Genome Editing Technology, CRISPR Cas-9, Provides a Potential Future for Xenotransplantation: Can Pigs Become Our New Organ Donors?

Organ shortage has been a significant issue in United States for many decades. There were over 116,000 people on the transplant waiting list as of August 2017, with a new person added every 10 minutes. Animals have been considered as potential organ donors for humans, with the pig being the most ideal candidate because of its excellent breeding profile, low maintenance costs, large litters, rapid growth and organ similarity. A notable challenge that comes with porcine organs are endogenous retroviruses that establish themselves in the DNA of offspring in utero, thereby allowing for no time to prevent infection and integration. Porcine endogenous retroviruses (PERVs) have the ability to infect human cells and therefore must be removed or inactivated before considering transplantation. Genome editing technology, CRISPR-cas9, has been recently successful in targeting and inactivating PERVs in porcine fetal cell lines. Using PERVinactivated cells, reproductive technologies have allowed for fertilization, implantation and the successful birth of 37 PERV-inactivated piglets from 17 sows. At this time, 15 piglets remain alive with the oldest piglet being 4 months of age. The success of this technology takes us one step closer to finding potential organ donors outside of our own species and instilling hope back into those who may need an organ transplant in the future

Functional impairment of reading in patients with dry eye

BACKGROUND/AIMS: To evaluate the impact of dry eye on reading performance. METHODS: Out-loud and silent reading in patients with clinically significant dry eye (n=41) and controls (n=50) was evaluated using standardised texts. Dry eye measures included tear film break-up time, Schirmer's test and corneal epithelial staining. Symptoms were assessed by the Ocular Surface Disease Index (OSDI). RESULTS: The dry eye group had a greater proportion of women as compared with the control group but did not differ in age, race, education level or visual acuity (p≥0.05 for all). Out-loud reading speed averaged 148 words per minute (wpm) in dry eye subjects and 163 wpm in controls (p=0.006). Prolonged silent reading speed averaged 199 wpm in dry eye subjects versus 226 wpm in controls (p=0.03). In multivariable regression models, out-loud and sustained silent reading speeds were 10 wpm (95% CI −20 to −1 wpm, p=0.039) and 14% (95% CI −25% to −2%, p=0.032) slower, respectively, in dry eye subjects as compared with controls. Greater corneal staining was associated with slower out-loud (−2 wpm/1 unit increase in staining score, 95% CI =−3 to −0.3 wpm) and silent (−2%, 95% CI −4 to −0.6 wpm) reading speeds (p<0.02 for both). Significant interactions were found between OSDI score and word-specific features (longer and less commonly used words) on out-loud reading speed (p<0.05 for both). CONCLUSIONS: Dry eye is associated with slower out-loud and silent reading speeds, providing direct evidence regarding the functional impact of dry eye. Reading speed represents a measurable clinical finding that correlates directly with dry eye severity

International Public Health Research Involving Interpreters: a Case Study from Bangladesh

Background: Cross-cultural and international research are important components of public health research, but the challenges of language barriers and working with interpreters are often overlooked, particularly in the case of qualitative research. Methods: A case-study approach was used to explore experiences of working with an interpreter in Bangladesh as part of a research project investigating women's experiences of emergency obstetric care. The case study: Data from the researcher's field notes provided evidence of experiences in working with an interpreter and show how the model of interviewing was adapted over time to give a more active role to the interpreter. The advantages of a more active role were increased rapport and "flow" in interviews. The disadvantages included reduced control from the researcher's perspective. Some tensions between the researcher and interpreter remained hard to overcome, irrespective of the model used. Independent transcription and translation of the interviews also raised questions around accuracy in translation. Conclusion: The issues examined in this case study have broader implications for public health research. Further work is needed in three areas: 1) developing effective relationships with interpreters; 2) the impact of the interpreter on the research process; and 3) the accuracy of the translation and level of analysis needed in any specific public health research. Finally, this paper highlights the importance to authors of reflecting on the potential impact of translation and interpretation on the research process when disseminating their research

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Low-frequency vibratory exercise reduces the risk of bone fracture more than walking: a randomized controlled trial

BACKGROUND: Whole-body vibration (WBV) is a new type of exercise that has been increasingly tested for the ability to prevent bone fractures and osteoporosis in frail people. There are two currently marketed vibrating plates: a) the whole plate oscillates up and down; b) reciprocating vertical displacements on the left and right side of a fulcrum, increasing the lateral accelerations. A few studies have shown recently the effectiveness of the up-and-down plate for increasing Bone Mineral Density (BMD) and balance; but the effectiveness of the reciprocating plate technique remains mainly unknown. The aim was to compare the effects of WBV using a reciprocating platform at frequencies lower than 20 Hz and a walking-based exercise programme on BMD and balance in post-menopausal women. METHODS: Twenty-eight physically untrained post-menopausal women were assigned at random to a WBV group or a Walking group. Both experimental programmes consisted of 3 sessions per week for 8 months. Each vibratory session included 6 bouts of 1 min (12.6 Hz in frequency and 3 cm in amplitude with 60° of knee flexion) with 1 min rest between bouts. Each walking session was 55 minutes of walking and 5 minutes of stretching. Hip and lumbar BMD (g·cm(-2)) were measured using dual-energy X-ray absorptiometry and balance was assessed by the blind flamingo test. ANOVA for repeated measurements was adjusted by baseline data, weight and age. RESULTS: After 8 months, BMD at the femoral neck in the WBV group was increased by 4.3% (P = 0.011) compared to the Walking group. In contrast, the BMD at the lumbar spine was unaltered in both groups. Balance was improved in the WBV group (29%) but not in the Walking group. CONCLUSION: The 8-month course of vibratory exercise using a reciprocating plate is feasible and is more effective than walking to improve two major determinants of bone fractures: hip BMD and balance

Malignant neuroectodermal tumor with melanocytic and rhabdomyoblastic differentiation

Malignant melanoma can metastasize widely and vary significantly in its histological appearance; it rarely presents as a deep-seated mass without an obvious primary site elsewhere. Malignant peripheral nerve sheath tumor (MPNST) is a high-grade sarcoma characterized by conventional and epithelioid subtypes. MPNST can demonstrate heterologous differentiation, usually in the form of osteosarcomatous, chondrosarcomatous, or rhabdomyosarcomatous differentiation. MPNST does not harbor true melanocytic differentiation, although epithelioid MPNST typically is diffusely S-100 protein positive and superficially can resemble malignant melanoma. An unusual intra-abdominal mass was recently encountered with features of both melanoma and conventional or epithelioid MPNST containing a fascicular spindle cell component, an epithelioid component with melanocytic differentiation, as well as a rhabdomyosarcomatous component. The terminology “malignant neuroectodermal tumor with melanocytic and rhabdomyoblastic differentiation” is proposed to describe this neoplasm, reflecting the unusual concomittant lines of differentiation as well as offering a possible rationale for nosologically challenging aspects of this neoplasm

High-Frequency, Low-Magnitude Vibration Does Not Prevent Bone Loss Resulting from Muscle Disuse in Mice following Botulinum Toxin Injection

High-frequency, low-magnitude vibration enhances bone formation ostensibly by mimicking normal postural muscle activity. We tested this hypothesis by examining whether daily exposure to low-magnitude vibration (VIB) would maintain bone in a muscle disuse model with botulinum toxin type A (BTX). Female 16–18 wk old BALB/c mice (N = 36) were assigned to BTX-VIB, BTX-SHAM, VIB, or SHAM. BTX mice were injected with BTX (20 µL; 1 U/100 g body mass) into the left hindlimb posterior musculature. All mice were anaesthetized for 20 min/d, 5 d/wk, for 3 wk, and the left leg mounted to a holder. Through the holder, VIB mice received 45 Hz, ±0.6 g sinusoidal acceleration without weight bearing. SHAM mice received no vibration. At baseline and 3 wk, muscle cross-sectional area (MCSA) and tibial bone properties (epiphysis, metaphysis and diaphysis) were assessed by in vivo micro-CT. Bone volume fraction in the metaphysis decreased 12±9% and 7±6% in BTX-VIB and BTX-SHAM, but increased in the VIB and SHAM. There were no differences in dynamic histomorphometry outcomes between BTX-VIB and BTX nor between VIB and SHAM. Thus, vibration did not prevent bone loss induced by a rapid decline in muscle activity nor produce an anabolic effect in normal mice. The daily loading duration was shorter than would be expected from postural muscle activity, and may have been insufficient to prevent bone loss. Based on the approach used in this study, vibration does not prevent bone loss in the absence of muscle activity induced by BTX

Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress

Acknowledgments We thank Alexander Johnson (yhb1D/D), Karl Kuchler (sodD/D mutants), Janet Quinn (hog1D/D, hog1/cap1D/D, trx1D/D) and Peter Staib (ssu1D/D) for providing mutant strains. We acknowledge helpful discussions with our colleagues from the Microbial Pathogenicity Mechanisms Department, Fungal Septomics and the Microbial Biochemistry and Physiology Research Group at the Hans Kno¨ll Institute (HKI), specially Ilse D. Jacobsen, Duncan Wilson, Sascha Brunke, Lydia Kasper, Franziska Gerwien, Sea´na Duggan, Katrin Haupt, Kerstin Hu¨nniger, and Matthias Brock, as well as from our partners in the FINSysB Network. Author Contributions Conceived and designed the experiments: PM HW IMB AJPB OK BH. Performed the experiments: PM CD HW. Analyzed the data: PM HW IMB AJPB OK BH. Wrote the paper: PM HW OK AJPB BH.Peer reviewedPublisher PD

A new implicit review instrument for measuring quality of care delivered to pediatric patients in the emergency department

BackgroundThere are few outcomes experienced by children receiving care in the Emergency Department (ED) that are amenable to measuring for the purposes of assessing of quality of care. The purpose of this study was to develop, test, and validate a new implicit review instrument that measures quality of care delivered to children in EDs.MethodsWe developed a 7-point structured implicit review instrument that encompasses four aspects of care, including the physician's initial data gathering, integration of information and development of appropriate diagnoses; initial treatment plan and orders; and plan for disposition and follow-up. Two pediatric emergency medicine physicians applied the 5-item instrument to children presenting in the highest triage category to four rural EDs, and we assessed the reliability of the average summary scores (possible range of 5-35) across the two reviewers using standard measures. We also validated the instrument by comparing this mean summary score between those with and without medication errors (ascertained independently by two pharmacists) using a two-sample t-test.ResultsWe reviewed the medical records of 178 pediatric patients for the study. The mean and median summary score for this cohort of patients were 27.4 and 28.5, respectively. Internal consistency was high (Cronbach's alpha of 0.92 and 0.89). All items showed a significant (p &lt; 0.005) positive correlation between reviewers using the Spearman rank correlation (range 0.24 to 0.39). Exact agreement on individual items between reviewers ranged from 70.2% to 85.4%. The Intra-class Correlation Coefficient for the mean of the total summary score across the two reviewers was 0.65. The validity of the instrument was supported by the finding of a higher score for children without medication errors compared to those with medication errors which trended toward significance (mean score = 28.5 vs. 26.0, p = 0.076).ConclusionThe instrument we developed to measure quality of care provided to children in the ED has high internal consistency, fair to good inter-rater reliability and inter-rater correlation, and high content validity. The validity of the instrument is supported by the fact that the instrument's average summary score was lower in the presence of medication errors, which trended towards statistical significance