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Biomedical subjects

Piero Portincasa

Publications and source records attributed to Piero Portincasa.

At least 37 records · Page 2Linked to original sources
PubMed2005

Modulation of cholesterol crystallization in bile. Implications for non-surgical treatment of cholesterol gallstone disease.

The first step in cholesterol gallstone disease is precipitation of cholesterol crystals in bile. In gallbladder bile. cholesterol is normally solubilized together with bile salts and phospholipids to form mixed micellar structures. When cholesterol in bile is in excess, vesicles (i.e. phospholipid-cholesterol globular structures: liquid crystals) form which become supersaturated in cholesterol. Early aggregation and precipitation of cholesterol molecules into submicroscopic nuclei occurs from these supersaturated vesicles. This crucial step is followed by precipitation and agglomeration of cholesterol crystals which then become visible at light microscopy. Here we describe the mechanism of cholesterol crystallization and its modulation in vivo and in vitro. Recent advances on the role of ursodeoxycholate as an agent preventing the precipitation of cholesterol crystals in bile will be highligthed.

Animals↗
PubMed2005

Contribution of canalicular glutathione efflux to bile formation. From cholestasis associated alterations to pharmacological intervention to modify bile flow.

At least one third of the bile flow is driven osmotically by the amount of hepatic glutathione excreted into canalicular spaces. Beyond the importance of this secretory mechanism for bile formation, the excretion of glutathione is an important way to discharge toxic anionic compounds deriving from liver metabolism of exogenous and endogenous substances. Thus, biliary secretion of glutathione and its conjugates really works as a major detoxification system for the hepatocytes. Derangement of hepatic and/or biliary glutathione status can occur in several experimental animal models of liver injury and in human diseases. In the present review, we will focus on mechanisms of bile glutathione efflux and changes associated with cholestatic conditions. Novel findings on the role of water channels and of the multidrug resistant proteins in bile salt-independent bile formation, will also be discussed. New routes of intervention to modify bile flow for therapeutic purposes are considered.

Animals↗
PubMed2005

Drugs affecting biliary lipid secretion and gallbladder motility: their potential role in gallstone treatment and prevention.

Gallstone disease in the Western world has an estimated prevalence of 10-15% and more than 75% are cholesterol-enriched gallstones. Defective gallbladder motility has been identified as an important pathogenic factor for cholesterol gallstone disease. Various agents may enhance or impair postprandial gallbladder motility, and their effects on interdigestive gallbladder and intestinal motility should also be taken into account. Patients in high-risk situations for gallstone disease, and those chronically treated with drugs inhibiting gallbladder motility (e.g. somatostatin analogues) may benefit from improving gallbladder motility with prokinetic agents. Whether such a strategy can really prevent gallstone formation is still unknown, long-term studies are lacking so far. The efficacy of bile acid therapy with UDCA for gallstone dissolution or for prevention in high risk patients is limited and hampered by high recurrence rates. The efficacy of UDCA in prevention of colics or gallstone related complications in symptomatic patients with gallbladder stones with contraindications for operation or on the waiting list should be explored further, since several retrospective studies showed favourable outcomes with this strategy.

Animals↗
PubMed2005

The emerging problem of nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) is an increasing recognized form of chronic liver condition affecting both children and adults within the wide spectrum of fatty liver diseases. Recently NASH has been often associated with insulin resistance and has shown potential harmful evolution towards end-stage liver disease. Its incidence and prevalence is increasing, paralleling the rise in obesity and diabetes mellitus in Western Countries. Once all the other causes of persistent elevation of serum transaminase levels are excluded, the diagnosis of NASH can be only confirmed by liver histology. Non-invasive diagnostic tools, however, are awaited to allow the follow-up of patients at higher risk for major liver dysfunction. This article focus on current thoughts on the natural history and clinical presentation of NASH and describes current trends in the diagnosis and treatment of this emerging condition.

Diet↗
PubMed2004

Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in beta-thalassemia major adults.

AIM: Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstone formation in beta-thalassemia major. METHODS: Twenty-three patients with beta-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography), orocecal transit (OCTT, H(2)-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests), bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography) was examined before and during 8-12 mo follow-up. RESULTS: Gallstones and/or biliary sludge were found in 13 (56%) patients. beta-thalassemia major patients had increased fasting (38.0+/-4.8 mL vs 20.3+/-0.7 mL, P = 0.0001) and residual (7.9+/-1.3 mL vs 5.1+/-0.3 mL, P = 0.002) volume and slightly slower emptying (24.9+/-1.7 min vs 20.1+/-0.7 min, P = 0.04) of the gallbladder, together with longer OCTT (132.2+/-7.8 min vs 99.7+/-2.3 min, P = 0.00003) than controls. No differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.7+/-1.2 vs 4.9+/-0.2, P = 0.027), greater appetite (P = 0.000004) and lower health perception (P = 0.00002) than controls. Autonomic dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder volume. CONCLUSION: Adult beta-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in beta-thalassemia major.

Adolescent↗
PubMed2004

Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C.

Hemolysis is a frequent adverse effect of ribavirin (RBV). It has been suggested that oxidative stress plays a role, but mechanisms and predictive risk factors for severe forms remain unknown. Markers of redox status were determined in erythrocytes of 34 patients with hepatitis C-four of them with glucose-6-phosphate-dehydrogenase (G6PD) deficiency-before and during treatment with RBV and interferon (IFN) and were compared with 10 healthy control subjects. In addition, erythrocytes were incubated with RBV, and the effects of dipyridamole (DPD), diethylmaleate (DEM), and glutathione ester (GSHE) were studied in vitro. Of the 30 patients without G6PD deficiency who were treated with RBV and IFN-alpha, five developed major hemolysis (Delta hemoglobin > 6 g/dL) and 25 developed minor hemolysis (Delta hemoglobin < 2.5 g/dL). Patients with major hemolysis had lower median pretreatment values of membrane protein sulfhydrils than patients with minor hemolysis (28.4 vs. 36.7 nmol/mg, P <.001). Erythrocytes of G6PD-deficient patients were not more susceptible to RBV-induced hemolysis. In in vitro incubations of erythrocytes, DEM enhanced the RBV-induced decrease of glutathione, protein sulfhydrils, and osmotic resistance. Supplementation of GSHE and DPD prevented the RBV-induced decrease in osmotic resistance, adenosyl triphosphate (ATP), and 2,3-diphosphoglycerate (DPG), the loss of glutathione and protein sulfhydrils, and the formation of thiobarbituric acid reactive substances (TBARs). In conclusion, the data indicate that low membrane protein sulfhydrils prior to therapy but not G6PD deficiency are predictive of RBV-induced major hemolysis. In vitro, GSHE and DPD reduce the RBV-associated oxidative stress in erythrocytes and prevent the increase in osmotic fragility, suggesting that these compounds might decrease the risk of hemolysis in patients.

Adult↗
PubMed2004

Total thyroidectomy is improved by loupe magnification.

With this study, we verified if a microsurgical approach with magnification could improve the outcome of total thyroidectomy. Ninety-seven patients were consecutively randomized into group A (surgery with x 2.5 magnification and microsurgical instruments, n = 47) or group B (surgery with no magnification, n = 50). The mean operative time was 125 +/- 4.0 min in group A, and 150 +/- 4.0 min in group B (P = 0.00012). The recurrent laryngeal nerve was identified in all patients of group A, and in 96.8% of group B. The overall morbidity rate was 4.0% in group A and 25.5% in group B (P = 0.0038). This study indicates that a microsurgical approach with magnification is feasible, reduces surgical time, and improves the outcome in total thyroidectomy.

Adult↗
PubMed2004

Smooth muscle function and dysfunction in gallbladder disease.

The gallbladder epithelium and smooth muscle layer are exposed to concentrated biliary solutes, including cholesterol and potentially toxic hydrophobic bile salts, which are able to influence muscle contraction. Physiologically, gallbladder tone is regulated by spontaneous muscle activity, hormones, and neurotransmitters released into the muscle from intrinsic neurons and extrinsic sympathetic nerves. Methods to explore gallbladder smooth muscle function in vitro include cholecystokinin (CCK) receptor-binding studies and contractility studies. In human and animal models, studies have focused on cellular and molecular events in health and disease, and in vitro findings mirror in vivo events. The interplay between contraction and relaxation of the gallbladder muscularis leads in vivo to appropriate gallbladder emptying and refilling during fasting and postprandially. Defective smooth muscle contractility and/or relaxation are found in cholesterol stone-containing gallbladders, featuring a type of gallbladder leiomyopathy; defects of CCKA receptors and signal transduction may coexist with abnormal responses to oxidative stress and inflammatory mediators. Abnormal smooth musculature contractility, impaired gallbladder motility, and increased stasis are key factors in the pathogenesis of cholesterol gallstones.

Animals↗
PubMed2004

Effect of dietary restriction and N-acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats.

The age-related changes of glutathione (GSH) levels and the effect of hypocaloric regimen and N-acetylcysteine (NAC) supplementation were investigated in intestinal mucosa and liver mitochondria of 28 months rats. Old rats exhibited lower proteins, GSH and protein sulphydrils (PSH) concentrations, higher GSH-peroxidase (GSH-Px) activity and protein carbonyl deposit, partial inhibition of succinate stimulated mitochondrial state III respiration and decreased mitochondrial nitrosothiols (RSNO) concentration. Lower electric potential and current intensity were found in the colonic mucosa. Old rats undergone hypocaloric regimen showed higher intestinal concentrations of GSH, lower oxidized protein accumulation and GSH-Px activity and higher mitochondrial RSNO levels. Mitochondrial state III respiration and intestinal transport were improved. NAC supplementation enhanced GSH and PSH levels in the ileal but not in the colonic mucosa, GSH and RSNO in liver mitochondria, while GSH-Px and protein carbonyls were decreased everywhere. Mitochondrial respiration ameliorated. In conclusion, ageing is characterized by a spread decrease of GSH concentrations, increased protein oxidation and decreased mitochondrial NO content. Hypocaloric diet ameliorated intestinal transport and, as well as NAC, was effective in enhancing GSH levels but at different extent according to the investigated districts. Both interventions reduced the age-associated increase of GSH-Px and protein carbonyls and improved mitochondrial respiration.

Acetylcysteine↗
PubMed2004

Effects of growth hormone deficiency and recombinant growth hormone therapy on postprandial gallbladder motility and cholecystokinin release.

In addition to cholecystokinin, other hormones have been suggested to be involved in regulation of postprandial gallbladder contraction. We aimed to evaluate effects of growth hormone (GH) on gallbladder contractility and cholecystokinin release. Gallbladder and gastric emptying (by ultrasound) and cholecystokinin release were determined before and after 6 months of recombinant human GH (rhGH) therapy in 12 patients with GH deficiency, after either a mixed (n = 5) or a liquid (n = 7) meal. Basal postprandial gallbladder contraction was severely impaired (19 +/- 2 and 26 +/- 3% of fasting volume after mixed and liquid meal, respectively). Histology and cholecystokinin sulfation patterns in duodenal biopsies from two patients were normal. After 6 months of rhGH therapy, fasting gallbladder volumes increased (from 20.8 +/- 0.9 to 25.9 +/- 1.1 mL, P < 0.05) and postprandial gallbladder emptying was restored (70 +/- 6 and 70 +/- 7% of fasting volume after mixed and liquid meal, respectively), without change of gastric emptying. Cholecystokinin secretion after a mixed meal and gallbladder sensitivity to cholecystokinin were significantly enhanced during rhGH replacement compared to the basal state. Postprandial cholecystokinin release, gallbladder responsiveness to cholecystokinin, and gallbladder emptying are severely impaired in the absence of GH. Reversibility during GH suppletion suggests its involvement in regulation of gallbladder contractility.

Adolescent↗
PubMed2003

Biliary pronucleating proteins and apolipoprotein E in cholesterol and pigment stone patients.

BACKGROUND/AIMS: Although cholesterol gallstone patients exhibit higher biliary cholesterol saturation than pigment stone patients, underlying mechanisms that affect stone type are unknown. We hypothesized that pronucleating proteins, hydrophobic bile salts or apolipoprotein E genotype affect stone type. We therefore compared these putative factors in cholesterol and pigment stone patients. METHODS: In 74 cholesterol and 12 pigment stone patients, bile lipids, various pronucleating proteins, crystallization and apolipoprotein E genotype were determined. RESULTS: Crystallization was enhanced, and cholesterol saturation higher in case of cholesterol stones, without any difference in bile salt composition. Concentrations of mucin (0.91+/-0.08 versus 0.31+/-0.06 mg/ml: P<0.0001), protein, IgM, IgG, IgA, haptoglobin, alpha1-acid glycoprotein and haptoglobin were 2-6-fold higher in cholesterol stone patients. Twenty cholesterol stone pts (27%) but only one pigment stone pt (8%) had at least one epsilon4 allele. There was a significant difference in allele frequencies between both groups (cholesterol stones similar to Dutch population: epsilon2 0.074, epsilon3 0.770, epsilon4 0.156: pigment stones: epsilon2 0.250, epsilon3 0.708, epsilon4 0.042). CONCLUSIONS: Various pronucleating biliary proteins are markedly higher in cholesterol than pigment stone patients. Also, apolipoprotein E genotype differs between cholesterol and pigment stone patients. These factors may affect gallstone type.

Adult↗
PubMed2003

Mitochondrial glutathione content determines the rate of liver regeneration after partial hepatectomy in eu- and hypothyroid rats.

BACKGROUND/AIMS: Mitochondrial glutathione has been postulated to affect mitochondrial function and liver regeneration. METHODS: Mitochondrial respiration, total and oxidized glutathione, and liver regeneration were assessed after partial hepatectomy in glutathione-depleted and in hypothyroid rats with/without supplementation of glutathione ester. RESULTS: Mitochondrial, cytosolic and circulating glutathione levels were lower in glutathione-depleted rats. Hepatectomy was followed by significant changes of intra- and extracellular glutathione and of mitochondrial respiration. In glutathione-deficient rats, the recovery of mitochondrial function and the liver regeneration were delayed. Administration of glutathione ester partially corrected the fall of cytosolic and mitochondrial glutathione following hepatectomy, reduced mitochondrial oxidative damage, and accelerated the restoration of mitochondrial respiration and the rate of liver regeneration. In hypothyroid rats, intracellular glutathione homeostasis and mitochondrial respiration were impaired already at baseline; slower regeneration and mitochondrial oxidative alterations were observed after hepatectomy. Glutathione ester ameliorated the regenerative response in hypothyroid rats by providing higher concentrations of cytosolic and mitochondrial glutathione. CONCLUSIONS: Glutathione depletion and hypothyroidism affect the mitochondrial function during liver regeneration. Liver regenerates more slowly in glutathione-depleted and in hypothyroid rats. The earlier restoration of mitochondrial function and the higher rate of proliferation in glutathione ester treated rats suggest that the maintenance of intracellular glutathione facilitates liver regeneration.

Animals↗
PubMed2003

Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting ROME II criteria for irritable bowel syndrome.

AIM: Psychological factors, altered motility and sensation disorders of the intestine can be variably associated with irritable bowel syndrome (IBS). Such aspects have not been investigated simultaneously. The aim of this paper was to evaluate gastrointestinal motility and symptoms, psychological spectrum and quality of life in a large group of IBS patients in southern Italy. METHODS: One hundred IBS patients (F:M=73:27, age 48+/-2 years, mean+/-SE) fulfilling ROME II criteria matched with 100 healthy subjects (F:M=70:30, 45+/-2 years). Dyspepsia, bowel habit, alexithymia, psycho-affective profile and quality of life were assessed using specific questionnaires. Basally and postprandially, changes in gallbladder volumes and antral areas after liquid meal and orocaecal transit time (OCTT) were measured respectively by ultrasonography and H(2)-breath test. Appetite, satiety, fullness, nausea, and epigastric pain/discomfort were monitored using visual-analogue scales. RESULTS: Compared with controls, IBS patients had increased dyspepsia (score 12.6+/-0.7 vs 5.1+/-0.2, P<0.0001), weekly bowel movements (12.3+/-0.4 vs 5.5+/-0.2, P<0.00001, comparable stool shape), alexithymia (score 59.1+/-1.1 vs 40.5+/-1.0, P=0.001), poor quality of life and psycho-affective profile. IBS patients had normal gallbladder emptying, but delayed gastric emptying (T50: 35.5+/-1.0 vs 26.1+/-0.6 min, P=0.00001) and OCTT (163.0+/-5.4 vs 96.6+/-1.8 min, P=0.00001). Fullness, nausea, and epigastric pain/discomfort were greater in IBS than in controls. CONCLUSION: ROME II IBS patients have a pan-enteric dysmotility with frequent dyspepsia, associated with psychological morbidity and greatly impaired quality of life. The presence of alexithymia, a stable trait, is a novel finding of potential interest to detect subgroups of IBS patients with different patterns recovered after therapy.

Abdominal Pain↗
PubMed2003

Significant factors associated with fatal outcome in emergency open surgery for perforated peptic ulcer.

AIM: To evaluate the main factors associated with mortality in patients undergoing surgery for perforated peptic ulcer referred to an academic department of general surgery in a large southern Italian city. METHODS: One hundred and forty-nine consecutive patients (M:F ratio=110:39, mean age 52 yrs, range 16-95) with peptic ulcer disease were investigated for clinical history (including age, sex, previous history of peptic ulcer, associated diseases, delayed abdominal surgery, ulcer site, operation type, shock on admission, postoperative general complications, and intra-abdominal and/or wound infections), serum analyses and radiological findings. RESULTS: The overall mortality rate was 4.0%. Among all factors, an age above 65 years, one or more associated diseases, delayed abdominal surgery, shock on admission, postoperative abdominal complications and/or wound infections, were significantly associated (chi2) with increased mortality in patients undergoing surgery (0.0001<P<0.03). CONCLUSION: Factors such as concomitant diseases, shock on admission, delayed surgery, and postoperative abdominal and wound infections are significantly associated with fatal outcomes and need careful evaluation within the general workup of patients admitted for perforated peptic ulcer.

Academic Medical Centers↗
PubMed2003

Pathobiology of cholesterol gallstone disease: from equilibrium ternary phase diagram to agents preventing cholesterol crystallization and stone formation.

The primum movens in cholesterol gallstone formation is hypersecretion of hepatic cholesterol, chronic surpersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles. Associated events include biochemical defects (increased biliary mucin, and increased proportions of hydrophobic bile salts in the intestine and gallbladder), motility defects (gallbladder smooth muscle hypocontractility in vitro and gallbladder stasis in vivo, sluggish intestinal transit), and an abnormal genetic background. The study of physical-chemical factors and pathways leading to cholesterol crystallization in bile has clinical relevance and the task can be carried out in different ways. The lithogenicity of bile is investigated in artificial model biles made by three biliary lipids - cholesterol, bile salts and phospholipids - variably combined in systems plotting within the equilibrium ternary phase diagram; also, crystallization propensity of ex vivo incubated human bile is studied by biochemical analysis of precipitated crystals, polarizing quantitative light microscopy and turbidimetric methods. The present review will focus on the recent advances in the field of pathobiology of cholesterol gallstones, by underscoring the role of early events like water transport, lipid transport, crystallization phenomena - including a genetic background - in gallstone pathogenesis. Agents delaying or preventing precipitation of cholesterol crystals and gallstone formation in bile will also be discussed.

Animals↗
PubMed2002

Contractility in vitro and mitochondrial response in small and large rabbit bowel after anastomosis.

Leakage of a large bowel anastomosis remains the most serious postoperative complication in gastrointestinal surgery. In a recent experimental study we found that surgically induced hypoxia resulted in more derangement of a variety of biochemical markers in the large bowel (LB) than in the small bowel (SB). We explored the question of whether spontaneous and agonist-induced contractility of SB and LB muscle strips was influenced by surgical procedures and how contractility was related to energetic oxidative metabolism capacity in smooth muscle mitochondria. Sixty male New Zealand rabbits were operated on under general anesthesia. Segments of ileum and colon were resected from each rabbit, and an end-to-end anastomosis was constructed. A representative subset of segments from SB (n = 14) and LB (n = 14) at time 0 was used as controls. Tracts containing an anastomosis were resected at days 2, 7, and 14 after operation. At each time point, 20 segments adjacent to the anastomosis of both SB and LB were used for tensiometric and biochemical studies. Tensiometric studies demonstrated modifications in the smooth muscle function at both the acute and chronic stages with intestinal inflammation that may contribute to surgical stress-associated abnormal motility. Biochemical data showed that the respiratory capacity of the resected LB was more impaired than that of the SB. In both SB and LB, changes in respiratory activity preceded tensiometric changes. Thus abnormalities of contractility after surgical stress are more evident in LB than SB in segments adjacent to the anastomoses. This could be the consequence of abnormal biochemical changes, as adenosine triphosphate (ATP) is required for membrane potential maintenance, calcium homeostasis, and actin-myosin interactions.

Anastomosis, Surgical↗
PubMed2002

Incorporation of cholesterol in sphingomyelin- phosphatidylcholine vesicles has profound effects on detergent-induced phase transitions.

Vesicle <--> micelle transitions are important phenomena during bile formation and intestinal lipid processing. The hepatocyte canalicular membrane outer leaflet contains appreciable amounts of phosphatidylcholine (PC) and sphingomyelin (SM), and both phospholipids are found in the human diet. Dietary SM enrichment inhibits intestinal cholesterol absorption. We therefore studied detergent-induced vesicle --> micelle transitions in SM-PC vesicles. Phase transitions were evaluated by spectrophotometry and cryotransmission electron microscopy (cryo-TEM) after addition of taurocholate (3-7 mM) to SM-PC vesicles (4 mM phospholipid, SM/PC 40%/60%, without or with 1.6 mM cholesterol). After addition of excess (5-7 mM) taurocholate, SM-PC vesicles were more sensitive to micellization than PC vesicles. As shown by sequential cryo-TEM, addition of equimolar (4 mM) taurocholate to SM-PC vesicles induced formation of open vesicles, then (at the absorbance peak) fusion of bilayer fragments into large open structures (around 200 nm diameter) coexisting with some multilamellar or fused vesicles and thread-like micelles and, finally, transformation into an uniform picture with long thread-like micelles. Incorporation of cholesterol in the SM/PC bilayer changed initial vesicular shape from spherical into ellipsoid and profoundly increased detergent resistance. Disk-like micelles and multilamellar vesicles, and then extremely large vesicular structures, were observed by sequential cryo-TEM under these circumstances, with persistently increased absorbance values by spectrophotometry. These findings may be relevant for bile formation and intestinal lipid processing. Inhibition of intestinal cholesterol absorption by dietary SM enrichment may relate to high resistance against bile salt-induced micellization of intestinal lipids in presence of the sphingolipid.

Bile Acids and Salts↗