Deficiency of nuclear receptor interaction protein leads to cardiomyopathy by disrupting sarcomere structure and mitochondrial respiration.

BACKGROUND: Cardiomyopathy is a common and lethal complication in patients with limb-girdle muscular dystrophy (LGMD), one of the most prevalent forms of muscular dystrophy. The pathogenesis underlying LGMD-related cardiomyopathy remains unclear. NRIP (gene name DCAF6), a Ca2+-dependent calmodulin binding protein, was reduced in dystrophic muscles from LGMD patients. Mice lacking NRIP exhibit a myopathic phenotype resembling that in LGMD patients, making NRIP deficiency a potential culprit leading to cardiomyopathy. This study aimed to determine if NRIP deficiency leads to cardiomyopathy and to explore the underlying molecular mechanisms. METHODS AND RESULTS: NRIP expression was reduced in both human and mouse failing hearts. Muscle-specific NRIP knockout (MCK-Cre::Dcaf6flox/flox) mouse heart and isolated cardiomyocytes exhibited markedly reduced contractility. Transmission electron microscopy revealed abnormal sarcomere structures and mitochondrial morphology in MCK-Cre::Dcaf6flox/flox hearts. Protein co-immunoprecipitation and confocal imaging revealed that NRIP interacts with α-actinin 2 (ACTN2) at the Z-disc. We found that NRIP facilitated ACTN2-mediated F-actin bundling, and that NRIP deficiency resulted in reduced binding between Z-disc proteins ACTN2 and Cap-Z. In addition, NRIP-deficiency led to increased mitochondrial ROS and impaired mitochondrial respiration/ATP production owing to elevated cellular NADH/NAD+ ratios. Treatment with mitochondria-directed antioxidant mitoTEMPO or NAD+ precursor nicotinic acid restored mitochondrial function and cardiac contractility in MCK-Cre::Dcaf6flox/flox mice. CONCLUSIONS: NRIP is essential to maintain sarcomere structure and mitochondrial/contractile function in cardiomyocytes. Our results revealed a novel role for NRIP deficiency in the pathogenesis of LGMD and heart failure. Targeting NRIP, therefore, could be a powerful new approach to treat myocardial dysfunction in LGMD and heart failure patients.

The learning curve for laparoscopic inguinal hernia repair: a newly qualified surgeon perspective.

BACKGROUND: The number of cases required to overcome the learning curve (LC) for laparoscopic extra-peritoneal inguinal hernia repair (TEP) varies widely in the literature. Less is known about the LC for inexperienced surgeons performing this procedure early in their career. The present study describes the technical challenges of TEP repair and the LC from the perspective of a recently qualified general surgeon. MATERIALS AND METHODS: Retrospective analysis of a single-surgeon experience of TEP repairs performed during the first 2 y of practice from 2011-2013. Patient demographics, hernia details, operative details, and postoperative outcome were all assessed. The CUSUM method was used to analyze the LC for operative time. RESULTS: There were 149 consecutive patients (mean age, 56 ± 17, 146 males, 24 bilateral, BMI 26 ± 4) followed for a median of 15 (4-26) mo. Direct herniae accounted for 61% of the cohort, and 16% were recurrent open presentations. The major complication and recurrence rate were <2%, and minor complications including urinary retention (15%) were reported. Re-admission rate was 6%. CUSUM analysis suggested an inflection point at 18 cases after which operative times were stabilized. CONCLUSIONS: For less experienced surgeons, standard surgical training provides for TEP hernia repair with satisfactory major complication, conversion, and recurrence rates. Minor complication rates can still be reduced further with further training and supervision from experienced peers.

Stem Cell-Based Delivery of Gold/Chlorin e6 Nanocomplexes for Combined Photothermal and Photodynamic Therapy.

Combining photothermal and photodynamic modalities has shown encouraging therapeutic efficacy against various malignant cancers. Developing a delivery method for targeting and penetrating tumors is still a major focus for advancing this therapeutic approach. Herein, we report a novel strategy involving the utilization of stem cells as a live carrier to codeliver photothermal and photodynamic agents for cancer therapy. To this end, a novel gold nanorod (AuNR)-PEG-PEI (APP)/chlorin e6 (Ce6)-loaded adipose-derived stem cell (ADSC) system is proposed in which AuNRs and Ce6 act as the photothermal and photodynamic agents, respectively. To integrate with stem cells, the APP/Ce6 nanocomplexes exhibit advantages of low drug leakage, low cytotoxicity, efficient cellular uptake, and redox-responsive release. After loading of APP/Ce6 nanocomplexes, the ADSCs still maintained good tumor tropism and were capable of penetrating into the tumor spheroids. The photothermal effect induced by exposure to near-infrared light irradiation at 808 nm promoted the release of Ce6 from the stem cells into the surroundings and hence increased its availability to treat cancer cells. APP/Ce6-loaded ADSCs exerted effective dose-dependent in vitro anticancer activities via anticipated photothermal and photodynamic effects. In a murine CT26 colon cancer model, APP/Ce6 delivered by ADSCs resulted in superior tumor suppression compared to other delivery strategies. It was also noted that in vivo applications of APP/Ce6-loaded ADSCs did not induce noticeable detrimental effects on normal tissues/organs.

Magnetic ternary nanohybrids for nonviral gene delivery of stem cells and applications on cancer therapy.

Cancer toxic agent-expressing mesenchymal stem cells (MSCs), which possess inherent tumor migration and penetration capabilities, have received increasing attention in cancer therapy. To ensure that this approach is successful, safe and efficient gene delivery methods for stem cell engineering must be developed. Methods: In this study, a magnetic ternary nanohybrid (MTN) system comprising biodegradable cationic materials, nucleic acids, and hyaluronic acid-decorated superparamagnetic iron oxide nanoparticles was proposed to construct stem cells expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via magnetic force and receptor dual targeting. Results: The CD44/magnetic force-mediated enhanced cellular uptake of MTNs by human mesenchymal cells (hMSCs) was confirmed in vitro. Highly efficient transfection was attained using MTNs without having any detrimental effect on the tumor migration and penetration capabilities of hMSCs. TRAIL expressed by the MTN-transfected hMSCs displayed strong anticancer effects through the activation of caspase-3 apoptotic signaling. The MTN-transfected hMSCs can be clearly imaged using magnetic resonance imaging techniques in vivo. In an orthotopic xenograft cancer model, MTN-transfected TRAIL-expressing hMSCs significantly suppressed the progression of human glioma (U87MG) and prolonged the survival of the animal. Conclusions: These findings suggest the considerable potential of utilizing MTNs for effectively constructing tumor toxic agent-expressing stem cells for treating malignant cancers.

Multifunctional PEGylated Albumin/IR780/Iron Oxide Nanocomplexes for Cancer Photothermal Therapy and MR Imaging.

A multifunctional albumin/superparamagnetic iron oxide nanoparticle (SPIO) nanocomplex system to deliver IR780, a photothermal agent, for cancer theranostic applications was proposed in this study. Single emulsion method was utilized to fabricate the human albumin/IR780/SPIO (HISP) nanocomplexes with a hydrophobic core (SPIO and IR780) and a hydrophilic shell (human serum albumin (HSA) and poly (ethylene glycol) (PEG)). Effects of PEGylation on the size and surface potential of nanocomplexes were analyzed. Nanospheres containing uniformly dispersed SPIO was observed using Transmission Electron Microscopy (TEM) imaging. As a potential magnetic resonance (MR) imaging agent, the HISP displayed dose-dependent T2-weighted imaging contrast (R2 = 81.6 mM-1s-1). Good colloidal stability was verified from the nanocomplexes under difference circumstances. The nanocomplexes were taken up by cancer cells efficiently and led to significant photothermal-mediated cancer cell death upon short-term near infrared (NIR) irradiation in vitro. Via intravenous injection, PEG-HISP can efficiently deliver IR780 to tumor sites and showed strong photothermal effect compared to free drug on the mice model. Significant tumor suppression by the photothermal treatments using PEG-HISP was demonstrated from the mice CT26 xenograft model. Good safety profile of the PEG-HISP was confirmed from histological examination and liver functional analysis. Taken together, the results suggest that PEG-HISP is a safe and robust nano-theranostic platform for advanced anti-cancer treatment.

Recruiting older people for research through general practice: the Brief Risk Identification Geriatric Health Tool trial.

AIM: To describe successful methods of recruitment and identify practice characteristics related to increased recruitment of older people for a randomised controlled trial. METHODS: General practices in three regions of New Zealand and community-dwelling patients aged 75+ were recruited for the Brief Risk Identification Geriatric Health Tool trial. General practitioners (GPs) were faxed invitations with telephone follow-up. Reply-paid cards with telephone follow-up were used to invite older people. GP and practice characteristics were examined in relationship to recruitment rate. RESULTS: During 2007-2008, 158 of 438 GPs (36%) in 60 of 116 practices approached (52%) were recruited. Regional variation was marked and 3893 of 8308 invited (49%) older people were recruited. The GP's length of time at the practice and training in New Zealand was associated with recruitment success. CONCLUSIONS: Despite variability in practice recruitment, a reasonably large and representative sample of older people was recruited through general practices.

Validation of quality of life and functional measures for older people for telephone administration.

INTRODUCTION: Quality of life (QoL) and functional status are important aspects of health especially for older people. Efficient and valid ways of measuring older people's health is of great importance. AIM: This project aims to establish the reliability of use of (1) a quality of life measure, the WHOQOL-BREF, and (2) a functional measure, the Nottingham Extended Activities of Daily Living scale (NEADL), for use over the telephone. METHODS: With ethical approval, patients over age 75 years (65 years if Maori) have been enrolled in the BRIGHT trial; a randomised controlled trial testing a practice-based screening initiative to prevent disability. Participants with possible disability, defined as being unable to get in and out of the car or take hot drinks from one room to another, completed a telephone interview including the two measures. Seventy participants repeated the two measures during a face-to-face interview within three months. RESULTS: Both WHOQOL-BREF and NEADL scores for the two forms of administration produced high Pearson correlation coefficients. There was good agreement for the WHOQOL-BREF as shown by th Bland-Altman graphs; however there was a tendency of a greater negative difference the greater the average score became (higher level of function) for the NEADL. DISCUSSION: This study shows that telephone interviews can generally provide a valid method to assess the quality of life and function in older people.