Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency.

IntroductionHereditary factor X (FX) deficiency is a rare bleeding disorder affecting 1:500 000 to 1:1 000 000 of individuals. Until recently, no specific replacement factor concentrate was available.AimThe aim of this study was to assess safety and efficacy of a new, high‐purity plasma‐derived FX concentrate (pdFX) in subjects with hereditary FX deficiency.MethodsSubjects aged ≥12 years with moderate or severe FX deficiency (plasma FX activity <5 IU dL−1) received 25 IU kg−1 pdFX as on‐demand treatment or short‐term prophylaxis for 6 months to 2 years. Subjects assessed pdFX efficacy for each bleed; at end‐of‐study, investigators assessed overall pdFX efficacy. Blood samples for pharmacokinetic analysis were obtained at baseline and ≥6 months. Safety was assessed by adverse events (AEs), inhibitor development and changes in laboratory parameters.ResultsSixteen enrolled subjects (six aged 12–17 years; 10 aged 18–58 years) received a total of 468 pdFX infusions. In the 187 analysed bleeds, pdFX efficacy was categorized as excellent, good, poor or unassessable in 90.9%, 7.5%, 1.1% and 0.5% of bleeds respectively; 83% of bleeds were treated with one infusion. For pdFX, mean (median; interquartile range) incremental recovery and half‐life were 2.00 (2.12; 1.79–2.37) IU dL−1 per IU kg−1 and 29.4 (28.6; 25.8–33.1) h respectively. No serious AEs possibly related to pdFX or evidence of FX inhibitors were observed, and no hypersensitivity reactions or clinically significant trends were detected in laboratory parameters.ConclusionThese results demonstrate that a dose of 25 IU kg−1 pdFX is safe and efficacious for on‐demand treatment and short‐term prophylaxis in subjects with moderate or severe hereditary FX deficiency

Effects of highly active antiretroviral therapy on semen parameters of a cohort of 770 HIV-1 infected men

Background HIV-1 infected patients show impaired semen parameters. Currently, it is not clear whether HIV-1 infection itself or antiretroviral therapy have an effect on semen parameters. We aim evaluate semen quality in a large cohort of fertile HIV-1 infected men under stable highly active antiretroviral therapy (HAART) and to assess the effect of HAART type and duration on semen parameters. Materials and methods Between January 2010 and June 2014, we enrolled in a retrospective case-control study 770 HIV-1 patients under stable HAART asking a reproductive counselling with their HIV negative partner. Co-infections with HBV or HCV, genital tract infections and known causes of infertility represented exclusion criteria. Semen samples were analysed and compared with the WHO reference values. A multivariate analysis including HAART type and duration, age, viral load and CD4 count, was performed on 600 patients out of 770. Results The median values of all semen parameters were significantly lower among HIV-1 infected patients compared to the WHO reference group, with a significant proportion of patients having values below the 5th percentile of the WHO reference value. In a multivariate analysis, only age and viral load negatively impacted progressive motility (\u3b2 -0.3 (95% CI: -0.5; -0.0) %, p&lt;0.05) and semen morphology (\u3b2 -0.00 (95% CI: -0.00; -0.00) %, p0.01), while no associations were detected as regards HAART type and duration. Conclusions HIV-1 infected patients showed a significant impairment of semen parameters compared to the reference values. HAART type and duration showed no associations with semen quality. Further research is needed to investigate implications for clinical care of HIV infected men desiring a child

Tulathromycin disturbs blood oxidative and coagulation status

The aim of this study was to determine the effect of tulathromycin on serum oxidative status and coagulation factors in rabbits. Tulathromycin was administered to eight rabbits, and blood samples were obtained 0, 1, 5, 10 and 15 days after treatment. Indicators of serum oxidative status (malondialdehyde, nitric oxide, superoxide dismutase, retinol and -carotene) and coagulation values (antithrombin III, fibrinogen) were measured after tulathromycin treatment. In addition, routine serum biochemical values (creatine kinase-MB, lactate dehydrogenase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, creatinine, blood urea nitrogen, cholesterol, triglyceride, high density lipoprotein, amylase, total protein, albumin, glucose and calcium), haemacell counts (white and red blood cells) and arterial blood gas parameters (packed cell volume, hemoglobin, pH, partial pressure of carbon dioxide, partial pressure of oxygen, actual bicarbonate, standard bicarbonate, total carbon dioxide, base excess in vivo, base excess in vitro, oxygen saturation, sodium and potassium) were also determined. Tulathromycin increased (P &lt; 0.05) the levels of malondialdehyde, nitric oxide and superoxide dismutase activity, and decreased (P &lt; 0.05) the level of antithrombin III. In conclusion, tulathromycin may cause oxidative damage and coagulation disorders during the treatment period.Key words: Tulathromycin, oxidative damage, coagulation disorder

Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status

Cataloged from PDF version of article.The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is involved in cell survival and anti-apoptotic signaling. Akt has been shown to be constitutively expressed in a variety of human tumors including hepatocellular carcinoma (HCC). In this report we analyzed the status of Akt pathway in three HCC cell lines, and tested cytotoxic effects of Akt pathway inhibitors LY294002, Wortmannin and Inhibitor VIII. In Mahlavu human hepatoma cells Akt was constitutively activated, as demonstrated by its Ser473 phosphorylation, downstream hyperphosphorylation of BAD on Ser136, and by a specific cell-free kinase assay. In contrast, Huh7 and HepG2 did not show hyperactivation when tested by the same criteria. Akt enzyme hyperactivation in Mahlavu was associated with a loss of PTEN protein expression. Akt signaling was inhibited by the upstream kinase inhibitors, LY294002, Wortmannin, as well as by the specific Akt Inhibitor VIII in all three hepatoma cell lines. Cytotoxicity assays with Akt inhibitors in the same cell lines indicated that they were all sensitive, but with different IC50 values as assayed by RT-CES. We also demonstrated that the cytotoxic effect was through apoptotic cell death. Our findings provide evidence for its constitutive activation in one HCC cell line, and that HCC cell lines, independent of their Akt activation status respond to Akt inhibitors by apoptotic cell death. Thus, Akt inhibition may be considered as an attractive therapeutic intervention in liver cancer. © Springer Science+Business Media, LLC 2010

Recent Advances in Soil Liquefaction Engineering and Seismic Site Response Evaluation

Over the past decade, major advances have occurred in both understanding and practice with regard to engineering treatment of seismic soil liquefaction and assessment of seismic site response. Seismic soil liquefaction engineering has evolved into a sub-field in its own right, and assessment and treatment of site effects affecting seismic site response has gone from a topic of controversy to a mainstream issue addressed in most modem building codes and addressed in both research and practice. This rapid evolution in the treatment of both liquefaction and site response issues has been pushed by a confluence of lessons and data provided by a series of earthquakes over the past eleven years, as well as by the research and professional/political will engendered by these major seismic events. Although the rate of progress has been laudable, further advances are occurring, and more remains to be done. As we enter a “new millenium”, engineers are increasingly well able to deal with important aspects of these two seismic problem areas. This paper will highlight a few major recent and ongoing developments in each of these two important areas of seismic practice, and will offer insights regarding work/research in progress, as well as suggestions regarding further advances needed. The first part of the paper will address soil liquefaction, and the second portion will (briefly) address engineering assessment of seismic site response

Comparison of chemotherapy and hematopoietic stem cell transplantation pre and postterm DMFT scores: A preliminary study

Aims: Chemotherapy is frequently used as a conditioning regimen to destroy malignant marrow cells before transplantation. Xerostomia, dysphagia, altered taste perception, mucositis, soft‑tissue ulceration, and infection are common adverse oral effects of chemotherapy. The study was aimed to compare decayed, missing, filled teeth (DMFT) scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy.Materials and Methods: Thirty‑six patients undergoing HSCT were included in the study. Apre‑HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of periodontal infections, and extraction of all teeth with advanced periodontal disease. Upon completion of dental treatment, the importance of rigorous and effective oral hygiene was reemphasized, and patients were recalled 6 months later. DMFT scores were calculated prior to the initiation of HSCT treatment and 6 months after transplantation.Statistical Analysis Used: Regression analysis was used to evaluate the effects of HSCT and chemotherapy on DMFT scores.Results: Wilcoxon T test showed a statistically significant difference in DMFT scores before and after HSCT (P &lt; 0.001). Conclusions: DMFT scores were found to increase after chemotherapy and HSCT, suggesting that the risk of infection is higher among HSCT patients when compared to other individuals. The results emphasize the need for dental examinations as an integral part of examination and treatment planning for patients undergoing HSCT and chemotherapy.Key words: Chemotherapy, decayed missing filled teeth scores, hematopoietic stem cell transplantatio

Local variation of hashtag spike trains and popularity in Twitter

We draw a parallel between hashtag time series and neuron spike trains. In each case, the process presents complex dynamic patterns including temporal correlations, burstiness, and all other types of nonstationarity. We propose the adoption of the so-called local variation in order to uncover salient dynamics, while properly detrending for the time-dependent features of a signal. The methodology is tested on both real and randomized hashtag spike trains, and identifies that popular hashtags present regular and so less bursty behavior, suggesting its potential use for predicting online popularity in social media.Comment: 7 pages, 7 figure

Periconceptional Maternal One-Carbon Biomarkers are Associated with Embryonic Development According to the Carnegie Stages

STUDY QUESTION: Is periconceptional maternal one-carbon (I-C) metabolism associated with embryonic morphological development in non-malformed ongoing pregnancies? SUMMARY ANSWER: Serum vitamin B12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) are associated with embryonic development according to the Carnegie stages. WHAT IS KNOWN ALREADY: Derangements in maternal I-C metabolism affect reproductive and pregnancy outcomes, as well as future health of the offspring. STUDY DESIGN, SIZE, DURATION: Between 2010 and 2014, women with singleton ongoing pregnancies were enrolled in a prospective periconceptional cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 234 pregnancies, including 138 spontaneous or IUI pregnancies with strict pregnancy dating and 96 pregnancies derived from IVF, ICSI or cryopreserved embryo transfer (IVF/ICSI pregnancies), underwent longitudinal transvaginal three-dimensional ultrasound (3D US) scans from 6+0 up to 10+2 weeks of gestation. Carnegie stages were defined using internal and external morphologic criteria in a virtual reality system. Maternal venous blood samples were collected at enrollment for serum vitamin B12, RBC folate and plasma tHcy assessment. Associations between biomarker concentrations and longitudinal Carnegie stages were investigated using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: We performed a median of three 3D US scans per pregnancy (range 1-5) resulting in 600 good quality data sets for the Carnegie stage annotation (80.5%). Vitamin B12 was positively associated with embryonic development in the total study population (\u3b2 = 0.001 (95% CI: 0.000; 0.002), P < 0.05) and in the subgroup of strictly dated spontaneous pregnancies (\u3b2 = 0.002 (95% CI: 0.001; 0.003), P < 0.05). Low vitamin B12 concentrations (-2SD, 73.4 pmol/l) were associated with delayed embryonic development by 1.4 days (95% CI: 1.3-1.4) compared with high concentrations (+2SD, 563.1 pmol/l). RBC folate was positively associated with Carnegie stages only in IVF/ICSI pregnancies (\u3b2 = 0.001 (95% CI: 0.0005; 0.0015), P < 0.05). In this group, low RBC folate concentrations (-2SD, 875.4 nmol/l) were associated with a 1.8-day delay (95% CI: 1.7-1.8) in development compared with high concentrations (+2SD, 2119.9 nmol/l). tHcy was negatively associated with embryonic development in the total study population (\u3b2 = -0.08 (95% CI: -0.14; -0.02), P < 0.01), as well as in the IVF/ICSI subgroup (\u3b2 = -0.08 (95% CI: -0.15; -0.01), P < 0.05). High tHcy concentrations (+2SD, 10.4 \ub5mol/l) were associated with a delay of 1.6 days (95% CI: 1.5-1.7) in embryonic development compared with low concentrations (-2SD, 3.0 \ub5mol/l). LIMITATIONS, REASONS FOR CAUTION: The study was performed in a tertiary care center, resulting in high rates of folic acid supplement use and comorbidity that may reduce the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS: In periconceptional care, maternal I-C biomarkers should be taken into account as predictors of embryonic morphological development. Combining embryonic size measurements with morphological assessment could better define normal embryonic development. STUDY FUNDING/COMPETING INTEREST(S): The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. RPMST is CSO of the startup company Slimmere Zorg and CEO of eHealth Care Solutions. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable

Search for chameleons with CAST

In this work we present a search for (solar) chameleons with the CERN Axion Solar Telescope (CAST). This novel experimental technique, in the field of dark energy research, exploits both the chameleon coupling to matter ($\beta_{\rm m}$) and to photons ($\beta_{\gamma}$) via the Primakoff effect. By reducing the X-ray detection energy threshold used for axions from 1$\,$keV to 400$\,$eV CAST became sensitive to the converted solar chameleon spectrum which peaks around 600$\,$eV. Even though we have not observed any excess above background, we can provide a 95% C.L. limit for the coupling strength of chameleons to photons of $\beta_{\gamma}\!\lesssim\!10^{11}$ for $1<\beta_{\rm m}<10^6$.Comment: 8 pages, 12 figure