Transplantation of allogeneic/xenogeneic pancreatic islets containing coherent microcapsules in adult pigs.
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Animals↗
Biomedical subjects
P Brunetti
Publications and source records attributed to P Brunetti.
Moderate and large doses of ethanol differentially affect hepatic protein metabolism in humans.
The intake of approximately 70 g of alcohol impairs liver protein metabolism in healthy humans. To establish the threshold at which alcohol impairs hepatic protein metabolism in humans we compared the effects of 500 mL of water (control study), 300 (28.4 g ethanol) or 750 mL (71 g ethanol) of table wine on hepatic protein metabolism in three groups of healthy nonalcoholic volunteers. Hepatic protein metabolism was estimated (L-[1-14C]leucine infusion) by measuring the fractional secretory rates of albumin and fibrinogen during the overnight postabsorptive state (basal) and the subsequent administration of water or two different amounts of wine (300 or 750 mL) given with a liquid glucose-lipid-amino acid meal. During the meal, water did not affect fibrinogen fractional secretory rate and increased albumin fractional secretory rate by approximately 50% (P < 0.01). The 300 mL of wine increased albumin secretory rate by only approximately 20% (P < 0.01 vs. basal, P < 0.04 vs. water) and did not affect fibrinogen secretory rate. The 750 mL of wine profoundly impaired hepatic protein metabolism, decreasing the fractional secretory rates of albumin (P < 0.01 vs. water and 300 mL wine) and fibrinogen (P < 0.04 vs. water and 300 mL of wine) below the postabsorptive values. These results demonstrate that a moderate dose of alcohol (28 g, approximately 2 drinks) slightly affects postprandial hepatic protein metabolism by blunting the meal-induced increase in albumin synthesis, whereas it does not interfere with fibrinogen synthesis as do higher doses.
Adult↗
Etiological diagnosis of primary adrenal insufficiency using an original flowchart of immune and biochemical markers.
Approximately 70-80% of cases of primary adrenal insufficiency are classified as idiopathic. An effective protocol for the etiological diagnosis of primary adrenal insufficiency is needed to ensure correct patient management. With the aim of developing an algorithm for the etiological diagnosis of primary adrenal insufficiency, we studied 56 Italian patients with nonsurgical primary adrenal insufficiency and 24 French patients with X-linked adrenoleukodystrophy (ALD) for serum levels of adrenal cortex, steroid-21-hydroxylase (21OHAb), islet cell (ICA), glutamate decarboxylase (GAD65Ab), IA2/ICA512 (ICA512Ab), thyroid peroxidase (TPOAb) autoantibodies, and plasmatic concentrations of very long chain fatty acids (VLCFA). High levels of 21OH and adrenal cortex antibodies were found in 35/42 (83%) and 17/42 (40%) Italian patients with idiopathic adrenal insufficiency, respectively. Levels of adrenal autoantibodies correlated inversely with disease duration (P < 0.0001). Elevated VLCFA were found in 4/42 (10%) idiopathic patients. A total of 34/35 (97%) idiopathic patients with a disease duration of less than 20 yr was positive for either 21OHSAb or elevated levels of VLCFA. None of 14 patients with posttuberculosis adrenal insufficiency had elevated levels of either adrenal antibodies or VLCFA. ICA, GAD65Ab, ICA512Ab, and TPOAb were found in 6/56 (11%), 8/56 (14%), 4/56 (7%), and 23/56 (41%) patients, respectively. None of 24 French ALD patients with adrenal insufficiency was positive for organ-specific autoantibodies. The measuring of 21OH antibodies and plasma VLCFA levels enabled a correct diagnosis of autoimmune (89%) and ALD (8%) in 97% of patients with idiopathic primary adrenal insufficiency of less than 20 yr of duration. The results of our study have important therapeutic and prognostic implications.
Adolescent↗
Oral granisetron as prophylaxis for nausea and vomiting during fluorescein angiography. A multicentre, double-blind, randomised, parallel group, placebo-controlled study.
BACKGROUND: Prophylaxis with oral Granisetron was assessed in patients undergoing fluorescein angiography (FAG) in order to evaluate its efficacy in reducing patients' discomfort due to nausea and vomiting (4% > 20%) and to ensure completion of the investigation. EXPERIMENTAL PLAN: Multicentre, randomised, double-blind, placebo-controlled study, with a follow-up visit performed 24 hrs after FAG. ENVIRONMENT: Five Anaesthesia/Resuscitation and Ophthalmology operational units participated in the study. PATIENTS: 120 patients (24 from each Centre) of both sexes and aged > 18 years, suffering from retinal disorders, were enrolled after informed consent. Pregnancy, lactation, anti-neoplastic treatment, ASA status IV/V were main exclusion criteria. All recruired patients completed the study. INTERVENTIONS: Ophthalmological evaluation was performed 30 days before and the same day as FAG. Anaesthesiological assessment on the same day as FAG, recording, BP, HR, ASA status, allergic diathesis, allergy to medications and contrast media, concomitant treatments. Oral Granisetrom 1 mg or placebo was given on an empty stomach 1 hr before the injection of 5 ml 20% fluorescein in 3 sec. A follow-up examination was done 24 hrs after FAG. SURVEY: In both groups nausea, retching and vomiting were seen after fluorescein injection. RESULTS: The study demonstrated that Granisetron is more active than placebo in controlling nausea (3 cases vs 4), and retching (2 vs 6). It was significantly more effective than placebo in the prevention of vomiting (0 vs 3). Efficacy was evaluated with chi 2, p < or = 0.05). CONCLUSIONS: The results suggest that Granisetron may be indicated as prophylaxis in patients undergoing FAG in order to prevent or control emesis, improve patients' comfort and ensure successful outcome of the investigation.
Administration, Oral↗
Alginate/polyaminoacidic coherent microcapsules for pancreatic islet graft immunoisolation in diabetic recipients.
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Alginates↗
Effects of alginate/polyaminoacidic coherent microcapsule transplantation in adult pigs.
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Alginates↗
Nicotinamide counteracts alcohol-induced impairment of hepatic protein metabolism in humans.
We have recently shown that a large amount of wine (750 mL, approximately 70 g of alcohol) markedly impairs postprandial hepatic protein metabolism in healthy subjects. This is probably due to the shift in the intracellular redox state (increased NADH/NAD+) induced by ethanol oxidation. If this hypothesis is true, the administration of nicotinamide (NAD+ precursor) should provide NAD+ in excess and thus correct the NADH/NAD+ abnormalities and prevent the ethanol hepatotoxicity. Whole-body protein metabolism and the fractional secretory rates of hepatic (albumin, fibrinogen) and extra-hepatic (immunoglobulin G, IgG) plasma proteins were measured in the basal postabsorptive and in the absorptive states in 15 healthy subjects, that had been assigned to three groups matched for age and body mass index. During the absorptive state (intragastric meal), the three groups received water (control), 750 mL of wine, or 750 mL of wine + 1.25 g of nicotinamide, respectively. The redox state was estimated by determining the plasma lactate/pyruvate ratio. Compared with the basal state, wine alone increased the lactate/pyruvate ratio twofold and depressed the fractional secretory rates of albumin and fibrinogen (P < 0.01 vs. control and nicotinamide); nicotinamide reduced the effects of wine on the lactate/pyruvate ratio (P < 0.02 vs. wine alone) and prevented the reduction of albumin and fibrinogen secretory rates (P > 0.05 vs. control). These results indicate that nicotinamide counteracts the acute hepatotoxic effects of ethanol by ameliorating the redox state.
Adult↗
21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry.
The diagnostic specificity of recombinant 21-hydroxylase autoantibodies (21OH-Ab) for Addison's disease was tested in adult patients with either Graves' disease (GD), insulin-dependent diabetes mellitus (IDDM), or polyendocrinopathy, as well as in healthy controls. Using a radiobinding assay with in vitro translated recombinant human 21-hydroxylase, we found 21OH-Ab in 24/28 (86%) idiopathic Addison patients, and using an immunofluorescence assay we found adrenal cortex autoantibodies (ACA) in 12/28 (43%) patients (P = 0.002). All the 12 ACA-positive sera were also positive for 21OH-Ab and ACA were found in 11/15 (73%) patients with less than 15 years and in 1/13 (8%) patients with 15-38 years of disease duration (P = 0.002). 21OH-Ab were present in 3/92 (3%) patients with GD, in 1/180 (0.6%) with IDDM and in 0/106 healthy subjects. The 21OH-Ab-positive GD and IDDM patients were also positive for ACA. None of 17 patients with polyendocrinopathy, but without Addison's disease, had 21OH-Ab. None of the 180 Belgian IDDM patients had Addison' s disease or developed an adrenal insufficiency at follow up. In two out of three Graves patients, the presence of 21OH-Ab was associated with clinical and biochemical signs of adrenal insufficiency. Of the 89 21OH-Ab-negative patients with GD none had Addison's disease at the time of blood sampling, and 79 were followed up for 5.6-7.5 years and none developed clinical signs of adrenal insufficiency. We conclude that the presence of 21OH-Ab in patients with endocrine autoimmune diseases is highly specific for Addison's disease.
Addison Disease↗
Late post-prandial hypoglycaemia as the sole presenting feature of secreting pancreatic beta-cell adenoma in a subtotally gastrectomized patient.
In this paper we describe for the first time late post-prandial hypoglycaemia as the sole presenting feature of an insulinoma in a patient who had previously undergone subtotal gastrectomy. The symptoms of hypoglycaemia always occurred 1-3 h after meals, not in the fasting state. Because of the history of gastrectomy and because post-prandial hypoglycaemia was reproduced by an oral glucose tolerance test, the diagnosis of reactive hypoglycaemia was made. Eighteen months later a fasting test was performed: venous plasma glucose decreased from 3.8 mmol/l to 2.7 mmol/l between 14 and 20 h of fast while plasma immunoreactive insulin did not decrease and plateaued at 185 pmol/l. Plasma C-peptide (0.9 nmol/l) and proinsulin (70 pmol/l, split 64, 65) were also elevated. All islet hormones increased in response to i.v. glucose and were suppressed after diazoxide. Although pre-operative procedures were negative in localizing an insulinoma, the patient underwent an operation and an insulinoma was detected at the body level of the pancreas. Thus, insulinoma should be considered in the differential diagnosis of reactive hypoglycaemia in gastrectomized patients. Response of islet hormones to glucose and their suppression by diazoxide are evidence of a secreting insulinoma even in the absence of preoperative localization of the pancreatic adenoma.
Blood Glucose↗
Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a nonselective defect.
To determine the contribution of clinically overt diabetic autonomic neuropathy (DAN) to reduced plasma adrenaline responses to hypoglycemia in IDDM and to establish its selectivity for hypoglycemia, we studied 17 IDDM patients (7 without DAN [DAN-] and 10 with DAN [DAN+]), of whom 5 had and 5 did not have postural hypotension (DAN+PH+ and DAN+PH-, respectively), and 8 nondiabetic subjects on 2 different occasions, i.e., clamped hypoglycemia (steps from 5.0 to 2.2 mmol/l plasma glucose) and 30-min steady-state exercise at 55% V(O[2max]). Recent antecedent hypoglycemia was meticulously prevented before the studies to exclude hypoglycemia as a cause of reduced responses of adrenaline to hypoglycemia. In DAN- patients, maximal responses of adrenaline to hypoglycemia were reduced (2.44 +/- 0.58 nmol/l vs. 4.9 +/- 0.54 nmol/l in nondiabetic patients) (P < 0.05). In DAN+, adrenaline responses initiated at a lower plasma glucose and were lower than in DAN- (DAN+PH-, 1.06 +/- 0.38 nmol/l; DAN+PH+, 0.84 +/- 0.27 nmol/l; P < 0.001, but NS between PH- and PH+). In response to exercise, adrenaline increased less in DAN- (0.89 +/- 0.11 nmol/l) patients than in nondiabetic subjects (1.19 +/- 0.14 nmol/l; NS) and only to 0.36 +/- 0.07 nmol/l in DAN+PH- and 0.23 +/- 0.09 nmol/l in DAN+PH+ (P < 0.001 vs. DAN- and nondiabetic subjects). These results were confirmed when nondiabetic and DAN- subjects repeated the exercise at 60 watts (35 and 41% of V(O[2max]), respectively), i.e., at the same absolute workload of DAN+ patients. Thus, DAN (both PH+ and PH-) contributes to reduced responses of adrenaline to hypoglycemia independently of recent antecedent hypoglycemia. The adrenaline defect in DAN is not selective for hypoglycemia.
3-Hydroxybutyric Acid↗
Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM.
To assess the mechanisms of fasting hyperglycemia in NIDDM patients with mild elevation of fasting plasma glucose (FPG) compared with NIDDM patients with overt hyperglycemia, we studied 29 patients with NIDDM, who were divided in two groups according to their fasting plasma glucose (<7.8 and > or =7.8 mmol/l for groups A and B, respectively), and 16 control subjects who were matched with NIDDM patients for age, sex, and body mass index. All subjects were infused with [3-3H]glucose between 10:00 P.M. and 10:00 A.M. during overnight fasting to determine glucose fluxes. In 27 subjects (17 diabetic and 10 control), [U-14C]alanine was simultaneously infused between 4:00 A.M. and 10:00 A.M. to measure gluconeogenesis (GNG) from alanine. Arterialized-venous plasma samples were collected every 30 min for measurement of glucose fluxes, GNG, and glucoregulatory hormones. In group A, plasma glucose, rate of systemic glucose production (SGP), and GNG were greater than in control subjects (7.2 +/- 0.2 vs. 4.9 +/- 0.1 mmol/l, 10.9 +/- 0.2 vs. 9.5 +/- 0.3 micromol x kg(-1) x min(-1), and 0.58 +/- 0.04 vs. 0.37 +/- 0.02 micromol x kg(-1) x min(-1), respectively, for group A and control subjects; mean value 8:00 A.M.-10:00 A.M., all P < 0.05). Both increased SGP and GNG correlated with plasma glucose in all subjects (r = 0.77 and r = 0.75, respectively, P < 0.005). Plasma counterregulatory hormones did not differ in NIDDM patients compared to control subjects. The present studies demonstrate that SGP and GNG are increased in NIDDM patients without overt fasting hyperglycemia. Thus these metabolic abnormalities primarily contribute to early development of overnight and fasting hyperglycemia in NIDDM.
Alanine↗
Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation.
To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN-]; 13 with DAN [DAN+]; of the latter, 7 had orthostatic hypotension [DAN+PH+] and 6 did not [DAN+PH-]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from approximately 20 to approximately 2 episodes/patient-month while HbA1c increased from 6.2 +/- 0.3 to 6.9 +/- 0.2% (P < 0.05). Responses of adrenaline improved more in DAN- patients (from 1.17 +/- 0.12 to 2.4 +/- 0.22 nmol/l) than in DAN+PH- (from 0.75 +/- 0.25 to 1.56 +/- 0.23 nmol/l) and DAN+PH+ patients (from 0.80 +/- 0.24 to 1.15 +/- 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 +/- 0.37 nmol/l, P < 0.05), whereas glycemic thresholds normalized only in DAN-, not DAN+. Autonomic symptoms of hypoglycemia improved but remained lower in DAN- (6.2 +/- 0.6) than in nondiabetic subjects (8.1 +/- 1.1) and lower in DAN+PH+ (4 +/- 0.8) than in DAN+PH- subjects (5.1 +/- 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN+ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.
Adult↗
Long-term intensive insulin therapy in IDDM: effects on HbA1c, risk for severe and mild hypoglycaemia, status of counterregulation and awareness of hypoglycaemia.
UNLABELLED: The present studies were designed to assess the percentage of HbA1c, frequency, and awareness of hypoglycaemia (H) during long-term intensive therapy (IT) of insulin-dependent diabetes mellitus (IDDM). From 1981 to 1994, 112 IDDM patients were on IT. HbA1c was 7.17 +/- 0.16% (non-diabetic subjects 3.8-5.5%), the frequency of severe H 0.01 +/- 0.009 episodes/patient-year, frequency of mild symptomatic H 35.6 +/- 2.9 episodes/patient-year. IDDM patients with HbA1c < or = 5.5% (Group I, n = 10), between 6.1-7.0% (Group II, n = 12), and > or = 7.6% (Group III, n = 11) were studied to assess responses of counterregulatory hormones, symptoms and cognitive function during experimental, stepped H. Compared to 18 non-diabetic subjects, Group I exhibited high thresholds (plasma glucose had to decrease more than normal to evoke responses), and impaired responses of adrenaline, unawareness of H and delayed onset of cognitive dysfunction at the lowest glycaemic plateau (2.3 mmol/l). Group II had normal thresholds and responses, whereas Group III had low thresholds. Frequency of mild H was higher in Group I (54.5 +/- 1.9 episodes/patient-year) than in Group II and III (33.7 +/- 3.5 and 20.4 +/- 2.5 episodes/patient-year, respectively, p < 0.001) and correlated with percentage of HbA1c (r = -0.82). IN CONCLUSION: IT can maintain near-normal HbA1c and is compatible with low frequency of severe H. However, if HbA1c is less than 6.0%, mild, symptomatic H is excessively frequent and causes impaired counterregulation and H unawareness. Efforts should be made not only to maintain HbA1c < or = 7.0%, but also to prevent, recognize and reverse iatrogenic H unawareness during long-term IT of IDDM by maintaining HbA1c > 6.0%.
3-Hydroxybutyric Acid↗
A rapid qualitative method to assess in vitro immunobarrier competence of pancreatic islets containing alginate/polyaminoacidic microcapsules.
A quick method for the qualitative evaluation of immunoisolatory properties associated with islet-containing alginate/poly-L-ornithine (AG/PLO) microcapsules is described. In particular, we examined a new AG/PLO coherent microcapsule (CM) prototype that was recently developed in our laboratory, although the procedure could be applicable to other capsule types as well. We observed no binding of immunoglobulins (Ig) contained in islet cell antibody (ICA)-positive human sera (> 60 Juvenile Diabetes Foundation units, JDT U) to pig islets, enveloped within AG/PLO CM, under indirect immunofluorescence examination. Also, CM were shown to inhibit human lymphocyte proliferative capacity fully, as assessed by the 3H-thymidine incorporation rate, in in vitro mixed xenogeneic pig islet/human lymphocyte co-cultures. These results provided us with a preliminary method to attempt standardization of basic physical/chemical properties which should be associated with an immunoisolatory membrane for islet allo/xenograft immunoprotection.
Analysis of Variance↗
Absence of circulating adrenal autoantibodies in adult-onset X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is a frequent cause of adrenal insufficiency in young-adult patients with Addison's disease. As the contribution of an autoimmune process in the destruction of steroid cells in ALD is unclear, the aim of the present study was to evaluate the occurrence of adrenal-, thyroid- and islet-specific and non organ-specific autoantibodies in adult ALD patients. In all 5 patients, Addison's disease was the first manifestation of ALD. None of the ALD patients were positive for adrenal cortex autoantibodies in an indirect immunofluorescence assay, or for 21-hydroxylase autoantibodies in a radiobinding assay with recombinant human antigen. Similarly, we found neither non-organ specific autoantibodies (such as anti-nuclear, anti-ribosomal, anti-mitochondria, anti-smooth-muscle, anti-liver/kidney microsomal or anti-reticulin autoantibodies), nor islet-cell antibodies or glutamic acid decarboxylase (GAD65 or GAD67) autoantibodies, nor thyroglobulin autoantibodies in the sera of the 5 ALD patients. Two out of five patients were positive for thyroid microsomal autoantibodies. One of the two latter thyroid antibody-positive patients had clinical symptoms of hypothyroidism, and the other presented high levels of circulating TSH but no clinical signs or symptoms of hypothyroidism. Our study demonstrates that adult ALD is not immediately associated with the presence of adrenal autoantibodies and suggests that adrenal insufficiency is not mediated by an autoimmune process in adult ALD patients.
Addison Disease↗
Culture maintenance of isolated adult porcine pancreatic islets in three-dimensional gel matrices: morphologic and functional results.
Adult porcine pancreatic islets are attractive for morphological and functional investigations but are difficult to obtain and use. In particular, the islet isolation and purification process is hampered by the lack of an outer capsule membrane, with predisposition to fragmentation. Attempts to culture maintain pig islets and preserve viability and functional competence have also been difficult. We found that placement of isolated porcine islets in biocompatible three-dimensional hydrogel matrices, made of calcium alginate and poly-L-ornithine, would improve morphology, as well as secretory responses to rapid glucose concentration changes.
Analysis of Variance↗
Red blood cell ghosts are affected by adrenoleucodystrophy.
X-linked adrenoleucodystrophy is a disorder occurring in different clinical forms, characterized by adrenal, gonadal and nervous system dysfunction. The basis of the illness is a derangement of the peroxisomal system necessary to oxidize very long-chain fatty acids that accumulate in various tissues. The diagnosis relies on clinical signs and symptoms and on biochemical findings. The six reported cases presented idiopathic adrenal insufficiency. We measured the lipid composition of red blood cell (RBC) ghosts of patients and control subjects. The distribution of phosphorus among phospholipid classes was unaffected; we could not demonstrate any differences between the fatty acid patterns of RBC membrane, either in total lipid extracts or in separated lipid classes. However, we found an increase in total lipid (both phospholipid and cholesterol), in membrane viscosity and in the Na+/K(+)-dependent ATPase. Therefore, we report four main findings on ghosts in adrenoleucodystrophy patients: (a) very long-chain fatty acids do not accumulate; (b) the lipid-protein ratio increases; (c) fluidity decreases; and (d) the activity of ATPase increases. The last finding is proposed as a possible biochemical marker of the illness. We conclude that adrenoleucodystrophy affects deeply RBC membranes.
Adrenoleukodystrophy↗
X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients.
X-Linked adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in tissue and body fluids. ALD is due to mutation of a gene located in Xq28 that encodes a peroxisomal transporter protein of unknown function. The most common phenotype of ALD is the cerebral form (45%) that develops in boys between 5-12 yr. Adrenomyeloneuropathy (AMN) involves the spinal cord and peripheral nerves in young adults (35%). Adrenal insufficiency (Addison's disease) is frequently associated with AMN or cerebral ALD and may remain the only clinical expression of ALD (8% of cases). The prevalence of ALD among adults with Addison's disease remains unknown. To evaluate this prevalence, we performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 yr at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of 14 patients (35%), elevated plasma concentrations of very long chain fatty acids were detected. None of these patients had adrenocortical antibodies. By electrophysiological tests and magnetic resonance imaging it was determined that two patients had cerebral ALD, one had adrenomyeloneuropathy with cerebral involvement, and two had preclinical AMN. Our data support the hypothesis that ALD is a frequent cause of idiopathic Addison's disease in children and adults.
Addison Disease↗