203
13. Viallet J, MacLean JD, Goresky CA, Staudt M, Routhier G, Law C. Arctic trichinosis presenting as prolonged diarrhea. Gastroenterology 1986; 91: 938-46. 14. Sanmartin Duran ML, Leiro J, Santamarina MT, Ubeira FM, Orallo F. The effect of intestinal trichinellosis on the acetylcholine-induced contractions of isolated duodenum of mice. Med Sci Res 1988; 16: 461-62. 15. Centers for Disease Control. Trichinosis—Hawaii. MMWR 1987; 36: 14-16. 16. Zimmerman WJ. An approach to safe microwave cooking of pork roasts containing Trichinella spiralis. J Food Sci 1983; 48: 1715-18.
GRANULOMATOUS REACTION IN TOTAL HIP ARTH ROPLASTY
Charnley, when he introduced total hip arthroplasty, effectively introduced plastics into routine clinical practice. Initially polytetrafluoroethylene (PTFE, ’Teflon’) was used, because of its non-stick property, as interposition shells in an attempt to simulate the damaged articular cartilage. Later it was shaped into a socket, this time articulating with the metal femoral head replacement. In the early clinical trials the socket was not cemented. At that stage the"new operation" of hip arthroplasty was reported in The Lancet.1 Within a few years it became obvious that PTFE was not ideal because rapid wear in the body led to socket migration and extensive bone destruction. Charnleyz in 1963 and Scales and Stinson4 in 1964 mentioned this complication, and Charnley subsequently returned to the subject.4,5 However, these were brief comments; when, in 1962, Charnley showed experimentally that high-density polyethylene (HDP) had much better wear properties, the "teflon experience" was largely forgotten, and HDP became the material of choice. Long-term clinical results of cemented total hip arthroplasty, with HDP for the socket, have highlighted the increasing frequency of component loosening; these findings draw attention, once again, to the effects of wear debris on the tissues housing the implant, and on the way in which they may contribute to component loosening. Granuloma formation is the tissue response to wear debris; the typical appearance of an HDP granuloma is that of a fibrous membrane, often of considerable thickness, between the implant and bone. The membrane contains histiocytes and foreign body giant cells with HDP, or other wear debris particles, within them. When it lies free within the dependent part of the joint cavity it is an amorphous, acellular, pink-staining caseous material that resembles tubercular caseation. There are two apparently opposing views about the effect of the granuloma. One suggestion is that HDP wear particles stimulate the histiocytic reaction, which adversely effects the bone-cement interface, thereby loosening the implant.6,7 Rose and his colleagues,8 after extensive research and review of literature, concluded that"... the chief question is that of biological effects of the debris and not of mechanical problems due to dimensional changes". The alternative view is that the presence of HDP wear debris in the bone-cement interface is brought about by loosening. The destructive changes resulting from direct contact between HDP and bone would support this notion.9,lO Even with cemented sockets, 30% have shown wear on their external surface when revised for loosening;"1 such changes can only occur after the socket has become loose, and the presence of HDP wear particles can be readily explained as the result of loosening. The HDP socket does
randomly: the metal head bores for itself a new roughly cylindrical path which leads to restriction of angular movements, impingement of the neck of the stem on the rim of the socket, and socket loosening. Even with the most destructive changes found with PTFE, the intrapelvic granuloma thus formed went on to calcification and sometimes new bone formation, indicating a healing process, provided the movement of the granuloma had ceased. 12 These results seem to indicate the benign nature of the plastic wear debris and the adverse effects of mechanical loosening. More recently Tallroth and colleagues13 have reported their experience; these researchers use the term "aggressive" with respect to the granulomatous reaction, and suggest that it may be the result of a foreign body giant cell reaction due to acrylic cement, and possibly to a metallic implant. At the same time, they illustrate cases of inadequate fixation, early failure of fixation, and in one instance an uncemented femoral head replacement with appearances compatible with deep infection. not wear
The controversy is of more than academic interest. It highlights one of the crucial issues-wear and its effects, mechanical or biological, on the fixation of the components. Since movement under load will inevitably lead to wear and wear debris, the logical conclusion of the tissue reaction theory is that loosening and failure are inevitable. However, if the changes in geometry are more important, much is to be gained from the study of materials (wear, friction, and frictional torque). There is little doubt that in patients with excessive wear of the HDP socket, changes in geometry of the joint, loosening, and the damaging effects of the wear debris being mechanically pumped within the cavity containing the loose implant will lead to increasing loss of bone stock and more difficult revision surgery. For that reason regular follow-up by serial radiographs is essential. An uncomfortable thought is that those who identified the acrylic cement as the main cause of the problem, and therefore turned to uncemented arthroplasties, may have adopted the worst aspects of both techniques-ie, allowing the immediate ingress of the wear debris to the bone-implant interface while making no effort to reduce the mechanical problems resulting from wear.
1.
Charnley J. Arthroplasty of the hip. A
new
operation. Lancet 1961; i:
1129-32. 2.
Charnley J. Tissue reactions to polytetrafluoroethylene. Lancet 1963; ii:
1379. 3. Scales JT, Stinson NE. Tissue reactions to polytetrafluoroethylene. Lancet 1964; ii: 169. 4. Chamley J. Low friction arthroplasty of the hip joint. In: Progress in clinical rheumatology. 1965: 339-47. 5. Charnley J. J Bone Joint Surg 1966; 48A: 819. 6. Willert HG, Semlitsch M. Reaction of the articular capsule to artificial joint prostheses. In: Williams D, ed. Biocompatibility of implant materials. Tunbridge Wells: Pitman, 1976: 40-48. 7. Vemon-Roberts, D, Freeman MAR. The tissue response to total joint replacement prostheses. In: Swanson SAV, Freeman MAR, eds. The scientific basis of joint replacement. Tunbridge Wells: Pitman, 1977: 86-129. 8. Rose RM, Nusbaum HJ, Schneider H, et al. On the true wear rate of ultra-high molecular weight polyethylene in total hip prosthesis. J Bone Joint Surg 1980; 62A: 537-49. 9. Mendes DG, Walker PS, Figarola F, Bullough PG. Total surface hip replacement in the dog: a clinical and pathological study. J Bone Joint Surg 1972; 54A: 1124-25. 10. Wroblewski BM. Wear of high-density polyethylene on bone and cartilage. J Bone Joint Surg 1979; 618: 498-500. 11. Wroblewski BM, Lynch M, Atkinson JR, Dowson D, Isaac GH. External wear of the polyethylene socket in cemented total hip arthroplasty. J Bone Joint Surg 1987; 69B: 61-63.
204
12. Wroblewski B. Wear and loosening of the socket in the Charnley low-friction arthroplasty of the hip. Orthop Clin N Am 1988; 19: 627-30. 13. Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS. Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg 1988; 71B: 571-75.
responsiveness, although a p value of 0-06 was thought to be consistent with a weak association. In some women asthma symptoms improved and they needed less therapy, but again the picture was mixed, with no clear correlations with hormone levels. There was the expected increase in heartburn, but this did not correlate with bronchial hyperresponsiveness as measured by methacholine
challenge. ASTHMA, PROGESTERONE, AND PREGNANCY pregnancy progesterone levels rise steeply; they peak in the third trimester, typically 50-100 times baseline values. These high levels inhibit the formation of gap junctions (pathways of low electrical resistance) in the smooth muscle of the uterus, which remains largely relaxed and poorly contractile. Progesterone levels fall abruptly immediately before parturition, and uterine contractility increases sharply because gap junction formation suddenly increases.1 It has been suggested that this hormonal effect on smooth muscle might apply in other parts of the body, notably the gut, in which relaxation of the oesophageal sphincter is often associated with reflux symptoms that are
During reach
a
troublesome in late pregnancy.2 Bronchial smooth muscle might also be expected to follow the same pattern, with relative relaxation during pregnancy and increased contractility at the onset of labour. If true, clinical implications for patients with asthma, especially those with long-standing disease and associated bronchial smooth muscle hypertrophy, might be dramatic. In reality, there is little consistent evidence that pregnancy profoundly influences the severity of asthma, except in occasional individuals. Many researchers have reported the symptoms of asthma during pregnancy; the consistent finding is that symptoms may worsen, remain unchanged, or improve in variable numbers of individuals. The proportions with such changes have varied considerably, the extremes being reported by Gluck,3who found that 14% of patients improved and 43% worsened, and White et awlwho found that 69% improved and only 6% worsened during pregnancy. Schaefer and Silverman could detect no change in asthma symptoms in 93% of 293 5 pregnant women. Most reports on asthma during pregnancy mention the difficulty of making accurate observations during a time of rapidly changing physiology-the height of the fundus in the third trimester may be a more important cause of breathlessness than is worsening asthma. The frequent sense of wellbeing during pregnancy may mask symptoms and lead to a reduction in therapy, without objective improvement in serial peak flow measurements. Conversely, increased gastro-oesophageal reflux may lead to worsening asthma. Juniper and her colleagues in Hamilton have lately reported a detailed prospective study of asthma during pregnancy.6 They began with careful evaluation of 20 women of child-bearing potential before conception. The 16 who conceived during the study period were then followed throughout pregnancy, with assessment of symptoms, drug requirements, progesterone and oestriol levels, and of bronchial hyperresponsiveness by means of methacholine challenge. Not surprisingly, these women behaved in different ways. Overall, there was a slight but not significant reduction (improvement) in bronchial hyperresponsiveness; 11showed an improvement compared with baseline but 5 a deterioration. There was no clear statistical correlation between progesterone levels and bronchial hypermost
These
mostly negative findings are open to several interpretations. The first is that progesterone does not affect smooth muscle of the bronchial wall in the same way as that of the myometrium and perhaps the gut. The second, favoured by Juniper and her colleagues, is that the effects of progesterone on bronchial smooth muscle are countered by other biological effects during pregnancy--eg, increased free cortisol levels. The third interpretation, for which there is much experimental support, is that measurement of bronchial hyperresponsiveness by methacholine challenge reflects not only smooth muscle contractility but also many complex interactions within the bronchial wall in response to an inflammatory stimulus.8 Nevertheless, occasionally there are compelling clinical reasons to suspect that changing progesterone levels can be important. For example, severe premenstrual asthma can sometimes be completely prevented by injection of progesterone at the appropriate time.9 In such patients there seems little doubt that the sudden fall in progesterone before menstruation is highly associated with clinical asthma and presumably bronchial smooth muscle contractility. All this reinforces conventional clinical wisdom about asthma in pregnancy: namely, that it is impossible to predict hormonal effects on the airways. Most women appear to be little influenced by pregnancy, but there are exceptions in both directions. Previously, asthma could be devastating in its effects on both mother and fetus, but it is now clear that with good management even the most severe types of asthma can be associated with a normal outcome of pregnancy and childbirth.lO Fortunately, none of the usual anti-asthma drugs is harmful in normal doses, to either mother or fetus, and asthma should be managed with the same attention to detail as at any other time. Continuous monitoring of peak flow is strongly recommended in all but the mildest cases.
1. Garfield
RE, Sims S, Daniel EE. Gap junctions: their presence and in myometrium during parturition. Science 1977; 198:
necessity
958-60. 2. Fisher RS, Roberts
GS, Grabowski CJ, Cohen S. Altered lower sphincter function during early pregnancy. Gastroenterology 1978; 74: 1233-37. 3. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-68. 4. White RJ, Coutts II, Gibbs CJ, MacIntyre C. A prospective study of asthma during pregnancy and the puerperium. Respir Med 1989; 83: oesophageal
103-06. 5. Schaefer G, Silverman F. Pregnancy complicated by asthma. Am J Obstet Gynecol 1961; 82: 182-91. 6. Juniper EF, Daniel EE, Roberts RS, Kline PA, Hargreave FE, Newhouse MT. Improvement in airway responsiveness and asthma severity during pregnancy. Am Rev Respir Dis 1989; 140: 924-31. 7. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-98. 8. Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 1987; 73: 561-72. 9. Benyon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; ii: 370-71. 10. Apter AJ, Greenberger MD, Patterson MD. Outcomes of pregnancy in adolescents with severe asthma. Arch Intern Med 1989; 149: 2571-75.
13. Viallet J, MacLean JD, Goresky CA, Staudt M, Routhier G, Law C. Arctic trichinosis presenting as prolonged diarrhea. Gastroenterology 1986; 91: 938-46. 14. Sanmartin Duran ML, Leiro J, Santamarina MT, Ubeira FM, Orallo F. The effect of intestinal trichinellosis on the acetylcholine-induced contractions of isolated duodenum of mice. Med Sci Res 1988; 16: 461-62. 15. Centers for Disease Control. Trichinosis—Hawaii. MMWR 1987; 36: 14-16. 16. Zimmerman WJ. An approach to safe microwave cooking of pork roasts containing Trichinella spiralis. J Food Sci 1983; 48: 1715-18.
GRANULOMATOUS REACTION IN TOTAL HIP ARTH ROPLASTY
Charnley, when he introduced total hip arthroplasty, effectively introduced plastics into routine clinical practice. Initially polytetrafluoroethylene (PTFE, ’Teflon’) was used, because of its non-stick property, as interposition shells in an attempt to simulate the damaged articular cartilage. Later it was shaped into a socket, this time articulating with the metal femoral head replacement. In the early clinical trials the socket was not cemented. At that stage the"new operation" of hip arthroplasty was reported in The Lancet.1 Within a few years it became obvious that PTFE was not ideal because rapid wear in the body led to socket migration and extensive bone destruction. Charnleyz in 1963 and Scales and Stinson4 in 1964 mentioned this complication, and Charnley subsequently returned to the subject.4,5 However, these were brief comments; when, in 1962, Charnley showed experimentally that high-density polyethylene (HDP) had much better wear properties, the "teflon experience" was largely forgotten, and HDP became the material of choice. Long-term clinical results of cemented total hip arthroplasty, with HDP for the socket, have highlighted the increasing frequency of component loosening; these findings draw attention, once again, to the effects of wear debris on the tissues housing the implant, and on the way in which they may contribute to component loosening. Granuloma formation is the tissue response to wear debris; the typical appearance of an HDP granuloma is that of a fibrous membrane, often of considerable thickness, between the implant and bone. The membrane contains histiocytes and foreign body giant cells with HDP, or other wear debris particles, within them. When it lies free within the dependent part of the joint cavity it is an amorphous, acellular, pink-staining caseous material that resembles tubercular caseation. There are two apparently opposing views about the effect of the granuloma. One suggestion is that HDP wear particles stimulate the histiocytic reaction, which adversely effects the bone-cement interface, thereby loosening the implant.6,7 Rose and his colleagues,8 after extensive research and review of literature, concluded that"... the chief question is that of biological effects of the debris and not of mechanical problems due to dimensional changes". The alternative view is that the presence of HDP wear debris in the bone-cement interface is brought about by loosening. The destructive changes resulting from direct contact between HDP and bone would support this notion.9,lO Even with cemented sockets, 30% have shown wear on their external surface when revised for loosening;"1 such changes can only occur after the socket has become loose, and the presence of HDP wear particles can be readily explained as the result of loosening. The HDP socket does
randomly: the metal head bores for itself a new roughly cylindrical path which leads to restriction of angular movements, impingement of the neck of the stem on the rim of the socket, and socket loosening. Even with the most destructive changes found with PTFE, the intrapelvic granuloma thus formed went on to calcification and sometimes new bone formation, indicating a healing process, provided the movement of the granuloma had ceased. 12 These results seem to indicate the benign nature of the plastic wear debris and the adverse effects of mechanical loosening. More recently Tallroth and colleagues13 have reported their experience; these researchers use the term "aggressive" with respect to the granulomatous reaction, and suggest that it may be the result of a foreign body giant cell reaction due to acrylic cement, and possibly to a metallic implant. At the same time, they illustrate cases of inadequate fixation, early failure of fixation, and in one instance an uncemented femoral head replacement with appearances compatible with deep infection. not wear
The controversy is of more than academic interest. It highlights one of the crucial issues-wear and its effects, mechanical or biological, on the fixation of the components. Since movement under load will inevitably lead to wear and wear debris, the logical conclusion of the tissue reaction theory is that loosening and failure are inevitable. However, if the changes in geometry are more important, much is to be gained from the study of materials (wear, friction, and frictional torque). There is little doubt that in patients with excessive wear of the HDP socket, changes in geometry of the joint, loosening, and the damaging effects of the wear debris being mechanically pumped within the cavity containing the loose implant will lead to increasing loss of bone stock and more difficult revision surgery. For that reason regular follow-up by serial radiographs is essential. An uncomfortable thought is that those who identified the acrylic cement as the main cause of the problem, and therefore turned to uncemented arthroplasties, may have adopted the worst aspects of both techniques-ie, allowing the immediate ingress of the wear debris to the bone-implant interface while making no effort to reduce the mechanical problems resulting from wear.
1.
Charnley J. Arthroplasty of the hip. A
new
operation. Lancet 1961; i:
1129-32. 2.
Charnley J. Tissue reactions to polytetrafluoroethylene. Lancet 1963; ii:
1379. 3. Scales JT, Stinson NE. Tissue reactions to polytetrafluoroethylene. Lancet 1964; ii: 169. 4. Chamley J. Low friction arthroplasty of the hip joint. In: Progress in clinical rheumatology. 1965: 339-47. 5. Charnley J. J Bone Joint Surg 1966; 48A: 819. 6. Willert HG, Semlitsch M. Reaction of the articular capsule to artificial joint prostheses. In: Williams D, ed. Biocompatibility of implant materials. Tunbridge Wells: Pitman, 1976: 40-48. 7. Vemon-Roberts, D, Freeman MAR. The tissue response to total joint replacement prostheses. In: Swanson SAV, Freeman MAR, eds. The scientific basis of joint replacement. Tunbridge Wells: Pitman, 1977: 86-129. 8. Rose RM, Nusbaum HJ, Schneider H, et al. On the true wear rate of ultra-high molecular weight polyethylene in total hip prosthesis. J Bone Joint Surg 1980; 62A: 537-49. 9. Mendes DG, Walker PS, Figarola F, Bullough PG. Total surface hip replacement in the dog: a clinical and pathological study. J Bone Joint Surg 1972; 54A: 1124-25. 10. Wroblewski BM. Wear of high-density polyethylene on bone and cartilage. J Bone Joint Surg 1979; 618: 498-500. 11. Wroblewski BM, Lynch M, Atkinson JR, Dowson D, Isaac GH. External wear of the polyethylene socket in cemented total hip arthroplasty. J Bone Joint Surg 1987; 69B: 61-63.
204
12. Wroblewski B. Wear and loosening of the socket in the Charnley low-friction arthroplasty of the hip. Orthop Clin N Am 1988; 19: 627-30. 13. Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS. Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg 1988; 71B: 571-75.
responsiveness, although a p value of 0-06 was thought to be consistent with a weak association. In some women asthma symptoms improved and they needed less therapy, but again the picture was mixed, with no clear correlations with hormone levels. There was the expected increase in heartburn, but this did not correlate with bronchial hyperresponsiveness as measured by methacholine
challenge. ASTHMA, PROGESTERONE, AND PREGNANCY pregnancy progesterone levels rise steeply; they peak in the third trimester, typically 50-100 times baseline values. These high levels inhibit the formation of gap junctions (pathways of low electrical resistance) in the smooth muscle of the uterus, which remains largely relaxed and poorly contractile. Progesterone levels fall abruptly immediately before parturition, and uterine contractility increases sharply because gap junction formation suddenly increases.1 It has been suggested that this hormonal effect on smooth muscle might apply in other parts of the body, notably the gut, in which relaxation of the oesophageal sphincter is often associated with reflux symptoms that are
During reach
a
troublesome in late pregnancy.2 Bronchial smooth muscle might also be expected to follow the same pattern, with relative relaxation during pregnancy and increased contractility at the onset of labour. If true, clinical implications for patients with asthma, especially those with long-standing disease and associated bronchial smooth muscle hypertrophy, might be dramatic. In reality, there is little consistent evidence that pregnancy profoundly influences the severity of asthma, except in occasional individuals. Many researchers have reported the symptoms of asthma during pregnancy; the consistent finding is that symptoms may worsen, remain unchanged, or improve in variable numbers of individuals. The proportions with such changes have varied considerably, the extremes being reported by Gluck,3who found that 14% of patients improved and 43% worsened, and White et awlwho found that 69% improved and only 6% worsened during pregnancy. Schaefer and Silverman could detect no change in asthma symptoms in 93% of 293 5 pregnant women. Most reports on asthma during pregnancy mention the difficulty of making accurate observations during a time of rapidly changing physiology-the height of the fundus in the third trimester may be a more important cause of breathlessness than is worsening asthma. The frequent sense of wellbeing during pregnancy may mask symptoms and lead to a reduction in therapy, without objective improvement in serial peak flow measurements. Conversely, increased gastro-oesophageal reflux may lead to worsening asthma. Juniper and her colleagues in Hamilton have lately reported a detailed prospective study of asthma during pregnancy.6 They began with careful evaluation of 20 women of child-bearing potential before conception. The 16 who conceived during the study period were then followed throughout pregnancy, with assessment of symptoms, drug requirements, progesterone and oestriol levels, and of bronchial hyperresponsiveness by means of methacholine challenge. Not surprisingly, these women behaved in different ways. Overall, there was a slight but not significant reduction (improvement) in bronchial hyperresponsiveness; 11showed an improvement compared with baseline but 5 a deterioration. There was no clear statistical correlation between progesterone levels and bronchial hypermost
These
mostly negative findings are open to several interpretations. The first is that progesterone does not affect smooth muscle of the bronchial wall in the same way as that of the myometrium and perhaps the gut. The second, favoured by Juniper and her colleagues, is that the effects of progesterone on bronchial smooth muscle are countered by other biological effects during pregnancy--eg, increased free cortisol levels. The third interpretation, for which there is much experimental support, is that measurement of bronchial hyperresponsiveness by methacholine challenge reflects not only smooth muscle contractility but also many complex interactions within the bronchial wall in response to an inflammatory stimulus.8 Nevertheless, occasionally there are compelling clinical reasons to suspect that changing progesterone levels can be important. For example, severe premenstrual asthma can sometimes be completely prevented by injection of progesterone at the appropriate time.9 In such patients there seems little doubt that the sudden fall in progesterone before menstruation is highly associated with clinical asthma and presumably bronchial smooth muscle contractility. All this reinforces conventional clinical wisdom about asthma in pregnancy: namely, that it is impossible to predict hormonal effects on the airways. Most women appear to be little influenced by pregnancy, but there are exceptions in both directions. Previously, asthma could be devastating in its effects on both mother and fetus, but it is now clear that with good management even the most severe types of asthma can be associated with a normal outcome of pregnancy and childbirth.lO Fortunately, none of the usual anti-asthma drugs is harmful in normal doses, to either mother or fetus, and asthma should be managed with the same attention to detail as at any other time. Continuous monitoring of peak flow is strongly recommended in all but the mildest cases.
1. Garfield
RE, Sims S, Daniel EE. Gap junctions: their presence and in myometrium during parturition. Science 1977; 198:
necessity
958-60. 2. Fisher RS, Roberts
GS, Grabowski CJ, Cohen S. Altered lower sphincter function during early pregnancy. Gastroenterology 1978; 74: 1233-37. 3. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-68. 4. White RJ, Coutts II, Gibbs CJ, MacIntyre C. A prospective study of asthma during pregnancy and the puerperium. Respir Med 1989; 83: oesophageal
103-06. 5. Schaefer G, Silverman F. Pregnancy complicated by asthma. Am J Obstet Gynecol 1961; 82: 182-91. 6. Juniper EF, Daniel EE, Roberts RS, Kline PA, Hargreave FE, Newhouse MT. Improvement in airway responsiveness and asthma severity during pregnancy. Am Rev Respir Dis 1989; 140: 924-31. 7. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-98. 8. Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 1987; 73: 561-72. 9. Benyon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; ii: 370-71. 10. Apter AJ, Greenberger MD, Patterson MD. Outcomes of pregnancy in adolescents with severe asthma. Arch Intern Med 1989; 149: 2571-75.
