and Bioengineering, West of Scotland Health Boards, and Department of Nuclear Medicine, Stobhill General Hospital, Glasgow G21 3UW
in progress similar data obtained with a dry-heated covering a shorter observation period have been reported.4The human plasma used for manufacturing of the pasteurised FVIII was obtained predominantly from the USA, as our
work
was
and
product
that used for conventional non-heated concentrates. In vitro studiesl2 indicate that the biological activity of contaminating HTLV-III is destroyed by pasteurisation; however, the viral antigens are probably resistant to such treatment. The total absence of antibodies in group A indicates that the amount of antigen administered by substitutions was not sufficient to induce an immune response to inactivated virus. On the other hand seroconversion in patients in group C probably resulted from exposure to live replicating HTLV-III. However, seropositivity does not indicate whether those patients currently harbour the virus. Since the implications of HTLV-III seropositivity for an individual patient are still unknown it seems quite reasonable to was
previously unexposed haemophiliacs only.
treat
with heat-treated
concentrates
Universitäts-Kinder Klinik, Göttinger
J. MÖSSELER
Rehabilitations Klinic und Haemophilic Zentrum,
K. SCHIMPF
Heidelberg
KinderKlinic,
Department of Statistics, University of Glasgow
D. J. SUMNER K. HOWIE T. AITCHISON
Department of Materia Medica, University of Glasgow
J. L. REID
H. L. ELLIOTT
INABILITY OF PASTEURISED FACTOR VIII PREPARATIONS TO INDUCE ANTIBODIES TO HTLV-III AFTER LONG-TERM TREATMENT
SIR,-Avian (RSV)1 and human (LAV) retroviruses can be inactivated by heat treatment in solution, the virus-inactivating step that has been used since 1979 in the manufacture of pasteurised factor VIII concentrate (FVIII) (’Haemate P’; Behringwerke, Marburg), primarily to avoid transmission of serum hepatitis. We have compared the prevalence of antibodies to human T-lymphotropic virus type III (HTLV-III) in patients treated with
pasteurised FVIII or with non-heated conventional preparations. Serum samples of 113 patients from three German haemophilia centres were tested by ELISA test with a confirmative immunoprecipitation test.318 previously untreated haemophiliacs received pasteurised FVIII exclusively for up to six years (group A); in 15 patients the treatment was changed from conventional to pasteurised product before March, 1983 (group B); 100 patients received non-heated conventional FVIII (group C). FACTOR VIII SUBSTITUTION AND HTLV-III ANTIBODIES
Medizinischen Hochschule, Lübeck
G. AUERSWALD
Stiftung Rehabilitation Deutsches Primatenzentrum, Göttingen, West Germany D-3400
H. BAYER J. SCHNEIDER G. HUNSMANN
J, Mauler R, Friis R, Bauer H. Safety of human blood products: Inactivation of retroviruses by heat treatment at 60°C. Proc Soc Exp Biol Med (in
1. Hilfenhaus
2.
press). Spire B, Dormont D, Barré-Sinoussi F, Montagnier L, Chermann JC. Inactivation of lymphadenopathy-associated virus of heat, gamma rays and ultraviolet light. Lancet 1985; i: 188-89.
Bienzle U, Schneider J, Hunsmann G. HTLV-III antibody frequency and severity of lymphadenopathy. Lancet 1984; ii: 1347. 4. Rouzioux C, Chamaret S, Montagnier L, et al. Absence of antibodies to AIDS in haemophiliacs treated with heat-treated factor VIII concentrate. Lancet 1985; i: 3.
Bayer H,
271-72.
BETA-ADRENERGIC AGONISTS AND CORTICOTROPIN SECRETION
SIR,-Your leading article on the function of adrenaline (March 9,
561). states that adrenaline "stimulates P2 receptors on the pituitary gland causing corticotropin release". The reference cited is of an in-vitro study on mouse anterior pituitary tumour cells, the physiological relevance of which is unknown.’ In-vitro studies of normal rat adenohypophyseal cells have shown no evidence of a p
stimulant effect of adrenaline
or
noradrenaline
on
the secretion of
proopiocortin-derived peptides.2-4 Other investigators using supraphysiological concentrations of noradrenaline (in excess of 10 found a stimulant effect on cultured rat adenohypophyseal cells in vitro. S,6 As the adenohypophysis is not innervatedand the concentration of noradrenaline in the portal plasma is not in excess of that in peripheral of to these is man, importance findings, physiological especially unclear. In contrast, the rodent neurointermediate lobe cells possess &bgr; adrenoceptors9and respond in vitro to (3 adrenergic agonists increasing the secretion of proopiocortin-derived
nmol/1)
have
hypophyseal plasma,
peptides.4,b
EFFECT OF
PRENALTEROL, SALBUTAMOL,
AND METHOXAMINE ON
CORTICOTROPIN AND CORTISOL SECRETION
tB11 positive oetore
All
cnange
01 treatment.
patients in
group A were antibody negative after treatment six years, while 60% of the patients in group C had antibodies to HTLV-III. 3 patients in group B had antibodies to HTLV-III before the change of treatment. Thus, no seroconversion was observed during treatment with pasteurised FVIII (table). Our data demonstrate that pasteurised FVIII, in contrast to nonheated concentrate, does not induce antibodies to HTLV-III. While
lasting up
to
Results are means±SEM maximum change from baseline in 6 normal subjects. differences from saline.
covanance,
Analysis of
SIR,-In his review of Anticoagulants and Myocardial Infarction (March 2, p 492), Dr Poller states that his British system "is widely regarded as the model for other countries". May I point out that animal thromboplastin is used in more than 95% of laboratories worldwide. Also, the batch of British comparative thromboplastin recently accepted by WHO and other thromboplastins have been calibrated against the primary international reference preparation coded 6740, a mixture of human brain thromboplastin and absorbed ox plasma. The international calibration of commercial thromboplastin has now been approved by WHO and all the international professional bodies concerned. Do we still need to use thromboplastin prepared from human brain as a routine bench reagent? In the words of Professor Sen,l "It is time for the British to
fall in line with the rest of the world and abandon the use of an of human brain".
extract
Diagnostic Reagents Ltd, Thame,
Fig 1-ARF in an unselected series of patients. 23 responses
were
excluded for sexual disorder
not
K. W. E. DENSON
Oxon OX9 3NY
related
to
impotence.
*p<0-05;**p<0-01.
1. Sen NN. Standardisation of oral
anticoagulant treatment Br Med J 1984; 288: 1693.
BLOOD PRESSURE AND CORRELATIONS
Fig 2-Distribution of potent and impotent men by number of ARF.
*p
**p
in the hypogastrico cavernous axis2and to the nocturnal penile tumescence test (NPT) and intracavernous injection of papaverine test.3Moreover, we excluded patients referred for intermittent claudication who were already impotent. We have established that the PBPI limits for non-arteriogenic impotence are
changes
0-91 ±0-07. We agree that a PBPI below 0-65 means severe arteriogenic impotence. Nevertheless several patients have values in the range 0-65-0-91 yet have arteriographic changes in their penile arteries.2Not all may be impotent but impotence may develop in the presence of some other factor (endocrine, neurological, or venous, or performance anxiety)-just as in coronary heart disease, where lesions of the arterial tree do not necessarily imply a myocardial infarction. Isolated impotence, previously thought to be mainly psychogenic, is a complex multifactorial disease where the arterial component should be considered, with a view to avoidance of ARF. Reversal of impotence by giving up smoking has been reported in one short series.4 We agree with Dr Khosla and Dr West in hoping that this kind of study will lead to enlarged smoking prevention
SiR,—Dr Gill and colleagues (March 9, p 568), discussing the relation between initial blood pressure (BPI) and its fall with treatment (ABP), draw attention to the problem of overinterpretation of data based on statistical correlations. We support their view that pathophysiological conclusions derived from such analyses are inappropriate but wish to make some additional comments. Gill et al state that, if pre-treatment and post-treatment values have equal variance and are not correlated, then the expected correlation coefficient between ABP and BPI would be around 0-71. They illustrate this by using the first two columns ofa random numbers table as the initial and achieved blood pressures (BPI and BP2). However, they do not stress sufficiently clearly that, in practice, pre-treatment and post-treatment blood pressures will be highly correlated. If the coefficient of correlation between BPI and BP2 is p, the correlation coefficient between ABP and BPI is the square root of (I-Q)/2; this will be zero if there is a perfect correlation between BPI and BP 2 (Q = I). An observed correlation between ABP and BPI might therefore reflect the poor quality of data pairing (ie, before and after on the same person). By application of Oldham’s transformation Gill et al proceed to suggest that such correlations between ABP and PBPI are almost always spurious. This suggestion is itself misleading. We have examined four data sets obtained from thirty-three studies on antihypertensive drugs in hypertensives and normotensives done in this department. From the maximum changes in supine systolic BP during a single dose we have calculated the correlation coefficients of ABP vs BPI and of ABP
vs (BP 1 + BP2)/2 (see table). Although the correlation coefficients are all reduced after the Oldham transformation, they remain positive and three are significant. This suggests that there is a real,, albeit weak, relation
CORRELATION COEFFICIENTS
nrosrammes.
Centre d’Etude et de Recherches de 18 rue Boissière, 75116 Paris, France 1. 2. 3.
4.
l’Impuissance,
R. VIRAG P. BOUILLY D. FRYDMAN
Bouilly P, Virag R. The epidemiology of impotence. In: Proceedings of 1st World Meeting on Impotence. Paris: Ceri Edition (in press). Virag R. L’exploration Doppler de l’impuissance. Angeiologie 1980; 32: 117-23. Virag R, Frydman D, Legman M, Floresco J, Bouilly P. Hemodynamic evaluation of arterial and venous lesions as a cause of impotence. Int Angiol 1984; 3: 241-45 Forsberg L, Olson C. Impotence, smoking and &bgr; blocking drugs. Fertil Steril 1979; 31: 589-91
*p<0’05;
j-p<0.001.
1111 between the degree of hypertension and the fall in BP. This relation is clearly not peculiar to calcium channel blockers. As pointed out by Gill et al, it is unlikely that several pharmacologically different antihypertensive drugs and placebo all affect the fundamental mechanism of raised BP in a similar manner. However, all the active agents shown in the table have their major action in reducing arteriolar tone and peripheral resistance; and even a placebo may have its effect by withdrawal of increased
vascular tone. Other effects which may be common to all agents could produce a relation between the change in BP and the degree of hypertension (for example, regression to the mean). Clearly, an antihypertensive agent which produces a fall of 60 mm Hg in a subject with a systolic pressure of 200 mm Hg would be most unlikely to have the same effect in a subject with a systolic pressure of only 100 mm Hg. If we wish to predict for an individual antihypertensive agent the likely lowering of BP, given the initial pressure, it is the relation between BPI and ABP that is important, even though the apparent correlation between the variables merely reflects inversely the correlation between measurements in the same individual. Department of Clinical Physics and Bioengineering, West of Scotland Health Boards, and Department of Nuclear Medicine, Stobhill General Hospital, Glasgow G21 3UW
in progress similar data obtained with a dry-heated covering a shorter observation period have been reported.4The human plasma used for manufacturing of the pasteurised FVIII was obtained predominantly from the USA, as our
work
was
and
product
that used for conventional non-heated concentrates. In vitro studiesl2 indicate that the biological activity of contaminating HTLV-III is destroyed by pasteurisation; however, the viral antigens are probably resistant to such treatment. The total absence of antibodies in group A indicates that the amount of antigen administered by substitutions was not sufficient to induce an immune response to inactivated virus. On the other hand seroconversion in patients in group C probably resulted from exposure to live replicating HTLV-III. However, seropositivity does not indicate whether those patients currently harbour the virus. Since the implications of HTLV-III seropositivity for an individual patient are still unknown it seems quite reasonable to was
previously unexposed haemophiliacs only.
treat
with heat-treated
concentrates
Universitäts-Kinder Klinik, Göttinger
J. MÖSSELER
Rehabilitations Klinic und Haemophilic Zentrum,
K. SCHIMPF
Heidelberg
KinderKlinic,
Department of Statistics, University of Glasgow
D. J. SUMNER K. HOWIE T. AITCHISON
Department of Materia Medica, University of Glasgow
J. L. REID
H. L. ELLIOTT
INABILITY OF PASTEURISED FACTOR VIII PREPARATIONS TO INDUCE ANTIBODIES TO HTLV-III AFTER LONG-TERM TREATMENT
SIR,-Avian (RSV)1 and human (LAV) retroviruses can be inactivated by heat treatment in solution, the virus-inactivating step that has been used since 1979 in the manufacture of pasteurised factor VIII concentrate (FVIII) (’Haemate P’; Behringwerke, Marburg), primarily to avoid transmission of serum hepatitis. We have compared the prevalence of antibodies to human T-lymphotropic virus type III (HTLV-III) in patients treated with
pasteurised FVIII or with non-heated conventional preparations. Serum samples of 113 patients from three German haemophilia centres were tested by ELISA test with a confirmative immunoprecipitation test.318 previously untreated haemophiliacs received pasteurised FVIII exclusively for up to six years (group A); in 15 patients the treatment was changed from conventional to pasteurised product before March, 1983 (group B); 100 patients received non-heated conventional FVIII (group C). FACTOR VIII SUBSTITUTION AND HTLV-III ANTIBODIES
Medizinischen Hochschule, Lübeck
G. AUERSWALD
Stiftung Rehabilitation Deutsches Primatenzentrum, Göttingen, West Germany D-3400
H. BAYER J. SCHNEIDER G. HUNSMANN
J, Mauler R, Friis R, Bauer H. Safety of human blood products: Inactivation of retroviruses by heat treatment at 60°C. Proc Soc Exp Biol Med (in
1. Hilfenhaus
2.
press). Spire B, Dormont D, Barré-Sinoussi F, Montagnier L, Chermann JC. Inactivation of lymphadenopathy-associated virus of heat, gamma rays and ultraviolet light. Lancet 1985; i: 188-89.
Bienzle U, Schneider J, Hunsmann G. HTLV-III antibody frequency and severity of lymphadenopathy. Lancet 1984; ii: 1347. 4. Rouzioux C, Chamaret S, Montagnier L, et al. Absence of antibodies to AIDS in haemophiliacs treated with heat-treated factor VIII concentrate. Lancet 1985; i: 3.
Bayer H,
271-72.
BETA-ADRENERGIC AGONISTS AND CORTICOTROPIN SECRETION
SIR,-Your leading article on the function of adrenaline (March 9,
561). states that adrenaline "stimulates P2 receptors on the pituitary gland causing corticotropin release". The reference cited is of an in-vitro study on mouse anterior pituitary tumour cells, the physiological relevance of which is unknown.’ In-vitro studies of normal rat adenohypophyseal cells have shown no evidence of a p
stimulant effect of adrenaline
or
noradrenaline
on
the secretion of
proopiocortin-derived peptides.2-4 Other investigators using supraphysiological concentrations of noradrenaline (in excess of 10 found a stimulant effect on cultured rat adenohypophyseal cells in vitro. S,6 As the adenohypophysis is not innervatedand the concentration of noradrenaline in the portal plasma is not in excess of that in peripheral of to these is man, importance findings, physiological especially unclear. In contrast, the rodent neurointermediate lobe cells possess &bgr; adrenoceptors9and respond in vitro to (3 adrenergic agonists increasing the secretion of proopiocortin-derived
nmol/1)
have
hypophyseal plasma,
peptides.4,b
EFFECT OF
PRENALTEROL, SALBUTAMOL,
AND METHOXAMINE ON
CORTICOTROPIN AND CORTISOL SECRETION
tB11 positive oetore
All
cnange
01 treatment.
patients in
group A were antibody negative after treatment six years, while 60% of the patients in group C had antibodies to HTLV-III. 3 patients in group B had antibodies to HTLV-III before the change of treatment. Thus, no seroconversion was observed during treatment with pasteurised FVIII (table). Our data demonstrate that pasteurised FVIII, in contrast to nonheated concentrate, does not induce antibodies to HTLV-III. While
lasting up
to
Results are means±SEM maximum change from baseline in 6 normal subjects. differences from saline.
covanance,
Analysis of