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Ursodeoxycholic acid improves bilirubin but not albumin in primary biliary cirrhosis: further evidence for nonefficacy.

BACKGROUND/AIM: In randomised controlled trials (RCTs) of ursodeoxycholic acid (UDCA), although serum bilirubin is frequently reduced, its effect on disease progression and mortality is unclear. As serum albumin is an established independent prognostic marker, one might expect less deterioration of serum albumin values in a UDCA-treated group. We therefore modelled the typical evolution of serum bilirubin and albumin levels over time in UDCA-untreated patients and compared it with the observed levels in UDCA RCTs. METHODS: Multilevel modelling was used to relate the evolution of serum albumin to serum bilirubin and time since patient referral. For each considered RCT, the derived model was used to predict the relationship between final mean serum albumin and bilirubin concentration, adjusted for mean serum albumin at referral and followup duration. RESULTS: Five RCTs were eligible in terms of available data, of which two had long followup. In all trials, serum albumin did not significantly differ between UDCA- and placebo-treated patients, despite the UDCA effect on serum bilirubin. Therefore, there is no evidence over time for changes or maintenance of albumin levels for UDCA-treated patients above the levels predicted for placebo-treated patients. CONCLUSIONS: Our findings suggest that UDCA does not alter serum albumin in a way that is consistent with its effect on serum bilirubin. Therefore, reductions in serum bilirubin of UDCA-treated PBC do not parallel another validated and independent prognostic marker, further questioning the validity of serum bilirubin reduction with UDCA as a surrogate therapeutic marker

Immunosuppression and HCV recurrence after liver transplantation

SummaryHCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens.From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency.There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed

Human kinetochores are swivel joints that mediate microtubule attachments.

Chromosome segregation is a mechanical process that requires assembly of the mitotic spindle - a dynamic microtubule-based force-generating machine. Connections to this spindle are mediated by sister kinetochore pairs, that form dynamic end-on attachments to microtubules emanating from opposite spindle poles. This bi-orientation generates forces that have been reported to stretch the kinetochore itself, which has been suggested to stabilise attachment and silence the spindle checkpoint. We reveal using three dimensional tracking that the outer kinetochore domain can swivel around the inner kinetochore/centromere, which results in large reductions in intra-kinetochore distance (delta) when viewed in lower dimensions. We show that swivel provides a mechanical flexibility that enables kinetochores at the periphery of the spindle to engage microtubules. Swivel reduces as cells approach anaphase, suggesting an organisational change linked to checkpoint satisfaction and/or obligatory changes in kinetochore mechanochemistry may occur before dissolution of sister chromatid cohesion

Letter to the editors

We read with interest the study by Manzia et al. [1] onthe effect of maintenance of mycophenolate mofetil(MMF) monotherapy on progression of recurrent hepati-tis C virus (HCV) after liver transplantation.The authors concluded: MMF ''monotherapy may cur-rently represent the preferred immunosuppressive alterna-tive for the long-term management of liver transplantrecipients with HCV infection''. However, we believe thatthey should exert great caution in coming to this conclu-sion, as their results [1] have not been properly evaluatedwithin the context of the complete picture of the pub-lished literature on the subject.Our group recently published a review on the role ofMMF and azathioprine in liver transplantation withregard to acute rejection, renal dysfunction and HCVrecurrence [2]. Considering HCV recurrence, we showedthat between 2001 and 2007, 17 studies evaluated MMFand HCV recurrence; among these, only two studies [3,4]found a decreased severity of HCV recurrence with MMFand one of these had no multivariate analysis [3] – citedby Manzia et al. Nine studies (reported in reference 2)documented similar severity of HCV recurrence; however,six studies [5–10] showed increased severity of HCVrecurrence, but only one of these [10] was cited byManzia et al.Therefore, the study by Manzia et al. [1] representsonly the third study out of 18 (17%) showing a beneficialtherapeutic effect of MMF on HCV progression after livertransplantation, whereas 33% shows a deleterious effect.For this reason, in omitting to cite this literature, Maniaet al. have gone against the available evidence in statingthat MMF is the preferred immunosuppressive alternativefor long-term regimen in patients transplanted for HCV-related cirrhosis.Moreover, although Manzia et al. [1] showed in theirpatient cohort a positive association between a favorableeffect of MMF monotherapy on the progression of hepa-tic fibrosis in HCV liver transplant patients, there are sev-eral methodological issues. There was no multivariateanalysis evaluating MMF with respect to fibrosis progres-sion. This is especially important, as the study was retro-spective and nonrandomized and with only 15 patientsper arm. Although other studies have also been retrospec-tive and nonrandomized [2], several have included multi-variate analyses.Thus, overall, the current published evidence for MMFwith respect to the severity of fibrosis and HCV recur-rence does not suggest a beneficial effect. If anything, apotential adverse effect is shown as we pointed out in ourreview [2], although we acknowledged then, and now thatthe evidence is weak.Giacomo Germani

Beta-blockers in cirrhosis: Therapeutic window or an aspirin for all?

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KiT : a MATLAB package for kinetochore tracking

Summary: During mitosis, chromosomes are attached to the mitotic spindle via large protein complexes called kinetochores. The motion of kinetochores throughout mitosis is intricate and automated quantitative tracking of their motion has already revealed many surprising facets of their behaviour. Here, we present ‘KiT’ (Kinetochore Tracking)—an easy-to-use, open-source software package for tracking kinetochores from live-cell fluorescent movies. KiT supports 2D, 3D and multi-colour movies, quantification of fluorescence, integrated deconvolution, parallel execution and multiple algorithms for particle localization

Probing microtubule polymerisation state at single kinetochores during metaphase chromosome motion

Kinetochores regulate the dynamics of attached microtubule bundles (kinetochore-fibres, K-fibres) to generate the forces necessary for chromosome movements in mitosis. Current models suggest that poleward-moving kinetochores are attached to depolymerising K-fibres and anti-poleward-moving kinetochores to polymerising K-fibres. How the dynamics of individual microtubules within the K-fibre relate to poleward and anti-poleward movements is poorly understood. To investigate this, we developed a live-cell imaging assay combined with computational image analysis that allows eGFP-tagged EB3 (also known as MAPRE3) to be quantified at thousands of individual metaphase kinetochores as they undergo poleward and anti-poleward motion. Surprisingly, we found that K-fibres are incoherent, containing both polymerising and depolymerising microtubules – with a small polymerisation bias for anti-poleward-moving kinetochores. K-fibres also display bursts of EB3 intensity, predominantly on anti-poleward-moving kinetochores, equivalent to more coherent polymerisation, and this was associated with more regular oscillations. The frequency of bursts and the polymerisation bias decreased upon loss of kinesin-13, whereas loss of kinesin-8 elevated polymerisation bias. Thus, kinetochores actively set the balance of microtubule polymerisation dynamics in the K-fibre while remaining largely robust to fluctuations in microtubule polymerisation