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This work aims at calculating and releasing tabulated values of dose conversion coefficients, DgNDBT, for mean glandular dose (MGD) estimates in digital breast tomosynthesis (DBT). The DgNDBT coefficients are proposed as unique conversion coefficients for MGD estimates, in place of dose conversion coefficients in mammography (DgNDM or c, g, s triad as proposed in worldwide quality assurance protocols) used together with the T correction factor. DgNDBT is the MGD per unit incident air kerma measured at the breast surface for a 0° projection and the entire tube load used for the scan. The dataset of polyenergetic DgNDBT coefficients was derived via a Monte Carlo software based on the Geant4 toolkit. Dose coefficients were calculated for a grid of values of breast characteristics (breast thickness in the range 20–90 mm and glandular fraction by mass of 1%, 25%, 50%, 75%, 100%) and the simulated geometries, scan protocols, irradiation geometries and typical spectral qualities replicated those of six commercial DBT systems (GE SenoClaire, Hologic Selenia Dimensions, GE Senographe Pristina, Fujifilm Amulet Innovality, Siemens Mammomat Inspiration and IMS Giotto Class). For given breast characteristics, target/filter combination, tube voltage and half value layer (HVL), two spectra with two HVL values have been simulated in order to permit MGD estimates from experimental HVL values via mathematical interpolation from tabulated values. The adopted breast model assumes homogenous composition of glandular and adipose tissues; it includes a 1.45 mm thick skin envelope in place of the 4–5 mm envelope commonly adopted in dosimetry protocols. The simulation code was validated versus AAPM Task group 195 Monte Carlo reference data sets (absolute differences not higher than 1.1%) and by comparison to relative dosimetry measurements with radiochromic film in a PMMA test object (differences within the maximum experimental uncertainty of 11%). The calculated coefficients show maximum relative deviations of −17.6% and +6.1% from those provided by the DBT dose coefficients adopted in the EUREF protocol and of 1.5%, on average, from data in the AAPM TG223 report. A spreadsheet is provided for interpolating the tabulated DgNDBT coefficients for arbitrary values of HVL, compressed breast thickness and glandular fraction, in the corresponding investigated ranges, for each DBT unit modeled in this work.

Purpose: In cone-beam computed tomography dedicated to the breast (BCT), the mean glandular dose (MGD) is the dose metric of reference, evaluated from the measured air kerma by means of normalized glandular dose coefficients (DgNCT). This work aimed at computing, for a simple breast model, a set of DgNCT values for monoenergetic and polyenergetic X-ray beams, and at validating the results vs. those for patient specific digital phantoms from BCT scans. Methods: We developed a Monte Carlo code for calculation of monoenergetic DgNCT coefficients (energy range 4.25–82.25 keV). The pendant breast was modelled as a cylinder of a homogeneous mixture of adipose and glandular tissue with glandular fractions by mass of 0.1%, 14.3%, 25%, 50% or 100%, enveloped by a 1.45 mmthick skin layer. The breast diameter ranged between 8 cm and 18 cm. Then, polyenergetic DgNCT coefficients were analytically derived for 49-kVp W-anode spectra (half value layer 1.25–1.50mm Al), as in a commercial BCT scanner. We compared the homogeneous models to 20 digital phantoms produced from classified 3D breast images. Results: Polyenergetic DgNCT resulted 13% lower than most recent published data. The comparison vs. patient specific breast phantoms showed that the homogeneous cylindrical model leads to a DgNCT percentage difference between −15% and +27%, with an average overestimation of 8%. Conclusions: A dataset of monoenergetic and polyenergetic DgNCT coefficients for BCT was provided. Patient specific breast models showed a different volume distribution of glandular dose and determined a DgNCT 8% lower, on average, than homogeneous breast model.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.

The rationale of this study is to perform a personalized dosimetry in digital mammography, using Monte Carlo simulations. We developed a GEANT4-based application that reproduces mammographic investigations editable in different setups and conditions. Mean Glandular Dose (MGD) is estimated for different compressed breast sizes and compositions. Breast compositions are obtained with homogeneous mixture of glandular and adipose tissues. The simulated setup reproduces the Hologic Selenia® Dimensions® Mammography System and the TASMIPM tool for deriving the photon fluence from the X-ray source has been employed. The influence of different skin models is also investigated, deriving the mean glandular dose in the breast using adipose tissue for different skin thicknesses, from 2 mm to 5 mm, and a dedicated composition found in literature with the specific thickness of 1.45 mm. We denoted different photon shielding properties on the MGD values.

Purpose: To provide mean glandular dose (MGD) estimates via Monte Carlo (MC) simulations as a function of the breast models and scan parameters in mammography, digital breast tomosynthesis (DBT) and dedicated breast CT (BCT). Methods: The MC code was based on GEANT4 toolkit. The simulated compressed breast was either a cylinder with a semi-circular section or ad hoc shaped for oblique view (MLO). In DBT we studied the influence of breast models and exam parameters on the T-factors (i.e. the conversion factor for the calculation of the MGD in DBT from that for a 0-degree projection), and in BCT we investigated the influence on the MGD estimates of the ion chamber volume used for the air kerma measurements. Results: In mammography, a model representative of a breast undergoing an MLO view exam did not produce substantial differences (0.4%) in MGD estimates, when compared to a conventional cranio-caudal (CC) view breast model. The beam half value layer did not present a significant influence on T-factors in DBT (< 0.8%), while the skin model presented significant influence on MGD estimates (up to 3.3% at 30 degrees scan angle), increasing for larger scan angles. We derived a correction factor for taking into account the different ion chamber volume used in MGD estimates in BCT. Conclusions: A series of MC code modules for MGD estimates in 2D and 3D breast imaging have been developed in order to take into account the most recent advances in breast models.

Objective: The purpose of this study is to investigate potential factors associated with patient survival (primary outcome) and need for mechanical ventilation (secondary outcome) for people living with HIV

We computed normalized glandular dose (DgN) coefficients for mean glandular dose estimates in contemporary 2D mammography units, taking into account a realistic homogeneous model for the breast. We developed a Monte Carlo code based on the simulation toolkit GEANT4 ver. 10.00. The breast was modelled as a cylinder with a semi-cylindrical section with a radius of 10 cm, enveloped in a 1.45-mm thick skin layer, as found out in recent reports from the University of California Davis team in the analysis of breast computed tomography clinical scans. The compressed breast thickness was between 3 cm and 8 cm. The DgN coefficients were calculated for monoenergetic X-ray beams between 4.25 keV and 49.25 keV and were fitted with polynomial curves. Polyenergetic DgN coefficients were then computed for spectra obtained for various anode/filter combinations as adopted in routine clinical practice: Mo/Mo 30 μm (2540 kV), Mo/Rh 25 μm (2540 kV), Rh/Rh 25 μm (2540 kV), W/Ag 50 μm (2634 kV), W/Al 500 μm (2638 kV), W/Al 700 μm (2840 kV) and W/Rh 50 μm (2435 kV). Monoenergetic DgN curve fit coefficients and polyenergetic DgNp coefficients were released for research and clinical work. Polyenergetic DgN coefficients were 6% higher than those provided in the reference literature, on average. The differences ranges between -18% and 30%; 50% of the computed coefficients differed by less than 10%. The dataset of DgN coefficients are provided as tables (49 pages) for varying glandular fraction by mass and compressed breast thickness. Moreover, a computer code has been developed for generating user specific coefficients DgNp for user defined X-ray spectra up to 49 kV, calculated by spectral weighting from the dataset of monoenergetic DgN coefficients.

Treatment of a pathogenic disease process is interpreted as the optimal control of a dynamic system. Evolution of the disease is characterized by a non-linear, fourth-order ordinary differential equation that describes concentrations of pathogens, plasma cells, and antibodies, as well as a numerical indication of patient health. Without control, the dynamic model evidences sub-clinical or clinical decay, chronic stabilization, or unrestrained lethal growth of the pathogen, depending on the initial conditions for the infection. The dynamic equations are controlled by therapeutic agents that affect the rate of change of system variables. Control histories that minimize a quadratic cost function are generated by numerical optimization over a fixed time interval, given otherwise lethal initial conditions. Tradeoffs between cost function weighting of pathogens, organ health, and use of therapeutics are evaluated. Optimal control solutions that defeat the pathogen and preserve organ health are demonstrated for four different approaches to therapy. It is shown that control theory can point the way toward new protocols for treatment and remediation of human diseases. Copyright © 2002 John Wiley & Sons, Ltd.

This work aimed at calculating the complete set of monoenergetic (DgN) and polyenergetic (DgNp) normalized glandular dose coefficients for mean glandular dose estimate in mammography. We have developed a Monte Carlo code based on GEANT4 toolkit, for DgN calculation, which relies on the standard physics list Option4. Influence of the breast model, the compression paddle and the bremsstrahlung process on DgN and DgNp normalized glandular dose coefficients in mammography was studied. Breast skin thickness was varied in the range 1.45–5 mm. It was modeled both as an adipose skin layer (5 mm thick – as in EU protocols for mammography) and as a real skin composition (as adopted in USA protocols). Significant differences in the calculated DgN have been observed when 1.45 mm skin thickness is adopted. At 15 keV a skin thickness of 1.45 mm produces values up to 25% or 20% higher than in the model adopted in the USA (4 mm skin) or EU protocol (5 mm adipose layer), respectively. The discrepancy reduces for higher energies. For routinely used mammographic spectra, a skin thickness of 4 mm produces DgNp values up to 32% lower than those with a breast model with 1.45 mm thickness. The bremsstrahlung processes in the breast tissue had small influence on DgN coefficients. Finally, based on the model consideration, DgNp coefficients for spectra used in mammography were provided and compared with those routinely adopted, based on USA and EU protocols.

A number of antiangiogenic agents have been developed as pharmaceuticals and are currently being tested in clinical studies. Potential strategies to enhance the activity of angiogenesis inhibitors could be to combine them, or better still, to administer them either sequentially or concurrently with cytotoxic drugs. Chemotherapy would be a more appropriate initial choice for patients with advanced disease since cytostatic agents can induce a fast regression of the tumor and cancer-related symptoms. Antiangiogenic treatment could be used after chemotherapy in patients who achieve disease remission to prolong the time to progression, the symptom-free interval and the overall survival. Antiangiogenic treatment is likely to attain an important role in the adjuvant setting. In fact, it could be used for prolonged periods after radical surgery to maintain dormancy of residual tumor cells. In spite of these promising preclinical data, several points need to be clarified before the initiation of clinical trials. In fact, certain misconceptions may interfere with their optimum design and result analysis.

We describe a patient who suffered from impaired ocular motility from age 10 years and at 16 years developed ptosis, proximal weakness and progressive fatigability. At 35 years she developed massive myoclonic jerks, and head and distal tremor. A muscle biopsy showed a high percentage of cytochrome c oxidase negative fibers but no ragged-red fibers. A novel heteroplasmic mutation (8342G--A) was found in the mitochondrial transfer RNA(Lys) gene by single-strand conformation polymorphism screening, followed by sequence and restriction fragment length polymorphism analysis. Approximately 80% of muscle mitochondrial DNA (mtDNA) harbored the mutation, while the mutation was absent in lymphocyte DNA of the proband, as well as of her mother, daughter and a maternal aunt. However, the pathogenicity of the mutation was confirmed by restriction fragment length polymorphism analysis of single muscle fibers, which revealed a significantly greater level of mutant mtDNA in cytochrome c oxidase negative over cytochrome c oxidase positive fibers.

Objective. Asthma is a disease with elevated prevalence within the general population. Although general practitioners (GPs) are among the first health-care professionals to whom patients refer for their symptoms, there are few evaluations of this disease based on data provided by the GPs. The aim of this observational study is to assess the impact of asthma and comorbid allergic rhinitis on individual/social burden, quality of life, and disease control in asthmatic patients of Italian GPs. Methods. Throughout Italy, 107 GPs enrolled 995 patients diagnosed with asthma and using anti-asthmatic drug prescriptions, or with asthma-like symptoms during the previous 12 months. Data were collected through questionnaires filled out by GPs and patients. Results. Of the 995 asthmatic patients, 60.6 had concomitant allergic rhinitis (RA), 39.4 had asthma alone. The latter, compared to those with RA, showed significantly lower prevalence of intermittent asthma (37.5 vs. 55.6) and higher prevalence of mild, moderate, and severe persistent asthma (28.4 vs. 23.2, 28.7 vs. 18.8, and 5.4 vs 2.4, respectively). Individual/social burden due to asthma was frequent and increased with disease severity: 87.5 of severe persistent asthma patients reported at least one medical consultation in the last 12 months, 37.5 emergency department visits, 26.7 hospitalization, and 62.5 limitations in daily activities. Control and quality of life were inversely associated with disease severity and were worse in patients with RA than in those with asthma alone. Conclusions. This study showed the negative impact of high severity levels and comorbid allergic rhinitis on quality of life of asthmatic patients and on individual/social burden due to asthma in an Italian GPs setting. © 2012 Informa Healthcare USA, Inc.

Background and purpose To carry out an observational epidemiological survey (Studio Morfeo), to determine: (1) the frequency of insomnia in a large Italian population presenting directly to the general physician (GP); (2) the impact of insomnia on the quality of life, on the use of health-care resources and on co-morbidity. Patients and methods The study was accomplished by GPs, trained by sleep specialists accredited by the Italian Association of Sleep Medicine. Only patients spontaneously presenting to their GP for medical problems were surveyed. Each GP was asked to enroll at least five patients across a routine week of medical activity including both morning and afternoon clinics. The first patient of each weekday was recruited after obtaining written consent. According to the responses to the sleep-related questions, patients were classified into three categories: (1) no insomnia, (2) level 1 insomnia with absence of day-time dysfunction and (3) level 2 insomnia with presence of day-time dysfunction. Results A total of 3284 patients were enrolled by 738 GPs in this Italian survey. Insomnia was reported by 64% of all interviewed patients, with 20% classified as level 1 and 44% as level 2. Logistic analysis indicated that depression (odds ratio, 2.70), involvement of >1 organ systems (odds ratio, 1.24), female gender (odds ratio, 1.19), unemployment (odds ratio, 1.18), low education (odds ratio, 1.18) and increasing age (odds ratio, 1.02) were the major risk factors for insomnia. Conclusions Our findings indicate that insomnia is a frequent disturbance in the Italian primary care population, is associated with high risk of co-morbid conditions, and results in increased use of health-care resources.

Therapeutic enhancement of humoral immune response to microbial attack is addressed as the stochastic optimal control of a dynamic system. Without therapy, the modeled immune response depends upon the initial concentration of pathogens in a simulated attack. Immune response can be augmented by agents that kill the pathogen directly, that stimulate the production of plasma cells or antibodies, or that enhance organ health. Using a generic mathematical model of immune response to the infection (i.e., of the dynamic state of the system), previous papers demonstrated optimal (open-loop) and neighboring-optimal (closed-loop) control solutions that defeat the pathogen and preserve organ health, given initial conditions that otherwise would be lethal [Optimal Contr. Appl. Methods 23 (2002) 91, Bioinformatics 18 (2002) 1227] . Therapies based on separate and combined application of the agents were derived by minimizing a quadratic cost function that weighted both system response and drug usage, providing implicit control over harmful side effects. Here, we focus on the effects that corrupted or incomplete measurements of the dynamic state may have on neighboring-optimal feedback control. Imperfect measurements degrade the precision of feedback adjustments to therapy; however, optimal state estimation allows the feedback strategy to be implemented with incomplete measurements and minimizes the expected effects of measurement error. Complete observability of the perturbed state for this four state example is provided by measurement of four of the six possible pairs of two variables, either set of three variables, or all four variables. The inclusion of state estimation extends the applicability of optimal control theory for developing new therapeutic protocols to enhance immune response.

We assessed the validity of an Italian language version of the Epworth sleepiness scale (ESS). The translated ESS was compared to the multiple sleep latency test (MSLT), considered the gold standard for the diagnosis of excessive daytime sleepiness (EDS). Within the context of a multicentric national study on narcolepsy (Gruppo Italiano Narcolessia Studio Epidemiologico Nazionale, GINSEN) involving 17 Italian sleep centres, we compared the two diagnostic tests on 91 prospectively recruited subjects with suspected EDS (34 with narcolepsy, 16 with obstructive sleep apnea syndrome, 19 with idiopathic hypersomnia, and 22 with other sleep, neurologic or psychiatric disorders). ESS scores were inversely correlated with mean sleep latency values, as measured with MSLT (rho = −0.31, p

Motivation: Therapeutic enhancement of innate immune response to microbial attack is addressed as the optimal control of a dynamic system. Interactions between an invading pathogen and the innate immune system are characterized by four non-linear, ordinary differential equations that describe rates of change of pathogen, plasma cell, and antibody concentrations, and of an indicator of organic health. Without therapy, the dynamic model evidences sub-clinical or clinical decay, chronic stabilization, or unrestrained lethal growth of the pathogen; the response pattern depends on the initial concentration of pathogens in the simulated attack. In the model, immune response can be augmented by therapeutic agents that kill the pathogen directly, that stimulate the production of plasma cells or antibodies, or that enhance organ health. A previous paper demonstrated open-loop optimal control solutions that defeat the pathogen and preserve organ health, given initial conditions that otherwise would be lethal (Stengel et al. (2002)). Therapies based on separate and combined application of the agents were derived by minimizing a quadratic cost function that weighted both system response and control usage, providing implicit control over harmful side effects. Results: We demonstrate the ability of neighboring–optimal feedback control to account for a range of unknown initial conditions and persistent input of pathogens by adjusting the therapy to account for perturbations from the nominal-optimal response history. We examine therapies that combine open-loop control of one agent with closed-loop control of another. We show that optimal control theory points the way toward new protocols for treatment and cure of human diseases. Contact: stengel@princeton.edurghiglia@princeton.edunkulkarn@princeton.edu * To whom correspondence should be addressed.

Aim This phase II trial evaluated the biomodulation of 5-fluorouracil (5-FU) plus folinic acid (FA) with or without ifosfamide (IFO) in chemotherapy-naive patients with colorectal cancer. Patients and methods Forty-eight patients were randomized to receive: FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3), arm A; or FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3) plus IFO (2,000 mg/m2 in 1000 mL 5% dextrose in a 2-hr infusion, days 1 to 3), arm B. Mesna was added during and after IFO to prevent hemorrhagic cystitis. Treatment was repeated every 21 days in both arms. Results Forty-five patients were assessable for response: in arm A, 5 patients achieved a partial response (overall response, 25%), and in arm B, 2 patients achieved a complete and 1 a partial response (overall response, 12%). Time to failure was 3.5 months (range, 1–38) in patients treated with 5-FU plus FA, and 3 months (range, 1–21) in patients treated with the IFO combination. The median survival time was 13.5 months (range, 1–49 months) in arm A and 16 months (range, 1–43 months) in arm B. Diarrhea, stomatitis and vomiting were the most common nonhematologic toxicities in both arms. The most notable hematologic toxicity was leukopenia; 15% and 20% of patients experienced grade 4 in arm A and arm B, respectively. Conclusions IFO does not increase the activity of the 5-FU plus FA combination in advanced colorectal cancer.

The increased incidence of hepatocellular carcinoma in patients affected with haemochromatosis has previously been attributed to cirrhosis. However, some cases of hepatocellular carcinoma without cirrhosis have recently been reported in patients with haemochromatosis, leading to reconsideration of the role of iron in the tumorigenesis of hepatocellular carcinoma. We describe a 79 year old male patient affected with haemochromatosis and with a multinodular hepatocellular carcinoma, but without any evidence of cirrhosis. The absence of any other cancer risk factor (alcohol abuse, liver viral infections, heredity) has lead us to reconsider the possible role of iron as a direct carcinogen in the onset of hepatocellular carcinoma in patients with haemochromatosis.