486
Cerebral MRS in infant with suspected
Reye’s syndrome SIR,-We have used proton magnetic
spectroscopy (MRS) to examine the brain of an 8-month-old comatose boy with encephalopathy and hyperammonaemia. Two regions (about 10 cm3) in parietal white and occipital grey matter were examined at days 2,4, and 8 with quantitative localised proton MRS (TE 30 ms, TR 1-5 s).1 On admission the child was comatose-after a short prodromal illness, which included exposure to varicella and administration of aspirin. A clinical diagnosis of Reye’s syndrome was made on the basis of raised blood ammonia, abnormal liver function tests, and negative lumbar puncture. After reaching a maximum stage III, his course improved and blood chemistry became normal. Aminoacid screen was negative. Needle liver biopsy on day 8 revealed fatty infiltration but not the pathognomonic mitochondrial electron-microscopic changes of Reye’s syndrome.’ The boy was discharged on day 10, with somewhat reduced functional (about 8 weeks) and gross motor skills (about 4 months). resonance
Comparison of the MRS spectra from days 2 and 8 (figure b and c, white matter) with that of a normal age-matched control (figure a)
indicated major disturbances in cerebral biochemistry. The peak of N-acetyl residues, which is a neuronal marker, was strongly reduced. The creatine plus phosphocreatine level [Cr + PCr] was decreased by 30-50%. Lactate was in small excess on day 2. The spectral region between 2-1and 2-5ppm was increased on day 2, but virtually normal on day 8 (day 4 was intermediate). The difference spectrum (figure d) revealed that this change was caused by 15 mmol/1 glutamine (figure e). Thus, intracellular glutamine on day 2 was about 20 mmol/l, which is close to the maximum measured in experimental hyperammonaemia in animals.3 Further abnormalities included the appearance and subsequent disappearance of an unassigned resonance at 3-62 ppm (day 2, "X"), an "overshoot" of choline on day 4, and the near absence of myo-inositol by day 8. These fmdings with lH-MRS offer new insight into the clinical events. The considerable loss of N-acetyl residues probably reflects neuronal damage, with its long-term neurological consequences."s A cerebral glutamine concentration of 20 mmol/1 may contribute to the severe neurological picture. However, neither this finding nor ammonia toxicity6 alone is likely to explain the reduction in [Cr + PCr]. Rather, because the liver is essential to creatine synthesis 7,8 we propose that severe liver damage is the main cause for the low cerebral creatine. The high mortality and the long-term neurological sequelae in patients with Reye’s syndrome may be explained by a similar chain of cerebral and extracerebral events. Research Institutes, and California Institutes of Technology, Pasadena, California 91105, USA
THOMAS ERNST BRIAN D. Ross
Pediatric Intensive Care Unit, Huntington Memorial Hospital, Pasadena
RICARDO FLORES
Huntington Medical
R, Farrow NA, Ross BD. Localised ’H NMR spectroscopy in patients with chronic encephalopathy: analysis of changes in cerebral glutamine, choline and inositols. NMR Biomed 1991; 4: 109-16. Thaler MM, Perman JA. In: Rudolph AM, Hoffman JIE, eds. Pediatrics. Los Altos Appleton and Lang, 1987: 999-1000. Hawkins RA, Jessy J. Hyperammonemia does not impair brain function in the absence of net glutamine synthesis. Biochem J 1991; 277: 697-703. van der Knaap MS, van der Grond J, van Rijen PC, Faber JAJ, Valk J, Willemse K Age-dependent changes in localised proton and phosphorus MR spectroscopy of the brain. Radiology 1990; 176: 509-13. Ross BD, Kreis R, Ernst T. Clinical tools for the 90s: magnetic resonance spectroscopy and metabolite imaging. Eur J Radiol 1992; 14: 128-40. McCandless DW, Schenker S. Effect of acute ammonia intoxification in energy stores in cerebral reticulum activating system. Exp Brain Res 1981; 44: 325-30. Daly MM. Guanidinoacetate methyltransferase activity in tissues and cultured cells Arch Biochem Biophys 1985; 236: 576-84. Newsholme EA, Leech AR, eds. Biochemistry for the medical sciences. New York Wiley, 1983: 952.
1 Kreis
2. 3. 4.
5. 6 7.
8.
Comparisons of olsalazine and mesalazine in prevention of relapse in ulcerative colitis
In-vivo proton M RS spectra from parietal white matter region in infant brain.
(a) 10 month-old normal infant, (b) patient, day 2 after admission, (c) day 8, (d) difference (b-c) between days 2 and day 8, (e) solution with 15 mmol/i glutamine. All spectra were scaled Lac= lactate (13 parts per million [ppm]), NA=N-acetyl residues (2-02 ppm), Gln=glutamine (2-10-250 and 3.65-3’90 ppm), Cr+PCr-creatine+phosphocreatine (3 03 ppm), Cho= choline-containing compounds (3 23 ppm), ml = myo-inositol (3 56ppm),X==unassigned (3 62 ppm) Occipital grey matter region gave almost identical results mM mmoi/!
SIR,-Dr Courtney and colleagues (May 23, p 1279) conclude that olsalazine (Dipentum) is "clearly superior to" mesalazine (Asacol) in reducing the rate of relapse in ulcerative colitis. They speculate that olsalazine delivers 5-aminosalicylic acid (5-ASA) to the left colon more effectively than does mesalazine. These seem to us to be rather strong statements in view of the potential flaws in the design and analysis of their study. As the product licence holder for Asacol in the USA and Canada, we think that it is appropriate to point out these possible shortcomings. The study was not double-blind; it is described as observerblind. This presumably means that the physician assessing the response to treatment did not know which drug the patient was receiving. Since the patients received undisguised commercial formulations of olsalazine or mesalazine, with obvious differences in appearance and dosage schedule, the assessing physician may have been effectively unblinded by comments from the patient, Additionally, Courtney et al do not state that the person dispensing the drug, or the statistician, were blinded. The report states that colonoscopy was done on study entry and exit, but does not indicate whether remission of disease at study
487
or subsequent relapse, was confirmed endoscopically. Remission was defined as "absence of symptoms or the presence of onlv mild stable symptoms of colitis"; and relapse as "development of new symptoms of colitis sufficiently severe to warrant the introduction of systemic steroid therapy". These definitions seem to us to be rather vague for a controlled clinical trial. Reliance on symptomatology may be reasonable in normal clinical practice, but as Courtney et al draw firm conclusions about the relative efficacy of olsalazine and mesalazine, one might expect to see data on the endoscopic appearance of the bowel. With respect to the methods of analysis, the decisions about which patients to include in the per-protocol and intention-to-treat analyses are not adequately explained. The patients listed in table n as excluded from the per-protocol analysis were described as "having violated the protocol or were withdrawn prematurely from the study for other reasons". Which patients were withdrawn prematurely is not clear, and no data are provided on the outcome of treatment in these excluded patients. In the intention-to-treat analysis, protocol violations at entry were included as treatment failures. This action is reasonable if these patients were randomised and treated, except that all these patients were in the mesalazine group. Since the study was not double-blind, could this have introduced an undue bias against mesalazine? The per-protocol analysis excluded patients with a "significant adverse effect". One would expect these patients to be included in the per-protocol analysis as treatment failures, if the event caused withdrawal from the study. In fact the report provides too few details on adverse reactions to establish how these data affected the analysis. Table n lists four patients lost to follow-up, one in the olsalazine group and three in the mesalazine group. Courtney et al state that the one patient lost to follow-up from the olsalazine group was excluded from both the per-protocol and intention-to-treat analyses; why were the three mesalazine patients treated differently? We wonder what the result of the study would be if the analysis were based more directly on the status of the patients’ ulcerative colitis at the last point of follow-up. Because of these potential flaws, we believe that Courtney’s investigation is inadequate to support the conclusions drawn. More convincing evidence for a difference in clinical performance between olsalazine and mesalazine is needed before suggesting that either product is an inferior formulation.
entry,
Procter and Gamble Pharmaceuticals, PO Box 191, Norwich, New York 13815, USA
JOHN E. GAIT NANCY A. SIMERL
to
that the blind randomisation and assessment must exclude the difficulties our critics perceive. All patients were measured by the same criteria and the result stands as a clinically relevant finding in this group of patients. We conclude that Dipentum is superior to Asacol in maintenance treatment of ulcerative colitis. Several publicationsl-4 support our contention that more 5-ASA is delivered to the colon by Dipentum than by Asacol. We postulate that the greater efficacy of Dipentum over Asacol in the left hemi-colon is due to greater mucosal presentation of 5-ASA from the more liquid stool of the Dipentum treated patients. We see this hypothesis as innovative, even provocative, rather than "convenient". It also complements the suggestion by Riley et a15 that a prolonged transit time may be disadvantageous to patients with colitis by promoting intracolonic conversion of active 5-ASA to inactive N-acetyl-5-ASA. Thus we could further suggest that olsalazine is more effective in preventing relapse in ulcerative colitis by a combination of several mechanisms-namely, near complete colonic delivery of 5-ASA by bacterial azoreduction, enhanced mucosal presentation of 5-ASA in a more liquid stool, and decreased acetylation/inactivation of 5-ASA to N-Acetyl-5-ASA due to decreased transit time. Departments of Medicine and Gastroenterology, Beaumont Hospital, Dublin 9, Ireland
Dr
Courtney,
whose
reply
follows.-ED. L.
M. G. COURTNEY
1. Rao
SSC, Read NW, Holdsworth CD. Influence of olsalazine on gastrointestinal in ulcerative colitis. Gut 1987; 28: 1474-77. 2. Rijk MCM, van Schail A, Van Tongeren JHM. Disposition of 5-aminosalicylic acid by 5-aminosalicylic acid-delivering compounds. Scand J Gastroenterol 1988; 23: transit
107-12. 3. Laursen LS, Stokholm M, Bukhave K, Rask-Madsen J, Lauritsen K. Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum alues and urinary excretion. Gut 1990; 31: 1271-76. 4. Wadworth AN, Fitton A. Olsalazine, a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in inflammatory bowel disease. Drugs 1991; 41: 647-64. 5. Riley SA, Tavares IA, Bishai PM, Bennett A, Mani V. Mesalazine release from coated tablets: effect of dietary fibre. Br J Clin Pharmacol 1991; 32: 248-50.
Serum
Department of Regulatory and Medical Affairs,
***This letter has been shown
analysis we can only state that the text and data are self-explanatory, easy to assimilate, and do not require a rewrite here except to state
L-arginine in hypercholesterolaemia
SIR,-Dr Jeserich and colleagues (Feb 29, p 561) report reduced in concentrations plasma L-arginine patients with hypercholesterolaemia, a finding that has possible therapeutic implications in such patients. We have measured serum L-arginine in 11 patients with type IIa hypercholesterolaemia and 11 age-matched patient controls with normal cholesterol concentrations.
SiR,—Dr Gait and Ms Simerl may not have understood the purpose of our study or the reasons for our conclusions. We are suprised that the department of regulatory and medical affairs of a major pharmaceutical company should require clarification of the phase "observer-blind", especially since this is explained in the methods section of our paper. Articles are often limited by pressure on space; the detailed structure of the study and separation of the blinded assessing clinicians and statistician from the monitoring clinical trial nurses could not be described in detail but was alluded to in the methods section. Remission was confirmed endoscopically and histologically for all trial entrants as stated in the methods. Our definitions of remission and relapse may seem "vague" to Gait and Simerl but have been found by us, as practising clinicians, to be robust and workable. This study was an attempt to mimic clinical practice in St James’s Hospital and we feel that the results will have a greater relevance to normal clinical practice than those emanating from studies with artificial restraints of more elaborate trials. A single centre study in which the clinicans have clear and well-grounded understanding of each others’ practice has a great advantage of less inter-observer variation over a multicentre study with much larger numbers of collaborating clinicians, however well systematised and categorised that study may appear on paper. In response to Gait and Simerl’s difficulties with the methods of
L-arginine was measured by gradient elution ion-exchange chromatography (Rank Hilger Chromaspek) and detected fluorimetrically; cholesterol was measured enzymatically on a Hitachi 704 analyser. All 22 patients had serum triglyceride concentrations below 25mmol/1 and none had previously received In lipid-lowering agents. nearly all patients with hypercholesterolaemia, this was a new finding and they are thus unlikely to have received specific dietary advice. The mean ages of patients and controls were, respectively, 53-9 years (SD 10 1, range 34-0-65-3) and 53-2 years (10-2, 33-8-67-2), and serum cholesterol and L-arginine concentrations were 9-4 mmol/1 (0-84, 8-0-10-9) and 109-3 Eunol/1 (26-3, 74-171) in the patients and 5-7 mmol/1 (0-83, 4-4-7-1) and 111-6 l1llol/1 (30-7, 60-164), respectively, in the controls. The serum L-arginine concentrations
in the
two
groups
were
very similar and do not accord with
Jeserich and colleagues’ of reduced plasma L-arginine concentrations in fmdings hypercholesterolaemic patients. We believe that L-arginine supplements are unlikely to provide a useful adjunctive or preventative treatment in such patients. Department of Chemical Pathology, Royal Gwent Hospital, Newport, Gwent NP9 2UB, UK
D. A. OLEESKY M. D. PENNEY S. FIROOZMAND
Cerebral MRS in infant with suspected
Reye’s syndrome SIR,-We have used proton magnetic
spectroscopy (MRS) to examine the brain of an 8-month-old comatose boy with encephalopathy and hyperammonaemia. Two regions (about 10 cm3) in parietal white and occipital grey matter were examined at days 2,4, and 8 with quantitative localised proton MRS (TE 30 ms, TR 1-5 s).1 On admission the child was comatose-after a short prodromal illness, which included exposure to varicella and administration of aspirin. A clinical diagnosis of Reye’s syndrome was made on the basis of raised blood ammonia, abnormal liver function tests, and negative lumbar puncture. After reaching a maximum stage III, his course improved and blood chemistry became normal. Aminoacid screen was negative. Needle liver biopsy on day 8 revealed fatty infiltration but not the pathognomonic mitochondrial electron-microscopic changes of Reye’s syndrome.’ The boy was discharged on day 10, with somewhat reduced functional (about 8 weeks) and gross motor skills (about 4 months). resonance
Comparison of the MRS spectra from days 2 and 8 (figure b and c, white matter) with that of a normal age-matched control (figure a)
indicated major disturbances in cerebral biochemistry. The peak of N-acetyl residues, which is a neuronal marker, was strongly reduced. The creatine plus phosphocreatine level [Cr + PCr] was decreased by 30-50%. Lactate was in small excess on day 2. The spectral region between 2-1and 2-5ppm was increased on day 2, but virtually normal on day 8 (day 4 was intermediate). The difference spectrum (figure d) revealed that this change was caused by 15 mmol/1 glutamine (figure e). Thus, intracellular glutamine on day 2 was about 20 mmol/l, which is close to the maximum measured in experimental hyperammonaemia in animals.3 Further abnormalities included the appearance and subsequent disappearance of an unassigned resonance at 3-62 ppm (day 2, "X"), an "overshoot" of choline on day 4, and the near absence of myo-inositol by day 8. These fmdings with lH-MRS offer new insight into the clinical events. The considerable loss of N-acetyl residues probably reflects neuronal damage, with its long-term neurological consequences."s A cerebral glutamine concentration of 20 mmol/1 may contribute to the severe neurological picture. However, neither this finding nor ammonia toxicity6 alone is likely to explain the reduction in [Cr + PCr]. Rather, because the liver is essential to creatine synthesis 7,8 we propose that severe liver damage is the main cause for the low cerebral creatine. The high mortality and the long-term neurological sequelae in patients with Reye’s syndrome may be explained by a similar chain of cerebral and extracerebral events. Research Institutes, and California Institutes of Technology, Pasadena, California 91105, USA
THOMAS ERNST BRIAN D. Ross
Pediatric Intensive Care Unit, Huntington Memorial Hospital, Pasadena
RICARDO FLORES
Huntington Medical
R, Farrow NA, Ross BD. Localised ’H NMR spectroscopy in patients with chronic encephalopathy: analysis of changes in cerebral glutamine, choline and inositols. NMR Biomed 1991; 4: 109-16. Thaler MM, Perman JA. In: Rudolph AM, Hoffman JIE, eds. Pediatrics. Los Altos Appleton and Lang, 1987: 999-1000. Hawkins RA, Jessy J. Hyperammonemia does not impair brain function in the absence of net glutamine synthesis. Biochem J 1991; 277: 697-703. van der Knaap MS, van der Grond J, van Rijen PC, Faber JAJ, Valk J, Willemse K Age-dependent changes in localised proton and phosphorus MR spectroscopy of the brain. Radiology 1990; 176: 509-13. Ross BD, Kreis R, Ernst T. Clinical tools for the 90s: magnetic resonance spectroscopy and metabolite imaging. Eur J Radiol 1992; 14: 128-40. McCandless DW, Schenker S. Effect of acute ammonia intoxification in energy stores in cerebral reticulum activating system. Exp Brain Res 1981; 44: 325-30. Daly MM. Guanidinoacetate methyltransferase activity in tissues and cultured cells Arch Biochem Biophys 1985; 236: 576-84. Newsholme EA, Leech AR, eds. Biochemistry for the medical sciences. New York Wiley, 1983: 952.
1 Kreis
2. 3. 4.
5. 6 7.
8.
Comparisons of olsalazine and mesalazine in prevention of relapse in ulcerative colitis
In-vivo proton M RS spectra from parietal white matter region in infant brain.
(a) 10 month-old normal infant, (b) patient, day 2 after admission, (c) day 8, (d) difference (b-c) between days 2 and day 8, (e) solution with 15 mmol/i glutamine. All spectra were scaled Lac= lactate (13 parts per million [ppm]), NA=N-acetyl residues (2-02 ppm), Gln=glutamine (2-10-250 and 3.65-3’90 ppm), Cr+PCr-creatine+phosphocreatine (3 03 ppm), Cho= choline-containing compounds (3 23 ppm), ml = myo-inositol (3 56ppm),X==unassigned (3 62 ppm) Occipital grey matter region gave almost identical results mM mmoi/!
SIR,-Dr Courtney and colleagues (May 23, p 1279) conclude that olsalazine (Dipentum) is "clearly superior to" mesalazine (Asacol) in reducing the rate of relapse in ulcerative colitis. They speculate that olsalazine delivers 5-aminosalicylic acid (5-ASA) to the left colon more effectively than does mesalazine. These seem to us to be rather strong statements in view of the potential flaws in the design and analysis of their study. As the product licence holder for Asacol in the USA and Canada, we think that it is appropriate to point out these possible shortcomings. The study was not double-blind; it is described as observerblind. This presumably means that the physician assessing the response to treatment did not know which drug the patient was receiving. Since the patients received undisguised commercial formulations of olsalazine or mesalazine, with obvious differences in appearance and dosage schedule, the assessing physician may have been effectively unblinded by comments from the patient, Additionally, Courtney et al do not state that the person dispensing the drug, or the statistician, were blinded. The report states that colonoscopy was done on study entry and exit, but does not indicate whether remission of disease at study
487
or subsequent relapse, was confirmed endoscopically. Remission was defined as "absence of symptoms or the presence of onlv mild stable symptoms of colitis"; and relapse as "development of new symptoms of colitis sufficiently severe to warrant the introduction of systemic steroid therapy". These definitions seem to us to be rather vague for a controlled clinical trial. Reliance on symptomatology may be reasonable in normal clinical practice, but as Courtney et al draw firm conclusions about the relative efficacy of olsalazine and mesalazine, one might expect to see data on the endoscopic appearance of the bowel. With respect to the methods of analysis, the decisions about which patients to include in the per-protocol and intention-to-treat analyses are not adequately explained. The patients listed in table n as excluded from the per-protocol analysis were described as "having violated the protocol or were withdrawn prematurely from the study for other reasons". Which patients were withdrawn prematurely is not clear, and no data are provided on the outcome of treatment in these excluded patients. In the intention-to-treat analysis, protocol violations at entry were included as treatment failures. This action is reasonable if these patients were randomised and treated, except that all these patients were in the mesalazine group. Since the study was not double-blind, could this have introduced an undue bias against mesalazine? The per-protocol analysis excluded patients with a "significant adverse effect". One would expect these patients to be included in the per-protocol analysis as treatment failures, if the event caused withdrawal from the study. In fact the report provides too few details on adverse reactions to establish how these data affected the analysis. Table n lists four patients lost to follow-up, one in the olsalazine group and three in the mesalazine group. Courtney et al state that the one patient lost to follow-up from the olsalazine group was excluded from both the per-protocol and intention-to-treat analyses; why were the three mesalazine patients treated differently? We wonder what the result of the study would be if the analysis were based more directly on the status of the patients’ ulcerative colitis at the last point of follow-up. Because of these potential flaws, we believe that Courtney’s investigation is inadequate to support the conclusions drawn. More convincing evidence for a difference in clinical performance between olsalazine and mesalazine is needed before suggesting that either product is an inferior formulation.
entry,
Procter and Gamble Pharmaceuticals, PO Box 191, Norwich, New York 13815, USA
JOHN E. GAIT NANCY A. SIMERL
to
that the blind randomisation and assessment must exclude the difficulties our critics perceive. All patients were measured by the same criteria and the result stands as a clinically relevant finding in this group of patients. We conclude that Dipentum is superior to Asacol in maintenance treatment of ulcerative colitis. Several publicationsl-4 support our contention that more 5-ASA is delivered to the colon by Dipentum than by Asacol. We postulate that the greater efficacy of Dipentum over Asacol in the left hemi-colon is due to greater mucosal presentation of 5-ASA from the more liquid stool of the Dipentum treated patients. We see this hypothesis as innovative, even provocative, rather than "convenient". It also complements the suggestion by Riley et a15 that a prolonged transit time may be disadvantageous to patients with colitis by promoting intracolonic conversion of active 5-ASA to inactive N-acetyl-5-ASA. Thus we could further suggest that olsalazine is more effective in preventing relapse in ulcerative colitis by a combination of several mechanisms-namely, near complete colonic delivery of 5-ASA by bacterial azoreduction, enhanced mucosal presentation of 5-ASA in a more liquid stool, and decreased acetylation/inactivation of 5-ASA to N-Acetyl-5-ASA due to decreased transit time. Departments of Medicine and Gastroenterology, Beaumont Hospital, Dublin 9, Ireland
Dr
Courtney,
whose
reply
follows.-ED. L.
M. G. COURTNEY
1. Rao
SSC, Read NW, Holdsworth CD. Influence of olsalazine on gastrointestinal in ulcerative colitis. Gut 1987; 28: 1474-77. 2. Rijk MCM, van Schail A, Van Tongeren JHM. Disposition of 5-aminosalicylic acid by 5-aminosalicylic acid-delivering compounds. Scand J Gastroenterol 1988; 23: transit
107-12. 3. Laursen LS, Stokholm M, Bukhave K, Rask-Madsen J, Lauritsen K. Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum alues and urinary excretion. Gut 1990; 31: 1271-76. 4. Wadworth AN, Fitton A. Olsalazine, a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in inflammatory bowel disease. Drugs 1991; 41: 647-64. 5. Riley SA, Tavares IA, Bishai PM, Bennett A, Mani V. Mesalazine release from coated tablets: effect of dietary fibre. Br J Clin Pharmacol 1991; 32: 248-50.
Serum
Department of Regulatory and Medical Affairs,
***This letter has been shown
analysis we can only state that the text and data are self-explanatory, easy to assimilate, and do not require a rewrite here except to state
L-arginine in hypercholesterolaemia
SIR,-Dr Jeserich and colleagues (Feb 29, p 561) report reduced in concentrations plasma L-arginine patients with hypercholesterolaemia, a finding that has possible therapeutic implications in such patients. We have measured serum L-arginine in 11 patients with type IIa hypercholesterolaemia and 11 age-matched patient controls with normal cholesterol concentrations.
SiR,—Dr Gait and Ms Simerl may not have understood the purpose of our study or the reasons for our conclusions. We are suprised that the department of regulatory and medical affairs of a major pharmaceutical company should require clarification of the phase "observer-blind", especially since this is explained in the methods section of our paper. Articles are often limited by pressure on space; the detailed structure of the study and separation of the blinded assessing clinicians and statistician from the monitoring clinical trial nurses could not be described in detail but was alluded to in the methods section. Remission was confirmed endoscopically and histologically for all trial entrants as stated in the methods. Our definitions of remission and relapse may seem "vague" to Gait and Simerl but have been found by us, as practising clinicians, to be robust and workable. This study was an attempt to mimic clinical practice in St James’s Hospital and we feel that the results will have a greater relevance to normal clinical practice than those emanating from studies with artificial restraints of more elaborate trials. A single centre study in which the clinicans have clear and well-grounded understanding of each others’ practice has a great advantage of less inter-observer variation over a multicentre study with much larger numbers of collaborating clinicians, however well systematised and categorised that study may appear on paper. In response to Gait and Simerl’s difficulties with the methods of
L-arginine was measured by gradient elution ion-exchange chromatography (Rank Hilger Chromaspek) and detected fluorimetrically; cholesterol was measured enzymatically on a Hitachi 704 analyser. All 22 patients had serum triglyceride concentrations below 25mmol/1 and none had previously received In lipid-lowering agents. nearly all patients with hypercholesterolaemia, this was a new finding and they are thus unlikely to have received specific dietary advice. The mean ages of patients and controls were, respectively, 53-9 years (SD 10 1, range 34-0-65-3) and 53-2 years (10-2, 33-8-67-2), and serum cholesterol and L-arginine concentrations were 9-4 mmol/1 (0-84, 8-0-10-9) and 109-3 Eunol/1 (26-3, 74-171) in the patients and 5-7 mmol/1 (0-83, 4-4-7-1) and 111-6 l1llol/1 (30-7, 60-164), respectively, in the controls. The serum L-arginine concentrations
in the
two
groups
were
very similar and do not accord with
Jeserich and colleagues’ of reduced plasma L-arginine concentrations in fmdings hypercholesterolaemic patients. We believe that L-arginine supplements are unlikely to provide a useful adjunctive or preventative treatment in such patients. Department of Chemical Pathology, Royal Gwent Hospital, Newport, Gwent NP9 2UB, UK
D. A. OLEESKY M. D. PENNEY S. FIROOZMAND
