Showing papers by "St Bartholomew's Hospital published in 1991"

Inhibition of Neointimal Smooth Muscle Accumulation After Angioplasty by an Antibody to PDGF

Abstract: Approximately 30 to 40 percent of atherosclerotic coronary arteries treated by angioplasty or by bypass surgery occlude as a result of restenosis. This restenosis is due principally to the accumulation of neointimal smooth muscle cells, which is also a prominent feature of the advanced lesions of atherosclerosis. The factors responsible for the accumulation of intimal smooth muscle cells have not been identified. Platelet-derived growth factor (PDGF) is a potent smooth muscle chemoattractant and mitogen. It is present in platelets and can be formed by endothelium, smooth muscle, and monocyte-derived macrophages. The development of an intimal lesion in the carotid artery of athymic nude rats induced by intraarterial balloon catheter deendothelialization was inhibited by a polyclonal antibody to PDGF. These data demonstrate that endogenous PDGF is involved in the accumulation of neointimal smooth muscle cells associated with balloon injury and may be involved in restenosis after angioplasty, and perhaps in atherogenesis as well.

Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid

Abstract: The fundus of the guinea-pig stomach actively dilates in response to low increases in intragastric pressure. This physiological response, now called adaptive relaxation, accommodates the intake of liquid or food. It is independent of external innervation, resistant to ganglion blockade, but reflex in origin. The nerves involved are neither adrenergic nor cholinergic in nature. Non-adrenergic, non-cholinergic (NANC) nerves have now been recognized in many parts of the gastrointestinal tract and have recently been linked with release of nitric oxide (NO) on electrical stimulation. Here we show that adaptive relaxation in isolated stomach of the guinea pig is mediated by a NANC neurotransmitter substance indistinguishable from NO derived from L-arginine. This is substantiated by inhibition of adaptive relaxation by NG-monomethyl-L-arginine or N omega-nitro-L-arginine methyl ester, both inhibitors of NO synthesis, and by methylene blue, an inhibitor of soluble guanylate cyclase. There are two distinct neuronal pathways signalling NO-dependent adaptive relaxation, as evidenced by tetrodotoxin sensitivity. The first is a local reflex arc, the afferent fibres of which sense changes in intragastric pressure. The second is stimulated by an agonist for ganglionic nicotinic receptors. Thus, the functional significance of NO release from NANC nerves in the stomach is to bring about adaptive relaxation through a reflex response to increases in intragastric pressure.

By how much does dietary salt reduction lower blood pressure? III--Analysis of data from trials of salt reduction.

Abstract: OBJECTIVE--To determine whether the reduction in blood pressure achieved in trials of dietary salt reduction is quantitatively consistent with estimates derived from blood pressure and sodium intake in different populations, and, if so, to estimate the impact of reducing dietary salt on mortality from stroke and ischaemic heart disease. DESIGN--Analysis of the results of 68 crossover trials and 10 randomised controlled trials of dietary salt reduction. MAIN OUTCOME MEASURE--Comparison of observed reductions in systolic blood pressure for each trial with predicted values calculated from between population analysis. RESULTS--In the 45 trials in which salt reduction lasted four weeks or less the observed reductions in blood pressure were less than those predicted, with the difference between observed and predicted reductions being greatest in the trials of shortest duration. In the 33 trials lasting five weeks or longer the predicted reductions in individual trials closely matched a wide range of observed reductions. This applied for all age groups and for people with both high and normal levels of blood pressure. In people aged 50-59 years a reduction in daily sodium intake of 50 mmol (about 3 g of salt), attainable by moderate dietary salt reduction would, after a few weeks, lower systolic blood pressure by an average of 5 mm Hg, and by 7 mm Hg in those with high blood pressure (170 mm Hg); diastolic blood pressure would be lowered by about half as much. It is estimated that such a reduction in salt intake by a whole Western population would reduce the incidence of stroke by 22% and of ischaemic heart disease by 16% [corrected]. CONCLUSIONS--The results from the trials support the estimates from the observational data in the accompanying two papers. The effect of universal moderate dietary salt reduction on mortality from stroke and ischaemic heart disease would be substantial--larger, indeed, than could be achieved by fully implementing recommended policy for treating high blood pressure with drugs. However, reduction also in the amount of salt added to processed foods would lower blood pressure by at least twice as much and prevent some 75,000 [corrected] deaths a year in Britain as well as much disability.

Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease.

Abstract: Serum tumour necrosis factor alpha (TNF alpha) concentrations were measured by enzyme linked immunoadsorbent assay in 31 normal children and during 65 episodes of clinical remission and 54 episodes of relapse in 92 children with chronic inflammatory bowel disease. An appreciable rise in TNF alpha was found only in children in relapse of ulcerative colitis and colonic Crohn's disease. The group of children with small bowel Crohn's disease in relapse did not show increases of TNF alpha above control concentrations, despite an equivalent rise in disease indices. Height velocity was depressed in children with relapse of large bowel Crohn's disease and ulcerative colitis compared with the equivalent condition in remission. The impairment of growth velocity was significantly greater in relapse of large bowel Crohn's disease and ulcerative colitis than in small bowel Crohn's disease alone, although for the subgroups in stage 1 puberty (prepubertal) the differences were not significant. Inadequate growth in chronic inflammatory bowel disease is currently ascribed to inadequate nutrition and TNF alpha may contribute to this through its cachexia inducing effects. It may, in addition, diminish pituitary growth hormone release. These results suggest that production of TNF alpha may be associated with growth failure in relapse of colonic inflammatory bowel disease.

Decreases in regional cerebral blood-flow with normal aging

Abstract: Positron emission tomographic (PET) images of regional cerebral blood flow (rCBF) from 30 normal, resting volunteers aged 30 to 85 years were analysed to identify areas where rCBF fell with age. Images were anatomically normalised, and a pixel-by-pixel linear regression was performed to remove differences in global CBF between subjects. Pixels at which rCBF then showed a significant (p less than 0.01) negative correlation with age were identified. They were displayed as a statistical parametric map (SPM) of correlations. We demonstrate an age-related decrease in adjusted rCBF in the cingulate, parahippocampal, superior temporal, medial frontal, and posterior parietal cortices bilaterally, and in the left insular and left posterior prefrontal cortices (omnibus significance, chi 2 = 2,291, p less than 0.0001, df = 1). Decreases in rCBF suggest a regionally specific loss of cerebral function with age. The affected areas were all limbic, or association, cortices. Therefore, these decreases may constitute the cerebral substrate of the cognitive changes that occur during normal aging.

By how much does dietary salt reduction lower blood pressure? II--Analysis of observational data within populations.

Abstract: OBJECTIVE--To determine whether the estimates of the size of the association between blood pressure and sodium intake derived from studies of individuals within populations can be quantitatively reconciled with our estimates derived from comparisons of the average blood pressure and sodium intake between different populations. DESIGN--Examination of data from 14 published studies that correlated blood pressure recordings in individuals against measurements of their 24 hour sodium intake (within population studies). MAIN OUTCOME MEASURE--Comparison of observed differences in blood pressure per 100 mmol/24 h difference in sodium intake in each within population study with predicted differences calculated from the between population data, after allowing for the underestimation of the true association of blood pressure with sodium intake caused by the large day to day variation in 24 hour sodium intake within individuals. RESULTS--The underestimation bias inherent in the within populations studies reduced the regression slope of blood pressure on single measures of 24 hour sodium intake to between a half and a quarter of the true value (for example, in one study from 6.0 to 2.4 mm Hg/100 mmol/24 h). Estimates from between population comparisons of the regression slope of blood pressure on sodium intake, after adjustment to take this underestimation bias into account, were similar to the values actually observed in the within population studies. CONCLUSION--The within population studies confirm our estimates from between population comparisons of the magnitude of the association between blood pressure and sodium intake.

D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1.

Abstract: Approximately 15 to 20% of primary breast cancers and an even higher proportion of squamous cell carcinomas of the head and neck show amplification of DNA markers on band q13 of human chromosome 11. However, known genes within the amplified region, such as the FGF-related oncogenes INT-2 and HST-1, are very rarely expressed in these tumors. Here we show that another candidate oncogene, designated D11S287, implicated in the pathogenesis of parathyroid adenomas, is also amplified in breast cancers. Significantly, it is consistently coamplified with INT-2 and HST-1 in 36 out of 202 primary tumors, including one case in which the amplified unit did not encompass the translocation breakpoint marker BCL-1. This implies that D11S287 is on the same side of the breakpoint as INT-2, and pulsed-field gel electrophoresis indicates that D11S287 is less than 250 kb from the BCL-1 marker. Since D11S287 RNA was present at elevated levels in a group of tumors and cell lines in which the 11q13 region is amplified, it may be the key oncogene on this amplified unit, and could also be activated by BCL-1 translocations.

Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome.

Abstract: Summary. objective To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushing's syndrome. design An evaluation of the standard clinical practice at one institution. patients Ninety-one patients with Cushing's syndrome: 57 pituitary-dependent Cushing's disease, 10 adrenocortical adenomas, six adrenocortical carcinomas and 18 ectopic ACTH syndrome. measurements The acute response to metyrapone was assessed by measuring cortisol, 11-desoxycortisol and ACTH at 0, 1, 2, 3, 4 hours after a test dose of 750 mg of metyrapone. The longer-term effect of metyrapone was judged by measuring serum cortisol at 0900, 1200, 1500, 1800, 2100 and sometimes 2400 h and calculating a mean. results A test dose of 750 mg of metyrapone decreased serum cortisol levels within 2 hours In all groups of patients and this effect was sustained at 4 hours. At the same time, serum 11-desoxycortisol levels Increased in all patients, while plasma ACTH Increased In patients with pituitary Cushing's disease and the ectopic ACTH-syndrome. Fifty-three patients with Cushing's disease were followed on short-term metyrapone therapy (1 to 16 weeks) before other more definitive therapy. Their mean cortisol levels (median 654 nmol/l, range 408–2240) dropped to the target range of < 400 nmol/l in 40 patients (75%) on a median metyrapone dose of 2250 mg/day (range 750–6000). Metyrapone was given long term In 24 patients with Cushing's disease who had been given pituitary Irradiation, for a median of 27 months (range 3–140) with adequate control of hypercortisolaemia in 20 (83%). In 10 patients with adrenocortical adenomas and six with adrenocortical carcinomas, metyrapone in a median dose of 1750 mg/day (range 750–6000) reduced their mean cortisol levels (median 847 nmol/l, range 408–2000) to < 400 nmol/l in 13 patients (81%). In 18 patients with the ectopic ACTH-syndrome the ‘mean cortisol levels', obtained from five or six samples on the test day (median 1023 nmol/l, range 823–6354) were reduced to < 400 nmol/l In 13 patients (70%), on a median dose of 4000 mg/day (range 1000–6000). Reduction of cortisol levels was clearly associated with clinical and biochemical Improvement. The medication was well tolerated. Transient hypoadrenalism and hirsutism were unusual but were the most common side-effects. conclusions In our experience metyrapone remains a most useful agent for controlling cortisol levels in the management of Cushing's syndrome of all types.

Inhibitory effects of urine on the polymerase chain reaction for cytomegalovirus DNA.

Abstract: The inhibitory effects of urine samples taken from neonates and older children, some of which were known to be infected with cytomegalovirus, on the polymerase chain reaction (PCR) were investigated. Urea was the major inhibitory component of urine and inhibited the PCR at a concentration of more than 50 mM. Urine samples from older children were more inhibitory than those from neonates. This correlated with the higher concentration of urea generally found in urine samples from older children compared with neonatal urines. Two of 13 neonatal urine samples, however, were inhibitory despite low urea concentrations--presumably due to metabolites derived from parenteral nutrition. The inhibitory effects of urine were effectively removed by simple dialysis or ultrafiltration. The sensitivity and specificity of PCR for detecting cytomegalovirus DNA in urine were further improved by using "nested" primers and a modified PCR protocol entailing the use of reduced reactants in the first 20 cycles of a two-stage 50 cycle PCR.

Strategies for prevention of osteoporosis and hip fracture.

Abstract: In England in 1985, 37600 people aged 65 years and over fractured a hip.' On average 3170 acute hospital beds a day were committed to people over 65 with hip fracture-nearly a quarter of all orthopaedic beds. Table I shows the age and sex distribution of patients with hip fracture. In all, 82% of those aged 65 and over were women, ofwhom 83% were aged 75 and over. On the basis of the present incidence (table II) almost one women in four living to the age of 90 in England can expect to have a hip fracture. Age specific rates

The assessment of visuo-spatial neglect after acute stroke.

Abstract: Forty four consecutive patients with acute hemispheric stroke and forty seven elderly controls with no neurological disease were assessed for visuo-spatial neglect, using a modified neglect test battery. Neglect was found to be equally common in patients with right hemisphere and left hemisphere stroke three days after stroke (72% versus 62%). It was more severe in those with a right hemisphere stroke and resolved more frequently in those with a left hemisphere stroke. The battery was validated against an occupational therapist9s assessment of neglect on self-care tasks. The inter-observer reliability was good and it was possible to monitor changes over time with the battery.

The induction of a specific protease for insulin-like growth factor binding protein-3 in the circulation during severe illness.

Abstract: The insulin-like growth factors (IGF-I and IGF-II) are almost completely bound in the circulation to specific binding proteins (IGFBPs). These IGFBPs appear to play a pivotal role in maintaining circulating levels and modulating the delivery of the IGFs to the tissues. A large proportion of the circulating IGFs are bound with high affinity to one of the binding proteins. IGFBP-3. The mechanism by which these IGFs are transferred from the circulatory pool to the tissue receptors is at present unclear. Recent studies in late pregnancy have demonstrated the presence of specific proteases which may modify the IGFBPs such that their affinities for the IGFs are reduced. In this paper, we have demonstrated the presence of a heat-sensitive cation-dependent proteolytic enzyme specific for IGFBP-3 in the serum of five severely ill patients. The activity of this protease was found to vary in these patients, becoming more apparent during fasting than when studied after commencement of parenteral nutrition, indicating that one of the influencing factors in the activity of this protease is the nutritional intake of the patient. Age- and sex-matched healthy adults were also studied in a similar protocol, but no proteolytic modification of any of the IGFBPs was found in any of the samples examined. As the levels of both IGF-I and IGF-II were found to be low in the patients, the presence of a circulatory protease suggests that this may be an adaptive response to increase the bioavailability of the IGFs and possibly to improve the nitrogen retention and counter the catabolic state in severe illness.

Social networks, health, and emotional well-being among the oldest old in London.

Abstract: A survey of the health and social circumstances of 662 people aged 85 and over, living at home in inner London, was conducted in 1987. A primary aim was to analyze the structure of social support networks of the sample in relation to respondents' emotional well-being and met and unmet needs for practical help. The conceptual and methodological framework that was applied to the study was derived from the theory of social networks. In confirmation of the common assumption that people aged 85+ are different from younger elderly people, as they are the "survivors," high levels of social support and informal help were given to most respondents. Although associations were found between social network variables and the provision of informal help, multifactorial analysis showed that health status explained more of the variation in emotional well-being.

Importance of maternal history of non-insulin dependent diabetic patients.

Abstract: OBJECTIVE--To assess the family history of diabetes in non-insulin dependent diabetes mellitus with particular emphasis on parental phenotype. DESIGN--Family histories were obtained from an existing computerised database and supplemented by postal questionnaires. SETTING--Diabetic service of a provincial teaching hospital. SUBJECTS--A total of 1326 patients with non-insulin dependent diabetes who had been referred to diabetic clinics over the past 10 years and from whom data had been collected for inclusion in the database, of whom 347 had affected first degree relatives. Nineteen non-white patients were excluded because of the differential hereditability of the disease, and 230 (70%) patients with an affected first degree relative responded to the postal questionnaire. RESULTS--Mothers were implicated in significantly more cases than fathers in patients with a single affected parent: 125 mothers and 48 fathers from database; 82 mothers and 34 fathers from postal questionnaire; p less than 0.001 in both cases. CONCLUSIONS--Maternal influences seem to have an important role in the inheritance of non-insulin dependent diabetes.

A family of clostridial and streptococcal ligand‐binding proteins with conserved C‐terminal repeat sequences

Abstract: Analysis of the derived amino acid sequences of toxins A and B from Clostridium difficile has identified an extraordinarily large number of repeat amino acid units in the C-terminal regions of the proteins. Nearly one third of each of the proteins consist of repeating units which appear, at least in the case of toxin A, to be responsible for carbohydrate binding. Similar repeat units are also found in the C-terminal region of four glucosyltransferases from Streptococcus mutans and Streptococcus downei, and in four lytic enzymes from Streptococcus pneumoniae and its bacteriophages (HB-3, Cp-1 and Cp-9). In each case the repeats constitute the ligand-binding portion of the respective enzymes. A glucan-binding protein from S. mutans, which lacks enzymatic activity, has similar repeats spanning almost the entire molecule. This family of ligand-binding proteins appears to be of modular design, with one module consisting of a repetitive ligand-binding domain located in the C-terminal region and the other module(s) providing enzymatic functions.

The concentration of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in human umbilical cord serum at delivery: relation to fetal weight.

Abstract: Serum levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-1 (IGFBP-1) have been determined by radioimmunoassay in the maternal circulation (n = 91) and in the umbilical artery (n = 56) and vein (n = 90) of man. In both the umbilical artery and vein, the concentration of serum IGF-I showed an inverse correlation with birthweight (P less than 0.005 and P less than 0.001 respectively); the mean serum IGF-I levels in the small-for-gestational-age (SGA) group were significantly higher than those in average-for-gestational-age (AGA) neonates (P less than 0.01 and P less than 0.001 respectively). However, maternal serum IGF-I showed no association with birthweight and there was no significant difference between the SGA and AGA groups. These observations imply that the production of IGF-I in the maternal and fetal compartments is independent and that there is unlikely to be transfer of IGF-I across the placenta. Serum IGFBP-1 levels in both maternal and umbilical cord blood (artery and vein) showed an inverse relation to birthweight (P less than 0.001, P less than 0.005 and P less than 0.001 respectively). Increased IGFBP-1 levels in the umbilical artery and vein were observed in the SGA group. These findings suggest that IGFBP-1 might inhibit the action of IGF-I in both the maternal and the fetal compartments and that the rise in IGFBP-1 could be a primary factor in retardation of fetal growth. Alternatively, circulating IGF-I and IGFBP-1 levels may only be a secondary reflection of local tissue events involved in fetal growth.

The significance of circulating cells carrying t(14;18) in long remission from follicular lymphoma.

Abstract: Peripheral blood mononuclear cell fractions from 15 patients in continuous clinical remission from follicular lymphoma for longer than 10 years were examined for cells carrying the t(14;18) translocation using the polymerase chain reaction (PCR). The assay used was able to detect one positive cell in approximately 5 x 10(5) cells (a single 14q+ molecule in 2.5 micrograms DNA). Cells positive for t(14;18) were found in six of eight patients initially presenting with stage III or IV disease, compared with zero of seven of those with stage I or II disease (P less than .05). In two cases 14q+ junction regions were also successfully amplified from formalin-fixed biopsy material obtained at presentation 12 and 17 years previously. In both, sequence analysis demonstrated that the cells circulating in remission belonged to the original clone. These results indicate that cells bearing t(14;18) frequently persist in the peripheral blood in long remission of advanced follicular lymphoma and question the value of the...

The diagnosis and differential diagnosis of Cushing's syndrome.

Abstract: Cushing's syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.

Reoxygenation-dependent decrease in mitochondrial NADH:CoQ reductase (complex I) activity in the hypoxic/reoxygenated rat heart

Abstract: Reoxygenation of the hypoxic myocardium results in a number of processes, including an O2-dependent increase in total tissue Ca2+ and cell lysis in which mitochondrial electron transport plays a key role. In the present study we have isolated mitochondria from perfused rat hearts subjected to hypoxia and found no change in their respiratory function relative to controls. In contrast, mitochondria isolated immediately after reoxygenation of hypoxic-perfused hearts exhibited a specific and significant decrease in NADH:CoQ reductase (Complex I; EC 1.6.5.3) activity, as measured both polarographically and spectrophotometrically. Isolated cardiomyocytes subjected to a similar protocol of hypoxia/reoxygenation also exhibited a specific decrease in Complex I activity. Myocardial perfusion with media containing Ruthenium Red protected against the reoxygenation-dependent loss of Complex I activity. These observations taken together suggest that mitochondrial Ca2+ uptake on reoxygenation is implicated in the mechanism of the specific loss of Complex I activity.

The composition of body tissues. (II) Fetus to young adult

Abstract: The composition of body tissues is a function of the age, nutrition, state of health and physical activity of the individual. In this paper, the effects of age on the composition of healthy tissues are reviewed. Eleven soft tissues (adipose tissue, blood--whole, brain--whole, heart, kidney, liver, lung, muscle--skeletal, placenta, skin and spleen) and cortical bone are considered. Elemental compositions, mass and electron densities are tabulated for the tissues, as a function of age, from fetus to young adult. Although the compositions given here are predominantly for healthy tissues, reported changes because of dietary influences are briefly discussed.

Simplified procedures for applying the polymerase chain reaction to routinely fixed paraffin wax sections.

Abstract: The polymerase chain reaction was applied to the analysis of DNA contained in archival paraffin wax embedded material. DNA suitable for the reaction was obtained from these tissues by simple extraction methods, without previous dewaxing of tissue sections. When compared with unfixed material, the reaction efficiency was compromised, so that an increased number of amplification cycles were required to produce equivalent amounts of amplified product. This in turn led to an increase in amplification artefacts, which can be minimised by a simple modification of the standard reaction. Amplification of relatively large DNA fragments was not always successful, and it seems prudent to bear this in mind when designing oligonucleotide primers which are to be used for the amplification of archival material. The efficiency of the procedure can be improved by dividing the amplification cycles into two parts: this reduces the amount of reagent needed, is relatively simple and inexpensive, and can be performed in one working day.

Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies.

Abstract: Data were analyzed from 33 prospective studies to assess the evidence for a long-term association of low serum cholesterol with cancer. In subjects with cancer diagnosed within two years of the cholesterol measurement or causing death within five years (n=4,661), the level of serum cholesterol was on average lower than in controls by 0.18 (SE=0.02) mmol/l in men and 0.11 (SE=0.04) mmol/l in women; this effect can be attributed to preclinical cancer. For cancers presenting after these intervals (n=22,030), the average differences were smaller but statistically significant (0.04 [SE=0.01] mmol/1 [P<0.001] in men, and 0.03 [SE=0.01] mmol/1 [P=0.005] in women), equivalent to about a 15 percent increase in cancer incidence in the lowest cholesterol quintile. This cannot be attributed entirely to preclinical cancer. In men, there was significant (P=0.01) heterogeneity between studies as to the extent of a long-term association. The heterogeneity could be substantially explained by socioeconomic status, the association being pronounced in studies of manual workers but absent in studies of professional men. The overall long-term association was attributable mainly to lung cancer in men, and partly to hemopoietic cancers (representing prolongation of survival by treatment). Colon cancer and other cancers unrelated to smoking showed no long-term association with low cholesterol. The data collectively do not justify concern that lowering serum cholesterol to reduce ischemic heart-disease risk might cause cancer. The long-term association with lung cancer is probably caused by smoking and we propose a mechanism.

The potential and limitations of meta-analysis.

Abstract: Accepted for publication October 1990 We are currently witnessing an "epidemic" of meta-analyses and overviews in the scientific literature. This is a relatively new phenomenon and this article addresses some of the important issues raised by their increasing use. In particular the differing applications and limitations of meta analysis are discussed, with a review of the analytic methods used and the problems and biases encountered.

Effect of Antecedent Glucose Control on Cerebral Function During Hypoglycemia

Abstract: Objective The incidence of both severe and asymptomatic hypoglycemia is increased threefold in intensively treated diabetic patients. To examine whether this reflects cerebral adaptation to low blood glucose levels, we investigated the effect of preceding glycemic experience on hormonal, EEG, and evoked potential responses to experimentally induced hypoglycemia with the slow-fall clamp. Research Design and Methods Three groups were examined: well-controlled diabetic patients and patients with insulinoma (group 1), poorly controlled diabetic patients (group 2), and nondiabetic subjects (group 3). Results The glucose threshold for epinephrine release was lower in group 1 (2.3 ± 0.1 vs. 3.0 ± 0.3 and 3.1 ± 0.1 mM, P P P Conclusions The glycemic threshold for hormonal responses to hypoglycemia falls in individuals with intensively treated diabetes or insulinomas, but these patients are more likely to develop EEG abnormalities during hypoglycemia. This disparity helps explain the increased vulnerability of intensively treated patients to severe hypoglycemia.