464
be detected with solochrome azurine, so even in the stained areas the amount of the element need not be very high. That urinary aluminium after desferrioxamine increased only slightly (patient one) or not at all (patient two) reflects the small amounts of aluminium involved. Moreover, aluminium buried within trabeculae may not be available for chelation, and the desferrioxamine test was, like the biopsies, carried out more than 6 months after the contamination incident. We have examined several thousand biopsy specimens stained with solochrome azurine from normal subjects and from patients with metabolic bone disease and had previously found positive staining for aluminium only in two groups-patients undergoing regular dialysis and those with renal failure not on dialysis who were ingesting aluminium-containing phosphate binders. The findings in the patients described here show that in certain circumstances normal individuals can absorb and retain increased quantities of aluminium. can
We thank Dr R. J. Newman and Dr C. A. N. Jarvis for referring the patients and Dr Peter Ackrill for his help.
two
REFERENCES
Berlyne GM, Yagil R, Ben Ari J, Weinberger G, Knopf E, Danovitch GM. Aluminium toxicity in rats. Lancet 1972; i: 564-68. 2. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome: possible aluminum intoxication. N Engl J Med 1976; 294: 1.
184-88.
DB, Levis JA, Bukes JS, Alfrey AC. Dialysis encephalopathy in peritoneal dialysis. JAMA 1980; 244: 365-66. 4. Nathan E, Pederson S. Dialysis encephalopathy in a non-dialysed uraemic boy treated with aluminium hydroxide orally. Acta Pediatr 3. Smith
Scand 1980; 69: 793-96. EM, Luck VA, Hynson WV, et al. The effect of aluminium hydroxide on calcium, phosphorus and aluminium balances, the serum parathyroid hormone concentration and the aluminium content of bone in patients with chronic renal failure. Clin Sci 1972; 43: 519-31. 6. Cam JM, Luck VA, Eastwood JB, de Wardener HE. The effect of aluminium hydroxide orally on calcium, phosphorus and aluminium metabolism in normal subjects. Clin Sci Mol Med 1976; 51: 407-14. 5. Clarkson
Greger JL, Baier MJ. Excretion and retention of low or moderate levels of aluminium by human subjects. Food Chem Toxicol 1983; 21: 473-77. 8. Anon. Water poisoning in Cornwall. Lancet 1988; ii: 465. 9. Water Pollution at Lowermoor, North Cornwall. Report of the Lowermoor Incident Health Advisory Group (Chairman: Professor Dame Barbara Clayton), July, 1989. 10. Denton J, Freemont AJ, Ball J. The detection and distribution of aluminium in bone. J Clin Pathol 1984; 37: 136-42. 11. Ellis MA, Pang MMC, Mawhinney WHB, Skillen AW. Demonstration 7.
of aluminium in iliac bone: correlation between aluminium and solochrome azurine staining techniques with data on flameless absorption spectrophotometry. J Clin Pathol 1988; 41: 1171-75. 12. Commission of the European Communities. Council Directive of 15 July 1980 relating to the quality of water intended for human consumption (80/778/EEC). Off J Eur Comm 1980; L229: 11-29.
13. Slanina P, Palkeborn Y, Frech W, Cedergren A. Aluminium concentrations in the brain and bone of rats fed citric add, aluminium citrate or aluminium hydroxide. Food Chem Toxicol 1984; 22: 391-97.
14. Campistol JM, Cases A, Botey A, Revert A. Acute aluminium encephalopathy in a uremic patient. Nephron 1989; 51: 103-06.
Preliminary report: furunculosis and hypoferraemia
16 patients furunculosis
with but
significantly
lower
recurrent
staphylococcal
without anaemia had iron concentrations
serum
than normal laboratory reference values, 8 controls with single furuncles, or 10 controls with acne conglobata. There were no significant differences in serum glucose or iron binding the studied. between groups capacity Furunculosis resolved after 3-4 weeks’ treatment with iron supplements in all but 1 patient. The relation between iron and susceptibility to infection is unclear, but merits further
investigation.
Recurrent staphylococcal furunculosis is painful (and sometimes disabling), is highly infectious, and may be the first sign of an underlying disease, such as diabetes mellitus. It is most likely to occur if skin or nasal carriage of the infecting strain persists within a family,1 but several years ago we noted a patient in whom very severe recurrent staphylococcal furunculosis was associated with a low haemoglobin (below 10 g/dl) and a very low serum iron concentration (below 5 µmol/1). Iron supplementation was associated with resolution of the furunculosis, which has not
investigated other staphylococcal furunculosis to
recurred for nearly 6 years. We have
patients
with
recurrent
determine whether this condition is associated with low serum iron concentrations.
Patients and methods Recurrent staphylococcal furunculosis was defined as 6 or more furuncles caused by Staphylococcus aureus over 3 consecutive months. Three groups of patients who attended our clinics between 1978 and 1987 were studied prospectively. 16 had recurrent staphylococcal furunculosis (9 female, 7 male; mean age 22 years, range 11-41), 9 had had furunculosis for over 1 year. Two control groups were also studied: all 8 patients (4 F, 4 M; mean age 20 years) with a single furuncle and no history of recurrent furunculosis who were seen over the same period, and 10 patients (5 F, 5 M; mean age 23 years) with severe acne conglobata, randomly selected from 88 similar patients seen between 1978 and 1987. Acne conglobata is a chronic and often severe inflammatory disease of the pilosebaceous units of the skin, ahnost invariably caused by Staph epidermidis,
ADDRESSES: Department of Internal Medicine, Sophia Hospital, Zwolle (M. C Weijmer, MD); Departments of Dermatology, St Elisabeth Gasthuis, Haarlem, and Royal Netherlands Navy Hospital, Overveen (H. Neering, MD); and Department of Internal Medicine, St Elisabeth Gasthuis, Haarlem, Netherlands (C Welten, MD). Correspondence to Dr M C. Weijmer, Department of Internal Medicine, Sophia Hospital, PO Box 10400, NL-8000 GK Zwolle, Netherlands.
465
BIOCHEMICAL DATA
which is sometimes misdiagnosed as severe furunculosis. All the patients with acne conglobata had had symptoms for over 9 months, and all had been treated with tetracyclines. Furuncle cultures were taken from 13 of the 16 patients with recurrent staphylococcal furunculosis (the other 3 had already been given amoxycillin before referral) and from all 8 patients with a single furuncle. Haemoglobin, serum iron and glucose concentrations, and total iron binding capacity were measured by standard techniques. Students’st test was used for statistical comparisons between
How could iron affect cellular responses to infection? Baggs and Miller1s suggested that inability to produce and deliver cells that contained myeloperoxidase could decrease resistance to infections because myeloperoxidase activity is dependent on iron.16 Reduced cellular peroxidase has been observed in some patients with severe iron deficiency;17-19 iron-containing enzymes, such as succinic dehydrogenase, cis-aconitase, and myeloperoxidase-which are thought necessary for phagocytosis and bacterial killing-are also depressed in iron deficiency. Can iron affect growth of Staph aureus in vitro? Kadurugamuwa et apo found that the doubling time of Staph aureus in culture media was independent of the iron content of the medium, but Staph aureus showed an increased iron uptake when higher concentrations of iron were added to the culture. Are these effects observed in vivo? Zurovsky et a121 and LaForce and colleagues22 found that serum iron concentrations fell after injection of Staph aureus in baboons and mice, respectively. However, Staph aureus can grow in iron-deprived conditions, possibly because of production of
groups.
siderophores.23,24
*122-15’3 3 g/d! for women, 14-0-17 Median values shown (SD)
3g/d!formen.
susceptibility to infection remains findings in patients with recurrent
The role of iron in
Results
Staph aureus was found in all 13 cultures from patients with furunculosis; 11 strains were penicillin-resistant. In 1 culture Staph epidermidis was also found, and another
recurrent
also had a strain of Pneumococcus. Biochemical data are shown in the table. Patients with recurrent furunculosis had significantly lower serum iron than patients with a single furuncle or acne conglobata (p < 0-001) or normal controls. There were no significant differences between the groups for haemoglobin, serum glucose, and iron-binding capacity. The iron-binding percentage was low in all 10 patients with recurrent furunculosis tested (median 18-6%, normal range
25-55). All 16 patients with recurrent staphylococcal furunculosis had supplementary iron for 3-4 weeks (ferrous sulphate in 5, ferrous fumarate in 9); serum iron had returned to normal within 5-6 weeks in all 7 patients retested. Symptoms resolved within 3-4 weeks in all but 1 woman, in whom no obvious predisposing cause has yet been found.
Discussion Recurrent staphylococcal furunculosis has not been linked with iron deficiency, although several predisposing factors1,2 are directly or indirectly related to iron deficiency. A relation between iron and infections has been noted,3-S but the underlying mechanisms are unclear. Indeed, iron deficiency and iron overload, have both been connected with an increased susceptibility to infection.6--10 Likehite et alll found significantly reduced phagocytosis of Staph aureus by iron-deficient rabbit neutrophils. Chandra12 did not observe decreased neutrophil phagocytosis in iron-deficient children, but he and Saraya13 observed defective intracellular bactericidal activity against Staph aureus and of phagocytosis-induced reduction of nitroblue tetrazolium in neutrophils from 12 children with iron-deficiency anaemia; these defects were corrected by iron supplementation. MacDougall and colleaguesl4 described similar findings in iron-deficient children with and without anaemia, which indicates that effects in neutrophils are independent of
haemoglobin concentration; similarly, none of our patients had anaemia.
unclear,
but
our
staphylococcal furunculosis indicate that
there may be a relation between low serum iron concentrations and susceptibility to infection. This merits further investigation-not least because iron supplementation is effective, simple, and inexpensive.
REFERENCES 1. Editorial. Recurrent staphylococcal furunculosis. Lancet 1985; ii: 81-82. 2. Dahl MV. Strategies for the management of recurrent furunculosis. South Med J 1987; 80: 352-56. 3. Bullen JJ. The significance of iron in infection. Rev Infect Dis 1981; 3: 1127-37. 4. Weinberg ED. Iron and infection. Microbiol Rev 1978; 42: 45-66. 5. Griffiths E. Availability of iron and survival of bacteria in infection. In: Easmon CSF, Jeljasewicz J, Brown MRW, Lambert PA, eds. Medical microbiology, vol 3. London: Academic Press, 1983: 153-77. 6. Bondestam M, Foucard T, Gebre-Medhin M. Subclinical trace element deficiency in children with undue susceptibility to infections. Acta Paediatr Scand 1985; 74: 515-20. 7. Ehrhardt P. Iron deficiency in young Bradford children from different ethnic groups. Br Med J 1986; 292: 90-93. 8. Andelman MB, Sered BR. Utilisation of dietary iron by term infants. Am J Dis Child 1966; 111: 45-55. 9. Buckley RH. Iron deficiency anemia: its relationship to infection susceptibility and host defence. J Pediatr 1975; 86: 993-95. 10. Lukens JN. Iron deficiency and infection: fact or fable? Am J Dis Child 1975; 129: 160-62. 11. Likehite V, Rodvien R, Croby WH. Depressed phagocytic function exhibited by polymorphonuclear leucocytes from chronically iron deficient rabbits. Br J Haematol 1976; 34: 251-55. 12. Chandra RK. Reduced bactericidal capacity of polymorphs in iron deficiency. Arch Dis Child 1973; 48: 864-66. 13. Chandra RK, Saraya AK. Impaired immunocompetence associated with iron deficiency. J Pediatr 1975; 86: 899-902. 14. MacDougall LG, Anderson R, McNab GM, Katz J. Immune response in iron deficient children. Impaired cellular mechanism with altered humoral components. J Pediatr 1975; 86: 833-43. 15. Baggs RB, Miller SA. Nutritional iron deficiency as a determinant of host resistance in the rat. J Nutr 1973; 103: 1554-60. 16. Klebanoff SJ. Myeloperoxidase: contribution to the microbicidal activity of intact leucocytes. Science 1970; 169: 1095-97. 17. Higashi O, Sato Y, Takamatsu H, Oyama M. Mean cellular peroxidase (MCP) of leukocytes in iron deficiency anemia. Tohoku J Exp Med 1967; 93: 105-13 18. Katshushima N. Peroxidase content per single myeloid cell and in plasma. Its clinical significance in pediatrics. Tohoku J Exp Med 1963; 79:
466
250-66. 19. Prasad JS. Leucocyte function in iron-deficiency anemia. Am J Clin Nutr 1979; 32: 550-52. 20. Kadurugamuwa JL, Anwar H, Brown MR, Shand GH, Ward KH. Media for study of growth kinetics and envelope properties of iron-deprived bacteria. J Clin Microbiol 1987; 25: 849-55. 21. Zurovsky Y, Laburn H, Mitchell D, MacPhail AP. Responses of baboons to traditionally pyrogenic agents. Can J Physiol Pharmacol 1987; 65: 1402-07.
FM, Boose DS, Ellison RT. Effect of aerosolized E coli and S iron and iron-binding proteins in lung-lavage fluid. J Infect Dis 1986; 154: 959-65. 23. Marcellis JH, Daas-Slagt HJD, Korstanje JAAH. Iron equipment and chelator production of staphylococci, Streptococcus faecalis and
22. LaForce
aureus on
enterobacteriaceae. Antonie van Leeuwenhoek 1978; 44: 257-67. 24. Maskell JP. The functional interchangeability of enterobacterial and staphylococcal iron chelators. Antonie van Leeuwenhoek 1980; 46: 343-57.
BOOKSHELF Comprehensive
Medicinal
Chemistry
Editor-in-chief, Corwin Hansch. Oxford: Pergamon Press. 1990. Pp 5464 in 6 volumes. D 145;$1995. ISBN 0-080325300. This is a beautifully produced six-part magnum opus of medicinal chemistry. Each of the first five volumes (number 6 is a cumulative index and drug compendium) contains well over 700 pages of close-packed text liberally interspersed with chemical structures, figures, and tables. More than 250 contributors have been recruited from 15 countries. The referencing is comprehensive and remarkably up-to-date, 1986 to 1989 for individual chapters, depending, I assume, on how efficient the author was in keeping to deadline. An impressive achievement but will anyone (librarians excepted) buy it? First, a bird’s eye view of the content. Vol 1: General principles
(811 pages)
another 100 pages or so. The next section on bioactive materials includes classification, computer-aided selection, assay methods, and genetic engineering. The volume ends with 14 monographs under the general heading of socioeconomic factors in drug
development. Vol 2: Enzymes and other molecular targets
enjoyed
the overview
monographs
(887 pages)
on
a
Vol 5: Biopharmaceutics
(756 pages) was back firmer ground. The principles of Now, pharmacokinetics and dynamics are well covered (as they have been in numerous other texts, sometimes by the same authors). Of particular interest to me were the pieces on stereoselectivity, pharmacogenetics, and chronokinetics. There follow 6 chapters on analytical methodology-in less detail than I expected. The final section deals with chemistry and pharmacy in drug development including physicochemical principles, formulations, routes of administration, delivery system technology, and drug targeting. I
on
Vol 6: Cumulative
subject index and drug compendium
(877 pages) Each of the previous 5 books contains a subject index and these combined in the first 236 pages of number 6. A complete contents list can be found at the beginning of each volume and these indices, together with detailed contents at the head of each chapter, provide convenient access to the material. I found the system easy to use and, with a few exceptions, satisfactorily accessible. The whole exercise is finished off with a drug compendium. Over 5500 compounds that have been used or studied as medicinal agents in man are covered. The format has been standardised to include generic name, chemical structure, chemical abstracts registry number, molecular weight and formula, classification, manufacturing company, log P data, ionisation constant pKa, citations in the previous volumes, and key references. The complete compendium will be available later as an electronic threedimensional database.
enzyme structure,
nomenclature, classification, catalysis, and inhibition. Thereafter, it is every person for himself/herself depending on special interests. Therein, you will find (among other things) details of drugs acting on oxygenases and reductases, prostaglandins and leukotrienes, purines and pyrimidines, and ion transport and phosphodiesterases, followed by chapters on steroids, coagulation, fibrinolysis, and haemostasis. The last two parts deal with agents acting on cell walls (3 chapters) and nucleic acids (5 chapters).
Vol 3.- Membranes and receptors
(1280 pages) Various receptors for biological molecules including membranes and second messenger pathways, neurotransmitters and autocoids, lymphokines and cytokines, peptides, and intracellular targets are considered. Their basic biology is covered together with structureactivity relations of drugs that bind to them. Detail is variable but coverage tends to be comprehensive and the overall level of presentation is high. The 32 chapters contain something for everyone.
Vol 4: Quantitative
provided
are
The story begins with a historical perspective of drug development and introduction together with a chapter on the evolution of the pharmaceutical industry. For some reason, there are separate contributions from India and China. Basic physiology and immunology ("targets of biologically active molecules") fill
I
three-dimensional vision of molecular structures, welcome diversion.
drug design (766 pages)
This volume led me into uncharted waters. Molecular modelling,
physicochemical properties, and molecular graphics are not normally the province of the clinical pharmacologist. I felt more comfortable with structure-activity relation and pattern recognition. The ’Stereoopticon 707’, included to improve one’s
Medicinal
chemistry has
seen
past decade and has reached
substantial an
growth in the
enormous
level of
complexity. Superspecialisation is the order of the day and so multidisciplinary collaborations are essential. The preface boasts "a milestone in the literature of the subject in terms of coverage, clarity and presentation" with which I agree. The set is aimed at "academic and industrial researchers in chemistry, biology, medicine and pharmacy", many of whom will be interested in laying hands on a copy but few of whom will buy it at this price. Overall, it is too broad in scope for most busy scientists battling with specific problems thrown up in their daily work; nor does it contain sufficient detail to satisfy the specialist-information that can only be obtained from recent papers and reviews. (Updating this series, I imagine, will be a nightmare.) Students of all denominations will find the set daunting as its "browsability" factor is very low. It will probably sit on library shelves to be consulted by those wishing a superficial overview of an area unfamiliar to them. It is not easy to understand why this massive work has been produced and marketed as a single 6-volume set since the parts are self-contained and are likely to appeal to different readerships. This, of course, can be easily
be detected with solochrome azurine, so even in the stained areas the amount of the element need not be very high. That urinary aluminium after desferrioxamine increased only slightly (patient one) or not at all (patient two) reflects the small amounts of aluminium involved. Moreover, aluminium buried within trabeculae may not be available for chelation, and the desferrioxamine test was, like the biopsies, carried out more than 6 months after the contamination incident. We have examined several thousand biopsy specimens stained with solochrome azurine from normal subjects and from patients with metabolic bone disease and had previously found positive staining for aluminium only in two groups-patients undergoing regular dialysis and those with renal failure not on dialysis who were ingesting aluminium-containing phosphate binders. The findings in the patients described here show that in certain circumstances normal individuals can absorb and retain increased quantities of aluminium. can
We thank Dr R. J. Newman and Dr C. A. N. Jarvis for referring the patients and Dr Peter Ackrill for his help.
two
REFERENCES
Berlyne GM, Yagil R, Ben Ari J, Weinberger G, Knopf E, Danovitch GM. Aluminium toxicity in rats. Lancet 1972; i: 564-68. 2. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome: possible aluminum intoxication. N Engl J Med 1976; 294: 1.
184-88.
DB, Levis JA, Bukes JS, Alfrey AC. Dialysis encephalopathy in peritoneal dialysis. JAMA 1980; 244: 365-66. 4. Nathan E, Pederson S. Dialysis encephalopathy in a non-dialysed uraemic boy treated with aluminium hydroxide orally. Acta Pediatr 3. Smith
Scand 1980; 69: 793-96. EM, Luck VA, Hynson WV, et al. The effect of aluminium hydroxide on calcium, phosphorus and aluminium balances, the serum parathyroid hormone concentration and the aluminium content of bone in patients with chronic renal failure. Clin Sci 1972; 43: 519-31. 6. Cam JM, Luck VA, Eastwood JB, de Wardener HE. The effect of aluminium hydroxide orally on calcium, phosphorus and aluminium metabolism in normal subjects. Clin Sci Mol Med 1976; 51: 407-14. 5. Clarkson
Greger JL, Baier MJ. Excretion and retention of low or moderate levels of aluminium by human subjects. Food Chem Toxicol 1983; 21: 473-77. 8. Anon. Water poisoning in Cornwall. Lancet 1988; ii: 465. 9. Water Pollution at Lowermoor, North Cornwall. Report of the Lowermoor Incident Health Advisory Group (Chairman: Professor Dame Barbara Clayton), July, 1989. 10. Denton J, Freemont AJ, Ball J. The detection and distribution of aluminium in bone. J Clin Pathol 1984; 37: 136-42. 11. Ellis MA, Pang MMC, Mawhinney WHB, Skillen AW. Demonstration 7.
of aluminium in iliac bone: correlation between aluminium and solochrome azurine staining techniques with data on flameless absorption spectrophotometry. J Clin Pathol 1988; 41: 1171-75. 12. Commission of the European Communities. Council Directive of 15 July 1980 relating to the quality of water intended for human consumption (80/778/EEC). Off J Eur Comm 1980; L229: 11-29.
13. Slanina P, Palkeborn Y, Frech W, Cedergren A. Aluminium concentrations in the brain and bone of rats fed citric add, aluminium citrate or aluminium hydroxide. Food Chem Toxicol 1984; 22: 391-97.
14. Campistol JM, Cases A, Botey A, Revert A. Acute aluminium encephalopathy in a uremic patient. Nephron 1989; 51: 103-06.
Preliminary report: furunculosis and hypoferraemia
16 patients furunculosis
with but
significantly
lower
recurrent
staphylococcal
without anaemia had iron concentrations
serum
than normal laboratory reference values, 8 controls with single furuncles, or 10 controls with acne conglobata. There were no significant differences in serum glucose or iron binding the studied. between groups capacity Furunculosis resolved after 3-4 weeks’ treatment with iron supplements in all but 1 patient. The relation between iron and susceptibility to infection is unclear, but merits further
investigation.
Recurrent staphylococcal furunculosis is painful (and sometimes disabling), is highly infectious, and may be the first sign of an underlying disease, such as diabetes mellitus. It is most likely to occur if skin or nasal carriage of the infecting strain persists within a family,1 but several years ago we noted a patient in whom very severe recurrent staphylococcal furunculosis was associated with a low haemoglobin (below 10 g/dl) and a very low serum iron concentration (below 5 µmol/1). Iron supplementation was associated with resolution of the furunculosis, which has not
investigated other staphylococcal furunculosis to
recurred for nearly 6 years. We have
patients
with
recurrent
determine whether this condition is associated with low serum iron concentrations.
Patients and methods Recurrent staphylococcal furunculosis was defined as 6 or more furuncles caused by Staphylococcus aureus over 3 consecutive months. Three groups of patients who attended our clinics between 1978 and 1987 were studied prospectively. 16 had recurrent staphylococcal furunculosis (9 female, 7 male; mean age 22 years, range 11-41), 9 had had furunculosis for over 1 year. Two control groups were also studied: all 8 patients (4 F, 4 M; mean age 20 years) with a single furuncle and no history of recurrent furunculosis who were seen over the same period, and 10 patients (5 F, 5 M; mean age 23 years) with severe acne conglobata, randomly selected from 88 similar patients seen between 1978 and 1987. Acne conglobata is a chronic and often severe inflammatory disease of the pilosebaceous units of the skin, ahnost invariably caused by Staph epidermidis,
ADDRESSES: Department of Internal Medicine, Sophia Hospital, Zwolle (M. C Weijmer, MD); Departments of Dermatology, St Elisabeth Gasthuis, Haarlem, and Royal Netherlands Navy Hospital, Overveen (H. Neering, MD); and Department of Internal Medicine, St Elisabeth Gasthuis, Haarlem, Netherlands (C Welten, MD). Correspondence to Dr M C. Weijmer, Department of Internal Medicine, Sophia Hospital, PO Box 10400, NL-8000 GK Zwolle, Netherlands.
465
BIOCHEMICAL DATA
which is sometimes misdiagnosed as severe furunculosis. All the patients with acne conglobata had had symptoms for over 9 months, and all had been treated with tetracyclines. Furuncle cultures were taken from 13 of the 16 patients with recurrent staphylococcal furunculosis (the other 3 had already been given amoxycillin before referral) and from all 8 patients with a single furuncle. Haemoglobin, serum iron and glucose concentrations, and total iron binding capacity were measured by standard techniques. Students’st test was used for statistical comparisons between
How could iron affect cellular responses to infection? Baggs and Miller1s suggested that inability to produce and deliver cells that contained myeloperoxidase could decrease resistance to infections because myeloperoxidase activity is dependent on iron.16 Reduced cellular peroxidase has been observed in some patients with severe iron deficiency;17-19 iron-containing enzymes, such as succinic dehydrogenase, cis-aconitase, and myeloperoxidase-which are thought necessary for phagocytosis and bacterial killing-are also depressed in iron deficiency. Can iron affect growth of Staph aureus in vitro? Kadurugamuwa et apo found that the doubling time of Staph aureus in culture media was independent of the iron content of the medium, but Staph aureus showed an increased iron uptake when higher concentrations of iron were added to the culture. Are these effects observed in vivo? Zurovsky et a121 and LaForce and colleagues22 found that serum iron concentrations fell after injection of Staph aureus in baboons and mice, respectively. However, Staph aureus can grow in iron-deprived conditions, possibly because of production of
groups.
siderophores.23,24
*122-15’3 3 g/d! for women, 14-0-17 Median values shown (SD)
3g/d!formen.
susceptibility to infection remains findings in patients with recurrent
The role of iron in
Results
Staph aureus was found in all 13 cultures from patients with furunculosis; 11 strains were penicillin-resistant. In 1 culture Staph epidermidis was also found, and another
recurrent
also had a strain of Pneumococcus. Biochemical data are shown in the table. Patients with recurrent furunculosis had significantly lower serum iron than patients with a single furuncle or acne conglobata (p < 0-001) or normal controls. There were no significant differences between the groups for haemoglobin, serum glucose, and iron-binding capacity. The iron-binding percentage was low in all 10 patients with recurrent furunculosis tested (median 18-6%, normal range
25-55). All 16 patients with recurrent staphylococcal furunculosis had supplementary iron for 3-4 weeks (ferrous sulphate in 5, ferrous fumarate in 9); serum iron had returned to normal within 5-6 weeks in all 7 patients retested. Symptoms resolved within 3-4 weeks in all but 1 woman, in whom no obvious predisposing cause has yet been found.
Discussion Recurrent staphylococcal furunculosis has not been linked with iron deficiency, although several predisposing factors1,2 are directly or indirectly related to iron deficiency. A relation between iron and infections has been noted,3-S but the underlying mechanisms are unclear. Indeed, iron deficiency and iron overload, have both been connected with an increased susceptibility to infection.6--10 Likehite et alll found significantly reduced phagocytosis of Staph aureus by iron-deficient rabbit neutrophils. Chandra12 did not observe decreased neutrophil phagocytosis in iron-deficient children, but he and Saraya13 observed defective intracellular bactericidal activity against Staph aureus and of phagocytosis-induced reduction of nitroblue tetrazolium in neutrophils from 12 children with iron-deficiency anaemia; these defects were corrected by iron supplementation. MacDougall and colleaguesl4 described similar findings in iron-deficient children with and without anaemia, which indicates that effects in neutrophils are independent of
haemoglobin concentration; similarly, none of our patients had anaemia.
unclear,
but
our
staphylococcal furunculosis indicate that
there may be a relation between low serum iron concentrations and susceptibility to infection. This merits further investigation-not least because iron supplementation is effective, simple, and inexpensive.
REFERENCES 1. Editorial. Recurrent staphylococcal furunculosis. Lancet 1985; ii: 81-82. 2. Dahl MV. Strategies for the management of recurrent furunculosis. South Med J 1987; 80: 352-56. 3. Bullen JJ. The significance of iron in infection. Rev Infect Dis 1981; 3: 1127-37. 4. Weinberg ED. Iron and infection. Microbiol Rev 1978; 42: 45-66. 5. Griffiths E. Availability of iron and survival of bacteria in infection. In: Easmon CSF, Jeljasewicz J, Brown MRW, Lambert PA, eds. Medical microbiology, vol 3. London: Academic Press, 1983: 153-77. 6. Bondestam M, Foucard T, Gebre-Medhin M. Subclinical trace element deficiency in children with undue susceptibility to infections. Acta Paediatr Scand 1985; 74: 515-20. 7. Ehrhardt P. Iron deficiency in young Bradford children from different ethnic groups. Br Med J 1986; 292: 90-93. 8. Andelman MB, Sered BR. Utilisation of dietary iron by term infants. Am J Dis Child 1966; 111: 45-55. 9. Buckley RH. Iron deficiency anemia: its relationship to infection susceptibility and host defence. J Pediatr 1975; 86: 993-95. 10. Lukens JN. Iron deficiency and infection: fact or fable? Am J Dis Child 1975; 129: 160-62. 11. Likehite V, Rodvien R, Croby WH. Depressed phagocytic function exhibited by polymorphonuclear leucocytes from chronically iron deficient rabbits. Br J Haematol 1976; 34: 251-55. 12. Chandra RK. Reduced bactericidal capacity of polymorphs in iron deficiency. Arch Dis Child 1973; 48: 864-66. 13. Chandra RK, Saraya AK. Impaired immunocompetence associated with iron deficiency. J Pediatr 1975; 86: 899-902. 14. MacDougall LG, Anderson R, McNab GM, Katz J. Immune response in iron deficient children. Impaired cellular mechanism with altered humoral components. J Pediatr 1975; 86: 833-43. 15. Baggs RB, Miller SA. Nutritional iron deficiency as a determinant of host resistance in the rat. J Nutr 1973; 103: 1554-60. 16. Klebanoff SJ. Myeloperoxidase: contribution to the microbicidal activity of intact leucocytes. Science 1970; 169: 1095-97. 17. Higashi O, Sato Y, Takamatsu H, Oyama M. Mean cellular peroxidase (MCP) of leukocytes in iron deficiency anemia. Tohoku J Exp Med 1967; 93: 105-13 18. Katshushima N. Peroxidase content per single myeloid cell and in plasma. Its clinical significance in pediatrics. Tohoku J Exp Med 1963; 79:
466
250-66. 19. Prasad JS. Leucocyte function in iron-deficiency anemia. Am J Clin Nutr 1979; 32: 550-52. 20. Kadurugamuwa JL, Anwar H, Brown MR, Shand GH, Ward KH. Media for study of growth kinetics and envelope properties of iron-deprived bacteria. J Clin Microbiol 1987; 25: 849-55. 21. Zurovsky Y, Laburn H, Mitchell D, MacPhail AP. Responses of baboons to traditionally pyrogenic agents. Can J Physiol Pharmacol 1987; 65: 1402-07.
FM, Boose DS, Ellison RT. Effect of aerosolized E coli and S iron and iron-binding proteins in lung-lavage fluid. J Infect Dis 1986; 154: 959-65. 23. Marcellis JH, Daas-Slagt HJD, Korstanje JAAH. Iron equipment and chelator production of staphylococci, Streptococcus faecalis and
22. LaForce
aureus on
enterobacteriaceae. Antonie van Leeuwenhoek 1978; 44: 257-67. 24. Maskell JP. The functional interchangeability of enterobacterial and staphylococcal iron chelators. Antonie van Leeuwenhoek 1980; 46: 343-57.
BOOKSHELF Comprehensive
Medicinal
Chemistry
Editor-in-chief, Corwin Hansch. Oxford: Pergamon Press. 1990. Pp 5464 in 6 volumes. D 145;$1995. ISBN 0-080325300. This is a beautifully produced six-part magnum opus of medicinal chemistry. Each of the first five volumes (number 6 is a cumulative index and drug compendium) contains well over 700 pages of close-packed text liberally interspersed with chemical structures, figures, and tables. More than 250 contributors have been recruited from 15 countries. The referencing is comprehensive and remarkably up-to-date, 1986 to 1989 for individual chapters, depending, I assume, on how efficient the author was in keeping to deadline. An impressive achievement but will anyone (librarians excepted) buy it? First, a bird’s eye view of the content. Vol 1: General principles
(811 pages)
another 100 pages or so. The next section on bioactive materials includes classification, computer-aided selection, assay methods, and genetic engineering. The volume ends with 14 monographs under the general heading of socioeconomic factors in drug
development. Vol 2: Enzymes and other molecular targets
enjoyed
the overview
monographs
(887 pages)
on
a
Vol 5: Biopharmaceutics
(756 pages) was back firmer ground. The principles of Now, pharmacokinetics and dynamics are well covered (as they have been in numerous other texts, sometimes by the same authors). Of particular interest to me were the pieces on stereoselectivity, pharmacogenetics, and chronokinetics. There follow 6 chapters on analytical methodology-in less detail than I expected. The final section deals with chemistry and pharmacy in drug development including physicochemical principles, formulations, routes of administration, delivery system technology, and drug targeting. I
on
Vol 6: Cumulative
subject index and drug compendium
(877 pages) Each of the previous 5 books contains a subject index and these combined in the first 236 pages of number 6. A complete contents list can be found at the beginning of each volume and these indices, together with detailed contents at the head of each chapter, provide convenient access to the material. I found the system easy to use and, with a few exceptions, satisfactorily accessible. The whole exercise is finished off with a drug compendium. Over 5500 compounds that have been used or studied as medicinal agents in man are covered. The format has been standardised to include generic name, chemical structure, chemical abstracts registry number, molecular weight and formula, classification, manufacturing company, log P data, ionisation constant pKa, citations in the previous volumes, and key references. The complete compendium will be available later as an electronic threedimensional database.
enzyme structure,
nomenclature, classification, catalysis, and inhibition. Thereafter, it is every person for himself/herself depending on special interests. Therein, you will find (among other things) details of drugs acting on oxygenases and reductases, prostaglandins and leukotrienes, purines and pyrimidines, and ion transport and phosphodiesterases, followed by chapters on steroids, coagulation, fibrinolysis, and haemostasis. The last two parts deal with agents acting on cell walls (3 chapters) and nucleic acids (5 chapters).
Vol 3.- Membranes and receptors
(1280 pages) Various receptors for biological molecules including membranes and second messenger pathways, neurotransmitters and autocoids, lymphokines and cytokines, peptides, and intracellular targets are considered. Their basic biology is covered together with structureactivity relations of drugs that bind to them. Detail is variable but coverage tends to be comprehensive and the overall level of presentation is high. The 32 chapters contain something for everyone.
Vol 4: Quantitative
provided
are
The story begins with a historical perspective of drug development and introduction together with a chapter on the evolution of the pharmaceutical industry. For some reason, there are separate contributions from India and China. Basic physiology and immunology ("targets of biologically active molecules") fill
I
three-dimensional vision of molecular structures, welcome diversion.
drug design (766 pages)
This volume led me into uncharted waters. Molecular modelling,
physicochemical properties, and molecular graphics are not normally the province of the clinical pharmacologist. I felt more comfortable with structure-activity relation and pattern recognition. The ’Stereoopticon 707’, included to improve one’s
Medicinal
chemistry has
seen
past decade and has reached
substantial an
growth in the
enormous
level of
complexity. Superspecialisation is the order of the day and so multidisciplinary collaborations are essential. The preface boasts "a milestone in the literature of the subject in terms of coverage, clarity and presentation" with which I agree. The set is aimed at "academic and industrial researchers in chemistry, biology, medicine and pharmacy", many of whom will be interested in laying hands on a copy but few of whom will buy it at this price. Overall, it is too broad in scope for most busy scientists battling with specific problems thrown up in their daily work; nor does it contain sufficient detail to satisfy the specialist-information that can only be obtained from recent papers and reviews. (Updating this series, I imagine, will be a nightmare.) Students of all denominations will find the set daunting as its "browsability" factor is very low. It will probably sit on library shelves to be consulted by those wishing a superficial overview of an area unfamiliar to them. It is not easy to understand why this massive work has been produced and marketed as a single 6-volume set since the parts are self-contained and are likely to appeal to different readerships. This, of course, can be easily
