Search PubMed⌕ Search

Biomedical subjects

J R Peters

Publications and source records attributed to J R Peters.

At least 37 records · Page 2Linked to original sources
PubMed1998

Bone mineral density, collagen type 1 alpha 1 genotypes and bone turnover in premenopausal women with diabetes mellitus.

Osteopenia is a recognised complication of diabetes mellitus which could be due to abnormal bone turnover or disturbances in the calcium/parathyroid hormone/vitamin D axis or both. Genetic factors also play an important part in determining bone mass although this has not been studied in diabetes. Recently a polymorphism of the collagen type 1 alpha 1 (COL1A1) gene has been shown to be associated with low bone mass in British women. To identify subjects with diabetes who may be at risk of developing osteoporosis and fractures, we analysed bone mineral density in relation to the biochemical markers of bone turnover, calcium homeostasis and the COL1A1 genotype in a group of premenopausal women with Type I (insulin-dependent) diabetes mellitus (n = 31), Type II (non-insulin dependent) diabetes mellitus (n = 21) and control subjects (n = 20). Bone mineral density was lower at the femoral neck in the subjects with Type I diabetes (p = 0.08) as were serum 25-hydroxyvitamin D compared with control subjects (p = 0.023) and this was negatively correlated with serum collagen type 1 C-terminal propeptide (r = -0.56, p < 0.001). Bone mineral density in Type II diabetes was not different from control subjects, after correction for body mass index. Bone resorption was, however, raised in the Type II diabetic subjects as reflected by the higher urinary deoxypyridinoline values (p = 0.016) and lower collagen type 1 C-terminal propeptide:deoxypyridinoline ratio (p = 0.04). In the whole group studied, subjects with the COL1A1 's' genotype had lower bone mineral density at the femoral neck (p = 0.01) which was partly attributable to a lower body mass index. Following multiple regression analysis body mass index and collagen type 1 C-terminal propeptide concentrations remained determinants of bone mass at all three sites, whereas genotype appeared to be a predictor of bone mass at the femoral neck only. We conclude that measurement of these variables could prove useful in firstly identifying those diabetic women at risk of osteoporosis and secondly guiding therapeutic intervention.

Adult↗
PubMed1998

Electron spin resonance spectroscopic detection of oxygen-centred radicals in human serum following exhaustive exercise.

Free radicals or oxidants are continuously produced in the body as a consequence of normal energy metabolism. The concentration of free radicals, together with lipid peroxidation, increases in some tissues as a physiological response to exercise - they have also been implicated in a variety of pathologies. The biochemical measurement of free radicals has relied in the main on the indirect assay of oxidative stress by-products. This study presents the first use of electron spin resonance (ESR) spectroscopy in conjunction with the spin-trapping technique, to measure directly the production of radical species in the venous blood of healthy human volunteers pre- and post-exhaustive aerobic exercise. Evidence is also presented of increased lipid peroxidation and total antioxidant capacity post-exercise.

Adolescent↗
PubMed1998

Glutamate pathways mediate somatostatin responses to glucose in normal and diabetic rat hypothalamus.

We investigated the role of hypothalamic glutamate receptors in mediating the stimulatory effect of low glucose (< 5 mM) on somatostatin release. We also studied whether alteration in glutamate release might contribute to the reduced hypothalamic somatostatin response to low glucose observed in diabetic (Goto-Kakizaki) rat hypothalami. Hypothalamic somatostatin release in response to incubation with 1 mM D-glucose was inhibited by the ionotropic glutamate receptor antagonists MK801, D-AP5 and DNQX but not by the metabotropic antagonists L-AP3 or MCPG. The release of somatostatin was increased by the ionotropic agonists NMDA, AMPA and kainate but not by metabotropic agonists t-ACPD or L-AP4. Basal and peak glutamate release in response to incubation with 1 mM glucose, were significantly lower from GK hypothalami There were no significant differences in the basal or stimulated release of serine and GABA. These data indicate that ionotropic NMDA/AMPA/kainate receptors and not metabotropic receptors mediate the effects of glucose on rat hypothalamic somatostatin release. Reduced hypothalamic somatostatin release in response to low glucose in diabetic (Goto-Kakizaki) rats may well be secondary, at least in part, to reduced glutamate release.

Amino Acids↗
PubMed1998

The demand for hospital services for patients with epilepsy.

PURPOSE: To describe the patterns of inpatient and outpatient hospital care for patients with epilepsy in our health district. METHODS: Routine hospital data for the health district of South Glamorgan (population 408,000) underwent record linkage to identify those records relating to the same patients and to flag those records for patients with epilepsy. This data was analyzed to determine inpatient and outpatient activity by specialty and compared with the nonepileptic population. RESULTS: We identified 2.267 patients representing a prevalence of 0.56%. The average age was 46 years in both male and female patients. This group, which constituted 1.5% of the hospital population, was responsible for 2.8% of all admissions but, because of increased length of stay, utilized 7.3% of all bed days. The total cost of care for this group lies between these two extreme values and is dependent on case severity. The patterns of associated diagnoses differed considerably in three arbitrary age groups (0-18, 19-55, >55 years). CONCLUSIONS: This study quantifies for the first time the level of demand that this subpopulation places on the service as a whole, and begins to illustrate that there may be evidence for cost containment by, for example, a reduction in multiple admissions. The demand for inpatient services is greater than we would have predicted.

Adolescent↗
PubMed1998

The epidemiology and cost of inpatient care for peripheral vascular disease, infection, neuropathy, and ulceration in diabetes.

OBJECTIVE: To describe the epidemiology and costs of the acute care of peripheral vascular disease, infection, neuropathy, and ulceration in a U.K. population with special consideration of those patients with diabetes. RESEARCH DESIGN AND METHODS: Routine data describing inpatient care for a 4-year period were analyzed (financial years 1991/1992 to 1994/1995). These data had undergone record-linkage to draw together records from the same patients, and records of patients with diabetes were flagged. Cost estimates were determined by attributing a diagnosis-related group cost-weight to each record. RESULTS: A total of 4,245 admissions (1.2% of all admissions) had a primary diagnosis of peripheral vascular disease, infection, neuropathy, or ulceration, and 7,379 (2.1%) admissions had these categories recorded in any one of six diagnostic fields. These figures were generated by 3,159 and 4,751 patients, respectively. This represented a range of crude annual incidence of admission of between 1.9 and 2.9 per 1,000 people. Patients with diabetes accounted for 625 (15.4%) of primary admissions, a crude annual incidence of admission of 18.8 per 1,000. The age-standardized relative risk of admission for patients with diabetes to the nondiabetic population was 7.61 for men and 6.85 for women. The length of stay for patients with diabetes was almost twice that of the nondiabetic population (15.5 vs. 8.7 days). The relative risk of hospital mortality (diabetes vs. non-diabetes) was 2.83. Surgical procedures were carried out on 857 patients, 272 (31.2%) with diabetes. This represented an age-standardized relative risk of 31.19. The estimated cost of admissions for primary diagnoses in these categories over 4 years was 6,128,211 pounds ($9,743,855). Patients with diabetes accounted for 1,236,623 pounds ($1,966,230), an excess of 87% attributable to the diabetic state. CONCLUSIONS: Diabetes is confirmed as a significant risk factor for peripheral vascular disease, infection, neuropathy, and ulceration. The severity of these disorders in terms of increased risk of hospital mortality, length of stay, and risk of surgical procedure is also demonstrated for those patients with diabetes.

Communicable Diseases↗
PubMed1997

Estimation of unascertained diabetes prevalence: different effects on calculation of complication rates and resource utilization.

The incidence and prevalence of insulin-dependent (Type 1) diabetes mellitus (IDDM) in populations are both well defined. In the more prevalent non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), which is responsible for the bulk of diabetes-related morbidity, true prevalence is uncertain because of delayed diagnosis and problems of definition, particularly with increasing age. Estimates therefore vary widely. We have previously presented evidence of increased relative probability of hospital admission for people with diabetes. These absolute and relative rates of admission were based on a large scale community-derived prevalence for diabetes of 1.36%. Assuming that the true prevalence of diabetes is higher, recalculation of activity data in a sensitivity analysis suggests a theoretical maximum prevalence of diabetes of 5% in our population, since a higher value would imply less morbidity associated with diabetes than 'non-diabetes'. This approach identifies the possible range of unascertained diabetes in a population and defines it in functional terms as that state carrying any excess risk of admission for complications when compared to non-diabetes. Higher estimates of prevalence have little impact on the calculation of overall resource use for diabetes, since the great majority of costs are related to fixed hospital activity for people with identified diabetes. The unascertained diabetes sub-group will cost little by comparison. Paradoxically, the tendency to use higher estimates of unascertained diabetes increases the denominator for calculation of complication rates and reduces both the absolute and relative risk of complications. This dilutes the epidemiological significance of diabetes in the aetiology of its related complications.

Cerebrovascular Disorders↗
PubMed1997

Hospital utilization as a function of social deprivation: diabetes vs non-diabetes.

We tested the hypothesis that a relationship between ill health and deprivation exists for patients with diabetes, distinct from that experienced by the non-diabetic population. Age standardized admission and appointment rates and proportion of total activity for patients with and without diabetes were determined by electoral ward and correlated with the Townsend index of social deprivation for the health district of South Glamorgan (population 408,000). Both diabetic (r = 0.78, p < 0.001) and non-diabetic (r = 0.74, p < 0.001) in-patient admissions were positively correlated with social deprivation. This relationship also existed for attended out-patient appointments (r = 0.67, p < 0.001 and r = 0.45, p < 0.01, respectively). The proportion of diabetic to non-diabetic admissions by ward also showed a positive correlation for in-patients (r = 0.47, p < 0.001). This remained true for IDDM (r = 0.23, not significant) and NIDDM (r = 0.62, p < 0.001) diabetes, for admissions for coronary heart disease (r = 0.50, p < 0.001) and cerebrovascular disease (r = 0.29, p < 0.05), elective admissions (r = 0.30, p > 0.05), and emergency admissions (0.46, p < 0.001). Our results suggest that secondary care utilization is positively correlated with social deprivation and that this relationship is stronger in the diabetic population. This may be due to different prevalence rates or increased complications requiring hospital treatment in different social circumstances. Further research is required to examine these factors more closely.

Age Factors↗
PubMed1997

NHS acute sector expenditure for diabetes: the present, future, and excess in-patient cost of care.

We set out to determine the present proportion of in-patient revenue used for the care of diabetes and its related complications and to use these data to determine (1) the trend in future hospital costs for the condition and (2) the excess cost of admissions for diabetic patients over and above that expected had these patients not had diabetes, using a cross-sectional descriptive study in conjunction with a population modelling exercise in a District Health Authority with a resident population of 408 000 people. The crude proportion of admissions for people with diabetes was 7.0% of activity in financial year 1994/5 (of 115929 total in-patient and day case admissions). Patients with diabetes occupied 10.7 % of bed days and had a crude mean length of stay of 10.7 days vs 6.7 days for the non-diabetic group. The proportion of revenue used for their treatment was 8.7 %. This translated locally to 11.9 M. In year 2011 overall cost of in-patient care is predicted to increase by 9.4 %, however, the proportion of revenue used for the care of people with diabetes will increase by 15% because of age-related effects. The excess cost associated with treating diabetes is estimated to be 82% of admissions for the diabetic population, 88% of their bed days, and 86% of expenditure associated with their care. Most of this excess cost is associated with the recognised vascular complications of diabetes. We conclude that the cost of in-patient care for patients with diabetes is notably disproportionate to the population prevalence of diabetes-9 % compared to 1.36% in South Glamorgan-and will increase disproportionately with time. As much of the long-term morbidity is known to be preventable by earlier intervention, strategies should reflect the imperative to reduce the burden of diabetes.

Adolescent↗
PubMed1997

Proximal tubular reabsorption of growth hormone and sodium/fluid in normo- and microalbuminuric insulin-dependent diabetes mellitus.

Proximal tubular dysfunction may be implicated in the pathogenesis of diabetic nephropathy. An investigation of proximal tubular function was carried out by assessing proximal tubular sodium-reabsorption and low molecular weight protein excretion in a group of patients with type 1 diabetes mellitus. Normoalbuminuric [group A, n = 6, albumin excretion rate (AER) mean (range) 4 (0-10) micrograms/min], and microalbuminuric [group B, n = 6, AER 88 (35-198) micrograms/min] patients with type 1 diabetes were compared with matched controls. Simultaneous lithium and growth hormone (GH) clearance and urinary beta 2-microglobulin excretion were assessed. Fasting plasma glucose at the start of the study was [median (range)] 13 (10.2-15.1), 9.3 (5.9-15) and 4.1 (4.0-5.0) mmol/l in groups A, B and controls, respectively, with a mean coefficient of variation during the study of 3.9% (group A) and 5.2% (group B). There was no significant difference in plasma glucose levels between patients in groups A and B. Urinary GH excretion was raised in the patients with microalbuminuria (group B; P < 0.05), although there was no difference in serum GH clearance rate between the patient groups and controls. Urinary GH correlated with B 2-microglobulin in the diabetic subjects (r = 0.665, P < 0.05) and with the degree of microalbuminuria in group B patients (r = 1, P < 0.01). Urinary GH was also greater than 10 microU, the median value observed in the controls, in 5 of 6 (83%) patients in group A. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) measured by constant infusion of 51Cr-ethylene diamine tetra-acetic acid (EDTA) and I125-para-amino hippuric acid (PAH), respectively, showed relative hyperfiltration in the normoalbumiruric group compared with controls (P < 0.05) and group B (P < 0.05). Absolute proximal reabsorption of sodium and of water (APRNa and APRH2O) was significantly higher in group A patients (P < 0.05). Although GFR was significantly higher in group A patients, no differences were found in fractional proximal reabsorption of sodium and water (FPRNa+H2O) or end proximal delivery between the patient groups and controls. Therefore, the measurement of protein reabsorptive capacity provides a more sensitive marker of renal tubular impairment in type 1 diabetes than sodium/fluid reabsorptive capacity. In patients with microalbuminuria, both glomerular and tubular damage may coexist. Our results stress the usefulness of markers of renal tubular function in monitoring the course of diabetic nephropathy. This study also shows that assessment of GH clearance has promise as a marker of renal tubular protein reabsorptive capacity.

Absorption↗
PubMed1997

Patterns and costs of hospital care for coronary heart disease related and not related to diabetes.

OBJECTIVE: To describe the epidemiology and costs of coronary heart disease (CHD) requiring hospital admission, with particular reference to diabetes. SETTING: The former South Glamorgan Health Authority, South Wales. METHODS: Routine hospital activity data were record linked and all diabetic and non-diabetic individuals over a four year period (1991-95) were identified. A cost weight was included for each admission based on diagnosis related groups. RESULTS: There were 10,214 patients admitted with a primary diagnostic code for CHD, representing an incidence of 6.3 per 1000 per annum. Including all CHD and non-CHD admissions, these individuals were responsible for 17% of acute inpatient activity. Men had a consistently higher age specific prevalence of CHD than women. The age adjusted relative risk of CHD for patients with diabetes compared with those without was 4.1 for men and 5.5 for women. Patients with diabetes accounted for 16.9% of CHD related admissions and had a fourfold increased probability of undergoing a cardiac procedure. The total cost of CHD was estimated to be 6% of NHS revenue at 1994-95 pay and prices. Patients with diabetes were responsible for 16% of this expenditure. This translated to an estimated NHS acute hospital expenditure for CHD of 1.1 billion pounds per year at 1994-95 pay and prices. CONCLUSIONS: CHD was responsible for a larger proportion of NHS expenditure than had previously been reported. Nearly one in five acute hospital admissions were for patients whose condition included cardiac problems. The relation between diabetes and CHD was particularly evident, and may offer opportunities for disease prevention.

Acute Disease↗
PubMed1997

Epidemiology and costs of acute hospital care for cerebrovascular disease in diabetic and nondiabetic populations.

BACKGROUND AND PURPOSE: Little is known about the pattern of cerebrovascular disease (CVD) for diabetic and nondiabetic patients or about the cost of treatment for CVD in the United Kingdom. The purpose of this study was to extend previous work to describe the epidemiology and cost of acute care of CVD as a frequent comorbidity of diabetes in a UK population (408 000 people). METHODS: Routine data describing inpatient care for a 4-year period were analyzed (financial years 1991/1992 to 1994/1995). These data had undergone record linkage to draw together records from the same patients. Cost estimates were determined by attributing a diagnosis-related group cost weight to each record. Mortality data from an overlapping period were supplied by the Office of Population Censuses and Surveys. RESULTS: There were 11 196 CVD admissions (3.1% of all admissions). Of these, 7351 (66%) were primary diagnoses. These admissions were generated by 5358 patients (3904 primary diagnosis). For people with diabetes, the incidence rate was between 23 and 32.8 per 1000 per year compared with 2.4 to 3.3 per 1000 for the population as a whole, depending on the use of primary and subsidiary codes. The age-adjusted relative risk of stroke in diabetic men versus nondiabetic men was 3.70 (95% confidence interval, 3.53 to 3.88) and in women was 4.35 (95% confidence interval, 4.37 to 4.76). We describe other epidemiological relationships. The cost of CVD is between pounds 1.1 and pounds 1.6 million per 100 000 population-at least pounds 0.7 million per 100 000 for CVD alone. Approximately 15% of this value is related to diabetes, and an estimated 94% of this diabetes-related expenditure is potentially avoidable. CONCLUSIONS: CVD represents a major source of expenditure for health services, and diabetes is confirmed as a major risk factor within this disease group. Differences between diabetic and nondiabetic inpatient patterns of CVD may reflect greater incidence of comorbidities in the former.

Acute Disease↗
PubMed1996

Patterns of in and out-patient activity for diabetes: a district survey.

The objective was to describe, by means of a retrospective study of three years' routine District information (financial years 1991/92 to 1993/94), the in- and out-patient activity for patients with diabetes, and compare this with the non-diabetic population. The clinical resource usage by patients with diabetes relative to those without was estimated by (a) their relative probability of admission by specialty, (b) attendance rates at out-patient clinics, (c) primary diagnosis, and (d) operations and procedures. The setting was a District Health Authority with a population of 408 000. All in-patient and out-patient records were reclassified as attributable to a patient with or without diabetes by cross-referral to routine records of patients with identified diabetes from separate hospital databases. The main outcome measures were: (a) relative frequency, and crude and age-specific relative probability of admission by specialty, ICD9 primary diagnosis, and OPCS4 primary operation and procedure, and (b) out-patient attendance rates by specialty. Patients with diabetes were responsible for 5.5% of admissions and 6.4% of out-patient attendances. However, because of increased length of stay, patients with diabetes occupy 9.4% of bed days. The relative risk of admission for diabetes related complications was: coronary heart disease 11.8 (95% CI = 11.4-12.3), cerebrovascular disease 11.8 (10.8-12.8), neuropathy and peripheral vascular disease 15.6 (13.6-17.9), eye complications 10.4 (9.3-11.7), and renal disease 14.7 (12.6-17.3). Recognised diabetes related vascular (9.3-11.7), and renal disease 14.7 (12.6-17.3). Recognised diabetes related vascular complications accounted for at least 23% of admissions of patients with diabetes. The relative risk of admission for diagnoses and procedures not known to be related to diabetes were similar for non-diabetic and diabetic patients. The pattern of out-patient activity mirrored that of the relative probability of admission. It is concluded that previous estimates of the proportion of NHS resources used for the treatment of patients with diabetes had been significantly underestimated. Patients with diabetes were found to occupy 1 in 10 non-obstetric, non-psychiatric beds. Many of these admissions were for diagnoses and procedures that are known to be related to diabetes.

Age Factors↗
PubMed1996

Desensitisation of somatostatin, TRH and GHRH responses to glucose in the diabetic (Goto-Kakizaki) rat hypothalamus.

We have studied the effects of glucose on the release of somatostatin (SS), TRH and GHRH from incubated hypothalami of normal and genetically diabetic, Goto-Kakizaki (GK) rats. The active isomer D-glucose caused a dose-related inhibition of SS, TRH and GHRH from normal rat hypothalami over a 20-min incubation period in vitro. In contrast, in GK rats the effects of glucose on TRH and SS were significantly reduced and the effects on GHRH were abolished. These data indicate that the sensitivity of SS-, TRH- and GHRH-producing hypothalamic neurones is reduced in diabetic rats. The effect is most pronounced for GHRH release as there was no change in the release of this peptide with increasing glucose concentrations. In conclusion, it appears that the diabetic state in GK rats causes differential desensitisation (GHRH > TRH and SS) of neuronal responses to subsequent changes in glucose concentrations in vitro. This may be due to alterations in the neurotransmitter control and/or a reduction in number, affinity or function of glucose transporters on these peptidergic neurones or other intermediary neuronal pathways.

Animals↗
PubMed1995

Effects of cholinergic modulation on serum insulin-like growth factor-I and its binding proteins in normal and diabetic subjects.

OBJECTIVE: We wished to study alterations in serum insulin-like growth factor-I (IGF-I) and its binding proteins in subjects with insulin dependent diabetes mellitus (IDDM) and possible relations with metabolic and GH secretory status, before and after cholinergic modulation. In addition, we have investigated whether cholinergic modulation exerts any effects on IGF-I secretion, independently of any actions on GH secretory status. DESIGN: All subjects received GH releasing hormone (GHRH) 1-44; 80 micrograms i.v.) alone and 60 minutes following 120 mg of pyridostigmine orally or 200 mg of pierenzepine orally. The three tests were carried out in random order at least one week apart. Blood was sampled at 15-minute intervals over 120 minutes. PATIENTS: Twelve male subjects with IDDM and no clinical evidence of complications were selected on the basis of HbA1 levels to provide a wide range of metabolic control. Six normal male subjects were also studied. MEASUREMENTS: Serum IGF-I, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were measured at regular intervals throughout the study. Fasting plasma glucose and HbA1 were measured before each study to provide measures of metabolic control. RESULTS: Serum IGF-I and IGFBP-3 levels were significantly lower while serum IGFBP-I levels were significantly higher in the diabetic subjects. Pirenzepine had no effect on serum IGF-I, IGFBP-1 or IGFBP-3 in diabetic subjects but caused a significant increase in serum IGF-I and IGFBP-3 levels in normal subjects. Pyridostigmine had no effect on IGF-I, IGFBP-1 or IGFBP-3 in either diabetic or normal subjects. IGFBP-1 levels were significantly correlated with fasting plasma glucose but no correlation was demonstrated between measures of diabetic control and serum IGF-I or IGFBP-3 levels in diabetic subjects, nor was there any correlation between GH responses to GHRH alone or after pirenzepine or pyridostigmine pretreatment and serum levels of IGF-I, IGFBP-1 or IGFBP-3. CONCLUSION: These data confirm that subjects with IDDM have reduced serum IGF-I and IGFBP-3 and increased IGFBP-1 levels, the latter being directly related to the fasting plasma glucose concentrations. The absence of any relation between changes in the IGF-I system and altered GH neuroregulation after cholinergic modulation suggests that changes in IGF-I are not the sole contributors to the altered GH neuroregulation which occurs in IDDM. We have also shown an acute stimulatory effect of pirenzepine on serum IGF-I and IGFBP-3 in normal subjects which is not present in IDDM although the underlying mechanisms is unknown.

Blood Glucose↗
PubMed1995

Hypothalamic mediation of reduced GH secretion in diabetic rats: evidence for reduced cholinergic inhibition of somatostatin release.

The Goto-Kakizaki (GK) rat is a new model of diabetes mellitus and in this study we have characterized the diabetic and growth hormone (GH) secretory status of male GK rats at 6 and 16 weeks of age. We have also investigated the role of endogenous somatostatin (SS) and cholinergic manipulation on the GH responses to GH-releasing hormone (GHRH). GK rats were non-obese with significant fasting hyperglycaemia, hyperinsulinaemia and absent insulin responses to IV glucose. The GH response to GHRH was reduced at 16 weeks compared with normal, age-matched Wistar rats but no differences were observed at 6 weeks. Pretreatment of older rats (16 weeks) with anti-somatostatin antibodies (SS-Ab) significantly increased GH responses to GHRH in both normal and GK groups. Cholinergic augmentation with pyridostigmine (PD) reversed the blunted GH responses to GHRH in older GK rats but had no effect in the normal or young (6 weeks) GK rats. These results indicate that SS release mediates the blunted GH response to GHRH in GK rats and that reduced hypothalamic cholinergic signalling to the somatostatinergic neurone may mediate the increase in SS release. This view is supported by the results from in vitro studies in which cholinergic muscarinic blockade with pirenzepine (PIR) caused dose-related stimulation of SS release from normal rat hypothalami but was without effect on GK rat hypothalami. The cause of this alteration in hypothalamic function is, at present, unknown.

Acetylcholine↗