Worldwide epidemiology and modes of transmission of delta hepatitis

Conclusions Since the discovery of HDV in 1977 byRizzetto and collegues (10), several studies regarding the pathogenesis, natural history and epidemiology of this infection have been accumulated. It emerges that HDV is an agent with unusual biologic properties which requires HBV replication for its expression. Given the obligatory association between HDV and HBV, transmission of HDV follows the same routes of HBV transmission. This implies that one expects HDV infection to be much more prevalent in countries with high HBsAg carrier rates. This is true in most areas of the world but not in Far East Asia. Endemicity of HDV is maintained in the community through the network of HBsAg carriers. HDV can be transmitted to HBV positive and negative individuals, but survives only after encountering the carrier. Recent outbreaks of severe epidemics of fulminant hepatitis due to HDV among the Yucpa Indians in Northern Venezuela, pointed out very clearly that HDV superinfection is an ominous risk for all populations where HBV is endemic.     

Infections with the hepatitis B virus associated delta agent in an isolated West-African community

The occurrence of delta agent (delta) infection in the native population of the isolated Gbawein and Wroughbarh Clan region of Grand Bassa County, Liberia was studied. Sera of 97 patients with epilepsy, 73 non-epileptic relatives, and 31 non-epileptic control subjects were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs) and antibody to delta antigen (anti-delta). Of the 201 individuals tested 76 (37.8%) were HBsAg positive; the overall infection rate (HBsAg and anti-HBs positives) was 68.7%. No correlation with clinical disease could be established. Markers of delta infection were detected in seven index cases. All subjects with anti-delta were HBsAg positive except one, who was anti-HBs positive with a low titre of anti-delta (less than 1:10(2)), which is indicative of a recent delta infection. Mothers of six delta infected index cases were available for testing, one was found HBsAg and anti-delta positive, while the other five were anti-HBs positive and anti-delta negative. No delta infections occurred in children of HBV negative mothers. Presence of delta markers varied significantly (P less than 0.02) among HBsAg carriers of the Kpelle (18%) and the Bassa (2%) language group. A comparable difference in delta markers was observed among HBsAg carriers of the Gbawein (17%) and the Wroughbarh (4%) clans.     

Recurring duodenal ulcer. Evaluation of previous complications as a predictive factor of ulcer recurrence after eradication of Helicobacter pylori

Duodenal ulcer is a chronic disease, punctuated by acute relapses. The pathogenic mechanism in 90-100% of cases is infection by Helicobacter pylori. Two major strains exist of this bacterium: I strain, which secretes a vacuolating cytotoxin (Vac-A), and another protein named cytotoxin-associated (Cag-A) and type II strain, unable to produce both proteins and unable to produce duodenal pathology. We sought to identify the natural history of relapsing duodenal ulcer after cure of the bacterial infection. In particular, we followed the outcome of patients who repeatedly had bled from their recurrent ulcer disease, after success in eliminating the microorganism from the stomach. None of 12 repeated bleeders had an ulcer recurrence after the cure of Helicobacter pylori infection. Only 3 (5%) of 60 frequent relapser had a new episode of duodenal ulcer during a follow-up reinfection by Helicobacter pylori. We demonstrated that the cure of bacterial infection is also the cure of duodenal ulcer recurrence, but for a few cases, in the latter, event one could hypothesize a defect in the production of growth factors (Epidermal Growth Factor, Fibroblast Growth Factor) or of cellular polyamines synthesis. It is important to improve the diagnosis of reinfection by implementing the urea breath test.     

A point mutation in the MET oncogene abrogates metastasis without affecting transformation

The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF), known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, we exploited a single-hit oncogenic version of MET, able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. We mutagenized the signal transducer docking site of Met (Y¹³⁴⁹VHVX₃Y¹³⁵⁶VNV), which has the uncommon property of binding and activating multiple src homology region 2 (SH2)-containing intracellular effectors. Notably, a point mutation (H¹³⁵¹ → N) increased the transforming ability of the oncogene but abolished its metastatic potential. This mutation duplicates the Grb2 binding site, super-activating the Ras pathway and preventing the binding of the other intracellular transducers. Complementation in trans with another nonmetastatic mutant (N¹³⁵⁸ → H), recruiting all the transducers downstream to Met except Grb2, rescued the invasive–metastatic phenotype. It is concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.     

Risk factors for early and late mortality in hospitalized older patients: the continuing importance of functional status

BACKGROUND: Prognostic information collected at hospital admission may be useful in defining care objectives and in deciding on therapy for older people. The aim of our study was to identify admission risk factors for in-hospital and postdischarge mortality. METHODS: The study included 987 patients aged 70 years and older admitted to the geriatric ward of San Giovanni Battista Hospital in Torino during 1995 and 1996. Demographic, clinical, and functional variables were collected on admission to hospital and examined as potential risk factors for mortality during hospitalization and at 5 years of follow-up. RESULTS: During their hospital stay, 147 patients (14.9%) died. Risk factors independently associated with in-hospital mortality included functional impairment (Activities of Daily Living [ADL]) (OR [odds ratio] 1.73, CI [confidence interval] 95% 1.02-2.95), dependence related to medical conditions (OR 2.18, CI 95% 1.39-3.42), cerebrovascular disease (OR 3.23, CI 95% 1.64-6.37), cancer (OR 4.52, CI 95% 1.99-10.24), albumin 3.0-3.4 g/dl (OR 4.51, CI 95% 2.76-7.35), albumin <3.0 g/dl (OR 6.83, CI 95% 3.59-13.0), creatinine 1.5-3 mg/dl (OR 2.23, CI 95% 1.36-3.65), creatinine >3 mg/dl (OR 2.55, CI 95% 1.10-5.93), and fibrinogen >/=452 mg/dl (OR 1.91, CI 95% 1.26-2.89). During the 5-year follow-up, 553 patients (67.7%) died. Variables independently associated with mortality in multivariate analysis were age 75-84 years (HR [hazard ratio] 1.40, CI 95% 1.10-1.78), >/=85 years (HR 2.08, CI 95% 1.59-2.72), male sex (HR 1.50, CI 95% 1.24-1.81), ADL dependency (HR 1.24, CI 95% 1.01-1.52), >/=5 errors on Short Portable Mental Status Questionnaire (HR 1.34, CI 95% 1.10-1.63), dependence on Dependence Medical Index (HR 1.36, CI 95% 1.10-1.67), presence of cancer (HR 2.58, CI 95% 1.80-3.71), hemoglobin /=2 (HR 1.49, CI 95% 1.14-1.95). CONCLUSIONS: A complete functional and clinical evaluation at hospital admission permits identification of patients at higher risk of early and long-term mortality.     

Two mutations affecting conserved residues in the Met receptor operate via different mechanisms

We have investigated the mechanism by which two oncogenic mutations (M1268T and D1246H/N; Amino-acids are numbered according to Schmidt et al., 1999) affecting conserved residues in the catalytic domain of the Met receptor, activate its transforming potential. Both mutations were previously found in tumorigenic forms of the Ret and Kit receptors, respectively. The mutated residues are located either in the P+1 loop (M) or within the activation loop (A-loop) (D), which in a number of receptor tyrosine kinases harbors a pair of tandem tyrosines (Y1252-1253 in Met). Ligand-induced dimerization promotes their phosphorylation, and locks the A-loop into an open conformation. When unphosphorylated, the tandem tyrosines inhibit enzymatic activity by blocking the active site. Upon Y-->F mutation of Y1252-1253, neither ligand binding nor Tpr-mediated dimerization can release this block. Here we show that the M1268T mutation partially rescues the kinase activity (and the transforming ability) of the Y1252-1253F Tpr-Met mutant, but is completely dependent on dimerization for its effect. In contrast, the two D1246H/N mutants strictly depend on Y1252-1253 for activity. Surprisingly, however, they constitutively activate the isolated cytoplasmic TK domain of Met (Cyto-Met). These data indicate that the two mutations operate via distinct mechanisms.     

Acute myocardial infarction andHelicobacter pylori seropositivity

Infectious agents including Helicobacter pylori, have been linked to coronary heart diseases on epidemiological and pathogenetic grounds. Classical risk factors fail to explain all the epidemiological variations of the disease. Our aim was to investigate the association of acute myocardial infarction with Helicobacter pylori infection in a case-control study by comparing a group of male patients with a control group of blood donors matched for sex and age. We investigated the classical cardiovascular risk factors in all patients. We studied 44 consecutive male patients, aged 40-65 years, admitted for acute myocardial infarction to the Coronary Care Unit at Novi Ligure Hospital in northern Italy. Helicobacter pylori infection was assessed by measurement of antibodies (IgG) against Helicobacter pylori in blood. Volunteer blood donors attending Molinette Hospital Blood Bank in Turin, northern Italy served as controls. Among the patients we investigated the presence of hypertension, cholesterol and glucose levels in serum, fibrinogen in plasma, smoking habits, and social class. Helicobacter pylori infection was present in 34 of 44 (77%) patients and in 183 of 310 (59%) controls (P<0.05); the odds ratio was 2.36 (95% confidence interval 1.08-5.31). Classical cardiovascular risk factors did not differ among patients with and without Helicobacter pylori infection. In conclusion, patients with acute myocardial infarction had a significantly higher prevalence of Helicobacter pylori infection than the control population. The classical risk factors for cardiovascular diseases were equally distributed among patients irrespective of their Helicobacter pylori status.     

Amplification of hepatitis delta virus RNA sequences by polymerase chain reaction: a tool for viral detection and cloning

In this investigation we have evaluated the feasibility of using the polymerase chain reaction (PCR) for hepatitis delta virus (HDV) RNA detection, cloning and sequencing. Total RNA from HDV-infected liver and serum samples was purified and Moloney murine leukaemia virus (M-MLV) reverse transcribed. HDV cDNA was then directly amplified with Taq polymerase using three pairs of specific primers. It was possible to amplify a region of about 1200 bp in three partially overlapping fragments including the whole HDAg-ORF. A DNA fragment of the expected size was repeatedly obtained from an initial sample of less than 0.1 pg of liver RNA and from 10 pl of infected serum. An amplified fragment of 359 bp obtained by PCR from an infected woodchucks' liver was sequenced. The sequence was 91.8% and 98.6% identical to previously published HDV sequences. In addition, amplified and 32P-radiolabelled HDV sequences were shown to hybridize specifically to HDV RNA extracted from HDV-infected liver and serum. In conclusion this technique promises to be of great value in the appraisal of HDV infection, rapid synthesis of HDV probes and analysis of the genetic variability of the virus.     

Role of iron metabolism and oxidative damage in postmenopausal bone loss

It has been suggested that iron-deficient rats have lower bone mass than iron-replete animals, but a clear association between bone and iron repletion has not been demonstrated in humans. A growing body of evidences also suggests a relation between lipid oxidation and bone metabolism and between iron metabolism and LDL oxidation. Iron availability to cells also depends on haptoglobin (Hp) phenotypes. Hp has also important antioxidant properties according to its phenotype, hence we evaluate whether Hp phenotype could influence bone density, iron metabolism and lipid oxidation. This cross-sectional study enrolled 455 postmenopausal women affected by osteoporosis (260) or not (195). Bone mineral density, markers of bone and iron metabolism, levels of oxidized LDL (oxLDL) and Hp phenotype were measured in all the subjects. Hp 1.1 and 2.2 frequency was higher and Hp 2.1 was lower in the patients with fragility fractures (80) compared with the controls. We therefore evaluate different Hp phenotypes as risk or protective factors against fragility fracture: Hp 2.1 is a protective factor against fracture while 1.1 is an important and 2.2 a moderate risk factor for fragility fractures. Lower serum iron was associated with elevated transferrin in patients with Hp 1.1; moreover patients had relative iron deficiency compared with the controls and fractured patients had higher level of oxLDL. We found that both iron metabolism and oxLDL varies according to Hp phenotypes and are predictive of bone density. Our data indicate that Hp 2.1 is a protective factor for fragility fractures, depending on its role on iron metabolism and its antioxidant properties.     

Titration of the infectivity of hepatitis D virus in chimpanzees

The infectivity of hepatitis D virus (HDV) was evaluated by intravenous inoculation of chimpanzees. HDV was present in the inoculum at a titer of 10(11) chimpanzee infectious doses (CID). In contrast, the titer of hepatitis B virus (HBV) in the same inoculum was 10(6) CID. All HBV-infected chimpanzees inoculated with less than or equal to 10(-11) dilutions of the HDV-positive plasma were superinfected; an animal receiving a 10(-12) dilution did not develop markers of HDV replication in serum or liver. All HDV-infected chimpanzees had marked elevations of serum alanine aminotransferase activities. The incubation period from exposure to development of hepatitis was inversely related to the dose of HDV inoculum, although the severity and duration of hepatitis were independent of it. All animals recovered and rapidly developed antibody to hepatitis D antigen.