Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study.

OBJECTIVES: The lower esophageal sphincter (LES), surrounded by diaphragmatic muscle, prevents gastroesophageal reflux. When these structures become incompetent, gastric contents may cause gastroesophageal reflux disease (GERD). For treatment, lifestyle interventions are always recommended. We hypothesized that by actively training the crura of the diaphragm as part of the LES using breathing training exercises, GERD can be positively influenced. METHODS: A prospective randomized controlled study was performed. Patients with non-erosive GERD or healed esophagitis without large hernia and/or previous surgery were included. Patients were randomized and allocated either to active breathing training program or to a control group. Quality of life (QoL), pH-metry, and on-demand proton pump inhibitor (PPI) usage were assessed at baseline and after 4 weeks of training. For long-term follow-up, all patients were invited to continue active breathing training and were further assessed regarding QoL and PPI usage after 9 months. Paired and unpaired t-test was used for statistical analysis. RESULTS: Nineteen patients with non-erosive GERD or healed esophagitis were randomized into two groups (10 training group and 9 control group). There was no difference in baseline patient characteristics between the groups and all patients finished the study. There was a significant decrease in time with a pH<4.0 in the training group (9.1±1.3 vs. 4.7±0.9%; P<0.05), but there was no change in the control group. QoL scores improved significantly in the training group (13.4±1.98 before and 10.8±1.86 after training; P<0.01), but no changes in QoL were seen in the control group. At long-term follow-up at 9 months, patients who continued breathing exercise (11/19) showed a significant decrease in QoL scores and PPI usage (15.1±2.2 vs. 9.7±1.6; 98±34 vs. 25±12 mg/week, respectively; P<0.05), whereas patients who did not train had no long-term effect. CONCLUSIONS: We show that actively training the diaphragm by breathing exercise can improve GERD as assessed by pH-metry, QoL scores and PPI usage. This non-pharmacological lifestyle intervention could help to reduce the disease burden of GERD.

Intestinal secretion induced by vasoactive intestinal polypeptide. A comparison with cholera toxin in the canine jejunum in vivo.

The effect of vasoactive intestinal polypeptide (VIP) on intestinal water and electrolyte transport and transmucosal potential difference was investigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte solution. VIP (0.08 mug/kg per min) was administered directly into the superior mesenteric artery by continuous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentration of 12,460 pg/ml reached the loops. VIP caused secretion of water and electrolytes; for example, chloride: control, 8 mueq/cm per h absorption; VIP, 92 mueq/cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chloride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium secretion. VIP caused a slight increase in protein output into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.

Effect of somatostatin and atropine infusion on intestinal transit time and fructose absorption in the perfused human jejunum.

Somatostatin has previously been shown to reduce nutrient absorption from the human jejunum. These studies were designed to examine whether changes in intestinal motility may be responsible for the inhibitory effect of somatostatin on intestinal absorption. Using triple-lumen perfusion techniques in healthy volunteers, somatostatin infusion (8 micrograms/kg/h) prolonged mean transit time from 9 to 16 min in a 30-cm jejunal test segment as estimated from dye dilution curves. Somatostatin infusion significantly reduced jejunal fructose absorption. Atropine (10 micrograms/kg/h, i.v.) caused a similar prolongation of mean transit time in the perfused jejunum. However, unlike somatostatin, atropine significantly increased fructose absorption. The observation that somatostatin and atropine affect absorption in opposite ways while prolonging intestinal transit time in a similar fashion suggests that the effects of somatostatin and atropine are due to a direct influence on absorption at the mucosal level that is independent of any effect on intestinal motility.

Exposure to elevated D-glucose concentrations modulates vascular endothelial cell vasodilatory response.

The possible role of endothelial dysfunction in early stages of uncomplicated diabetes mellitus was investigated in porcine aortic endothelial cells. Prolonged exposure to various D-glucose concentrations resulted in concentration-dependent amplification of agonist-induced Ca2+ mobilization, whereas L-glucose and D-mannitol failed to mimic the effect of D-glucose. This stimulatory effect of high D-glucose on endothelial Ca2+ mobilization could be antagonized by coincubation with cytochalasin B, which prevented D-glucose uptake into the cells. In agreement with its effect on agonist-induced Ca2+ response, prolonged preincubation with pathological D-glucose concentrations amplified formation of endothelium-derived relaxing factor, which is well established to be strictly attributable to increases in endothelial free Ca2+. In contrast to endothelium-derived relaxing factor formation stimulated by receptor-interacting autacoids, preincubation with high D-glucose failed to modulate A 23,187-induced endothelium-derived relaxing factor formation, which is attributable to unphysiological increases in endothelial free Ca2+ by this ionophore. Similar to its effect on D-glucose-mediated amplification of agonist-stimulated Ca2+ mobilization, cytochalasin B abolished the stimulatory effect of high D-glucose on endothelium-derived relaxing factor formation. We therefore suggest that prolonged exposure to pathological high D-glucose concentrations results in an enhanced endothelium-derived relaxing factor formation caused by amplification of agonist-stimulated Ca2+ mobilization in endothelial cells. This mechanism may be of particular importance representing a possible basis of pathological vasodilation and reduced peripheral resistance in early stages of diabetes mellitus.

Intracellular mechanisms involved in D-glucose-mediated amplification of agonist-induced Ca2+ response and EDRF formation in vascular endothelial cells.

Prolonged treatment of vascular endothelial cells with pathologically high D-glucose amplifies autacoid-induced Ca2+ mobilization and thus formation of nitric oxide. This study investigated the Ca2+ source for the change in endothelial CA2+ response on agonist stimulation. Pretreatment with high D-glucose (44 vs. 5 mM) enhanced release of intracellular Ca2+ by bradykinin as a result of a 2.0-fold increased formation of inositol 1,4,5-trisphosphate. High D-glucose also amplified Ca2+ influx (2.0-fold). In high D-glucose preincubated cells, stimulation with bradykinin significantly increased transplasmalemmal 45Ca2+ flux (3.2-fold) and caused a 2.0-fold increase in permeability to Mn2+, a surrogate for endothelial plasma membrane Ca2+ channels. A significant 2.0-fold increase occurred in the maximal slope, suggesting a higher rate of Mn2+ (Ca2+) influx. Ca2+ influx, stimulated by an inositol phosphate-independent depletion of intracellular Ca2+ stores with 2,5-di-(tert-butyl)-hydroquinone was also significantly increased 2.4-fold by high D-glucose, with no effect on intracellular Ca2+ release. D-glucose failed to modulate resting or stimulated cAMP levels. We suggest that prolonged exposure to pathologically high D-glucose increases formation of inositol polyphosphates, thus increasing Ca2+ release. Ca2+ entry is increased by amplification of unknown signal transduction mechanisms triggered by Ca2+ store depletion.

Evaluation of HbA1c determination methods in patients with hemoglobinopathies.

OBJECTIVE: To evaluate commercially available determination methods for HbA1c in patients with hemoglobin variants. RESEARCH DESIGN AND METHODS: HbA1c values were determined with various commercially available methods, including ion-exchange high-performance liquid chromatography (HPLC), boronate affinity assay, and immunoagglutination in patients with the hemoglobin mutations Hb Graz, Hb Sherwood Forest, Hb O Padova, Hb D, and Hb S. RESULTS: The effect of hemoglobinopathies on glycohemoglobin measurements was highly method dependent. The HPLC methods for HbA1c determination lacked the resolution necessary to differentiate hemoglobin variants. They demonstrated additional peaks in the chromatograms and HbA1c results either too low or too high compared with the nondiabetic reference range. With all immunoassays, Hb Graz demonstrated falsely low values. The other hemoglobinopathies in our study caused falsely low and/or high HbA1c results in immunoagglutination methods. The boronate affinity method showed values in an acceptable range for all hemoglobin variants. CONCLUSIONS: Because of the local occurrence of Hb variants and the ethnic origin of a given population, every individual laboratory must establish and validate its own assay method. In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants could cause mismanagement of diabetes resulting from false HbA1c determinations.

Evaluation of a structured outpatient group education program for intensive insulin therapy.

OBJECTIVE: To determine the efficacy and safety of a structured diabetes teaching and treatment program (DTTP) in patients with insulin-dependent diabetes mellitus (IDDM) in an outpatient setting. RESEARCH DESIGN AND METHODS: All patients with IDDM who completed a structured 5-day outpatient DTTP were reevaluated after a mean follow-up of 3 years. A standardized interview was used to assess frequency of severe hypoglycemia, type of insulin treatment, self-monitoring, and other diabetes-related parameters. HbA1c was measured by high-performance liquid chromatography. RESULTS: Of 205 patients, 4 (2%) died during the observation period. HbA1c in the 201 surviving patients decreased significantly from 8.7 +/- 2.0 to 7.5 +/- 1.2% at follow-up (P < 0.001); frequency of severe hypoglycemia decreased from a mean of 0.46 to 0.13 per patient per year (P < 0.001). Hospital admission due to acute metabolic disturbances decreased from 4.5 +/- 11.1 to 1.4 +/- 6.7 days/patient-year (P < 0.001). At follow-up, intensive insulin therapy was carried out by 98% of the patients, and 80% of the patients reported three or more measurements of blood glucose per day. Diabetes-related knowledge had a positive (P < 0.01) and body mass index a negative (P < 0.02) influence on improving HbA1c assessed by multiple regression analysis. Severe hypoglycemia after DTTP was associated with a history of severe hypoglycemia before DTTP (P < 0.001) and the existence of overt diabetic nephropathy (P < 0.05). CONCLUSIONS: A structured outpatient DTTP as used in this study is able to improve overall metabolic control and decrease the frequency of severe hypoglycemia in patients with IDDM.

Validation of home blood glucose meters with respect to clinical and analytical approaches.

OBJECTIVE: To evaluate the clinical and analytical accuracy of home blood glucose meters. RESEARCH DESIGN AND METHODS: Six blood glucose meters--Reflolux S (Boehringer Mannheim, Mannheim, Germany), One Touch II (LifeScan, Milpitas, CA), Glucocard Memory (Menarini, Florence, Italy), Precision QID (Medisense, Cambridge, U.K.), HaemoCue (HaemoCue, Angelholm, Sweden), and Accutrend alpha (Boehringer Mannheim, Mannheim, Germany)--were compared with a reference method (Beckman Glucose Analyzer II) under controlled conditions (glucose clamp technique). Validation of the blood glucose meters was accomplished by clinically oriented approaches (error grid analysis), statistical approaches (variance components analysis), and by the criteria of the American Diabetes Association (ADA), which recommend a target variability of < 5%. RESULTS: A total of 1,794 blood glucose monitor readings and 299 reference values ranging from 2.2 to 18.2 mmol/l were analyzed (705 readings < 3.89 mmol/l, 839 readings between 3.89 and 9.99 mmol/l, and 250 readings > 9.99 mmol/l). According to error grid analysis, only Reflolux S and Glucocard M had 100% of estimations within the clinically acceptable zones A and B. Assessment of analytical accuracy revealed substantial differences between the glucose meters after separation of the data into defined glycemic ranges. None of the devices met the ADA criteria. CONCLUSIONS: To evaluate accuracy of blood glucose meters, error grid analysis, as well as statistical models, are helpful means and should be performed together. Analytical performance of currently available home blood glucose meters differs substantially within defined glycemic ranges.

Acute effects of amiodarone on ultrastructure and electrical activity of isolated guinea pig hearts.

STUDY OBJECTIVE: The aim was to evaluate the effects of tissue concentration of amiodarone on ultrastructure and electrical activity in isolated spontaneously beating Langendorff perfused guinea pig hearts. DESIGN: Group 1: The influence of 10 microM amiodarone over a period of 1 h in a non-recirculated perfusate on conduction intervals, heart rate, creatine kinase concentration in the coronary effluent, coronary flow, and drug accumulation was determined. Group 2: Ultrastructural changes after 30 min and 60 min perfusion with amiodarone were examined. Group 3: Cardiac refractoriness was evaluated following 30 min and 60 min of perfusion with amiodarone. EXPERIMENTAL PREPARATIONS: Isolated hearts of guinea pigs (200-300 g) were used: group 1, n = 6 animals; group 2, n = 3 for each time span; and group 3, n = 6 for each time span. MEASUREMENTS AND MAIN RESULTS: A steady state for the effects of amiodarone on atrioventricular and intraventricular conduction [+31(SEM 5)%, p less than 0.01% +47(12)%, p less than 0.01, respectively] and on heart rate [-30(9)%, p less than 0.01] was reached after 15 min, and on His bundle conduction [+38(17)%, p less than 0.01] after 30 min. QT duration was not affected throughout the duration of the experiment. Cardiac refractoriness was significantly prolonged following 30 min perfusion with 10 microM amiodarone, and was further significantly increased following 60 min perfusion. Amiodarone tissue concentration increased to 365(39) nmol.g-1 wet weight, and this was accompanied by an increase in creatine kinase concentration in the coronary effluent. Coronary flow stayed constant throughout the whole experiment. At the end of the experiment electron microscopic examination of the myocardium of the left ventricle showed accumulation, fusion, and vacuolisation of mitochondria, and perinuclear oedema. CONCLUSIONS: These observations suggest that amiodarone, as well as exerting acute electrophysiological effects, creates ultrastructural changes which probably contribute to its effectiveness in arrhythmias caused by scarred myocardium.

Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status.

Osteopenia is an important clinical manifestation of hyperprolactinemia. Bone loss in these patients has mainly been attributed to concomitant deficiency of gonadal hormones rather than to hyperprolactinemia per se. Parathyroid hormone-related peptide (PTHrP) is expressed in human mammary tissue, and elevated circulating PTHrP levels as well as concomitant hypercalcemia have been described during lactation. We sought to determine circulating PTHrP levels in patients with long-standing hyperprolactinemia and whether PTHrP may exert possible systemic effects on bone and mineral metabolism. We studied 45 patients (30 women and 15 men) with persisting hyperprolactinemia 6 +/- 4 years (mean +/- SD) after trans-sphenoidal surgery for prolactin-producing pituitary adenomas. PTHrP levels in 117 healthy controls were 10.6 +/- 7.3 pmol-eq/l (mean +/- SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 30.3 +/- 13.4 pmol-eq/l (p < 0.001, n = 45), and in patients with humoral hypercalcemia of malignancy PTHrP levels were 52.9 +/- 29.6 (p < 0.001 to controls and hyperprolactinemic patients). Fifty-three percent of hyperprolactinemic patients (n = 24) had clearly elevated PTHrP levels (> 2 SD). Retrospective immunocytochemical studies of the removed pituitary adenomas from 19 patients generally showed a higher degree of immunoreactivity for PTHrP (1-34) in all but one case when compared with normal pituitary tissue. Patients with elevated circulating PTHrP levels showed in most instances strong immunoreactivity to PTHrP in 70-100% of tumor cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatographically purified immunoglobulin G of endemic and sporadic goiter patients stimulates FRTL5 cell growth in a mitotic arrest assay.

A strain of differentiated rat thyroid cells (FRTL5) in continuous culture was used to study the presence of thyroid growth-promoting immunoglobulins (TGI) in the serum of patients with endemic and sporadic euthyroid goiters. To identify true in vitro cell proliferation a microscopic mitotic arrest assay was used. Immunoglobulins G (IgGs) were prepared with QAE-Sephadex A-50 or protein-A-Sepharose. A positive growth stimulation index was found in IgG preparations of 65 of 71 patients with endemic goiter and in 9 of 14 IgG preparations of patients with sporadic goiter. IgG preparations of 15 control subjects from an area where endemic goiter due to iodine deficiency does not occur and of 18 subjects without iodine deficiency and without thyroid enlargement living in the endemic area did not stimulate FRTL5 cell growth. FRTL5 cell growth stimulation with IgGs of these euthyroid goiter patients could only be detected when IgG was tested in combination with a small dose of TSH. Immunoprecipitation with polyclonal and monoclonal antihuman IgG was able to abolish the growth-promoting effects. In 32 blinded samples the Feulgen cytobiochemical assay, formerly used to detect TGI, was compared with the FRTL5 mitotic arrest assay. The two methods showed similar results. Our observations of chromatographically purified IgG promoting thyroid cell proliferation in vitro provide good evidence that IgG was responsible for thyroid cell growth in vitro and suggest that autoimmune growth mechanisms may be involved in the pathogenesis of both endemic and sporadic goiters.

VIPoma syndrome.

Since the description of the watery diarrhea syndrome by Verner and Morrison 29 years ago, clinical and experimental observations have elucidated the pathophysiology of this disease. Vasoactive intestinal polypeptide (VIP) is produced and released by a tumor of the pancreatic islets or by a tumor of neural crest origin such as a ganglioneuroma. Under normal conditions, current evidence suggests that VIP is a neurotransmitter in the central and peripheral nervous systems and particularly in the peptidergic nervous system. The low VIP plasma concentration observed in healthy subjects is viewed as a neuronal overflow since it has been impossible to ascertain any endocrine role for circulating VIP. Markedly elevated VIP plasma levels in the VIPoma syndrome lead to intestinal secretion with severe secretory diarrhea, resulting in hypovolemia, hypokalemia, and acidosis. These symptoms subside after successful tumor removal. Approximately 50 percent of patients have metastatic spread at the time of diagnosis. For these patients, a new and promising therapeutic modality is available in the form of a subcutaneously administered somatostatin analogue that relieves symptoms through potent inhibition of VIP release from tumor tissue.

Effect of 1,25-dihydroxyvitamin D3 on calcium and magnesium absorption in the healthy human jejunum and ileum.

In calcium deficiency states such as chronic renal failure, 1,25-dihydroxyvitamin D3 increases calcium and magnesium absorption toward normal levels. In the present study, the ability of exogenous 1,25-dihydroxyvitamin D3 to increase calcium and magnesium absorption above normal rates in healthy subjects was investigated. Steady-state perfusion studies were performed in 30 cm segments of jejunum and ileum before and after one week of 1,25-dihydroxyvitamin D3 administration (2 micrograms per day, 10 subjects). Serum 1,25-dihydroxyvitamin D concentration increased from 25.8 +/- 2.5 pg/ml to 56.4 +/- 6.6 (mean +/- SEM, p less than 0.05). In the basal state, calcium absorption was significantly higher in the jejunum than in the ileum. Vitamin D administration resulted in a significant increase in calcium absorption which was quantitatively similar in both the jejunum and ileum. The changes in net movement were due to an increase in lumen-to-plasma flux of calcium; the plasma-to-lumen flux remained unchanged. Jejunal magnesium absorption also was enhanced by 1,25-dihydroxyvitamin D3. These studies demonstrate that in healthy persons, exogenous 1,25-dihydroxyvitamin D3 increases calcium absorption in both the jejunum and the ileum, and increases magnesium absorption in the jejunum.

Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C.

CsA-induced hepatotoxicity is a rare disorder in renal transplant recipients when low doses are administered and whole blood trough levels of CsA are regularly monitored. However, there is controversy about the clinical value of measuring CsA-metabolites, whose contribution to immunosuppression and toxicity is not fully understood. To assess the relation between low-dose CsA therapy and hepatotoxicity, we studied 128 renal transplant recipients attending our nephrology clinic. Eight of these patients had markedly elevated liver function tests. Three patients while receiving very low doses of oral CsA (< 3.8 mg/kg of body weight) presented marked derangements of CsA metabolism with abnormally increased CsA-metabolite levels. Parent drug levels were in the normal range. All 3 patients had chronic infection with hepatitis C virus and revealed histomorphologic evidence of hepatotoxicity. Hepatic dysfunction normalized when CsA was withdrawn or reduced by 50%. It is likely that hepatitis C virus infection interferes with CsA metabolism and/or biliary CsA-excretion and thus is responsible for CsA and/or metabolite-induced hepatotoxicity despite very low doses of CsA.

Evidence of accelerated gastric emptying in longstanding diabetic patients after ingestion of a semisolid meal.

UNLABELLED: This study investigated the prevalence of accelerated gastric emptying in 40 consecutive nonselected patients with longstanding insulin-dependent diabetes mellitus (range 11-54 yr; mean 27 yr). METHODS: The gastric emptying of a semisolid meal labeled with 99mTc was continuously recorded with a dual-head gamma camera for 90 min in patients who were supine. RESULTS: Eleven patients demonstrated delayed gastric emptying, but three male diabetics showed accelerated gastric emptying with retention values that were different from controls already after 10 min of recording (89% +/- 3% versus 96% +/- 4%; p < 0.02). During the 90-min segment, accelerated gastric emptying reduced initial gastric contents to 11% +/- 8% (p < 0.001) as compared to 50% +/- 10% in control subjects and 78% +/- 6% (p < 0.001) in patients with delayed gastric emptyings. Accelerated gastric emptying was characterized by an almost equal initial meal distribution in proximal and distal compartments of stomach, both emptying approximately 90% of their contents within 90 min. Normal and delayed gastric emptying was characterized by a 60%-40% initial ratio of meal distribution between gastric compartments. During normal emptying, both compartments reduced contents with approximately 50%, but delayed gastric emptying was caused by only a 15% reduction of proximal contents accompanied by a 34% reduction in distal contents. CONCLUSION: Recording in the supine position to abolish gravitational influences demonstrated accelerated gastric emptying of a firm semisolid meal with a prevalence of 8%. However, delayed gastric emptying was shown as the predominant gastric manifestation of longstanding insulin-dependent diabetes mellitus with a prevalence of 28%.

Radiolabeled octreotide for the demonstration of somatostatin receptors in malignant lymphoma and lymphadenopathy.

UNLABELLED: This prospective study evaluated somatostatin receptor-specific scintigraphy as a clinical tool for routine detection of malignant lymphoma. METHODS: Forty-one consecutive patients were examined using 111In-DTPA-D-Phe-1-octreotide. Thirty-four patients had diagnoses of Hodgkin's disease (n = 11) or non-Hodgkin's lymphoma (n = 23) previously verified and staged by hematology, histology and imaging methods (CT, chest x-ray and abdominal ultrasonography). The remaining seven patients initially suspected of presenting lymphoma (n = 5) or lymphoma recurrence after chemotherapy and radiotherapy (n = 2) were subsequently shown to have other diseases. Planar images were recorded 4, 24 and 48 hr after intravenous injection and evaluated without knowledge of other results. In case of negative planar scintigraphy, additional SPECT images were obtained. Since these failed to increase sensitivity, they were omitted after 15 negative recordings. RESULTS: Octreotide scintigraphy did not yield false-positive results. The sensitivity for detecting Hodgkin's disease was 70% and varied from 88% in the neck and chest to 13% in the abdomen and pelvis. The sensitivity for non-Hodgkin's lymphoma was not influenced by localization and amounted uniformly to 35% but varied with the degree of malignancy between 44% (high-grade) and 29% (low-grade malignancy). CONCLUSION: Our results suggest that radiolabeled octreotide is better suited to characterize somatostatin receptor expressing lymphomas than to localize lesion sites. It is useful for imaging Hodgkin's disease, especially above the diaphragm.

Cardiovascular effects of vasoactive intestinal peptide in healthy subjects.

Hypotension and flushing are occasionally observed in patients with pancreatic cholera syndrome. Similar effects are produced when vasoactive intestinal polypeptide (VIP) is administered to healthy subjects. To characterize further these responses, serial measurements of heart rate, blood pressure, cardiac output and forearm blood flow were made in 6 healthy subjects during constant VIP infusion (400 pmol/kg/hr for 100 minutes). VIP infusion caused sustained vasodilatation and decreased total peripheral resistance and mean arterial pressure by 30 and 12%, respectively. Forearm resistance decreased by 65%. The effects on cardiac output and stroke volume were biphasic. During the early phase of VIP infusion (0 to 70 minutes), heart rate and cardiac output increased with only minor changes in stroke volume. Later (71 to 100 minutes) the tachycardia persisted, but cardiac output decreased toward control levels due to decreased stroke volume. Echocardiograms during the infusion demonstrated increased left ventricular contractility as defined by the relation between end-systolic wall stress and shortening fraction. These data document potent vasodilatory and inotropic actions of VIP. It is likely that intravascular volume losses from increased intestinal secretion account for the decreased stroke volume seen late in the VIP infusion period and immediately thereafter. The tachycardia appears to be an appropriate compensatory mechanism to maintain blood pressure in the presence of vasodilatation and loss of intervascular volume. These observations provide an explanation for the cardiovascular findings in patients with sudden release of VIP from tumors.

Increased plasma concentrations of circulating intercellular adhesion molecule-1 (cICAM-1) in patients with necrotizing pancreatitis.

The intercellular adhesion molecule-1 (ICAM-1), a membrane glycoprotein, is important in the adhesion of cytokine-stimulated leukocytes to the endothelium of microvessels and their transendothelial migration. Circulating isoforms of ICAM-1 (cICAM-1) are known to be elevated in human serum as an indirect consequence of inflammatory responses. The aim of this study was to investigate whether cICAM-1 levels are elevated in patients with acute pancreatitis within 48 h of the onset of abdominal pain and whether cICAM-1 levels correlate with the severity of the tissue damage. Twenty-five consecutive patients admitted to a medical ICU had elevated cCAM-1 concentrations of 548 +/- 68 ng/ml, significantly different when compared to a control group of 18 healthy subjects (343 +/- 29; p = 0.018). According to the findings of contrast-enhanced CT or laparotomy patients were further divided in a group with acute edematous pancreatitis and a group with acute necrotizing pancreatitis. Pancreatic necrosis was associated with cICAM-1 levels of 729 +/- 106 ng/ml, significantly different from patients with mild disease (367 +/- 48) and controls (p < 0.001). Plasma cICAM-1 levels were not significantly different between healthy subjects and patients with mild pancreatitis. A significant correlation was found between cICAM-1 and C-reactive protein, an acute phase reactant and marker of necrotizing pancreatitis (r = 0.62; p < 0.01). The sensitivity and specificity for the detection of edematous or necrotizing pancreatitis of cICAM-1 plasma concentrations (cutoff point at 500 ng/ml) were 75% and 85%, respectively. These results suggest an enhanced release of ICAM-1 into plasma in the early stage of acute necrotizing pancreatitis. Leukocyte-endothelial cell adhesion may be associated with the inflammatory process of necrotizing tissue damage in acute pancreatitis. It could thus serve as a marker or predictor of a severe clinical course of pancreatitis.

Sulfoconjugated and free plasma catecholamine levels at rest and during exercise in patients with idiopathic dilated cardiomyopathy.

Plasma levels of sulfoconjugated (sc) catecholamines (CA) have been shown to be increased with activation of the sympathoadrenal system in a number of clinical settings. We evaluated the relation between scCA and clinical or hemodynamic parameters of patients with idiopathic dilated cardiomyopathy (IDC) at rest and during incremental exercise testing. Eleven healthy subjects, nine patients in New York Heart Association (NYHA) functional class I (IDC-A group) and 11 in NYHA functional class II and III (IDC-B group) performed a symptom-limited, graded bicycle exercise test. Resting, peak and various postexercise levels of plasma free and scCA were determined by high-pressure liquid chromatography. Resting CA levels obtained in the supine position were remarkable for elevations of free norepinephrine (NE) in IDC-B patients (355 +/- 157 ng/l) as compared to IDC-A patients (177 +/- 54, p = 0.006) or healthy controls (193 +/- 74, p = 0.007). Similarly, scNE was highest in IDC-B patients with 1856 +/- 1089 ng/l, followed by IDC-A (1028 +/- 187, p = 0.025) and control subjects (1109 +/- 440, p = 0.025). There was a highly significant correlation between free and scNE (r = 0.76, p < 0.0005). Whereas resting free dopamine (DA) levels were comparable in all three groups, scDA was found to be elevated clearly in IDC-B patients (8772 +/- 2097 ng/l) and significantly different to IDC-A (5786 +/- 2481, p = 0.01) or control subjects (4892 +/- 1575, p = 0.0005). The NYHA functional class and maximum exercise performance correlated best with resting scDA (r = 0.68, p = 0.001 and r = 0.56, p = 0.005, respectively). At peak exercise, IDC-B patients exhibited a significant decrease in scNE and sc epinephrine (E) (from 1856 +/- 1089 to 1495 +/- 932 ng/l, p < 0.005 and from 491 +/- 173 to 282 +/- 143 ng/l, p < 0.01) compared to controls (from 1109 +/- 444 to 1094 +/- 548 ng/l and from 379 +/- 200 to 329 +/- 134 ng/l). In IDC-B patients this decrease in scNE and scE at peak exercise was related inversely to the rise in free NE and E (r = -0.81, p < 0.005 and r = -0.68, p < 0.05). Resting hemodynamic indices generally were reflected better by some free CA rather than by conjugated forms or by parameters of clinical performance. These findings suggest that in addition to free or scNE levels, resting scDA is elevated in symptomatic patients with IDC.(ABSTRACT TRUNCATED AT 400 WORDS)

Hemoglobin Sherwood Forest detected by high performance liquid chromatography for hemoglobin A1c.

Hb Sherwood Forest has been so far identified in only one patient in 1977. This study describes the second detection of this hemoglobin variant by routine high performance liquid chromatography (HPLC) in a diabetic patient and her healthy grand niece. In both, glycosylated hemoglobin (HbA1c) values were excessively elevated (52%), as determined by HPLC with a cation exchange column. The latex agglutination test showed values of HbA1c in the expected normal range. Citrate agar electrophoresis revealed a hemoglobin variant with a mobility similar to HbF. Amino acid analysis and DNA sequence analysis revealed an Arg-->Thr exchange at codon 104 of the beta-chain. This sequence has been described as Hb Sherwood Forest in 1977. The hemoglobin variant is clinically silent and might be confused with excessively high HbA1c in routine measurement of glycosylated hemoglobin.