MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies

MicroRNAs (miRNAs) have emerged as key regulators orchestrating a wide range of inflammatory and fibrotic diseases. However, the role of miRNAs in degenerative shoulder joint disorders is poorly understood. The aim of this explorative case-control study was to identify pathology-related, circulating miRNAs in patients with chronic rotator cuff tendinopathy and degenerative rotator cuff tears (RCT). In 2017, 15 patients were prospectively enrolled and assigned to three groups based on the diagnosed pathology: (i) no shoulder pathology, (ii) chronic rotator cuff tendinopathy, and (iii) degenerative RCTs. In total, 14 patients were included. Venous blood samples (“liquid biopsies”) were collected from each patient and serum levels of 187 miRNAs were determined. Subsequently, the change in expression of nine candidate miRNAs was verified in tendon biopsy samples, collected from patients who underwent arthroscopic shoulder surgery between 2015 and 2018. Overall, we identified several miRNAs to be progressively deregulated in sera from patients with either chronic rotator cuff tendinopathy or degenerative RCTs. Importantly, for the several of these miRNAs candidates repression was also evident in tendon biopsies harvested from patients who were treated for a supraspinatus tendon tear. As similar expression profiles were determined for tendon samples, the newly identified systemic miRNA signature has potential as novel diagnostic or prognostic biomarkers for degenerative rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research^® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. Inc. J Orthop Res 38:202–211, 2020     

Application of the Pareto principle to identify and address drug-therapy safety issues

Purpose

Adverse drug events (ADE) and medication errors (ME) are common causes of morbidity in patients presenting at emergency departments (ED). Recognition of ADE as being drug related and prevention of ME are key to enhancing pharmacotherapy safety in ED. We assessed the applicability of the Pareto principle (～80 % of effects result from 20 % of causes) to address locally relevant problems of drug therapy.

Methods

In 752 cases consecutively admitted to the nontraumatic ED of a major regional hospital, ADE, ME, contributing drugs, preventability, and detection rates of ADE by ED staff were investigated. Symptoms, errors, and drugs were sorted by frequency in order to apply the Pareto principle.

Results

In total, 242 ADE were observed, and 148 (61.2 %) were assessed as preventable. ADE contributed to 110 inpatient hospitalizations. The ten most frequent symptoms were causally involved in 88 (80.0 %) inpatient hospitalizations. Only 45 (18.6 %) ADE were recognized as drug-related problems until discharge from the ED. A limited set of 33 drugs accounted for 184 (76.0 %) ADE; ME contributed to 57 ADE. Frequency-based listing of ADE, ME, and drugs involved allowed identification of the most relevant problems and development of easily to implement safety measures, such as wall and pocket charts.

Conclusions

The Pareto principle provides a method for identifying the locally most relevant ADE, ME, and involved drugs. This permits subsequent development of interventions to increase patient safety in the ED admission process that best suit local needs.     

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with subsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM.     

GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment

Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.     

New Hepatitis E Virus Genotype in Camels,the Middle East

In a molecular epidemiology study of hepatitis E virus (HEV) in dromedaries in Dubai, United Arab Emirates, HEV was detected in fecal samples from 3 camels. Complete genome sequencing of 2 strains showed >20% overall nucleotide difference to known HEVs. Comparative genomic and phylogenetic analyses revealed a previously unrecognized HEV genotype.Hepatitis E virus (HEV) belongs to the family Hepeviridae and genus Hepevirus. Among humans worldwide, HEV is the most common cause of acute viral hepatitis. The disease is generally self-limiting, but mortality rates are high among pregnant women and young infants. Chronic HEV infection is a problem for immunocompromised patients, such as those who have received a solid organ transplant and those with HIV infection. In addition to humans, HEV has been found in the other mammals: pigs, boar, deer, rodents, ferrets, rabbits, mongoose, bats, cattle, sheep, foxes, minks, and horses (1–3). Among the 4 known HEV genotypes, HEV1 and HEV2 infect only humans; whereas, HEV3 and HEV4 can infect humans, pigs, and other mammals. Human infections with HEV3 and HEV4 have been associated with consumption of raw or undercooked pork or game meat (4). Traditionally, HEV infection is mainly transmitted through water contaminated with infected feces. Since water supplies and sanitary infrastructures have been improved, animals have become a major source of human HEV infection. We detected HEV in fecal samples from dromedary camels in the Middle East.     

Cost‐effectiveness analysis of preoperative transfusion in patients with sickle cell disease using evidence from the TAPS trial

The study's objective was to assess the cost‐effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low‐ or medium‐risk surgery. Seventy patients with sickle cell disease (HbSS/Sß⁰thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost‐effectiveness analysis based on evidence from that trial is presented. A decision‐analytic model is used to incorporate long‐term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality‐adjusted life years (QALYs), are reported from the ‘within‐trial’ analysis and for the decision‐analytic model. The probability of cost‐effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from ?£813 to £26. All scenarios suggested preoperative transfusion had a probability of cost‐effectiveness >0.79 at a cost‐effectiveness threshold of £20 000 per QALY.     

Wall shear stress in the stented superficial femoral artery in peripheral arterial disease

Objective

Local changes in wall shear stress (WSS) contribute to vascular wall thickening and subsequent stenosis. Restenosis after stenting is a major concern, especially in the superficial femoral artery (SFA) of patients with peripheral arterial disease (PAD). Local alterations in WSS after stenting might contribute to restenosis/reocclusion. To test the hypothesis that WSS is impaired along the stented SFA segment, we studied the profile of WSS along the femoro-popliteal axis after stent placement in a cross-sectional design.

Methods

Eighty-seven patients with PAD (89 limbs) were included one day after stenting of the SFA. Flow velocities (peak and mean) and vessel diameter were measured by duplex ultrasound in five predefined segments along the femoro-popliteal axis, at rest and after exercise (30 toe raises); WSS (peak and mean) was calculated from flow velocities, vessel diameter and whole blood viscosity.

Results

WSS progressively declined along the stented segment at rest (peak WSS, p < 0.0001; mean WSS, p < 0.05); after exercise, WSS increased in all segments (all p < 0.001), but, again, progressively declined along the stent (peak WSS, p < 0.0001; mean WSS, p < 0.05). The internal vessel diameter remained unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis (all p > 0.05).

Conclusion

In PAD patients with SFA stenting WSS is impaired along the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/reocclusion needs further investigation.     

Impaired polysaccharide responsiveness without agammaglobulinaemia in three patients with hypomorphic mutations in Bruton Tyrosine Kinase—No detection by newborn screening for primary immunodeficiencies

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.