Insulin Minimal Model Indexes and Secretion: Proper Handling of Uncertainty by a Bayesian Approach

The identification of the insulin minimal model (MM) for the estimation of insulin secretion rate (ISR) and physiological indexes (e.g. beta-cell sensitivity) requires the knowledge of C-peptide (CP) kinetics. The four parameters of the two-compartment model of CP kinetics in a given individual can be derived either from an additional bolus experiment or, more frequently, from a population model. However, in both situations, the CP kinetics is uncertain and, in MM identification, it should be treated as such. This paper shows how to handle CP kinetics uncertainty by using a Bayesian methodology. In seven subjects, MM indexes and ISR were estimated together with their confidence intervals, using either the bolus data or the population model to assess CP kinetics. The two main results that arise from the application of the new methodology are: (i) the use of the population model in place of the bolus data to determine CP kinetics does not affect, on average, the point estimates of ISR profile and MM parameters but only the confidence intervals which becomes wider (less than 50%); (ii) in both the bolus and population situation neglecting the uncertainty of CP kinetics, as done in MM literature so far, introduces no bias, on average, on point estimates of MM indexes but only an underestimation of confidence intervals.     

Surface properties and cell response of low metal ion release Ti-6Al-7Nb alloy after multi-step chemical and thermal treatments

Ti-6Al-7Nb samples treated by innovative multi-step chemical and thermal processes were characterized in order to evaluate their surface properties and cell interaction. The main object was to asses if the treatments were effective in order to obtain a surface presenting at the same time bone-like apatite induction ability, low metal ion release, good cell response and high protein binding. The morphology, crystallographic structure, porosity and wettability of the treated materials were investigated, as well as their interaction with simulated body fluid during soaking for different times. Cytotoxicity, protein adsorption tests and in vitro fibroblast and osteoblast-like cell cultures were also performed.     

Vestibular and audiological findings in the Alport syndrome

Alport syndrome (AS) is caused by mutations in collagen IV, which is widespread in the basement membranes of many organs, including the kidneys, eyes, and ears. Whereas the effects of collagen IV changes in the cochlea are well known, no changes have been described in the posterior labyrinth. The aim of this study was to investigate both the auditory and the vestibular function of a group of individuals with AS. Seventeen patients, aged 9–52, underwent audiological tests including pure‐tone and speech audiometry, immittance test and otoacoustic emissions and vestibular tests including video head impulse test, rotatory test, and vestibular evoked myogenic potentials. Hearing loss affected 25% of the males and 27.3% of the females with X‐linked AS. It was sensorineural with a cochlear localization and a variable severity. 50% of the males and 45.4% of the females had a hearing impairment in the high‐frequency range. Otoacoustic emissions were absent in about one‐third of the individuals. A peripheral vestibular dysfunction was present in 75% of the males and 45.4% of the females, with no complaints of vertigo or dizziness. The vestibular impairment was compensated and the vestibulo‐ocular reflex asymmetry was more evident in rotatory tests carried out at lower than higher speeds; a vestibular hypofunction was present in all hearing impaired ears although it was also found in subjects with normal hearing. A posterior labyrinth injury should be hypothesized in AS even when the patient does not manifest hearing disorders or evident signs of renal failure.     

Production and Characterization of a Human Recombinant Monoclonal Fab Fragment Specific for Influenza A Viruses

A human recombinant monoclonal Fab fragment that specifically recognizes all the influenza A virus strains tested was produced in transformed Escherichia coli using the phage display technique. No strain of influenza B virus reacted with it. It was purified after four cycles of panning and by a single passage through an immunoaffinity column. About 1 mg of pure monoclonal antibody was obtained from 1 liter of culture medium in 3 working days. The Fab fragment reacted with a viral 27-kDa protein, which could reasonably be a matrix protein. Indirect immunofluorescence tests performed on virus-infected MDCK cells showed that this Fab fragment was at least equally efficient as other commercial monoclonal antibody-based systems in detecting influenza A viral infections. The potential advantages of human recombinant Fabs on murine monoclonal antibodies are discussed.     

Screening of HIV-1 isolates by reverse heteroduplex mobility assay and identification of non-B subtypes in Italy

OBJECTIVE: The increasing prevalence of HIV-1 transmission through heterosexual contacts and the growing number of immigrants from non-Western countries, where non-B subtypes and recombinant forms are prevalent, suggest the possible emergence in Italy of a new epidemic wave of HIV-1 non-B subtypes as well as recombinant forms. METHODS: The distribution of HIV-1 subtypes has been evaluated in 63 seropositive individuals residing in Italy, most of whom were infected through a sexual route during the last 5 years. A modified heteroduplex mobility assay (HMA) strategy, reverse HMA (rHMA), has been developed in our laboratory, allowing rapid identification of divergent-from-B-subtype isolates, which have been subsequently characterized by detailed molecular and phylogenetic analyses. RESULTS: Five samples show, on rHMA, an electrophoretic pattern compatible with a non-B subtype classification. Their phylogenetic analysis, performed on both env and gag regions, confirms the rHMA subtyping prediction, given that 3 samples fall into the "A-family" subtype and 2 into the G subtype. The 5 non-B-subtype HIV-1 isolates have been identified among 23 variants (prevalence, 21.74%) isolated during the 2000 to 2001 period in heterosexuals. In parallel, B-subtype isolates show high levels of intrasubtype nucleotide divergence, compatible with a constant HIV-1 molecular diversification. CONCLUSION: The Italian HIV-1 epidemic is still mostly attributable to the B subtype, which shows an increasing nucleotide heterogeneity. Heterosexual transmission and the interracial blending, however, are slowly introducing novel HIV-1 subtypes, and the data indicate that rHMA represents a powerful tool for HIV-1 biomolecular screening in epidemics characterized by a mono-/dual-subtype predominance.     

Radiotherapy and combination chemotherapy with carmustine,vincristine, and procarbazine (BVP) in primary brain tumors

Summary 26 patients with astrocytoma grade 11–111, and 36 with malignant glioma (astrocytoma grade IV or glioblastoma) were submitted three days after surgery to a cycle of combination chemotherapy, including BCNU, VCR, PCZ (BVP). Eighteen days after surgery, patients received 40 Gy (astrocytoma grade 11–111) or 45 Gy (malignant glioma) of megavoltage whole-brain irradiation, with an additional boost to the tumor bed of 20 Gy, delivered in 6 weeks. Vincristine was injected weekly during radiotherapy. At the end of radiotherapy, patients received BVP every 6 weeks for at least 8 cycles or until a recurrence or progressive disease. Performance status of grade 1 or 2 was achieved in 15 (60%) and in 5 (20%), respectively, of patients with astrocytoma grade 11–111 after 6 months, and in 6 ps. (29%) and in 9 ps. (42%) after 12 months of follow-up. Only 2 (5.5%) and 18 (64%) patients with malignant glioma achieved a performance status of grade 1 or 2 after 6 months, and these proportions are 6% and 35%, respectively, after 12 months. After a 5-year follow-up, 59% of patients with astrocytoma are still alive, with a median survival time of 60+ months, whereas only 4% of patients with malignant glioma are alive, with a median of 11.2 months.     

HBV pre-vaccination screening in hospital personnel: Cost-effectiveness analysis

The purpose of this study was to identify the most cost effective method for screening subjects for hepatitis B vaccination. Such a method would ideally permit detection of all susceptible individuals at the lowest possible cost.Two-hundred-five hospital workers from the Piedmont region of Italy participated in the study. The sero-epidemiological conditions of this group with regard to hepatitis B markers was representative of hospital workers in this region as a whole. All subjects, excluding carriers, persons with anti-HBs titers 10 mIU and subjects positive for anti-HBc at a 1/100 dilution, were vaccinated. Their responses were evaluated 15 days and 1 month after vaccination. The presence of a booster effect following vaccination was correlated with the immunological status of the subject at the time of pre-vaccination screening.In the light of the results obtained, 5 screening procedures and the procedure of vaccination without screening were evaluated. The most cost effective screening strategy proved to be that of sequential testing for anti-HBc, anti-HBs and finally HBsAg and vaccination of the following subjects: those who were negative for anti-HBc, those who were anti-HBc-positive with anti-HBs titers 10相似文献   

Cellular uptake and metabolic reduction of pentavalent to trivalent arsenic as determinants of cytotoxicity and morphological transformation

Cytotoxicity, morphological neoplastic transformation, cellularuptake and metabolic reduction were determined in BALB/3T3 CIA31-1-1 cells for trivalent arsenic (sodium arsenite, As³⁺)and for pentavalent arsenic (sodium arsenate, As⁵⁺). The levelsof cellular uptake of⁷³As-labelled sodium arsenite and arsenatewere dose-dependent and highest in the first hour. At equimolarconcentration (3 x 10^–6 M), cellular uptake was 4-foldhigher for As³⁺ than for As⁵⁺. Cytotoxicity was higher for As³⁺than for As⁵⁺, but when correlated to total As cell burden itshowed no significant difference for the two forms. Morphologicaltransformation focus assays showed transforming activity forboth As³⁺ and As⁵⁺, with relative transformation frequenciesalso of 4:1. Recovery from the cytosol after exposure for 1–24h was >90% for either form of absorbed As. Exposure to As³⁺yielded 100% as As³⁺ in cytosol, but exposure to As⁵⁺ yielded>70% as As³⁺, showing a high rate of intracellular metabolicreduction. No methylated metabolites were detected by ion-exchangechromatography. After 24-h incubation in cell-free medium, oxidationof As³⁺ to As⁵⁺ occurred up to 30% of the dose, but incubationin the presence of cells lowered the oxidation level to 4%.As⁵⁺ was recovered unchanged from cell-free medium (24-h incubation),but in the presence of the cells it yielded up to 5% as As³⁺within 24 h and the cumulative release of As³⁺ by cells exposedto As⁵⁺ was dose-dependent. Glutathione depletion by diethylmaleateinhibited reduction of As⁵⁺ to As³⁺ by these cells up to 25%of controls, showing that As⁵⁺ reduction is partly dependenton glutathione. These results suggest that As³⁺ is the formresponsible for the cytotoxic and transforming effects, independentlyof the valence state of the inorganic arsenic in the culturemedium.