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Showing papers by "University of Modena and Reggio Emilia published in 1996"


Journal ArticleDOI
TL;DR: It is proposed that mitochondria represent a selective target for HS-mediated protection against oxidative injury and is correlated best with the expression of the 70-kDa HSP, hsp70.
Abstract: Heat shock (HS) proteins (HSPs) induce protection against a number of stresses distinct from HS, including reactive oxygen species. In the human premonocytic line U937, we investigated in whole cells the effects of preexposure to HS and exposure to hydrogen peroxide (H2O2) on mitochondrial membrane potential, mass, and ultrastructure. HS prevented H2O2-induced alterations in mitochondrial membrane potential and cristae formation while increasing expression of HSPs and the protein product of bcl-2. Protection correlated best with the expression of the 70-kDa HSP, hsp70. We propose that mitochondria represent a selective target for HS-mediated protection against oxidative injury.

406 citations


Journal Article
TL;DR: PSC in Italy mainly follows a benign course and among clinical features recorded at presentation, serum cholesterol, AST, haemoglobin and albumin may provide some objective criteria to assess disease severity.
Abstract: Objective Because large-scale reports of PSC in the Mediterranean area we are still lacking, in this study we evaluated by Kaplan-Meyer analysis the natural history of primary sclerosing cholangitis (PSC) in Italy and by means of other statistical methods we identified the variables most useful in predicting survival of such patients. Design Retrospective multicentre study of unselected patients with PSC. Several variables involving sex, age, associated diseases, clinical features, laboratory, cholangiographic and histological findings at presentation and clinical outcome at data recording were collected by means of a detailed questionnaire. Setting 16 Italian university and regional hospitals all over the country, thus giving a geographically representative population. Patients A total of 117 PSC patients (73 men and 44 women); median age 35 years. Methods Survival analysis was performed by the Kaplan-Meyer method; the prognostic influence on survival of collected data was evaluated by univariate chi(2) analysis with Wilcoxon and log-rank tests. The same prognostic variables were also evaluated by multivariate analysis (Cox model), using a stepwise regression procedure. All statistical analyses were performed using the SAS statistical software. Results At presentation 70% of patients were symptomatic; symptoms did not relate to liver histology. Both intra- and extrahepatic bile duct lesions were detected in 46% of patients at cholangiography. Inflammatory bowel disease was found in 54% of symptomatic patients, ulcerative colitis was 36% of total. Clinical outcome (91/117): 15 underwent liver transplantation or died from liver disease (cholangiocarcinoma). Survival at 10 years was 74%. Features of poor prognosis were cholesterol, aspartate aminotransferase (AST), haemoglobin and albumin. Conclusion PSC in Italy mainly follows a benign course and among clinical features recorded at presentation, serum cholesterol, AST, haemoglobin and albumin may provide some objective criteria to assess disease severity.

116 citations


Journal ArticleDOI
TL;DR: It is suggested that encoding duration in the hundreds of milliseconds range is a process based on an internal clock mechanism that varies as a function of the processing load.
Abstract: We have studied the distortion of perceived time in a patient with left neglect. This patient consistently over-estimated the duration of stimuli in the neglected space. Overestimation was observed both with an interval comparison (300/700 ms) and with a time production (1 s) paradigm. We suggest that encoding duration in the hundreds of milliseconds range is a process based on an internal clock mechanism. The functioning of that clock varies as a function of the processing load.

109 citations


Journal ArticleDOI
TL;DR: It is proposed that primitive NK-like activity appeared early in evolution, as well as other CD and MHC class I and class II markers, in earthworm coelomocytes.

96 citations


Journal ArticleDOI
TL;DR: In this article, the authors examined the immune system of healthy and old individuals and found that most immune parameters are indeed well preserved even at this far advanced age, and that the most important phenomenon of immunosenescence is the involution of the thymus.
Abstract: In recent decades, major theoretical and technological advances have been achieved in the field of immunology. These have allowed the scientific community to analyse the immune system in a much more sophisticated manner than was possible even 20 years ago. Moreover, great theoretical changes have also occurred in gerontology-in particular, the hypothesis has been put forward that ageing and diseases are two different phenomena, and that successful ageing, i.e. ageing in good psychophysical conditions, is really possible for most humans and animals. Immunosenescence was then carefully investigated, either in selected healthy people of advanced age or in the oldest old people, such as healthy centenarians. The main results showed that most immune parameters are indeed well preserved even at this far advanced age. This paper deals with some of the most important theoretical problems of immunosenescence. An immunological tenet was that the most important phenomenon of immunosenescence is the involution of the thymus. In most textbooks and papers it is taken for granted that the thymus starts its involution immediately after puberty. When people aged 60-65 were considered old, it was not difficult to think that they could live for the rest of their life with a fully involuted thymus. The findings on centenarians challenge this tenet, as they have only a small reduction of T lymphocytes, and a relatively normal number of virgin and memory T cells, together with a functional T cell repertoire. Other observations reported here on centenarians, concerning the activity of B lymphocytes and the cytokine network, as well as those on the well-preserved innate immunity and the cells' capability of undergoing proliferation after appropriate stimuli, suggest that complex immune changes occur with age, but also indicate that we have to modify our attitude, to grasp the new scenario which is emerging. Immunosenescence can no longer be considered as a unidirectional deterioration, and this complex phenomenon is much better described by terms such as 'remodelling', 'reshaping' or 'retuning'.

56 citations


Journal ArticleDOI
TL;DR: The duodenal papilla and periampullary region are sites with high prevalence of macro- and microscopic adenomas in patients with FAP, however, the data do not seem to support a higher frequency and malignancy potential of such lesions as compared to polyps in the rest of the duodenum.
Abstract: Background:Patients with familial adenomatous polyposis (FAP) are traditionally considered to be at high risk for duodenal-papillary and periampullary adenomas and cancer.Aim:To evaluate prospectively the prevalence, histology and clinical significance of ampullary and periampullary macroscopic and

45 citations


Journal Article
TL;DR: These results are the first to describe this type of earthworm non-specific "inflammatory" response in vitro against tumor cells.

41 citations


Journal ArticleDOI
TL;DR: In this paper, the same authors used Co2(CO)8 as the transition metal and polyethylene glycols as the phase transfer catalyst in an organic solvent/20% aqueous NaOH two-phase system under mild conditions (1 bar CO, room temperature).

38 citations


Journal ArticleDOI
TL;DR: The results demonstrate that, although the vesicle-associated form of CaMPKII is catalytically indistinguishable from the soluble form, it exhibits distinct characteristics concerning its association with thevesicle membrane and with SYNI.

29 citations


Journal ArticleDOI
TL;DR: In this article, a prospective study was done to evaluate the putative pulsatile pattern of serum activin A in serial specimens of blood collected during a certain amount of time (every 15 min for 3 h).
Abstract: The aim of the present study was to determine the characteristics of activin A secretion in women with normal and abnormal pregnancy. With this purpose, a prospective study was done to evaluate the putative pulsatile pattern of serum activin A in serial specimens of blood collected during a certain amount of time (every 15 min for 3 h). A group of pregnant women (N = 24) participated in a cross-sectional study. They were subdivided into three groups: healthy pregnant women (N = 8), patients with preterm labor (N = 8) and patients with gestational diabetes (N = 8) before and after insulin therapy. Secretory pulses of serum activin A were determined in all patients with a specific frequency and amplitude by using two different computerized analyses, i.e. DETECT and CLUSTER. Mean +/- SEM values of serum activin A were significantly higher in patients with preterm labor and gestational diabetes than in controls (p < 0.01), showing a significant decrease following insulin therapy in diabetic patients (p < 0.01). Specific pulses of serum activin A levels were observed in all women. The mean pulse frequency did not change significantly between healthy controls and the different pathological groups. Patients with gestational diabetes after insulin therapy showed a pulse frequency that was significantly higher than in controls (p < 0.05). When the mean peak amplitude of activin A pulses was evaluated, patients with preterm labor or gestational diabetes showed values that were significantly higher than in healthy pregnant women (p < 0.01) A significant, inverse correlation between pulse frequency and amplitude was found both in healthy pregnant women (p < 0.05) and in patients with gestational diabetes (p < 0.001). The present study showed that circulating activin A levels in pregnant women change in a pulsatile pattern whose pulse amplitude is modified in the presence of gestational diseases, such as preterm labor or gestational diabetes.

28 citations


Journal ArticleDOI
TL;DR: Reduction of the claws on the fourth pair of legs is interpreted as a convergent adaptation of interstitial soil-dwelling tardigrades, and H. degenerans is attributed to a new genus, Pseudohexapodibius, belonging to the family Macrobiotidae.
Abstract: We interpret reduction of the claws on the fourth pair of legs as a convergent adaptation of interstitial soil-dwelling tardigrades. Tardigradrdigrades Hexapodibius degenerans, Macrobiotus pseudohufelandi, and M. xerophilus are re-examined and H. degenerans re-described. Due to the absence of true claws on the fourth pair of legs and to the symmetry of its claws on the first three pairs of legs, H. degenerans is attributed to a new genus, Pseudohexapodibius, belonging to the family Macrobiotidae. On the basis of the peculiar type of claws, without a distinct peduncle, M. pseudohufelandi and M. xerophilus are attributed to another new genus of Macrobiotidae, Xerobiotus. Additional key words: Tardigrada, Pseudohexapodibius degenerans, Xerobiotus pseudohufelandi, Xerobiotus xerophilus Many animals that colonize interstitial soil habitats and lack organs suitable for digging possess appendages that are appreciably smaller than those found in their surface dwelling counterparts. A striking example is seen in the Collembola, whose members living on the soil surface (epiedaphic) have long legs and antennae and a strongly developed abdominal furca, whereas those always living underground among the interstices (euedaphic) have short antennae, short legs, and a vestigial furca limited to anal spines that are no longer suitable for jumping (for review see Schaller 1970). Tardigrades are almost always interstitial animals, but the space they can exploit differs when they colonize marine or freshwater sediments, mosses and lichens on tree-trunks or rocks, leaf litter, or soils covered by moss or grass turf but rich in inorganic material. Tardigrades interstitial in soil rich in inorganic material have been considered only recently (Fleeger & Hummon 1975; Manicardi & Bertolani 1987), except for a first and exceptional paper by Ramazzotti (1959), and remain poorly known to date. However, in this kind of habitat various genera and species of eutardigrades have been identified that differ from those living in freshwater, mosses, lichens, and leaf litter, in that they are characterized by very short legs and especially claws, which may sometimes even be absent a Corresponding author: Roberto Bertolani, Dipartimento di Biologia Animale, Universita di Modena, Via Universita, 4, 1-41100 Modena, Italy. Phone: ++39 59 225067; fax: ++39 59 581069; e-mail: bertolan@c220.unimo.it from some or all of the legs. Among these is the genus Hexapodibius, represented by 5 species, including Hexapodibius degenerans BISEROV 1990. When this species was described (Biserov 1990), it was compared with Parhexapodibius xerophilus DASTYCH 1978, the most similar species, and therefore attributed to the family Calohypsibiidae. However, Dastych & Alberti (1990) re-analyzed P. xerophilus by SEM and more correctly attributed the species to the family Macrobiotidae and the genus Macrobiotus. That conclusion and the strong similarity between the two species in many characters prompted us to investigate H. degenerans, M. xerophilus, and also another related species, Macrobiotus pseudohufelandi IHAROS 1966, in greater depth. Based on the symmetry of the claws on each pair of legs-the claws on either side of the leg axis are mirror-images of each other-we concluded that H. degenerans also belongs to the family Macrobiotidae, and not to Calohypsibiidae. Moreover, H. degenerans (on the first three pairs of legs), M. pseudohufelandi, and M. xerophilus show a type of claw peculiar among Macrobiotidae, characterized by the absence of a septum separating the basal part from the rest of the claw, and therefore without a distinct peduncle. As the absence of claws on the hind legs distinguishes Hexapodibius and Haplohexapodibius from other genera in Calohypsibiidae, the same character must be useful at genus level also for Macrobiotidae. For H. degenerans, which almost entirely lacks claws on the hind legs, we erect the new genus PseuThis content downloaded from 207.46.13.110 on Fri, 09 Dec 2016 05:43:58 UTC All use subject to http://about.jstor.org/terms

Journal ArticleDOI
TL;DR: The results suggest that depression, memory and metamemory are rather closely related in non-severely depressed older individuals, albeit with slightly different patterns in men and women, and that some areas of metamamory are congruent with objective functioning regardless of the level of depressive symptoms.


Journal Article
TL;DR: Encouraging results of this study confirm the need for further investigation on the role of systemic medical therapy in the treatment of CINs and suggest a possible therapeutic synergism between alpha-IFN 2a and 13cRA when used in combination.
Abstract: Recent in vitro studies have suggested a possible therapeutics synergism between α-IFN 2a and 13cRA in certain neoplasias, while encouraging in vivo findings strongly support the enhanced effectiveness of the two agents when used in combination. The specific aim of our study was to evaluate the efficacy and the toxicity of the association of 13cRA and α-IFN 2a in patients with CIN II and CIN III who refused surgical treatment. Twenty-one patients (aged between 25 and 58 years), of which 14 were CIN II and 7 CIN III, entered the study. 13cRA (orally at 0.5-1 mg/Kg/day) and α-IFN 2a (intramuscular at 3 x 10 6 I.U./day for the first 15 days, then 3 times/week for the following four weeks) were administered simultaneously for eight consecutive weeks. 13/21 (62%) histologically verified objective responses (6 complete and 7 partial) were achieved. We also obtained 8 stable diseases. Compliance was generally good and no delays in therapy due to toxicity were recorded (except for two patients presenting WHO degree III cutaneous and mucosal toxicity which regressed one week after suspending treatment). Human Papilloma Virus (HPV) was initially detected in 16/21 (76%) patients, while HPV negativization after treatment was observed in 3/16 (19%). Although preliminary and requiring long-term assessment, the encouraging results of this study confirm the need for further investigation on the role of systemic medical therapy in the treatment of CINs.

Journal ArticleDOI
TL;DR: It is reported here for the first time that an interference between AP-1 and GR in the binding to DNA consensus sequences-previously described in other biological systems-also occurs during apoptosis induced by glucocorticoids in lymphoid cells.
Abstract: The early molecular events of glucocorticoid-induced apoptosis have been investigated by studying glucocorticoid receptor levels, as well as binding activities to GRE and AP-1 sequences, using nuclear extracts from dexamethasone (Dex)-treated rat thymocytes. When the time-course of glucocorticoid-receptor complexes in nuclei of thymocytes was evaluated by binding studies using the tritiated ligand, we found that nuclear accumulation of radioactive complexes occurred in the first hour of incubation, and was followed by a progressive decline. This trend was confirmed by immunoblotting of nuclear proteins using a monoclonal anti-glucocorticoid receptor antibody. When the kinetics of binding activity to AP-1 and GRE sequences were studied, using nuclear extracts prepared from Dex-treated thymocytes in gel shift assays, we found peaks at 1 and 2 h after Dex treatment, and a return to basal levels in the following hours. Binding specificity was proved by competition studies using non-radioactive sequences, including mutated AP-1. Unexpectedly, however, protein binding to GRE was better competed for by AP-1 sequence than by GRE itself. Data obtained using the super gel shift assay suggested that AP-1/Jun can be responsible for the high affinity for the GRE sequence. Thus, we report here for the first time that an interference between AP-1 and GR in the binding to DNA consensus sequences - previously described in other biological systems - also occurs during apoptosis induced by glucocorticoids in lymphoid cells.

Journal ArticleDOI
TL;DR: It is indicated that serotoninergic and noradrenergic/ adrenergic pathways are involved in the immunoneuroendocrine modulation of hypothalamus-pituitary-adrenal function in rats, and is probably mediated by the activation of 5-HT2C receptors and of alpha 1- adrenoceptors.
Abstract: In order to elucidate the mechanism of action of immune agents on corticosterone secretion, the present study evaluated the possible involvement of some neuronal pathways (serotoninergic, noradrenergic/adrenergic) in the lipopolysaccharide (LPS)-induced corticosterone release in male rats. Serotoninergic antagonists, mianserin (5-HT2c receptor blocker) or pindolol (SHT1A receptor blocker) or noradrenergic/adrenergic antagonists, prazosin (α1-adrenoceptor blocker) or propranolol (β-adrenoceptor blocker), were intraperitoneally (i.p.) injected before (5 mm) the administration of LPS. In each experiment a group of rats i.p. injected with vehicle served as controls. Animals were sacrificed by decapitation 90 min after administration of LPS and trunk blood was collected for corticosterone radioimmunoassay. Results showed that pretreatment with mianserin, but not with pindolol, significantly reduced plasma corticosterone levels following administration of LPS (p<0.05); prazosin attenuated the plasma corticoster...

Journal Article
TL;DR: The prognosis was better for women, significantly for colon cancer and the excess death risk was reduced by 25-30% from 1978-79 to 1984-85 and among different geographical areas, no significant differences were found.
Abstract: In population based from four Italian cancer registries (Varese, Modena, Latina, Ragusa), five-years relative survival was 34% for colon cancer patients (no. = 1864) and 28% from rectum cancer patients (no. = 1117). However, rectum cancer patients showed higher survival rates in the first year of follow-up, which is possibly due to earlier diagnosis for sites more accessible to clinical examination. For colorectal cancer, age was an important prognostic factor, both in univariate and in multivariate analysis, adjusting for competitive mortality, sex, geographical area and year of diagnosis. In the same multivariate analysis, the prognosis was better for women, significantly for colon cancer and the excess death risk was reduced by 25-30% from 1978-79 to 1984-85. No significant differences were found among different geographical areas, possibly because of the low number of patients from some of the participating cancer registries.

Journal ArticleDOI
TL;DR: In this article, the effect of microwave absorption on bulk crystallization of glasses belonging to the M2O-CaO-SiO2-ZrO2 system (where M+ Li, Na, K).
Abstract: The potential for microwave processing of a single phase material is often limited due to the dependence of dielectric losses upon the chemical bonding and temperature of the material. We will present results showing the effect of microwave absorption on bulk crystallization of glasses belonging to M2O-CaO-SiO2-ZrO2 system (where M+ Li, Na, K). The glass samples were devitrified using both microwave and conventional heating. The effect of Li+, Na+, K+ on crystallization is quite remarkable and is a function of ion size. This is true especially in the microwave heating where the important dielectric losses observed in silicate glasses are related to the motion of alkali cations throughout the glass matrix. X-ray diffraction analysis was performed on the powdered samples to determine crystalline phases. Results of microstructure and microanalysis on these glass-ceramic samples will also be presented.

Journal ArticleDOI
TL;DR: In this paper, a survey of the literature on real options and illustrates both the contingent claims analysis approach and the stochastic dynamic programming approach to real option valuation is presented. And a simple model of real option is presented where qualitative value and quantitative value are aggregated through a vague, fuzzy approach.
Abstract: Italian Abstract: Questa tesi tratta problemi di valutazione delle opzioni cosiddette "reali". La prima parte descrive le due tecniche di valutazione principali (contingent claims analysis e programmazione dinamica stocastica), la seconda parte si concentra sulle opzioni "comuni" (cioe, condivise con altri agenti economici); studia gli effetti dell'interazione competitiva sul valore delle opzioni e presenta un approccio 'vago' che tiene in considerazioni variabili di tipo qualitativo oltre alle variabili di tipo quantitativo. Viene presentato un semplice modello di opzione reale con una variabile quantitativa e una variabile qualitativa, che sono aggregate mediante un approccio fuzzy. English Abstract: This thesis deals with real options. The first part is a survey of the literature on real options and illustrates both the contingent claims analysis approach and the stochastic dynamic programming approach to real option valuation. The second part focuses on shared options; it studies the effect of competitive interaction on real option valuation and presents a 'vague' approach for taking into account qualitative aspects of real options. A simple model of real option is presented where qualitative value and quantitative value are aggregated through a vague, fuzzy approach.

01 Jan 1996
TL;DR: In this paper, a mudanca na tecnologia de queima da tradicional biqueima for o processo de monoqueima rapida envolveu diferentes formulacoes e composicoes de vidrados baseados em novos tipos of vidros.
Abstract: Resumo: A mudanca na tecnologia de queima da tradicional biqueima para o processo de monoqueima rapida envolveu diferentes formulacoes e composicoes de vidrados baseados em novos tipos de vidros. Considerando-se as propriedades quimicas e fisico-quimicas, os vitro-cerâmicos parecem ser adequados para a obtencao de bons vidrados para revestimentos. Recentemente, alguns vidrados industriais baseados nos sistemas classicos Li2O-Al2O3-SiO2, CaO-MgO-SiO2 e MgO-Al2O3-SiO2 encontraram aplicacoes praticas como vidrados para queima rapida de revestimentos, resultando em pisos cerâmicos com acentuada resistencia a abrasao e ao desgaste e melhores propriedades mecânicas.

Journal ArticleDOI
TL;DR: Patients with advanced and previously uniformly treated multiple myeloma were randomised between cyclophosphamide and epirubicin, administered on an outpatient basis and had low haematological toxicity.
Abstract: In a multicentre study, 83 patients with advanced and previously uniformly treated multiple myeloma (MM) were randomised between cyclophosphamide (600 mg m-2) and epirubicin (70 mg m-2), administered every 3 weeks for three courses and both associated with prednisone and interferon-alpha2b. Both regimens were administered on an outpatient basis and had low haematological toxicity. Clinical results were similar. Overall response rate (43%) and median response and survival (5.9 and 14.1 months respectively) compare well with those obtained with more aggressive chemotherapy schedules.

Proceedings ArticleDOI
11 Jun 1996
TL;DR: The paper discusses the motivation of the above choice and the characteristics of the selected algorithm, and presents two versions of the parallel object characterized by different workload strategies and different performance.
Abstract: The work concerns the adoption of distributed-memory MIMD parallel machines for the implementation of two-dimensional object recognition in digital images. The paper discusses the motivation of the above choice and the characteristics of the selected algorithm, and presents two versions of the parallel object characterized by different workload strategies and different performance.

Journal Article
TL;DR: A scheme of radiological follow-up for patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy with intensified controls (every 2 months) during the period with the highest risk of recurrence (13-20 months) and four-monthly controls during the first year and after 31 months of FU is suggested.
Abstract: The authors analysed the patterns of recurrence of osteosarcoma of the extremities treated between 1959 and 1989 either with surgery alone (1959-71) or with combined surgery and adjuvant (1972-82) or neoadjuvant chemotherapy (1983-89). In a total of 452 patients with recurrent osteosarcoma, the initial site of metastasis was the lung in 88% of cases independently of the type of treatment received. The mean period of onset of pulmonary metastasis differed according to the type of treatment performed: 8 months for patients treated with surgery alone; 15.9 months for those treated with adjuvant chemotherapy and 20.3 months for patients treated with neoadjuvant chemotherapy. The incidence of metastases appearing within 12 months of FU was 87%, 56% and 21% respectively. In a most recent and effective neoadjuvant protocol (66% DFS), the incidence of recurrence owing to pulmonary metastasis during the first year of FU was 2% and as much as 75% of all recurrences were concentrated in the following 18 months. Surgery for pulmonary metastasis in patients undergoing chemotherapy was performed in 54 cases with secondary healing in 14 (26%). On the basis of these results the authors suggest a scheme of radiological follow-up for patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy with intensified controls (every 2 months) during the period with the highest risk of recurrence (13-20 months) and four-monthly controls during the first year and after 31 months of FU. In order to increase the efficacy of FU controls during the high-risk period, the a. propose using CT controls instead of chest X-rays at months 14, 20 and 26.

Book ChapterDOI
01 Jan 1996
TL;DR: Experimental studies have shown that iron exert a fibrogenic and mitogenic effect on hepatic stellate cells (HSC), the ultimate effectors of liver fibrogenesis.
Abstract: Iron is essential for all living organisms. However, if present in excess or in molecular forms able to catalyze free radical reactions, toxicity arises. The paradigm of iron-induced organ disease is genetic hemochromatosis (GH), in which fibrosis, cirrhosis and cancer of the liver are common findings. Iron-toxicity is mainly due to its ability to catalyze free radical reactions which lead to membrane damage, enzyme inactivation and genotoxicity. In fact, high incidence of liver cancer has been reported in hemochromatosis, while the molecular basis for this carcinogenic effect is still elusive. Fibrosis is quite common in patients with iron overload. Recent experimental studies have shown that iron exert a fibrogenic and mitogenic effect on hepatic stellate cells (HSC), the ultimate effectors of liver fibrogenesis. Through direct or indirect mechanisms, iron-generated free-radical species and/or by-products of peroxidative oxidation of biological membranes may lead to hepatocyte damage or direct stimulation of HSC. Finally, iron, in conjunction with other hepatotoxins (e.g. alcohol, viruses, etc.) may dramatically enhance liver damage and accelerate progression of liver disease.