© 1995 American Heart Association, Inc.
Articles |
Longitudinal Study of Associations of Microalbuminuria With the Insulin Resistance Syndrome and Sodium-Lithium Countertransport in Nondiabetic Subjects
From the Department of Medicine, University College London Medical School, London, England.
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Abstract |
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Abstract Microalbuminuria in diabetic patients is associated with ischemic heart disease and insulin resistance. We previously found a 9% prevalence of microalbuminuria in a nondiabetic population that we have reassessed, investigating associations of microalbuminuria with hypertension, dyslipidemia, hyperinsulinemia, and sodium-lithium countertransport. Of 125 subjects reexamined, 42 had been microalbuminuric 3 years previously. Twelve of these (29%) were microalbuminuric on at least one sample at follow-up, and 30 (76%) were normoalbuminuric on two. Of the 79 previously normoalbuminuric subjects, 12 (15%) became microalbuminuric on one sample, while 67 (85%) remained normoalbuminuric. Subjects who were microalbuminuric at both screening and recall were older (mean±SD, 65.9±11 versus 59.1±10.2 years, P=.04), with a higher waist-to-hip ratio (0.93±0.09 versus 0.86±0.08, P=.008) and at recall, on univariate analysis, had higher specific insulin (44.2 [range, 16.9 to 157.0] versus 28.4 [7.4 to 129.0] pmol/L, P=.005), intact proinsulin (5.1 [1.5 to 11.0] versus 3.0 [0.8 to 14.6] pmol/L, P=.003), and des-31,32-proinsulin (5.0 [0.5 to 9.8] versus 1.0 [0.5 to 12.2] pmol/L, P=.004) concentrations. There was also a significant difference in des-31,32-proinsulin concentration, after adjustment for covariates (P=.013), between subjects classified either as microalbuminuric or as normoalbuminuric at screening. There was no difference in body mass index; fasting blood glucose; systolic or diastolic blood pressure; total, HDL, or LDL cholesterol; triglycerides; plasminogen activator inhibitor-1; or sodium-lithium countertransport activity between consistently normoalbuminuric and persistently microalbuminuric subjects. We found a positive relationship of changes in albumin excretion rate with those in HDL cholesterol concentrations over the follow-up period (r=.25, P=.009) but none with changes in fasting blood glucose, blood pressure, other lipids, insulin, or proinsulin-like molecules. In conclusion, microalbuminuria is an unstable phenomenon over a period of 3 years in nondiabetic subjects, with a coefficient of variation of
60% on two paired samples over this time. It is
associated with increased concentrations of insulin and of
proinsulin-like molecules but not with other features of the insulin
resistance syndrome.
Key Words: microalbuminuria • insulin resistance • proinsulin-like molecules • plasminogen activator inhibitor-1 • sodium-lithium countertransport
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Introduction |
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Microalbuminuria in diabetes not only precedes clinical nephropathy1 but also has increasingly been recognized as a powerful predictor of IHD. A number of studies have independently demonstrated increased cardiovascular mortality in both IDDM2 and NIDDM subjects with microalbuminuria.3 4 5 We previously reported a prevalence of microalbuminuria of 10% in nondiabetic subjects >40 years old and described an associated increase in CHD of approximately sixfold in this group.6 Other work has shown a similar relationship of cardiovascular disease with microalbuminuria in nondiabetic subjects.7
The mechanism of an association in diabetic patients between IHD and microalbuminuria or nephropathy is little understood, because, although glycemic exposure is documented to play an important role in the development of renal disease,8 there is little evidence to suggest that this might mediate IHD.9 Furthermore, since diabetic nephropathy develops in only one third of patients with IDDM,10 it is likely that other determinants are perhaps more important.
As a possible explanation for this association, some groups have described not only adverse changes in cardiovascular risk factors in microalbuminuric patients, such as elevated blood pressure11 and dyslipidemia,12 13 14 15 but also insulin resistance.16 17 18 Since hyperinsulinemia has also been described in nondiabetic subjects with microalbuminuria,19 it might be postulated that microalbuminuria, through its association with insulin resistance, antedates the development of NIDDM, perhaps predicting its development independently of associations with elevated blood pressure.20
Studies have described a familial clustering of renal involvement in subjects with IDDM,21 and recent work has involved the search for a genetic antecedent that may explain this and perhaps also the underlying relationship with IHD. The parents of patients with diabetic nephropathy have higher blood pressures than those of subjects with IDDM but without renal involvement,22 and thus, a common mechanism may predispose to both hypertension and nephropathy. Patients with essential hypertension have increased rates of erythrocyte SLC,23 and this may be a candidate mechanism linking microalbuminuria with hypertension or IHD. Increased rates of SLC have been demonstrated in nephropathic patients with both NIDDM and IDDM.18 24 25 26 In some studies, SLC has been associated with insulin resistance18 27 28 or hypertriglyceridemia,18 26 29 so the relationship of microalbuminuria and insulin resistance may be determined in part by their mutual associations with SLC. No study has yet examined potential relationships between microalbuminuria and SLC in the absence of diabetes and hypertension.
The Goodinge Study, conducted between 1990 and 1991, was a general practice–based investigation of 1046 randomly selected nondiabetic white subjects between 40 and 75 years old to investigate associations between microalbuminuria and cardiovascular risk factors. This study demonstrated a 9% prevalence of microalbuminuria.30 The present study was designed to reinvestigate subjects studied during the Goodinge Study to (1) define the course of microalbuminuria in nondiabetic subjects, (2) examine the relationships between microalbuminuria in nondiabetic subjects and features of the insulin resistance syndrome, and (3) establish whether increased rates of SLC are evident in individuals with microalbuminuria in the absence of diabetes.
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Methods |
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Subjects
The Goodinge Study has been described previously.30 31 In brief, 1671 white subjects 40 to 75 years old were selected from an age-sex register of a group practice and invited to participate, and 1046 (62.3%) attended. Of the 1046 subjects examined during the screening phase of the study, 959 subjects had full documentation of glucose tolerance and AER and were eligible for inclusion in the recall investigation, being between 40 and 75 years old, nondiabetic, of European origin, and without potential confounders for microalbuminuria, namely penicillamine or angiotensin-converting enzyme inhibitor treatment, or urinary tract infection. Of these subjects, 108 were microalbuminuric (AER, 20 to 200 µg/min) on either a daytime or overnight urine sample or both during the screening stage. One subject with impaired glucose tolerance was excluded, and of the remainder, a random selection of 86 (80.5%) were traced. Thirty-five individuals did not respond to two invitations, 3 others had died, one had had a stroke, and 5 were taking anticoagulant or antihypertensive medication that could not be stopped, leaving 42 available for study.
For each previously microalbuminuric subject attending at recall, 2 subjects who were normoalbuminuric on both occasions were also invited. These were selected from the total cohort by matching for age (±10 years), sex, BMI (±5 kg/m2), and CHD status, with further subjects invited if these failed to attend. A total of 164 normoalbuminuric individuals were recalled, of whom 3 had died and 73 did not reply. Five of these were excluded, 4 being on antihypertensive medication and 1 taking lithium. Therefore, 83 subjects were seen, 2 individuals on lipid-lowering therapy being asked to discontinue their drugs 48 hours before the examination.
Forty-two subjects who were microalbuminuric at screening on one or both samples attended for reinvestigation, and these were found to be representative of all eligible microalbuminuric subjects, there being no significant difference in age, sex, BMI, SBP or DBP, daytime or overnight AER, total or HDL cholesterol, and triglycerides. Of a total of 700 eligible subjects, 79 subjects who were normoalbuminuric on two urine samples at screening were recruited, 4 others being normoalbuminuric on one sample at screening but failing to provide a second collection. One subject who was normoalbuminuric at screening provided only a single (normoalbuminuric) sample at recall, so could not be classified. There was again no difference between those restudied and other subjects in the above variables, except age: nonattenders were significantly younger than attenders (mean age, 47.6 versus 54.4 years, P<.001). While this is a limitation in terms of the representativeness of the normoalbuminuric subjects restudied, it nevertheless resulted in closer matching of age between the normoalbuminuric and microalbuminuric subjects.
Studies were approved by the Ethical Committee of Islington Health Authority, and all participating subjects recalled gave informed oral consent.
Procedures
Screening methods at the Goodinge phase of the study
involved fasting plasma glucose concentrations at baseline and at 1 and
2 hours of an oral glucose tolerance test. Serum total and HDL
cholesterol, triglycerides, insulin, and
proinsulin-like molecules were measured on the fasting sample. Blood
pressure measurements were taken with a random-zero sphygmomanometer
(Hawksley) with a large cuff for subjects with arm circumference >33
cm and using Korotkoff phases I to V. Height was measured without
shoes, and subjects were weighed (Seca) wearing only light clothing.
Timed day and night urine samples were obtained for AER. Subjects at
the screening phase of the study also filled in a detailed medical
questionnaire.
Subjects were restudied 35.2±4.5 months (mean±SD) after the Goodinge phase and were seen in the Department of Medicine, University College London Medical School, Whittington Hospital after an overnight fast. Before the study, all individuals completed a daytime (8 AM to 10 PM) and overnight (10PM to 8 AM) urine collection. These samples were tested for blood, protein, leukocytes, and nitrites with Ames Multistix and if they were positive, a midstream urine specimen was sent for culture. Any indicated treatment was prescribed and another 24-hour collection organized. AER (micrograms per minute) was calculated for daytime and overnight samples.
On the subject's arrival, a brief medical and social history was recorded, including details of cardiovascular disease and family history of vascular disease.32 Height in meters and weight in kilograms were measured in light clothing and without shoes with a stadiometer and balance (Seca). From these, BMI was calculated as kilograms per meter squared. Waist and hip circumferences were measured in triplicate with a steel tape at the level of the umbilicus and greater trochanter, respectively, for the calculation of WHR, and skinfold thickness was measured in triplicate over the body of the triceps muscle and immediately below the scapula with Holtain calipers for calculation of STR.
Supine blood pressure was measured in duplicate for calculation of means after a 15-minute rest. Measurements were made by a single observer using a random-zero sphygmomanometer (Hawksley) using Korotkoff phases I to V. Fasting venous blood glucose was measured, and if blood glucose concentration was >5 mmol/L, a 75-g oral glucose tolerance test was subsequently performed (n=5). One subject was found to have impaired glucose tolerance, but none had NIDDM. Fasting blood was also collected for the determination of plasma insulin, proinsulin and des-31,32-proinsulin, total cholesterol, HDL cholesterol, triglycerides, PAI-1 activity, and SLC activity.
Assays
Plasma glucose concentration at screening was measured by
a glucose oxidase method (Beckman). At recall, blood glucose
concentration was measured with a BM glucometer
(Boehringer-Mannheim) previously calibrated against
laboratory glucose measurements (r=.95). At both screening
and recall phases, urinary albumin was measured with an
in-house ELISA adapted from the method of Chesham et al33
as described by Gould et al.30 Insulin and proinsulin-like
molecules were measured with in-house specific two-site
immunoenzymometric assays34 35 with monoclonal antibodies
supplied by Serono Diagnostics, total serum
cholesterol by a cholesterol esterase method
(Boehringer-Mannheim), and HDL cholesterol with a
CHOD-PAP assay after phosphotungstic acid precipitation.36
Serum triglycerides were determined by an enzymatic
spectrophotometric method37 (Roche
Diagnostics). LDL cholesterol was calculated
with the Friedewald formula.38 PAI-1 activity was
determined by a colorimetric assay (Biopool).
Erythrocyte SLC activity was determined by the method of Canessa et
al,23 as later modified by Mangili et al,25
the assay having intra-assay and interassay CVs of 5.8% and 11.5%,
respectively (n=64).
Classification
The classifications used for analyses were those of the
World Health Organization, in which impaired glucose tolerance was
defined as a 2-hour plasma glucose concentration of 7.8 to 11.0 mmol/L
on oral glucose tolerance test39 and hypertension as
either an SBP 
160 or a DBP 95 mm Hg or the patient's being on
therapy at screening or recall.40
Because of the variability of AER in these subjects and the consequent
instability of the classification groups, we performed several
different analyses. First, we grouped the subjects according to
their change in or consistency of status between screening
and recall, using the definition of microalbuminuria as
AER 20 µg/min but 
200 µg/min on either a daytime or overnight
collection. We then examined the data separately on screening and
recall samples, defining microalbuminuria either as an
AER of 20 to 200 µg/min on either or both samples or as a geometric
mean AER 20 µg/min.
Statistical Analyses
Analyses were performed with the SPSS
statistical package. Comparisons between groups were made with the
Student's t test or ANOVA with logarithmic transformation
of skewed data. Correlations were also performed with logarithmic
transformation of skewed data. However, changes in variables were
analyzed with the Mann Whitney U test for
comparisons and Spearman rank for correlations to analyze
negative values. A value of P=.05 is considered significant,
although, since multiple comparisons were performed, a more rigorous
criterion might be considered appropriate. Nevertheless, the raw data
are presented.
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Results |
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Of the 42 subjects who were microalbuminuric at screening, 8 had an increased AER on both screening samples, with the remaining 34 microalbuminuric on a single sample only (23 daytime and 11 overnight). At follow-up, 12 of the 42 (29%) were still microalbuminuric on at least one sample, while 30 were normoalbuminuric on both. Of the 8 subjects who were microalbuminuric on both samples at screening, 5 (63%) remained microalbuminuric at follow-up (1 on one sample, 4 on both) (Figure
, top).
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Of the 79 previously normoalbuminuric subjects, 12 (15%)
became microalbuminuric over the 3-year period (8 on a
single sample, 4 on both), while 67 (85%) remained
normoalbuminuric (on one single sample). Thus, 42 subjects
changed category between the screening phase and follow-up study.
Variability of AER as a continuous variable was also calculated and
expressed as a CV. For the 124 subjects who provided paired urine
samples at recall, the CV was 28.4%, while for the 113 subjects who
provided paired samples at both screening and recall, the CV of the
geometric mean AER over a period of 3 years was 59.8% (Figure
,
bottom).
The clinical characteristics of the different subject groups,
classified according to screening and recall
microalbuminuria status, are shown in Table 1. ANOVA showed significant differences between the four
groups in terms of age, WHR, and plasma concentrations of insulin,
intact proinsulin, and des-31,32-proinsulin, which were also apparent
in paired comparisons of consistently
normoalbuminuric and persistently
microalbuminuric subjects. Differences for insulin,
proinsulin, and des-31,32-proinsulin concentrations across the four
categories did not remain significant after correction for age, BMI,
WHR, and plasma glucose (insulin adjusted, P=.34;
proinsulin, P=.43; des-31,32-proinsulin, P=.063),
and there was also no significant difference between groups in
proinsulin concentrations as a proportion of all insulin-like molecules
(ANOVA, P=.63). Similar paired comparisons adjusted for
confounding variables were also no longer significant. There was no
significant difference in SLC between the four groups (ANOVA,
P=.82). SBP and DBP and total, HDL, and LDL
cholesterol, triglyceride, PAI-1, and fasting
glucose concentrations were also similar between groups.
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Paired comparisons were also made separately on screening and recall data according to two different definitions of microalbuminuria. The 42 subjects who were microalbuminuric on screening (AER, 20 to 200 µg/min on day, night, or both samples) had higher concentrations of des-31,32-proinsulin than the 79 subjects who were normoalbuminuric at screening (3.2 [0.4 to 30.1] versus 0.9 [0.5 to 18.0] pmol/L; P=.006), and this difference remained significant after adjustment for age, BMI, WHR, and plasma glucose concentration (P=.013). However, these two groups were not significantly different in terms of any of the other variables studied. In the same categories at recall, 24 subjects were microalbuminuric and 100 were normoalbuminuric. The microalbuminuric subjects had higher concentrations of intact proinsulin (3.7 [1.5 to 15.0] versus 3.0 [0.8 to 14.6] pmol/L; P=.04), but this difference was no longer significant after adjustment for age, obesity, and plasma glucose (P=.23). No other differences were apparent between the two groups classified at recall.
We then characterized our subjects according to geometric mean AER 20
or <20 µg/min at screening (Table 2) and recall
(Table 3). By this classification, 12 subjects were
microalbuminuric at screening and 102
normoalbuminuric. Comparison of these groups again showed
microalbuminuric subjects to be older, with higher levels
of specific insulin and borderline elevated concentrations of
proinsulin and des-31,32-proinsulin. When adjusted for age, obesity,
and blood glucose concentrations, differences in fasting insulin
concentration were no longer significant (P=.12). When the
study population was similarly divided according to geometric mean AER
at recall, 15 subjects were found to be microalbuminuric.
The differences between groups were less clear by this
analysis, only the difference between WHRs reaching statistical
significance and that of intact proinsulin, borderline
significance.
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A number of variables were measured at both screening and recall.
Changes in these variables between screening and recall were
compared between groups (Table 4). Changes in
triglyceride concentrations differed significantly between
the persistently microalbuminuric and consistently
normoalbuminuric cohorts, but there was no difference in
BMI, SBP, DBP, glucose, insulin or insulin-like
molecules, or total, LDL, or HDL cholesterol between
the groups. We found a significant positive relationship between
changes in mean log AER (AER) and HDL cholesterol
(r=.25, P=.009) but no relationship between
AER and those in any of the other variables between screening
and recall.
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We then repeated all the above analyses excluding hypertensive subjects (10 normoalbuminuric, 7 microalbuminuric at screening; 14 normoalbuminuric, 3 microalbuminuric at recall) and found no difference in our results.
SLC rate was found to be positively associated with WHR (r=.19, P=.04), des-31,32-proinsulin levels (r=.20, P=.03), triglyceride concentrations (r=.23, P=.01), and PAI-1 activity (r=.38, P<.001) but not with any of the other variables: age (r=-.12, P=.19), BMI (r=.12, P=.19), STR (r=.17, P=.07), SBP (r=.03, P=.74), DBP (r=.09, P=.30), plasma glucose (r=.09, P=.32), insulin (r=.15, P=.09), intact proinsulin (r=.13, P=.14), total cholesterol (r=-.07, P=.45), HDL cholesterol (r=-.08, P=.37), LDL cholesterol (r=-.11, P=.22), or geometric mean AER at screening (r=-.01, P=.96) or at recall (r=-.04, P=.70).
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Discussion |
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We studied 42 white subjects with normal glucose tolerance and microalbuminuria and 79 with normoalbuminuria. Because we were studying healthy subjects on two occasions over a period of 3 years and needed to maximize subject compliance, we estimated AER both at screening and at recall on two rather than three collections, as would be usual in diabetic patients. In consequence, we used for our main classification of microalbuminuria an AER of 20 to 200 µg/min on either or both collections. We found that only 29% of individuals identified as microalbuminuric at screening remained so at follow-up, while 15% of normoalbuminuric subjects changed category. Microalbuminuria is thus a highly unstable variable in nondiabetic subjects. Nevertheless, we have previously shown it to be powerfully related to cardiovascular risk in this population.6 These observations suggest that, allowing for biological variability, the relationship between microalbuminuria (or its genetic or environmental determinants) and cardiovascular risk is stronger than previous reports indicate.
Earlier cross-sectional studies of microalbuminuria in nondiabetic subjects have demonstrated positive relationships with insulin concentrations19 41 and with components of the insulin resistance syndrome.41 42 43 One longitudinal study in a population with a high prevalence of glucose intolerance suggested that microalbuminuria precedes the development of NIDDM20 and proposed that insulin resistance may underlie this predisposition. However, in this population at low risk for NIDDM, we found that only one microalbuminuric individual developed impaired glucose tolerance, and none NIDDM, over the 3-year follow-up period. As an alternative hypothesis, microalbuminuria may be a consequence of insulin resistance, a possibility suggested by the more frequent development of microalbuminuria in NIDDM subjects with increased insulin resistance.44 It should be pointed out, however, that antecedence does not necessarily imply causation, as can be seen from the contrasting sequences in these two quoted studies,20 44 in which microalbuminuria and insulin resistance were investigated.
We have found relationships of microalbuminuria with elevated concentrations of insulin, measured with a specific assay, and of proinsulin-like molecules, but all of the relationships of microalbuminuria with hyperinsulinemia were largely explained by the confounding effects of age, obesity, and glycemia. There was, however, a significant relationship of microalbuminuria at screening with elevated concentrations of des-31,32-proinsulin. No relationships were seen with concentrations of triglyceride, HDL cholesterol, or PAI-1 activity, features of the insulin resistance syndrome. Moreover, in longitudinal studies, microalbuminuric subjects did not develop hyperglycemia, hyperinsulinemia, or dislipidemia, except that persistently microalbuminuric subjects showed a small increase in triglyceride concentration over 3 years compared with persistently normoalbuminuric subjects.
When analyzed as relationships between changes in variables over the 3-year period, the only significant association was an increase in HDL cholesterol concentration in subjects with increasing AER, in contrast to the decrease predicted by the insulin resistance hypothesis.
These observations challenge the theory that the increased cardiovascular risk in nondiabetic subjects with microalbuminuria is mediated by the cardiovascular risk factors that together compose the insulin resistance syndrome45 : hypertriglyceridemia, low concentrations of HDL cholesterol, hypertension, and high PAI-1 activity.46 Elevated concentrations of des-31,32-proinsulin may be a sensitive indicator of pancreatic dysfunction47 and have been described in adults who were of low birth weight,48 an association perhaps explained by the common antecedent of protein malnutrition in utero during pancreatic development.49 We previously described an association between microalbuminuria in nondiabetic subjects and short stature,30 suggesting that the relationship between microalbuminuria, cardiovascular risk, and perhaps even diabetes might be the consequence of intrauterine growth retardation as a common antecedent. It should be noted, however, that in the subjects we studied, the concentrations of proinsulin-like molecules as a proportion of all insulin-like molecules were not elevated. Phillips and colleagues50 suggested that elevated concentrations of proinsulin-like molecules, as opposed to an increased proinsulin-to-insulin ratio, may be more closely linked with insulin resistance than with ß-cell dysfunction.
Our study differs in several respects from earlier studies in which hyperinsulinemia was demonstrated to coexist with microalbuminuria. First, we not only defined subjects on the basis of two timed urine collections (in contrast to other studies that may have used only a single untimed sample19 41 ) but also reinvestigated all subjects after a 3-year interval and repeated the paired urine collections. Furthermore, we used, for the first time, a specific assay for insulin that does not cross-react with proinsulin-like molecules,51 concentrations of which we have found to be elevated in microalbuminuric subjects. Nosadini's group18 29 52 suggested that in insulin resistant states, NIDDM, and essential hypertension, microalbuminuria clusters with insulin resistance and elevated rates of SLC. It is possible that in less insulin resistant subject groups, these associations are less pronounced. It is clear, however, that the presence or absence of insulin resistance in nondiabetic subjects cannot be defined on the basis of fasting insulin concentrations, and the investigation of microalbuminuric subjects by the euglycemic hyperinsulinemic clamp remains to be published.
We found no difference in erythrocyte SLC rate between normoalbuminuric and microalbuminuric subjects, whichever categorization was used to define microalbuminuria. We also found no relationship between rate of SLC and geometric mean AER at either screening or recall. Associations of SLC with nephropathy have been described in several studies in subjects with IDDM,24 25 26 although in NIDDM subjects these observations are less consistent.18 53 It is possible that elevated rates of SLC are associated more strongly with progression of microalbuminuria to clinical nephropathy than with microalbuminuria per se, although such a hypothesis would argue against any role of elevated SLC underlying the extra cardiovascular risk, which is shared by microalbuminuric and clinically proteinuric subjects.54 Alternatively, it has been proposed that abnormalities of SLC associated with diabetic nephropathy may be the consequence of alternations in affinity constant, rather than maximal velocity, of the transporter,55 which might not be detected by the method of Canessa et al23 that we used. In our study, we found no relationship between rates of SLC and any of the features of the insulin resistance syndrome, in contrast to previous studies in hypertensive and diabetic subjects.18 26 28 29
In conclusion, our longitudinal study has demonstrated that individuals with microalbuminuria have increased levels of proinsulin, des-31,32-proinsulin, and insulin, which may in part be dependent on age and obesity as confounding variables. Ratios of proinsulin to insulin are similar between microalbuminuric and normoalbuminuric subjects. However, we found no evidence to suggest that microalbuminuria in nondiabetic subjects is associated with elevated rates of SLC or abnormalities in cardiovascular risk factors, which are considered to be components of the insulin resistance syndrome. In our longitudinal study, nondiabetic microalbuminuric subjects did not develop glucose intolerance or features of the insulin resistance syndrome. The association of microalbuminuria with elevated concentrations of insulin-like molecules, a likely surrogate for insulin resistance, may represent cause, consequence, or association through a common antecedent. However, we have been unable to determine any sequential changes in the measured variables in these subjects over 3 years.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We would like to thank the Wellcome Trust for support for the screening phase and the British Heart Foundation for funding the recall phase of this study. We are also grateful to Diabetes and Related Diseases Research (DRDR) and to the Mrs Joan Oliver Bequest and Mrs Sue Hammerson Trust for additional funding and support for aspects of the study.
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Footnotes |
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Reprint requests to Prof John S. Yudkin, Department of Medicine, University College London Medical School, Whittington Hospital, `G' Block, Archway Wing, Archway Rd, London N19 3UA, England.
Received February 19, 1995; accepted June 16, 1995.
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References |
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