336 muscle disease nor were there any necropsy findings. Winters awl. described an increased frequency of mitral-valve prolapse in patients with myotonic muscular dystrophy but none of their patients had stroke and none were examined at necropsy. We have seen a patient who represents the predictable clinical culmination of these associated disorders: myotonic dystrophy, mitral-valve prolapse, and stroke. A 55-year-old man was found to have myotonia during adolescence and subsequently the classic manifestations of myotonic dystrophy developed: distal muscle atrophy and weakness, hatchet facies, frontal balding, testicular atrophy, and cataract. He had a history of hypothyroidism, cholelithiasis, and cholecystitis. In addition, he had polycystic kidney disease and intermittent cardiac arrhythmias including atrial fibrillation. There was a harsh blowing pansystolic heart murmur along the left sternal border, and echocardiography showed prolapse of the posterior mitral-valve leaflet. The patient’s younger brother also has myotonic dystrophy and polycystic kidneys. The patient’s only child, a 24-year-old daughter, has no muscle disease and a normal intravenous pyelogram. Both his parents died in their 80s of "uræmia", neither being known to have polycystic kidneys or muscle disease. His mother had cataract. In his last month of life, the patient’s left arm became paralysed but this resolved spontaneously in one and a half hours. Three weeks later he had a severe right hemiparesis and speech impairment. His hospital course was complicated by cardiac arrhythmias, aspiration pneumonia, and respiratory insufficiency requiring prolonged ventilatory assistance. He.died on the tenth hospital day. Necropsy revealed a large pulmonary embolus, massive bilateral polycystic kidney disease, polycystic disease involving the liver and pancreas, chronic cholecystitis, and testicular, adrenal, and thyroid atrophy. The heart weighed 500 g and was remarkable for a thickened, malformed, posterior mitral-valve leaflet that was cupped and oval. There were no blood clots or thrombi in the atria or ventricles, nor on the mitral valve. Microscopically, the posterior leaflet of the mitral valve showed myxoid change and disruption of the elastic layer due to increased mucopolysaccharides. The myocardium showed selective myocardial cell necrosis and myxoid change. The brain showed softening of the central portion of the left hemisphere associated with a 3-4 mm occlusion at the origin of the left middle cerebral artery. There were no berry aneurysms. Numerous microscopic sections of the occluded portion of the middle cerebral artery revealed a fibrin-platelet clot, typical of an embolus. No myxomatous tissue was identified in the clot. This patient represents both an additional example of stroke complicating mitral-valve prolapse and an example of myotonic dystrophy associated with mitral-valve prolapse. The pathology and clinical history in the present case confirms the speculation of Kostuk et al. 1,2 that stroke complicating mitralvalve prolapse is embolic and presumably arises from thrombi developing in and around the abnormal mitral valve. Cardiac arrhythmia may also play a role in the formation or release of these thrombi.4 It is likely that mitral-valve prolapse and stroke are more common in myotonic dystrophy than has been previously recognised and clinicians should have an increased awareness of this association. Although mitral valve prolapse is a relatively common condition, our experience with this patient and the study of Winters et awl. suggest that its association with myotonic dystrophy is more than coincidental. We also note that both hypothyroidism and gallbladder disease have an increased incidence in myotonic dystrophy,4.5 and there has been one previous report of polycystic kidney disease associated with myotonic dystrophy.6 It is not clear whether et
3. Winters, S. J., Schreiner, B., Griggs, R. C., Rowley, P., Nanda, N. C. Ann. intern. Med. 1976, 85, 19. 4. Cohen, H. E. Lancet, 1977, ii, 923. 5. Brumlik, J., Maier, R. J. Archs intern. Med. 1972, 129, 120. 6. Schwindt, W. D., Bernhardt, L. C., Peters, H. A. Postgrad. Med. 1969, 46, 80. 7. Emery, A. E. H., Oleesky, S., Williams, R. T. J. med. Genet. 1967, 4, 26.
associations represent the chance occurrence of separate diseases, genetic linkage of the disorders, or the pleiomorphic effect of the myotonic dystrophy gene.
Departments of Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington 98195, U.S.A.
A. W. COOK T. D. BIRD A. M. SPENCE R. A. PAGON J. F. WALLACE
INDUCTION OF CUTANEOUS VASCULITIS BY REPEATED COLD CHALLENGE IN COLD URTICARIA an effort to elucidate the effects of cold-tolerance in cold urticaria,’ we have carried out light microscopy and electronmicroscopic studies on the skin of several patients with essential acquired cold urticaria before and after
SIR,-In
treatment
repeated cold challenge. Eight patients aged
16-53 years with cold urticaria of 6 13 years duration were included. One arm of each subject was intermittently cooled either by repeated immersion in cold water (7-15°C) or by ice application for 5 min every 30 min (total of 7-15 applications). After the first cold challenge, the skin of all subjects became urticated with varying degrees of erythema and oedema. The cedema tended to increase with repeated cooling but faded 3--48 h after the experiment. One patient had marked bruising after repeated ice applications. Biopsy specimens from inflamed skin taken after both single and repeated cold challenge were processed for light microscopy and electronmicroscopy. After repeated cold challenge in five patients, there were histological features of vasculitis principally affecting venules in middle and deep dermal zones and subcutaneous tissue. There was endothelial swelling (see figure), a perivascular cellular infiltrate of neutrophils, eosinophils, erythrocytes, and monocytes and fibrin deposition. Electronmicroscopy showed that numerous neutrophils and eosinophils had undergone cytolysis or degranulation. Mast cells were variably degranulated. These vasculitic features tended to be most pronounced in patients responding poorly to cold desensitisation; they were not seen in biopsy specimens taken at intervals of up to 5 h after a single cold challenge. Vasculitis may occur during chronic recurrent urticaria not associated with cold in a small group of patients with arthralmonths
1.
to
Bentley-Phillips,
C. B., Kobza Black, A.,
Greaves, M. W. Lancet, 1976, ii,
63.
Mid-dermal vasculitic change after repeated cold challenge in cold urticaria. I p.m plastic section stained with basic fuchsin and methylene-blue. V=venule; N=neutrophil; E=eosinophil; —=50 p.m.
337
gia, abdominal pain, and glomerulonephritis.2,3Such patients usually have complement disorders and raised erythrocyte-sedimentation rates. We found no haematological abnormalities, serum cryoglobulins, or evidence of systemic disease in any of our patients whose serum-complement (C3) levels were normal (six patients) or slightly raised (two patients). The presence of neutrophils and eosinophils in the inflammatory infiltrate after multiple cold challenge is of especial interest because chemotactic factors for eosinophils4 and neutrophils’ have previously been found in venous blood from urticated skin following cold challenge in cold urticaria. Cold urticaria is an expression of an immediate hypersensitivity reaction in which histamine is thought to be the major inflammatory mediator.6 Vasculitis has not previously been described as a feature of essential acquired cold urticaria, so its arousal by repeated cold challenge in our patients presumably reflects sustained injury to small cutaneous blood vessels. Whether this injury is due mainly to pharmacological or to immunological processes or to a mixture of both needs further clarification. R. A. J. EADY M. W. GREAVES
Institute of Dermatology, London E9 6BX
MECILLINAM
SIR,-Our experience of the activity of mecillinam against gram-negative bacilli has been less favourable than that of Dr Chattopadhyay and Dr Thomas (Jan. 28, p. 214). Our methods were very similar, except for the use of ’Iso-sensitest’ agar (Oxoid) and a standardised inoculum of 105 colony-forming units of bacteria. When mecillinam was tested against ampicillin (and amoxycillin) resistant enterobacteria its activity was comparable with that of carbenicillin, but it was less active than seven cephalosporins and cefoxitin (see table). We studied 87 recent isolates from urines and 11 from wounds; all were from different patients with no epidemiological connection. We did not observe the bimodal distribution of mecillinam susceptibilities reported by Chattopadhyay and Thomas who IN-VITRO SUSCEPTIBILITY OF
98
the antibiotic’ mecillinam (carbenicillin and cephaloridine, cephalothin, cephazolin, and cefamandole) was partially inac-
tivated, and all six antibiotics were very vulnerable to P4actamase preparations, including the clinically important enzyme from Escherichia coli (TEM)2 This susceptibility can be correlated with a large-inoculum effect, which is most striking with mecillinam. Enzyme susceptibility and inoculum effect were minimal with cephradine, cefuroxime, and cefoxitin, while cephalexin gave intermediate values. Despite our disappointment with the antibacterial activity of mecillinam, and its vulnerability to &bgr;-lactamases, the antibiotic’s unusual mode of action, discussed in your editorial of Feb. 4 (p. 252), is of great interest. Unlike other p-lactam agents, it converts gram-negative rods to large osmotically stable round or oval cells, over a wide range of concentrations. This effect is probably due-at least in E.coli-to the affinity of the antibiotic for the type 2 "penicillin-binding protein" only, which seems to have the extraordinarily specific function of producing transpeptidation (a final stage in cell-wall synthesis) at the "corners" of the bacterial cell. This uniquely restricted effect of mecillinam is complementary to the action of other p-lactam antibiotics that inhibit cell-wall synthesis at different sites. On this basis, the combination of mecillinam with other p-lactam agents would be expected to be synergistic, and indeed this is often the case both in vitro and in vivo, notably with amoxycillin or cephradine.4 There are, nevertheless, important economic implications if combinations of expensive antibiotics come into widespread use in the future. Gifts of mecillinam, cefoxitin, cefuroxime, and cefamandole were received from Leo Laboratories, Merck Sharp and Dohme, Glaxo Laboratories, and Eli Lilly and Co., respectively.
Department of Bacteriology, Westminster Medical School, London SW1P 2AR
M. BAKHTIAR S. SELWYN
*** A line was dropped from our mecillinam editorial last week (restored in American edition). The second sentence was meant to say: "Other penicillins are synthesised from aminopenicillanic acid; mecillinam is derived from amidinopenicillanic acid, and its antibacterial spectrum is different."—ED. L
AMPICILLIN-RESISTANT
GRAM-NEGATIVE BACILLI TO BETA-LACTAM ANTIBIOTICS
BACTERIAL OVERGROWTH SYNDROME AFTER ACUTE NONSPECIFIC DIARRHŒA
SIR,-In support of the findings of Roberts
et
a1.5
we
have
recently patients (male aged 49, female aged 67) with bacterial overgrowth syndrome following acute nonspecific diarrhoea. Each had travelled to Mexico where they had an acute episode of watery diarrhoea (8-10 bowel movements/day) which lasted for five days and then became chronic (3-5 unformed stools/day and weight loss). The patients were seen by us 1 month and 3 months respectively after the initial episode. There was no anatomical abnormality. Infectious diarrhoea was ruled out because stool culture for Shigella, Salmonella, enterotoxigenic Eschericia coli (heat-labile or heat-stabletoxin-producing) and Vibrio parahcemolyticus was negative. No ova or parasites were seen in the stool preparation. There was no significant antibody titre to heat-labile toxin of enteroseen two
* Susceptible
to
10 mg/l of antibiotic (except for carbenicillin 50
mg/1). t Results with cephalothin, cephalexin, cephradine, cephazolin, cefuroxime, cefoxitin, and cefamandole were similar in these conventional tests.
found minimum inhibitory concentrations (M.!.c.s) either between 0.1and 1 mg/1 or 100 mg/1 and above. When test systems were used which allowed bacteria to enter the logarithmic growth phase and produce p4actamases before encountering 2. Soter, N. A., Austen, K. F., Gigli, I. J. invest. Derm. 1974, 63, 485. 3. Soter, N. A. New Engl. J. Med. 1977, 296, 1440. 4. Soter, N. A., Wasserman, S. I., Austen, K. F. ibid. 1976, 294, 698. 5. Wasserman, S. I., Soter, N. A., Center, D. M., Austen, K. F. J. clin. Invest.
1977, 60, 189. 6. Kaplan, A. P., Gray, L., Shaff, R. E., Horakova, Z., Beaven, M. A. Allergy clin. Immun. 1975, 55, 394.
E. coli. colonisation factor of E. coli H-10407 was Duodenal biopsy was normal and Giardia lamblia was absent both by direct observation and by routine histology. In duodenal aspirates, a pure culture of Pseudomonas (108 colonies/ml) was recovered from patient 1 and Enterobacter (106 colonies/ml) and a-Streptococcus (102 colonies/ml) from patient 2.
toxigenic negative.
117 were P. mirabilis.
J.,
1. Bakhtiar, M., Selwyn, S. Proc. 10th int. Chemother. Congr. (in the 2. Selwyn, S. J. antimicrob. Chemother. 1977, 3, 161. 3. Spratt, B. G. ibid. 1977, 3, suppl. B, p. 13. 4. Kerry, D. W., Hamilton-Miller, J. M. T., Brumfitt, W. ibid. 1977, 3,
B, p. 53. 5. Roberts, S. H., James, O., Jarvis, E. H. Lancet, 1977, ii, 1193.
press). Suppl.
3. Winters, S. J., Schreiner, B., Griggs, R. C., Rowley, P., Nanda, N. C. Ann. intern. Med. 1976, 85, 19. 4. Cohen, H. E. Lancet, 1977, ii, 923. 5. Brumlik, J., Maier, R. J. Archs intern. Med. 1972, 129, 120. 6. Schwindt, W. D., Bernhardt, L. C., Peters, H. A. Postgrad. Med. 1969, 46, 80. 7. Emery, A. E. H., Oleesky, S., Williams, R. T. J. med. Genet. 1967, 4, 26.
associations represent the chance occurrence of separate diseases, genetic linkage of the disorders, or the pleiomorphic effect of the myotonic dystrophy gene.
Departments of Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington 98195, U.S.A.
A. W. COOK T. D. BIRD A. M. SPENCE R. A. PAGON J. F. WALLACE
INDUCTION OF CUTANEOUS VASCULITIS BY REPEATED COLD CHALLENGE IN COLD URTICARIA an effort to elucidate the effects of cold-tolerance in cold urticaria,’ we have carried out light microscopy and electronmicroscopic studies on the skin of several patients with essential acquired cold urticaria before and after
SIR,-In
treatment
repeated cold challenge. Eight patients aged
16-53 years with cold urticaria of 6 13 years duration were included. One arm of each subject was intermittently cooled either by repeated immersion in cold water (7-15°C) or by ice application for 5 min every 30 min (total of 7-15 applications). After the first cold challenge, the skin of all subjects became urticated with varying degrees of erythema and oedema. The cedema tended to increase with repeated cooling but faded 3--48 h after the experiment. One patient had marked bruising after repeated ice applications. Biopsy specimens from inflamed skin taken after both single and repeated cold challenge were processed for light microscopy and electronmicroscopy. After repeated cold challenge in five patients, there were histological features of vasculitis principally affecting venules in middle and deep dermal zones and subcutaneous tissue. There was endothelial swelling (see figure), a perivascular cellular infiltrate of neutrophils, eosinophils, erythrocytes, and monocytes and fibrin deposition. Electronmicroscopy showed that numerous neutrophils and eosinophils had undergone cytolysis or degranulation. Mast cells were variably degranulated. These vasculitic features tended to be most pronounced in patients responding poorly to cold desensitisation; they were not seen in biopsy specimens taken at intervals of up to 5 h after a single cold challenge. Vasculitis may occur during chronic recurrent urticaria not associated with cold in a small group of patients with arthralmonths
1.
to
Bentley-Phillips,
C. B., Kobza Black, A.,
Greaves, M. W. Lancet, 1976, ii,
63.
Mid-dermal vasculitic change after repeated cold challenge in cold urticaria. I p.m plastic section stained with basic fuchsin and methylene-blue. V=venule; N=neutrophil; E=eosinophil; —=50 p.m.
337
gia, abdominal pain, and glomerulonephritis.2,3Such patients usually have complement disorders and raised erythrocyte-sedimentation rates. We found no haematological abnormalities, serum cryoglobulins, or evidence of systemic disease in any of our patients whose serum-complement (C3) levels were normal (six patients) or slightly raised (two patients). The presence of neutrophils and eosinophils in the inflammatory infiltrate after multiple cold challenge is of especial interest because chemotactic factors for eosinophils4 and neutrophils’ have previously been found in venous blood from urticated skin following cold challenge in cold urticaria. Cold urticaria is an expression of an immediate hypersensitivity reaction in which histamine is thought to be the major inflammatory mediator.6 Vasculitis has not previously been described as a feature of essential acquired cold urticaria, so its arousal by repeated cold challenge in our patients presumably reflects sustained injury to small cutaneous blood vessels. Whether this injury is due mainly to pharmacological or to immunological processes or to a mixture of both needs further clarification. R. A. J. EADY M. W. GREAVES
Institute of Dermatology, London E9 6BX
MECILLINAM
SIR,-Our experience of the activity of mecillinam against gram-negative bacilli has been less favourable than that of Dr Chattopadhyay and Dr Thomas (Jan. 28, p. 214). Our methods were very similar, except for the use of ’Iso-sensitest’ agar (Oxoid) and a standardised inoculum of 105 colony-forming units of bacteria. When mecillinam was tested against ampicillin (and amoxycillin) resistant enterobacteria its activity was comparable with that of carbenicillin, but it was less active than seven cephalosporins and cefoxitin (see table). We studied 87 recent isolates from urines and 11 from wounds; all were from different patients with no epidemiological connection. We did not observe the bimodal distribution of mecillinam susceptibilities reported by Chattopadhyay and Thomas who IN-VITRO SUSCEPTIBILITY OF
98
the antibiotic’ mecillinam (carbenicillin and cephaloridine, cephalothin, cephazolin, and cefamandole) was partially inac-
tivated, and all six antibiotics were very vulnerable to P4actamase preparations, including the clinically important enzyme from Escherichia coli (TEM)2 This susceptibility can be correlated with a large-inoculum effect, which is most striking with mecillinam. Enzyme susceptibility and inoculum effect were minimal with cephradine, cefuroxime, and cefoxitin, while cephalexin gave intermediate values. Despite our disappointment with the antibacterial activity of mecillinam, and its vulnerability to &bgr;-lactamases, the antibiotic’s unusual mode of action, discussed in your editorial of Feb. 4 (p. 252), is of great interest. Unlike other p-lactam agents, it converts gram-negative rods to large osmotically stable round or oval cells, over a wide range of concentrations. This effect is probably due-at least in E.coli-to the affinity of the antibiotic for the type 2 "penicillin-binding protein" only, which seems to have the extraordinarily specific function of producing transpeptidation (a final stage in cell-wall synthesis) at the "corners" of the bacterial cell. This uniquely restricted effect of mecillinam is complementary to the action of other p-lactam antibiotics that inhibit cell-wall synthesis at different sites. On this basis, the combination of mecillinam with other p-lactam agents would be expected to be synergistic, and indeed this is often the case both in vitro and in vivo, notably with amoxycillin or cephradine.4 There are, nevertheless, important economic implications if combinations of expensive antibiotics come into widespread use in the future. Gifts of mecillinam, cefoxitin, cefuroxime, and cefamandole were received from Leo Laboratories, Merck Sharp and Dohme, Glaxo Laboratories, and Eli Lilly and Co., respectively.
Department of Bacteriology, Westminster Medical School, London SW1P 2AR
M. BAKHTIAR S. SELWYN
*** A line was dropped from our mecillinam editorial last week (restored in American edition). The second sentence was meant to say: "Other penicillins are synthesised from aminopenicillanic acid; mecillinam is derived from amidinopenicillanic acid, and its antibacterial spectrum is different."—ED. L
AMPICILLIN-RESISTANT
GRAM-NEGATIVE BACILLI TO BETA-LACTAM ANTIBIOTICS
BACTERIAL OVERGROWTH SYNDROME AFTER ACUTE NONSPECIFIC DIARRHŒA
SIR,-In support of the findings of Roberts
et
a1.5
we
have
recently patients (male aged 49, female aged 67) with bacterial overgrowth syndrome following acute nonspecific diarrhoea. Each had travelled to Mexico where they had an acute episode of watery diarrhoea (8-10 bowel movements/day) which lasted for five days and then became chronic (3-5 unformed stools/day and weight loss). The patients were seen by us 1 month and 3 months respectively after the initial episode. There was no anatomical abnormality. Infectious diarrhoea was ruled out because stool culture for Shigella, Salmonella, enterotoxigenic Eschericia coli (heat-labile or heat-stabletoxin-producing) and Vibrio parahcemolyticus was negative. No ova or parasites were seen in the stool preparation. There was no significant antibody titre to heat-labile toxin of enteroseen two
* Susceptible
to
10 mg/l of antibiotic (except for carbenicillin 50
mg/1). t Results with cephalothin, cephalexin, cephradine, cephazolin, cefuroxime, cefoxitin, and cefamandole were similar in these conventional tests.
found minimum inhibitory concentrations (M.!.c.s) either between 0.1and 1 mg/1 or 100 mg/1 and above. When test systems were used which allowed bacteria to enter the logarithmic growth phase and produce p4actamases before encountering 2. Soter, N. A., Austen, K. F., Gigli, I. J. invest. Derm. 1974, 63, 485. 3. Soter, N. A. New Engl. J. Med. 1977, 296, 1440. 4. Soter, N. A., Wasserman, S. I., Austen, K. F. ibid. 1976, 294, 698. 5. Wasserman, S. I., Soter, N. A., Center, D. M., Austen, K. F. J. clin. Invest.
1977, 60, 189. 6. Kaplan, A. P., Gray, L., Shaff, R. E., Horakova, Z., Beaven, M. A. Allergy clin. Immun. 1975, 55, 394.
E. coli. colonisation factor of E. coli H-10407 was Duodenal biopsy was normal and Giardia lamblia was absent both by direct observation and by routine histology. In duodenal aspirates, a pure culture of Pseudomonas (108 colonies/ml) was recovered from patient 1 and Enterobacter (106 colonies/ml) and a-Streptococcus (102 colonies/ml) from patient 2.
toxigenic negative.
117 were P. mirabilis.
J.,
1. Bakhtiar, M., Selwyn, S. Proc. 10th int. Chemother. Congr. (in the 2. Selwyn, S. J. antimicrob. Chemother. 1977, 3, 161. 3. Spratt, B. G. ibid. 1977, 3, suppl. B, p. 13. 4. Kerry, D. W., Hamilton-Miller, J. M. T., Brumfitt, W. ibid. 1977, 3,
B, p. 53. 5. Roberts, S. H., James, O., Jarvis, E. H. Lancet, 1977, ii, 1193.
press). Suppl.
