The cost of diagnosing Type 2 diabetes mellitus by clinical opportunistic screening in general practice.

AIMS: Type 2 diabetes is associated with serious complications and shortens life. Its prevalence is increasing rapidly worldwide and no cure is available. One logical response is to diagnose the condition as early as possible. Clinical opportunistic screening is one mechanism for making the diagnosis before symptoms are reported. This paper reports the cost of using this technique in UK general practice. METHODS: In one UK general practice, the electronic medical records were searched to determine the number of blood glucose and oral glucose tolerance tests undertaken for non-pregnant adults without known diabetes over three consecutive years. The laboratory, staff and administrative costs associated with these screening tests were calculated. The records of all patients newly diagnosed with Type 2 diabetes during the same period were reviewed to identify diagnoses made by clinical opportunistic screening. Total costs were divided by the number of diagnoses to determine a cost per diagnosis detected by opportunistic screening. RESULTS: During the study period, 5720 screening tests were conducted for 2763 patients. Over the 3 years, 86 patients were diagnosed with Type 2 diabetes, 54 (63%) via screening (yield 2.0%; number needed to screen 51.2). The screening costs totalled £ 20,372. The average cost per new screen-detected diagnosis was £ 377. CONCLUSIONS: Almost two-thirds of new cases of Type 2 diabetes can be detected before symptoms are reported, at reasonable cost by opportunistic screening in general practice, without the use of extra resources. As an affordable alternative to population screening, clinical opportunistic screening merits further consideration.

Sex pheromone of the tsetse fly: isolation, identification, and synthesis of contact aphrodisiacs.

Sex pheromones isolated from the cuticle of the female tsetse fly, Glossina morsitans morsitans Westwood, release mating behavior in the male fly at ultrashort range or upon contact with baited decoys. Three active components were identified as 15,19-dimethylheptatriacontane, 17,21-dimethylheptatriacontane, and 15,19,23-trimethylheptatriacontane. Chemical and biological comparisons show that the natural and synthetic compounds are identical.

Studying scientific discovery by computer simulation.

BACON is a computer program that simulates some of the important processes of scientific discovery. When provided with data about temperatures before and after two substances are brought into contact, the program infers the concept of specific heat and arrives at Black's law of temperature equilibrium. Comparison of BACON's discovery methods with historical records of Black's work casts light on the relation between data-driven and theory-driven discovery.

Myotonic response induced by inhibitors of cholesterol biosynthesis.

Steroid inhibitors of cholesterogenesis containing nitrogen-substituted side chains induced electromyographic myotonia in rats. Cholesterol reduction or desmosterol accumulation, per se, did not cause myotonia, and cholestrol feeding prevented drug-induced myotonia. Desmosterol accumulation in combination with a specific drug effect may cause the observed myotonia.

Spatial and temporal organization of the dominant frequencies in the fibrillating heart: body surface potential mapping in a rare case of sustained human ventricular fibrillation.

AIMS: The aim of this study was to assess the spatial and temporal variability of dominant fibrillation frequencies in a rare case of sustained human ventricular fibrillation (VF). METHODS AND RESULTS: Body surface potential mapping was performed in a patient with sustained VF and who was supported by a biventricular assist device. Dominant frequencies at 54 body sites were calculated from two recordings obtained 38 days apart. Variability of dominant frequencies between recordings and across body sites was quantified. Median dominant frequencies within recordings varied between 6.1 and 7.2 Hz in recording 1 and 5.6 and 6.6 Hz in recording 2, indicating a significant reduction in dominant frequencies between the recordings (P < 0.0001). Dominant frequencies differed across body sites by a mean (range) of 1.7 (0.4-2.8) Hz. CONCLUSION: In this rare case of sustained VF, there was significant spatial and temporal variability of VF dominant frequencies. These findings should be considered in future ECG studies on VF where the spatial variability of dominant frequency might not otherwise have been considered.

Validation of an algorithm to reveal the U wave in atrial fibrillation.

Major cardiac organisations recommend U wave abnormalities should be reported during ECG interpretation. However, U waves cannot be measured in patients with atrial fibrillation (AF) due to the obscuring fibrillatory wave. The aim was to validate a U wave measurement algorithm for AF patients. Multi-beat averaging was applied to ECGs of 25 patients during paroxysms of AF and the presence of U waves compared to those from the same patients during sinus rhythm (SR). In a further database of 10 long-term AF recordings, the number of beats for effective U wave extraction by the algorithm was calculated. U waves were revealed in all AF recordings and there was no significant difference between the presence of U waves in AF and SR (p = 0.88). U wave amplitude was significantly increased in AF (mean (s.d.) amplitude 55 (39) AF vs 37 (28) µV SR, p = 0.005). The presence of U waves could easily be discerned when as few as 10 beats were used in the algorithm. The study demonstrates the validity of the algorithm to reveal U waves in AF recordings. The algorithm offers the potential to detect U wave abnormalities in patients with AF.

Regulation of human lipolysis. In vivo observations on the role of adrenergic receptors.

Changes in the plasma free fatty acids of a pancreatectomized subject and in free fatty acids and insulin in 10 normal subjects in response to the in vivo infusion of epinephrine alone, epinephrine plus phentolamine, and epinephrine plus propranolol indicate that both alpha and beta adrenergic receptors are present in human adipose tissue. Under the experimental conditions used, adipose tissue appeared to be more responsive to epinephrine than did the cardiovascular system.

Pharmacological characterizations of adrenergic receptors in human adipocytes.

Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the effects of adrenergic agents on receptor-specific biochemical responses. Adrenergic binding studies showed the following results: [(3)H]dihydroalprenolol binding (beta adrenergic) B(max) 280 fmol/mg protein, K(D) 0.38 nM; [(3)H]para-aminoclonidine binding (alpha-2 adrenergic) B(max) 166 fmol/mg protein, K(D) 0.49 nM; [(3)H]WB 4101 binding (alpha-1 adrenergic) B(max) 303 fmol/mg protein, K(D) 0.86 nM. In adipocytes from subcutaneous adipose tissue, [(3)H]dihydroergocryptine binding indicated the presence of alpha-2 but not alpha-1 receptors. Beta and alpha-2 adrenergic receptors appeared to be positively and negatively coupled to adenylate cyclase, respectively. Cells or cell membranes were incubated with epinephrine (10 muM) alone and in combination with the antagonists yohimbine (alpha-2) and prazosin (alpha-1). Epinephrine alone prompted a modest increase in adenylate cyclase activity, cyclic AMP, and glycerol release, an index of lipolysis. Yohimbine (0.1 muM) greatly enhanced these actions whereas prazosin was without effect. The beta agonist, isoproterenol, stimulated glycerol release, whereas the alpha-2 agonist, clonidine, inhibited lipolysis and cyclic AMP accumulation. To assess further alpha-1 receptors, cells were incubated with [(32)P]phosphate and epinephrine (10 muM) alone and in combination with prazosin and yohimbine. Epinephrine alone caused a three- to fourfold increase in (32)P incorporation into phosphatidylinositol. Prazosin (0.1 muM) blocked this action whereas yohimbine (0.1 muM) was without effect. Thus, in a homogeneous cell preparation, the human adipocyte appears to have three different adrenergic receptors, each of which is coupled to a distinct biochemical response.

A study on stability analysis of atrial repolarization variability using ARX model in sinus rhythm and atrial tachycardia ECGs.

BACKGROUND: The interaction between the PTa and PP interval dynamics from the surface ECG is seldom explained. Mathematical modeling of these intervals is of interest in finding the relationship between the heart rate and repolarization variability. OBJECTIVE: The goal of this paper is to assess the bounded input bounded output (BIBO) stability in PTa interval (PTaI) dynamics using autoregressive exogenous (ARX) model and to investigate the reason for causing instability in the atrial repolarization process. METHODS: Twenty-five male subjects in normal sinus rhythm (NSR) and ten male subjects experiencing atrial tachycardia (AT) were included in this study. Five minute long, modified limb lead (MLL) ECGs were recorded with an EDAN SE-1010 PC ECG system. The number of minute ECGs with unstable segments (Nus) and the frequency of premature activation (PA) (i.e. atrial activation) were counted for each ECG recording and compared between AT and NSR subjects. RESULTS: The instability in PTaI dynamics was quantified by measuring the numbers of unstable segments in ECG data for each subject. The unstable segments in the PTaI dynamics were associated with the frequency of PA. The presence of PA is not the only factor causing the instability in PTaI dynamics in NSR subjects, and it is found that the cause of instability is mainly due to the heart rate variability (HRV). CONCLUSION: The ARX model showed better prediction of PTa interval dynamics in both groups. The frequency of PA is significantly higher in AT patients than NSR subjects. A more complex model is needed to better identify and characterize healthy heart dynamics.

Insulin inhibition of lipolysis of human adipocytes: the role of cyclic adenosine monophosphate.

To gain information on the manner in which insulin suppresses lipolysis in man, isolated adipocytes, prepared from subcutaneous adipose tissue, were incubated with insulin (100 microunits/ml) alone and in combination with isoproterenol (10(-7) M or 10(-8) M). Cyclic AMP concentration was measured at 60 min; glycerol release, used as an index of lipolysis, was determined at 45 and 75 min. Insulin consistently reduced both basal and stimulated cyclic AMP and glycerol release: the degree of suppression of each was comparable. In subsequent experiments, the ability of insulin to suppress glycerol release stimulated by isoproterenol, theophylline, and dibutyryl cyclic AMP (dbcAMP), respectively, was compared. Insulin substantially reduced the raised levels of cyclic AMP and glycerol release prompted by isoproterenol and theophylline, but it had little effect on increases caused by dbcAMP. These findings support the view that reduction in cyclic AMP is an important component in the regulation of fat mobilization by insulin.

In-vitro observations on isolated adipose tissue cells from hyperobese subjects.

Isolated adipose tissue cells were prepared from subcutaneous samples obtained from nine morbidly obese subjects weighing from 187 to 306% of ideal body weight. The responsiveness of these adipocytes to a number of test substances was determined by measuring cellular cyclic AMP concentration at one-half hour and glycerol release at four hours. Theophylline (10(-3) M) and epinephrine (10(-5) M) stimulated lipolysis; theophylline stimulated an increase in cyclic AMP, while epinephrine failed to prompt a significant change in the nucleotide. Neither the alpha blocker, phentolamine (10(-5) M), nor the beta blocker, propranolol (3 X 10(-5) M), affected lipolysis or cyclic AMP; when these agents were incubated in combination with epinephrine, changes occurred indicative of the presence of both alpha and beta adrenergic receptor sites. Insulin significantly reduced both basal and stimulated lipolysis but failed to affect cyclic AMP. With minor exceptions, adipocytes from hyperobese subjects behaved similarly to cells from unselected donors; at the concentration used, there was no evidence of resistance to insulin.

Cost-effectiveness of regional poison control centers.

BACKGROUND: Poison exposures are a significant public health concern. Despite the impact that regional poison control centers have on reducing morbidity and mortality associated with poison exposures, they are facing a serious financial crisis today resulting in an increased emphasis on their economic justification. METHODS: Using decision-analysis techniques, the cost-effectiveness of the treatment of poison exposures with the services of a regional poison control center compared with treatment without access to any poison control center was evaluated. The relative cost-effectiveness was modeled based on 2 outcomes (morbidity and mortality) for each of 4 typical poison exposures. Additionally, analyses were conducted to test the sensitivity of the cost-effectiveness ratios to outcome probability, average inpatient and emergency department costs, and proportion of poison exposures treated on site by the regional poison control center. A societal perspective was adopted. RESULTS: The regional poison control center was substantially more cost-effective than the treatment of poison exposures without the services of a regional poison control center for both outcomes (morbidity and mortality) in each of the poison exposures considered. The results of the sensitivity analyses demonstrated that the outcomes of the decision analyses do not change regardless of the type of poison exposure, outcome considered, clinical outcome probabilities, average inpatient and emergency department costs, and proportion of poison-exposure cases treated on site by a regional poison control center. CONCLUSIONS: The regional poison control center is consistently more cost-effective in the treatment of poison exposures with an average cost-effectiveness ratio (cost per successful outcome) approximately half of that achieved without the services of a regional poison control center. Finally, significant cost savings to society are realized for each additional successful outcome obtained with a regional poison control center.

Normal free fatty acid response to isoproterenol in pseudohypoparathyroidism.

The lipolytic response to isoproterenol infusion was examined in seven normal subjects and six patients with pseudohypoparathyroidism type I [two had deficiency of the hormone receptor-cyclase coupling protein (N-protein) and four did not]. Despite blunted plasma cAMP responses to isoproterenol in both subgroups of pseudohypoparathyroidism patients, the serum FFA responses were normal. We conclude that changes in plasma cAMP do not reflect the adequacy of the lipolytic response to isoproterenol.

The effect of fulminant hepatic failure on protein C antigen and activity.

In eighteen patients with fulminant hepatic failure (FHF), in grade III or IV coma, both protein C antigen and activity were significantly decreased (0.35 +/- 0.03 u/ml and 0.35 +/- 0.03 u/ml respectively). There was a significant correlation between protein C antigen and activity (r = 0.61, p less than 0.01). Protein C antigen levels were inversely correlated with prothrombin time (r = -0.57, p less than 0.05) as were protein C activity levels (r = -0.57, p less than 0.05). There was also significant correlations between fibrinogen and protein C antigen (r = 0.69, p less than 0.01) and protein C activity (r = 0.61, p less than 0.01). These results demonstrate that the naturally occurring inhibitor of coagulation, protein C, is present at low levels in FHF and this is probably due to the lack of synthesis of the protein in the damaged liver. The low levels of protein C may make these patients more susceptible to the disseminated intravascular coagulation which is known to occur in FHF and this in turn will lead to a further reduction in protein C levels.

Increased factor VIII complex in fulminant hepatic failure.

In 30 patients with fulminant hepatic failure (FHF) all three components of the factor VIII complex were significantly increased (VIIIC = 6.43 +/- 1.12 u/ml; VIIIRAg = 3.91 +/- 0.25 u/ml; VIIIvWF = 3.89 +/- 0.29 u/ml). There was good correlation between all three parameters in control subjects, but only between VIIIRAg and VIIIvWF (r = 0.67; p less than 0.001) in patients with FHF. VIIIC was significantly higher than VIIIRAg and VIIIvWF. These results suggest that VIIIC and VIIIRAg are increased by different mechanisms in FHF. These processes may include endothelial cell damage, reduced reticuloendothelial system function and lack of production of inactivating substances by the damaged liver. Platelet adhesion to glass beads was increased in FHF (36.4 +/- 5.9% compared to 16.6 +/- 2.1%, p less than 0.01). There was no significant correlation between platelet adhesion and any of the parameters of the factor VIII complex. Thus the increase in platelet adhesion cannot be due to the increase in VIIIvWF in FHF.

Heparin response and clearance in acute and chronic liver disease.

Patients with liver disease are at risk of bleeding due to abnormalities of the clotting system although they must be anticoagulated if they require haemodialysis or haemoperfusion. The anticoagulant of choice is heparin. In this study we have investigated heparin kinetics in patients with fulminant hepatic failure (FHF) after a single intravenous dose of heparin (2,500 units) and found there was an increased clearance of heparin whether measured by its anti-Xa effect (t 1/2 = 27.8 +/- 2.9 min compared to t 1/2 = 50.2 +/- 2.7 min in normal controls p less than 0.001) or by the whole blood activated clotting time (t 1/2 = 23.7 +/- 2.2 min compared to t 1/2 = 37.0 +/- 2.0 min p less than 0.001). There was a decreased peak level of heparin measured by anti-Xa effect (peak level in FHF = 0.48 +/- 0.05 u/ml and in controls = 0.69 +/- 0.04 u/ml, p less than 0.02), but an increased sensitivity to heparin (sensitivity in FHF = 0.072 +/- 0.011 sec/unit, in controls 0.033 +/- 0.003 sec/unit, p less than 0.001). Patients with FHF had very low levels of antithrombin III (AT III), but there was no correlation between this and any parameters of heparin effect or clearance. In a group of patients with chronic liver disease heparin kinetics did not differ from controls despite low levels of AT III. The changes in heparin kinetics in FHF are likely to be complex with the balance between the proteins that act as cofactors, (e.g. AT III) and the proteins that have heparin neutralising activity, controlling the response of added heparin.

Site of free-fatty-acid inhibition of lipolysis by human adipocytes.

When human adipocytes were incubated in albumin-free buffer, isoproterenol failed to stimulate an increase in either cyclic AMP or glycerol release. Cells incubated for 1/2 hr with 4% albumin and isoproterenol had a striking increase in cyclic AMP; this effect was markedly reduced when FFA concentration was increased by the addition of sodium oleate. When incubation was prolonged to 4 hr, the cyclic AMP concentration of stimulated cells fell towards the basal level. This decline in the level of cyclic AMP was prevented by frequent change in buffer. The ability of epinephrine and sodium fluoride to stimulate the adenylyl cyclase of human adipocyte membranes was not affected by the addition of sodium oleate. However, when intact cells were preincubated for 1 hr with added sodium oleate, the responsiveness to epinephrine of membranes derived from the cells was reduced. No such alternation in responsiveness to sodium fluoride occurred. These results indicate that the inhibitory effect of FFA on lipolysis is associated with a reduced production of cyclic AMP; the latter effect may be the consequence of FFA inhibition of adenylyl cyclase.

The role of free fatty acids in the regulation of lipolysis by human adipose tissue cells.

The effect of added fatty acid on lipolysis and cyclic AMP concentration of human adipose tissue cells was studied. The addition of sodium oleate decreased the lipolytic response of adipocytes to 10(-7) M isoproterenol. Inhibition was detectable with the lowest quantity of oleate added, 0.2 mM, and was progressively greater with increasing quantities of added fatty acid. Palmitic and linoleic acids were as effective as oleic acid in suppressing isoproterenol-stimulated lipolysis. Suppression of cyclic AMP formation was detectable within one minute after the addition of oleate. Cyclic AMP formation, suppressed by accumulated fatty acids, could not be stimulated by the addition of fresh isoproterenol. However, after the accumulated fatty acids were removed by buffer change, cyclic AMP formation was stimulated by fresh isoproterenol. These findings are consistent with the view that fatty acids are physiologically significant regulators of lipolysis.

Studies on desensitization of adrenergic receptors of human adipocytes.

The studies described here were undertaken to determine whether or not desensitization of human adipocyte beta and alpha-2 adrenergic receptors could be demonstrated. Cells, isolated from peritoneal adipose tissue obtained from patients undergoing elective abdominal surgery, were preincubated for 3 hr in buffer alone or in the presence of isoproterenol, 10-5M. Cells in both sets of flasks were then washed and exposed to isoproterenol for 1/2 hr; cyclic AMP was then measured as an end point of beta receptor activation. Cells which had had no prior exposure to isoproterenol responded significantly greater to isoproterenol than did cells that had had prior exposure to the catecholamine, The beta receptor characteristics of cells undergoing beta desensitization were assessed using [3H] dihydroalprenolol. Compared to control cells, adipocytes exposed to isoproterenol had a reduction in Bmax while KD values were the same. Thus desensitization of beta adrenergic receptors of human adipocytes occurs and is associated with down regulation in the number of beta receptors. In comparable studies, preincubation with epinephrine 10-5M did not affect the response of cells to a subsequent exposure to this catecholamine. In alpha-2 receptor binding assays, there was a decreased number of [3H]p-aminoclonidine binding sites, but the level of [3H]yohimbine binding was not altered following the incubation with epinephrine. Thus, desensitization of alpha-2 receptors was not demonstrated.

A simple micromanipulator for multiple uses in freely moving rats: electrophysiology, voltammetry, and simultaneous intracerebral infusions.

An inexpensive, easily fabricated micromanipulator is described that can be used for single-unit recording or voltammetry in freely moving rats. The basic design is configured around the standard coupling system between a plastic syringe and corresponding needle hub. The device can be used with glass or metal microelectrodes for electrophysiology or carbon-fiber or carbon-disk microelectrodes for voltammetry. With either recording technique, the micromanipulator also can accommodate a 33-ga infusion cannula, which allows drugs to be administered directly to the recording site. The entire assembly is lightweight and can be used with a head-mounted amplifier system for relatively noise-free recording.