Insulin- and glucagon-independent effects of calcitonin gene-related peptide in the conscious dog.

Calcitonin gene-related peptide (CGRP) causes vasodilation in many vascular beds, resulting in hypotension and tachycardia. The current studies were conducted in overnight-fasted conscious dogs to determine the effect of different CGRP dosages on carbohydrate metabolism and catecholamine release resulting from hemodynamic changes. During a pancreatic clamp, dogs received intraportal infusions of CGRP at 13, 26, and 52 (n = 3) or 52, 105, and 210 pmol x kg(-1) x min(-1) (n = 4; 60 minutes at each rate). Blood pressure decreased (P < .05) and the heart rate and hepatic blood flow (HBF) increased a maximum of 100% and 30%, respectively (P < .05). For the five CGRP infusion rates, arterial plasma epinephrine increased approximately 1.3-, 2.4-, 7.4-, 12-fold, and eightfold basal, respectively; norepinephrine increased about 2.3-, 3.3-, 4.1-, 4.6-, and 4.8-fold basal, respectively; and cortisol increased about twofold, 3.4-fold, fivefold, sixfold, and 6.2-fold basal, respectively. At CGRP infusion rates of 52 pmol x kg(-1) x min(-1) or higher, increases (P < .05) occurred for plasma glucose, endogenous glucose production (EndoRa), and net hepatic uptake of gluconeogenic substrates (maximum change, 24 mg/dL, 1.3 mg x kg(-1) x min(-1), and 9.9 micromol x kg(-1) x min(-1), respectively). Arterial blood glycerol concentrations increased only a maximum of 30%. At the two highest CGRP infusion rates, glycerol returned to basal concentrations and arterial plasma nonesterified fatty acids (NEFAs) decreased. The increased net hepatic uptake of gluconeogenic substrates during CGRP infusion was sufficient to account for 49% to 58% of the increase in EndoRa. CGRP has no apparent direct effects on hepatic carbohydrate metabolism, but the catecholamines, at levels similar to those observed during CGRP infusion, stimulate hepatic glycogenolysis. Therefore, some factor(s) other than CGRP, probably an increase in circulating catecholamine concentrations, would appear to be responsible for at least 42% to 51% of the increase in EndoRa.

High incidence of appropriate implantable cardioverter-defibrillator therapy in patients with syncope of unknown etiology and inducible ventricular arrhythmias.

OBJECTIVES: This study evaluates the hypothesis that in patients with syncope of unknown origin, inducible ventricular arrhythmias are specific arrhythmias and therefore should be appropriately treated. BACKGROUND: Although syncope is a common clinical entity, the evaluation and treatment of patients with syncope without a clear etiology are not well defined. Many patients with syncope of undetermined origin undergo invasive electrophysiologic evaluation. Abnormalities of the sinus node, prolongation of conduction times or inducible arrhythmias found at these evaluations are usually assumed to be the cause of syncope and are therefore treated. However, whether tachyarrhythmias are truly the cause of syncope, and whether treatment of these tachyarrhythmias can prevent recurrent syncope and arrhythmic death, is unknown. METHODS: This study included 50 consecutive patients with syncope of undetermined origin, ventricular tachyarrhythmias at electrophysiologic evaluation and treatment with an implantable cardioverter-defibrillator. RESULTS: Ventricular stimulation led to sustained monomorphic ventricular tachycardia in 36 patients, nonsustained ventricular tachycardia in 5 and ventricular fibrillation in 9. Over a 23 +/- 15-month (mean +/- SD) follow-up period, 18 patients received appropriate implantable cardioverter-defibrillator shock. Actuarial probability of appropriate therapy was 22% at 1 year and 50% at 3 years. Recurrent syncope was seen in five patients, three of whom had appropriate defibrillatory detections at the time of syncope. Four patients died (sudden death in one, congestive heart failure in two). CONCLUSIONS: In patients with syncope of undetermined origin and inducible ventricular tachyarrhythmias, appropriate implantable cardioverter-defibrillator therapy is common at follow-up. Sudden cardiac death is uncommon. This low incidence of sudden cardiac death and high incidence of appropriate defibrillator therapy support the current practice of using implantable cardioverter-defibrillators in patients with syncope of unknown origin and inducible ventricular arrhythmias.

Medicare: past, present and future.

The history of the Medicare program, including changes that have been enacted over the years in an effort to control spiraling costs, is reviewed. Medigap insurance and preventive medical care for the elderly are examined, as is the impact of Medicare coverage for the terminally ill. Trends indicate that the Medicare system as presently structured is not financially viable. The question is: what will replace it?

A clinical information system transition: a nursing perspective.

The authors present the framework used within the Department of Nursing at Baystate Medical Center, Springfield, Massachusetts, to design, test, and implement the TDS 7000 Series (Eclipsys, Atlanta, GA). The TDS system was named the Patient Care Information System for Baystate Health Systems to reflect the commitment to patient care.

Inability of hyperglycemia to counter the ability of glucagon to increase net glucose output and activate glycogen phosphorylase in the perfused rat liver.

We examined the ability of hyperglycemia to alter the ability of glucagon to activate phosphorylase and stimulate glucose output in perfused rat livers. The livers were perfused with a Krebs-Henseleit buffer containing washed bovine erythrocytes and albumin at 37 degrees C for 90 or 120 minutes, In the first 60 minutes, the livers were perfused with insulin (10 microU/mL), glucagon (11 pg/mL), and glucose (105, 230, or 440 mg/dL). In the second 30 or 60 minutes, the glucagon concentration in the perfusate was elevated to 44, 88, 176 or 352 pg/mL or the infusion of glucagon was terminated. In the presence of glucose at 105 mg/dL, the termination of glucagon infusion decreased phosphorylase activity and glucose output. In contrast, the elevation of glucagon from 11 to 352 pg/mL activated phosphorylase and increased net glucose output in a dose-dependent manner. A linear correlation was observed between net glucose output and glycogen phosphorylase activity. An elevation of the glucose concentration from 105 to 230 or 440 mg/dL decreased net glucose output from 0.81 +/- 0.03 to 0.66 +/- 0.09 or -0.004 +/- 0.21 mg/min/100 g body weight, respectively, but did not cause significant change in phosphorylase-a activity (105 mg/dl, 50 +/- 11; 230 mg/dL, 40 +/- 2; 440 mg/dL, 69 +/ 3 mU/mg protein). The elevation of the glucagon concentration from 11 to 88 microU/mL in the presence of glucose at 105, 230, or 440 mg/dL increased net glucose output by 0.65 +/- 0.06, 0.61 +/- 0.08 or 0.64 +/- 0.26 mg/min 100 g body weight and raised phosphorylase-a activity by 65 +/- 5, 82 +/- 11, or 55 +/- 4 mU/mg protein, respectively. These results suggest that hyperglycemia decreases net hepatic glucose output without changing the activity of phosphory-lase-a. Further hyperglycemia does not alter the ability of glucagon to activate phosphorylase or to stimulate net hepatic glucose output.

The impact of defibrillator discharges on psychological functioning of implantable cardioverter defibrillator recipients.

A lag exists with respect to our understanding of the psychological demands and rehabilitation needs of individuals who have undergone implantable cardioverter defibrillator (ICD) implantation. The ICD is designed to transmit an electric shock to the heart to treat a potentially life-threatening arrhythmia. This study specifically examined the impact of defibrillator discharges on the psychological functioning of ICD recipients. A questionnaire was self-administered to 33 individuals who have been living with the ICD for at least 6 months. Results revealed that levels of anger and depression were significantly higher in those subjects who reported a lower discharge rate, while sense of well-being was significantly higher in those subjects who reported a greater discharge rate. Possible explanations for our findings were proposed as well as implications for clinical intervention were discussed.

Evidence that the brain of the conscious dog is insulin sensitive.

The aim of this study was to determine whether a selective increase in the level of insulin in the blood perfusing the brain is a determinant of the counterregulatory response to hypoglycemia. Experiments were carried out on 15 conscious 18-h-fasted dogs. Insulin was infused (2 mU/kg per min) in separate, randomized studies into a peripheral vein (n = 7) or both carotid and vertebral arteries (n = 8). This resulted in equivalent systemic insulinemia (84 +/- 6 vs. 86 +/- 6 microU/ml) but differing insulin levels in the head (84 +/- 6 vs. 195 +/- 5 microU/ml, respectively). Glucose was infused during peripheral insulin infusion to maintain the glucose level (56 +/- 2 mg/dl) at a value similar to that seen during head insulin infusion (58 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and similar hypoglycemia; steady state plasma epinephrine (792 +/- 198 vs. 2394 +/- 312 pg/ml), norepinephrine (404 +/- 33 vs. 778 +/- 93 pg/ml), cortisol (6.8 +/- 1.8 vs. 9.8 +/- 1.6 micrograms/dl) and pancreatic polypeptide (722 +/- 273 vs. 1061 +/- 255 pg/ml) levels were all increased to a greater extent during head insulin infusion (P < 0.05). Hepatic glucose production, measured with [3-3H]glucose, rose from 2.6 +/- 0.2 to 4.3 +/- 0.4 mg/kg per min (P < 0.01) in response to head insulin infusion but remained unchanged (2.6 +/- 0.5 mg/kg per min) during peripheral insulin infusion. Similarly, gluconeogenesis, lipolysis, and ketogenesis were increased twofold (P < 0.001) during head compared with peripheral insulin infusion. Cardiovascular parameters were also significantly higher (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog (a) the brain is directly responsive to physiologic elevations of insulin and (b) the response includes a profound stimulation of the autonomic nervous system with accompanying metabolic and cardiovascular changes.

Effects of hyperinsulinemia on the subsequent hormonal response to hypoglycemia in conscious dogs.

The aim of this study was to determine if differing periods of prior hyperinsulinemic nonhypoglycemia can modify the subsequent counterregulatory response to hypoglycemia. Experiments were carried out on 19 normal 18-h fasted conscious dogs. Insulin was infused intraportally at 8 mU.kg-1.min-1 for 3 h on two occasions and 3.5 h on a third separate occasion. This resulted in similar steady-state arterial insulin levels during each protocol (4,370 +/- 433 pmol/l). Each animal was maintained at a similar plasma glucose nadir (2.8 +/- 0.6 mmol/l) for 2 or 2.5h, depending on the protocol. In protocol I (n = 7) plasma glucose was allowed to fall to the desired hypoglycemic plateau by 30 min. In a second group of dogs (protocol II, n = 5) there was a 30-min period of euglycemic hyperinsulinemia followed by a 30-min fall (similar to protocol I) in plasma glucose. In a third group of dogs (protocol III, n = 7), there was an initial 15-min period of euglycemic hyperinsulinemia followed by a 45-min fall in plasma glucose. Differing periods of euglycemic hyperinsulinemia had distinct effects on subsequent counterregulation. During the final 2 h of hypoglycemia the incremental area under the curve (AUC) for glucagon was significantly greater in protocol I vs. II (3.0 +/- 1.0, -0.5 +/- 0.2 micrograms.l-1.min-1, P < 0.02, respectively). Conversely, catecholamine levels were increased in protocol II (30 min prior hyperinsulinemic euglycemia) compared with protocol I (epinephrine 1,448 +/- 268, 855 +/- 119 nmol.l-1.min-1; norepinephrine 244 +/- 30, 166 +/- 23 nmol.l-1.min-1, respectively, P < 0.05). During protocol III, glucagon and catecholamine levels were intermediate between protocols I (no euglycemic hyperinsulinemia) and II (30 min euglycemic hyperinsulinemia).(ABSTRACT TRUNCATED AT 250 WORDS)

Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease characterized by focal demyelination of the white matter of the brain and spinal cord. Central nervous system damage appears to be mediated by infiltrating T lymphocytes and macrophages, and a central role for autoreactive CD4+ T cells has been proposed. However, the initial immune events that lead to the chronic process of MS remain unidentified. We now present evidence that a subset of T lymphocytes bearing gamma/delta T-cell antigen receptors has been activated in patients with recent-onset disease. Cells recovered from the cerebrospinal fluid of subjects with MS were cultured for short periods of time in medium supplemented with T-cell growth factors. Expansions of V delta 1 and V delta 2 T-cell receptor-bearing lymphocytes were found only in cell populations obtained from subjects with recent-onset disease. Similar populations were not expanded in subjects with chronic MS or other neurological diseases. Junctional region sequencing showed the expanded gamma/delta T cells to be oligoclonal in nature, suggestive of specific stimulation by antigen. These results reveal a fundamental difference in the immunopathogenesis of acute vs. chronic disease and provide additional insight into the autoimmune nature of MS.

Regulation of net hepatic substrate balance by phenacylimidazolium ions in the conscious dog.

Phenacylimidazolium ions have the capacity to promote hepatic glycogen synthesis in vitro via activation of glycogen synthase and inactivation of phosphorylase. The purpose of the present study was to determine whether these compounds alter net hepatic substrate balance in vivo. Following a control period somatostatin was infused into 42h-fasted, conscious dogs and insulin (3X-basal) and glucagon (basal) were replaced intraportally. The glucose load to the liver was doubled with a peripheral glucose infusion and the phenacylimidazolium compound, 254236 (EX; n = 5) was infused intraportally at varying rates in four separate periods (0 (P1), 0.5 (P2), 1.0 (P3), 2.0 (P4) mumol kg-1 min-1). In a separate group of animals (C; n = 5) saline was infused intraportally during P1-P4 to match the volume rate of delivery that occurred in EX. In C net hepatic glucose uptake was 8.5 +/- 1.7 mumol kg-1 min-1 during P1 and did not change significantly throughout the study. In EX net hepatic glucose uptake increased (p < 0.05) from 9.0 +/- 2.5 during P1 to 16.2 +/- 3.1 mumol kg-1 min-1 during P4. Whereas net hepatic lactate output was evident throughout P1-P4 in C, the liver consistently switched to net lactate uptake during P3 (1.2 +/- 1.7 mumol kg-1 min-1) and P4 (2.2 +/- 1.0 mumol kg-1 min-1) in EX. Sympathoadrenal activation (increased catecholamines) was evident in EX during period 4. The increased hepatic retention of carbon (glucose and lactate) coincident with 254236 infusion in conscious dogs is less than that observed in vitro but is consistent with a role for phenacylimidazolium ions in promoting hepatic glycogen synthesis.

Locating MRIs through marginal analysis.

The location decision for a magnetic resonance imaging (MRI) services facility is evaluated through marginal analysis. Both population-based and referral-based data are applied. The results provide input for a series of practical recommendations for MRI service providers.

Effects of differing insulin levels on response to equivalent hypoglycemia in conscious dogs.

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia. Insulin was infused intraportally into normal 18-h-fasted conscious dogs at 2 (low, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during the high dose to maintain plasma glucose similar to low (50 +/- 1 mg/dl). Despite similar plasma glucose levels, epinephrine (2,589 +/- 260, 806 +/- 180 pg/ml), norepinephrine (535 +/- 60, 303 +/- 55 pg/ml), cortisol (12.1 +/- 1.5, 5.8 +/- 1.2 micrograms/dl), and pancreatic polypeptide (1,198 +/- 150, 598 +/- 250 pg/ml) were all increased in the presence of high-dose insulin (P < 0.05). Glucagon levels were similar during both insulin infusions. Hepatic glucose production, measured with [3-3H]-glucose, rose from 2.6 +/- 0.2 to 4.7 +/- 0.3 mg.kg-1.min-1 in response to high insulin (P < 0.01) but remained unchanged, 3.0 +/- 0.5 mg.kg-1.min-1, during low-dose infusions. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. By the final hour of the high-dose euglycemic clamps, cortisol (2.4 +/- 0.4 to 4.8 +/- 0.8 micrograms/dl) and norepinephrine (125 +/- 34 to 278 +/- 60 pg/ml) had increased (P < 0.05) compared with baseline. Plasma epinephrine levels remained unchanged during both series of euglycemic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficiency of compensation for absence of fall in insulin during exercise.

To assess compensation for the absence of the exercise-induced fall in insulin, dogs underwent 150 min of treadmill exercise with insulin infused intraportally with (IC + Glc; n = 7) or without (IC; n = 6) glucose clamped. Glucose production (Ra), gluconeogenic conversion (Conv), and intrahepatic gluconeogenic efficiency (Eff) were assessed with tracers ([3H]glucose, [14C]alanine) and arteriovenous differences. Glucose fell by 6 +/- 4 and 11 +/- 2 mg/dl at 30 min of exercise and by 8 +/- 2 and 36 +/- 5 mg/dl at 150 min in IC + Glc and IC. Glucagon rose by 16 +/- 8 and 55 +/- 17 pg/ml by 30 min of exercise and by 18 +/- 6 and 93 +/- 22 pg/ml by 150 min in IC + Glc and IC. Norepinephrine was unaffected by the glycemic decrement in IC, whereas epinephrine was greater for the last 60 min of exercise. Ra rose by an average of 0.9 +/- 0.3 and 3.7 +/- 0.2 mg.kg-1.min-1 in IC + Glc and IC. Conv rose by 91 +/- 39 and 325 +/- 75% in IC + Glc and IC at 150 min of exercise, and Eff rose by 87 +/- 57 and 358 +/- 99%. The compensatory Ra exceeded the maximum possible gluconeogenic rate, indicating that glycogenolysis was also stimulated. In summary, in the absence of the exercise-induced fall in insulin 1) glycemia falls approximately fourfold faster; 2) minimal glycemic decrements elicit a large and rapid increase in Ra; 3) this compensation involves a glycogenolytic and gluconeogenic response; 4) the accelerated gluconeogenic rate is due, in large part, to stimulation of Eff; and 5) the compensatory Ra is likely mediated, in part, by glucagon. Hence, although the fall in insulin is essential for normal glucoregulation during exercise, a highly sensitive counterregulatory response prevents severe hypoglycemia. The remarkable sensitivity of the liver to small changes in glycemia implies that the normal coupling of the exercise-induced increase in Ra to glucose utilization may be signaled by small, nearly imperceptible changes in glucose.

Accuracy of rhythm classification using a data log system in implantable cardioverter defibrillators.

Because the presence or absence of symptoms alone may be insufficient to correctly diagnose the rhythm for which implantable cardioverter defibrillator therapy is delivered, we hypothesized that the addition of data log information available in Telectronics ATP 4210 may improve the accuracy of rhythm classification. With this system the recorded ventricular electrogram cycle length is reported on a beat-to-beat basis immediately before, during, and after the tachyarrhythmia is detected. Using this information recorded from the data log in 32 separate tachyarrhythmia episodes in 20 patients, we compared the sensitivity, specificity, and predictive accuracy of rhythm classification on the basis of symptoms alone, data log alone, and data log combined with symptoms. While classification based on symptoms alone is highly specific (10/10 episodes), it is insensitive and has an overall predictive accuracy of 53%. By contrast, data log is sensitive (90%) and specific (91%) with better predictive accuracy (94%) than symptoms alone (P = 0.002). The addition of symptoms to information on beat-to-beat cycle length from data log resulted in a slight increase in predictive accuracy.

Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work.

The effects of the exercise-induced rise in glucagon were studied during 2.5 h of treadmill exercise in 18-h fasted dogs. Five dogs were studied during paired experiments in which pancreatic hormones were clamped at basal levels during a control period (using somatostatin and intraportal hormone replacement), then altered during exercise to stimulate the normal exercise-induced fall in insulin, while glucagon was 1) increased to mimic its normal exercise-induced rise (SG) and 2) maintained at a basal level (BG). Six additional dogs were studied as described with saline infusion alone (C). Gluconeogenesis (GNG) and glucose production (Ra) were measured using tracers [( 3-3H]glucose and [U-14C]alanine) and arteriovenous differences. Glucose fell slightly during exercise in C and was infused in SG and BG so as to mimic the response in C. Glucagon rose from 60 +/- 3 and 74 +/- 5 pg/ml to 118 +/- 14 and 122 +/- 17 pg/ml with exercise in C and SG and was unchanged from basal in BG (67 +/- 6 pg/ml). In C, SG, and BG, insulin fell during exercise by 5 +/- 1, 6 +/- 1, and 6 +/- 1 microU/ml. Ra rose from 3.3 +/- 0.2 and 3.0 +/- 0.2 mg.kg-1.min-1 to 8.6 +/- 0.8 and 9.5 +/- 1.5 mg.kg-1.min-1 with exercise in C and SG, but from only 3.0 +/- 0.2 to 5.5 +/- 0.8 mg.kg-1.min-1 in BG. GNG increased by 248 +/- 38 and 183 +/- 75% with exercise in C and SG but by only 56 +/- 21% in BG. Intrahepatic gluconeogenic efficiency was also enhanced by the rise in glucagon increasing by 338 +/- 55 and 198 +/- 52% in C and SG but by only 54 +/- 46% in BG. The rise in hepatic fractional alanine extraction was 0.38 +/- 0.04 and 0.33 +/- 0.04 during exercise in C and SG and only 0.08 +/- 0.06 in BG. Ra was increased beyond that which could be explained by effects on GNG alone, hence hepatic glycogenolysis must have also been enhanced by the rise in glucagon. In conclusion, in the dog, the exercise-induced rise in glucagon 1) controls approximately 65% of the increase in Ra, 2) increases hepatic glycogenolysis and GNG, and 3) enhances GNG by stimulating precursor extraction by the liver and precursor conversion to glucose within the liver.