Lane Medical Library

Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients.

PLoS One. 2015;10(12):e0143731

Authors: Hai X, Landeras V, Dobre MA, DeOreo P, Meyer TW, Hostetter TH

Abstract
Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

PMID: 26650937 [PubMed - as supplied by publisher]

Structure and Functional Characterization of a Bile Acid 7α Dehydratase BaiE in Secondary Bile Acid Synthesis.

Proteins. 2015 Dec 9;

Authors: Bhowmik S, Chiu HP, Jones DH, Chiu HJ, Miller MD, Xu Q, Farr CL, Ridlon JM, Wells JE, Elsliger MA, Wilson IA, Hylemon PB, Lesley SA

Abstract
Conversion of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) to the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) is performed by a few species of intestinal bacteria in the genus Clostridium through a multistep biochemical pathway that removes a 7α-hydroxyl group. The rate-determining enzyme in this pathway is bile acid 7α-dehydratase (baiE). In this study, we report crystal structures of apo-BaiE and its putative product-bound (3-oxo-Δ(4,6) - lithocholyl-Coenzyme A (CoA)) complex. BaiE is a trimer with a twisted α+β barrel fold with similarity to the Nuclear Transport Factor 2 (NTF2) superfamily. Tyr30, Asp35 and His83 form a catalytic triad that is conserved across this family. Site-directed mutagenesis of BaiE from Clostridium scindens VPI 12708 confirmed that these residues are essential for catalysis and also confirmed the importance of other conserved residues, Tyr54 and Arg146, which are involved in substrate binding and affect catalytic turnover. Steady state kinetic studies revealed that the BaiE homologs are able to turn over 3-oxo-Δ(4) -bile acid and CoA-conjugated 3-oxo-Δ(4) -bile acid substrates with comparable efficiency questioning the role of CoA-conjugation in the bile acid metabolism pathway. This article is protected by copyright. All rights reserved.

PMID: 26650892 [PubMed - as supplied by publisher]

Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study.

Alzheimer Dis Assoc Disord. 2015 Dec 8;

Authors: Walter S, Marden JR, Kubzansky LD, Mayeda ER, Crane PK, Chang SC, Cornelis M, Rehkopf DH, Mukherjee S, Glymour MM

Abstract
BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result.
METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including β-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation.
RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant.
CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.

PMID: 26650880 [PubMed - as supplied by publisher]

Mixed chimerism evolution is associated with T regulatory type 1 (Tr1) cells in a β-thalassemic patient after haploidentical haematopoietic stem cell transplantation.

Chimerism. 2015 Dec 9;:1-5

Authors: Andreani M, Gianolini ME, Testi M, Battarra M, Tiziana G, Morrone A, Sodani P, Lucarelli G, Roncarolo MG, Gregori S

Abstract
In a cohort of β-Thalassemia (β-Thal) transplanted with haploidentical-HSCT we identified one transplanted patient characterized by persistent mixed chimerism (PMC) for several months after HSCT. In this unique β-Thal patient we assessed the donor engraftment overtime after transplantation, the potential loss of the non-shared HLA haplotype, and the presence of CD49b(+)LAG-3(+) T regulatory type 1 (Tr1) cells, previously demonstrated to be associated with PMC after HLA-related HSCT for β-Thal. The majority of the patient's erythrocytes were of donor origin, whereas T cells were initially mostly derived from the recipient, no HLA loss, but an increased frequency of circulating Tr1 cells were observed. For the first time, we showed that when the proportion of residual donor cells decreases, the frequency of CD49b(+)LAG-3(+) Tr1 cells declines, reaching the levels present in healthy subjects. These findings confirm previous results obtained in transplant related settings for β-Thal, and supported the central role of Tr1 cells in promoting and maintaining PMC after allo-HSCT.

PMID: 26650878 [PubMed - as supplied by publisher]

Effects of D2 or combined D1/D2 receptor antagonism on the methamphetamine-induced one-trial and multi-trial behavioral sensitization of preweanling rats.

Psychopharmacology (Berl). 2015 Dec 9;

Authors: Mohd-Yusof A, Veliz A, Rudberg KN, Stone MJ, Gonzalez AE, McDougall SA

Abstract
RATIONALE: There is suggestive evidence that the neural mechanisms mediating one-trial and multi-trial behavioral sensitization differ, especially when the effects of various classes of dopamine (DA) agonists are examined.
OBJECTIVE: The purpose of the present study was to determine the role of the D2 receptor for the induction of one-trial and multi-trial methamphetamine sensitization in preweanling rats.
METHODS: In a series of experiments, rats were injected with saline or raclopride (a selective D2 receptor antagonist), either alone or in combination with SCH23390 (a selective D1 receptor antagonist), 15 min prior to treatment with the indirect DA agonist methamphetamine. Acute control groups were given two injections of saline. This pretreatment regimen occurred on either postnatal days (PD) 13-16 (multi-trial) or PD 16 (one-trial). On PD 17, rats were challenged with methamphetamine and locomotor sensitization was determined.
RESULTS: Blockade of D2 or D1/D2 receptors reduced or prevented, respectively, the induction of multi-trial methamphetamine sensitization in young rats, while the same manipulations had minimal effects on one-trial behavioral sensitization.
CONCLUSIONS: DA antagonist treatment differentially affected the methamphetamine-induced sensitized responding of preweanling rats depending on whether a one-trial or multi-trial procedure was used. The basis for this effect is uncertain, but there was some evidence that repeated DA antagonist treatment caused nonspecific changes that produced a weakened sensitized response. Importantly, DA antagonist treatment did not prevent the one-trial behavioral sensitization of preweanling rats. The latter result brings into question whether DA receptor stimulation is necessary for the induction of psychostimulant-induced behavioral sensitization during early ontogeny.

PMID: 26650612 [PubMed - as supplied by publisher]

Analysis of COPII vesicles indicates a role for the Emp47-Ssp120 complex in transport of cell surface glycoproteins.

Traffic. 2015 Dec 9;

Authors: Margulis NG, Wilson JD, Bentivoglio CM, Dhungel N, Gitler AD, Barlowe C

Abstract
Coat protein complex II (COPII) vesicle formation at the endoplasmic reticulum (ER) transports nascent secretory proteins forward to the Golgi complex. To further define the machinery that packages secretory cargo and targets vesicles to Golgi membranes, we performed a comprehensive proteomic analysis of purified COPII vesicles. In addition to previously known proteins, we identified new vesicle proteins including Coy1, Sly41 and Ssp120, which were efficiently packaged into COPII vesicles for trafficking between the ER and Golgi compartments. Further characterization of the putative calcium-binding Ssp120 protein revealed a tight association with Emp47 and in emp47Δ cells Ssp120 was mislocalized and secreted. Genetic analyses demonstrated that EMP47 and SSP120 display identical synthetic positive interactions with IRE1 and synthetic negative interactions with genes involved in cell wall assembly. Our findings support a model in which the Emp47-Ssp120 complex functions in transport of plasma membrane glycoproteins through the early secretory pathway.

PMID: 26650540 [PubMed - as supplied by publisher]

A K(+)-selective CNG channel orchestrates Ca2(+) signalling in zebrafish sperm.

Elife. 2015 Dec 9;4

Authors: Fechner S, Alvarez L, Bönigk W, Müller A, Berger T, Pascal R, Trötschel C, Poetsch A, Stölting G, Siegfried KR, Kremmer E, Seifert R, Kaupp UB

Abstract
Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca2(+) signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K(+) channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca2(+) influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca2(+) entry. Ca2(+) induces spinning-like swimming, different from swimming of sperm from other species. The 'spinning' mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization.

PMID: 26650356 [PubMed - as supplied by publisher]

Cosmological Relaxation of the Electroweak Scale.

Phys Rev Lett. 2015 Nov 27;115(22):221801

Authors: Graham PW, Kaplan DE, Rajendran S

Abstract
A new class of solutions to the electroweak hierarchy problem is presented that does not require either weak-scale dynamics or anthropics. Dynamical evolution during the early Universe drives the Higgs boson mass to a value much smaller than the cutoff. The simplest model has the particle content of the standard model plus a QCD axion and an inflation sector. The highest cutoff achieved in any technically natural model is 10^{8}  GeV.

PMID: 26650289 [PubMed - as supplied by publisher]

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

J Neurooncol. 2015 Dec 9;

Authors: Chang E, Pohling C, Natarajan A, Witney TH, Kaur J, Xu L, Gowrishankar G, L D'Souza A, Murty S, Schick S, Chen L, Wu N, Khaw P, Mischel P, Abbasi T, Usmani S, Mallick P, Gambhir SS

Abstract
Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.

PMID: 26650066 [PubMed - as supplied by publisher]

Your gut microbiome, deconstructed.

Nat Biotechnol. 2015 Dec 9;33(12):1238-1240

Authors: Dodd D, Tropini C, Sonnenburg JL

PMID: 26650010 [PubMed - as supplied by publisher]

Patenting parthenotes in the US and Europe.

Nat Biotechnol. 2015 Dec 9;33(12):1232-1234

Authors: Senatore V, Scott CT, Sebastiano V

PMID: 26650007 [PubMed - as supplied by publisher]

Reproducibility: Experimental mismatch in neural circuits.

Nature. 2015 Dec 9;

Authors: Südhof TC

PMID: 26649825 [PubMed - as supplied by publisher]

Comparative Study of the Limitations and Challenges in Atom-Transfer C-H Oxidations.

Org Lett. 2015 Dec 9;

Authors: Adams AM, Du Bois J, Malik HA

Abstract
A comparative study is disclosed that seeks to highlight the current limitations and challenges that exist in the field of atom-transfer C-H oxidations. State-of-the-art methods are benchmarked in order to showcase clear differences and similarities. A novel Mn-mediated method for C-H oxidation is disclosed that serves as a rapid and simple method for aliphatic C-H hydroxylation. Finally, two methods that allow for C-H oxidation in the presence of pyridine-containing substrates are studied, something that is rare in the field but of great interest to the chemical community.

PMID: 26649767 [PubMed - as supplied by publisher]

Birth and Evolution of Chiselling and Drilling Techniques for Removing Ear Canal Exostoses.

Otol Neurotol. 2016 Jan;37(1):109-114

Authors: Mudry A, Hetzler D

Abstract
The main surgical techniques used to remove ear canal exostoses are drilling and/or, chiselling. The aim of this study was to identify the origins and subsequent evolution of, the surgical removal of ear canal exostoses in the 19th century. A critical review and, compilation of primary and secondary historical sources was conducted. Two techniques for removal of exostoses were developed in the latter part of the 19th century and have largely remained unchanged. This demonstrates the importance of that era in the history of ear surgery.

PMID: 26649611 [PubMed - as supplied by publisher]

Are Epigenetic Changes the Key to the Elusive Mechanism for the Long-lasting Effects of Anesthetic Drugs that Persist after Emergence?

Anesthesiology. 2015 Dec 9;

Authors: Degos V, Flood P

PMID: 26649425 [PubMed - as supplied by publisher]

Novel Treatments for Thymoma and Thymic Carcinoma.

Front Oncol. 2015;5:267

Authors: Rajan A, Wakelee H, Giaccone G

PMID: 26649279 [PubMed - as supplied by publisher]

Altered Innervation Pattern in Ligaments of Patients with Basal Thumb Arthritis.

J Wrist Surg. 2015 Nov;4(4):284-291

Authors: Ludwig CA, Mobargha N, Okogbaa J, Hagert E, Ladd AL

Abstract
Purpose The population of mechanoreceptors in patients with osteoarthritis (OA) lacks detailed characterization. In this study, we examined the distribution and type of mechanoreceptors of two principal ligaments in surgical subjects with OA of the first carpometacarpal joint (CMC1). Methods We harvested two ligaments from the CMC1 of eleven subjects undergoing complete trapeziectomy and suspension arthroplasty: the anterior oblique (AOL) and dorsal radial ligament (DRL). Ligaments were divided into proximal and distal portions, paraffin-sectioned, and analyzed using immunoflourescent triple staining microscopy. We performed statistical analyses using the Wilcoxon Rank Sum test and ANOVA with post-hoc Bonferroni and Tamhane adjustments. Results The most prevalent nerve endings in the AOL and DRL of subjects with OA were unclassifiable mechanoreceptors, which do not currently fit into a defined morphological scheme. These were found in 11/11 (100%) DRLs and 7/11 (63.6%) AOLs. No significant difference existed with respect to location within the ligament (proximal versus distal) of mechanoreceptors in OA subjects. Conclusion The distribution and type of mechanoreceptors in cadavers with no to mild OA differ from those in surgical patients with OA. Where Ruffini endings predominate in cadavers with no to mild OA, unclassifiable corpuscles predominate in surgical patients with OA. These findings suggest an alteration of the mechanoreceptor population and distribution that accompanies the development of OA. Clinical Relevance Identification of a unique type and distribution of mechanoreceptors in the CMC1 of symptomatic subjects provides preliminary evidence of altered proprioception in OA.

PMID: 26649261 [PubMed - as supplied by publisher]

Stem Cell-Based Therapeutics to Improve Wound Healing.

Plast Surg Int. 2015;2015:383581

Authors: Hu MS, Leavitt T, Malhotra S, Duscher D, Pollhammer MS, Walmsley GG, Maan ZN, Cheung AT, Schmidt M, Huemer GM, Longaker MT, Lorenz HP

Abstract
Issues surrounding wound healing have garnered deep scientific interest as well as booming financial markets invested in novel wound therapies. Much progress has been made in the field, but it is unsurprising to find that recent successes reveal new challenges to be addressed. With regard to wound healing, large tissue deficits, recalcitrant wounds, and pathological scar formation remain but a few of our most pressing challenges. Stem cell-based therapies have been heralded as a promising means by which to surpass current limitations in wound management. The wide differentiation potential of stem cells allows for the possibility of restoring lost or damaged tissue, while their ability to immunomodulate the wound bed from afar suggests that their clinical applications need not be restricted to direct tissue formation. The clinical utility of stem cells has been demonstrated across dozens of clinical trials in chronic wound therapy, but there is hope that other aspects of wound care will inherit similar benefit. Scientific inquiry into stem cell-based wound therapy abounds in research labs around the world. While their clinical applications remain in their infancy, the heavy investment in their potential makes it a worthwhile subject to review for plastic surgeons, in terms of both their current and future applications.

PMID: 26649195 [PubMed - as supplied by publisher]

Does Music Training Enhance Literacy Skills? A Meta-Analysis.

Front Psychol. 2015;6:1777

Authors: Gordon RL, Fehd HM, McCandliss BD

Abstract
Children's engagement in music practice is associated with enhancements in literacy-related language skills, as demonstrated by multiple reports of correlation across these two domains. Training studies have tested whether engaging in music training directly transfers benefit to children's literacy skill development. Results of such studies, however, are mixed. Interpretation of these mixed results is made more complex by the fact that a wide range of literacy-related outcome measures are used across these studies. Here, we address these challenges via a meta-analytic approach. A comprehensive literature review of peer-reviewed music training studies was built around key criteria needed to test the direct transfer hypothesis, including: (a) inclusion of music training vs. control groups; (b) inclusion of pre- vs. post-comparison measures, and (c) indication that reading instruction was held constant across groups. Thirteen studies were identified (n = 901). Two classes of outcome measures emerged with sufficient overlap to support meta-analysis: phonological awareness and reading fluency. Hours of training, age, and type of control intervention were examined as potential moderators. Results supported the hypothesis that music training leads to gains in phonological awareness skills. The effect isolated by contrasting gains in music training vs. gains in control was small relative to the large variance in these skills (d = 0.2). Interestingly, analyses revealed that transfer effects for rhyming skills tended to grow stronger with increased hours of training. In contrast, no significant aggregate transfer effect emerged for reading fluency measures, despite some studies reporting large training effects. The potential influence of other study design factors were considered, including intervention design, IQ, and SES. Results are discussed in the context of emerging findings that music training may enhance literacy development via changes in brain mechanisms that support both music and language cognition.

PMID: 26648880 [PubMed - as supplied by publisher]

Editorial: Emergent Neural Computation from the Interaction of Different Forms of Plasticity.

Front Comput Neurosci. 2015;9:145

Authors: Gilson M, Savin C, Zenke F

PMID: 26648864 [PubMed - as supplied by publisher]

Age-related mutations and chronic myelomonocytic leukemia.

Leukemia. 2015 Dec 9;

Authors: Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D, Pomicter AD, Reynolds KR, Eiring AM, Kronenberg Z, Sherman RL, Tyner JW, Dalley BK, Dao KH, Yandell M, Druker BJ, Gotlib J, O'Hare T, Deininger MW

Abstract
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, while an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing (WES) followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL, and NRAS as well as the novel CMML genes FAT4, ARIH1, DNAH2, and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes, and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage biased aged hematopoietic system.Leukemia accepted article preview online, 09 December 2015. doi:10.1038/leu.2015.337.

PMID: 26648538 [PubMed - as supplied by publisher]

Long-term neural and physiological phenotyping of a single human.

Nat Commun. 2015;6:8885

Authors: Poldrack RA, Laumann TO, Koyejo O, Gregory B, Hover A, Chen MY, Gorgolewski KJ, Luci J, Joo SJ, Boyd RL, Hunicke-Smith S, Simpson ZB, Caven T, Sochat V, Shine JM, Gordon E, Snyder AZ, Adeyemo B, Petersen SE, Glahn DC, Reese Mckay D, Curran JE, Göring HH, Carless MA, Blangero J, Dougherty R, Leemans A, Handwerker DA, Frick L, Marcotte EM, Mumford JA

Abstract
Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders.

PMID: 26648521 [PubMed - in process]

Improving response rates and evaluating nonresponse bias in surveys: AMEE Guide No. 102.

Med Teach. 2015 Dec 9;:1-12

Authors: Phillips AW, Reddy S, Durning SJ

Abstract
Robust response rates are essential for effective survey-based strategies. Researchers can improve survey validity by addressing both response rates and nonresponse bias. In this AMEE Guide, we explain response rate calculations and discuss methods for improving response rates to surveys as a whole (unit nonresponse) and to questions within a survey (item nonresponse). Finally, we introduce the concept of nonresponse bias and provide simple methods to measure it.

PMID: 26648511 [PubMed - as supplied by publisher]

The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence.

Dev Psychopathol. 2015 Dec 9;:1-13

Authors: Quintin EM, Jo B, Hall SS, Bruno JL, Chromik LC, Raman MM, Lightbody AA, Martin A, Reiss AL

Abstract
Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.

PMID: 26648140 [PubMed - as supplied by publisher]

In vivo high-resolution magic angle spinning magnetic and electron paramagnetic resonance spectroscopic analysis of mitochondria-targeted peptide in Drosophila melanogaster with trauma-induced thoracic injury.

Int J Mol Med. 2015 Dec 8;

Authors: Constantinou C, Apidianakis Y, Psychogios N, Righi V, Mindrinos MN, Khan N, Swartz HM, Szeto HH, Tompkins RG, Rahme LG, Tzika AA

Abstract
Trauma is the most common cause of mortality among individuals aged between 1 and 44 years and the third leading cause of mortality overall in the US. In this study, we examined the effects of trauma on the expression of genes in Drosophila melanogaster, a useful model for investigating genetics and physiology. After trauma was induced by a non-lethal needle puncture of the thorax, we observed the differential expression of genes encoding for mitochondrial uncoupling proteins, as well as those encoding for apoptosis-related and insulin signaling-related proteins, thus indicating muscle functional dysregulation. These results prompted us to examine the link between insulin signaling and mitochondrial dysfunction using in vivo nuclear magnetic resonance (NMR) with complementary electron paramagnetic resonance (EPR) spectroscopy. Trauma significantly increased insulin resistance biomarkers, and the NMR spectral profile of the aged flies with trauma-induced thoracic injury resembled that of insulin-resistant chico mutant flies. In addition, the mitochondrial redox status, as measured by EPR, was significantly altered following trauma, indicating mitochondrial uncoupling. A mitochondria-targeted compound, Szeto-Schiller (SS)-31 that promotes adenosine triphosphate (ATP) synthesis normalized the NMR spectral profile, as well as the mitochondrial redox status of the flies with trauma-induced thoracic injury, as assessed by EPR. Based on these findings, we propose a molecular mechanism responsible for trauma-related mortality and also propose that trauma sequelae in aging are linked to insulin signaling and mitochondrial dysfunction. Our findings further suggest that SS-31 attenuats trauma-associated pathological changes.

PMID: 26648055 [PubMed - as supplied by publisher]

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

Nat Commun. 2015;6:10001

Authors: Alioto TS, Buchhalter I, Derdak S, Hutter B, Eldridge MD, Hovig E, Heisler LE, Beck TA, Simpson JT, Tonon L, Sertier AS, Patch AM, Jäger N, Ginsbach P, Drews R, Paramasivam N, Kabbe R, Chotewutmontri S, Diessl N, Previti C, Schmidt S, Brors B, Feuerbach L, Heinold M, Gröbner S, Korshunov A, Tarpey PS, Butler AP, Hinton J, Jones D, Menzies A, Raine K, Shepherd R, Stebbings L, Teague JW, Ribeca P, Giner FC, Beltran S, Raineri E, Dabad M, Heath SC, Gut M, Denroche RE, Harding NJ, Yamaguchi TN, Fujimoto A, Nakagawa H, Quesada V, Valdés-Mas R, Nakken S, Vodák D, Bower L, Lynch AG, Anderson CL, Waddell N, Pearson JV, Grimmond SM, Peto M, Spellman P, He M, Kandoth C, Lee S, Zhang J, Létourneau L, Ma S, Seth S, Torrents D, Xi L, Wheeler DA, López-Otín C, Campo E, Campbell PJ, Boutros PC, Puente XS, Gerhard DS, Pfister SM, McPherson JD, Hudson TJ, Schlesner M, Lichter P, Eils R, Jones DT, Gut IG

Abstract
As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

PMID: 26647970 [PubMed - in process]

Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study.

Vasc Med. 2015 Dec 7;

Authors: McDermott MM, Liu K, Green D, Greenland P, Tian L, Kibbe M, Tracy R, Shah S, Wilkins JT, Huffman M, Zhao L, Huang CC, Auerbach A, Liao Y, Skelly CL, McCarthy W, Lloyd Jones D

Abstract
Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.

PMID: 26647446 [PubMed - as supplied by publisher]

Giant Abdominal Aortic Aneurysms: A Case Series and Review of the Literature.

Vasc Endovascular Surg. 2015 Nov;49(8):242-6

Authors: Ullery BW, Itoga NK, Lee JT

Abstract
INTRODUCTION: Giant abdominal aortic aneurysms (AAAs), defined as those measuring greater than 13.0 cm in transverse diameter, represent a rare clinical entity and present unique anatomic challenges.
METHODS: A retrospective review of a prospectively maintained aneurysm database from 2000 to 2013 was performed at a single academic referral center. Preoperative comorbid status, aneurysm characteristics, procedural details, and perioperative course were recorded for all patients.
RESULTS: Four patients (male, n = 3) with a mean age of 75.2 years (range, 71-80 years) underwent open repair of giant AAAs. The mean AAA size was 14.4 cm (range, 13.2-15.5 cm). All giant AAAs were associated with neck length <10 mm and/or severe neck angulation. At a mean follow-up of 22 months, there has been 1 late death due to nonaneurysm-related causes.
CONCLUSION: Due to anatomic limitation with currently available aortic endografts, giant AAAs have been traditionally repaired using a standard open surgical approach. The feasibility of endovascular aortic aneurysm repair (EVAR) with or without the use of adjunct techniques, including snorkel/chimney or fenestrated EVAR, has yet to be elucidated.

PMID: 26647427 [PubMed - in process]

Glycocalyx Engineering with a Recycling Glycopolymer that Increases Cell Survival In Vivo.

Angew Chem Int Ed Engl. 2015 Nov 13;

Authors: Woods EC, Yee NA, Shen J, Bertozzi CR

Abstract
Synthetic glycopolymers that emulate cell-surface mucins have been used to elucidate the role of mucin overexpression in cancer. However, because they are internalized within hours, these glycopolymers could not be employed to probe processes that occur on longer time scales. In this work, we tested a panel of glycopolymers bearing a variety of lipids to identify those that persist on cell membranes. Strikingly, we found that cholesterylamine (CholA) anchored glycopolymers are internalized into vesicles that serve as depots for delivery back to the cell surface, allowing for the display of cell-surface glycopolymers for at least ten days, even while the cells are dividing. As with native mucins, the cell-surface display of CholA-anchored glycopolymers influenced the focal adhesion distribution. Furthermore, we show that these mimetics enhance the survival of nonmalignant cells in a zebrafish model of metastasis. CholA-anchored glycopolymers therefore expand the application of glycocalyx engineering in glycobiology.

PMID: 26647316 [PubMed - as supplied by publisher]

ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.

Hum Mol Genet. 2015 Dec 8;

Authors: Halim D, Hofstra RM, Signorile L, Verdijk RM, van der Werf CS, Sribudiani Y, Brouwer RW, van IJcken WF, Dahl N, Verheij JB, Baumann C, Kerner J, van Bever Y, Galjart N, Wijnen RM, Tibboel D, Burns AJ, Muller F, Brooks AS, Alves MM

Abstract
Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin γ-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modelling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modelling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility.Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.

PMID: 26647307 [PubMed - as supplied by publisher]

Use of mobile phones for improving vaccination coverage among children living in rural hard-to-reach areas and urban streets of Bangladesh.

Vaccine. 2015 Nov 29;

Authors: Uddin MJ, Shamsuzzaman M, Horng L, Labrique A, Vasudevan L, Zeller K, Chowdhury M, Larson CP, Bishai D, Alam N

Abstract
In Bangladesh, full vaccination rates among children living in rural hard-to-reach areas and urban streets are low. We conducted a quasi-experimental pre-post study of a 12-month mobile phone intervention to improve vaccination among 0-11 months old children in rural hard-to-reach and urban street dweller areas. Software named "mTika" was employed within the existing public health system to electronically register each child's birth and remind mothers about upcoming vaccination dates with text messages. Android smart phones with mTika were provided to all health assistants/vaccinators and supervisors in intervention areas, while mothers used plain cell phones already owned by themselves or their families. Pre and post-intervention vaccination coverage was surveyed in intervention and control areas. Among children over 298 days old, full vaccination coverage actually decreased in control areas - rural baseline 65.9% to endline 55.2% and urban baseline 44.5% to endline 33.9% - while increasing in intervention areas from rural baseline 58.9% to endline 76*8%, difference +18.8% (95% CI 5.7-31.9) and urban baseline 40.7% to endline 57.1%, difference +16.5% (95% CI 3.9-29.0). Difference-in-difference (DID) estimates were +29.5% for rural intervention versus control areas and +27.1% for urban areas for full vaccination in children over 298 days old, and logistic regression adjusting for maternal education, mobile phone ownership, and sex of child showed intervention effect odds ratio (OR) of 3.8 (95% CI 1.5-9.2) in rural areas and 3.0 (95% CI 1.4-6.4) in urban areas. Among all age groups, intervention effects on age-appropriate vaccination coverage were positive: DIDs +13.1-30.5% and ORs 2.5-4.6 (p<0.001 in all comparisons). Qualitative data showed the intervention was well-accepted. Our study demonstrated that a mobile phone intervention can improve vaccination coverage in rural hard-to-reach and urban street dweller communities in Bangladesh. This small-scale successful demonstration should serve as an example to other low-income countries with high mobile phone usage.

PMID: 26647290 [PubMed - as supplied by publisher]

Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the PREVENT IV Trial.

Circulation. 2015 Dec 8;

Authors: Harskamp RE, Alexander JH, Ferguson TB, Hager R, Mack MJ, Englum B, Wojdyla D, Schulte PJ, Kouchoukos NT, de Winter RJ, Gibson CM, Peterson ED, Harrington RA, Smith PK, Lopes RD

Abstract
BACKGROUND: -The internal mammary artery (IMA) is the preferred conduit for bypassing the left anterior descending (LAD) artery in patients undergoing coronary artery bypass grafting (CABG). Systematic evaluation of the frequency and predictors of IMA failure and long-term outcomes is lacking.
METHODS AND RESULTS: -PREVENT IV trial participants who underwent IMA-LAD revascularization and had 12-18-month angiographic follow-up (n=1539) were included. Logistic regression with fast false selection rate methods was used to identify characteristics associated with IMA failure (≥75% stenosis). The relationship between IMA failure and long-term outcomes including death, myocardial infarction, and repeat revascularization was assessed using Cox regression. IMA failure occurred in 132 participants (8.6%). Predictors of IMA graft failure were LAD stenosis <75% (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.19-2.59), additional bypass graft to diagonal branch (OR, 1.92; 95% CI, 1.33-2.76), and not having diabetes (OR, 1.82; 95% CI, 1.20-2.78). LAD stenosis and additional diagonal graft remained predictive of IMA failure in an alternative model that included angiographic failure or death before angiography as the outcome. IMA failure was associated with a significantly higher incidence of subsequent acute (<14 days of angiography) clinical events, mostly due to a higher rate of repeat revascularization.
CONCLUSIONS: -IMA failure was common and associated with higher rates of repeat revascularization, and patients with intermediate LAD stenosis or with an additional bypass graft to the diagonal branch had increased risk for IMA failure. These findings raise concerns regarding competitive flow and the benefit of CABG in intermediate LAD stenosis without functional evidence of ischemia. Clinical Trial Registration Information-ClinicalTrials.gov. Identifier: NCT00042081.

PMID: 26647082 [PubMed - as supplied by publisher]

Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease.

Neurosurg Focus. 2015 Nov;39(5):E4

Authors: Ali R, Goubran M, Choudhri O, Zeineh MM

Abstract
The goal of this paper was to review the effectiveness of using 7-T MRI to study neuroimaging biomarkers for Alzheimer's disease (AD). The authors reviewed the literature for articles published to date on the use of 7-T MRI to study AD. Thus far, there are 3 neuroimaging biomarkers for AD that have been studied using 7-T MRI in AD tissue: 1) neuroanatomical atrophy; 2) molecular characterization of hypointensities; and 3) microinfarcts. Seven-Tesla MRI has had mixed results when used to study the 3 aforementioned neuroimaging biomarkers for AD. First, in the detection of neuroanatomical atrophy, 7-T MRI has exciting potential. Historically, noninvasive imaging of neuroanatomical atrophy during AD has been limited by suboptimal resolution. However, now there is compelling evidence that the high resolution of 7-T MRI may help overcome this hurdle. Second, in detecting the characterization of hypointensities, 7-T MRI has had varied success. PET scans will most likely continue to lead in the noninvasive imaging of amyloid plaques; however, there is emerging evidence that 7-T MRI can accurately detect iron deposits within activated microglia, which may help shed light on the role of the immune system in AD pathogenesis. Finally, in the detection of microinfarcts, 7-T MRI may also play a promising role, which may help further elucidate the relationship between cerebrovascular health and AD progression.

PMID: 26646928 [PubMed - in process]

Introduction: Neuroimaging of degenerative and traumatic encephalopathies.

Neurosurg Focus. 2015 Nov;39(5):E1

Authors: Law M, Wintermark M, Liu C, Van Horn JD

PMID: 26646925 [PubMed - in process]

Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy.

J Clin Gastroenterol. 2015 Dec 5;

Authors: Chaung KT, O'Brien C, Ha NB, Nguyen NH, Trinh HN, Nguyen MH

Abstract
BACKGROUND: Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long-term outcome data comparing maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA)<40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders.
METHODS: This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV=0.5 mg partial responders (detectable HBV DNA after ≥12 mo on ETV) who maintained ETV=0.5 mg daily (n=29) or switched to either ETV=1.0 mg daily (n=32) or ETV/tenofovir (TDF)=0.5 mg/300 mg (n=25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV=0.5 mg, comparison at regimen "switch time" was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan-Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS.
RESULTS: In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline alanine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log10 IU/mL, P=0.05) and HBV DNA at regimen switch point (2.9 vs. 3.7 vs. 3.6 log10 IU/mL, P=0.0014) were lower in the ETV=0.5 mg cohort compared with those switched to ETV=1.0 mg or ETV/TDF, respectively. The ETV=0.5 mg cohort also had the shortest duration of ETV=0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P<0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV=0.5 mg or ETV=1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV=0.5 mg and ETV=1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multivariate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV=0.5 mg, indicated that the ETV/TDF combination (HR=12.19, P<0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR=0.77, P=0.02) and at switch point (HR=0.46, P=0.002) were negatively associated with CVS. ETV=1.0 mg dose was not a predictor for CVS compared with ETV=0.5 mg.
CONCLUSIONS: Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV=0.5 mg daily compared with ETV=0.5 mg or ETV=1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV=0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients.

PMID: 26646801 [PubMed - as supplied by publisher]

Exposure-wide epidemiology: revisiting Bradford Hill.

Stat Med. 2015 Dec 8;

Authors: Ioannidis JP

Abstract
Fifty years after Bradford Hill published his extremely influential criteria to offer some guides for separating causation from association, we have accumulated millions of papers and extensive data on observational research that depends on epidemiologic methods and principles. This allows us to re-examine the accumulated empirical evidence for the nine criteria, and to re-approach epidemiology through the lens of exposure-wide approaches. The lecture discusses the evolution of these exposure-wide approaches and tries to use the evidence from meta-epidemiologic assessments to reassess each of the nine criteria and whether they work well as guides for causation. I argue that of the nine criteria, experiment remains important and consistency (replication) is also very essential. Temporality also makes sense, but it is often difficult to document. Of the other six criteria, strength mostly does not work and may even have to be inversed: small and even tiny effects are more plausible than large effects; when large effects are seen, they are mostly transient and almost always represent biases and errors. There is little evidence for specificity in causation in nature. Biological gradient is often unclear how it should it modeled and thus difficult to prove. Coherence remains usually unclear how to operationalize. Finally, plausibility as well as analogy do not work well in most fields of investigation, and their invocation has been mostly detrimental, although exceptions may exist. Copyright © 2015 John Wiley & Sons, Ltd.

PMID: 26646432 [PubMed - as supplied by publisher]

Electrocardiogram ST Analysis During Labor: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Obstet Gynecol. 2015 Dec 7;

Authors: Saccone G, Schuit E, Amer-Wåhlin I, Xodo S, Berghella V

Abstract
OBJECTIVE: To compare the effectiveness of cardiotocography plus ST analysis with cardiotocography alone during labor.
DATA SOURCES: Randomized controlled trials were identified by searching electronic databases.
METHODS OF STUDY SELECTION: We included all randomized controlled trials comparing intrapartum fetal monitoring with cardiotocography plus ST analysis with cardiotocography alone. The primary outcome (ie, perinatal composite outcome) was a composite of intrapartum fetal death, neonatal death, Apgar score 3 or less at 5 minutes, neonatal seizure, metabolic acidosis (defined as umbilical arterial pH 7.05 or less, and extracellular fluid base deficit 12 mmol/L or greater), intubation for ventilation at delivery, or neonatal encephalopathy.
TABULATION, INTEGRATION, AND RESULTS: Six randomized controlled trials, which included 26,529 laboring singletons with cephalic presentation at term, were analyzed. Compared with women who were randomized to cardiotocography, those who were randomized to ST analysis and cardiotocography had a similar incidence of perinatal composite outcome (1.5% compared with 1.6%; relative risk [RR] 0.90, 95% confidence interval [CI] 0.74-1.10; five studies), neonatal metabolic acidosis (0.5% compared with 0.7%; RR 0.74, 95% CI 0.54-1.02; five studies), admission to the neonatal intensive care unit (5.4% compared with 5.5%; RR 0.99, 95% CI 0.90-1.10; six studies), perinatal death (0.1% compared with 0.1%; RR 1.71, 95% CI 0.67-4.33; six studies), neonatal encephalopathy (0.1% compared with 0.2%; RR 0.62, 95% CI 0.25-1.52; six studies), cesarean delivery (13.8% compared with 14.0%; RR 0.96, 95% CI 0.85-1.08; six studies), and operative delivery (either cesarean or operative vaginal delivery) (23.9% compared with 25.1%; RR 0.93, 95% CI 0.86-1.01; six studies).
CONCLUSION: The use of ST analysis during labor as an adjunct to the standard cardiotocography does not improve perinatal outcomes or decrease cesarean delivery.

PMID: 26646135 [PubMed - as supplied by publisher]

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

Obstet Gynecol. 2015 Dec 7;

Authors: Parker WH, Kaunitz AM, Pritts EA, Olive DL, Chalas E, Clarke-Pearson DL, Berek JS, Leiomyoma Morcellation Review Group

Abstract
The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 46-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

PMID: 26646134 [PubMed - as supplied by publisher]

Comprehensive motion-compensated highly accelerated 4D flow MRI with ferumoxytol enhancement for pediatric congenital heart disease.

J Magn Reson Imaging. 2015 Dec 9;

Authors: Cheng JY, Hanneman K, Zhang T, Alley MT, Lai P, Tamir JI, Uecker M, Pauly JM, Lustig M, Vasanawala SS

Abstract
PURPOSE: To develop and evaluate motion-compensation and compressed-sensing techniques in 4D flow MRI for anatomical assessment in a comprehensive ferumoxytol-enhanced congenital heart disease (CHD) exam.
MATERIALS AND METHODS: A Cartesian 4D flow sequence was developed to enable intrinsic navigation and two variable-density sampling schemes: VDPoisson and VDRad. Four compressed-sensing methods were developed: A) VDPoisson scan reconstructed using spatial wavelets; B) added temporal total variation to A; C) VDRad scan using the same reconstruction as in B; and D) added motion compensation to C. With Institutional Review Board (IRB) approval and Health Insurance Portability and Accountability Act (HIPAA) compliance, 23 consecutive patients (eight females, mean 6.3 years) referred for ferumoxytol-enhanced CHD 3T MRI were recruited. Images were acquired and reconstructed using methods A-D. Two cardiovascular radiologists independently scored the images on a 5-point scale. These readers performed a paired wall motion and functional assessment between method D and 2D balanced steady-state free precession (bSSFP) CINE for 16 cases.
RESULTS: Method D had higher diagnostic image quality for most anatomical features (mean 3.8-4.8) compared to A (2.0-3.6), B (2.2-3.7), and C (2.9-3.9) with P < 0.05 with good interobserver agreement (κ ≥ 0.49). Method D had similar or better assessment of myocardial borders and cardiac motion compared to 2D bSSFP (P < 0.05, κ ≥ 0.77). All methods had good internal agreement in comparing aortic with pulmonic flow (BA mean < 0.02%, r > 0.85) and compared to method A (BA mean < 0.13%, r > 0.84) with P < 0.01.
ONCLUSION: Flow, functional, and anatomical assessment in CHD with ferumoxytol-enhanced 4D flow is feasible and can be significantly improved using motion compensation and compressed sensing. J. Magn. Reson. Imaging 2015.

PMID: 26646061 [PubMed - as supplied by publisher]

Facial Nerve Outcome and Tumor Control Rate as a Function of Degree of Resection in Treatment of Large Acoustic Neuromas: Preliminary Report of the Acoustic Neuroma Subtotal Resection Study.

Neurosurgery. 2015 Nov 28;

Authors: Monfared A, Corrales E, Theodosopoulos P, Blevins NH, Oghalai JS, Selesnick SH, Lee H, Gurgel RK, Hansen MR, Nelson RF, Gantz B, Kutz W, Isaacson B, Roland P, Amdur R, Jackler R

Abstract
BACKGROUND: Patients with large vestibular schwannomas are at high risk of poor facial nerve (cranial nerve VII [CNVII]) function after surgery. Subtotal resection potentially offers better outcome, but may lead to higher tumor regrowth.
OBJECTIVE: To assess long-term CNVII function and tumor regrowth in patients with large vestibular schwannomas.
METHODS: Prospective multicenter nonrandomized cohort study of patients with vestibular schwannoma ≥2.5 cm who received gross total resection, near total resection, or subtotal resection. Patients received radiation if tumor remnant showed signs of regrowth.
RESULTS: Seventy-three patients had adequate follow-up with mean tumor diameter of 3.33 cm. Twelve received gross total resection, 22 near total resection, and 39 subtotal resection. Fourteen (21%) remnant tumors continued to grow, of which 11 received radiation, 1 had repeat surgery, and 2 no treatment. Four of the postradiation remnants (36%) required surgical salvage. Tumor regrowth was related to non-cystic nature, larger residual tumor, and subtotal resection. Regrowth was 3 times as likely with subtotal resection compared to gross total resection and near total resection. Good CNVII function was achieved in 67% immediately and 81% at 1-year. Better immediate nerve function was associated with smaller preoperative tumor size and percentage of tumor left behind on magnetic resonance image. Degree of resection defined by surgeon and preoperative tumor size showed weak trend toward better late CNVII function.
CONCLUSION: Likelihood of tumor regrowth was 3 times higher in subtotal resection compared to gross total resection and near total resection groups. Rate of radiation control of growing remnants was suboptimal. Better immediate but not late CNVII outcome was associated with smaller tumors and larger tumor remnants.
ABBREVIATIONS: CNVII, cranial nerve VIIGTR, gross total resectionHB, House-BrackmannMRI, magnetic resonance imageNTR, near total resectionSTR, subtotal resection.

PMID: 26645964 [PubMed - as supplied by publisher]

Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.

Nat Commun. 2015;6:10049

Authors: Leipold E, Hanson-Kahn A, Frick M, Gong P, Bernstein JA, Voigt M, Katona I, Oliver Goral R, Altmüller J, Nürnberg P, Weis J, Hübner CA, Heinemann SH, Kurth I

Abstract
Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity.

PMID: 26645915 [PubMed - in process]

Toward Development of Psychosocial Measures for Automated Insulin Delivery.

J Diabetes Sci Technol. 2015 Dec 7;

Authors: Weissberg-Benchell J, Hood K, Laffel L, Heinemann L, Ball D, Kowalski A, Peters A, Damiano E, Schiller M, Davis A, Beck S, Barnard K

Abstract
The INSPIRE study working group launched its initial workshop in February 2015 to facilitate collaboration among key stakeholders interested in automated insulin delivery (AID) systems and the psychosocial outcomes of individuals who may use these new technologies. Specifically, the INSPIRE team's goal is to facilitate measure development assessing the psychosocial factors associated with AID systems. A second working group was held to foster exchange among key stakeholders in AID system development. Patient, health care provider, engineering, industry, academic, regulatory and payer perspectives were presented. The INSPIRE working group will continue to serve as a platform to encourage open dialogue among all stakeholders with the aim of facilitating technology that offers minimal user burden and maximum benefit from both a psychological and physiologic perspective.

PMID: 26645792 [PubMed - as supplied by publisher]

Regulation of the Water Channel Aquaporin-2 via 14-3-3 Theta (θ) and Zeta (ζ).

J Biol Chem. 2015 Dec 8;

Authors: Moeller HB, Slengerik-Hansen J, Aroankins T, Assentoft M, MacAulay N, Moestrup SK, Bhalla V, Fenton RA

Abstract
The 14-3-3 family of proteins are multifunctional proteins that interact with many of their cellular targets in a phosphorylation-dependent manner. Here, we determined that 14-3-3 proteins interact with phosphorylated forms of the water channel aquaporin-2 (AQP2) and modulate its function. With the exception of sigma (σ), all 14-3-3 isoforms were abundantly expressed in mouse kidney and mouse kidney collecting duct cells (mpkCCD14). Long-term treatment of mpkCCD14 cells with the type 2 vasopressin receptor agonist dDAVP increased mRNA and protein levels of AQP2 alongside 14-3-3 beta (β) and zeta (ζ), whereas levels of 14-3-3 eta (η) and theta (θ) were decreased. Co-immunoprecipitation (co-IP) studies in mpkCCD14 cells uncovered an AQP2:14-3-3 interaction that was modulated by acute dDAVP treatment. Additional co-IP studies in HEK293 cells determined that AQP2 interacts selectively with 14-3-3 ζ and θ. Use of phosphatase inhibitors in mpkCCD14 cells, co-IP with phosphorylation deficient forms of AQP2 expressed in HEK293 cells, or surface plasmon resonance studies determined that the AQP2:14-3-3 interaction was modulated by phosphorylation of AQP2 at various sites in its carboxyl-terminus, with ser256 phosphorylation critical for the interactions. shRNA-mediated knockdown of 14-3-3 ζ in mpkCCD14 cells resulted in increased AQP2 ubiquitylation, decreased AQP2 protein half-life and reduced AQP2 levels. In contrast, knockdown of 14-3-3 θ resulted in increased AQP2 half-life and increased AQP2 levels. In conclusion, this study demonstrates phosphorylation-dependent interactions of AQP2 with 14-3-3 θ and ζ. These interactions play divergent roles in modulating AQP2 trafficking, phosphorylation, ubiquitylation and degradation.

PMID: 26645691 [PubMed - as supplied by publisher]

The Role of Anxiety Control and Treatment Implications of Informant Agreement on Child PTSD Symptoms.

J Clin Child Adolesc Psychol. 2015 Dec 8;:1-12

Authors: Humphreys KL, Weems CF, Scheeringa MS

Abstract
The goal of this study is to examine parent and child agreement of child posttraumatic stress disorder (PTSD) symptoms pre- and posttreatment, as well as potential moderators of agreement including treatment responder status, child anxiety control, and parent self-reported PTSD symptoms. We examined child self-reported and parent-reported child PTSD symptoms from the Diagnostic Interview Schedule for Children. Of the 141 parent-child pairs, the mean age of children was 12.72 (SD = 3.40), 53% were female, and 54% were Black. A subsample of participants (n = 47) was assessed after completion of a cognitive behavioral therapy treatment for PTSD. Moderate levels of agreement were found at baseline, though Criterion D (increased arousal) symptoms had lower levels of agreement than the other symptom clusters. Symptom agreement was lower at posttreatment. Treatment responders had higher levels of baseline informant agreement than treatment nonresponders. Child perceived anxiety control significantly moderated informant agreement, such that pairs with children who had high levels of perceived control of their anxiety had lower PTSD symptom agreement where children reported lower symptoms relative to their parents. Contrary to expectations, parent self-reported PTSD did not moderate parent-child symptom agreement. Factors associated with higher parent-child agreement of child PTSD symptoms were being a PTSD treatment responder and children with lower perceived anxiety control. These findings have potential implications for determining those who may benefit from greater symptom monitoring over the course of intervention and potential alternative intervention approaches.

PMID: 26645622 [PubMed - as supplied by publisher]

A small-molecule antagonist of the β-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis.

Cancer Res. 2015 Dec 8;

Authors: Fang L, Zhu Q, Neuenschwander M, Specker E, Wulf-Goldenberg A, Weis WI, von Kries JP, Birchmeier W

Abstract
Wnt/beta-catenin signaling is a highly conserved pathway essential for embryogenesis and tissue homeostasis. However, deregulation of this pathway can initiate and promote human malignancies, especially of the colon and head and neck. Therefore, Wnt/beta-catenin signaling represents an attractive target for cancer therapy. We performed high-throughput screening (HTS) using AlphaScreen and ELISA techniques to identify small molecules that disrupt the critical interaction between beta-catenin and the transcription factor TCF4 required for signal transduction. We found that compound LF3, a 4-thioureido-benzenesulfonamide derivative, robustly inhibited this interaction. Biochemical assays revealed clues that the core structure of LF3 was essential for inhibition. LF3 inhibited Wnt/beta-catenin signals in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. LF3 also suppressed features of cancer cells related to Wnt signaling, including high cell motility, cell cycle progression, and the overexpression of Wnt target genes. However, LF3 did not cause cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under non-adherent conditions. Finally, LF3 reduced tumor growth and induced differentiation in a mouse xenograft model of colon cancer. Collectively, our results strongly suggest that LF3 is a specific inhibitor of canonical Wnt signaling with anticancer activity that warrants further development for preclinical and clinical studies as a novel cancer therapy.

PMID: 26645562 [PubMed - as supplied by publisher]

Correlates of poor glycemic control among patients with diabetes initiating hemodialysis for end-stage renal disease.

BMC Nephrol. 2015;16(1):204

Authors: Rhee JJ, Ding VY, Rehkopf DH, Arce CM, Winkelmayer WC

Abstract
BACKGROUND: Maintaining tight glycemic control is important for prevention of diabetes-related outcomes in end-stage renal disease patients with diabetes, especially in light of their poor prognosis. This study aimed to determine factors associated with poor glycemic control among U.S. patients with diabetes mellitus initiating hemodialysis for end-stage renal disease.
METHODS: Using data from the U.S. Renal Data System, electronic health records of a large national dialysis provider, and U.S. Census data, we performed a cross-sectional multivariable Poisson regression analysis to characterize risk factors associated with poor glycemic control, defined as glycated hemoglobin (HbA1c) >7 vs. ≤7 %, in adult patients with diabetes who initiated hemodialysis at an outpatient facility between 2006 and 2011.
RESULTS: Of 16,297 patients with diabetes, 21.2 % had HbA1c >7 %. In multivariable analysis, younger patients, patients of Native American race, and those of Hispanic ethnicity had higher prevalence of poor glycemic control. Independent correlates of poor glycemic control further included higher platelet count, white blood cell count, and ferritin; higher body mass index, systolic blood pressure, total cholesterol and triglyceride concentrations; lower HDL and albumin concentrations; lower normalized protein catabolic rate; and higher estimated glomerular filtration rate at initiation of dialysis (all P < 0.05). No independent associations were found with area-level socioeconomic indicators. Occurrence of diabetes in patients <40 years of age, a proxy for type 1 diabetes, was associated with poor HbA1c control compared with that in patients ≥40 years of age, which was classified as type 2 diabetes. These findings were robust to the different outcome definitions of HbA1c >7.5 % and >8 %.
CONCLUSION: In this cohort of incident end-stage renal disease patients with diabetes, poor glycemic control was independently associated with younger age, Native American race, Hispanic ethnicity, higher body mass index, and clinical risk factors including atherogenic lipoprotein profile, hypertension, inflammation, and markers indicative of malnutrition and a more serious systemic disease.

PMID: 26645204 [PubMed - in process]