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Type I thyroplasty is widely used to improve voice production in patients affected by unilateral vocal fold paralysis. Almost two-thirds of laryngologists report using Silastic® implants to medialize the vocal fold, with implant size, shape, and location determined experientially. However, post-surgical complications arising from this procedure (extrusion, migration, resizing) necessitate revision in 4.5–16% of patients. To improve initial surgical outcomes, we have developed a subject-specific modeling tool, PhonoSim, which uses model reconstruction from MRI scans to predict the optimal implantation location. Eleven vocal fold sample sides from eight larynges of New Zealand white rabbits were randomized to two groups: PhonoSim informed (n = 6), and control (no model guidance, n = 5). Larynges were scanned ex vivo in the abducted configuration using a vertical-bore 11.7 T microimaging system, and images were used for subject-specific modeling. The PhonoSim tool simulated vocal fold adduction for multiple implant location placements to evaluate vocal fold adduction at the medial surface. The best implant placement coordinates were output for the 6 samples in the PhonoSim group. Control placements were determined by the same surgeon based on anatomical landmarks. Post-surgical MRI scans were performed for all samples to evaluate medialization in implanted vocal folds. Results show that PhonoSim-guided implantation achieved higher vocal fold medialization relative to controls (28 to 55% vs. − 29 to 39% respectively, in the glottal area reduction), suggesting that this tool has the potential to improve outcomes and revision rates for type I thyroplasty. [ABSTRACT FROM AUTHOR]

Objective: To describe levels of loneliness in cancer caregivers over a 6 month time period, and to examine factors that influence changes in loneliness in caregivers over time. Methods: Prospective, repeated measures design was utilized to examine levels of loneliness and factors that influence loneliness in 129 family caregivers of individuals undergoing cancer treatment at three time points over a 6 month period. Measures included: PROMIS global health and sleep disturbance; NIH Toolbox loneliness, self‐efficacy and perceived stress; Family Care Inventory mutuality scale; and Caregiver Reaction Assessment. Results: Approximately one third (30.2%, n = 39) of the caregivers had high levels of loneliness, and levels of loneliness did not change over the three time points (P =.985). For any given time point, caregivers who were not married (P =.008), not working (P =.027), with worse mental health (P =.015), more perceived‐stress (P <.0001), and more caregiver burden (P =.003) reported higher levels of loneliness. Conclusion: This study provides guidance for clinicians attempting to identify at‐risk caregivers by confirming the findings of previous research that caregivers with higher burden, stress and in poor mental health are at increased risk for loneliness. This study provides preliminary evidence that continuing to work during the caregiving trajectory may be beneficial to caregivers by reducing levels of loneliness. Future research is needed to confirm these findings and to examine novel interventions to reduce loneliness in cancer caregivers. [ABSTRACT FROM AUTHOR]

In the present study, we tested whether polycystic kidney disease ( PKD) is associated with renal tissue hypoxia and oxidative stress, which, in turn, contribute to the progression of cystic disease and hypertension., Lewis polycystic kidney ( LPK) rats and Lewis control (Lewis) rats were treated with tempol (1 mmol/L in drinking water) from 3 to 13 weeks of age or remained untreated., The LPK rats developed polyuria, uraemia and proteinuria. At 13 weeks of age, LPK rats had greater mean arterial pressure (1.5-fold), kidney weight (sixfold) and plasma creatinine (3.5-fold) than Lewis rats. Kidneys from LPK rats were cystic and fibrotic., Renal hypoxia was evidenced by staining for pimonidazole adducts and hypoxia-inducible factor ( HIF)-1α in cells lining renal cysts and upregulation of HIF-1α and its downstream targets vascular endothelial growth factor ( VEGF), glucose transporter-1 (Glut-1) and heme oxygenase 1 ( HO-1). However, total HO activity did not differ greatly between kidney tissue from LPK compared with Lewis rats., Renal oxidative and/or nitrosative stress was evidenced by ninefold greater immunofluorescence for 3-nitrotyrosine in kidney tissue from LPK compared with Lewis rats and a > 10-fold upregulation of mRNA for p47phox and gp91phox. Total renal superoxide dismutase (SOD) activity was sevenfold less and expression of SOD1 mRNA was 70% less in kidney tissue from LPK compared with Lewis rats. In LPK rats, tempol treatment reduced immunofluorescence for 3-nitrotyrosine and HIF1A mRNA while upregulating VEGF and p47phox mRNA expression, but otherwise had little impact on disease progression, renal tissue hypoxia or hypertension., Our findings do not support the hypothesis that oxidative stress drives hypoxia and disease progression in PKD. [ABSTRACT FROM AUTHOR]

Background: Nephronophthisis (NPHP) as a cause of cystic kidney disease is the most common genetic cause of progressive renal failure in children and young adults. NPHP is characterized by abnormal and/or loss of function of proteins associated with primary cilia. Previously, we characterized an autosomal recessive phenotype of cystic kidney disease in the Lewis Polycystic Kidney (LPK) rat. Results: In this study, quantitative trait locus analysis was used to define a ~1.6Mbp region on rat chromosome 10q25 harbouring the lpk mutation. Targeted genome capture and next-generation sequencing of this region identified a non-synonymous mutation R650C in the NIMA (never in mitosis gene a)- related kinase 8 (Nek8) gene. This is a novel Nek8 mutation that occurs within the regulator of chromosome condensation 1 (RCC1)-like region of the protein. Specifically, the R650C substitution is located within a G[QRC]LG repeat motif of the predicted seven bladed beta-propeller structure of the RCC1 domain. The rat Nek8 gene is located in a region syntenic to portions of human chromosome 17 and mouse 11. Scanning electron microscopy confirmed abnormally long cilia on LPK kidney epithelial cells, and fluorescence immunohistochemistry for Nek8 protein revealed altered cilia localisation. Conclusions: When assessed relative to other Nek8 NPHP mutations, our results indicate the whole propeller structure of the RCC1 domain is important, as the different mutations cause comparable phenotypes. This study establishes the LPK rat as a novel model system for NPHP and further consolidates the link between cystic kidney disease and cilia proteins. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus is a multi-organ autoimmune disorder associated with autoantibodies of complex diversity. Antiphospholipid antibodies (aPL), which are commonly associated with lupus, create a pro-thrombotic tendency, but are also associated with non-thrombotic neurological features. Movement disorders are rare neuropsychiatric complications of lupus and antiphospholipid syndrome, and autoimmune and thromboembolic disease mechanisms have been proposed. We describe the clinical features, investigation findings, treatment, and outcome of six paediatric participants with movement disorders associated with lupus and/or aPL (six females, median age 13y, range 8-15). To examine the autoantibody hypothesis, we used a neuronal cell line with dopaminergic characteristics and measured serum antibody binding to neuronal cell-surface antigens using flow cytometry. For comparison with the six participants, we used serum from healthy individuals ( n=12, six females, median age 11y, range 9-13) and children with other neurological diseases ( n=13, seven females, median age 7y, range 2-15). Of the six participants, two had lupus only, two had lupus with aPL, and two had aPL only. The movement disorder was chorea in four and parkinsonism in two. All four participants with chorea had aPL and movement disorder relapses. The two participants with parkinsonism did not have aPL, but had a progressive course until rituximab or plasma exchange resulted in neuropsychiatric remission. All six participants demonstrated elevated serum antibody binding to neuronal cell-surface antigens compared with healthy individuals and those with other neurological diseases. This report supports the association of chorea with aPL, but suggests a different autoimmune mechanism operates in lupus parkinsonism. The presence of antibody binding to neuronal cell-surface antigens supports a possible direct action of autoantibodies on neurons in patients with movement disorders associated with lupus and aPL. [ABSTRACT FROM AUTHOR]