- Email: [email protected]
PSEUDOHYPOPARATHYROIDISM: CONTINUING PARADOX
439
mortality of 6% from operation for established complications (a figure many would regard as rather high) and of zero for elective resection as part of another procedure, they calculated that with the average age of patients having operations being between 35 and 40 years, surgeons would have to remove 800 uncomplicated Meckel’s to prevent 1 death. Is it possible to detect diverticula that have a particular risk? Over a quarter of the complications are due to adhesion bands to the umbilicus causing volvulus or intestinal obstruction, and these can easily be detected without mobilising the small intestine at appendicectomy or laparotomy. Attempts at detection of ectopic tissue by palpation, in one study,5 were correct in only 17 of 33 cases subjected to histological examination. Three other facts to be borne in mind are pointed out in Williams’ balanced review:bcoexistence of acute appendicitis and acute Meckel’s diverticulitis is very rare; a diverticulum may be as far as 180 cm from the ileocaecal valve so a cursory look at the last 70 cm of ileum is inadequate; and bleeding from a Meckel’s diverticulum nearly always occurs in the young. We may from all this evidence suggest the following
guidelines: (1) In the presence of acute appendicitis no search should be made for a Meckel’s diverticulum. (2) If during an operation for abdominal pain a normal appendix is found a diverticulum should be sought and both should be removed. (3) In a child or young adult, if a diverticulum is found during a non-acute operation, it should be removed, particularly if it is narrow-necked, provided the patient’s general condition and the nature of the primary operation are appropriate. (4) The finding of an adhesive band to the umbilicus, at any age, during a laparotomy is an indication for dividing the band between ligatures and resecting the diverticulum if appropriate. (5) In a patient over 40, an incidental non-adherent Meckel’s should be left alone. The final decision must be left to the judgment of the surgeon, but he need not feel guilty if he leaves a Meckel’s diverticulum in a patient.
PSEUDOHYPOPARATHYROIDISM: CONTINUING PARADOX ALTHOUGH pseudohypoparathyroidism (PSP), first described by Albright et al,1 is a rare hereditary disorder, it is much studied because it poses fundamental questions about the action of parathyroid hormone. It is characterised symptoms and signs of hypoparathyroidism with distinctive skeletal and developmental defects, including short stature, .round face and obesity, subcutaneous bone-formation, and some degree of mental retardation.2 The paradox of this condition is that the patients are hypocalcaemic and hyperphosphataemic even though the circulating level of immunoreactive parathyroid hormone is almost always raised. Moreover, work with a very sensitive bioassay has not resolved the paradox since the levels of biologically active parathyroid hormone in such patients were normal or even t
by
slightly raised.3,4 5 Von
Hedenberg
C.
Surgical indications
in Meckel’s diverticulum. Acta Chir Scand
1969; 135: 530-33. Williams RS. Meckel’s diverticulum. Br J Surg 1981; 68: 477-80. 1 Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism—an example of "Seabright-Bantam Syndrome". Endocrinology 1942; 30: 922-32. 2 Nagant de Deuxchaisnes C, Krane SM. Hypoparathyroidism. In: Avioli LV, Krane SM, eds Metabolic bone disease, vol 2. New York: Academic Press, 1978; 217-445. 3 Nagant de Deuxchaisnes C, Fischer JA, Dambacher MA, et al. Dissociation of parathyroid hormone bioactivity and immunoreactivity in pseudohypoparathyroidism type I. JClin Endocrinol Metab 1981; 53: 1105-09. 6
could be resolved if there were some endresistance to parathyroid hormone, as originally organ suggested by Albright et al. Thus, almost by definition,5,6 all PSP patients have a deficient urinary cAMP response to exogenous parathyroid hormone. This is not found’ in those relatives of PSP patients who show the somatic features but are not hypoparathyroid-a condition that has been called pseudopseudohypoparathyroidism.8 Moreover there are some subjects who have all the features of PSP, but who have a normal urinary cAMP response to exogenous parathyroid hormone even though they show no phosphaturic or calcaemic response.9 The discoveryl° that the adenylate cyclase activity, in response to parathyroid hormone was reduced in a renal plasma-membrane preparation from a PSP patient (when tested at suboptimal concentrations of ATP), but could be normalised by the addition of GTP, led to the conceptll,12 that the "end-organ resistance" was due to a defect of the guanine nucleotide regulatory protein (G or N unit) that couples the parathyroid-hormone receptor to the catalytic unit of the adenylate cyclase. This would be expected to be a generalised defect and agrees with the findings of occasional disorders of other endocrine systems in PSP patients. These include elevated levels of thyroid stimulating hormone (TSH) and of TSH responses to thyrotropin releasing hormone (TRH); deficient prolactin release in response to TRH and parathyroid hormone (PTH); and resistance to glucagon. 6,11,12 There are now several reports confirming that the activity of the G or N unit may be reduced by about 50% in renal plasma membranes, red blood cells, fibroblasts, and platelets from PSP patients,l,12 and that this defect is associated with the somatic features of the disease. 6, " However, this defect does not occur in.all PSP patients. Thus in one of the studies on erythrocyte membranes,b only thirteen of twenty-nine patients investigated had this defect. Moreover, there is some controversy as to whether or not the N-unit defect results in any great diminution in the production of cAMP by fibroblasts, from PSP patients, exposed to various agents that stimulate the production ofcAMP in these cells.13,14 Perhaps the most telling point is the finding that the N unit is deficient in some patients with pseudopseudohypoparathyroidism The
paradox
Allgrove J, Adami S, Jayaweera P, Chayen J, O’Riordan JLH. Biologically active parathyroid hormone in pseudohypoparathyroidism. Calcif Tissue Int 1981; 33 suppl: A189 5. Chase LR, Melson GL, Aurbach GD. Pseudohypoparathyroidism: defective excretion of 3’5’-AMP in response to parathyroid hormone. J Clin Invest 1969; 48: 1832-44. 6. Levine MA, Downs RW, Jr, Moses AM, Breslau NA, Marx SJ, Lasker RD, Aurbach GD, Spiegel AM. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74: 545-56. 7. Fischer JA, Bourne HR, Dambacher MA, Tschopp F, De Meyer R, Devogelaer J-P, Werder EA, Nagant de Deuxchaisnes C. Pseudohypoparathyroidism. Inheritance and expression of deficient receptor-cyclase coupling protein activity. Clin Endocrinol (Oxf) (in press). 8. Albright F, Forbes AP, Henneman PH. Pseudopseudohypoparathyroidism. Trans Assoc Am Phys 1952; 65: 337-50. 9. Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: A possible defect in the reception of the cAMP signal. N Engl JMed 1973, 289: 1056-60. 10. Drezner MK, Burch WM, Jr. Altered activity of the nucleotide regulatory site in the parathyroid hormone-sensitive adenylate cyclase from the renal cortex ofa patient with pseudohypoparathyroidism J Clin Invest 1978; 62: 1222-27. 11. Spiegel AM, Levine MA, Marx SJ, Aurbach GD Pseudohypoparathyroidism: the molecular basis for hormone resistance-a retrospective. N Engl J Med 1982; 307: 4.
679-81. 12. Van Dop C, Bourne HR. Pseudohypoparathyroidism. Annu Rev Med 1983; 34: 259-66. 13. Bourne HR, Kaslow HR, Brickman AS, Farfel Z. Fibroblast defect in pseudohypo-
parathyroidism, type I. reduced activity of receptor-cyclase coupling protein. J Clin Endocrinol Metab 1981; 53: 636-40. MA, Eil C, Downs RW, Jr, Spiegel AM. Impaired adenylate cyclase activity in cultured fibroblasts from patients with pseudohypoparathyroidism. Endocrinology
14. Levine
1982; 110 (suppl): A384.
440
who show
a
normal
urinary
cAMP response
to
exogenous
parathyroid hormone.7 There are also clinical findings that go against the concept that the end-organ resistance can be explained solely by a defect of the N-unit activity. Firstly, some of the responses to exogenous parathyroid hormone have returned in PSP patients after their serum calcium levels have become normal as a result of treatment with vitamin D. Secondly, parathyroidectomy on one PSP patient resulted in a return of the phosphaturic and calcaemic responses to exogenous parathyroid hormone.2 Thirdly, of the six PSP patients, of whom only one showed reduced N-unit activity, none showed end-organ resistance to arginine vasopressin,l5 which, like parathyroid hormone is thought to act through the adenylate cyclase system. 16 And, finally, a proportion of PSP patients show evidence of hyperparathyroid bone disease.12 Thus there are strong grounds for feeling that the paradox of PSP cannot be satisfactorily explained solely in terms of the activity of the N unit. Some new findings have suggested an alternative mechanism for end-organ resistance: PSP plasma inhibits the action of parathyroid hormone in the cytochemical bioassay of this -hormone. In this assay, plasma, or the standard reference preparation of parathyroid hormone, is applied to segments of guineapig kidney maintained in organ-culture. When exogenous parathyroid hormone is added to the plasma of normal subjects, or those with hyperparathyroidism or hypoparathyroidism, the response in these segments is commensurate with the amount added-that is, there is "recovery" of 50-90% of the exogenous hormone. However, when this was done with the plasma of ten PSP patients, the amount recovered ranged from less than 1 % up to 35%. This "inhibition" of the exogenous parathyroid hormone cannot be due to a deficient N unit in the guineapig renal segments and was not due to rapid proteolysis or to circulating antibodies to PTH;17 therefore it must be due to some factor present in PSP plasma. Interestingly, it was not found" in the plasma of the PSP patient who had previously undergone parathyroidectomy.2 Thus the "inhibition" is probably due to immunoreactive parathyroid hormone with which PSP plasma is richly endowed, that lacks biological activity on the kidney, acting very much as do certain synthetic parathyroid-hormone peptides, such as 3-34 PTH. These bind to renal receptors without stimulating adenylate cyclase activity.18 Moreover, in vitro, the 3-34 peptide inhibited the stimulation of renal adenylate cyclase by the biologically active 1-34 PTH18,19 and caused dissociation of cAMP production and calcium-release in bone explants.2o PSP is a disorder which may well involve several metabolic errors. Although changes in the activity of the N unit may play some part in its manifestation, it seems likely that subtle modifications of the PTH molecule secreted by, or made in 15. Moses AM, Coulson BB. Absence of overlapping resistance to vasopressin and parathyroid hormone in patients with nephrogenic diabetes insipidus and pseudohypoparathyroidism J Clin Endocrinol Metab 1982, 55: 699-702. 16 Dousa TP Cyclic AMP in regulation of renal transport. some basic unresolved questions. Curr Topics Membr Transport 1980; 13: 1401-13. 17. Loveridge N, Fischer JA, Nagant de Deuxchaisnes C, et al. Inhibition ofcytochemical bioactivity of parathyroid hormone by plasma in pseudohypoparathyroidism type I. J Clin Endocrinol Metab 1982; 54: 1274-75 18. Goltzman D, Peytremann A, Callahan E, Tregear GW, Potts JT, Jr. Analysis of the requirements for parathyroid hormone action in renal membranes with the use of inhibiting analogues J Biol Chem 1975; 250: 3199-203. 19 McGowan JA, Chen TC, Fragola J, Puschett JB, Rosenblatt M. Parathyroid hormone: Effects of the 3-34 fragment in vivo and in vitro. Science 1983; 219: 67-69. 20. Herrmann-Erlee MPM, Nijweide PJ, van der Meer JM, Ooms MAC. Action of bPTH and bPTH fragments on embryonic bone in vitro: dissociation of the cyclic AMP and bone resorbing response. Calcif Tissue Int 1983; 35: 70-77.
the circulation in these PSP patients are of at least equal importance. Thus the abnormal preponderance of immunoreactive parathyroid hormone over biologically active hormone in these patients may involve molecules of the hormone that are modified so that they bind to the renal receptors without stimulating adenylate cyclase activity and block the receptor from responding to the much lower concentrations (eg, 1 % of the total) of biologically active hormone.3,4 These modified molecules are present in such excess that they even block the action of exogenous -2 parathyroid hormone, whether administered to the patient’-’ or applied to segments of the guineapig kidney. 17 Depending on the extent of the modifications, the parathyroid hormone molecules may or may not be as inactive on bone as they are on the kidney.
VACCINES IN BULK THE World Health Organisation’s Expanded Programme Immunisation has set itself the formidable target of ensuring immunisation services for all the world’s infants and pregnant women by the end of the decade. Developing countries, besides being most in need in terms of deaths and illness due to poliomyelitis, tetanus, measles, and so on, also tend to be the ones without vaccine production units of their own. They have to buy from outside, and with economies already hard pressed for foreign currency. Any device for making importation less painful is welcome. Since 1979 the Pan American Health Organisation (PAHO) has been helping out with a revolving fund to spread the load.’ The scheme covers most countries in Latin America and the Caribbean but less than half the population (Brazil being one on
non-participant). PAHO asks member countries what they need, puts huge orders out to tender, and passes on the very good prices it obtains, quality being assured by WHO standards. Once the vaccine has been safely delivered the recipient has two months to repay, but in its own currency. PAHO imposes a 3% service charge to cover, among other things, losses on currency transactions, and, as far as possible, PAHO reuses the pesos, sols, and colons in national programmes. Since there is repayment (and countries that fall into arrears cannot order more) all that is required is a once-and-for-all capital sum. Sadly this sum, set at$4 million, has not yet been reached: the result has been vaccines purchased with nothing left for cold chains or syringes, delays in quarterly orders for vaccines, and countries with large orders having had to deposit dollars, which defeats one of the objects of the fund. The price advantages are spectacular. 100 000 polio vaccine doses for Panama, for example, cost only$3700. That country would have had to find more than$20 000 for purchases outside the scheme, a differential that seems hard to justify on economies of scale alone. At a time of rising pharmaceutical prices, the cost of vaccines negotiated through the fund has fallen. It is not clear what the advantage of this scheme is over buying through WHO or UNICEF, and the Americas may be uniquely placed among the six WHO regions in having such uniformity of non-domestic production. All the same, something similar is being tried in the Western Pacific-and the PAHO initiative provides a proven model for the handling of essential drugs. 1. Carrasco
P, Umstead W. EPI Chron 1983; 37: 81-85.
in
the Americas: Benefits from revolving fund. WHO
mortality of 6% from operation for established complications (a figure many would regard as rather high) and of zero for elective resection as part of another procedure, they calculated that with the average age of patients having operations being between 35 and 40 years, surgeons would have to remove 800 uncomplicated Meckel’s to prevent 1 death. Is it possible to detect diverticula that have a particular risk? Over a quarter of the complications are due to adhesion bands to the umbilicus causing volvulus or intestinal obstruction, and these can easily be detected without mobilising the small intestine at appendicectomy or laparotomy. Attempts at detection of ectopic tissue by palpation, in one study,5 were correct in only 17 of 33 cases subjected to histological examination. Three other facts to be borne in mind are pointed out in Williams’ balanced review:bcoexistence of acute appendicitis and acute Meckel’s diverticulitis is very rare; a diverticulum may be as far as 180 cm from the ileocaecal valve so a cursory look at the last 70 cm of ileum is inadequate; and bleeding from a Meckel’s diverticulum nearly always occurs in the young. We may from all this evidence suggest the following
guidelines: (1) In the presence of acute appendicitis no search should be made for a Meckel’s diverticulum. (2) If during an operation for abdominal pain a normal appendix is found a diverticulum should be sought and both should be removed. (3) In a child or young adult, if a diverticulum is found during a non-acute operation, it should be removed, particularly if it is narrow-necked, provided the patient’s general condition and the nature of the primary operation are appropriate. (4) The finding of an adhesive band to the umbilicus, at any age, during a laparotomy is an indication for dividing the band between ligatures and resecting the diverticulum if appropriate. (5) In a patient over 40, an incidental non-adherent Meckel’s should be left alone. The final decision must be left to the judgment of the surgeon, but he need not feel guilty if he leaves a Meckel’s diverticulum in a patient.
PSEUDOHYPOPARATHYROIDISM: CONTINUING PARADOX ALTHOUGH pseudohypoparathyroidism (PSP), first described by Albright et al,1 is a rare hereditary disorder, it is much studied because it poses fundamental questions about the action of parathyroid hormone. It is characterised symptoms and signs of hypoparathyroidism with distinctive skeletal and developmental defects, including short stature, .round face and obesity, subcutaneous bone-formation, and some degree of mental retardation.2 The paradox of this condition is that the patients are hypocalcaemic and hyperphosphataemic even though the circulating level of immunoreactive parathyroid hormone is almost always raised. Moreover, work with a very sensitive bioassay has not resolved the paradox since the levels of biologically active parathyroid hormone in such patients were normal or even t
by
slightly raised.3,4 5 Von
Hedenberg
C.
Surgical indications
in Meckel’s diverticulum. Acta Chir Scand
1969; 135: 530-33. Williams RS. Meckel’s diverticulum. Br J Surg 1981; 68: 477-80. 1 Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism—an example of "Seabright-Bantam Syndrome". Endocrinology 1942; 30: 922-32. 2 Nagant de Deuxchaisnes C, Krane SM. Hypoparathyroidism. In: Avioli LV, Krane SM, eds Metabolic bone disease, vol 2. New York: Academic Press, 1978; 217-445. 3 Nagant de Deuxchaisnes C, Fischer JA, Dambacher MA, et al. Dissociation of parathyroid hormone bioactivity and immunoreactivity in pseudohypoparathyroidism type I. JClin Endocrinol Metab 1981; 53: 1105-09. 6
could be resolved if there were some endresistance to parathyroid hormone, as originally organ suggested by Albright et al. Thus, almost by definition,5,6 all PSP patients have a deficient urinary cAMP response to exogenous parathyroid hormone. This is not found’ in those relatives of PSP patients who show the somatic features but are not hypoparathyroid-a condition that has been called pseudopseudohypoparathyroidism.8 Moreover there are some subjects who have all the features of PSP, but who have a normal urinary cAMP response to exogenous parathyroid hormone even though they show no phosphaturic or calcaemic response.9 The discoveryl° that the adenylate cyclase activity, in response to parathyroid hormone was reduced in a renal plasma-membrane preparation from a PSP patient (when tested at suboptimal concentrations of ATP), but could be normalised by the addition of GTP, led to the conceptll,12 that the "end-organ resistance" was due to a defect of the guanine nucleotide regulatory protein (G or N unit) that couples the parathyroid-hormone receptor to the catalytic unit of the adenylate cyclase. This would be expected to be a generalised defect and agrees with the findings of occasional disorders of other endocrine systems in PSP patients. These include elevated levels of thyroid stimulating hormone (TSH) and of TSH responses to thyrotropin releasing hormone (TRH); deficient prolactin release in response to TRH and parathyroid hormone (PTH); and resistance to glucagon. 6,11,12 There are now several reports confirming that the activity of the G or N unit may be reduced by about 50% in renal plasma membranes, red blood cells, fibroblasts, and platelets from PSP patients,l,12 and that this defect is associated with the somatic features of the disease. 6, " However, this defect does not occur in.all PSP patients. Thus in one of the studies on erythrocyte membranes,b only thirteen of twenty-nine patients investigated had this defect. Moreover, there is some controversy as to whether or not the N-unit defect results in any great diminution in the production of cAMP by fibroblasts, from PSP patients, exposed to various agents that stimulate the production ofcAMP in these cells.13,14 Perhaps the most telling point is the finding that the N unit is deficient in some patients with pseudopseudohypoparathyroidism The
paradox
Allgrove J, Adami S, Jayaweera P, Chayen J, O’Riordan JLH. Biologically active parathyroid hormone in pseudohypoparathyroidism. Calcif Tissue Int 1981; 33 suppl: A189 5. Chase LR, Melson GL, Aurbach GD. Pseudohypoparathyroidism: defective excretion of 3’5’-AMP in response to parathyroid hormone. J Clin Invest 1969; 48: 1832-44. 6. Levine MA, Downs RW, Jr, Moses AM, Breslau NA, Marx SJ, Lasker RD, Aurbach GD, Spiegel AM. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983; 74: 545-56. 7. Fischer JA, Bourne HR, Dambacher MA, Tschopp F, De Meyer R, Devogelaer J-P, Werder EA, Nagant de Deuxchaisnes C. Pseudohypoparathyroidism. Inheritance and expression of deficient receptor-cyclase coupling protein activity. Clin Endocrinol (Oxf) (in press). 8. Albright F, Forbes AP, Henneman PH. Pseudopseudohypoparathyroidism. Trans Assoc Am Phys 1952; 65: 337-50. 9. Drezner M, Neelon FA, Lebovitz HE. Pseudohypoparathyroidism type II: A possible defect in the reception of the cAMP signal. N Engl JMed 1973, 289: 1056-60. 10. Drezner MK, Burch WM, Jr. Altered activity of the nucleotide regulatory site in the parathyroid hormone-sensitive adenylate cyclase from the renal cortex ofa patient with pseudohypoparathyroidism J Clin Invest 1978; 62: 1222-27. 11. Spiegel AM, Levine MA, Marx SJ, Aurbach GD Pseudohypoparathyroidism: the molecular basis for hormone resistance-a retrospective. N Engl J Med 1982; 307: 4.
679-81. 12. Van Dop C, Bourne HR. Pseudohypoparathyroidism. Annu Rev Med 1983; 34: 259-66. 13. Bourne HR, Kaslow HR, Brickman AS, Farfel Z. Fibroblast defect in pseudohypo-
parathyroidism, type I. reduced activity of receptor-cyclase coupling protein. J Clin Endocrinol Metab 1981; 53: 636-40. MA, Eil C, Downs RW, Jr, Spiegel AM. Impaired adenylate cyclase activity in cultured fibroblasts from patients with pseudohypoparathyroidism. Endocrinology
14. Levine
1982; 110 (suppl): A384.
440
who show
a
normal
urinary
cAMP response
to
exogenous
parathyroid hormone.7 There are also clinical findings that go against the concept that the end-organ resistance can be explained solely by a defect of the N-unit activity. Firstly, some of the responses to exogenous parathyroid hormone have returned in PSP patients after their serum calcium levels have become normal as a result of treatment with vitamin D. Secondly, parathyroidectomy on one PSP patient resulted in a return of the phosphaturic and calcaemic responses to exogenous parathyroid hormone.2 Thirdly, of the six PSP patients, of whom only one showed reduced N-unit activity, none showed end-organ resistance to arginine vasopressin,l5 which, like parathyroid hormone is thought to act through the adenylate cyclase system. 16 And, finally, a proportion of PSP patients show evidence of hyperparathyroid bone disease.12 Thus there are strong grounds for feeling that the paradox of PSP cannot be satisfactorily explained solely in terms of the activity of the N unit. Some new findings have suggested an alternative mechanism for end-organ resistance: PSP plasma inhibits the action of parathyroid hormone in the cytochemical bioassay of this -hormone. In this assay, plasma, or the standard reference preparation of parathyroid hormone, is applied to segments of guineapig kidney maintained in organ-culture. When exogenous parathyroid hormone is added to the plasma of normal subjects, or those with hyperparathyroidism or hypoparathyroidism, the response in these segments is commensurate with the amount added-that is, there is "recovery" of 50-90% of the exogenous hormone. However, when this was done with the plasma of ten PSP patients, the amount recovered ranged from less than 1 % up to 35%. This "inhibition" of the exogenous parathyroid hormone cannot be due to a deficient N unit in the guineapig renal segments and was not due to rapid proteolysis or to circulating antibodies to PTH;17 therefore it must be due to some factor present in PSP plasma. Interestingly, it was not found" in the plasma of the PSP patient who had previously undergone parathyroidectomy.2 Thus the "inhibition" is probably due to immunoreactive parathyroid hormone with which PSP plasma is richly endowed, that lacks biological activity on the kidney, acting very much as do certain synthetic parathyroid-hormone peptides, such as 3-34 PTH. These bind to renal receptors without stimulating adenylate cyclase activity.18 Moreover, in vitro, the 3-34 peptide inhibited the stimulation of renal adenylate cyclase by the biologically active 1-34 PTH18,19 and caused dissociation of cAMP production and calcium-release in bone explants.2o PSP is a disorder which may well involve several metabolic errors. Although changes in the activity of the N unit may play some part in its manifestation, it seems likely that subtle modifications of the PTH molecule secreted by, or made in 15. Moses AM, Coulson BB. Absence of overlapping resistance to vasopressin and parathyroid hormone in patients with nephrogenic diabetes insipidus and pseudohypoparathyroidism J Clin Endocrinol Metab 1982, 55: 699-702. 16 Dousa TP Cyclic AMP in regulation of renal transport. some basic unresolved questions. Curr Topics Membr Transport 1980; 13: 1401-13. 17. Loveridge N, Fischer JA, Nagant de Deuxchaisnes C, et al. Inhibition ofcytochemical bioactivity of parathyroid hormone by plasma in pseudohypoparathyroidism type I. J Clin Endocrinol Metab 1982; 54: 1274-75 18. Goltzman D, Peytremann A, Callahan E, Tregear GW, Potts JT, Jr. Analysis of the requirements for parathyroid hormone action in renal membranes with the use of inhibiting analogues J Biol Chem 1975; 250: 3199-203. 19 McGowan JA, Chen TC, Fragola J, Puschett JB, Rosenblatt M. Parathyroid hormone: Effects of the 3-34 fragment in vivo and in vitro. Science 1983; 219: 67-69. 20. Herrmann-Erlee MPM, Nijweide PJ, van der Meer JM, Ooms MAC. Action of bPTH and bPTH fragments on embryonic bone in vitro: dissociation of the cyclic AMP and bone resorbing response. Calcif Tissue Int 1983; 35: 70-77.
the circulation in these PSP patients are of at least equal importance. Thus the abnormal preponderance of immunoreactive parathyroid hormone over biologically active hormone in these patients may involve molecules of the hormone that are modified so that they bind to the renal receptors without stimulating adenylate cyclase activity and block the receptor from responding to the much lower concentrations (eg, 1 % of the total) of biologically active hormone.3,4 These modified molecules are present in such excess that they even block the action of exogenous -2 parathyroid hormone, whether administered to the patient’-’ or applied to segments of the guineapig kidney. 17 Depending on the extent of the modifications, the parathyroid hormone molecules may or may not be as inactive on bone as they are on the kidney.
VACCINES IN BULK THE World Health Organisation’s Expanded Programme Immunisation has set itself the formidable target of ensuring immunisation services for all the world’s infants and pregnant women by the end of the decade. Developing countries, besides being most in need in terms of deaths and illness due to poliomyelitis, tetanus, measles, and so on, also tend to be the ones without vaccine production units of their own. They have to buy from outside, and with economies already hard pressed for foreign currency. Any device for making importation less painful is welcome. Since 1979 the Pan American Health Organisation (PAHO) has been helping out with a revolving fund to spread the load.’ The scheme covers most countries in Latin America and the Caribbean but less than half the population (Brazil being one on
non-participant). PAHO asks member countries what they need, puts huge orders out to tender, and passes on the very good prices it obtains, quality being assured by WHO standards. Once the vaccine has been safely delivered the recipient has two months to repay, but in its own currency. PAHO imposes a 3% service charge to cover, among other things, losses on currency transactions, and, as far as possible, PAHO reuses the pesos, sols, and colons in national programmes. Since there is repayment (and countries that fall into arrears cannot order more) all that is required is a once-and-for-all capital sum. Sadly this sum, set at$4 million, has not yet been reached: the result has been vaccines purchased with nothing left for cold chains or syringes, delays in quarterly orders for vaccines, and countries with large orders having had to deposit dollars, which defeats one of the objects of the fund. The price advantages are spectacular. 100 000 polio vaccine doses for Panama, for example, cost only$3700. That country would have had to find more than$20 000 for purchases outside the scheme, a differential that seems hard to justify on economies of scale alone. At a time of rising pharmaceutical prices, the cost of vaccines negotiated through the fund has fallen. It is not clear what the advantage of this scheme is over buying through WHO or UNICEF, and the Americas may be uniquely placed among the six WHO regions in having such uniformity of non-domestic production. All the same, something similar is being tried in the Western Pacific-and the PAHO initiative provides a proven model for the handling of essential drugs. 1. Carrasco
P, Umstead W. EPI Chron 1983; 37: 81-85.
in
the Americas: Benefits from revolving fund. WHO