Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution

Total knee replacement (TKR) is a safe treatment for alleviating pain and restoring physical function in end-stage arthropathy of the knee. First reports of TKR in haemophiliacs date back to the mid-1970s, however detailed information on long-term outcome is scarce. This study evaluated factors influencing the outcome of 116 primary TKRs performed consecutively over 14 years at a single institution. Haemostatic management is discussed in patients with and without inhibitors. Orthopaedic outcome was measured by using the Hospital for Special Surgery knee-rating scale, knee flexion contracture and range of motion. At the end of follow-up period (median duration: 5·1 years) 96 prostheses (83%) were still in place with a 7-year removal-free survival of 81%, similar between human immunodeficiency virus-positive and -negative patients and lower in inhibitor than non-inhibitor patients (44% vs. 87%; P  < 0·05). Sixteen prostheses (14%) were removed for infection (nine) or aseptic loosening (seven) after a median of 4·5 years. Presence of inhibitors, continuous infusion, cementless prostheses and different primary surgeons were associated with an increased risk of infection; however, after adjustment, only primary surgeon was confirmed as an independent risk factor. These results show that TKR represents a safe and effective procedure in haemophiliacs if performed by a highly experienced surgeon.     

Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent adverse effect of treatment in cancer patients and survivors (1). CIPN significantly impacts quality of life as damage to sensory nerves may be permanent, and is often a dose-limiting factor during cancer treatment (2–4). Patients with CIPN report pain-related symptoms, including allodynia, hyper- or hypoalgesia, or pain that can be more severe than the pain associated with the original cancer (4). Despite increasing data on agents that protect sensory nerves, our limited understanding of the mechanisms of CIPN impedes effective treatment (5). Studies from model systems may be helpful in identifying molecules that protect sensory neuron morphology and function from the effects of chemotherapeutics.In the present study, we explored the mechanisms of CIPN induced by paclitaxel using two established models: Drosophila larval nociceptive neurons (6, 7) and primary dorsal root ganglia (DRG) neurons isolated from adult mouse (8). Similar to other peripheral neuropathies, CIPN models using paclitaxel, bortezomib, oxaliplatin, and vincristine report changes in unmyelinated intraepidermal nerve fibers (IENFs) that detect painful or noxious stimuli (9–14). These small fibers are embedded in the epidermis, and continuously turn over coincident with the turnover of skin (9, 15). Drosophila class IV nociceptive neurons are a favored model for genetic studies of nociceptive neuron development and signaling mechanisms (16). Prior studies showed that class IV neuron morphology is sensitive to paclitaxel and demonstrated morphological changes of nociceptive neurons at the onset and the end stage of paclitaxel-induced pathology (6, 7). Specifically, chronic treatment of high doses (30 μM) induce fragmentation and simplification of branching of sensory terminals (6). Additionally, acute treatments of moderate doses (10 to 20 μM) induced hyperbranching of sensory arbors without changing the branch patterns or degeneration (7). Nociceptive neurons in Drosophila larvae detect multiple qualities of noxious stimuli (17, 18), and project naked nerve terminals that are partially embedded in the epidermis (19, 20). Larvae have a stereotyped behavioral response toward noxious stimuli that can serve as a readout of nociceptive neuron function (17, 21). Nociceptive neurons in Drosophila larvae may therefore serve as a good in vivo model to study morphological and functional changes to sensory neurons induced by chemotherapeutics.Paclitaxel binds to tubulin and prevents microtubule disassembly. It is a commonly used chemotherapeutic drug for treatment of solid cancers, such as breast, ovarian, and lung cancers, by virtue of its ability to inhibit cell division. Paclitaxel causes chronic sensory neuropathy in patients and animal models (22–24). Several CIPN animal and in vitro models have also revealed acute effects of paclitaxel (7, 8, 24–26). While the mechanisms of acute and chronic neurodegeneration are likely to be distinct (27), how long-term treatment of paclitaxel can affect sensory neuron morphology and function, and how neuronal arbors can be protected against long-term toxicity is not understood.Several studies have shown that nociceptive sensory terminals share a close relationship with specific extracellular structures, most notably epidermal cells and the extracellular matrix (ECM). Thus, in addition to direct effects on neurons, paclitaxel could conceivably destabilize terminals by disrupting relationships with the extracellular environment. Indeed, a study in zebrafish indicates that epidermal cells are directly affected by paclitaxel and that epidermal changes precede neuronal degradation, indicating that degradation of neuronal substrates contributes to degeneration of adjacent arbors (25). For the most part, however, extracellular contributions to neuropathy induced by chemotherapeutics are still poorly characterized. It is therefore important to determine how sensory terminals are maintained in the context of a dynamic extracellular environment that itself may be sensitive to chemotherapeutics. Integrins are a key mediator of the interaction between cells and the ECM, and impact dendrite stabilization and maintenance in both vertebrate and invertebrate systems (20, 28, 29). Prior studies in other systems indicate that integrin levels at the surface are maintained by continuous recycling via tight regulation of the endosomal pathway rather than degradation and de novo synthesis (30). Decreased recycling or increased degradation could lead to depletion of the surface receptors (31, 32) responsible for arbor maintenance and, in turn, degeneration of nociceptive terminals. We therefore explored whether integrin–ECM interactions may impact sensory neuron maintenance upon paclitaxel-induced toxicity and how the endosomal–lysosomal pathway may be linked to the maintenance of sensory neurons.Here, we have used Drosophila and isolated mouse DRG neurons to investigate the pathological effect of paclitaxel in sensory neurons. Morphological changes in Drosophila neurons occurred at paclitaxel doses that also caused changes in thermal nociceptive behaviors. Cell-specific overexpression of integrins protected nociceptive neurons from morphological alterations and prevented the thermal nociceptive behavior deficits caused by paclitaxel in Drosophila. Transduction of integrins also protected adult mouse DRG sensory neurons from paclitaxel-induced toxicity in vitro, indicating that integrin-mediated protection is conserved in a vertebrate model of CIPN. We provide evidence that paclitaxel alters intracellular trafficking in both Drosophila and mouse models of CIPN. Furthermore, our biochemical analysis indicates a reduction of integrin surface availability, suggesting paclitaxel-induced recycling defects in mouse DRG neurons in vitro. Our study suggests that altered interactions between sensory neurons and their extracellular environment are an important contributor to paclitaxel-induced neuronal pathology, and that preventing these changes may offer a therapeutic approach.     

High rates of depressive symptoms among patients with systemic sclerosis are not explained by differential reporting of somatic symptoms

OBJECTIVE: Between 36% and 65% of patients with systemic sclerosis (SSc) report symptoms of depression above cutoff thresholds on self-report questionnaires. The objective of this study was to assess whether these high rates result from differential reporting of somatic symptoms related to the high physical burden of SSc. METHODS: Symptom profiles reported on the Center for Epidemiologic Studies Depression Scale (CES-D) were compared between a multicenter sample of 403 patients with SSc and a sample of respondents to an Internet depression survey, matched on total CES-D score, age, race/ethnicity, and sex. An exact nonparametric generalized Mantel-Haenszel procedure was used to identify differential item functioning between groups. RESULTS: Patients with SSc reported significantly higher frequencies (moderate to large effect size; P < 0.01) on 4 CES-D somatic symptom items: bothered, appetite, effort, and sleep. Internet respondents had higher item scores on 2 items that assessed interpersonal difficulties (unfriendly, large effect size; P < 0.01; disliked, large effect size; P < 0.01) and on 2 items that assessed lack of positive effect (happy, moderate effect size; P = 0.01; enjoy, large effect size; P < 0.01). Adjustment of standard CES-D cutoff criteria for potential bias due to somatic symptom reporting resulted in a reduction of only 3.6% in the number of SSc patients with significant symptoms of depression. CONCLUSION: High rates of depressive symptoms in SSc are not due to bias related to the report of somatic symptoms. The pattern of differential item functioning between the SSc and Internet groups, however, suggests some qualitative differences in depressive symptom presentation.     

Characterization of outer ring iodothyronine deiodinases in tissues of the saltwater crocodile (Crocodylus porosus)

The distribution and characterization of outer ring deiodination (ORD) using reverse triiodothyronine (rT3) and thyroxine (T4) as substrates is reported in microsomes of liver, kidney, lung, heart, gut, and brain tissues from juvenile saltwater crocodiles (Crocodylus porosus). In lung and heart only small amounts of rT3 ORD and T4 ORD were detected, while in brain only a small amount of T4 ORD was detected. More detailed characterization studies could be performed on liver, kidney, and gut microsomes. Reverse T3 outer ring deiodination (rT3 ORD) was the predominant activity in liver and kidney microsomes. The properties of crocodile liver and kidney rT3 ORD, such as preference for rT3 as substrate, a dithiothreitol (DTT) requirement of 10 mM, inhibition by propylthiouracil (PTU), and Michaelis-Menten (Km) constant in the micromolar range, correspond to the properties previously reported for a type I deiodinase. The temperature optimum for rT3 ORD was between 30 and 35 degrees. There was also rT3 ORD activity in gut microsomes, along with what appeared to be a type II-like, low-Km deiodinase with a substrate preference for T4. There was also a small amount of T4 ORD activity in liver and kidney microsomes. Liver T4 ORD, like a type II deiodinase, had a preference for T4 as substrate at low substrate concentrations and a DTT requirement of 15 mM and was insensitive to PTU. However, at high substrate concentrations the predominant activity was of the type I deiodinase nature. T4 ORD in liver had an optimal incubation temperature of 30 to 35 degrees. Gut microsomal T4 ORD was also type II-like at low substrate concentrations and type I-like at high substrate concentrations. Gut T4 ORD had an optimal incubation temperature of 25 to 30 degrees and a DTT requirement of 20 mM DTT. Kidney microsomal T4 ORD had the same optimal temperature and DTT requirement as that in gut microsomes; however, there was no competition by low substrate concentrations. These results suggest that ORD in juvenile saltwater crocodile kidney is most likely exclusively catalyzed by a type I-like deiodinase. Liver and gut ORD, in contrast, is catalyzed by two enzymes, with a predominance of a type I-like deiodinase in liver and a type II-like deiodinase in gut. Low-Km T3 IRD activity could not be detected in any tissues of the juvenile saltwater crocodile.     

Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women

OBJECTIVES: The objective of this study was to determine whether diastolic dysfunction is associated with increased risk of nonvalvular atrial fibrillation (NVAF) in older adults with no history of atrial arrhythmia. BACKGROUND: Few data exist regarding the relationship between diastolic function and NVAF. METHODS: The clinical and echocardiographic characteristics of patients age > or =65 years who had an echocardiogram performed between 1990 and 1998 were reviewed. Exclusion criteria were history of atrial arrhythmia, stroke, valvular or congenital heart disease, or pacemaker implantation. Patients were followed up in their medical records to the last clinical visit or death for documentation of first AF. RESULTS: Of 840 patients (39% men; mean [+/- SD] age, 75 +/- 7 years), 80 (9.5%) developed NVAF over a mean (+/- SD) follow-up of 4.1 +/- 2.7 years. Abnormal relaxation, pseudonormal, and restrictive left ventricular diastolic filling were associated with hazard ratios of 3.33 (95% confidence interval [CI], 1.5 to 7.4; p = 0.003), 4.84 (95% CI, 2.05 to 11.4; p < 0.001), and 5.26 (95% CI, 2.3 to 12.03; p < 0.001), respectively, when compared with normal diastolic function. After a number of adjustments, diastolic function profile remained incremental to history of congestive heart failure and previous myocardial infarction for prediction of NVAF. Age-adjusted Kaplan-Meier five-year risks of NVAF were 1%, 12%, 14%, and 21% for normal, abnormal relaxation, pseudonormal, and restrictive diastolic filling, respectively. CONCLUSIONS; The presence and severity of diastolic dysfunction are independently predictive of first documented NVAF in the elderly.     

Brief Report: Divergent low-density lipoprotein receptor (LDLR) linked to low VSV G-dependent viral infectivity and unique serum lipid profile in zebra finches

The low-density lipoprotein receptor (LDLR) is key to cellular cholesterol uptake and is also the main receptor for the vesicular stomatitis virus glycoprotein (VSV G). Here we show that in songbirds LDLR is highly divergent and lacks domains critical for ligand binding and cellular trafficking, inconsistent with universal structure conservation and function across vertebrates. Linked to the LDLR functional domain loss, zebra finches show inefficient infectivity by lentiviruses (LVs) pseudotyped with VSV G, which can be rescued by the expression of human LDLR. Finches also show an atypical plasma lipid distribution that relies largely on high-density lipoprotein (HDL). These findings provide insights into the genetics and evolution of viral infectivity and cholesterol transport mechanisms in vertebrates.     

Proximal improvement and higher-order resting state network change after multidomain cognitive training intervention in healthy older adults

GeroScience - Prior randomized control trials have shown that cognitive training interventions resulted in improved proximal task performance, improved functioning of activities of daily living,...