The Turkish delight: a pliable graft for rhinoplasty.
In nose surgery, carved or crushed cartilage used as a graft has some disadvantages, chiefly that it may be perceptible through the nasal skin after tissue resolution is complete. To overcome these problems and to obtain a smoother surface, the authors initiated the use of Surgicel-wrapped diced cartilage. This innovative technique has been used by the authors on 2365 patients over the past 10 years: in 165 patients with traumatic nasal deformity, in 350 patients with postrhinoplasty deformity, and in 1850 patients during primary rhinoplasty. The highlights of the surgical procedure include harvested cartilage (septal, alar, conchal, and sometimes costal) cut in pieces of 0.5 to 1 mm using a no. 11 blade. The fine-textured cartilage mass is then wrapped in one layer of Surgicel and moistened with an antibiotic (rifamycin). The graft is then molded into a cylindrical form and inserted under the dorsal nasal skin. In the lateral wall and tip of the nose, some overcorrection is performed depending on the type of deformity. When the mucosal stitching is complete, this graft can be externally molded, like plasticine, under the dorsal skin. In cases of mild-to-moderate nasal depression, septal and conchal cartilages are used in the same manner to augment the nasal dorsum with consistently effective and durable results. In cases with more severe defects of the nose, costal cartilage is necessary to correct both the length of the nose and the projection of the columella. In patients with recurrent deviation of the nasal bridge, this technique provided a simple solution to the problem. After overexcision of the dorsal part of deviated septal cartilage and insertion of Surgicel-wrapped diced cartilage, a straight nose was obtained in all patients with no recurrence (follow-up of 1 to 10 years). The technique also proved to be highly effective in primary rhinoplasties to camouflage bone irregularities after hump removal in patients with thin nasal skin and/or in cases when excessive hump removal was performed. As a complication, in six patients early postoperative swelling was more than usual. In 16 patients, overcorrection was persistent owing to fibrosis, and in 11 patients resorption was excessive beyond the expected amount. A histologic evaluation was possible in 16 patients, 3, 6, and 12 months postoperatively, by removing thin slices of excess cartilage from the dorsum of the nose during touch-up surgery. This graft showed a mosaic-type alignment of graft cartilage with fibrous tissue connection among the fragments. In conclusion, this type of graft is very easy to apply, because a plasticine-like material is obtained that can be molded with the fingers, giving a smooth surface with desirable form and long-lasting results in all cases. The favorable results obtained by this technique have led the authors to use Surgicel-wrapped diced cartilage routinely in all types of rhinoplasty.


Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility.
Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.


Evidence for the existence of substance P in the prepubertal rat ovary. I. Biochemical and physiologic studies.
The presence of substance P (SP) in the immature rat ovary was determined by radioimmunoassay (RIA) of acidic extracts. The extracts produced an inhibition-displacement curve of 125I-SP binding parallel to that generated by authentic SP in the SP RIA. Initial chromatographic characterization of ovarian SP in Sephadex G-25 revealed the presence of a molecular form that coeluted with authentic SP and a more abundant component that eluted earlier, suggesting the presence of a heavier peptide, immunologically similar to SP. Nevertheless, further characterization of these two seemingly different components by reversed-phase high-performance liquid chromatography (HPLC) demonstrated that both of them had a retention time similar to that of authentic SP. The ovarian concentration of SP-like immunoreactivity (SP-LI) varied in relation to the onset of puberty, with values increasing significantly between the late juvenile phase and the day of first proestrus. Substance P seems to be devoid of steroidogenic capacity since SP itself and its stable analog [pGlu5,MePhe8,Sar9]-SP5-11 (SP-A) failed to stimulate steroid secretion from either granulosa cells in culture or ovarian fragments in short-term incubation. Substance P also failed to stimulate prostaglandin E2 release from whole ovaries and to modify the steroidal response of cultured granulosa cells to follicle-stimulating hormone and to the beta 2-adrenergic agonist Zinterol. Production of SP-LI from granulosa cells in culture could not be detected under either basal or gonadotropin-stimulated conditions. These observations and the distribution of the peptide within the ovary presented in the companion paper (Dees et al., this issue) strongly suggest that SP is not directly involved in regulating steroidogenesis. Instead, SP may be a component of the so-called sensory innervation of the ovary, and among other undisclosed functions it may contribute to the regulation of ovarian blood flow.


Parasitic inhibition of cell death facilitates symbiosis.
Symbiotic microorganisms have had a large impact on eukaryotic evolution, with effects ranging from parasitic to mutualistic. Mitochondria and chloroplasts are prime examples of symbiotic microorganisms that have become obligate for their hosts, allowing for a dramatic extension of suitable habitats for life. Out of the extraordinary diversity of bacterial endosymbionts in insects, most are facultative for their hosts, such as the ubiquitous Wolbachia, which manipulates host reproduction. Some endosymbionts, however, have become obligatory for host reproduction and/or survival. In the parasitoid wasp Asobara tabida the presence of Wolbachia is necessary for host oogenesis, but the mechanism involved is yet unknown. We show that Wolbachia influences programmed cell death processes (a host regulatory feature typically targeted by pathogens) in A. tabida, making its presence essential for the wasps' oocytes to mature. This suggests that parasite strategies, such as bacterial regulation of host apoptosis, can drive the evolution of host dependence, allowing for a swift transition from parasitism to mutualism.


Asymmetrical effect of levodopa on the neural activity of motor regions in PD.
Parkinson's disease (PD) is a neurodegenerative illness often characterized by asymmetrical symptoms. However, the reason for this asymmetry and the cerebral correlates underlying symptom asymmetry are still not well understood. Furthermore, the effects of levodopa on the cerebral correlates of disease asymmetry have not been investigated. In this study, right-handed PD patients performed self-initiated, externally triggered and repetitive control finger movements with both their right and left hands during functional magnetic resonance imaging (fMRI) to investigate asymmetrical effects of levodopa on the hemodynamic correlates of finger movements. Patients completed two experimental sessions OFF and ON medication after a minimum of 12 hours medication withdrawal. We compared the effect of levodopa on the neural activation patterns underlying the execution of both the more affected and less affected hand for self-initiated and externally triggered movements. Our results show that levodopa led to larger differences in cerebral activity for movements of the more affected, left side: there were significant differences in activity after levodopa administration in regions of the motor cortico-striatal network when patients performed self-initiated and externally triggered movements with their left hand. By contrast, when patients used their right hand, levodopa led to differences in cerebellar activity only. As our patients were affected more severely on their left side, we propose that levodopa may help provide additional dopaminergic input, improving movements for the more severely affected side. These results suggest that the impact of reduced dopamine in the cortico-striatal system and the action of levodopa is not symmetrical.


Detectability of supernova neutrinos with an existing proton decay detector.
The 8000-ton water IMB nucleon decay detector has good sensitivity to the neutrino burst associated with the collapse of stars. It is particularly sensitive to the v(e) charged current interactions with protons but can also record other neutrino interactions through ve scattering. Signal, noise, physics objectives, and detector modifications that would enhance burst detection are discussed. The objectives include astrophysical questions about the pulse structure and power. It also may be possible with a distant source to study neutrino masses and neutrino oscillations.


Melatonin and the skeleton.
Melatonin may affect bone metabolism through bone anabolic as well as antiresorptive effects. An age-related decrease in peak melatonin levels at nighttime is well documented, which may increase bone resorption and bone loss in the elderly. In vitro, melatonin reduces oxidative stress on bone cells by acting as an antioxidant. Furthermore, melatonin improves bone formation by promoting differentiation of human mesenchymal stem cell (hMSC) into the osteoblastic cell linage. Bone resorption is reduced by increased synthesis of osteoprogeterin (OPG), a decoy receptor that prevents receptor activator of NK-κB ligand (RANKL) in binding to its receptor. Moreover, melatonin is believed to reduce the synthesis of RANKL preventing further bone resorption. In ovariectomized as well as nonovariectomized rodents, melatonin has shown beneficial effects on bone as assessed by biochemical bone turnover markers, DXA, and μCT scans. Furthermore, in pinealectomized animals, bone mineral density (BMD) is significantly decreased compared to controls, supporting the importance of sufficient melatonin levels. In humans, dysfunction of the melatonin signaling pathway may be involved in idiopathic scoliosis, and the increased fracture risk in nighttime workers may be related to changes in the circadian rhythm of melatonin. In the so-far only randomized study on melatonin treatment, no effects were, however, found on bone turnover markers. In conclusion, melatonin may have beneficial effects on the skeleton, but more studies on humans are warranted in order to find out whether supplementation with melatonin at bedtime may preserve bone mass and improve bone biomechanical competence.


Patient whiteboards to improve patient-centred care in the hospital.
Patient whiteboards facilitate communication between patients and hospital providers, but little is known about their impact on patient satisfaction and awareness. Our objectives were to: measure the impact in improving patients' understanding of and satisfaction with care; understand barriers for their use by physicians and how these could be overcome; and explore their impact on staff and patients' families. In 2012, we conducted a 3-week pilot of multidisciplinary whiteboard use with 104 inpatients on the general medicine service at Stanford University Medical Center. A brief, inperson survey was conducted with two groups: (1) 56 patients on two inpatient units with whiteboards and (2) 48 patients on two inpatient units without whiteboards. Questions included understanding of: physician name, goals of care, discharge date and satisfaction with care. We surveyed 25 internal medicine residents regarding challenges of whiteboard use, along with physical therapists, occupational therapists, case managers, consulting physicians and patients' family members (n=40). The use of whiteboards significantly increased the proportion of patients who knew: their physician (p≤=0.0001), goals for admission (p≤=0.0016), their estimated discharge date (p≤=0.049) and improved satisfaction with the hospital stay overall (p≤=0.0242). Physicians, ancillary staff and patient families all found the whiteboards to be helpful. In response, residents were also more likely to integrate whiteboard use into their daily work flow. Inpatient whiteboards help physicians and ancillary staff with communication, improve patients' awareness of their care team, admission plans and duration of admission, and significantly improve patient overall satisfaction.


Long-term maintenance of mouse embryonic stem cell pluripotency by manipulating integrin signaling within 3D scaffolds without active Stat3.
We engineered an acellular biomimetic microenvironment to regulate stem cell fate and applied it to maintain mouse embryonic stem (ES) cell self-renewal. In the 3D environment formed using hydrogel scaffolds in which specific integrin ligation was provided, Stat3 activation by exogenous leukemia inhibitory factor (LIF) no longer acted as a limiting factor for stem cell self-renewal. Instead, simultaneous stimulation of integrins α(5)β(1), α(v)β(5), α(6)β(1) and α(9)β(1) within the 3D scaffold greatly increased Akt1 and Smad 1/5/8 activation, which resulted in prolonged self-renewal of the ES cells. The ES cells exposed to the combined stimulation of the integrins for 4 wk in LIF-free 3D scaffolds maintained the spherical morphology of cell colonies without losing any activity of pluripotency. In conclusion, cell niche-specific integrin signaling within the 3D environment supported mouse ES cell self-renewal, and the resulting integrin signaling replaced Stat3 with Akt1 and Smad 1/5/8 as critical signals for mouse ES cell self-renewal.


Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions.
Autologous platelet rich plasma (PRP) is used increasingly in a variety of settings. PRP injections have been used for decades to improve angiogenesis and wound healing. They have also been offered commercially in urology with little to no data on safety or efficacy. PRP could theoretically improve multiple urologic conditions, such as erectile dysfunction (ED), Peyronie's disease (PD), and stress urinary incontinence (SUI). A concern with PRP, however, is early washout, a situation potentially avoided by conversion to platelet rich fibrin matrix (PRFM). Before clinical trials can be performed, safety analysis is desirable. We reviewed an initial series of patients receiving PRFM for urologic pathology to assess safety and feasibility. Data were reviewed for patients treated with PRFM at our center from November 2012 to July 2017. Patients were observed immediately post-injection and at follow-up for complications and tolerability. Where applicable, International Index of Erectile Function (IIEF-5) scores were reviewed before and after injections for ED and/or PD. Pad use data was collected pre/post injection for SUI. Seventeen patients were identified, with a mean receipt of 2.1 injections per patient. Post-procedural minor adverse events were seen in 3 men, consisting of mild pain at injection site and mild penile bruising. No patients experienced complications at follow-up. No decline was observed in men completing pre/post IIEF-5 evaluations. PRFM appears to be a safe and feasible treatment modality in patients with urologic disease. Further placebo-controlled trials are warranted.


Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer.
This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.


Treatment of maple syrup urine disease with high flow hemodialysis in a neonate.
Aygün F, Kıykım E, Aktuğlu-Zeybek Ç, Zubarioğlu T, Cam H. Treatment of maple syrup urine disease with high flow hemodialysis in a neonate. Turk J Pediatr 2019; 61: 107-110. Continious renal replacement therapy (CRRT) is a well recognizied treatment of choice in acute renal failure, however CRRT became a preferred treatment of metabolic emergencies with high leucine and ammonia levels like Maple syrup urine disease (MSUD). MSUD is a rare metabolic disorder caused by deficiency in the activity of the branched-chain a-ketoacid dehydrogenase complex. The toxic accumulation of branched chain amino acids during acute metabolic decompensation is associated with the appearance of permanent neurological symptoms. Four patients were admitted to our pediatric intensive care department with complains of poor feeding, vomitting, irratibility and coma. Physical examination of the neonates were similar having stupor, hypotonia and depressed newborn reflexes. The leucine levels were between 930-4400 μmol/L. The diagnosis of MSUD was confirmed in all four. They were treated successfully with high flow CRRT having the rates were between 4120 ml/h/1.73m2 and 9830 ml/h/1.73m2. Early treatment is essential to prevent neurotoxicity and death. CRRT is a choice of treatment in metabolic crisis of MSUD. Herein, we report the successful treatment of acute metabolic decompensation of MSUD with CRRT in 4 neonates.


A Brief History of Simulation Neuroscience.
Our knowledge of the brain has evolved over millennia in philosophical, experimental and theoretical phases. We suggest that the next phase is simulation neuroscience. The main drivers of simulation neuroscience are big data generated at multiple levels of brain organization and the need to integrate these data to trace the causal chain of interactions within and across all these levels. Simulation neuroscience is currently the only methodology for systematically approaching the multiscale brain. In this review, we attempt to reconstruct the deep historical paths leading to simulation neuroscience, from the first observations of the nerve cell to modern efforts to digitally reconstruct and simulate the brain. Neuroscience began with the identification of the neuron as the fundamental unit of brain structure and function and has evolved towards understanding the role of each cell type in the brain, how brain cells are connected to each other, and how the seemingly infinite networks they form give rise to the vast diversity of brain functions. Neuronal mapping is evolving from subjective descriptions of cell types towards objective classes, subclasses and types. Connectivity mapping is evolving from loose topographic maps between brain regions towards dense anatomical and physiological maps of connections between individual genetically distinct neurons. Functional mapping is evolving from psychological and behavioral stereotypes towards a map of behaviors emerging from structural and functional connectomes. We show how industrialization of neuroscience and the resulting large disconnected datasets are generating demand for integrative neuroscience, how the scale of neuronal and connectivity maps is driving digital atlasing and digital reconstruction to piece together the multiple levels of brain organization, and how the complexity of the interactions between molecules, neurons, microcircuits and brain regions is driving brain simulation to understand the interactions in the multiscale brain.


Functional characteristics of two human MATE transporters: kinetics of cimetidine transport and profiles of inhibition by various compounds.
Human multidrug and toxin extrusion protein 1 (hMATE1) and hMATE2-K are organic cation/H+ antiporters that have recently been identified and suggested to be involved in the renal brush border secretion of various organic cations. Information about functional characteristics of them has been accumulating, but still insufficient to fully understand their functions and respective roles. The present study was conducted to help clarify them. The cDNA of hMATE1 was isolated from human brain cDNA by RT-PCR and hMATE2-K cDNA was from human kidney cDNA. HEK293 cells were stably transfected with hMATE1 and hMATE2-K, and the cellular uptakes of [3H]cimetidine and [14C]tetraethylammonium (TEA) were evaluated. It was first found that both hMATE1 and hMATE2-K can transport cimetidine with high affinities, indicated by small Michaelis constants of 8.00 mM and 18.18 mM, respectively. These were much smaller than those for TEA (366 mM and 375 mM, respectively, for hMATE1 and hMATE2-K). Subsequent investigation using cimetidine as a probe substrate into the profiles of inhibition of the two hMATEs by various compounds indicated that they are similar in principle but different to some extent in substrate recognition, reflecting the modest differences in amino acid sequences between them. In fact, cimetidine transport by hMATE1 was correlated to that by hMATE2-K, which is 65% similar to hMATE1, but not as good as to that by rat MATE1, which is 86% similar. Cimetidine was demonstrated to be a high affinity substrate of both hMATEs. Subsequent evaluation of the inhibition of hMATEs by various compounds indicated no major difference in function or role between hMATE1 and hMATE2-K.


Relationship between echocardiogram and physical parameters in experienced resistance trainers: a pilot study.
A paucity of research exists concerning physiological factors influencing heart structure and function in strength athletes. This pilot study investigated whether body composition and muscle performance are associated with indices of cardiac structure and function in experienced resistance trainers. A cross-sectional study designed was employed to address the study aim. Seventeen males (median age 33.0 years) and eight females (median age 32.5 years) with backgrounds in bodybuilding and powerlifting participated in this study. Muscle performance, body composition and echocardiographic measures were performed. Mann-Whitney U-tests were used to examine differences between males and females. Spearman's Rho partial correlation analyses (adjusting for sex) were conducted to examine relationships between physical and echocardiogram parameters. Moderate to strong positive correlations were found between fat-free mass and aortic root, right ventricular internal dimension, interventricular septum thickness, left ventricular posterior wall thickness, left atrium area, left ventricular end-diastolic volume, and left ventricular end-systolic volume (r: 0.43-0.76, P≤0.03). Moderate to strong positive correlations were found between leg press 1RM and aortic root, left ventricular internal dimension diastole, left atrium area, left ventricular end-diastolic volume, and left ventricular end-systolic volume (r: 0.49-0.67, P≤0.02). Resistance trainers with greater fat-free mass and lower body strength appear to have larger cardiac structures. Changes in heart size and function are likely to result from long-term strenuous resistance training. Due to the suspected prevalence of performance enhancing drug use among powerlifters and bodybuilders, care is required to rule out pathological conditions.


Whole genome comparative analysis of channel catfish (Ictalurus punctatus) with four model fish species.
Comparative mapping is a powerful tool to study evolution of genomes. It allows transfer of genome information from the well-studied model species to non-model species. Catfish is an economically important aquaculture species in United States. A large amount of genome resources have been developed from catfish including genetic linkage maps, physical maps, BAC end sequences (BES), integrated linkage and physical maps using BES-derived markers, physical map contig-specific sequences, and draft genome sequences. Application of such genome resources should allow comparative analysis at the genome scale with several other model fish species. In this study, we conducted whole genome comparative analysis between channel catfish and four model fish species with fully sequenced genomes, zebrafish, medaka, stickleback and Tetraodon. A total of 517 Mb draft genome sequences of catfish were anchored to its genetic linkage map, which accounted for 62% of the total draft genome sequences. Based on the location of homologous genes, homologous chromosomes were determined among catfish and the four model fish species. A large number of conserved syntenic blocks were identified. Analysis of the syntenic relationships between catfish and the four model fishes supported that the catfish genome is most similar to the genome of zebrafish. The organization of the catfish genome is similar to that of the four teleost species, zebrafish, medaka, stickleback, and Tetraodon such that homologous chromosomes can be identified. Within each chromosome, extended syntenic blocks were evident, but the conserved syntenies at the chromosome level involve extensive inter-chromosomal and intra-chromosomal rearrangements. This whole genome comparative map should facilitate the whole genome assembly and annotation in catfish, and will be useful for genomic studies of various other fish species.


Naked mole rats activate neuroprotective proteins during hypoxia.
Naked mole rats are a long-lived animal model that age much like humans, but that can also withstand oxidative damage, cancer, neurodegenerative diseases, and severe hypoxic conditions, which is of particular interest to this study. The conditions of their underground burrows result in competition for oxygen consumption, yet despite this oxygen deprivation they emerge unscathed. To understand the mechanisms in place to facilitate neuronal preservation during hypoxia, we investigated the protein levels of well-known cell-stress factors. We found that under hypoxic conditions, nearly half of the proteins measured increased expression in brain, while only a few decreased. Under hypoxic conditions there appeared to be a HIF1α-centered response, where HIF1α and its interactors carbonic anhydrase 9, CITED2, p21/CIP1, and NFκB1, among others, were upregulated. Concurrently, a hypoxia-induced decrease of cytochrome c was consistent with decreased mitochondrial function and protection from apoptosis. The picture that emerges is one of neuroprotection, cell-cycle arrest, and the promotion of antiapoptotic functions, all of which are consistent with conserving energy and maintaining neural integrity under low oxygen levels. These results suggest how this species may be poised to face hypoxia and contribute to its remarkable ability to deal with myriad of other damaging factors and sets the stage for future work on the neuroprotective facilitators we identified.


Self-care of patient and caregiver DyAds in multiple chronic conditions: A LongITudinal studY (SODALITY) protocol.
To describe a research protocol for a study designed to examine self-care in patient and caregiver dyads in coping with multiple chronic conditions, to evaluate the influence of dyad self-care on: (a) patient mortality, quality of life, hospital admissions, and the unplanned access of care; and (b) the positive aspects of caregiving. The specific conceptual framework that we developed for this study considers the predictors of self-care (at patient, caregiver, and dyadic levels), the process of self-care and the outcomes of self-care in patient and caregiver dyads with multiple chronic conditions. These elements in patient and caregiver dyads have not been well-studied to date. This is a multicentre longitudinal study with data collection at 0, 6, and 12 months. We will use generic and specific tools to assess the predictors of self-care, the process of self-care and the outcomes of self-care in the dyads. The data will be analysed with descriptive and inferential statistics and multilevel modelling to control for the interdependent nature of dyadic data. The study was approved by an ethics committee and was funded by a grant from the Centre of Excellence for Nursing Scholarship Rome, in November 2015. This study seeks to determine the predictors and outcomes of self-care in patient and caregiver dyads within the context of multiple chronic conditions. The results of this study will inform clinical practice and research by identifying variables that are modifiable and therefore amenable to interventions.


Who is sleeping more efficient? Patients on peritoneal dialysis or hemodialysis.
Sleep disorder, a common complaint among patients with the end-stage renal disease can affect most aspects of life. Therefore, we aimed to compare sleep quality of patients with peritoneal dialysis (PD) and hemodialysis (HD). This cross-sectional study was conducted on patients on dialysis who were referred to three major centers of Shiraz. The Pittsburgh Sleep Quality Index (PSQI) was used to compare sleep quality between patients on PD and HD. We also assessed some baseline characteristics to find out if they were independent predictors of sleep quality. Spearman correlation coefficients, one and two sample t-test, Chi-square, or Fisher's exact test were used to analyze the data. P <0.05 was considered statistically significant. The Statistical Package for Social Sciences version 18.0 for Windows was used for data analyzing. A total of 144 patients including 63 (43.8%) men and 81 (56.2%) women with the mean age of 54.4 ± 11.8 years completed the questionnaire survey. The total PSQI score showed that 77 (54.6%) of all patients had sleep disturbances without statistical difference between genders (P >0.05). On the other hand, the prevalence of sleep disturbance in HD patients (70.1%) was significantly higher than PD patients (35.9%), (P <0.001). HD patients had a higher rate of poor sleep quality than PD patients. Further studies are necessary to investigate the causes of poor quality of sleep in these patients and also to investigate methods to improve sleep quality in this population.


The progestogen challenge test in postmenopausal women: clinical and morphologic aspects.
The clinical aspects and anatomopathological patterns of 150 postmenopausal women were studied using the progestogen challenge test. An endometrial biopsy was obtained and submitted to the progestogen test. A histopathological analysis of the uterine mucosa from women with a positive progestogen test revealed that the endometrium was active in 44 percent of cases and atrophic or inactive in 56 percent. In contrast, among women with a negative response, the endometrium was atrophic in 94 percent of cases and active in 6 percent. Analysis of clinical aspects did not show significant differences between groups in terms of age; age at menarche and at menopause; fasting blood glucose levels; or body mass. However, postmenopausal time was significantly shorter for women with a positive test, with a correlation between postmenopausal time of one to two years and test positivity. The progestogen challenge test for the detection of atrophic endometrium presented 78.57 percent sensitivity, 77.05 percent specificity, 44 percent positive predictive value, and 94 percent negative predictive value. Thus, when negative, the test is highly valuable, indicating the presence of atrophic endometrium in 94 percent of cases. False-negative results occurred in only 6 percent of the subjects, with no case of hyperplasia detected. However, when the response to the test was positive, the endometrium was atrophic in 56 percent of the cases. We suggest that, in order to avoid invasive procedures, the progestogen challenge test be combined with other methods such as transvaginal ultrasonography.


Identification of dopamine receptors across the extant avian family tree and analysis with other clades uncovers a polyploid expansion among vertebrates.
Dopamine is an important central nervous system transmitter that functions through two classes of receptors (D1 and D2) to influence a diverse range of biological processes in vertebrates. With roles in regulating neural activity, behavior, and gene expression, there has been great interest in understanding the function and evolution dopamine and its receptors. In this study, we use a combination of sequence analyses, microsynteny analyses, and phylogenetic relationships to identify and characterize both the D1 (DRD1A, DRD1B, DRD1C, and DRD1E) and D2 (DRD2, DRD3, and DRD4) dopamine receptor gene families in 43 recently sequenced bird genomes representing the major ordinal lineages across the avian family tree. We show that the common ancestor of all birds possessed at least seven D1 and D2 receptors, followed by subsequent independent losses in some lineages of modern birds. Through comparisons with other vertebrate and invertebrate species we show that two of the D1 receptors, DRD1A and DRD1B, and two of the D2 receptors, DRD2 and DRD3, originated from a whole genome duplication event early in the vertebrate lineage, providing the first conclusive evidence of the origin of these highly conserved receptors. Our findings provide insight into the evolutionary development of an important modulatory component of the central nervous system in vertebrates, and will help further unravel the complex evolutionary and functional relationships among dopamine receptors.


Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems.
Bile acids have emerged as strong signaling molecules capable of influencing various biological processes like inflammation, apoptosis, cancer progression and atherosclerosis depending on their chemistry. In the present study, we investigated the effect of major hydrophobic bile acids lithocholic acid (LCA) and deoxycholic acid (DCA) and hydrophilic bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) on angiogenesis. We employed human umbilical vein endothelial cells (HUVECs) and zebrafish embryos as model systems for studying the role of bile acids in angiogenesis. Our studies revealed that the hydrophilic CDCA enhanced ectopic vessel formation as observed by the increase in the number of sub-intestinal vessels (SIVs) in the zebrafish embryos. The pro-angiogenic role of CDCA was further corroborated by in vitro vessel formation studies performed with human umbilical vein endothelial cells (HUVECs), whereas the hydrophobic LCA reduced tubulogenesis and was toxic to the zebrafish embryos. We validated that CDCA enhances angiogenesis by increasing the expression of vascular growth factor receptors (VEGFR1 and VEGFR2) and matrix metalloproteinases (MMP9) and by decreasing the expression of adhesion protein vascular endothelial cadherin (VE-cadherin). Our work implicates that the nature of bile acids plays a critical role in dictating their biological functions and in regulating angiogenesis.


High-performance computing service for bioinformatics and data science.
Despite having an ideal setup in their labs for wet work, researchers often lack the computational infrastructure to analyze the magnitude of data that result from "-omics" experiments. In this innovative project, the library supports analysis of high-throughput data from global molecular profiling experiments by offering a high-performance computer with open source software along with expert bioinformationist support. The audience for this new service is faculty, staff, and students for whom using the university's large scale, CORE computational resources is not warranted because these resources exceed the needs of smaller projects. In the library's approach, users are empowered to analyze high-throughput data that they otherwise would not be able to on their own computers. To develop the project, the library's bioinformationist identified the ideal computing hardware and a group of open source bioinformatics software to provide analysis options for experimental data such as scientific images, sequence reads, and flow cytometry files. To close the loop between learning and practice, the bioinformationist developed self-guided learning materials and workshops or consultations on topics such as the National Center for Biotechnology Information's BLAST, Bioinformatics on the Cloud, and ImageJ. Researchers apply the data analysis techniques that they learned in the classroom in the library's ideal computing environment.


RNA-seq analysis of 2 closely related leukemia clones that differ in their self-renewal capacity.
The molecular mechanisms regulating self-renewal of leukemia stem cells remain poorly understood. Here we report the generation of 2 closely related leukemias created through the retroviral overexpression of Meis1 and Hoxa9. Despite their apparent common origin, these clonal leukemias exhibit enormous differences in stem cell frequency (from 1 in 1.4, FLA2; to 1 in 347, FLB1), suggesting that one of these leukemias undergoes nearly unlimited self-renewal divisions. Using next-generation RNA-sequencing, we characterized the transcriptomes of these phenotypically similar, but biologically distinct, leukemias, identifying hundreds of differentially expressed genes and a large number of structural differences (eg, alternative splicing and promoter usage). Focusing on ligand-receptor pairs, we observed high expression levels of Sdf1-Cxcr4; Jagged2-Notch2/1; Osm-Gp130; Scf-cKit; and Bmp15-Tgfb1/2. Interestingly, the integrin beta 2-like gene (Itgb2l) is both highly expressed and differentially expressed between our 2 leukemias (∼ 14-fold higher in FLA2 than FLB1). In addition, gene ontology analysis indicated G-protein-coupled receptor had a much higher proportion of differential expression (22%) compared with other classes (∼ 5%), suggesting a potential role regulating subtle changes in cellular behavior. These results provide the first comprehensive transcriptome analysis of a leukemia stem cell and document an unexpected level of transcriptome variation between phenotypically similar leukemic cells.


Measuring Disability in Population Based Surveys: The Interrelationship between Clinical Impairments and Reported Functional Limitations in Cameroon and India.
To investigate the relationship between two distinct measures of disability: self-reported functional limitations and objectively-screened clinical impairments. We undertook an all age population-based survey of disability in two areas: North-West Cameroon (August/October 2013) and Telangana State, India (Feb/April 2014). Participants were selected for inclusion via two-stage cluster randomised sampling (probability proportionate to size cluster selection and compact segment sampling within clusters). Disability was defined as the presence of self-reported functional limitations across eight domains, or presence of moderate or greater clinical impairments. Clinical impairment screening comprised of visual acuity testing for vision impairment, pure tone audiometry for hearing impairment, musculoskeletal functioning assessment for musculoskeletal impairment, reported seizure history for epilepsy and reported symptoms of clinical depression (depression adults only). Information was collected using structured questionnaires, observations and examinations. Self-reported disability prevalence was 5.9% (95% CI 4.7-7.4) and 7.5% (5.9-9.4) in Cameroon and India respectively. The prevalence of moderate or greater clinical impairments in the same populations were 8.4% (7.5-9.4) in Cameroon and 10.5% (9.4-11.7) in India. Overall disability prevalence (self-report and/or screened positive to a moderate or greater clinical impairment) was 10.5% in Cameroon and 12.2% in India, with limited overlap between the sub-populations identified using the two types of tools. 33% of participants in Cameroon identified to have a disability, and 45% in India, both reported functional limitations and screened positive to objectively-screened impairments, whilst the remainder were identified via one or other tool only. A large proportion of people with moderate or severe clinical impairments did not self-report functional difficulties despite reporting participation restrictions. Tools to assess reported functional limitation alone are insufficient to identify all persons with participation restrictions and moderate or severe clinical impairments. A self-reported functional limitation tool followed by clinical screening of all those who report any level of difficulty would identify 94% of people with disabilities in Cameroon and 95% in India, meeting the study criteria.


Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer.
We determined expression of 83 long non-coding RNAs (lncRNAs) and identified ZFAS1 to be significantly up-regulated in colorectal cancer (CRC) tissue. In cohort of 119 CRC patients we observed that 111 cases displayed at least two-times higher expression of ZFAS1 in CRC compared to paired normal colorectal tissue (P < 0.0001). By use of CRC cell lines (HCT116+/+, HCT116-/- and DLD-1) we showed, that ZFAS1 silencing decreases proliferation through G1-arrest of cell cycle, and also tumorigenicity of CRC cells. We identified Cyclin-dependent kinase 1 (CDK1) as interacting partner of ZFAS1 by pull-down experiment and RNA immunoprecipitation. Further, we have predicted by bioinformatics approach ZFAS1 to sponge miR-590-3p, which was proved to target CDK1. Levels of CDK1 were not affected by ZFAS1 silencing, but cyclin B1 was decreased in both cell lines. We observed significant increase in p53 levels and PARP cleavage in CRC cell lines after ZFAS1 silencing indicating increase in apoptosis. Our data suggest that ZFAS1 may function as oncogene in CRC by two main actions: (i) via destabilization of p53 and through (ii) interaction with CDK1/cyclin B1 complex leading to cell cycle progression and inhibition of apoptosis. However, molecular mechanisms behind these interactions have to be further clarified.


CpG motif in synthetic ODN primes respiratory burst of olive flounder Paralichthys olivaceus phagocytes and enhances protection against Edwardsiella tarda.
Effects of synthetic cytidine-phosphate-guanosine (CpG) oligodeoxynucleotide (ODN) on respiratory burst activity of olive flounder (Paralichthys olivaceus) head-kidney phagocytes and on protection against lethal infection with Edwardsiella tarda were investigated. Phagocytes precultured with a CpG ODN showed significantly higher chemiluminescence (CL) responses than phagocytes precultured with guanosine-phosphate-cytidine (GpC) ODN or culture medium alone (control) at all concentrations. Supernatants produced from leucocytes, which were pulsed with CpG ODN, induced significantly higher respiratory burst activity than supernatants produced by GpC ODN or culture medium alone. In an in vivo experiment, respiratory burst activities of the head kidney phagocytes in the groups injected either 0.25 or 0.5 microg fish(-1) of CpG ODN were significantly higher than those in the groups injected with GpC ODN or HBSS (control) at 3, 5 and 7 d after injection. The groups of fish injected with 0.25 or 0.5 microg of CpG ODN showed higher survival rates (83.3%) than groups treated with GpC ODN (33.3%) and a control group (8.3%) after challenge with E. tarda. The present in vitro and in vivo experiments have demonstrated the ability of synthetic CpG ODN to increase phagocyte respiratory burst activity and disease resistance in olive flounder.


Translaminar circuits formed by the pyramidal cells in the superficial layers of cat visual cortex.
Pyramidal cells in the superficial layers of the neocortex provide a major excitatory projection to layer 5, which contains the pyramidal cells that project to subcortical motor-related targets. Both structurally and functionally rather little is known about this interlaminar pathway, especially in higher mammals. Here, we made sparse ultrastructural reconstructions of the projection to layer 5 of three pyramidal neurons from layer 3 in cat V1 whose morphology, physiology, and synaptic connections with layers 2 and 3 were known. The dominant targets of the 74 identified synapses in layer 5 were the dendritic spines of pyramidal cells. The fractions of target spiny dendrites were 59, 61, and 84% for the three cells, with the remaining targets being dendrites of smooth neurons. These fractions were similar to the distribution of targets of unlabeled asymmetric synapses in the surrounding neuropil. Serial section reconstructions revealed that the target dendrites were heterogenous in morphology, indicating that different cell types are innervated. This new evidence indicates that the descending projection from the superficial layer pyramidal cells does not simply drive the output pyramidal cells that project to cortical and subcortical targets, but participates in the complex circuitry of the deep cortical layers.


Management of Malignant Wound Myiasis with Ivermectin, Albendazole, and Clindamycin (Triple Therapy) in Advanced Head-and-Neck Cancer Patients: A Prospective Observational Study.
Myiasis, tissue infestation by housefly larvae, is commonly found in malignant fungating wounds of cancer patients from climatic condition and lower socio-economic strata. It was aimed to study the effectiveness of systemic Ivermectin, Albendazole& Clindamycin (Triple Therapy) in reducing signs & symptoms associated with maggots in malignant head and neck wounds. 25 adult, advanced head and neck cancer patients presenting with maggots either from wound, oral cavity or nostril, with ECOG score 3 or less were enrolled in this study. Symptoms were assessed using Edmonton Symptom Assessment Scale (ESAS) and wound by Wound Assessment Tool - Hospice, at baseline and then Days 1, 3, 5, and 7. All patients received 3 days course of oral Ivermectin 12 mg per day, Albendazole 400 mg twice per day and Clindamycin 300 mg three times per day for 5 days along with Terpentine oil dressing. All patients received oral Morphine as per their pain score. Mean age (yrs) and weight (Kg) were 42.15 ± 8.23 and 52.31 ± 5.18 respectively. 84% patients were male. Mean oral morphine dose was 100.38 mg. There was significant decrease in number of maggots from day 0 (77.28 ± 13.465) to day 1 (20.60 ± 7.263; 73.34% reduction) to day 3 (1.52 ± 2.104; 92.62% reduction). We found statistically significant improvement (P = <0.05) in scores of wound and all other related symptoms on days 1, 3, 5 & 7, except bleeding, edema, nausea, anxiety, appetite loss and feeling of wellbeing, which remained same on Day 1, but improved afterward. Side effects were self-limiting. Systemic treatment with Ivermectin, Albendazole and Clindamycin (Triple Therapy) enhances the removal of maggots, early recovery and relief from distress and associated symptoms.


A method for the ultrastructural preservation of tiny percutaneous needle biopsy material from skeletal muscle.
Skeletal muscle biopsies require transecting the muscle fibers resulting, in structural damage near the cut ends. Classically, the optimal ultrastructural preservation has been obtained by the use of relatively large biopsies in which the tissue fibers are restrained by ligating to a suitable retaining support prior to excision, and by examining regions at some distance from the cut ends. However, these methods require invasive surgical procedures. In the present study, we present and substantiate an alternative approach that allows for the excellent ultrastructural preservation of needle biopsy samples, even the very small samples obtained through tiny percutaneous needle biopsy (TPNB). TPNB represents an advantage, relative to standard muscle biopsy techniques and to other needle biopsies currently in use, as in addition to not requiring a skin incision, it leaves no scars in the muscle and requires an extremely brief recovery period. It is most appropriate for obtaining repeated samples in horizontal studies, e.g., in order to follow changes with athletic training and/or aging in a single individual and for studies of sarcopenic muscles in elderly patients. Due to the small size of the sample, TPNB may present limited usefulness for classical pathology diagnostics. However, it offers the major advantage of allowing multiple samples within a single session and this may be useful under specific circumstances.


Measurement of quality of life and participant experience with the mindfulness-based stress reduction program.
Clinical studies of MBSR have reported efficacy in treating pain, mood disorders, arthritis, sleep disturbances, and stress. Several academic medical institutions in the United States offer MBSR to their patients, but it has never been offered at Mayo Clinic. The objective of this study was to collect quality-of-life data from subjects who participated in the first MBSR program offered at Mayo Clinic. The class was taught as a collaborative effort with the University of Minnesota that had an established MBSR program. Sixteen participants completed a validated, 12-question, linear analogue self-assessment instrument, administered at the beginning and end of the program. Comparison of assessment scores using paired t-tests showed statistically significant improvement in overall quality of life (P=0.04), mental well-being (P=0.005), physical well-being (P<0.001), emotional well-being (P<0.001), level of social activity (P=.02), and spiritual well-being (P=0.006). Although positive changes also were observed for frequency of pain, severity of pain, level of fatigue, level of support from friends and family, and financial and legal concerns, they were not statistically significant. A short intervention in the education of mindfulness significantly improved quality of life for participants.


Response of osteogenic sarcoma to neoadjuvant therapy: evaluated by 18F-FDG-PET.
The aim of this study was to evaluate the potential role of F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in assessing the chemotherapy response of osteosarcoma when compared with histologically assessed tumor necrosis. Fifteen patients were examined with whole-body FDG-PET prior to and following neoadjuvant therapy. The maximum standard uptake value (SUV max) of tumor and tumor to background ratio (TBR) prior to and following chemotherapy was used for semiquantitative PET imaging analysis. The SUV max of prechemotherapy and post-chemotherapy was recorded as SUV1 and SUV2. TBR1 and TBR2 represented prechemotherapy and post-chemotherapy TBR. TBR was calculated by drawing an identical region of interest over the tumor and the contralateral normal limb or pelvis. Tumor necrosis was classified according to Salzer-Kuntschik's criteria. Eight patients with more than 90% tumor necrosis were classified as showing good responses and seven patients with less than 90% tumor necrosis as showing poor responses. SUV2/SUV1, TBR2/TBR1, and TBR2 were significantly correlated with the tumor necrosis degree (P < 0.01, P < 0.001, P < 0.001). TBR2/TBR1 were below 0.46 in all the patients with favorable responses, and higher than 0.49 in all the patients with unfavorable responses. However, it was difficult to distinguish good responses from poor responses by SUV2/SUV1. FDG-PET is a promising tool to assess the chemotherapy response of osteosarcoma noninvasively. The TBR was better than SUV max in evaluating the chemotherapy response in this study.


Electroactive carbon nanoforms: a comparative study via sequential arylation and click chemistry reactions.
The reactivity of several carbon nanoforms (CNFs), single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs) and graphene, has been investigated through a combination of arylation and click chemistry Cu(I)-mediated azide-alkyne cycloaddition (CuAAC) reactions. The approach is based on the incorporation of electroactive π-extended tetrathiafulvalene (exTTF) units into the triazole linkers to modulate the electronic properties of the obtained conjugates. The introduction of strain, by bending the planar graphene sheet into a 3D carbon framework, is responsible for the singular reactivity observed in carbon nanotubes. The formed nanoconjugates were fully characterized by analytical, spectroscopic, and microscopic techniques (TGA, FTIR, Raman, UV-Vis-NIR, cyclic voltammetry, TEM and XPS). In the case of SWCNT conjugates, where the functionalization degree is higher, a series of steady-state and time resolved spectroscopy experiments revealed a photoinduced electron transfer from the exTTF unit to the electron-accepting SWCNT.


Validity of the Diplostomoidea and Diplostomida (Digenea, Platyhelminthes) upheld in phylogenomic analysis.
Higher systematics within the Digenea, Carus 1863 have been relatively stable since a phylogenetic analysis of partial nuclear ribosomal markers (rDNA) led to the erection of the Diplostomida Olson, Cribb, Tkach, Bray, and Littlewood, 2003. However, recent mitochondrial (mt) genome phylogenies suggest this order might be paraphyletic. These analyses show members of two diplostomidan superfamilies are more closely related to the Plagiorchiida La Rue, 1957 than to other members of the Diplostomida. A recent phylogeny based on partial cytochrome c oxidase I also indicates one of the groups implicated, the Diplostomoidea Poirier, 1886, is non-monophyletic. To determine if these results were robust to additional taxon sampling, we analyzed mt genomes from seven diplostomoids in three families. To choose between phylogenetic alternatives based on mt genomes and the prior rDNA-based topology, we analyzed hundreds of ultra-conserved genomic elements assembled from shotgun sequencing. The Diplostomida was paraphyletic in the mt genome phylogeny but supported in the ultra-conserved genomic element phylogeny. We speculate this mitonuclear discordance is related to ancient, rapid radiation in the Digenea. Both ultra-conserved genomic elements and mt genomes support the monophyly of the Diplostomoidea and show congruent relationships within it. The Cyathocotylidae Mühling, 1898 are early diverging descendants of a paraphyletic clade of Diplostomidae Poirier, 1886, in which are nested members of the Strigeidae Railliet, 1919; the results support prior suggestions that the Crassiphialinae Sudarikov, 1960 will rise to the family level. Morphological traits of diplostomoid metacercariae appear to be more useful for differentiating clades than those of adults. We describe a new species of Cotylurus Szidat, 1928, resurrect a species of Hysteromorpha Lutz, 1931, and find support for a species of Alaria Schrank, 1788 of contested validity. Complete rDNA operons from seven diplostomoid species are provided as a resource for future studies.


Current concept in dysplastic hip arthroplasty: Techniques for acetabular and femoral reconstruction.
Adult patients with developmental dysplasia of the hip develop secondary osteoarthritis and eventually end up with total hip arthroplasty (THA) at younger age. Because of altered anatomy of dysplastic hips, THA in these patients represents technically demanding procedure. Distorted anatomy of the acetabulum and proximal femur together with conjoined leg length discrepancy present major challenges during performing THA in patients with developmental dysplasia of the hip. In addition, most patients are at younger age, therefore, soft tissue balance is of great importance (especially the need to preserve the continuity of abductors) to maximise postoperative functional result. In this paper we present a variety of surgical techniques available for THA in dysplastic hips, their advantages and disadvantages. For acetabular reconstruction following techniques are described: Standard metal augments (prefabricated), Custom made acetabular augments (3D printing), Roof reconstruction with vascularized fibula, Roof reconstruction with pedicled iliac graft, Roof reconstruction with autologous bone graft, Roof reconstruction with homologous bone graft, Roof reconstruction with auto/homologous spongious bone, Reinforcement ring with the hook in combination with autologous graft augmentation, Cranial positioning of the acetabulum, Medial protrusion technique (cotyloplasty) with chisel, Medial protrusion technique (cotyloplasty) with reaming, Cotyloplasty without spongioplasty. For femoral reconstruction following techniques were described: Distraction with external fixator, Femoral shortening through a modified lateral approach, Transtrochanteric osteotomies, Paavilainen osteotomy, Lesser trochanter osteotomy, Double-chevron osteotomy, Subtrochanteric osteotomies, Diaphyseal osteotomies, Distal femoral osteotomies. At the end we present author's treatment method of choice: for acetabulum we perform cotyloplasty leaving only paper-thin medial wall, which we break during acetabular cup impacting. For femoral side first we peel of all rotators and posterior part of gluteus medius and vastus lateralis from greater trochanter on the very thin flake of bone. This method allows us to adequately shorten proximal femoral stump, with possibility of additional resection of proximal femur. Furthermore, several advantages and disadvantages of this procedure are also discussed.


Rodent models in translational circadian photobiology.
Over the last decades remarkable advances have been made in the understanding of the photobiology of circadian rhythms. The identification of a third photoreceptive system in the mammalian eye, in addition to the rods and cones that mediate vision, has transformed our appreciation of the role of light in regulating physiology and behavior. These photosensitive retinal ganglion cells (pRGCs) express the blue-light sensitive photopigment melanopsin and project to the suprachiasmatic nuclei (SCN)-the master circadian pacemaker-as well as many other brain regions. Much of our understanding of the fundamental mechanisms of the pRGCs, and the processes that they regulate, comes from mouse and other rodent models. Here we describe the contribution of rodent models to circadian photobiology, including both their strengths and limitations. In addition, we discuss how an appreciation of both rodent and human data is important for translational circadian photobiology. Such an approach enables a bi-directional flow of information whereby an understanding of basic mechanisms derived from mice can be integrated with studies from humans. Progress in this field is being driven forward at several levels of analysis, not least by the use of personalized light measurements and photoreceptor specific stimuli in human studies, and by studying the impact of environmental, rather than laboratory, lighting on different rodent models.


Crowd noise as a cue in referee decisions contributes to the home advantage.
The home advantage is one of the best established phenomena in sports (Courneya & Carron, 1992), and crowd noise has been suggested as one of its determinants (Nevill & Holder, 1999). However, the psychological processes that mediate crowd noise influence and its contribution to the home advantage are still unclear. We propose that crowd noise correlates with the criteria referees have to judge. As crowd noise is a valid cue, referee decisions are strongly influenced by crowd noise. Yet, when audiences are not impartial, a home advantage arises. Using soccer as an exemplar, we show the relevance of this influence in predicting outcomes of real games via a database analysis. Then we experimentally demonstrate the influence of crowd noise on referees' yellow cards decisions in soccer. Finally, we discuss why the focus on referee decisions is useful, and how more experimental research could benefit investigations of the home advantage.


Optimal provision of daytime NPH insulin in patients using the insulin analog lispro.
Insulin lispro improves early postprandial blood glucose control but can result in late interprandial hyperglycemia. As an approach to resolving this problem, we performed a randomized, crossover study with four treatment arms, comparing the daytime metabolic profile after either premeal lispro alone or premeal lispro with optimal daytime NPH insulin and with standard human regular insulin. Twelve C-peptide negative type 1 diabetic patients were studied on four separate study days, at least 7 days apart. On each study day, patients received one of the four study insulin treatments, in random order, with identical meals and snacks. The four treatments were 1) premeal human regular insulin before lunch and supper at unchanged dose; 2) premeal lispro (unchanged dose) at lunchtime and dinner; 3) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 6-h interval until dinner; and 4) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 8-h interval until dinner. All patients were using their usual premeal plus basal insulin regimen during the period of the study, with human regular insulin before meals and NPH insulin at bedtime. Postprandial blood glucose concentrations (1230-1500) were lower after reduced or usual lispro dose compared with human regular insulin (5.5+/-0.2 and 5.6+/-0.2 vs. 8.2+/-0.5 mmol/l, P < 0.001), with no difference between the lispro doses. However, prepran-Dial (1800) blood glucose levels deteriorated to higher levels after usual-dose lispro alone compared with either human regular insulin (P < 0.05) or reduced-dose lispro plus NPH (P < 0.05) (8.9+/-0.3 vs. 7.1+/-0.8 and 6.4+/-0.4 mmol/l), with no difference between human regular insulin and reduced-dose lispro plus NPH. During the 2 h between the usual and delayed mealtime, blood glucose concentrations remained controlled on lispro plus NPH (2000: 6.5+/-0.4 mmol/l). Reduced-dose lunchtime lispro plus NPH maintained the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control, even up to a late meal.


The changing role of the psychiatrist in board-and-care homes.
The role of the psychiatrist in board-and-care homes has been changing dramatically since a job description was published in 1989. The role has become more complex as a result of advances in psychopharmacology, the trend toward polypharmacy regimens, the necessity to evaluate the interaction potentials of drug combinations, and the emergence of more sophisticated treatment algorithms. Broad social trends have added to the complexity of board-and-care treatment, such as the tendency to release more severely disturbed patients from long-term-care facilities because of the increasing costs associated with institutionalization. However, treatment of these patients will continue to be expensive because of the higher costs of new drugs and of using medication combinations. Continued high-cost treatment will increase pressure to control costs by managed care companies, third-party payers, and government agencies. Although this paper describes the effects of these trends on board-and-care psychiatrists, they are also relevant to psychiatrists in general and to other practitioners.


Rise of Clinical Microbial Proteogenomics: A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC22.
Nontuberculous mycobacterial (NTM) species present a major challenge for global health with serious clinical manifestations ranging from pulmonary to skin infections. Multiomics research and its applications toward clinical microbial proteogenomics offer veritable potentials in this context. For example, the Mycobacterium abscessus, a highly pathogenic NTM, causes bronchopulmonary infection and chronic pulmonary disease. The rough variant of the M. abscessus UC22 strain is extremely virulent and causes lung upper lobe fibrocavitary disease. Although several whole-genome next-generation sequencing studies have characterized the genes in the smooth variant of M. abscessus, a reference genome sequence for the rough variant was generated only recently and calls for further clinical applications. We carried out whole-genome sequencing and proteomic analysis for a clinical isolate of M. abscessus UC22 strain obtained from a pulmonary tuberculosis patient. We identified 5506 single-nucleotide variations (SNVs), 63 insertions, and 76 deletions compared with the reference genome. Using a high-resolution LC-MS/MS-based approach (liquid chromatography tandem mass spectrometry), we obtained protein coding evidence for 3601 proteins, representing 71% of the total predicted genes in this genome. Application of proteogenomic approach further revealed seven novel protein-coding genes and enabled refinement of six computationally derived gene models. We also identified 30 variant peptides corresponding to 16 SNVs known to be associated with drug resistance. These new observations offer promise for clinical applications of microbial proteogenomics and next-generation sequencing, and provide a resource for future global health applications for NTM species.


Genomic instability induced by 50Hz magnetic fields is a dynamically evolving process not blocked by antioxidant treatment.
Increased level of micronuclei was observed in SH-SY5Y cells in a previous study at 8 and 15 days after exposure to extremely low frequency (ELF) magnetic fields (MF), indicating possible induction of genomic instability in the progeny of the exposed cells. The aim of this study was to further explore the induction of genomic instability by ELF MFs by increasing the follow-up time up to 45 days after exposure. Human SH-SY5Y neuroblastoma cells were exposed to a 50Hz, 100μT MF for 24h with or without co-exposure to menadione (MQ), a chemical agent that increases cellular superoxide production. Micronuclei, reactive oxygen species (ROS) and lipid peroxidation (LPO) were measured at 15, 30 and 45 days after exposure. To study the possible causal role of ROS in the delayed effects of MF, the antioxidant N-acetylcysteine (NAC) was administered before MF exposure. Consistently with the previous study, the level of micronuclei was statistically significantly elevated 15 days after exposure. A similar effect was observed at 30 days, but not at 45 days after exposure. The level of LPO was statically significantly decreased 30 and 45 days after exposure. Consistently with our previous findings, the MF effect did not depend on co-exposure to MQ. Treatment with NAC effectively decreased cellular ROS level and suppressed the effect of MQ on ROS, but it did not block the MF effect, indicating that increase in ROS is not needed as a causal link between MF exposure and induction of delayed effects. The results presented here are consistent with genomic instability that persists in the progeny of MF-exposed cells up to at least 30 days after exposure. Changes in LPO observed at 30 and 45 days after exposure indicates that the MF-initiated process may continue up to at least 45 days after exposure.


Immune function in severe, active rheumatoid arthritis. A relationship between peripheral blood mononuclear cell proliferation to soluble antigens and synovial tissue immunohistologic characteristics.
The immunohistology of synovium from a tender, swollen knee and peripheral blood cellular immune function were correlated in 24 clinically similar patients with active, seropositive rheumatoid arthritis who were not taking cytotoxic or long-acting antirheumatic drugs. The patients were classified as anergic (n = 6) or nonanergic (n = 18) on the basis of peripheral blood mononuclear cell proliferative responses to a battery of soluble recall antigens. The peripheral blood mononuclear cells of anergic patients failed to respond significantly to any soluble recall antigen, whereas cells from nonanergic patients responded to at least one such antigen. Multiple pieces of synovial tissue were obtained from each patient at arthroscopy. To minimize intrajoint variability, all pieces were analyzed and averaged to determine a composite profile of abnormalities. Synovial specimens from all six anergic patients had "high intensity" lymphocytic infiltration (group A). In sharp contrast, synovial specimens from 15 of 18 nonanergic patients had "low intensity" lymphocytic infiltration (group B) (P = 0.002). Group A tissues typically showed higher intensity T cell and plasma cell infiltration, more synovial lining layer hyperplasia, more HLA-DR bearing cells, and a higher ratio of Leu 3A/Leu 2A T cells than did group B. Group B tissues had fewer infiltrating cells (most of which were OKM1 and HLA-DR bearing), more extensive fibrin deposition, and far fewer T and plasma cells. Although these data do not imply that synovium from different joints in an individual patient are immunohistologically identical, they do provide evidence that peripheral blood mononuclear cell immune function reflects immunopathologic events in the biopsied joint. Moreover, the data further support the view that clinically active rheumatoid arthritis is, like certain other chronic inflammatory conditions, a heterogeneous disorder with polar subgroups.


Central nervous system lymphoma: characteristic findings on traditional and advanced imaging.
CNS lymphoma consists of 2 major subtypes: secondary CNS involvement by systemic lymphoma and PCNSL. Contrast-enhanced MR imaging is the method of choice for detecting CNS lymphoma. In leptomeningeal CNS lymphoma, representing two-thirds of secondary CNS lymphomas, imaging typically shows leptomeningeal, subependymal, dural, or cranial nerve enhancement. Single or multiple periventricular and/or superficial contrast-enhancing lesions are characteristic of parenchymal CNS lymphoma, representing one-third of secondary CNS lymphomas and almost 100% of PCNSLs. New CT and MR imaging techniques and metabolic imaging have demonstrated characteristic findings in CNS lymphoma, aiding in its differentiation from other CNS lesions. Advanced imaging techniques may, in the future, substantially improve the diagnostic accuracy of imaging, ultimately facilitating a noninvasive method of diagnosis. Furthermore, these imaging techniques may play a pivotal role in planning targeted therapies, prognostication, and monitoring treatment response.


Muscle atrophy in cancer: a role for nutrition and exercise.
Developing successful antineoplastic therapies has been a primary focus of cancer research, whereas less attention has been directed at body composition and metabolism in cancer patients. Here, we examine the metabolic implications of muscle atrophy in cancer as well as the potential factors that contribute to muscle atrophy, including energy imbalance, hormone perturbations, and inflammation. The role of nutrition and exercise interventions in maintaining muscle mass during the cancer trajectory is examined.


Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization.
Luman (also known as CREB3) is a type-II transmembrane transcription factor belonging to the OASIS family that localizes to the endoplasmic reticulum (ER) membrane under normal conditions. In response to ER stress, OASIS-family members are subjected to regulated intramembrane proteolysis (RIP), following which the cleaved N-terminal fragments translocate to the nucleus. In this study, we show that treatment of bone marrow macrophages (BMMs) with cytokines - macrophage colony-stimulating factor (M-CSF) and RANKL (also known as TNFSF11) - causes a time-dependent increase in Luman expression, and that Luman undergoes RIP and becomes activated during osteoclast differentiation. Small hairpin (sh)RNA-mediated knockdown of Luman in BMMs prevented the formation of multinucleated osteoclasts, concomitant with the suppression of DC-STAMP, a protein that is essential for cell-cell fusion in osteoclastogenesis. The N-terminus of Luman facilitates promoter activity of DC-STAMP, resulting in upregulation of DC-STAMP expression. Furthermore, Luman interacts with DC-STAMP, and controls its stability and localization. These results suggest that Luman regulates the multinucleation of osteoclasts by promoting cell fusion of mononuclear osteoclasts through DC-STAMP induction and intracellular distribution during osteoclastogenesis.


ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response.
The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR-complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism.


Time-distanced gates in long short-term memory networks.
The Long Short-Term Memory (LSTM) network is widely used in modeling sequential observations in fields ranging from natural language processing to medical imaging. The LSTM has shown promise for interpreting computed tomography (CT) in lung screening protocols. Yet, traditional image-based LSTM models ignore interval differences, while recently proposed interval-modeled LSTM variants are limited in their ability to interpret temporal proximity. Meanwhile, clinical imaging acquisition may be irregularly sampled, and such sampling patterns may be commingled with clinical usages. In this paper, we propose the Distanced LSTM (DLSTM) by introducing time-distanced (i.e., time distance to the last scan) gates with a temporal emphasis model (TEM) targeting at lung cancer diagnosis (i.e., evaluating the malignancy of pulmonary nodules). Briefly, (1) the time distance of every scan to the last scan is modeled explicitly, (2) time-distanced input and forget gates in DLSTM are introduced across regular and irregular sampling sequences, and (3) the newer scan in serial data is emphasized by the TEM. The DLSTM algorithm is evaluated with both simulated data and real CT images (from 1794 National Lung Screening Trial (NLST) patients with longitudinal scans and 1420 clinical studied patients). Experimental results on simulated data indicate the DLSTM can capture families of temporal relationships that cannot be detected with traditional LSTM. Cross-validation on empirical CT datasets demonstrates that DLSTM achieves leading performance on both regularly and irregularly sampled data (e.g., improving LSTM from 0.6785 to 0.7085 on F1 score in NLST). In external-validation on irregularly acquired data, the benchmarks achieved 0.8350 (CNN feature) and 0.8380 (with LSTM) on AUC score, while the proposed DLSTM achieves 0.8905. In conclusion, the DLSTM approach is shown to be compatible with families of linear, quadratic, exponential, and log-exponential temporal models. The DLSTM can be readily extended with other temporal dependence interactions while hardly increasing overall model complexity.


Dogs with heart diseases causing turbulent high-velocity blood flow have changes in platelet function and von Willebrand factor multimer distribution.
The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated dogs were divided into 4 groups: 14 Cavalier King Charles Spaniels (Cavaliers) with mitral valve prolapse (MVP) and no or minimal mitral regurgitation (MR), 17 Cavaliers with MVP and moderate to severe MR, 14 control dogs, and 10 dogs with subaortic stenosis (SAS). Clinical examinations and echocardiography were performed in all dogs. PFA100 closure times (the ability of platelets to occlude a hole in a membrane at high shear rates), platelet activation markers (plasma thromboxane B2 concentration, platelet surface P-selectin expression), platelet aggregation (in whole blood and platelet-rich plasma with 3 different agonists), and vWf multimers were analyzed. Cavaliers with moderate to severe MR and dogs with SAS had longer closure times and a lower percentage of the largest vWf multimers than did controls. Maximal aggregation responses were unchanged in dogs with SAS but enhanced in Cavaliers with MVP (regardless of MR status) compared with control dogs. No significant difference in platelet activation markers was found among groups. The data suggest that a form of platelet dysfunction detected at high shear rates was present in dogs with MR and SAS, possibly associated with a qualitative vWf defect. Aggregation results suggest increased platelet reactivity in Cavaliers, but the platelets did not appear to circulate in a preactivated state in either disease.


3D Bioprinting of the Sustained Drug Release Wound Dressing with Double-Crosslinked Hyaluronic-Acid-Based Hydrogels.
Hyaluronic acid (HA)-based hydrogels are widely used in biomedical applications due to their excellent biocompatibility. HA can be Ultraviolet (UV)-crosslinked by modification with methacrylic anhydride (HA-MA) and crosslinked by modification with 3,3'-dithiobis(propionylhydrazide) (DTP) (HA-SH) via click reaction. In the study presented in this paper, a 3D-bioprinted, double-crosslinked, hyaluronic-acid-based hydrogel for wound dressing was proposed. The hydrogel was produced by mixing HA-MA and HA-SH at different weight ratios. The rheological test showed that the storage modulus (G') of the HA-SH/HA-MA hydrogel increased with the increase in the HA-MA content. The hydrogel had a high swelling ratio and a high controlled degradation rate. The in vitro degradation test showed that the hydrogel at the HA-SH/HA-MA ratio of 9:1 (S9M1) degraded by 89.91% ± 2.26% at 11 days. The rheological performance, drug release profile and the cytocompatibility of HA-SH/HA-MA hydrogels with loaded Nafcillin, which is an antibacterial drug, were evaluated. The wound dressing function of this hydrogel was evaluated by Live/Dead staining and CCK-8 assays. The foregoing results imply that the proposed HA-SH/HA-MA hydrogel has promise in wound repair applications.


Accuracy of GE digital breast tomosynthesis vs supplementary mammographic views for diagnosis of screen-detected soft-tissue breast lesions.
To compare the accuracy of standard supplementary views and GE digital breast tomosynthesis (DBT) for assessment of soft-tissue mammographic abnormalities. Women recalled for further assessment of soft-tissue abnormalities were recruited and received standard supplementary views (typically spot compression views) and two-view GE DBT. The added value of DBT in the assessment process was determined by analysing data collected prospectively by radiologists working up the cases. Following anonymization of cases, there was also a retrospective multireader review. The readers first read bilateral standard two-view digital mammography (DM) together with the supplementary mammographic views and gave a combined score for suspicion of malignancy on a five-point scale. The same readers then read bilateral standard two-view DM together with two-view DBT. Pathology data were obtained. Differences were assessed using receiver operating characteristic analysis. The study population was 342 lesions in 322 patients. The final diagnosis was malignant in 113 cases (33%) and benign/normal in 229 cases (67%). In the prospective analysis, the performance of two-view DM plus DBT was at least equivalent to the performance of two-view DM and standard mammographic supplementary views-the area under the curve (AUC) was 0.946 and 0.922, respectively, which did not reach statistical significance. Similar results were obtained for the retrospective review-AUC was 0.900 (DBT) and 0.873 (supplementary views), which did not reach statistical significance. The accuracy of GE DBT in the assessment of screen detected soft-tissue abnormalities is equivalent to the use of standard supplementary mammographic views. The vast majority of evidence relating to the use of DBT has been gathered from research using Hologic equipment. This study provides evidence for the use of the commercially available GE DBT system demonstrating that it is at least equivalent to supplementary mammographic views in the assessment of soft-tissue screen-detected abnormalities.


Use of ethylene-vinyl alcohol copolymer as a liquid embolic agent to treat a peripheral arteriovenous malformation in a dog.
An 11-year-old castrated male Tibetan Mastiff was evaluated because of a visibly enlarged blood vessel and progressively worsening swelling of the right hind limb. On physical examination, the right hind limb was markedly larger than the left hind limb and the dog was minimally weight bearing on the affected limb. A bruit was auscultated over the affected region. Ultrasonography of the tarsal region of the right hind limb revealed an artery with turbulent flow that communicated with venous drainage. A CT scan confirmed the presence of an arteriovenous malformation (AVM). Embolization of the AVM with a liquid embolic agent (ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide) was elected. An arteriogram was performed prior to treatment and delineated the vessels that were targeted for embolization. The embolic agent was infused into the AVM, and a postinjection arteriogram confirmed complete occlusion of the AVM nidus and normal arterial flow to the paw with subsequent normal venous drainage. The circumference of the abnormal paw was 51 cm before the procedure and 22.9 cm at 4 weeks after the procedure. Additionally, the gait of the dog dramatically improved. No complications associated with the procedure developed. Peripheral AVMs in dogs are uncommon, and described treatment options are limited and generally associated with serious morbidity. A liquid embolic agent, ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide, was successfully administered in this case, and no morbidity was observed secondary to the procedure. Clinical success was characterized by substantial improvement in limb swelling and marked improvement in the gait of the dog.


Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study.
Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid. Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ≤ 7.5 mg/dL during days 3 to 7. Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol. In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.


Associations of office workers' objectively assessed occupational sitting, standing and stepping time with musculoskeletal symptoms.
We examined the association of musculoskeletal symptoms (MSS) with workplace sitting, standing and stepping time, as well as sitting and standing time accumulation (i.e. usual bout duration of these activities), measured objectively with the activPAL3 monitor. Using baseline data from the Stand Up Victoria trial (216 office workers, 14 workplaces), cross-sectional associations of occupational activities with self-reported MSS (low-back, upper and lower extremity symptoms in the last three months) were examined using probit regression, correcting for clustering and adjusting for confounders. Sitting bout duration was significantly (p < 0.05) associated, non-linearly, with MSS, such that those in the middle tertile displayed the highest prevalence of upper extremity symptoms. Other associations were non-significant but sometimes involved large differences in symptom prevalence (e.g. 38%) by activity. Though causation is unclear, these non-linear associations suggest that sitting and its alternatives (i.e. standing and stepping) interact with MSS and this should be considered when designing safe work systems. Practitioner summary: We studied associations of objectively assessed occupational activities with musculoskeletal symptoms in office workers. Workers who accumulated longer sitting bouts reported fewer upper extremity symptoms. Total activity duration was not significantly associated with musculoskeletal symptoms. We underline the importance of considering total volumes and patterns of activity time in musculoskeletal research.


Insulin-induced tyrosine dephosphorylation of paxillin and focal adhesion kinase requires active phosphotyrosine phosphatase 1D.
Insulin stimulation of fibroblasts rapidly induces the tyrosine dephosphorylation of proteins of 68 kDa and 125 kDa, in addition to the tyrosine phosphorylation of the insulin receptor beta-chain, insulin receptor substrates 1 and 2, and Shc. Using specific antibodies, the 68 kDa and 125 kDa proteins were identified as paxillin and focal adhesion kinase (pp125FAK) respectively. We have examined whether dephosphorylation of paxillin and pp125FAK requires interaction of the cells with the extracellular matrix. For this, cells were grown on poly(L-lysine) plates, and the tyrosine phosphorylation of pp125FAK and paxillin was increased by addition of lysophosphatidic acid. Under these conditions, insulin still induced the complete dephosphorylation of pp125FAK and paxillin, indicating that this process can occur independently of the interaction of integrins with extracellular matrix proteins. We also studied whether dephosphorylation of pp125FAK and paxillin results from the action of a phosphotyrosine phosphatase. It was found that phenylarsine oxide, a phosphotyrosine phosphatase inhibitor, prevented the insulin-induced dephosphorylation of pp125FAK and paxillin. Furthermore, this insulin-induced dephosphorylation was also impaired in cells expressing a dominant-negative mutant of phosphotyrosine phosphatase 1D (PTP 1D). Thus we have identified paxillin as a target for dephosphorylation by insulin. In addition, we have obtained evidence that the insulin-mediated dephosphorylation of paxillin and pp125FAK requires active PTP 1D.


Cognitive abilities on transitive inference using a novel touchscreen technology for mice.
Cognitive abilities are impaired in neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia. Preclinical models with strong endophenotypes relevant to cognitive dysfunctions offer a valuable resource for therapeutic development. However, improved assays to test higher order cognition are needed. We employed touchscreen technology to design a complex transitive inference (TI) assay that requires cognitive flexibility and relational learning. C57BL/6J (B6) mice with good cognitive skills and BTBR T+tf/J (BTBR), a model of ASD with cognitive deficits, were evaluated in simple and complex touchscreen assays. Both B6 and BTBR acquired visual discrimination and reversal. BTBR displayed deficits on components of TI, when 4 stimuli pairs were interspersed, which required flexible integrated knowledge. BTBR displayed impairment on the A > E inference, analogous to the A > E deficit in ASD. B6 and BTBR mice both reached criterion on the B > D comparison, unlike the B > D impairment in schizophrenia. These results demonstrate that mice are capable of complex discriminations and higher order tasks using methods and equipment paralleling those used in humans. Our discovery that a mouse model of ASD displays a TI deficit similar to humans with ASD supports the use of the touchscreen technology for complex cognitive tasks in mouse models of neurodevelopmental disorders.


Complications of Bilateral Neck Dissection in Thyroid Cancer From a Single High-Volume Center.
The morbidity of bilateral lateral neck dissection (BLND) for thyroid cancers has not been described in detail. This study delineates the specific complications arising from BLND for thyroid cancers at a single high-volume center. To determine the morbidity associated with BLNDs for differentiated thyroid cancers at our institution. This was a retrospective review of medical records performed to identify patients having undergone BLNDs for thyroid cancers by a single surgeon at an academic, tertiary medical center in Toronto, Ontario, Canada, from 1988 to 2015. Patients who underwent BLND for papillary, follicular, or medullary thyroid cancers were identified through operative procedure codes and review of operative and pathology reports. The indication for this procedure was suspicious bilateral lateral compartment on imaging and clinical examination. Sixty-two patients who underwent BLND for thyroid cancers, with or without total thyroidectomy and central compartment dissection, were identified. The main outcome measures for this study were unanticipated medical or surgical complications during the operation or in the postoperative period. Secondary measures were oncologic outcomes, including regional structural or biochemical recurrence. Of the 62 patients, 24 were male (39%), and 38 (61%) were female. Their mean age was 46 years (range, 17-80 years). The overall risk of permanent hypoparathyroidism was 37%. There was 1 case of unanticipated permanent recurrent nerve paralysis and 1 case of temporary nerve paresis. Postoperative chyle fistula occurred in 6 cases (10%). There were 3 readmissions within 30 days of surgery, 1 pulmonary embolism, and 1 perioperative mortality. Fifty percent of patients had pN0 contralateral necks despite preoperative clinical suspicion. Four patients were found to have anaplastic thyroid cancers intraoperatively. Five patients (8%) developed nodal recurrence in the neck. Four patients died of their disease within available follow-up (mean, 3.2 years). Bilateral lateral neck dissection for thyroid cancers confers a significant amount of morbidity, including a significant rate of hypoparathyroidism. Knowledge of the complications of this procedure, especially in the setting of questionable survival benefit, may assist in preoperative decision-making and patient counseling.


Genetic Incorporation of Olefin Cross-Metathesis Reaction Tags for Protein Modification.
Olefin cross-metathesis (CM) is a viable reaction for the modification of alkene-containing proteins. Although allyl sulfide or selenide side-chain motifs in proteins can critically enhance the rate of CM reactions, no efficient method for their site-selective genetic incorporation into proteins has been reported to date. Here, through the systematic evaluation of olefin-bearing unnatural amino acids for their metabolic incorporation, we have discovered S-allylhomocysteine (Ahc) as a genetically encodable Met analogue that is not only processed by translational cellular machinery but also a privileged CM substrate residue in proteins. In this way, Ahc was used for efficient Met codon reassignment in a Met-auxotrophic strain of E. coli (B834 (DE3)) as well as metabolic labeling of protein in human cells and was reactive toward CM in several representative proteins. This expands the use of CM in the toolkit for "tag-and-modify" functionalization of proteins.


Hospice use and high-intensity care in men dying of prostate cancer.
Hospice programs improve the quality of life and quality of death for men dying of cancer. We sought to characterize hospice use by men dying of prostate cancer and to compare the use of high-intensity care between those who did or did not enroll in hospice. We used linked Surveillance, Epidemiology, and End Results-Medicare data to identify a cohort of Medicare beneficiaries who died of prostate cancer between 1992 and 2005. We created 2 multivariable logistic regression models, one to identify factors associated with hospice use and one to determine the association of hospice use with the receipt of diagnostic and interventional procedures and physician visits at the end of life. Of 14,521 men dying of prostate cancer, 7646 (53%) used hospice for a median of 24 days. Multivariable modeling demonstrated that African American ethnicity (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.68-0.88) and higher Charlson comorbidity index (OR, 0.49; 95% CI, 0.44-0.55) were associated with lower odds of hospice use, while having a partner (OR, 1.23; 95% CI, 1.14-1.32) and more recent year of death (OR, 1.12; 95% CI, 1.11-1.14) were associated with higher odds of hospice use. Men dying of prostate cancer who enrolled in hospice were less likely (OR, 0.82; 95% CI, 0.74-0.91) to receive high-intensity care, including intensive care unit admissions, inpatient stays, and multiple emergency department visits. The proportion of individuals using hospice is increasing, but the timing of hospice referral remains poor. Those who enroll in hospice are less likely to receive high-intensity end-of-life care.


A drosomycin-GFP reporter transgene reveals a local immune response in Drosophila that is not dependent on the Toll pathway.
A hallmark of the systemic antimicrobial response of Drosophila is the synthesis by the fat body of several antimicrobial peptides which are released into the hemolymph in response to a septic injury. One of these peptides, drosomycin, is active primarily against fungi. Using a drosomycin-green fluorescent protein (GFP) reporter gene, we now show that in addition to the fat body, a variety of epithelial tissues that are in direct contact with the external environment, including those of the respiratory, digestive and reproductive tracts, can express the antifungal peptide, suggesting a local response to infections affecting these barrier tissues. As is the case for vertebrate epithelia, insect epithelia appear to be more than passive physical barriers and are likely to constitute an active component of innate immunity. We also show that, in contrast to the systemic antifungal response, this local immune response is independent of the Toll pathway.