- Email: [email protected]
Absence of association between respiratory symptoms in young adults and use of gas stoves in Belgium
that does not allude (even briefly) to work on this condition lacks balance. I that the term "geneocentric" might be appropriate. suggest
of
diabetes
epidemiological IJ
Perry
Department of Primary
Care and Population Sciences, The School of Medicine, London NW3 2PF. UK
Royal
Free Hospital
Wang PH, Korc M. Searching for the holy grail: the cause of diabetes. Lancet 1995; 346 (suppl): s4. Dowse GK, Spark RA, Mavo B, et al. Extraordinary prevalence of non-insulin dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea. Med J Aust l994; 160: 767-74. Perry IJ, Wannamethee SG, Walker MK, Thomson AG, Whincup PH, Shaper AG. Prospective study of risk factors for development of noninsulin-dependent diabetes in middle-aged British men. BMJ 1995;
1 2
3
4
5
310: 560-64. Rimm EB, Chan J, Stampfer MJ, Colditz GA, Willett WC. Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men. BMJ 1995; 310: 555-59. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36: 62-67.
Assessing the effects of pallidotomy in Parkinson’s disease SiR-Lozano and colleagues’ recently reported the first controlled clinical trial of the effect of pallidotomy in Parkinson’s disease. They found a significant reduction in "off" state scores in global akinesia (33%), rigidity (36%), postural instability and gait (23%), and in total motor score (30%). The Schawb and England scale, which gives a more functional index, changed by 46%. In trials for novel antiparkinson medication, the placebo effect has been estimated to be as high as 30%. If such variability were applicable to the pallidotomy data (which was an open not double-blinded trial) it would question the importance of these results. Although we have little doubt that there is a beneficial effect of pallidotomy, we think that there is a problem with the use of current scoring scales to evaluate its impact. To provide a more objective assessment of the effect of pallidotomy, we conducted a detailed clinical and neurophysiological analysis of six patients with Parkinson’s disease before and after electrophysiologically guided posteroventral pallidotomy (performed by R Bakay,J Vitek, and M DeLong at the Emroy University Hospital, Atlanta,
Figure: Change in performance of standardised arm movement tasks contralateral (operated arm) and ipsilateral (nonoperated arm) to pallidotomy in six patients with Parkinson’s disease. Flex: time to
perform self-paced and self-terminated 30° elbow flexion movements; % change in movement time is plotted before and 3 months after operation. Simple RT: time to press a button with index finger on receipt of a visual cue. Pegs: number of pegs placed in a Purdue pegboard in 30 s with either ipslateral or contralateral hand. Taps: number of finger taps made with one or other hand in 30 s. Data are means and standard errors. All effects on operated arm are significant (p>005,
1490
only tap data
are
significant
for
non-operated arm).
Georgia, USA). The total motor score (unified Parkinson’s disease rating scale) in the "off’ state improved by 39% (ie, similar to that recorded by Lozano et al). However, separate analysis of movements at shoulder, arm, wrist, finger, knee, and so on, revealed more drastic, although localised, changes. For example, wrist rigidity was reduced by 84% and arm bradykinesia improved by 54% on the operated side whereas there was only a 12‘% and 8% (respectively) change on the non-operated side. Measurements of the time taken to perform standardised arm flexion movements showed a minor (less than 20%) improvement on the operated side. More pronounced changes in the order of 45-50% were found in complex tasks involving fine distal control and coordination (the Purdue pegboard), repetitive movements (finger tapping), as well as in the simple reaction time task which involves movement pre-programming (see figure). We conclude that large changes in motor function in specific tasks or in specific parts of the body can be concealed if the usual Parkinson’s disease rating scales are employed. Our data provide objective confirmation that pallidotomy can produce improvement in motor function, particularly in tests assessing bradykinesia/akinesia, in the "off’ state in patients with Parkinson’s disease. *J A Obeso, G Linazasoro, J C Rothwell, M Jahanshahi, R Brown *Centro de Neurologia y Neurocirugia Funcional, Clinica Quiron, San Sebastian, Spain; and MRC Human Movement & Balance Unit, Institute of Neurology, London, UK
1
AM, Lang AE, Gaivez-Jimenez N, et al. Effects of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;
Lozano
346:1383-87.
Absence of association between respiratory symptoms in young adults and use of gas stoves in Belgium and colleagues (Feb 17, p 426)’ report an association of respiratory symptoms and lung function in young adults with the use of domestic gas appliances. For female gas stove users the risk of asthma-like symptoms was up to 2-88 times higher than that for non-users. These associations were not found for men, indicating a possible effect modification. The study was part of the European Community Respiratory Health Survey study (ECRHS) and it is therefore of interest to compare the results with those of other participating centres. In Belgium we obtained ECRHS questionnaire responses on respiratory symptoms and cooking on gas stoves from 1118 people in the same age-group living in the Antwerp area. We also showed the crude associations between gas cooking and most respiratory symptoms (table) (odds ratio [OR] up to 2-56), but no indication for a higher risk in women than in men. However, after adjustment by logistic regression for age, smoking, and urban versus suburban residence the associations became weak, except in women for waking with chest tightness in the past 12 months Thus, clearly the association between gas and cooking respiratory symptoms shown in England cannot be generalised to other populations. Unlike Jarvis and colleagues, we found no difference between sexes in reporting of symptoms, despite the described differences in cooking habits probably being comparable in both countries. Obviously other factors need to be considered to account for the difference in results between the two populations. We found, for example, that adjusting for occurrence of asthma in siblings, and for severe respiratory infection before the age
SiR Jarvis
(ORad=189).
of 5, further weakened the association between respiratory symptoms and gas cooking, especially in women. Was the reported association in females in the British study still found when correction was made for such personal and other environmental factors?
when those of possibly equal exposure (single people) considered separately. This finding is of interest, but information on marital status is not available from most centres and this form of analysis cannot be included in the international comparison. Leynaert and colleagues2 are wrong to attribute to us the view that differences between men and women are necessarily more likely to be due to differences in exposure. Wieringa and colleagues show inconsistent associations between gas appliances and respiratory disease in Belgium. They also suggest that adjustment for asthma in a sibling and respiratory infection before the age of 5 years may reduce our observed associations. We can think of no a priori reason why these factors should be confounding our observed association, and adjustment for both factors marginally but not significantly increases the odds in women and decreases the odds in men. As soon as the full international analysis is completed it will be submitted for publication. At present there is little evidence that additional variables to those used in the original East Anglian data set should be included.
*M Wieringa, J Weyler, P Vermeire University of Antwerp, Department of Epidemiology Universiteitsplein 1, B-2610, Antwerp, Belgium
Department of Public Health Medicine, United Medical and Dental Schools, St Thomas’s Hospital, London SE1 7EH, UK
even are
*Adjusted for area of residence, ever having smoked >1 year, and age-group. tall variables: in past 12 months. tp
gas cooking
*D Jarvis, S Chinn, and
Respiratory Medicine,
1 Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with use of domestic gas appliances. Lancet 1996; 347: 426-31.
1
2
Authors’ reply SIR-The publication of our study,’ which was based on data collected in England as part of the multicentre ECRHS, has prompted research groups from other countries that also took part in ECRHS to test whether our findings-a strong and consisted association between respiratory symptoms and the use of gas cooking in women-can be replicated in their own local data sets.2 The ECRHS has collected information on respiratory disease and exposure to known and suspected risk factors for asthma from over 17 000 people living in more than 30 centres in 14 different countries (some of which are not in Europe). The project management group agreed the following two-stage plan for analysis. First, data from individual centres could be aggregated to country level and analysed to identify potential risk factors for disease. Second, assuming that the analysis was accepted by the wider research community as being valid (for example by being accepted for publication), researchers would be provided with the appropriate variables from the combined data set for all centres to test whether their hypothesis held in all the populations studied. This approach was designed to prevent false associations arising from trawling through the immense combined ECRHS data set. However, analyses on the international data sets are complex and an inevitable delay occurs between the two stages. Data anomalies need clarification and supplementary information may be required for results to be appropriately interpreted. In the meantime, individual centres may choose to analyse their local data with methods that may or may not be adopted for the final
international analysis. We are examining the relation of domestic gas appliances and respiratory disease in the ECRHS international data set. There is wide variation in exposure to gas appliances, the nature of these appliances, and the type of gas they use. It would be premature to comment on the conclusions of colleagues from France and Belgium, but we can make the
following observations. Combined data from two of the four centres in France show that the difference between men and women persists
Luczynska,
P
Burney
Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with the use of domestic gas appliances. Lancet 1996; 347: 426-31. Leynaert B, Liard R, Bousquet J, Mesbah H, Neukirch F. Gas cooking and respiratory health in women. Lancet 1996; 347: 1052-53.
Selective toxicity of vincristine against chronic lymphocytic leukaemia in vitro SiR-It is generally assumed that vincristine, as are other Vinca alkaloids, is a cell-cycle-specific agent that blocks mitosis through metaphase arrest’ by specifically binding to tubulin. Other metabolic effects have been noticed, but only tubulin inhibition has been related to the cytotoxic effects of vincristine. Vincristine is used in several regimens for chronic lymphocytic leukaemia (CLL). However, a note on the use of vincristine in CLL has been cautionary sounded: the value of vincristine has not been proved in this disease, but because combination regimens previously established for other B-cell cancers happened to include vincristine, this drug has been given to a large number of patients with CLL. Since the majority of CLL cells are not mitotically active, the use of vincristine does not seem rational. While investigating the cytotoxicity of a number of chemotherapeutic agents against CLL cells in vitro, we noted a striking action of vincristine against lymphocytes from patients with CLL but not from normal healthy blood donors. We isolated peripheral blood mononuclear cells from 20 patients with CLL (>90% leukaemic B cells) and from 11 volunteers healthy by density gradient centrifugation. The cells were cultured in duplicate in 200 ilL aliquots (2X10/mL) on microtitre plates in RPMI 1640 medium containing 10% fetal calf serum. Vincristine concentrations were 0, 2, 10, 50, 250, and 1250 nmol/L. Toxicity was assessed by the reduction of macromolecular
protein synthesis or [3H]-leucine incorporation as an endpoint.3 The cells were incubated for 4 days. The tracer was added for the final 24 h, whereafter the proteins were precipitated with perchloric acid and the radioactivity in the macromolecular protein fraction was counted.3 Dose-response curves (figure) showed a remarkable difference in the response of CLL lymphocytes and normal lymphocytes. A statistically significant difference (t test) 1491
of
diabetes
epidemiological IJ
Perry
Department of Primary
Care and Population Sciences, The School of Medicine, London NW3 2PF. UK
Royal
Free Hospital
Wang PH, Korc M. Searching for the holy grail: the cause of diabetes. Lancet 1995; 346 (suppl): s4. Dowse GK, Spark RA, Mavo B, et al. Extraordinary prevalence of non-insulin dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea. Med J Aust l994; 160: 767-74. Perry IJ, Wannamethee SG, Walker MK, Thomson AG, Whincup PH, Shaper AG. Prospective study of risk factors for development of noninsulin-dependent diabetes in middle-aged British men. BMJ 1995;
1 2
3
4
5
310: 560-64. Rimm EB, Chan J, Stampfer MJ, Colditz GA, Willett WC. Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men. BMJ 1995; 310: 555-59. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36: 62-67.
Assessing the effects of pallidotomy in Parkinson’s disease SiR-Lozano and colleagues’ recently reported the first controlled clinical trial of the effect of pallidotomy in Parkinson’s disease. They found a significant reduction in "off" state scores in global akinesia (33%), rigidity (36%), postural instability and gait (23%), and in total motor score (30%). The Schawb and England scale, which gives a more functional index, changed by 46%. In trials for novel antiparkinson medication, the placebo effect has been estimated to be as high as 30%. If such variability were applicable to the pallidotomy data (which was an open not double-blinded trial) it would question the importance of these results. Although we have little doubt that there is a beneficial effect of pallidotomy, we think that there is a problem with the use of current scoring scales to evaluate its impact. To provide a more objective assessment of the effect of pallidotomy, we conducted a detailed clinical and neurophysiological analysis of six patients with Parkinson’s disease before and after electrophysiologically guided posteroventral pallidotomy (performed by R Bakay,J Vitek, and M DeLong at the Emroy University Hospital, Atlanta,
Figure: Change in performance of standardised arm movement tasks contralateral (operated arm) and ipsilateral (nonoperated arm) to pallidotomy in six patients with Parkinson’s disease. Flex: time to
perform self-paced and self-terminated 30° elbow flexion movements; % change in movement time is plotted before and 3 months after operation. Simple RT: time to press a button with index finger on receipt of a visual cue. Pegs: number of pegs placed in a Purdue pegboard in 30 s with either ipslateral or contralateral hand. Taps: number of finger taps made with one or other hand in 30 s. Data are means and standard errors. All effects on operated arm are significant (p>005,
1490
only tap data
are
significant
for
non-operated arm).
Georgia, USA). The total motor score (unified Parkinson’s disease rating scale) in the "off’ state improved by 39% (ie, similar to that recorded by Lozano et al). However, separate analysis of movements at shoulder, arm, wrist, finger, knee, and so on, revealed more drastic, although localised, changes. For example, wrist rigidity was reduced by 84% and arm bradykinesia improved by 54% on the operated side whereas there was only a 12‘% and 8% (respectively) change on the non-operated side. Measurements of the time taken to perform standardised arm flexion movements showed a minor (less than 20%) improvement on the operated side. More pronounced changes in the order of 45-50% were found in complex tasks involving fine distal control and coordination (the Purdue pegboard), repetitive movements (finger tapping), as well as in the simple reaction time task which involves movement pre-programming (see figure). We conclude that large changes in motor function in specific tasks or in specific parts of the body can be concealed if the usual Parkinson’s disease rating scales are employed. Our data provide objective confirmation that pallidotomy can produce improvement in motor function, particularly in tests assessing bradykinesia/akinesia, in the "off’ state in patients with Parkinson’s disease. *J A Obeso, G Linazasoro, J C Rothwell, M Jahanshahi, R Brown *Centro de Neurologia y Neurocirugia Funcional, Clinica Quiron, San Sebastian, Spain; and MRC Human Movement & Balance Unit, Institute of Neurology, London, UK
1
AM, Lang AE, Gaivez-Jimenez N, et al. Effects of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;
Lozano
346:1383-87.
Absence of association between respiratory symptoms in young adults and use of gas stoves in Belgium and colleagues (Feb 17, p 426)’ report an association of respiratory symptoms and lung function in young adults with the use of domestic gas appliances. For female gas stove users the risk of asthma-like symptoms was up to 2-88 times higher than that for non-users. These associations were not found for men, indicating a possible effect modification. The study was part of the European Community Respiratory Health Survey study (ECRHS) and it is therefore of interest to compare the results with those of other participating centres. In Belgium we obtained ECRHS questionnaire responses on respiratory symptoms and cooking on gas stoves from 1118 people in the same age-group living in the Antwerp area. We also showed the crude associations between gas cooking and most respiratory symptoms (table) (odds ratio [OR] up to 2-56), but no indication for a higher risk in women than in men. However, after adjustment by logistic regression for age, smoking, and urban versus suburban residence the associations became weak, except in women for waking with chest tightness in the past 12 months Thus, clearly the association between gas and cooking respiratory symptoms shown in England cannot be generalised to other populations. Unlike Jarvis and colleagues, we found no difference between sexes in reporting of symptoms, despite the described differences in cooking habits probably being comparable in both countries. Obviously other factors need to be considered to account for the difference in results between the two populations. We found, for example, that adjusting for occurrence of asthma in siblings, and for severe respiratory infection before the age
SiR Jarvis
(ORad=189).
of 5, further weakened the association between respiratory symptoms and gas cooking, especially in women. Was the reported association in females in the British study still found when correction was made for such personal and other environmental factors?
when those of possibly equal exposure (single people) considered separately. This finding is of interest, but information on marital status is not available from most centres and this form of analysis cannot be included in the international comparison. Leynaert and colleagues2 are wrong to attribute to us the view that differences between men and women are necessarily more likely to be due to differences in exposure. Wieringa and colleagues show inconsistent associations between gas appliances and respiratory disease in Belgium. They also suggest that adjustment for asthma in a sibling and respiratory infection before the age of 5 years may reduce our observed associations. We can think of no a priori reason why these factors should be confounding our observed association, and adjustment for both factors marginally but not significantly increases the odds in women and decreases the odds in men. As soon as the full international analysis is completed it will be submitted for publication. At present there is little evidence that additional variables to those used in the original East Anglian data set should be included.
*M Wieringa, J Weyler, P Vermeire University of Antwerp, Department of Epidemiology Universiteitsplein 1, B-2610, Antwerp, Belgium
Department of Public Health Medicine, United Medical and Dental Schools, St Thomas’s Hospital, London SE1 7EH, UK
even are
*Adjusted for area of residence, ever having smoked >1 year, and age-group. tall variables: in past 12 months. tp
gas cooking
*D Jarvis, S Chinn, and
Respiratory Medicine,
1 Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with use of domestic gas appliances. Lancet 1996; 347: 426-31.
1
2
Authors’ reply SIR-The publication of our study,’ which was based on data collected in England as part of the multicentre ECRHS, has prompted research groups from other countries that also took part in ECRHS to test whether our findings-a strong and consisted association between respiratory symptoms and the use of gas cooking in women-can be replicated in their own local data sets.2 The ECRHS has collected information on respiratory disease and exposure to known and suspected risk factors for asthma from over 17 000 people living in more than 30 centres in 14 different countries (some of which are not in Europe). The project management group agreed the following two-stage plan for analysis. First, data from individual centres could be aggregated to country level and analysed to identify potential risk factors for disease. Second, assuming that the analysis was accepted by the wider research community as being valid (for example by being accepted for publication), researchers would be provided with the appropriate variables from the combined data set for all centres to test whether their hypothesis held in all the populations studied. This approach was designed to prevent false associations arising from trawling through the immense combined ECRHS data set. However, analyses on the international data sets are complex and an inevitable delay occurs between the two stages. Data anomalies need clarification and supplementary information may be required for results to be appropriately interpreted. In the meantime, individual centres may choose to analyse their local data with methods that may or may not be adopted for the final
international analysis. We are examining the relation of domestic gas appliances and respiratory disease in the ECRHS international data set. There is wide variation in exposure to gas appliances, the nature of these appliances, and the type of gas they use. It would be premature to comment on the conclusions of colleagues from France and Belgium, but we can make the
following observations. Combined data from two of the four centres in France show that the difference between men and women persists
Luczynska,
P
Burney
Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with the use of domestic gas appliances. Lancet 1996; 347: 426-31. Leynaert B, Liard R, Bousquet J, Mesbah H, Neukirch F. Gas cooking and respiratory health in women. Lancet 1996; 347: 1052-53.
Selective toxicity of vincristine against chronic lymphocytic leukaemia in vitro SiR-It is generally assumed that vincristine, as are other Vinca alkaloids, is a cell-cycle-specific agent that blocks mitosis through metaphase arrest’ by specifically binding to tubulin. Other metabolic effects have been noticed, but only tubulin inhibition has been related to the cytotoxic effects of vincristine. Vincristine is used in several regimens for chronic lymphocytic leukaemia (CLL). However, a note on the use of vincristine in CLL has been cautionary sounded: the value of vincristine has not been proved in this disease, but because combination regimens previously established for other B-cell cancers happened to include vincristine, this drug has been given to a large number of patients with CLL. Since the majority of CLL cells are not mitotically active, the use of vincristine does not seem rational. While investigating the cytotoxicity of a number of chemotherapeutic agents against CLL cells in vitro, we noted a striking action of vincristine against lymphocytes from patients with CLL but not from normal healthy blood donors. We isolated peripheral blood mononuclear cells from 20 patients with CLL (>90% leukaemic B cells) and from 11 volunteers healthy by density gradient centrifugation. The cells were cultured in duplicate in 200 ilL aliquots (2X10/mL) on microtitre plates in RPMI 1640 medium containing 10% fetal calf serum. Vincristine concentrations were 0, 2, 10, 50, 250, and 1250 nmol/L. Toxicity was assessed by the reduction of macromolecular
protein synthesis or [3H]-leucine incorporation as an endpoint.3 The cells were incubated for 4 days. The tracer was added for the final 24 h, whereafter the proteins were precipitated with perchloric acid and the radioactivity in the macromolecular protein fraction was counted.3 Dose-response curves (figure) showed a remarkable difference in the response of CLL lymphocytes and normal lymphocytes. A statistically significant difference (t test) 1491