Showing papers by "University of Bologna published in 2001"

Nonalcoholic fatty liver disease a feature of the metabolic syndrome

Abstract: Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU m(-2) min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2) Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs -84% in control subjects; P = 0003) Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs 84% in control subjects (P = 0002) Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance

CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2

Abstract: This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis

Abstract: BACKGROUND—Hepatocellular carcinoma (HCC) is a major cause of death in cirrhotic patients. This neoplasm is associated with liver cirrhosis (LC) in more than 90% of cases. Early diagnosis and treatment of HCC are expected to improve survival of patients. AIMS—To assess the cost effectiveness of a surveillance programme of patients with LC for the early diagnosis and treatment of HCC. PATIENTS—A cohort of 313 Italian patients with LC were enrolled in the surveillance programme between March 1989 and November 1991. In the same period, 104 consecutive patients with incidentally detected HCC were referred to our centre and served as a control group. METHODS—Surveillance was based on ultrasonography (US) and α fetoprotein (AFP) determinations repeated at six month intervals. Risk factors for HCC were assessed by multivariate analysis (Cox model). Outcome measures analysed were: (1) number and size of tumours; (2) eligibility for treatment; and (3) survival of patients. Economic issues were: (1) overall cost of surveillance programme; (2) cost per treatable HCC; and (3) cost per year of life saved (if any). Costs were assessed according to charges for procedures at our university hospital. RESULTS—Surveillance lasted a mean of 56 (31) months (range 6-100). During the follow up, 61 patients (19.5%) developed HCC (unifocal at US in 49 cases), with an incidence of 4.1% per year of follow up. AFP, Child-Pugh classes B and C, and male sex were detected as independent risk factors for developing HCC. Only 42 (68.9%) of 61 liver tumours were treated by surgical resection, orthotopic liver transplantation, or local therapy. The cumulative survival rate of the 61 patients with liver tumours detected in the surveillance programme was significantly longer than that of controls (p=0.02) and multivariate analysis showed an association between surveillance and survival. The overall cost of the surveillance programme was US$753 226, the cost per treatable HCC was US$17 934, and the cost for year of life saved was US$112 993. CONCLUSION—Our surveillance policy of patients with LC requires a large number of resources and offers little benefit in terms of patient survival. The decision whether to adopt a surveillance policy towards HCC should rely on the prevalence of the disease in the population and on the resources of a particular country. Keywords: hepatocellular carcinoma; surveillance programme; cost effectiveness

The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology.

Abstract: Mitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension

Abstract: Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Particle reacceleration in the Coma cluster: radio properties and hard X‐ray emission

Abstract: The radio spectral index map of the Coma halo shows a progressive steepening of the spectral index with increasing radius. Such a steepening cannot be simply justified by models involving continuous injection of fresh particles in the Coma halo or by models involving diffusion of fresh electrons from the central regions. We propose a two-phase model in which the relativistic electrons injected in the Coma cluster by some processes (starbursts, AGNs, shocks, turbulence) during a first phase in the past are systematically reaccelerated during a second phase for a relatively long time (∼1 Gyr) up to the present time. We show that for reacceleration time-scales of ∼0.1 Gyr this hypothesis can well account for the radio properties of Coma C. For the same range of parameters which explain Coma C we have calculated the expected fluxes from the inverse Compton scattering of the Cosmic Microwave Background (CMB) photons, finding that the hard X-ray tail discovered by BeppoSAX may be accounted for by the stronger reacceleration allowed by the model. The possibility of extending the main model assumptions and findings to the case of the other radio haloes is also discussed, the basic predictions being consistent with the observations.

Presence of icaA and icaD genes and slime production in a collection of staphylococcal strains from catheter-associated infections.

Abstract: Both Staphylococcus epidermidis and Staphylococcus aureus are important causes of infections associated with catheters and other medical devices. It has recently been shown that not only S. epidermidis but also S. aureus can produce slime and carries the ica operon responsible for slime production. In the operon, coexpression of icaA and icaD is required for full slime synthesis. In this study, the presence of icaA and icaD was determined in a collection of 91 staphylococcal (68 S. epidermidis and 23 S. aureus) strains from intravenous catheter-associated infections, in 10 strains from the skin and mucosa of healthy volunteers, and in two reference strains by a PCR method. Slime-forming ability was tested on Congo red agar plates; 49% of S. epidermidis strains from catheters and, surprisingly, 61% of S. aureus strains were icaA and icaD positive and slime forming. All the saprophytic strains turned out to be negative for both icaA and icaD and also non-slime forming. Two S. aureus and one S. epidermidis strain from catheters, detected as icaA and icaD positive by PCR analysis and as slime forming (black colonies) at 24 h on Congo red agar, at 48 h exhibited tiny red spikes at the center of black colonies. The onset of these variants could not be ascribed to a mutagenic potential of Congo red, which, in the Ames test, was devoid of mutagenicity. PCR analysis showed that these red variants were negative for both icaA and icaD and even lacking the entire icaADBC operon. The data reported indicate an important role of ica genes as a virulence marker in staphylococcal infections from intravenous catheters.

Artificial Molecular-Level Machines: Which Energy To Make Them Work?†

Abstract: The concept of machine can be extended to the molecular level by designing and synthesizing (supra)molecular species capable of performing mechanical movements. The energy needed to make a machine work can be supplied as chemical energy, electrical energy, or light. When a chemical “fuel” is used, waste products are formed, whereas this is not the case when suitable photochemical or electrochemical energy inputs are employed. A number of elementary functions performed by molecular-level machines are illustrated, and more complex ones are foreseen.

Human oocyte cryopreservation: new perspectives regarding oocyte survival

Abstract: The success of human oocyte cryopreservation depends on morphological and biophysical factors that could influence oocyte survival after thawing. Various attempts to cryopreserve human oocytes have been performed with contrasting results. Therefore the effect of some factors, such as the presence or absence of the cumulus oophorus, the sucrose concentration in the freezing solution and the exposure time to cryoprotectants, on human oocyte survival after thawing were investigated. The oocytes were cryopreserved in 1,2-propanediol added with sucrose, using a slow-freezing-rapid-thawing programme. After thawing, the oocytes were inseminated by intracytoplasmic sperm injection (ICSI) and the outcomes of insemination and subsequent embryo development were also recorded. The post-thaw cryosurvival rate was not different for the oocytes cryopreserved with their cumuli partially removed mechanically (56%) when compared with those cryopreserved with their cumuli totally removed enzymatically (53%). On the contrary, a significantly higher survival rate was obtained when the oocytes were cryopreserved in the presence of a doubled sucrose concentration (0.2 mol/l) in the freezing solution and the survival rate was even higher when the sucrose concentration was tripled (0.3 mol/l) (60 versus 82% P < 0.001). Furthermore, a longer exposure time (from 10.5 to 15 min) to cryoprotectants, before lowering the temperature, significantly increased the oocyte survival rate (P < 0.005). Intracytoplasmic sperm injection produced a good fertilization rate (57%) of thawed oocytes and a high embryo cleavage rate (91%) and a satisfactory embryo morphology was observed (14 and 34% for grade I and grade II embryos respectively).

Growth and Agglomeration

Abstract: This article presents a model in which growth and geographic agglomeration of economic activities are mutually self-reinforcing processes. Economic agglomeration in one region spurs growth because it reduces the cost of innovation in that region through a pecuniary externality due to transaction costs. Growth fosters agglomeration because, as the sector at the origin of innovation expands, new firms tend to locate close to this sector. Agglomeration implies that all innovation and most production activities take place in the core region. However, as new firms are continuously created in the core, some relocate their production to the periphery.

HUman MicroNucleus Project: International database comparison for results with the cytokinesis-block micronucleus assay in human lymphocytes: I. Effect of laboratory protocol, scoring criteria, and host factors on the frequency of micronuclei

Abstract: Micronucleus (MN) expression in peripheral blood lymphocytes is well established as a standard method for monitoring chromosome damage in human populations. The first results of an analysis of pooled data from laboratories using the cytokinesis-block micronucleus (CBMN) assay and participating in the HUMN (HUman MicroNucleus project) international collaborative study are presented. The effects of laboratory protocol, scoring criteria, and host factors on baseline micronucleated binucleate cell (MNC) frequency are evaluated, and a reference range of "normal" values against which future studies may be compared is provided. Primary data from historical records were submitted by 25 laboratories distributed in 16 countries. This resulted in a database of nearly 7000 subjects. Potentially significant differences were present in the methods used by participating laboratories, such as in the type of culture medium, the concentration of cytochalasin-B, the percentage of fetal calf serum, and in the culture method. Differences in criteria for scoring micronuclei were also evident. The overall median MNC frequency in nonexposed (i.e., normal) subjects was 6.5 per thousand and the interquartile range was between 3 and 12 per thousand. An increase in MNC frequency with age was evident in all but two laboratories. The effect of gender, although not so evident in all databases, was also present, with females having a 19% higher level of MNC frequency (95% confidence interval: 14-24%). Statistical analyses were performed using random-effects models for correlated data. Our best model, which included exposure to genotoxic factors, host factors, methods, and scoring criteria, explained 75% of the total variance, with the largest contribution attributable to laboratory methods.

Biosynthesis, oxidation and conjugation of aliphatic polyamines in higher plants.

Abstract: This chapter will focus on polyamine biosynthesis, oxidation, conjugation processes, mainly to hydroxycinnamic acids, and compartmentation of enzymes, substrates and products, giving an overview about recent results especially in higher plants. New research advances regarding the cloning of the main cDNA encoding for polyamine biosynthetic and oxidative enzymes, will be taken into consideration.

Rectifiability and perimeter in the Heisenberg group

Abstract: In this paper, we fully extend to the Heisenberg group endowed with its intrinsic Carnot-Caratheodory metric and perimeter the classical De Giorgi's rectifiability divergence theorems.

Expressing the human genome.

Abstract: We have searched the human genome for genes encoding new proteins that may be involved in three nuclear gene expression processes: transcription, pre-messenger RNA splicing and polyadenylation. A plethora of potential new factors are implicated by sequence in nuclear gene expression, revealing a substantial but selective increase in complexity compared with Drosophila melanogaster and Caenorhabditis elegans. Although the raw genomic information has limitations, its availability offers new experimental approaches for studying gene expression.

Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels

Abstract: Morvan's 'fibrillary chorea' or Morvan's syndrome is characterized by neuromyotonia (NMT), pain, hyperhydrosis, weight loss, severe insomnia and hallucinations. We describe a man aged 76 years with NMT, dysautonomia, cardiac arrhythmia, lack of slow-wave sleep and abnormal rapid eye movement sleep. He had raised serum antibodies to voltage-gated K(+) channels (VGKC), oligoclonal bands in his CSF, markedly increased serum norepinephrine, increased serum cortisol and reduced levels and absent circadian rhythms of prolactin and melatonin. The neurohormonal findings and many of the clinical features were very similar to those in fatal familial insomnia, a hereditary prion disease that is associated with thalamic degenerative changes. Strikingly, however, all symptoms in our MFC patient improved with plasma exchange. The patient died unexpectedly 11 months later. At autopsy, there was a pulmonary adenocarcinoma, but brain pathology showed only a microinfarct in the hippocampus and no thalamic changes. The NMT and some of the autonomic features are likely to be directly related to the VGKC antibodies acting in the periphery. The central symptoms might also be due to the direct effects of VGKC antibodies, or perhaps of other autoantibodies still to be defined, on the limbic system with secondary effects on neurohormone levels. Alternatively, changes in secretion of neurohormones in the periphery might contribute to the central disturbance. The relationship between VGKC antibodies, neurohormonal levels, autonomic, limbic and sleep disorders requires further study.

Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value

Abstract: During the past two decades, hepatocellular carcinoma (HCC) has been one of the most intriguing diseases to treat. The problem of treatment remains open, especially for patients with underlying cirrhosis of the liver, which substantially reduces the possibility of aggressive treatment. The management of HCC on cirrhosis has progressively involved surgeons, hepatologists, oncologists, and interventional radiologists. Consequently, several different therapies are now available for these patients: liver resection (LR), orthotopic liver transplantation (OLT), percutaneous alcohol injection (PEI), transarterial chemoembolization (TACE), and radiofrequency ablation are applied worldwide by several different specialists. The routine evaluation of patients with chronic liver disease has led to a significant increase in the number of patients found to have preserved hepatic function and relatively small HCCs. The solitary type is the most common type at presentation. 1 The disease typically occurs in the seventh decade;2 the mean age of a large cohort of patients described by our group for demographic purposes was 61.5 years. 3 In the same group, more than half the patients were Child A. 2 All these considerations explain the increased number of patients with HCC on cirrhosis who require treatment and the number of methods proposed. Unfortunately, the scientific literature lacks prospective comparative evaluations of these treatments, with the exception of those proposed for palliation, 4 and there have been no accepted guidelines for managing the disease. Further, the reference standards for results obtained by different methods often refer to historical series that reflect the medical knowledge and expertise of a particular period. 5 For these reasons, we decided to perform a retrospective evaluation of the results obtained with a single procedure (LR) over a long period, with the aim of reassessing the standards for this single therapy to be considered when evaluating the wide spectrum of treatments for patients with HCC on cirrhosis.

Current and electromagnetic field associated with lightning-return strokes to tall towers

Abstract: An analysis of electric and magnetic fields radiated by lightning first and subsequent return strokes to tall towers is presented. The contributions of the various components of the fields, namely, static, induction, and radiation for the electric field, and induction and radiation for the magnetic field are illustrated and discussed. It is shown in particular that the presence of a tower tends, in general, to increase substantially the electric and magnetic field peaks and their derivatives. This increase is mainly caused by the presence of two oppositely propagating current wavefronts originating from the tower top and by the very high propagation velocity of current pulses within the tower, and depends essentially on the wavefront steepness of the channel-base current. Because of the last factor, the increase of the field magnitudes is found to be significantly higher for subsequent return strokes, which are characterized by much faster risetimes compared to first return strokes. The presented results are consistent with experimental observations of current in lightning strokes to the Toronto CN Tower and of the associated electric and magnetic fields measured 2 km away. These findings partially explain the fact that subsequent return strokes characterized by lower current peaks but higher front steepnesses and return stroke speeds may result in higher field peaks. The results obtained have important implications in electromagnetic (EM) compatibility. It is found that lightning strokes to tall metallic objects lead to increased EM field disturbances. Also, subsequent return strokes are to be considered an even more important source of EM interference than first return strokes. Indeed, EM fields from subsequent strokes are characterized by faster fronts and additionally, they may reach greater peaks than first strokes. Lastly, findings of this study emphasize the difficulty of extracting reliable lightning return stroke current information from remote EM field measurements using oversimplified formulae.

A gender--dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity.

Abstract: Current literature indicates that elevated IL-6 serum levels are associated with diseases, disability and mortality in the elderly. In this paper, we studied the IL-6 promoter genetic variability at -174 C/G locus and its effect on IL-6 serum levels in a total of 700 people from 60 to 110 years of age, including 323 centenarians. We found that the proportion of homozygotes for the G allele at -174 locus decreases in centenarian males, but not in centenarian females. Moreover, we found that, only among males, homozygotes for the G allele at -174 locus have higher IL-6 serum levels in comparison with carriers of the C allele. On the whole, our data suggest that those individuals who are genetically predisposed to produce high levels of IL-6 during aging, i.e. -174 locus GG homozygous men, are disadvantaged for longevity.