Knee moments of anterior cruciate ligament reconstructed and control participants during normal and inclined walking

Objectives: Prior injury to the knee, particularly anterior cruciate ligament (ACL) injury, is known to predispose one to premature osteoarthritis (OA). The study sought to explore if there was a biomechanical rationale for this process by investigating changes in external knee moments between people with a history of ACL injury and uninjured participants during walking: (1) on different surface inclines and (2) at different speeds. In addition we assessed functional differences between the groups. Participants: 12 participants who had undergone ACL reconstruction (ACLR) and 12 volunteers with no history of knee trauma or injury were recruited into this study. Peak knee flexion and adduction moments were assessed during flat (normal and slow speed), uphill and downhill walking using an inclined walkway with an embedded Kistler Force plate, and a ten-camera Vicon motion capture system. Knee injury and Osteoarthritis Outcome Score (KOOS) was used to assess function. Multivariate analysis of variance (MANOVA) was used to examine statistical differences in gait and KOOS outcomes. Results: No significant difference was observed in the peak knee adduction moment between ACLR and control participants, however, in further analysis, MANOVA revealed that ACLR participants with an additional meniscal tear or collateral ligament damage (7 participants) had a significantly higher adduction moment (0.33±0.12 Nm/kg m) when compared with those with isolated ACLR (5 participants, 0.1±0.057 Nm/kg m) during gait at their normal speed ( p<0.05). A similar (nonsignificant) trend was seen during slow, uphill and downhill gait. Conclusions: Participants with an isolated ACLR had a reduced adductor moment rather an increased moment, thus questioning prior theories on OA development. In contrast, those participants who had sustained associated trauma to other key knee structures were observed to have an increased adduction moment. Additional injury concurrent with an ACL rupture may lead to a higher predisposition to osteoarthritis than isolated ACL deficiency alone

Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats

Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks post-injection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection

Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway.

A systematic evaluation of the influence of sex on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver-targeted delivery of vector particles was between 5- to 13-fold higher in male mice compared with female mice, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the sex difference in transduction was observed with AAV-2- and AAV-5-based vectors, which use distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV inverted terminal repeat (ITR) in males compared with females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5alpha dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, sex did not have a significant effect on AAV gene transfer into nonhepatic tissue, indicating that there are distinct tissue- and sex-specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver

The Study of Financial Performance of Banking Sector of India

Banking sector reforms in India, strive to increase efficiency and profitability of the banking institutions, the existing banking institutions has to face the global competition. As a consequence, there has not only been rapid expansion in the number of banking institutions in the country, but the banking horizon of the country has also changed significantly with the entry of new private sector and foreign banks. As of now, the country has public sector, old private sector, new private sector and foreign banks operating side-by-side and giving cut-throat competition to each other. Apparently, these different types of banks differ significantly from each other in terms of financial performance including operational efficiency, profitability, productivity and credit efficiency. There is a general perception that new private sector banks and foreign banks are more efficient in financial performance than that of nationalized and old private sector banks. This study emphases on the financial performance of all the commercial banks of the country for the period of five years from the year 1997-1998 to 2001-2002. The aim of this study is to understand and to find out different types of efficiency level of all the commercial banks in India. The operational efficiency reveals the performance of banks regarding operational aspects. The profitability tells about banks financial strength with the same and other banking groups in the industry. The productivity parameter indicates the labour productivity of the employees of a bank. The credit efficiency parameter shows how the given credits are efficient and what will be the effect on solvency of the bank. All these parameters have been taken with different ratios for the period of five years. All the scheduled commercial banks in India have been selected by the researcher

Pan-European early switch/early discharge opportunities exist for hospitalised patients with methicillin-resistant <em>Staphylococcus</em> <em>aureus</em> complicated skin and soft-tissue infections

AbstractThe objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient

Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA.

Long-term expression of coagulation factor IX (FIX) has been observed in murine and canine models following administration of recombinant adeno-associated viral (rAAV) vectors into either the portal vein or muscle. These studies were designed to evaluate factors that influence rAAV-mediated FIX expression. Stable and persistent human FIX (hFIX) expression (> 22 weeks) was observed from 4 vectors after injection into the portal circulation of immunodeficient mice. The level of expression was dependent on promoter with the highest expression, 10% of physiologic levels, observed with a vector containing the cytomegalovirus (CMV) enhancer/beta-actin promoter complex (CAGG). The kinetics of expression after injection of vector particles into muscle, tail vein, or portal vein were similar with hFIX detectable at 2 weeks and reaching a plateau by 8 weeks. For a given dose, intraportal administration of rAAV CAGG-FIX resulted in a 1.5-fold or 4-fold higher level of hFIX compared to tail vein or intramuscular injections, respectively. Polymerase chain reaction analysis demonstrated predominant localization of the rAAV FIX genome in liver and spleen after tail vein injection with a higher proportion in liver after portal vein injection. Therapeutic levels of hFIX were detected in the majority of immunocompetent mice (21 of 22) following intravenous administration of rAAV vector without the development of anti-hFIX antibodies, but hFIX was not detected in 14 immunocompetent mice following intramuscular administration, irrespective of strain. Instead, neutralizing anti-hFIX antibodies were detected in all the mice. These observations may have important implications for hemophilia B gene therapy with rAAV vectors

Haemophilia, the journey in search of a cure. 1960–2020

The single most important step on the path to our modern understanding of blood coagulation and haemophilia in the 20th century was taken by British pathologist Robert Gwyn Macfarlane with his 1964 publication ‘An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier’. In the same year, Ratnoff and Davie in the USA reached the same conclusion. Macfarlane and Rosemary Biggs had previously, in 1952, discovered factor IX as the factor deficient in haemophilia B. In 1973, Arthur Bloom defined the distinct role of Factor VIII and von Willebrand factor in haemophilia A and von Willebrand’s disease respectively. This inspired the efforts of Tuddenham and his group towards the purification of Factor VIII which reached homogeneity in 1982, leading to the cloning of the Factor VIII gene in 1984 in collaboration with US scientists at Genentech, which in turn enabled development of safe recombinant factor concentrates for patients with haemophilia. Brownlee cloned the factor IX gene in 1982 at the Sir William Dunn Institute of Pathology in Oxford. This led eventually to the first successful trial of gene therapy for haemophilia B in 2011 by the Nathwani group at UCL, which built on pioneering work of US groups and was partnered with St Jude in Memphis where Nathwani started the project. This trial has fuelled the current quest for a functional cure of haemophilia A and B. The UK has, therefore, made a rich contribution to advances in haemostasis over the last 60 years, often in partnership with other groups across the world

Fractional calculus of a unified Mittag-Leffler function

The main aim of the paper is to introduce an operator in the space of Lebesgue measurable real or complex functions L(a, b). Some properties of the Riemann–Liouville fractional integrals and differential operators associated with the function E α,β,λ,μ,ρ,p γ,δ (cz; s, r) are studied and the integral representations are obtained. Some properties of a special case of this function are also studied by the means of fractional calculus.Головною метою роботи є введення оператора у просторі L(a,b) дійсних або комплексних Функцій, вимірних відносно міри Лебега. Вивчено деякі властивості дробових інтегралів Рімана-Ліувілля та диференціальних операторів, що відповідають функції Eγ,δα,β,λ,μ,ρ,p(cz;s,r). Отримано відповідні інтегральні зображення. Деякі властивості частинного випадку цієї функції також вивчено за допомогою дробового числення