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The purpose of this article is to describe the results of a clinical trial in which telephonic case management was evaluated as a supplement to substance abuse treatment. An interactive voice response system (IVR) was developed by the research team for use in the case management of randomly assigned participants in a clinical trial research project. The features of the software program facilitated a double caseload for the case manager as well as real-time data capture. At intake, no significant differences were found between participants in the telecommunication condition and the general project. Thus, the effectiveness of random assignment was supported. An IVR was useful for case management services, was less costly, and showed acceptability to clients. A reduction in time expenditure by using telecommunication occurred within three activity areas. Telecommunication facilitated client interaction and the use of case management, and it reduced provider time expenditure. As an alternative strategy, telecommunication case management can enhance cost effectiveness improvements.

Pre-ablation impedance was evaluated for its ability to detect electrode-tissue contact and allow creation of long uniform linear lesions with a multi-electrode ablation catheter. The study consisted of 2 parts, both of which used the in vivopig thigh muscle model. In part 1, a 7 Fr. multi-electrode catheter was held in 3 electrode-tissue contact conditions: (1) non-contact; (2) light contact with a 30g downward force; and (3) tight contact with a 90g downward force. Impedances were measured in unipolar, modified unipolar and bipolar configurations using a source with frequencies from 100Hz to 500kHz. Compared with non-contact, the impedance increased 35 +/- 22 % with 30g contact pressure and 68 +/- 40% when the contact pressure was increased to 90g across the range of frequencies studied. In part 2, the same catheter was held against the tissue with different forces. Pre-ablation impedance was measured using a 10kHz current. Phased radiofrequency energy was applied to the 5 electrodes simultaneously using 10W power at each electrode for 120s. A total of 32 linear lesions were created. The lesion dimensions correlated with pre-ablation impedance. A unipolar impedance > or = 190 Omega indicates 95% possibility to create a uniform linear lesion of at least 3mm depth with our ablation system. We conclude that pre-ablation impedance may be a useful indicator for predicting electrode-tissue contact and the ability to create a continuous and transmural linear lesion with a multi-electrode catheter.

Previous bacterial transport studies have utilized fluorophores which have been shown to adversely affect the physiology of stained cells. This research was undertaken to identify alternative fluorescent stains that do not adversely affect the transport or viability of bacteria. Initial work was performed with a groundwater isolate, Comamonas sp. strain DA001. Potential compounds were first screened to determine staining efficiencies and adverse side effects. 5-(And 6-)-carboxyfluorescein diacetate, succinimidyl ester (CFDA/SE) efficiently stained DA001 without causing undesirable effects on cell adhesion or viability. Members of many other gram-negative and gram-positive bacterial genera were also effectively stained with CFDA/SE. More than 95% of CFDA/SE-stained Comamonas sp. strain DA001 cells incubated in artificial groundwater (under no-growth conditions) remained fluorescent for at least 28 days as determined by epifluorescent microscopy and flow cytometry. No differences in the survival and culturability of CFDA/SE-stained and unstained DA001 cells in groundwater or saturated sediment microcosms were detected. The bright, yellow-green cells were readily distinguished from autofluorescing sediment particles by epifluorescence microscopy. A high throughput method using microplate spectrofluorometry was developed, which had a detection limit of mid-10(5) CFDA-stained cells/ml; the detection limit for flow cytometry was on the order of 1,000 cells/ml. The results of laboratory-scale bacterial transport experiments performed with intact sediment cores and nondividing DA001 cells revealed good agreement between the aqueous cell concentrations determined by the microplate assay and those determined by other enumeration methods. This research indicates that CFDA/SE is very efficient for labeling cells for bacterial transport experiments and that it may be useful for other microbial ecology research as well.

Early studies indicated that after successful thrombolytic recanalization, adjunctive percutaneous transluminal coronary angioplasty (PTCA) was not appropriate, even when a significant residual stenosis was present. The aim of this study was to assess in-hospital clinical outcomes of patients with acute myocardial infarction (AMI) who underwent successful recanalization after thrombolytic therapy. The relation between repeat AMI/unstable angina and the severity of the stenosis, as well as other angiographic and clinical features was also examined. One hundred patients with AMI of <10 hours underwent coronary angiography 2 hours after receiving thrombolytic therapy. Salvage PTCA +/- stenting was performed if recanalization was unsuccessful (Thrombolysis In Myocardial Infarction [TIMI] trial grade 0 to 2), and no PTCA was undertaken if there was brisk anterograde flow (TIMI 3). Angiographic analysis was performed to assess the severity of the residual lesion, as well as the presence or absence of thrombus. Forty patients had unsuccessful recanalization, and of these, 36 underwent attempted PTCA. Of the 60 patients with TIMI 3 flow, 15 required repeat angiography and PTCA after repeat AMI (n = 13) or unstable angina (n = 2) within 5 days. Receiver-operating characteristic analysis indicated an optimum percent diameter stenosis predictor of 85% for repeat AMI/unstable angina. There was no additional relation to age, gender, time to thrombolysis, the infarct-related artery, or the presence of culprit lesion thrombus. After recanalization, a high-grade stenosis >85% is common (n = 25, 42.4%). This is associated with a 54% repeat AMI/unstable angina risk-a ninefold increase in the incidence of such events than in patients with lesions <85%. Thus, patients with narrowings >85% may benefit from early intervention rather than a conservative approach. Narrowings <85% have a 94% probability of no repeat AMI/unstable angina and do not require early intervention.

Objective: To assess the outcome of a policy of emergency coronary angiography with or without rescue angioplasty in patients with acute myocardial infarction and ECG evidence of failed reperfusion after thrombolysis., Design: A cohort study., Setting: Regional cardiothoracic unit., Patients: 197 patients with acute myocardial infarction fulfilling a simple ECG criterion of failed reperfusion., Interventions: Emergency coronary angiography proceeding to rescue angioplasty for inadequate antegrade flow., Main Outcome Measures: Hospital mortality for all 197 patients; incidence of successful and failed rescue angioplasty; need for additional revascularisation in those receiving rescue angioplasty compared with those not treated in this way., Results: 197 patients had emergency angiography for ECG evidence of failed reperfusion; 156 patients received immediate rescue angioplasty. Overall hospital mortality for those undergoing rescue angioplasty was 11.5%. Rescue angioplasty achieved TIMI 2 (11) or TIMI 3 (124) in 135 patients, who had a hospital mortality of 5.9%. Failure to achieve at least TIMI 2 flow following rescue angioplasty occurred in 21 patients, with a hospital mortality of 48%. In the 41 patients in whom immediate rescue angioplasty was not performed, reinfarction or requirement for revascularisation occurred in 37%. Reinfarction occurred in three patients (1.9%) who had immediate rescue angioplasty. Hospital mortality for the whole cohort was 10.7%., Conclusions: A policy of emergency coronary angiography proceeding to rescue angioplasty where appropriate reduces mortality in a high risk group to a level less than expected for patients with acute myocardial infarction and ECG evidence of failed reperfusion. Unsuccessful rescue angioplasty is associated with a high mortality.

Objective: To determine whether a nonionic detergent (Triton WR 1339) can be used in cats to assess hepatic secretion of triglyceride., Animals: 28 healthy cats., Procedure: Triton WR 1339 was administered IV according to the following schedule: 5, 50, 150, and 250 mg/kg of body weight. Control cats did not receive an injection or received 0.9% NaCl or PBS solutions at the same osmolarity and volume as the 250 mg/kg group. Blood samples were collected throughout the 48-hour period after administration for determination of triglyceride and cholesterol concentrations and for RBC morphology and osmotic fragility studies., Results: Administration of Triton WR 1339 at 150 and 250 mg/kg caused profound hypertriglyceridemia. Triglyceride concentrations increased in a curvilinear fashion for the first 2 hours and remained increased for approximately 24 hours. Area under the time-concentration curve for triglyceride at 5 hours differed significantly among groups. At 12 and 24 hours, cholesterol was significantly higher in cats receiving 250 mg/kg. The most dramatic changes in osmotic fragility and RBC morphology were in cats receiving 250 mg/kg; 1 of these cats developed severe icterus and died 5 days later. Feeding rice and casein before administering Triton WR 1339 at 150 mg/kg did not appear to affect the hypertriglyceridemia response., Conclusions and Clinical Relevance: Triton WR 1339 can be administered IV to cats at a rate of 150 mg/kg to assess hepatic triglyceride secretion, although some cats may have increased RBC osmotic fragility. Higher dosages caused substantial adverse effects, whereas lower dosages did not alter plasma triglyceride concentration.

Objective: To determine whether simple, readily applicable ECG criteria will allow early prediction of inadequate (< TIMI 3) flow in the infarct related vessel in patients receiving thrombolytic treatment for acute myocardial infarction; and to determine the success of streptokinase in achieving adequate antegrade flow in the infarct related vessel two hours after starting treatment., Design: Cohort study., Setting: Regional cardiothoracic unit., Patients: 100 sequential patients with acute myocardial infarction., Interventions: Coronary angiography two hours after the initiation of thrombolytic treatment, proceeding to rescue angioplasty for inadequate flow in the infarct related vessel where appropriate., Main Outcome Measures: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of six ECG criteria for the detection of inadequate antegrade flow in the infarct related vessel., Results: The ECG test that performed best as a positive test for < TIMI 3 flow in the infarct related vessel was < 50% resolution of the ST segment elevation in the worst lead and no accelerated idioventricular rhythm. This had a sensitivity of 81%, specificity of 88%, positive predictive value of 87%, negative predictive value of 83%, and overall accuracy of 85%., Conclusions: Sensitive, specific, and simple ECG criteria are defined for diagnosing failure of thrombolytic treatment with streptokinase. These allow the early detection of patients at high risk of further adverse events from a persistently occluded vessel. They may be used without recourse to sophisticated equipment or complex analyses. Such patients can then be considered for alternative treatments or enrollment into appropriate research protocols.

A 58-year-old male underwent orthotopic cardiac transplantation for ischemic cardiomyopathy. At routine coronary angiography 2 years later, he was found to have severe concentric stenosis of the left main coronary artery but was asymptomatic. Revascularization was recommended on prognostic grounds and after discussion with his cardiac transplant surgeon, percutaneous coronary intervention with elective stenting was offered. This was performed successfully with a single stent and a good angiographic result was maintained 6 and 18 months later.

Developmental dyslexia is a complex syndrome whose exact cause remains unknown. It has been suggested that a problem with fatty acid metabolism may play a role, particularly in relation to the visual symptoms exhibited by many dyslexics. We explored this possibility using two self-report questionnaires, designed on the basis of clinical experience, to assess (1) clinical signs of fatty acid deficiency; and (2) symptoms associated with dyslexia in known dyslexic and non-dyslexic subjects. Dyslexic signs and symptoms included the auditory-linguistic and spoken language difficulties traditionally associated with the disorder, as well as visual problems (both with reading and more generally) and motor problems. Fatty acid deficiency signs were significantly elevated in dyslexic subjects relative to controls, particularly within males (P<0.001). In addition, the severity of these clinical signs of fatty acid deficiency was strongly correlated with the severity of dyslexic signs and symptoms not only in the visual domain, but also with respect to auditory, linguistic and motor problems. The pattern of relationships differed somewhat between dyslexic and control groups, and sex differences were also observed. Our findings support the hypothesis that fatty acid metabolism may be abnormal in developmental dyslexia, and indicate the need for further studies using more objective measures., (Copyright 2000 Harcourt Publishers Ltd.)

It has been proposed that developmental dyslexia may be associated with relative deficiencies in certain highly unsaturated fatty acids (HUFA). In children with attention-deficit/hyperactivity disorder, minor physical signs of fatty acid deficiency have been shown to correlate with blood biochemical measures of HUFA deficiency. These clinical signs of fatty acid deficiency were therefore examined in 97 dyslexic children in relation to reading and related skills, and possible sex differences were explored. Children with high fatty acid deficiency ratings showed poorer reading (P<0.02) and lower general ability (P<0.04) than children with few such clinical signs. Within males (n=72) these relationships were stronger, and fatty acid deficiency signs were also associated with poorer spelling and auditory working memory (P<0.05, P<0.005 respectively). Within females (n=25) no associations were significant. These results support the hypothesis that fatty acid deficiency may contribute to the severity of dyslexic problems, although sex differences merit further investigation., (Copyright 2000 Harcourt Publishers Ltd.)

The Jomed Covered Stent Graft (Jomed International AB, Helsingborg, Sweden) is marketed for treatment of coronary artery aneurysms, perforations, dissection or thrombus. Three cases are presented, two with aneurysms, one with an acute coronary perforation. Intravascular ultrasound (IVUS) identified the need for high-pressure deployment of the stent. Although it has been suggested that this stent might lead to reduced rates of restenosis, one case later developed proliferative and occlusive in-stent restenosis and another suffered stent thrombosis at one month shortly after discontinuing clopidogrel. This niche stent clearly has an important role, but high-pressure deployment, IVUS evaluation and prolonged antiplatelet therapy are strongly recommended.

It is uncertain whether frequent marijuana use adversely affects human brain function. Using PET, regional cerebral blood flow was compared in frequent marijuana users and comparable, non-using controls after at least 26 h of monitored abstention by all subjects. Marijuana users showed substantially lower brain blood flow than controls in a large region of posterior cerebellum, indicating altered brain function in frequent marijuana users. A cerebellar locus of some chronic and acute effects of marijuana is plausible, e.g. the cerebellum has been linked to an internal timing system, and alterations of time sense are common following marijuana smoking.

Pharmacologic agents may have a significant effect on the outcome of radiographic interpretation in small animal imaging. Alterations in the abdomen and thorax may represent artifactual or transient changes or changes reflecting cytotoxicity. Examples of agents that may influence the appearance of radiographs include anticonvulsants, sedatives, anesthetics, analgesics, antiinflammatories, gastrointestinal prokinetic drugs, antineoplastics, and hormones such as megestrol acetate. Radiographic studies may be part of a disease-monitoring process. It is important to understand how pharmaceuticals (e.g., chemotherapeutics or therapy for an underlying medical condition) affect the radiographic appearance. Caution should be exercised in the interpretation of radiographic studies because the findings may relate to the drug therapy rather than the underlying condition.

To investigate CNS effects of frequent marijuana use, brain tissue volume and composition were measured using magnetic resonance imaging (MRI) in 18 current, frequent, young adult marijuana users and 13 comparable, non-using controls. Automated image analysis techniques were used to measure global and regional brain volumes, including, for most regions, separate measures of gray and white matter. The marijuana users showed no evidence of cerebral atrophy or global or regional changes in tissue volumes. Volumes of ventricular CSF were not higher in marijuana users than controls, but were, in fact, lower. There were no clinically significant abnormalities in any subject's MRI. Sex differences were detected in several global volume measures.

To provide baseline data for various research studies at the University of Pittsburgh over a 10-year period, 266 healthy subjects (144 male, 122 female, aged 20-50 years) meeting certain criteria each completed a 14-night sleep diary. For each night, the diary allowed the subjective measurement of bedtime, wake time, time in bed (TIB), sleep efficiency, number of minutes of wake after sleep onset (WASO), alertness on awakening, and percentage of morning needing an alarm (or a person functioning as one). Weeknight versus weekend night differences in TIB (TIBdiff), weekday altertness, and reliance on alarms were examined as possible indicators of sleep debt. In addition, general descriptive data were tabulated. On average, bedtimes were at 23:48 and wake times at 07:23, yielding a mean TIB of 7 hours 35 minutes. As expected, bedtimes and wake times were later on weekend nights than on weeknights. Bedtimes were 26 minutes later, wake times 53 minutes later, yielding a mean weekend TIB increase of 27 minutes. Overall, subjects perceived their sleep latency to be 10.5 minutes, reported an average of one awakening during the night (with an average of 6.4 minutes of WASO), had a diary sleep efficiency of 96.3%, and awoke with an alterness rating of 69.5%. These variables differed little between weeknight and weekend nights. Subjects used an alarm (or a person functioning as an alarm) on 60.9% nights overall, 68.3% on weeknights, 42.5% on weekends. When TIBdiff was used as an estimate of sleep debt (comparing subjects with TIBdiff > 75 minutes with those with a TIBdiff < 30 minutes), the group with more "catch-up sleep" on weekends had shorter weeknight TIB durations (by about 24 minutes) and relied more on an alarm for weekday waking (by about 22%), indicating the possible utility of these variables as sleep debt indices.

Degradation experiments of benzoate by Pseudomonas putida resulted in enzymatic carbon isotope fractionations. However, isotopic temperature effects between experiments at 20 and 30 degrees C were minor. Averages of the last three values of the CO(2) isotopic composition (delta(13)C(CO2(g))) were more negative than the initial benzoate delta(13)C value (-26.2 per thousand Vienna Pee Dee Belenite (VPDB)) by 3.8, 3.4 and 3.2 per thousand at 20, 25 and 30 degrees C, respectively. Although the maximum isotopic temperature difference found was only 0.6 per thousand, more extreme temperature variations may cause larger isotope effects. In order to understand the isotope effects on the total inorganic carbon (TIC), a better measure is to calculate the proportions of the inorganic carbon species (CO(2)(g), CO(2)(aq) and HCO(3)(-)) and to determine their cumulative delta(13)C(TIC). In all three experiments delta(13)C(TIC) was more positive than the initial isotopic composition of the benzoate at a pH of 7. This suggests an uptake of (12)C in the biomass in order to match the carbon balance of these closed system experiments., (Copyright 2000 John Wiley & Sons, Ltd.)

Objective: To use an in vitro dilutional blood model to simulate aerobic hyperlactaemia, and to question whether base excess and anion gap distinguish aerobic from anaerobic lactate production., Methods: Cooled fresh blood was diluted (3:1) with nine different crystalloid solutions, each with a sodium concentration of 140 mmol/L but with strong ion difference values ranging from -5 mEq/L to 40 mEq/L due to varying concentrations of Cl(-), HCO(3)(-) and lactate anions. Normocapnic pH and base excess values post-dilution were determined by gas equilibration. Strong ion difference and anion gap values were measured., Results: There was close correlation between the normocapnic pH and both the diluent strong ion difference and the final strong ion difference of the diluted specimens (R(2) = 0.96 and 0.89 respectively). This was independent of lactate concentrations in diluent or in post-dilution plasma. Where lactate-containing crystalloid was added, base excess, normocapnic pH and anion gap were strongly correlated with the final plasma lactate concentrations (R(2) >or= 0.99). However, only at final lactate concentrations of approximately 10 - 15 mmol/L did values of base excess, normocapnic pH or anion gap indicate metabolic acidosis., Conclusions: Hyperlactaemia from any source reduces strong ion difference and base excess and increases the anion gap, but values may remain in the normal range until hyperlactaemia is severe. Abnormal base excess and anion gap values do not distinguish aerobic from anaerobic lactate production. Normal values merely reflect low sensitivity to small lactate elevations (aerobic or otherwise).

Objective: The objective was to assess primary care physicians' awareness of their patients' rated emotions, satisfaction, and opinion of the quality of their communication., Design: Diabetic patients (n = 261) and their primary care physicians (n = 44) each filled in a questionnaire following a routine medical visit. Patients were asked about the quality of communication with their physician, their satisfaction, and their experience of six emotions. Physicians were asked to estimate the patients' views on each of these questions. Physicians' awareness was measured by (1) correlating the physician and patient ratings, and (2) comparing mean ratings between physicians and patients., Results: Correlations between patients' and physicians' views of patients' emotions and satisfaction were weak to moderate in magnitude; for patients' opinion of communication quality, there was no correlation. All ratings showed a substantial discrepancy between physicians and patients, such that physicians thought patients' responses were more negative than they actually were., Conclusions: Although the causes of physicians' weak awareness of their patients' responses are not known, the results suggest that the patients' affective responses may be an especially neglected aspect of communication in the medical visit.

Introduction: Catheter ablation may prevent conduction of multiple atrial wavefronts and/or reduce the critical mass of atrial myocardium required to sustain fibrillation. The purpose of this study was to examine the effect of radiofrequency (RF) energy application on conduction in canine atria by performing high-density epicardial mapping and careful histologic examination of the ablation zone., Methods and Results: RF energy was applied to the right atrial endocardium in nine anesthetized mongrel dogs in an attempt to create a line of conduction block spanning the vertical length of a 504-channel epicardial mapping plaque. The mean length and width of the histologically determined ablation zone was 34 +/- 4 and 7.3 +/- 2.6 mm, respectively. No thrombus was present. Conduction block that spanned the mapping plaque in 6 of 9 animals was matched histologically by continuous transmural necrosis in five. In one, only a portion of the ablation zone was transmural; the remainder was wide but nontransmural. In 2 of 3 animals with conduction, a narrow region was present where continuous transmural necrosis was absent. In the other animal, conduction was present despite continuous transmural necrosis., Conclusion: Conduction block usually occurred when continuous transmural necrosis was present, and conduction usually persisted when continuous transmural necrosis was absent. However, important exceptions were observed, including block when the ablation zone was wide but nontransmural, and conduction despite a thin line of continuous transmural necrosis.

Background: The importance of the role of the autonomic nervous system (ANS) in the initiation and propagation of atrial fibrillation has been demonstrated in the condition of paroxysmal atrial fibrillation. However, the role of the ANS in patients with chronic atrial fibrillation is less clear. Some patients with chronic atrial fibrillation are resistant to the standard techniques of direct current (DC) cardioversion., Hypothesis: We sought to investigate whether excessive vagal tone might prevent the restoration of sinus rhythm and to establish that the abolition of vagal tone using intravenous atropine will facilitate DC cardioversion in patients with atrial fibrillation who are resistant to the standard cardioversion techniques., Methods: Beginning in August 1994, a change in the protocol for elective DC cardioversion of atrial fibrillation was made to include the use of intravenous atropine for patients resistant to the standard techniques of DC cardioversion., Results: Over a 2-year period, 140 elective cardioversions were performed for atrial fibrillation. Sinus rhythm could not be restored on 31 occasions. Intravenous atropine prior to a further 360 J shock with paddles in the anteroposterior position allowed sinus rhythm to be restored on nine occasions. Patients with successful cardioversion after atropine had significantly better left ventricular function than those who remained in atrial fibrillation (p = 0.001) as well as a tendency toward a smaller left atrium., Conclusion: This study suggests that high vagal tone, which is dominant in patients with structurally normal hearts, may prevent the termination of atrial fibrillation by standard techniques of DC cardioversion, and that the abolition of high vagal tone by atropine facilitates the restoration of sinus rhythm.

The Iowa Case Management Project (ICMP) was developed to evaluate the effectiveness of a comprehensive, solution-focused model of case management with rural clients in drug abuse treatment. For this preliminary report, 483 clients who were admitted to residential or outpatient treatment at a local facility volunteered to participate and were randomly assigned to one of four research conditions. Clients in three of the conditions received Iowa Case Management (ICM), while clients in the fourth condition received standard treatment services and served as the control group. Clients were assessed regarding psychosocial characteristics at intake and three additional times during the subsequent 12 months.

Stable isotope methods are potentially quite useful for validating natural or enhanced mineral degradation of contaminants. For this reason, a continuous flow gas chromatograph (GC), isotope ratio mass spectrometer (IRMS) has been coupled with a quadrupole mass selective detector (MSD) to allow simultaneous mass spectral and stable carbon isotope ratio data to be obtained from a single chromatographic analysis. This allows the target contaminant and any extra-cellular degradation intermediates to be both qualified and quantified. Previously acceptable limits of precision (0.3 parts per mil) are undesirable given the small fractionation observed during aerobic degradation. To further understand the fate of organic contaminants and to gain information about the metabolic degradative pathway employed by a microorganism, routine isotopic analyses on a range of analytes have been performed. Quantities of sample producing mass-44 ion beam signal (I(44)) of 2 x 10(-10) to 1 x 10(-8) A were analysed. When the IRMS was tuned for high sensitivity, ion source nonlinearities were overcome by peak height correction from an algorithm that was produced using known isotopic standards of varying concentrations. This led to sample accuracy of <0.01 per thousand and sample precision of 0.1 per thousand. Copyright 1999 John Wiley & Sons, Ltd.

Although considerable evidence indicates that dispositional empathy is associated with the degree of help that observers will offer needy targets, little is known about the effect of empathy on one's initial willingness to enter situations in which such needy targets might be found. Three studies were conducted to evaluate two related propositions: (1) that dispositional empathy influences such situational preferences, and (2) that this influence is mediated by the expectancies one holds regarding the emotions likely to occur in those situations. Using hypothetical judgments, Study 1 found support for both propositions. Study 2, in which participants believed that their responses actually committed them to encountering needy targets, provided further support for the model, as did Study 3, which examined the experiences of actual community volunteers. The theoretical and practical implications of these findings are discussed.

Objective: To investigate the effects of experimentally induced acute gastric dilatation on electrical and mechanical activities of the stomach in dogs., Animals: 7 healthy dogs., Procedure: Electrodes and strain-gauge force transducers were implanted on the serosal surface of the antrum and pylorus. Eight days later, baseline gastric electrical and contractile activities were recorded. The dogs were anesthetized and mechanically ventilated to maintain normocapnia while the stomach was distended (intragastric pressure, 30 mm Hg) for 180 minutes, using a thin compliant bag. Gastric electrical and contractile activities were recorded again on days 1 and 10 after dilatation. Recordings were analyzed to determine gastric slow-wave frequency, slow-wave dysrhythmia, propagation velocity of slow-waves, coupling of contractions to slow waves, motility index on the basis of relative contractile amplitudes, and onset of contractions after a standardized meal., Results: Electrical or contractile activities were not significantly different 18 hours after acute gastric dilatation (day 1). Arrhythmias were evident before and after gastric dilatation in dogs from which food was withheld and in dogs after consumption of a meal., Conclusions: Variables for assessing gastric electrical and contractile activities were unaffected 18 hours after acute gastric dilatation., Clinical Relevance: Analysis of results of this study indicated that altered electrical and contractile activities in dogs with short-term gastric dilatation are not likely to be secondary to the process of acute gastric dilatation.

Site-directed and second site suppressor mutagenesis identify an intrahelical salt bridge in the eleventh transmembrane segment of UhpT, the sugar phosphate carrier of Escherichia coli. Glucose 6-phosphate (G6P) transport by UhpT is inactivated if cysteine replaces either Asp388 or Lys391 but not if both are replaced. This suggests that Asp388 and Lys391 are involved in an intrahelical salt bridge and that neither is required for normal UhpT function. This interpretation is strengthened by the finding that mutations at Lys391 (K391N, K391Q, and K391T) are recovered as revertants of the inactive D388C variant. Further work shows that although the D388C variant is null for G6P transport, movement of 32Pi by homologous Pi/Pi exchange is unaffected. This raises the possibility that this derivative may have latent function, a possibility confirmed by showing that D388C is a gain-of-function mutation in which phosphoenolpyruvate (PEP) is the preferred substrate. Added study of the Pi/Pi exchange shows that in wild type UhpT this partial reaction is readily blocked by G6P but not PEP. By contrast, in the D388C variant, Pi/Pi exchange is unaffected by G6P but is inhibited by both PEP and 3-phosphoglycerate. These latter substrates are used by PgtP, a related Pi-linked antiporter, which lacks the Asp388-Lys391 salt bridge but has instead an uncompensated arginine at position 391. For this reason, we conclude that in both UhpT and PgtP position 391 can serve as a determinant of substrate selectivity by acting as a receptor for the anionic carboxyl brought into the translocation pathway by PEP.

A disorder of gastric motility should be suspected in patients with chronic vomiting. Imaging studies are used to confirm delayed gastric emptying, the most common form of a gastric motility disorder. Other causes of chronic vomiting, for example, metabolic or endocrine disorders, other abdominal disorders, mechanical causes of gastric obstruction, and lower gastrointestinal tract disease, are then ruled out. If no underlying cause is determined, a functional disorder of gastric emptying is presumptively diagnosed. Treatment consists of dietary management and gastric prokinetic agents. Cisapride is the drug of choice for treating delayed gastric emptying followed by erythromycin and ranitidine or nizatidine.

Idiopathic dilated cardiomyopathy is a primary myocardial disease which is characterised by left ventricular, or biventricular, dilatation and impaired contractility. The precise aetiology is unknown and the relative contribution of genetic and environmental factors is debated. We report two identical male twins of Caucasian origin with idiopathic dilated cardiomyopathy who presented within a few months of each other.

Objective: To determine effect of diets with variable n-6-to-n-3 fatty acid (FA) ratio on CD4+ and CD8+ T-lymphocyte subpopulations, and on results of routine laboratory analyses (CBC and total WBC count, serum biochemical analyses, and urinalysis)., Animals: 20 healthy, aged (9.5 to 11.5 years old) female Beagles., Procedure: Dogs were fed 1 of 3 diets that contained 6% fat by weight but differed in amounts of n-6 and n-3 FA. For 11 weeks, 6 dogs were fed a low concentration of n-3 FA (ratio, 31:1), 7 were fed a medium concentration (5.4:1), and 7 were fed a high concentration (1.4:1). Preprandial blood and urine samples were collected before beginning the study and at 8 weeks for evaluation of laboratory variables. Before and at 3, 6, and 8 weeks during the study, blood was drawn for total WBC and lymphocyte counts and for characterization of T-cell subpopulations. At 8 and 10 weeks, dogs were vaccinated with keyhole limpet hemocyanin suspension. Blood was drawn 4 days after each vaccination, and lymphocytes were isolated for flow cytometry. Effects of diet and vaccination on each variable were determined., Results: After vaccination, total lymphocyte count increased and CD4+ T lymphocyte count and the CD4(+)-to-CD8+ ratio decreased in dogs consuming the diet with n-6-to-n-3 FA ratio of 1.4:1., Conclusion: Feeding a diet with n-6-to-n-3 FA ratio of 1.4:1 had significant effects on CD4+ T lymphocytes in healthy, aged Beagles after vaccination.

A 52 year old man with severe chronic left ventricular failure (New York Heart Association class IV) was considered unsuitable for cardiac transplantation because of high and irreversible pulmonary vascular resistance (PVR). In an attempt to produce symptomatic improvement, metoprolol was cautiously introduced, initially at 6.25 mg twice daily. This was slowly increased to 50 mg twice daily over a two month period and continued thereafter. After four months of treatment the patient's symptoms had improved dramatically. His exercise tolerance had increased and diuretic requirements reduced to frusemide 160 mg/day only. Assessment of right heart pressures was repeated and, other than a drop in resting heart rate, there was little change in his pulmonary artery pressure or PVR. His right heart pressures were reassessed showing a pronounced reduction in pulmonary artery pressure and a significant reduction in PVR, which fell further with inhaled oxygen and sublingual nitrates. He was then accepted onto the active waiting list for cardiac transplantation. A possible mechanism of action was investigated by assessing responses to beta agonists during treatment. Not only was there pronounced improvement in PVR but it was also demonstrated that beta receptor subtype cross-regulation may have contributed to the mechanism of benefit.

Postembryonic skeletal ontogeny of the pelobatid frog Scaphiopus intermontanus is described based on a developmental series of cleared-and-stained, whole-mount specimens. The focus is on laboratory-reared individuals fed a herbivorous diet as larvae. Although there is variation in the timing of ossification of individual skeletal elements relative to developmental stages based on external morphological criteia, the sequence of skeletal development generally is conservative. Compared with its close relative, S. bombifrons, ossifications that occur during prometamorphosis tend to be slightly delayed in S. intermontanus; however, cranial bones that ossify during late metamorphic climax in S. intermontanus are delayed until post-metamorphosis in S. bombifrons. The differences in timing between the two species are consistent, however, with differences observed between two developmental series of S. intermontanus raised at two different temperatures. Noteworthy features of skeletal development in S. intermontanus include: 1) presence of palatine ossifications that form from independent centers of ossification and soon fuse with the postnarial portion of the vomers to form the compound vomeropalatine bones; 2) compound sphenethmoid that may arise from four or more endochondral centers of ossification and one dorsal, dermal center of ossification; and 3) presence of transverse processes and vestigal prezygapophyses on the first postsacral vertebra. The morphology of the larval orbitohyoideus and interhyoideus muscles is compared. The record of skeletal ontogeny and muscle morphology presented herein for the herbivorous larval morph can serve as a baseline for comparisons with the ontogeny of the carnivorous larval morph of Scaphiopus.

Societal values regarding the nature and consequences of patient autonomy and medical paternalism underscore the current debates surrounding informed consent and shared decision making. The debate is significant in that it both reflects and determines normative expectations for physician and patient conduct as well as the nature and form of the therapeutic relationship. Analysis of the literature describing communication differences between physicians of different genders indicates that female physicians show a greater affinity for collaborative models of patient-physician relationship than do their male colleagues. Female physicians spend more time with their patients, are more likely to engage their patients in discussions of their social and psychologic context, and deal more often with feelings and emotions. Moreover, female physicians facilitate partnership and patient participation in the medical exchange more effectively than do male physicians. The authors propose that the quality of the interactive process is critical to the establishment of a therapeutic relationship and that this process is related to physician gender. They also suggest that physician gender matters in the shaping of the patient-physician relationship through this interactive process.

Communication patterns between physicians and patients during the medical visit reveal behavioral gender differences. Studies suggest varying satisfaction levels depending on physician gender. The communication style of female physicians often includes slightly more focus on the patient's emotional and psychosocial concerns, more positively toned communications, and a more egalitarian style reflected in increased levels of patient participation. However, because patients' satisfaction with female physicians does not typically exceed that for male physicians, other factors may influence satisfaction ratings.

Objectives: This article summarizes the results of 153 studies published between 1977 and 1994 that evaluated the effectiveness of interventions to improve patient compliance with medical regimens., Methods: The compliance interventions were classified by theoretical focus into educational, behavioral, and affective categories within which specific intervention strategies were further distinguished. The compliance indicators broadly represent five classes of compliance-related assessments: (1) health outcomes (eg, blood pressure and hospitalization), (2) direct indicators (eg, urine and blood tracers and weight change), (3) indirect indicators (eg, pill count and refill records), (4) subjective report (eg, patients' or others' reports), and (5) utilization (appointment making and keeping and use of preventive services). An effect size (ES) r, defined as Fisher's Z transformation of the Pearson correlation coefficient, representing the association between each intervention (intervention versus control) and compliance measure was calculated. Both an unweighted and weighted r were calculated because of large sample size variation, and a combined probability across studies was calculated., Results: The interventions produced significant effects for all the compliance indicators (combined Z values more than 5 and less than 32), with the magnitude of effects ranging from small to large. The largest effects (unweighted) were evident for refill records and pill counts and in blood/urine and weight change studies. Although smaller in magnitude, compliance effects were evident for improved health outcomes and utilization. Chronic disease patients, including those with diabetes and hypertension, as well as cancer patients and those with mental health problems especially benefited from interventions., Conclusions: No single strategy or programmatic focus showed any clear advantage compared with another. Comprehensive interventions combining cognitive, behavioral, and affective components were more effective than single-focus interventions.

Objective: Our purpose was to present information about open surgical biopsy. It is hoped that this will be helpful when reviewing information about core needle biopsy, Study Design: Review of 461 open surgical biopsies for nonpalpable mammographic abnormalities was performed. All patients were managed by the Women's Health Center of Logansport. Core needle biopsy data came from the literature., Results: Open surgical biopsy compared favorably to core needle biopsy with regard to accuracy, cost, patient convenience, recovery, adequacy of specimen, identification of primary site, and cosmetics., Conclusion: Despite core needle biopsy marketing, open surgical biopsy has its advantages and should not be relegated to the museum.

The aim of the study was to evaluate the predictive value of the zona-free hamster egg penetration test (ZHEPT) for success in in-vitro fertilization (IVF) at various insemination concentrations ranging between 0.1 and >0.6 x 10(6)/ml. The ZHEPT was assessed using sperm samples from 87 couples undergoing IVF treatment. A similar test was simultaneously performed on the same semen sample following ionophore induction of the acrosome reaction (ZHEPTii test). Both the tests were poorly correlated with the fertilization rate of IVF at all the insemination concentrations except at >0.6 x 10(6)/ml, when there was good correlation between the ZHEPTii test and the fertilization rate. Following exclusion of two cases with an oocyte problem, further statistical analysis revealed that both the ZHEPT and ZHEPTii tests were poorly correlated with fertilization rate in IVF in this treatment group. This study suggests that the ZHEPT (with and without ionophore induction of the acrosome reaction) has a poor predictive value for the success of fertilization in IVF treatment at any insemination concentration.

Two explanations were tested for why patients who are less healthy tend to be less satisfied with their medical care than healthier patients. The explanations were (a) that poor health produces dissatisfaction directly and (b) that poor health produces dissatisfaction through the mediating effect of physicians' behavior. Two studies are presented that measured patients' health status, patients' satisfaction with care, and their physicians' communication as recorded on audiotape. In Study 1, 114 patients had first visits with rheumatologists; in Study 2, 649 patients had continuing-care visits with physicians in internal and family medicine. Causal modeling revealed that the first study supported the direct explanation. The second study also supported the direct explanation, as well as the mediation explanation with respect to the physician's use of social conversation.

Much controversy surrounds the clinical significance of an increased concentration of white blood cells (WBC) in the male ejaculate. The World Health Organization's classification of leukocytospermia is a concentration > 1 x 10(6) WBC/ml. The aim of this study was to assess the association of varying concentrations of leukocytes to sperm morphology evaluated by strict criteria. Semen samples were collected from a total of 79 patients. Round cells on the initial semen analysis were stained for identification of polymorphonuclear granulocytes (PMN) as the largest group (50-60%) of white blood cells using the Endtz Method commercially produced as Leucoscreen. Diff Quick Staining Kit was used for sperm morphology assessment and 200 spermatozoa were assessed per slide. Data were evaluated using two cut-off criteria, at 0.5 x 10(6) WBC/ml and 1 x 10(6) WBC/ml. Mann-Whitney U-values at both < and > 0.5 x 10(6)/ml PMN (P < 0.001) and at < and > 1.0 x 10(6)/ml PMN (P < 0.015) showed differences between percentage normal forms. Spearman's rank correlation coefficient for PMN concentration showed a negative correlation (P < 0.01) with percentage normal sperm morphology and positive correlation for midpiece abnormalities (P < 0.04). These data support the hypothesis that PMN have a role in the increase of abnormal spermatozoa, particularly those with midpiece abnormalities, by as yet unknown mechanisms.

Ligands that are transported by the maltose transport system of Escherichia coli must first bind to the periplasmic maltose-binding protein (MBP). However, binding of a ligand does not always lead to its transport. As reported earlier, reduced or oxidized maltodextrins bind tightly to MBP but are not transported; some mutant MBPs, such as MalE254, bind maltodextrins tightly but cannot produce their transport. In this study, UV differential spectroscopy and fluorescence emission spectroscopy were used to study the modes by which various ligands bind to MBP. Maltose binding produced a red shift in the fluorescence emission spectrum of wild type MBP and a sharp hypochromatic trend below 265 nm in its UV spectrum (R mode (for red)). On the other hand, binding of reduced, oxidized, or cyclic maltodextrins produced a pronounced blue shift in the fluorescence emission spectrum of wild type MBP and a peak at about 250 nm in its UV difference spectrum (B mode (for blue). Binding of reducing maltodextrins to wild type MBP produced spectral changes that seemed to be a mixture of predominantly R mode binding and some B mode binding, whereas their binding to mutant MBP MalE254 produced changes indicative of pure B mode binding. Thus, the ligands that are bound exclusively via the B mode to either the wild type or MalE254 MBP are not transported.

Binding of ligands to the maltose-binding protein (MBP) of Escherichia coli often causes a global conformational change involving the closure of its two lobes. We have introduced a cysteine residue onto each of these lobes by site-directed mutagenesis and modified these residues with spin labels. Using EPR spectroscopy, we examined the changes, caused by the ligand binding, in distance between the two spin labels, hence between the two lobes. The binding of both maltose and maltotetraose induced a considerable closure of the N- and C-terminal lobes of MBP. Little closure occurred upon the binding of maltotetraitol or beta-cyclodextrin. Previous study by fluorescence and UV differential absorbance spectroscopy (Hall, J. A., Gehring, K., and Nikaido, H. (1997) J. Biol. Chem. 272, 17605-17609) showed that maltose and a large portion of maltotetraose bound to MBP via one mode (R mode or "end-on" mode), which is physiologically active and leads to the subsequent transport of the ligands across the cytoplasmic membrane. In contrast, maltotetraitol and beta-cyclodextrin bound to MBP via a different mode (B mode or "middle" mode), which is physiologically inactive. The present work suggests that the B mode is nonproductive because ligands binding in this manner prevent the closure of the two domains of MBP, and, as a result, the resulting ligand-MBP complex is incapable of interacting properly with the inner membrane-associated transporter complex.

In the preceding two papers (Hall, J. A., Gehring, K., and Nikaido, H. (1997) J. Biol. Chem. 272, 17605-17609; Hall, J. A., Thorgeirson, T. E., Liu, J., Shin, Y.-E., and Nikaido, H. (1997) J. Biol. Chem. 272, 17610-17614), we showed that ligands that bind to the Escherichia coli maltose-binding protein (MBP) without producing the closure of its two lobes are not transported into the cytoplasm. Here, we examine various combinations of ligands, MBPs, and membrane-associated transporters, by utilizing reconstituted proteoliposomes, right side-out membrane vesicles, and intact cells. Closed forms of wild type MBP, complexed with maltose or maltodextrins, interacted with wild type transporter complex to stimulate the hydrolysis of ATP by MalK ATPase located on the other side of the membrane, as shown earlier for the maltose-MBP complex (Davidson, A. L., Shuman, H. A., and Nikaido, H. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 2360-2364). In contrast, open forms of liganded MBPs, such as the complex containing wild type MBP and reduced, oxidized, or cyclic maltodextrins or the complex containing the mutant MBP MalE254 and unmodified maltodextrins, did not stimulate ATP hydrolysis, suggesting that the proper interaction between the ligand-MBP complex and the external surface of the transporter requires the former to be in the closed conformation. However, when a mutant transporter containing MalG511 was used, the already significant basal level of ATP hydrolysis was further stimulated not only by ligand MBPs in the closed form but also by those in the open form (except that containing beta-cyclodextrin), data suggesting that the mutant transporter does not always require the closed MBP complex presumably because of its exceptionally strong affinity to MBP, described earlier (Dean, D. A., Hor, L.-I., Shuman, H. A., and Nikaido, H. (1992) Mol. Microbiol. 6, 2033-2040). Furthermore, this mutant transporter was able to transport reduced maltodextrin, and cells expressing the transporter were able to grow by using reduced maltodextrin, if the periplasmic concentrations of MBP were kept low so as not to inhibit the transport process.

The study was designed to assess the outcome of treatment with permanent dual-chamber pacing of elderly patients with falls, dizziness and syncope associated with the demonstration of a hypersensitive cardioinhibitory reflex. Questionnaires were sent to patients (and their general practitioners) who had been referred to a regional pacing centre with recurrent falls, dizziness or syncope diagnosed as likely to be secondary to cardioinhibitory carotid sinus syndrome or predominantly cardioinhibitory vasovagal syndrome. After pacemaker insertion, 84% of patients had no further syncope over a mean follow-up period of 10 (range 1.5 to 30) months. Minor symptoms persisted in only 40% of all patients. Symptoms were unchanged in 22%. It was concluded that permanent dual-chamber pacing is an effective treatment for elderly patients with recurrent falls, dizziness and syncope in whom a hypersensitive cardioinhibitory reflex is found. Good results were obtained in this group with a simple diagnostic work-up.

The purpose of this study was to characterize the lipid classes in hepatic and adipose tissues from cats with idiopathic hepatic lipidosis (IHL). Concentrations of triglyceride, phospholipid phosphorus, and free and total cholesterol were determined in lipid extracts of liver homogenates from 5 cats with IHL and 5 healthy control cats. Total fatty acid composition of liver and adipose tissue was also compared. Triglyceride accounted for 34% of liver by weight in cats with IHL (338 +/- 38 mg/g wet liver) versus 1% in control cats (9.9 +/- 1.0 mg/g wet liver, P < .001). The mass of cholesterol ester was significantly higher in triglyceride-free (TG-free) liver from cats with IHL (741 +/- 340 micrograms/g TG-free wet liver) compared to healthy cats (31 +/- 11 micrograms/g TG-free wet liver, P < .05). Total fatty acid composition of hepatic tissue in the 2 groups differed; palmitate was higher (19.5 +/- 1.1% of total fatty acids in cats with IHL versus 9.2 +/- 2.7% in controls, P < .05), stearate was lower (8.5 +/- 0.8% versus 16.8 +/- 1.1%, P < .05), oleate was higher (41.2 +/- 1.6% versus 31.1 +/- 1.8%, P < .05), and arachidonate was lower (1.2 +/- 0.2% versus 6.0 +/- 0.9%, P < .05). The total fatty acid composition of adipose tissue also differed between the 2 groups; palmitate was higher (26.2 +/- 1.2% in cats with IHL versus 21.3 +/- 0.6% in controls, P < .05), total monounsaturated fatty acids were higher (48.4 +/- 1.0% versus 45.0 +/- 0.8%, P < .05), linolenate was lower (13.3 +/- 1.6% versus 17.5 +/- 0.9%, P < .05), total (n-6) fatty acids were lower (13.8 +/- 1.38% versus 18.4 +/- 0.83%, P < .05), linolenate was lower (0.2 +/- 0.04% versus 0.7 +/- 0.06%, P < .06), and total (n-3) fatty acids were lower (0.3 +/- 0.02% versus 1.3 +/- 0.32%, P < .05). The fatty acid composition of both liver and adipose tissue was similar for stearate, oleate, linoleate, and linolenate in cats with IHL. These results support the hypothesis that the origin of hepatic triglyceride in cats with IHL is the mobilization of fatty acids from adipose tissue.

We studied the effects of feeding experimental diets containing (n-6) to (n-3) fatty acid ratios of 31:1, 5.4:1, and 1.4:1 to 20 healthy female geriatric Beagles (9.5-11.5 y) for 8-12 wk on various indices of the immune response. Compared with the 31:1 diet, consumption of the 5.4:1 and 1.4:1 diets significantly increased (n-3) fatty acids in plasma (2.17 +/- 0.64, 9.05 +/- 0.64, 17.46 +/- 0.64 g/100 g fatty acids, respectively, P < 0.0001). Although supplementation with (n-3) fatty acids did not significantly alter the humoral immune response to keyhole limpet hemocyanin (KLH), it significantly suppressed the cell-mediated immune response based on results of a delayed-type hypersensitivity (DTH) skin test. The DTH response after intradermal injection of KLH at 24 h was significantly lower in the group consuming the 1.4:1 diet compared with the group consuming the 5.4:1 (P = 0.02) or the 31:1 diets (P = 0.04), and remained significantly suppressed at 48 h in the group fed 1.4:1 relative to the group fed 31:1. After consumption of the 1.4:1 diet, stimulated mononuclear cells produced 52% less prostaglandin E2 (PGE2) than those from dogs fed the 31:1 diet (224 +/- 74 and 451 +/- 71 pmol/L, respectively, P = 0.04). Plasma concentration of alpha-tocopherol was 20% lower in dogs fed the 1.4:1 diet compared with those fed the 31:1 diet (P = 0.04), and lipid peroxidation was greater in both plasma (P = 0.03) and urine (P = 0.002). These data suggest that although a ratio of dietary (n-6) to (n-3) fatty acids of 1.4:1 depresses the cell-mediated immune response and PGE2 production, it increases lipid peroxidation and lowers vitamin E concentration.

Gastric electrical and contractile activities were assessed in healthy adult dogs on the eighth day after circumcostal gastropexy surgery, using serosal electrodes and strain gauge force transducers. Recordings were analysed to determine gastric slow wave frequency, presence of gastric slow wave dysrhythmias, gastric slow wave propagation velocity, coupling of gastric contractions to slow waves, a gastric motility index based on relative contractile amplitudes, and onset of gastric contractions after a standardised meal. Overall, gastric electrical and contractile activities were relatively unaffected by circumcostal gastropexy.

Aims: Long-term treatment with beta 1-selective adrenergic antagonists gives rise to cross-sensitisation of cardiac beta 2-adrenoceptor responses, with no corresponding alteration in beta 1-adrenoceptor responses. We performed a prospective randomised double-blind placebo-controlled cross-over study of the effects of nonselective beta-blockade with timolol on alpha-adrenergic and angiotensin II receptor mediated responses in normal subjects. We also wished to study the time course of beta 1- and beta 2-adrenergic responses after withdrawal of timolol., Methods: Six healthy males received timolol 10 mg twice daily or placebo for 14 days. On day 11 of treatment, vascular alpha 1-, alpha 2- and angiotensin II receptor responses were assessed by measuring the blood pressure increases in response to intravenous phenylephrine, alpha-methylnoradrenaline and angiotensin amide respectively, following one dose of timolol 10 mg (to block the beta-adrenergic effects of phenylephrine and alpha-methylnoradrenaline). Both systolic and diastolic blood pressure increased in response to each of these drugs, but these increases were not different on timolol treatment or placebo. Following cessation of treatment with timolol or placebo, beta 1- and beta 2-adrenoceptor mediated responses were assessed by measuring the heart rate responses to treadmill exercise and intravenous salbutamol infusion respectively. Half each of the subjects underwent this 2 days and 3 days respectively, after the end of treatment., Results: Both exercise-induced and salbutamol-induced tachycardia were not different following placebo or 3 days following the end of timolol treatment. However, 2 days following timolol treatment, both were attenuated; the reduction in salbutamol-induced tachycardia was significant, whilst the reduction in exercise tachycardia did not reach statistical significance. We also measured metabolic responses to exercise and to salbutamol infusion. Exercise induced a rise in plasma potassium and noradrenaline. Salbutamol produced a fall in plasma potassium, a rise in plasma glucose and insulin and also a rise in plasma noradrenaline. All of these changes were not different following placebo or 3 days after the end of timolol treatment; by contrast, 2 days following timolol treatment, all were significantly attenuated, with the exception of the rise in plasma glucose. In addition, the rise in both plasma glucose and insulin in response to an oral load of 75 g glucose were not different post-placebo, 2 or 3 days post-timolol., Conclusions: These results show that, following 14 days of nonselective beta-adrenoceptor blockade with timolol, there is evidence of residual beta-adrenoceptor blockade 2 days after drug withdrawal; this finding is in contrast with the known plasma profile of timolol (half-life 3-6 hours), but is consistent with our previous observations of the slow speeds of association and dissociation of timolol with beta-adrenoceptors in vitro. There is no evidence, in this study, of beta-adrenergic sensitisation following timolol withdrawal, nor of cross-regulation of vascular alpha 1-, alpha 2- or angiotensin II receptors in response to nonselective beta-adrenoceptor blockade.

In heart disease palliative care has received less attention than in cancer. In the Regional Study of Care for the Dying, carers of a random sample of deaths in 20 English health districts were interviewed about 10 months after the death. There were 675 respondents for patients dying with heart disease, and we report data on 600 deaths that were not sudden. 54% of patients died in hospital, 30% in their own home, 11% in a nursing or residential home, and 4% in other places. Half the patients were said to have known, or probably known, that they were likely to die; of these, 82% were said to have worked this out for themselves rather than been told by a doctor or nurse. More than one-third of patients (39%) died without an informal carer present. Respondents said that a quarter of the patients had wanted to die earlier: this desire was associated with older age and the number and severity of symptoms. The study suggests the need for health services to give greater attention to palliative care for patients dying with heart disease.