Dupuytren’s Disease: More Than Extension Deficit

Treatment outcomes for Dupuytren's disease can be measured in different ways. In addition to the classic outcome measures, ie extension limitation, this thesis provides insight into other, more patient-oriented outcome measures and provides a first step in predicting outcomes after surgical treatment

The antiproliferative drug doxorubicin inhibits liver fibrosis in bile duct-ligated rats and can be selectively delivered to hepatic stellate cells in vivo

Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis; therefore, pharmacological intervention with antiproliferative drugs may result in antifibrotic effects. In this article, the antiproliferative effect of three cytostatic drugs was tested in cultured rat HSC. Subsequently, the antifibrotic potential of the most potent drug was evaluated in vivo. As a strategy to overcome drug-related toxicity, we additionally studied how to deliver this drug specifically to HSC by conjugating it to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA). We investigated the effect of cisplatin, chlorambucil, and doxorubicin (DOX) on 5-bromo-2'-deoxyuridine incorporation in cultured HSC and found DOX to be the most potent drug. Treatment of bile duct-ligated (BDL) rats with daily i.v. injections of 0.35 mg/kg DOX from day 3 to 10 after BDL reduced alpha-smooth muscle actin-stained area in liver sections from 8.5 +/- 0.8 to 5.1 +/- 0.9% (P +/- 0.01) and collagen-stained area from 13.1 +/- 1.3 to 8.9 +/- 1.5% (P +/- 0.05). DOX was coupled to M6PHSA, and the organ distribution of this construct (M6PHSA-DOX) was investigated. Twenty minutes after i.v. administration, 50 +/- 6% of the dose was present in the livers, and colocalization of M6PHSA-DOX with HSC markers was observed. In addition, in vitro studies showed selective binding of M6PHSA-DOX to activated HSC. Moreover, M6PHSA-DOX strongly attenuated HSC proliferation in vitro, indicating that active drug is released after uptake of the conjugate. DOX inhibits liver fibrosis in BDL rats, and HSC-selective targeting of this drug is possible. This may offer perspectives for the application of antiproliferative drugs for antifibrotic purposes

Patient’s satisfaction beyond hand function in Dupuytren’s disease: analysis of 1106 patients

This study investigates the outcomes of 1106 patients with Dupuytren’s disease treated with limited fasciectomy or percutaneous needle fasciotomy over 16 years according to the different domains of patient-reported hand function. These patients completed the Michigan Hand Outcomes Questionnaire before and 3 months after surgery. Scores for the various outcome parameters were calculated and linear regression analyses were used to examine associations between the changes in digital extension d

Better patients’ treatment experiences are associated with better postoperative results in Dupuytren’s disease

This prospective study investigates the extent to which a better experience with healthcare delivery is associated with better postoperative treatment outcomes after surgery for Dupuytren’s contracture. Patients undergoing limited fasciectomy or percutaneous needle fasciotomy for Dupuytren’s contractures completed the Michigan Hand Outcomes Questionnaire before and 3 months after surgery, together with a patient reported experience measu

Purifying selection in corvids is less efficient on islands

Funding was provided by the European Research Council (ERCStG-336536 FuncSpecGen to J.B.W.W.), the Swedish Research Council Vetenskapsrådet (621-2013-4510 to J.B.W.W.), the Knut and Alice Wallenberg Foundation (to J.B.W.W.), the Lawski foundation (to V.E.K. and J.B.W.W.), the German Research Foundation (KU 3402/1-1 to V.E.K.), the UK’s Biotechnology and Biological Sciences Research Council (BB/G023913/2 to C.R.), and the New Zealand Marsden Fund (to G.R.H.).Theory predicts that deleterious mutations accumulate more readily in small populations. As a consequence, mutation load is expected to be elevated in species where life-history strategies and geographic or historical contingencies reduce the number of reproducing individuals. Yet, few studies have empirically tested this prediction using genome-wide data in a comparative framework. We collected whole-genome sequencing data for 147 individuals across seven crow species (Corvus spp.). For each species, we estimated the distribution of fitness effects of deleterious mutations and compared it with proxies of the effective population size Ne. Island species with comparatively smaller geographic range sizes had a significantly increased mutation load. These results support the view that small populations have an elevated risk of mutational meltdown, which may contribute to the higher extinction rates observed in island species.Publisher PDFPeer reviewe

Threshold Laws for the Break-up of Atomic Particles into Several Charged Fragments

The processes with three or more charged particles in the final state exhibit particular threshold behavior, as inferred by the famous Wannier law for (2e + ion) system. We formulate a general solution which determines the threshold behavior of the cross section for multiple fragmentation. Applications to several systems of particular importance with three, four and five leptons (electrons and positrons) in the field of charged core; and two pairs of identical particles with opposite charges are presented. New threshold exponents for these systems are predicted, while some previously suggested threshold laws are revised.Comment: 40 pages, Revtex, scheduled for the July issue of Phys.Rev.A (1998

Perioperative SARS-CoV-2 infections increase mortality, pulmonary complications, and thromboembolic events : a Dutch, multicenter, matched-cohort clinical study

Background: A direct comparison of severe acute respiratory syndrome coronavirus 2 positive patients with a severe acute respiratory syndrome coronavirus 2 negative control group undergoing an operative intervention during the current pandemic is lacking, and a reliable estimate of the assumed difference in morbidity and mortality between both patient categories remains unknown. Methods: We included all consecutive patients with a confirmed pre- or postoperative severe acute respiratory syndrome coronavirus 2 positive status (operated in 27 hospitals) and negative control patients (operated in 4 hospitals) undergoing emergency or elective operations. A propensity score-matched comparison of clinical outcomes was performed between severe acute respiratory syndrome coronavirus 2 positive and negative tested patients (control group). Primary outcome was overall 30-day mortality rate between both groups. Main secondary outcomes were overall, pulmonary, and thromboembolic complications. Results: In total, 161 severe acute respiratory syndrome coronavirus 2 positive and 342 control severe acute respiratory syndrome coronavirus 2 negative patients were included in this study. The 30-day overall postoperative mortality rate was greater in the severe acute respiratory syndrome coronavirus 2 positive cohort compared with the negative control group (16% vs 4% respectively; P = .007). After propensity score matching, the severe acute respiratory syndrome coronavirus 2 positive group consisted of 123 patients (median 70 years of age [interquartile range 59-77] and 55% male) were compared with 196 patients in the matched control group (median 69 years (interquartile range 58-75] and 53% male). The 30-day mortality rate and risk were greater in the severe acute respiratory syndrome coronavirus 2 positive group compared with the matched control group (12% vs 4%; P = .009 and odds ratio 3.4 [95% confidence interval 1.5-8.5]; P = .005, respectively). Overall, pulmonary and thromboembolic complications occurred more often in severe acute respiratory syndrome coronavirus 2 positive patients (P < .01). Conclusion: Patients diagnosed with perioperative severe acute respiratory syndrome coronavirus 2 have an increased risk of 30-day mortality, pulmonary complications, and thromboembolic events. These findings serve as an evidence-based argument to postpone elective surgery and selected emergency cases. (C) 2020 The Author(s). Published by Elsevier Inc

Factors affecting return to work after surgical treatment of trapeziometacarpal joint osteoarthritis

This study aimed to identify factors contributing to the timing of return to work after surgical treatment of trapeziometacarpal joint osteoarthritis and to calculate the costs of lost productivity. We included 627 patients with paid employment who underwent trapeziectomy and ligament reconstruction with tendon interposition. Time to return to work was measured through filling online questionnaires and analysed using survival analysis at 6 weeks and 3, 6 and 12 months after the surgery. Patients also filled in the Michigan Hand Outcomes Questionnaire. Costs of lost productivity were calculated using the human capital method. After 1 year, 78% of the patients returned to work. The median time to return to work was 12 weeks. Factors that significantly affected the time to return to work were occupational intensity (light, moderate or heavy physical labour), whether the dominant hand was treated and the Michigan Hand Outcomes Questionnaire work score and hand functi

Reduction of Fibrogenesis by Selective Delivery of a Rho Kinase Inhibitor to Hepatic Stellate Cells in Mice

One of the pathways activated during liver fibrosis is the Rho kinase pathway, which regulates activation, migration, and contraction of hepatic stellate cells (HSC). Inhibition of this kinase by the Rho kinase inhibitor Y27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] has been shown to reduce fibrosis in animal models. However, kinase expression is ubiquitous, so any inhibitor may affect many cell types. We hypothesize that cell-specific delivery of a kinase inhibitor will be beneficial. Therefore, we conjugated Y27632 to the carrier mannose-6-phosphate (M6P) human serum albumin (HSA), which is taken up specifically in activated HSC through the M6P/insulin-like growth factor II receptor. This conjugate decreased protein expression of phosphorylated myosin light chain 2 (pMLC2) and vinculin, downstream of Rho kinase, in activated primary HSC and decreased the migration and contraction of HSC. In an ex vivo model, free Y27632 decreased contractility of rat aortas, whereas the Y27-conjugate did not, showing that the Y27-conjugate does not affect nontarget tissue. In chronic CCl(4)-induced liver fibrosis, both free drug and conjugate reduced HSC activation; however, only the Y27-conjugate significantly reduced collagen deposition. Treatment with the Y27-conjugate, but not with free drug, reduced pMLC2 expression in livers 24 h after injection, demonstrating prolonged inhibition of the Rho kinase pathway. The Rho kinase inhibitor Y27632 can be specifically targeted to HSC using M6PHSA, decreasing its effects in nontarget tissues. The targeted drug effectively reduced fibrotic parameters in vivo via the inhibition of the Rho kinase pathway

Positive experience with treatment is associated with better surgical outcome in trapeziometacarpal osteoarthritis

The aim of this study was to investigate the association between patients’ experiences with trapeziometacarpal arthroplasty and treatment outcomes in terms of patient-reported outcome measures, grip and pinch strength. We included 233 patients who received a Weilby procedure for trapeziometacarpal osteoarthritis. Before surgery and 12 months after surgery, patients completed the Michigan Hand Outcomes Questionnaire, and their pinch and grip strengths were measured. At 3 months after surgery, a patient-reported experience measure was completed. Using regression analysis, significantly positive associations were found between the Michigan Hand questionnaire and the patient-reported experience measure, with the strongest significant associations being for patients’ experiences with information provision. No significant associations were found between the patients’ experience and strength outcomes. The results highlight the potential importance of positive experience with the treatment process to improve treatment outcomes in patients undergoing surgery for trapeziometacarpal osteoarthritis. Level of evidence: IV