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C De Angelis
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Endosonography in decision making and management of gastrointestinal endocrine tumors.
OBJECTIVE: gastroenteropancreatic (GEP) neuroendocrine tumors, suspected on clinical basis, are often difficult to localize. We report our experience with endoscopic ultrasonography (EUS) in the preoperative localization of pancreatic endocrine tumors (PETs), compared to other imaging modalities, and in staging and following up carcinoid tumors (CTs) of the gastrointestinal (GI) wall. METHODS: 50 patients (20 males; mean age 54 years), 39 with suspected PETs and 11 with GI CTs underwent EUS (Olympus GF-UM2 or GF-UM3). EUS data could be compared with resected specimens in 25 out of the 39 PETs and five out of the 11 CTs. RESULTS: in the PETs group 42 tumors (35<20 mm) were removed: 23 in the pancreas, eight in the duodenum, and 11 in the lymph nodes. EUS correctly localized 20 out of the 23 (87%) pancreatic tumors, included 11 out of the 12 (91.6%) insulinomas, three out of the eight (37.5%) duodenal gastrinomas, and ten out of the 11 (90.9%) metastatic lymph nodes. Furthermore EUS accurately evaluated the depth of parietal invasion of CTs in three out of four patients (75%) (two after and one prior to endoscopic resection). In three patients EUS was confirmed as normal on resected specimens (two pancreas and one stomach). In the PETs group, a correct localization was obtained by ultrasonography (US) only in 17.4% of cases, by computed tomography (CT) in 30.4%, by magnetic resonance imaging (MRI) in 25%, by angiography in 26.6%, and by somatostatin receptor scintigraphy in 15.4%. CONCLUSION: EUS must be considered the first-intention method in localizing PETs and is helpful in decision making and management of GEP endocrine tumors.
Alanine/EPR dosimetry in brachytherapy.
The paper reports the experimental procedure adopted to determine the absorbed dose rate in water per reference air kerma rate, D(Kr), (d, theta), along the transverse bisector axis of a 137Cs brachytherapy source. The dose rate measurements have been carried out at difference distances, d, from the source using alanine dosemeters in a water phantom. The reference air kerma rate, Kr, was determined adopting a 'direct procedure' that uses a spherical ionization chamber in air. The dose rate constant of the source examined was D(Kr) (1, pi/2) = 0.99 +/- 0.03 cGy h(-1) (microGy h(-1))(-1). The values of the radial dose function along the transverse axis, g(d), determined with an uncertainty of 3.4% (1sigma), were found to be in good agreement with the results reported in the literature. The uncertainty in dose rate value has been estimated as 2.8% (1sigma) for distances from the source up to 7 cm. Kr has been determined with 1.2% (1sigma) uncertainty. So D(r) (d, pi/2) values were determined with 3% (1sigma) uncertainty.
Lipoprotein (a) and apoprotein B in an apparently healthy population of fighter pilots and ground personnel: their significance as potential markers of atherosclerosis.
BACKGROUND: Individuals who carry cardiovascular risk factors (CVRF) have a higher incidence of cardiovascular pathology. Among the most commonly screened CVRF are apoprotein A and B and lipoprotein (a), which represent 'independent' risk factors for atherosclerosis. In the air force community, cardiovascular pathology has been reported as the primary reason for grounding pilots. DESIGN: The aim of this study was to evaluate the frequency of CVRF in an apparently healthy population of military fighter pilots (group B, n = 50), and military ground personnel (group A, n = 50) who were matched for age, sex and body mass index but not involved in flight activity, and to evaluate whether any particular pattern of CVRF might be related to flight. METHODS: Each subject fasted overnight, and underwent the following measurements: blood pressure and resting ECG recording; and determination of serum levels of total and high-density lipoprotein cholesterol, triglycerides, uric acid and plasma levels of glucose. In addition, serum levels of apolipoprotein A, B and lipoprotein (a) were detected. RESULTS: An overall risk index for coronary artery disease was calculated using the Framingham equation. This risk index was slightly but not significantly increased in group A compared with group B. By contrast, a significant increase in both apoprotein B (P < 0.005) and lipoprotein (a) (P < 0.0005) was found in group B compared with group A. No significant differences between groups were detected for the other parameters evaluated. CONCLUSIONS: We suggest the presence in group B of an underlying trend towards the development of atherosclerosis, which may not be identified by a routine approach. Moreover, on a purely theoretical basis with no experimental evidence, the issue of the possible pathophysiological mechanism of these findings and their relationship to flight environment is also addressed.
Transvaginal sonographic evaluation of endometrial polyps: a comparison with two dimensional and three dimensional contrast sonography.
Endometrial polyps are a frequent cause of menorrhagia and are often associated with infertility. Routine transvaginal (TV) ultrasound evaluation may detect intrauterine anomalies. Sonographic evaluation of the endometrium after uterine cavity distention, called hystero-sono-salpingography (HSSG), improves the resolutive effectiveness of TV sonography. Recently the development of three-dimensional (3D) scanning of the uterine cavity has provided accurate images. The purpose of this study was to compare conventional 2D and 3D scanning of the uterine cavity with or without saline contrast medium in the detection and evaluation of focal endometrial polyps. Twenty-three patients out of 642 women suggestive for intrauterine anomalies at routine TV sonogram were examined by 2D and 3D sonography before and after intrauterine saline contrast medium. Sonographic appearance was verified by hysteroscopic and histologic evaluation. Two-dimensional TV sonography diagnosed 23 polyps versus 16 confirmed at hysteroscopic and histologic examinations, revealing a specificity of 69.5%; 2D TV HSSG diagnosed 17 polyps, with a specificity of 94.1%; 3D TV sonography diagnosed 18 polyps, with a specificity of 88.8%; 3D HSSG diagnosed 16 polyps according to hysteroscopic and histologic findings, with a specificity of 100%. HSSG has been demonstrated to be an effective and suitable method in the detection of intrauterine anomalies, particularly with 3D sonography.
Handgrip increases endothelin-1 secretion in normotensive young male offspring of hypertensive parents.
OBJECTIVES: We tested the hypothesis that an abnormal response of plasma endothelin-1 (ET-1) is elicited by handgrip exercise (HG) in young normotensive offspring of hypertensive parents. BACKGROUND: It has been hypothesized that ET-1 is involved in blood pressure control and plays a pathophysiologic role in the development of clinical hypertension. METHODS: Two groups of healthy male subjects, 11 with hypertensive parents (group A) and 10 without a family history of hypertension (group B), underwent 4 min of HG at 50% maximal capacity. Heart rate and blood pressure and plasma levels of ET-1, epinephrine and norepinephrine were measured at baseline, peak HG, and after 2 (R2) and 10 (R10) min of recovery. RESULTS: Group A had higher norepinephrine levels than group B throughout the test (baseline 181+/-32 [SEM] vs. 96+/-12 pg/ml, p < 0.05; peak HG 467+/-45 vs. 158+/-12 pg/ml, p < 0.000001; R2 293+/-46 vs. 134+/-8 pg/ml, p < 0.01; RO1 214+/-27 vs. 129+/-10 pg/ml, p < 0.0005); no significant difference in epinephrine levels was detected. Compared with group B subjects, group A had higher baseline ET-1 levels (1.07+/-0.14 vs. 0.59+/-0.11 pg/ml, p < 0.02), which increased to a greater extent at peak HG (1.88+/-0.31 vs. 0.76+/-0.09 pg/ml, p < 0.005) and R2 (2.46+/-0.57 vs. 1.31+/-0.23 pg/ml, p < 0.05) and remained elevated at R10 (3.16+/-0.78 vs. 0.52+/-0.09 pg/ml, p < 0.002). Multivariate analysis demonstrated that only a family history of hypertension (chi-square=7.59, p=0.0059) and ET-1 changes during HG (chi-square=4.23, p=0.0398) were predictive of blood pressure response to HG and that epinephrine and norepinephrine were not. CONCLUSIONS: The response to HG in offspring of hypertensive parents produced increased ET-1 plasma levels and resulted in a sustained ET-1 release into the bloodstream during recovery compared with offspring of normotensive parents. This may be an important marker for future clinical hypertension.
Preoperative endoscopic ultrasonography in decision making and management for pancreatic endocrine tumors: a 6-year experience.
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Hypoxia triggers release of an endogenous inhibitor of Na(+)-K(+)-ATPase from midbrain and adrenal.
An endogenous inhibitor of Na(+)-K(+)-ATPase has been isolated from bovine hypothalamus and human plasma and structurally characterized as an isomer of the plant cardiac glycoside, ouabain (A. A. Tymiak, J. A. Norman, M. Bolgar, G. C. DiDonato, H. Lee, W. L. Parker, L.-C. Lo, N. Berova, K. Nakanishi, E. Haber, and G. T. Haupert, Jr. Proc.Natl.Acad.Sci. USA 90: 8189-8193, 1993; N. Zhao, L.-C. Lo, N. Berova, K. Nakanishi, J. H. Ludens, and G. T. Haupert, Jr. Biochemistry 34: 9893-9896, 1995). This hypothalamic inhibitory factor (HIF) acts on cardiovascular and renal tissues consistent with physiological regulation in vivo. Stimuli for the release of HIF from tissue are unknown. Hypoxia may be a stimulus for the elaboration of digitalis-like activity in humans, and high NaCl concentration in central nervous system stimulates ouabain-like activity in animals. We examined the ability of low O2 tension in vivo and in vitro to stimulate HIF release from midbrain and adrenal tissues in Wistar rats. In both tissues, hypoxia stimulated a remarkable release of an inhibitor cochromatographing with HIF, and this release was enhanced by 300 mM NaCl. Plasma from hypoxic rats also showed increased levels of the purified inhibitory activity. We conclude that hypoxia is a potent stimulus for the release of HIF or HIF-like activity and discuss the possibility that an Na(+)-K(+)-ATPase inhibitor could be involved in energy-conserving cellular adaptive responses to hypoxic or ischemic insult through ATP conservation.
Early activation of vascular endothelium in nonobese, nondiabetic essential hypertensive patients with multiple metabolic abnormalities.
Circulating soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) concentrations were evaluated in 93 nonobese essential hypertensive patients, of whom 16 had impaired glucose tolerance and hyperlipidemia (group I); 25 had impaired glucose tolerance (group II); 28 had hyperlipidemia (group III); and 24 had no metabolic abnormalities (group IV). A group of 22 healthy volunteers served as a control group. All groups were without clinical or ultrasound evidence of vascular lesion and were matched for age, sex, and BMI. Endothelial soluble adhesion molecules were measured at baseline, during an oral glucose tolerance test, and after 12 weeks of either enalapril or placebo treatments. Plasma soluble E-selectin, ICAM-1, and VCAM-1 were higher (P < 0.05) in group I and II than in the other groups (group I: E-selectin, 96.1+/-27.1; ICAM-1, 304.0+/-102.1; VCAM-1, 626.1+/-156.2 microg/l. Group II: E-selectin, 88.0+/-18.0; ICAM-1, 268.0+/-84.1; VCAM-1, 594.1+/-140.9 microg/I. Group III: E-selectin, 70.1+/-18.1; ICAM-1, 195.1+/-68.0; VCAM-1, 495.9+/-110.1 microg/l. Group IV: E-selectin, 65.1+/-16.1; ICAM-1, 168.1+/-64.0; VCAM-1, 472.1+/-108.2 microg/l). Soluble adhesins levels were not higher than normal in groups III and IV. Plasma soluble ICAM-1 concentrations increased in group I after glucose administration and were directly correlated with 2-h insulin levels (r=0.648, P=0.007). Compared with placebo, 12 weeks of enalapril treatment significantly (P < 0.0001) reduced soluble E-selectin, ICAM-1, and VCAM-1. Decrements of soluble adhesins were not dependent on enalapril-related blood pressure changes. Therefore, an early endothelial activation was present in essential hypertensive patients with impaired glucose tolerance, regardless of the presence of hyperlipidemia. ACE inhibition counteracted such endothelial activation.
Atrial natriuretic peptide levels in fetal blood in relation to inferior vena cava velocity waveforms.
OBJECTIVE: To determine whether blood levels of atrial natriuretic peptide in small for gestational age (SGA) fetuses are related to Doppler indices measured in arterial and venous vessels. METHODS: Atrial natriuretic peptide was assayed in fetal blood obtained at funipuncture in 42 third-trimester fetuses, of whom 11 were appropriate for gestational age (AGA) and 31 were SGA. Small for gestational age fetuses were divided into three groups according to Doppler findings in the umbilical artery and inferior vena cava: 1) normal in both vessels (n = 10); 2) abnormal in the umbilical artery but normal in the inferior vena cava (n = 10); and 3) abnormal in both vessels (n = 11). Atrial natriuretic peptide levels were related to Doppler indices and acid-base status of the fetal blood. RESULTS: Small for gestational age fetuses with abnormal waveforms in both vessels had higher atrial natriuretic peptide blood levels (median 544.8 pg/mL, range 404.2-1112.3) compared with AGA fetuses (median 316.8 pg/mL, range 159.3-470.1; P < or = .001), SGA fetuses with normal waveforms only in both vessels (median 299.8 pg/mL, range 242.6-480.5; P < or = .001), and SGA fetuses with abnormal waveforms only in the umbilical artery (median 367.6 pg/mL, range 192.7-748.9; P = .002). Blood levels of atrial natriuretic peptide were significantly related to the preload index in the inferior vena cava (p = 0.554, P < or = .001). This relation remained significant when the analysis was restricted to the SGA fetuses with abnormal waveforms in the umbilical artery and the inferior vena cava (p = 0.673, P = .03). CONCLUSIONS: Small for gestational age fetuses with abnormal velocity waveforms in the inferior vena cava have significantly higher concentrations of atrial natriuretic peptide. This may represent a compensatory mechanism in the SGA fetus for regulation of an abnormal hemodynamic condition.
Alanine dosimetry of proton therapy beams.
An analysis of some of the properties of the ESR-alanine dosimetry in therapeutic proton beams is reported. Thin alanine-based detectors (1 and 2 mm thick pellets and 0.25 mm thick films) were tested in a clinical 62 MeV proton beam. The response of the alanine detectors in unmodulated and modulated proton beams was studied in tissue equivalent phantoms. The dose assessed by alanine was compared to the dose provided by a Markus parallel plate ionization chamber, used for reference dosimetry. Experiments in the 5-250 Gy dose range showed linearity of alanine dose response and no significant differences in the alanine response per unit dose to gammas and protons. Agreement within the experimental uncertainties was found between the alanine and the Markus chamber depth dose curves, including the Bragg peak region.
Elevated albumin excretion in nonmodulating essential hypertensive patients.
Nonmodulating (NM) essential hypertensives are characterized by abnormal renal and aldosterone responses to angiotensin II. Recently, hyperinsulinemia, hypercholesterolemia, and an increased prevalence of family history of hypertension and myocardial infarction have been shown in NM hypertensives. Since an elevated urinary albumin excretion (UAE) has been indicated as a negative prognostic marker for cardiovascular diseases in essential hypertensives, we evaluated UAE in 50 male patients with mild to moderate essential hypertension (mean age 46.3 +/- 4.4 years), characterized as low renin (LR) (n = 14), modulating (M) (n = 20), and NM patients (n = 16) according to their renin profile and ability to modulate the aldosterone response to a graded infusion of angiotensin II. A group of 14 healthy male subjects (mean age 43.3 +/- 3.9 years) served as control. Resulting data showed that NM had significantly higher UAE (30.7 +/- 10.7 microg/min) than controls (11.9 +/- 2.7 microg/min, p < 0.0001), LR (22.1 +/- 8.4 microg/min, p < 0.05), and M patients (19.7 +/- 6.6 microg/min, p = 0.0001) when all fed a 200-mmol NaCl/day diet. On the contrary, differences in UAE disappeared when all subjects were on a low sodium regimen (10 mmol NaCl/day). Compared to LR and M patients, the NM ones also manifested higher low-density lipoprotein cholesterol levels (p < 0.05). Furthermore, these latter and UAE were positively correlated in NM patients (r = 0.579, p < 0.05) but not in the other subgroups. In conclusion, the current study demonstrates elevated UAE in NM patients, suggesting the NM phenotype is combined to an increased cardiovascular risk.
Isolation and characterization of a digoxin-like immunoreactive substance from human urine by affinity chromatography.
A series of observations has suggested that one or more digoxin-like immunoreactive substances (DLIS) in biological fluids is able to cross-react with the antidigoxin antibody. Whether this substance is the endogenous inhibitor of Na+/K+ ATPase has not been well established. The aim of this study was to identify and characterize DLIS from human urine. Treated urine from healthy men was run on an affinity chromatography column at a flow rate of 1 mL/min in which the ligand was an antibody (antiserum) to digoxin. Eluates from affinity chromatography were applied onto analytical reversed-phase HPLC. The active material was eluted with a linear gradient of acetonitrile (from 350 to 650 mL/L) and water. A second step in HPLC was carried out isocratically with 280 mL/L acetonitrile in water. We found a single peak showing cross-reactivity with antidigoxin antibody as measured by RIA. It showed the same retention time as that of a digoxin calibrator. This highly purified substance is able to displace [3H]ouabain from dog kidney-derived Na+/K+ ATPase, to inhibit Na+/K+ ATPase activity as measured by the 86Rb+ uptake in red blood cells and by coupled enzyme assay. Our results are consistent with the hypothesis that DLIS, as isolated by this particular digoxin antibody, is a single substance and an inhibitor of Na+/K+ ATPase.
Evaluation of stress induced by flight activity by measuring the hormonal response.
The aim of the present study was to quantitatively investigate the different levels of adaptation to flight and to evaluate the hormonal response to flight activity as a possible reliable tool to quantify the level of stress induced by flight. The hormonal response of growth hormone (GH), cortisol, and prolactin (PRL) to flight activity was evaluated in a group of student pilots (n = 11; all male; age 20 +/- 2 years) and flight instructors (n = 11; all male; age 27 +/- 2 years) of an Italian Air Force flight school. Blood samples were obtained immediately before and after a training flight session. Hormonal determination by RIA technique after flight showed a significant increase of plasma hormonal levels of GH, PRL, and cortisol in the students. Conversely, in the instructors only GH showed a significant increase versus preflight values, whereas PRL and cortisol did not show significant differences. Moreover, preflight hormonal levels of GH and PRL were significantly higher for student pilots compared to the same values for flight instructors. The data lead to establishing a close correlation between the hormonal response to flight activity and the level of tolerance and adaptation to flight-induced stress.
Effect of acute exposure to hypoxia on electrolytes and water metabolism regulatory hormones.
BACKGROUND: Many studies suggest the hypothesis that the pathology of high altitude could be due to an early alteration of the hormones that regulate sodium homeostasis. HYPOTHESIS: The aim of this study was to evaluate the behavior of these hormones during an acute exposure to hypobaric hypoxia. METHODS: We studied 26 young healthy pilot students (23.1 +/- 2.9 yrs) in a hypobaric chamber, for 3 h (samples collected at time 0, 120, and 180 min), at 5000 m ASL. RESULTS: The results show an early increase of plasma renin activity (PRA) paradoxically associated to a decrease of aldosterone plasma levels. This later returned to the baseline values at 180 min, whereas PRA remained increased throughout the exposure. Both arginine-vasopressin (ADH) and the atrial natriuretic peptide (ANP) significantly increased, while a new putative hormone, the so-called digoxin-like substance (DLS) did not show significant changes. CONCLUSIONS: Our data demonstrate a specific sensitivity of the hormonal systems to hypoxia, which may be influenced by the time of the exposure. The relationship with results previously reported is also addressed.
Plasma and urinary digitalis-like substance levels during atrial natriuretic peptide infusion in essential hypertensive patients.
In order to evaluate the effect of atrial natriuretic peptide (ANP) infusion on plasma and urinary digitalis-like substance (DLS) levels, 18 essential hypertensive males (mean age 45.6 +/- 3.8 y) were studied. After 1 week on a normal NaCl intake (120 mmol/24h), patients were randomly double-blindly assigned to receive either ANP (99-126) (0.3 microgram/kg/min) (number of patients = 10) or its vehicle (50 ml isotonic saline) (8 patients) over a period of 60 min, in supine position. Plasma and urinary DLS levels were measured at time -60, 0, 30, 60, 120, 180, and 240 min (infusion time from 0-60 min). During ANP infusion, plasma DLS levels decreased significantly (from 25.2 +/- 6.8 pg/ml at time 0 to 12.5 +/- 5.6 pg/ml at 60 min, p < 0.01), while urinary DLS excretion increased (from 60.5 +/- 26.1 pg/ml at time 0 to 246.3 +/- 34.2 pg/ml at 30 min, p < 0.0001). and 402.3 +/- 44.1 pg/ml at 60 min, p < 0.0001). After 3 h from the end of ANP infusion, both plasma and urinary DLS returned to baseline levels (20.5 +/- 14.4 pg/ml and 84.5 +/- 34.2 pg/ml, respectively). Taken together, our data show that ANP infusion significantly increases urinary DLS excretion, while decreasing its circulating levels. This phenomenon could explain the different response of ANP and DLS to some stimuli, such as acute volume expansion. In fact, the rapid increment of plasma ANP due to an acute increase of extracellular fluid volume might simultaneously inhibit the increase in circulating DLS levels by promoting the urinary excretion of this substance.
Age- and trauma-dependent modifications of neuromuscular junction and skeletal muscle structure in the rat. Effects of long-term treatment with Acetyl-L-Carnitine.
The influence of ageing and crushing of the sciatic nerve on the morphology of the neuromuscular junction (NMJ) and on the muscle fiber composition were studied in the rat soleus muscle using histochemical techniques associated with image analysis. The influence of a 6-month treatment with Acetyl-L-Carnitine (ALCAR, 150 mg/kg/day) on the age- and crushing-dependent changes of the NMJ and on age-related modifications of the muscle fiber composition was assessed as well. In control old and injured young rats a loss of complexity of the NMJ was observed. Treatment with ALCAR resulted in an increased endplate complexity both in old rats and in young rats injured by crushing, in comparison with respective controls. The structure of the rat soleus muscle changes with increasing age. Modification mainly consists in a type II fiber atrophy, and in the alteration of the peculiar mosaic organization of the soleus muscle fibers. In ALCAR-treated old rats, the morphology of the soleus muscle fibers was similar to that observed in adult animals. These findings suggest that treatment with ALCAR has a beneficial effect on NMJ and on muscle fiber structure in ageing or after nerve crushing. The possible mechanism of action of this 'trophic' effect of ALCAR-treatment is discussed.
Propionyl-L-carnitine prevents the progression of atherosclerotic lesions in aged hyperlipemic rabbits.
We have characterized the extent and the phenotype of total and proliferating cell population of aortic plaques in aged rabbits receiving a long-term low-dose cholesterol hyperlipemic diet, which represents an experimental model of atherosclerosis. For nine months, rabbits received the hypercholesterolemic diet alone or in addition to a treatment with propionyl-L-carnitine (PLC), a derivative of carnitine, an intramitochondrial carrier of fatty acids present in most cell types. We observed that, in both PLC-treated and control hyperlipemic rabbits, the ratio between proliferating macrophage-derived and smooth muscle cells was 2:1. PLC in addition to the hypercholesterolemic diet induced a marked lowering of plasma triglycerides, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) triglycerides, while plasma cholesterol was slightly and transiently reduced. Moreover, PLC-treated hyperlipemic rabbits exhibited a reduction of plaque thickness and extent, a slight but significant reduction of the percentage of macrophage-derived cells as compared to control hyperlipemic animals and a reduction of the number of both proliferating macrophage- and smooth muscle cell-derived foam cells. Finally, both proliferating and non-proliferating plaque cells expressed large amounts of macrophage colony-stimulating factor protein, in particular macrophage-derived foam cells. These results indicate that a modification of plasma lipemic pattern obtained by a long-term oral administration of PLC was associated with a decrease of plaque cell proliferation and severity of aortic atherosclerotic lesions.