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Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

A Finite Element workflow for the multiscale analysis of the aortic valve biomechanics was developed and applied to three physiological anatomies with the aim of describing the aortic valve interstitial cells biomechanical milieu in physiological conditions, capturing the effect of subject-specific and leaflet-specific anatomical features from the organ down to the cell scale. A mixed approach was used to transfer organ-scale information down to the cell-scale. Displacement data from the organ model were used to impose kinematic boundary conditions to the tissue model, while stress data from the latter were used to impose loading boundary conditions to the cell level. Peak of radial leaflet strains was correlated with leaflet extent variability at the organ scale, while circumferential leaflet strains varied over a narrow range of values regardless of leaflet extent. The dependency of leaflet biomechanics on the leaflet-specific anatomy observed at the organ length-scale is reflected, and to some extent emphasized, into the results obtained at the lower length-scales. At the tissue length-scale, the peak diastolic circumferential and radial stresses computed in the fibrosa correlated with the leaflet surface area. At the cell length-scale, the difference between the strains in two main directions, and between the respective relationships with the specific leaflet anatomy, was even more evident; cell strains in the radial direction varied over a relatively wide range ($$0.36-0.87$$ 0.36 - 0.87 ) with a strong correlation with the organ length-scale radial strain ($$R^{2}= 0.95$$ R 2 = 0.95 ); conversely, circumferential cell strains spanned a very narrow range ($$0.75-0.88$$ 0.75 - 0.88 ) showing no correlation with the circumferential strain at the organ level ($$R^{2}= 0.02$$ R 2 = 0.02 ). Within the proposed simulation framework, being able to account for the actual anatomical features of the aortic valve leaflets allowed to gain insight into their effect on the structural mechanics of the leaflets at all length-scales, down to the cell scale.

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic beta subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss.

Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein–2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.

HLA class I typing by standard microcytotoxicity testing has been unsatisfactory for 14.5% of 1644 cord blood samples. In this study, we evaluated the capacity of PCR-SSP in solving problems in HLA-A,B typing with serological methods. With this aim we have compared serology with PCR-SSP in 100 cord blood samples with doubtful or unreliable HLA-A,B typing. PCR-SSP was successful in amplifying HLA-A,B alleles in all 100 cord blood samples. Forty-six typings gave discrepant results with the 2 methods (serology and PCR-SSP). Typings were considered discrepant also in the case of inability to define a split. For 19 specimens, no serological conclusion was drawn due to high mortality of the cell suspension, while PCR-SSP allowed the definition of a clear typing. In 6 cases it was necessary to infer information from serology to define the current typing. Finally, in 3 other cases it was impossible to exclude or attribute the antigen/allele B67 or B4802. PCR-SSP for HLA-A,B can improve the overall reliability of HLA-A,B typing requiring a small amount of blood although, with the set of sequence specific primers adopted, a number of alleles are still poorly defined.

Many studies have shown that the bad lifestyles are the major factors thought to influence susceptibility to many diseases in our society and often these habits during the adolescence begin. The aim of the study was to evaluate the health promotion intervention effect in an orthodontic adolescent sample, in particular: deterring adolescents from smoking; discourage the use and abuse of alcoholic beverages; encourage the adherence to the Mediterranean style diet. A blinded randomized controlled trial will be performed. The participants will be adolescents aged 10 to 14 years that will receive a medical examination in the Complex Unit of Orthodontics. The sample will be followed for three years. The collected evidence would be a scientific support for decisions in public health, in order to increase the health of the young generations.

In 2009, to date 16 human cases of West Nile neuroinvasive disease (WNND) have been reported in Italy, in three regions: Veneto, Emilia-Romagna and Lombardia. The number of cases is higher compared with last year when nine cases were identified (eight cases of WNND and one case of West Nile fever) and the geographical distribution indicates spread from east to west.

Renal transplantation is an effective therapeutic tool for patients with end-stage renal diseases (ESRDs). Data reported in this article summarize the results obtained from 30 years' activity in the North Italy Transplant program (NITp), the first transplant organization in Italy that implemented a donor procurement and organ transplantation network. In the NITp kidney allocation is governed by a computerized algorithm, NITK3, put in place in 1997, aimed at ensuring equity, transparency and traceability during the stages of the allocation decision-making process. The NITp working group has recognized the NITK3 criteria and they are periodically reviewed following the results of the analysis of patients' transplantation odds. The results obtained with the use of the NITK3 algorithm have been very satisfactory: after 6 yrs, a significantly higher percentage of patients at immunological risk (sensitized or waiting for re-transplant), of patients waiting for3 yrs and of patients with 0-1 HLA A,B,DR mismatches have been transplanted. Moreover, a higher percentage of kidneys were used locally (in a hospital within the procurement area), and this is known to stimulate donor procurement. Finally, we performed a preliminary statistical analysis of transplants carried out from 1998-2002 in 5/16 centers of the NITp area, demonstrating the quality of the NITp program in terms of patient and graft survival, and that donor and recipient age are the variables significantly impacting on transplant results.

Renal transplantation is the best possibile form of treatment for chronic renal failure. It offers the patient a longer life expectancy when compared to dialysis. Aim of the study was to evaluate our results with live donor transplantation and the variables that influenced the long-term patient and graft survival.190 patients received a live donor kidney transplantation in our Hospital between 1984 and 2000. Thirty-eight of them received a graft from an HLA identical donor, 130 from an HLA haploidentical donor, 22 from a living unrelated donor (spouse). Fourteen patients underwent a pre-emptive transplantation. Aim of the study was to evaluate which variables could influence the long-term patient and graft survival.The median follow-up of recipients was 69.5 months. The 10-year patient and graft survival were 94.7% and 73.4% respectively. Graft half-life was 29.6 years. Six patients died. Twelve patients lost their graft because of vascular thrombosis and five patients because of rejection within the first six months. After the first year, 11 patients lost their graft because of chronic rejection and 4 after recurrence of the original disease. One hundred and forty-four patients are still under observation, and at the last examination their mean plasma creatinine was 2.0+/-1.1 mg/dl. At univariate statistical analysis the absence of locus DR incompatibility was associated with a trend toward a better long-term survival of both patient and graft (P=0.05), while less than one year of dialysis showed a significantly better survival rate (P0.01).Living-donor transplantation offers an excellent long-term patient and graft survival.

Nowadays organ transplantation is a life-saving procedure, or anyhow it can considerably improve the life quality of patients suffering from irreversible organ impairment. Monitoring transplantation outcome is the last step of a long process that starts with cadaver donor identification, selection and clinical management, and continues with organ allocation, patient evaluation, surgical operation and clinical follow-up. The National Transplantation Committee has been discussing many of these items and, in 1995, it set up two protocols, one on liver exchange for urgent patients and the other on transplantation in the pediatric patient. The protocols application has met many difficulties, mainly due to the uneven behaviours of the different inter-regional organizations. In this paper we comment on the two main aspects to be submitted to the next National Committee: organ allocation and transplantation outcome. As far as the last point is concerned, the enclosed data are based on the experience of the North Italy Transplant program (NITp), and on that of the major international registries. Without any doubt these data demontrate that organ transplantation is to be ascribed among the successes of medicine in the just closed century.

Hormone replacement therapy (HRT) in post-menopausal or ovariectomized women reduces mortality due to cardiovascular diseases, lowers morbidity due to osteoporosis and improves vasovagal symptoms. Long-term therapy, however, increase the risk of side-effects. HRT may decrease mammographic sensitivity, markedly increasing glandular density. Enlargement of pre-existing cysts and fibroadenomas has also been reported after HRT. The correlation between HRT and breast cancer is highly controversial. We examined 650 women: 550 of them (84.6%) received HRT (157 estrogens and 393 estrogens-progestins) and 100 (15.4%) refused treatment and were thus considered as a control group. All patients underwent mammography and DEXA before HRT and, during treatment, were followed-up yearly with mammography, often combined with US, and DEXA. Fisher's test was used for data analysis (confidence interval: 95%). The statistical analysis showed a significant difference between the HRT group and the control group only for the lumbar spine. Mammographic changes (Tab. II) were shown in 150 of 550 HRT patients. Increased breast density was the most frequent finding. Benign lesions arising de novo or increasing in size and/or number were observed in 41 of 150 patients (27.3%) in the HRT group, where 3 breast carcinomas were detected, versus 1 breast cancer only in the control group. HRT had a marked positive effect on bone mineral content (BMC) at 2 years' follow-up, but it remains debated if it reduces breast cancer risk. In conclusion, our results indicate that a yearly mammography is mandatory in long-term HRT subjects and US may be also needed in particularly dense breasts.

Two different instruments for nonpalpable breast lesion localization, with different patient position (prone and sitting), were evaluated in precision performances by measuring the mean needle deviation on X and Y axes in 150 and 100 examinations, respectively. Both instruments yielded precise information: some drawbacks were observed with the stereotaxic instrument fitted to the plain mammographic unit, due to imperfect fixation in the sitting position of the patient. The development of special seats could obviate the problem, thus allowing a further improvement in the performance of this kind of instruments.

The authors discuss the results from a series of 45 patients with breast lumps. All patients were studied by means of mammography, sonography, color Doppler US, and biopsy. Abnormal Doppler signal was observed in 94% of the patients with breast cancer. However, this finding is not specific because it can be occasionally found in benign lesions too. The use of color Doppler US is suggested in those cases where neither US nor mammography is conclusive.

A group of 20 football players (from 12 to 15 aged) has been taken for a boodless test of cardiology (such as polygraphic and echocardiographic test) at the beginning of a longitudinal study in order to give the exact meaning, as much as possible, to the fitness for an agonistic training. One of the subjects examined was not for that test because of his cardiomegaly, another one had an anomalous mitral valve, in both the subjects the clinic and instrumental side resulted within normal ranges only if searched by E.C.G. About the other athletes the starting parameters will be controlled again, after they will have been in that football team for 1-2 years more. The authors think the point that came out is very important and they hope everybody to execute those studies either to avoid some cardiopathies pass unnoticed to routine tests or to value the effects of training of heart sizes and performances.

The effect of tiropramide hydrochloride--a new spasmolytic drug with calmodulin-independent activity--in correcting alterations of intestinal transit, has been investigated in 40 IBS patients (20 with accelerated and 20 with delayed transit time). Intestinal transit has been evaluated by means of radioopaque markers. Tiropramide hydrochloride, at a dose of 100 mg t.i.d. for 4 weeks, was found significantly more effective than placebo both in normalizing intestinal transit time and in inducing symptomatic relief.

80 very young football players (from 8 to 12) have been examined for three months by some clinical and instrumental cardiologic tests (starting E.C.G. and after graduated stresses on a football court). The starting E.C.G. showed variable extresystolic arrhythmias in 8 subjects, without any sure signs of a cardiopathy, to point out by deeper tests (such as polygraphic, echocardiographic test and rx heart teleradiography). The above-mentioned arrhythmias felt the effects of training variably, since they regressed in 6 cases, however two subjects needed a pharmacological intervention. They are still talking over the meaning to give to extrasystolic arrhythmias in very young people in evaluation of attitude to agonism and in programming training.

During the past seven years an increasing number of hip fractures were treated in the new orthopaedic division of the Treviglio-Caravaggio Hospital. A survey was made of 246 cases treated in the 1972-1978 period. The mean age of the patients was found to be 69,9 years, and 64,6 % of them were women. Lateral fractures accounted for 66,6% of the cases and the mean age of these patients was 78 years. The average hospitalization time of the operated patients was 21,6 days and the mortality after 3 months was 16%. The Authors emphasize that the extensive adoption of surgical treatment in these fractures has improved the survival rate and shortened the hospitalization time.

We report a case of Usutu virus (USUV)-related illness in a patient that underwent an orthotropic liver transplant (OLT). Post transplant, the patient developed clinical signs of a possible neuroinvasive disease with a significant loss of cerebral functions. USUV was isolated in Vero E6 cells from a plasma sample obtained immediately before the surgery, and USUV RNA was demonstrated by RT-PCR and sequencing. This report enlarges the panel of emerging mosquito-borne flavivirus-related disease in humans.

OBJECTIVE:\ud We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy.\ud \ud METHODS:\ud A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered.\ud \ud RESULTS:\ud The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively.\ud \ud CONCLUSIONS:\ud This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

West Nile virus, genus Flavivirus, is transmitted between birds and occasionally other animals by ornithophilic mosquitoes. This virus also infects humans causing asymptomatic infections in about 85% of cases and

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV., Author Summary CHIKV is characterized by acute and chronic polyarthritis/polyarthralgia that can be debilitating and protracted. Currently there are no FDA-approved vaccines or specific antiviral treatments for CHIKV. We thus identified and characterized human monoclonal antibodies directed against CHIKV that could be utilized in prophylactic and immediate post-exposure settings. Such patient derived monoclonal antibodies could also provide useful information on critical antigens and epitopes for development of future vaccines and other biologics. We describe here the identification of two monoclonal antibodies (C9 and E8) isolated from recovered patients. C9 potently inhibited CHIKV infection in cells and prevented viremia and arthritis in a mouse model of CHIKV disease. The epitope for this antibody includes an amino-acid residue in a key acid-sensitive region of the E2 glycoprotein of CHIKV. Rearrangement of this region following exposure to low pH is critical for uncovering portions of the companion E1 glycoprotein, required for successful entry of CHIKV into cells. We hypothesize that binding of antibodies to this region stabilizes the native complex and thus prevents such rearrangements.

West Nile virus (WNV) is currently circulating in several European countries and, over recent decades, concomitantly with enhanced surveillance studies and improved diagnostic capabilities, an increase in the geographical distribution and in the number of cases in Europe has been documented. In Italy in 2011, 14 human cases of WNV neuroinvasive infections due to lineage 1 strains were registered in several Italian regions. Here we report WNV partial sequences obtained from serum samples of two patients living in different regions of Italy (Veneto and Sardinia). Phylogenetic analysis, performed on a fragment (566 nt) of the envelope gene, showed that WNV strains circulating in Italy in 2011 belong to lineage 1a, but are different from lineage 1a strains isolated in 2008–2009.The data reported here are consistent with the hypothesis of multiple recent introductions of WNV lineage 1a strains into Italy.

Background Treponema denticola is an oral spirochete involved in the pathogenesis and progression of periodontal disease. Of its virulence factors, the major surface protein (MSP) plays a role in the interaction between the treponeme and host. To understand the possible evolution of this protein, we analyzed the sequence of the msp gene in 17 T. denticola positive clinical samples. Methods Nucleotide and amino acid sequence of MSP have been determined by PCR amplification and sequencing in seventeen T. denticola clinical specimens to evaluate the genetic variability and the philogenetic relationship of the T. denticola msp gene among the different amplified sequence of positive samples. In silico antigenic analysis was performed on each MSP sequences to determined possible antigenic variation. Results The msp sequences showed two highly conserved 5' and 3' ends and a central region that varies substantially. Phylogenetic analysis categorized the 17 specimens into 2 principal groups, suggesting a low rate of evolutionary variability and an elevated degree of conservation of msp in clinically derived genetic material. Analysis of the predicted antigenic variability between isolates, demonstrated that the major differences lay between amino acids 200 and 300. Conclusion These findings showed for the first time, the nucleotide and amino acids variation of the msp gene in infecting T. denticola, in vivo. This data suggested that the antigenic variability found in to the MSP molecule, may be an important factor involved in immune evasion by T. denticola.