Herpesvirus Involvement in Lymphoma/Leukaemia and Related Disease

Human herpesvirus-6 (HHV-6) was first isolated from the peripheral blood of six individuals with lymphoproliferative or immunosuppressive disorders. Further studies identified HHV-6 DNA sequences in tumour biopsy samples from persons with lymphoma. Thus, initial findings suggested a link between HHV-6 and lymphoproliferative disease. This study was designed to examine further the association of HHV-6 with lymphomas and leukaemias by seroepidemiological investigations. Higher antibody titres to HHV-6 were identified in acute myeloid leukaemia, low-grade non-Hodgkin's lymphoma, and Hodgkin's disease (HD). Epidemiological evidence has lead to the proposition that HD, particularly in young adults, may have a viral aetiology and Epstein-Barr virus (EBV) has consistently been associated with this malignancy. Further analysis of both HHV-6 and EBV serology was carried out and the results suggested that the associations of both viruses with HD were relatively independent of each other. Thus, HD may be the result of an abnormal response to virus infection including EBV and HHV-6. To date there is little molecular evidence linking HHV-6 to HD, although recent studies have clearly demonstrated the presence of EBV within the tumour cells of the disease. In 1990, a human herpesvirus, distinct from those previously recognised, was isolated and named human herpesvirus-7 (HHV-7). The seroepidemiology of this virus in children and adults is presented in this dissertation. Infection with HHV-7 is widespread and infection occurs usually early in life. A likely vehicle for transmission is saliva. Herpesviruses have not only been associated with malignancy, but also chronic disease such as autoimmune conditions. EBV involvement has been proposed in the autoimmune disease, Sjogren's syndrome (SS). More recently HHV-6 has been linked to this condition. Viruses present within the epithelium of the salivary gland may play a role in the inflammation of such glands which is characteristically found in SS. This project studied possible viral involvement in SS by utilising the in vitro tissue culture of epithelial cells derived from salivary gland biopsies. The model proved useful as a means to study cytokine- mediated mechanisms of autoimmunity in particular the role of interferon-? and in the identification of putative retroviral antigens in salivary tissue

Calibration and Cross-Validation of Accelerometery for Estimating Movement Skills in Children Aged 8-12 Years

This study sought to calibrate triaxial accelerometery, worn on both wrists, waist and both ankles, during children’s physical activity (PA), with particular attention to object control motor skills performed at a fast and slow cadence, and to cross-validate the accelerometer cut-points derived from the calibration using an independent dataset. Twenty boys (10.1 ±1.5 years) undertook seven, five-minute bouts of activity lying supine, standing, running (4.5kmph−1) instep passing a football (fast and slow cadence), dribbling a football (fast and slow cadence), whilst wearing five GENEActiv accelerometers on their non-dominant and dominant wrists and ankles and waist. VO2 was assessed concurrently using indirect calorimetry. ROC curve analysis was used to generate cut-points representing sedentary, light and moderate PA. The cut-points were then cross-validated using independent data from 30 children (9.4 ± 1.4 years), who had undertaken similar activities whilst wearing accelerometers and being assessed for VO2. GENEActiv monitors were able to discriminate sedentary activity to an excellent level irrespective of wear location. For moderate PA, discrimination of activity was considered good for monitors placed on the dominant wrist, waist, non-dominant and dominant ankles but fair for the non-dominant wrist. Applying the cut-points to the cross-validation sample indicated that cut-points validated in the calibration were able to successfully discriminate sedentary behaviour and moderate PA to an excellent standard and light PA to a fair standard. Cut-points derived from this calibration demonstrate an excellent ability to discriminate children’s sedentary behaviour and moderate intensity PA comprising motor skill activity.N/

SERS enhancement of silver nanoparticles prepared by a template-directed triazole ligand strategy

Two advances in the development of a one-pot method to prepare silver nanoparticles (AgNPs) using the Tollens’ reagent are described. First, a template-directed process of AgNP synthesis using resorcinol triazole ligands bearing two pendent galactose sugars is shown. Second, the conversion of these AgNPs into SERS nanotags is demonstrated using malachite green isothiocyanate as the Raman reporter molecule

SERS enhancement of silver nanoparticles prepared by a template-directed triazole ligand strategy

Two advances in the development of a one-pot method to prepare silver nanoparticles (AgNPs) using the Tollens' reagent are described. First, a template-directed process of AgNP synthesis using resorcinol triazole ligands bearing two pendent galactose sugars is shown. Second, the conversion of these AgNPs into SERS nanotags is demonstrated using malachite green isothiocyanate as the Raman reporter molecule

Study of the luminous blue variable star candidate G26.47+0.02 and its environment

The luminous blue variable (LBV) stars are peculiar very massive stars. The study of these stellar objects and their surroundings is important for understanding the evolution of massive stars and its effects on the interstellar medium. We study the LBV star candidate G26.47+0.02. Using several large-scale surveys in different frequencies we performed a multiwavelength study of G26.47+0.02 and its surroundings. We found a molecular shell (seen in the 13CO J=1-0 line) that partially surrounds the mid-infrared nebula of G26.47+0.02, which suggests an interaction between the strong stellar winds and the molecular gas. From the HI absorption and the molecular gas study we conclude that G26.47+0.02 is located at a distance of ~4.8 kpc. The radio continuum analysis shows a both thermal and non-thermal emission toward this LBV candidate, pointing to wind-wind collision shocks from a binary system. This hypothesis is supported by a search of near-IR sources and the Chandra X-ray analysis. Additional multiwavelength and long-term observations are needed to detect some possible variable behavior, and if that is found, to confirm the binary nature of the system.Comment: accepted in A&A 01/05/201

Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin

Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analogue with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein-protein interaction

Effect of Direct Oral Anticoagulant, Patient, and Surgery Characteristics on Clinical Outcomes in the Perioperative Anticoagulation Use for Surgery Evaluation Study.

Introduction  The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) Study assessed a standardized perioperative management strategy in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) and required an elective surgery or procedure. The aim of this substudy is to analyze the safety of this management strategy across different patient subgroups, according to four presurgical variables: (1) DOAC type and dose, (2) surgery/procedure bleed risk, (3) patient renal function, and (4) age. Methods  Clinical outcomes analyzed included major bleeding (MB), arterial thromboembolism, any bleeding, and any thromboembolism. We used descriptive statistics to summarize clinical outcomes, where the frequency, proportion, and 95% confidence interval were reported. Fisher\u27s exact tests were used for testing the hypothesis of independence between the clinical outcome and patient characteristic, where the test p -values were reported. Results  There were 3,007 patients with atrial fibrillation requiring perioperative DOAC management. There was no significant difference in bleeding or thromboembolic outcomes according to DOAC type/dose regimen, renal function, or patient age. The rate of MB was significantly higher with high bleed risk procedures than low bleed risk procedures in apixaban-treated patients (2.9 vs. 0.59%; p  \u3c 0.01), but not in dabigatran-treated patients (0.88 vs. 0.91%; p  = 1.0) or rivaroxaban-treated patients (2.9 vs. 1.3%; p  = 0.06). The risk for thromboembolism did not differ according to surgery/procedure-related bleed risk. Conclusion  Our results suggest that in DOAC-treated patients who received standardized perioperative management, surgical bleed risk is an important determinant of bleeding but not thromboembolic outcomes, although this finding was not consistent across all DOACs. There were no differences in bleeding and thromboembolism according to DOAC type and dose, renal function, or age