Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice

Performance analysis of cables with attached tuned-inerter-dampers

Cables are structural elements designed to bear tensile forces and experience vibration problems due to their slenderness and low mass. In the field of civil engineering, they are mostly used in bridges where the vibrations are mainly induced by wind, rain, traffic and earthquakes. This paper proposes the use of a tuned-inerter-damper (TID) system, mounted on cables to suppress unwanted vibrations. These are to be attached transversally to the cable, in the vicinity of the support, connected between the deck and the cable. The potential advantage of using a TID system consists in the high apparent mass that can be produced by the inerter. Our analysis showed that the modal damping ratio obtained is much higher than in the case of traditional dampers or tuned mass dampers, leading to an improved overall response. An optimal tuning methodology is also discussed. Numerical results are shown with a cable subjected to both free and forced vibrations and the TID performance is improved when compared with equivalent dampers

Shake table testing of a tuned mass damper inerter (Tmdi)-equipped structure and nonlinear dynamic modeling under harmonic excitations

This paper presents preliminary experimental results from a novel shaking table testing campaign investigating the dynamic response of a two-degree-of-freedom (2DOF) physical specimen with a grounded inerter under harmonic base excitation and contributes a nonlinear dynamic model capturing the behavior of the test specimen. The latter consists of a primary mass connected to the ground through a high damping rubber isolator (HDRI) and a secondary mass connected to the primary mass through a second HDRI. Further, a flywheel-based rack-and-pinion inerter prototype device is used to connect the secondary mass to the ground. The resulting specimen resembles the tuned mass damper inerter (TMDI) configuration with grounded inerter analytically defined and numerically assessed by the authors in a number of previous publications. Physical specimens with three different inerter coefficients are tested on the shake table under sine-sweep excitation with three different amplitudes. Experimental frequency response functions (FRFs) are derived manifesting a softening nonlinear behavior of the specimens and enhanced vibration suppression with increased inerter coefficient. Further, a 2DOF parametric nonlinear model of the specimen is established accounting for non-ideal inerter device behavior and its potential to characterize experimental response time-histories, FRFs, and force-displacement relationships of the HDRIs and of the inerter is verified

Cross infection control measures and the treatment of patients at risk of Creutzfeldt Jakob disease in UK general dental practice

AIMS: To determine the suitability of key infection control measures currently employed in UK dental practice for delivery of dental care to patients at risk of prion diseases. MATERIALS AND METHODS: Subjects: Five hundred dental surgeons currently registered with the General Dental Council of the UK. Data collection: Structured postal questionnaire. Analysis: Frequencies, cross-tabulations and chi-squared analysis. RESULTS: The valid response rate to the questionnaire was 69%. 33% of practices had no policy on general disinfection and sterilisation procedures. Only 10 of the 327 responding practices (3%) possessed a vacuum autoclave. 49% of dentists reported using the BDA medical history form but less than 25% asked the specific questions recommended by the BDA to identify patients at risk of iatrogenic or familial CJD. However, 63% of practitioners would refer such patients, if identified, to a secondary care facility. Of the 107 practitioners who were prepared to provide dental treatment, 75 (70%) would do so using routine infection control procedures. CONCLUSIONS: Most of the dental practices surveyed were not actively seeking to identify patients at risk of prion diseases. In many cases, recommended procedures for providing safe dental care for such patients were not in place

The optimal succinylcholine dose for intubating emergency patients: retrospective comparative study

Background : Succinylcholine remains the drug of choice for satisfactory rapid-sequence tracheal intubation. It is not clear from the literature why the 1 mg/kg dose of succinylcholine has been traditionally used. The effective dose (ED95) of succinylcholine is less than 0.3 mg/kg. The dose of 1 mg/kg represents 3.5 to 4 times the ED95. Objectives : To compare the effect of the traditionally used 1 mg/kg of succinylcholine with lower doses of 0.6 mg/kg and 0.45 mg/kg on intubation condition regarding the onset time, duration of action, duration of abdominal fasciculation, and the intubation grading. Methods : This retrospective comparative study was carried into three groups of ASA III & IV (American Society of Anesthesiologist's Physical Status III and IV) non-prepared emergency patients who were intubated at emergency department of Hamad General Hospital, Doha, Qatar during January 1st 2007 to August 31, 2010. The Institutional Research Board (IRB) approval was obtained. This study was limited to 88 patients who received fentanyl 1 µg/kg followed by etomidate 0.3 mg/kg intravenously as induction agents and succinylcholine as a muscle relaxant agent in doses of 0.45 mg/kg, 0.6 mg/kg, or 1 mg/kg. Results : Increasing the succinylcholine dosage shortened the onset time, prolonged the duration of action, and prolonged the duration of abdominal fasciculation significantly (P<.001). Tracheal intubation was 100% successful in the three groups of patients. Conclusion : Succinylcholine dose of 0.45 mg/kg provides an optimal intubation condition in ASA III & IV emergency non-prepared patients. Duration of action of succinylcholine is dose dependent; reducing the dose allows a more rapid return of spontaneous respiration and airway reflexes

Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model

Abstract Background Mesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone. Methods Quadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression. Results Tendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24. Conclusions These data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine

Phase II study of sequential chemotherapy with docetaxel–estramustine followed by mitoxantrone–prednisone in patients with advanced hormone-refractory prostate cancer

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m−2 intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m−2 i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3–4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63–82%) obtained a ⩾50% PSA decline with 15 patients (37.5%; 95% CI 20–50%) that demonstrated a ⩾90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8–8.2 months) and 19.2 months (95% CI 13.9–24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC

Localized Intersections of Non-Extremal p-branes and S-branes

A class of solutions to Supergravity in 10 or 11 dimensions is presented which extends the non-standard or semi-local intersections of Dp-branes to the case of non-extremal p-branes. The type of non-extremal solutions involved in the intersection is free and we provide two examples involving black-branes and/or D-\bar{D} systems. After a rotation among the time coordinate and a relatively transverse radial direction the solutions admit the interpretation of an intersection among D-branes and S-branes. We speculate on the relevance of these configurations both to study time dependent phenomena in the AdS/CFT correspondence as well as to construct cosmological brane-world scenarios within String Theory admitting accelerating expansion of the Universe.Comment: 31 pages, latex file; v2: typos corrected and references adde