Lane Medical Library

Identification of Multipotent Progenitors that Emerge Prior to Hematopoietic Stem Cells in Embryonic Development.

Stem Cell Reports. 2014 Apr 8;2(4):457-72

Authors: Inlay MA, Serwold T, Mosley A, Fathman JW, Dimov IK, Seita J, Weissman IL

Abstract
Hematopoiesis in the embryo proceeds in a series of waves, with primitive erythroid-biased waves succeeded by definitive waves, within which the properties of hematopoietic stem cells (multilineage potential, self-renewal, and engraftability) gradually arise. Whereas self-renewal and engraftability have previously been examined in the embryo, multipotency has not been thoroughly addressed, especially at the single-cell level or within well-defined populations. To identify when and where clonal multilineage potential arises during embryogenesis, we developed a single-cell multipotency assay. We find that, during the initiation of definitive hematopoiesis in the embryo, a defined population of multipotent, engraftable progenitors emerges that is much more abundant within the yolk sac (YS) than the aorta-gonad-mesonephros (AGM) or fetal liver. These experiments indicate that multipotent cells appear in concert within both the YS and AGM and strongly implicate YS-derived progenitors as contributors to definitive hematopoiesis.

PMID: 24749071 [PubMed]

FOXO3 Promotes Quiescence in Adult Muscle Stem Cells during the Process of Self-Renewal.

Stem Cell Reports. 2014 Apr 8;2(4):414-26

Authors: Gopinath SD, Webb AE, Brunet A, Rando TA

Abstract
Skeletal muscle stem cells, or "satellite cells" (SCs), are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs). Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD) rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.

PMID: 24749067 [PubMed]

Spontaneous cardiomyocyte differentiation of mouse embryoid bodies regulated by hydrogel crosslink density.

Biomater Sci. 2013 Oct 1;1(10):1082-1090

Authors: Chung C, Pruitt BL, Heilshorn SC

Abstract
Cellular therapies have great potential to provide alternative treatment options for those suffering from heart disease. In order to optimize cell delivery for therapeutic efficacy, a greater understanding of parameters that impact stem cell differentiation, survival, growth, and development are needed. In this study, we examine the role of hydrogel crosslink density on spontaneous cardiomyocyte (CM) differentiation of murine embryoid bodies (EBs). CM differentiation was accelerated in hydrogels of low crosslink density, where 100% of the hydrogels were positive for CM differentiation compared to only 53% in the high crosslink density group after 8 days of culture. DNA microarray data suggests that enhanced CM differentiation in the low crosslink density hydrogels was not tissue specific but rather a result of favoured EB development and cell proliferation. Additionally, enhanced EB growth and differentiation in low crosslink density hydrogels was independent of RGD ligand density and not a consequence of enhanced diffusion. We also demonstrate that matrix metalloproteinase activity is required for spontaneous CM differentiation in 3D hydrogels. Low hydrogel crosslink density regulates spontaneous EB differentiation by promoting EB growth and development. Elucidating the effects of microenvironmental cues on cell differentiation can aid in the optimization of stem cell-based therapies for tissue regeneration.

PMID: 24748962 [PubMed - as supplied by publisher]

Psychological therapies for the management of chronic pain.

Psychol Res Behav Manag. 2014;7:115-124

Authors: Sturgeon JA

Abstract
Pain is a complex stressor that presents a significant challenge to most aspects of functioning and contributes to substantial physical, psychological, occupational, and financial cost, particularly in its chronic form. As medical intervention frequently cannot resolve pain completely, there is a need for management approaches to chronic pain, including psychological intervention. Psychotherapy for chronic pain primarily targets improvements in physical, emotional, social, and occupational functioning rather than focusing on resolution of pain itself. However, psychological therapies for chronic pain differ in their scope, duration, and goals, and thus show distinct patterns of treatment efficacy. These therapies fall into four categories: operant-behavioral therapy, cognitive-behavioral therapy, mindfulness-based therapy, and acceptance and commitment therapy. The current article explores the theoretical distinctiveness, therapeutic targets, and effectiveness of these approaches as well as mechanisms and individual differences that factor into treatment response and pain-related dysfunction and distress. Implications for future research, dissemination of treatment, and the integration of psychological principles with other treatment modalities are also discussed.

PMID: 24748826 [PubMed - as supplied by publisher]

A robust classifier to distinguish noise from FMRI independent components.

PLoS One. 2014;9(4):e95493

Authors: Sochat V, Supekar K, Bustillo J, Calhoun V, Turner JA, Rubin DL

Abstract
Analyzing Functional Magnetic Resonance Imaging (fMRI) of resting brains to determine the spatial location and activity of intrinsic brain networks-a novel and burgeoning research field-is limited by the lack of ground truth and the tendency of analyses to overfit the data. Independent Component Analysis (ICA) is commonly used to separate the data into signal and Gaussian noise components, and then map these components on to spatial networks. Identifying noise from this data, however, is a tedious process that has proven hard to automate, particularly when data from different institutions, subjects, and scanners is used. Here we present an automated method to delineate noisy independent components in ICA using a data-driven infrastructure that queries a database of 246 spatial and temporal features to discover a computational signature of different types of noise. We evaluated the performance of our method to detect noisy components from healthy control fMRI (sensitivity = 0.91, specificity = 0.82, cross validation accuracy (CVA) = 0.87, area under the curve (AUC) = 0.93), and demonstrate its generalizability by showing equivalent performance on (1) an age- and scanner-matched cohort of schizophrenia patients from the same institution (sensitivity = 0.89, specificity = 0.83, CVA = 0.86), (2) an age-matched cohort on an equivalent scanner from a different institution (sensitivity = 0.88, specificity = 0.88, CVA = 0.88), and (3) an age-matched cohort on a different scanner from a different institution (sensitivity = 0.72, specificity = 0.92, CVA = 0.79). We additionally compare our approach with a recently published method [1]. Our results suggest that our method is robust to noise variations due to population as well as scanner differences, thereby making it well suited to the goal of automatically distinguishing noise from functional networks to enable investigation of human brain function.

PMID: 24748378 [PubMed - in process]

Getting the Dead Out: Modern Treatment Strategies for Necrotizing Pancreatitis.

Dig Dis Sci. 2014 Apr 20;

Authors: Dua MM, Worhunsky DJ, Amin S, Louie JD, Park WG, Triadafilopoulos G, Visser BC

PMID: 24748229 [PubMed - as supplied by publisher]

Methods to Promote Germination of Dormant Setaria viridis Seeds.

PLoS One. 2014;9(4):e95109

Authors: Sebastian J, Wong MK, Tang E, Dinneny JR

Abstract
Setaria viridis has recently emerged as a promising genetic model system to study diverse aspects of monocot biology. While the post-germination life cycle of S. viridis is approximately 8 weeks long, the prolonged dormancy of freshly harvested seeds can more than double the total time required between successive generations. Here we describe methods that promote seed germination in S. viridis. Our results demonstrate that treating S. viridis seeds with liquid smoke or a GA3 and KNO3 solution improves germination rates to 90% or higher even in seeds that are 6 days post-harvest with similar results obtained whether seeds are planted in soil or on gel-based media. Importantly, we show that these treatments have no significant effect on the growth of the adult plant. We have tested these treatments on diverse S. viridis accessions and show variation in their response. The methods described here will help advance research using this model grass species by increasing the pace at which successive generations of plants can be analyzed.

PMID: 24748008 [PubMed - in process]

Diversity and transport of microorganisms in intertidal sands of the California Coast.

Appl Environ Microbiol. 2014 Apr 18;

Authors: Boehm AB, Yamahara KM, Sassoubre LM

Abstract
Forced by tides and waves, large volumes of seawater are flushed through the beach daily. Organic material and nutrients in seawater are remineralized and cycled as they pass through the beach. Microorganisms are responsible for most of the biogeochemical cycling in the beach, however, few studies have characterized their diversity in intertidal sands, and little work has characterized the extent to which microbes are transported between different compartments of the beach. The present study uses next generation massively parallel sequencing to characterize the microbial community present at 49 beaches along the coast of California. In addition, we characterize the transport of microorganisms within intertidal sands using laboratory column experiments. We identified extensive diversity in the beach sands. Nearly 1000 unique taxa were identified in sands from 10 or more unique beaches suggesting the existence of a group of 'cosmopolitan' sand microorganisms. A biogeographical analysis identified a taxa-distance relationship among the beaches. In addition, sands with similar grain size, organic carbon content, exposed to a similar wave climate, and having the same degree of anthropogenic influence tended to have similar microbial communities. Column experiments identified microbes readily mobilized by seawater infiltrating through unsaturated intertidal sands. The ease with which microbes were mobilized suggests intertidal sands may represent a reservoir of bacteria that seed the beach aquifer where they may partake in biogeochemical cycling.

PMID: 24747906 [PubMed - as supplied by publisher]

Subnanosecond incubation times for electric-field-induced metallization of a correlated electron oxide.

Nat Nanotechnol. 2014 Apr 20;

Authors: Brockman JS, Gao L, Hughes B, Rettner CT, Samant MG, Roche KP, Parkin SS

Abstract
Strong interactions, or correlations, between the d or f electrons in transition-metal oxides lead to various types of metal-insulator transitions that can be triggered by external parameters such as temperature, pressure, doping, magnetic fields and electric fields. Electric-field-induced metallization of such materials from their insulating states could enable a new class of ultrafast electronic switches and latches. However, significant questions remain about the detailed nature of the switching process. Here, we show, in the canonical metal-to-insulator transition system V2O3, that ultrafast voltage pulses result in its metallization only after an incubation time that ranges from ∼150 ps to many nanoseconds, depending on the electric field strength. We show that these incubation times can be accounted for by purely thermal effects and that intrinsic electronic-switching mechanisms may only be revealed using larger electric fields at even shorter timescales.

PMID: 24747840 [PubMed - as supplied by publisher]

In reply to letter entitled "Heart failure and breast cancer: emerging controversies regarding some cardioprotective strategies"

J Card Fail. 2014 Apr 16;

Authors: Witteles RM, Thakur A

PMID: 24747785 [PubMed - as supplied by publisher]

Optical Fano resonance of an individual semiconductor nanostructure.

Nat Mater. 2014 Apr 20;

Authors: Fan P, Yu Z, Fan S, Brongersma ML

Abstract
Fano resonances with a characteristic asymmetric line shape can be observed in light scattering, transmission and reflection spectra of resonant optical systems. They result from interference between direct and indirect, resonance-assisted pathways. In the nanophotonics field, Fano effects have been observed in a wide variety of systems, including metallic nanoparticle assemblies, metamaterials and photonic crystals. Their unique properties find extensive use in applications, including optical filtering, polarization selectors, sensing, lasers, modulators and nonlinear optics. We report on the observation of a Fano resonance in a single semiconductor nanostructure, opening up opportunities for their use in active photonic devices. We also show that Fano-resonant semiconductor nanostructures afford the intriguing opportunity to simultaneously measure the far-field scattering response and the near-field energy storage by extracting photogenerated charge. Together they can provide a complete experimental characterization of this type of resonance.

PMID: 24747781 [PubMed - as supplied by publisher]

Updating emotional content in working memory: A depression-specific deficit?

J Behav Ther Exp Psychiatry. 2014 Apr 4;45(3):368-374

Authors: Yoon KL, Lemoult J, Joormann J

Abstract
BACKGROUND AND OBJECTIVES: Interference from irrelevant negative material might be a key mechanism underlying intrusive ruminative thoughts in depression. Considering commonalities between depression and social anxiety and the presence of similar intrusive thoughts in social anxiety, the current study was designed to assess whether interference from irrelevant material in working memory is specific to depression or is also present in social anxiety disorder.
METHODS: To examine the effects of irrelevant emotional material on working memory performance, participants memorized two lists of words on each trial and were subsequently instructed to ignore one of the lists. Participants were then asked to indicate whether a probe word belonged to the relevant list or not.
RESULTS: Compared to control and social anxiety groups, the depression groups (both pure and comorbid with social anxiety disorder) exhibited greater difficulties removing irrelevant emotional material from working memory (i.e., greater intrusion effects). Greater intrusion effects were also associated with increased rumination.
LIMITATIONS: Although we included three clinical groups (depression, social anxiety, and the comorbid groups), the results are based on a relatively small number of participants.
CONCLUSIONS: The results indicate that difficulties removing irrelevant material from working memory might be unique to depression, and the ability to inhibit irrelevant information is relatively preserved in social anxiety disorder.

PMID: 24747511 [PubMed - as supplied by publisher]

Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma.

Nat Cell Biol. 2014 Apr 20;

Authors: Shin K, Lim A, Odegaard JI, Honeycutt JD, Kawano S, Hsieh MH, Beachy PA

Abstract
Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium. These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma in situ. Shh-expressing basal cells within this precursor lesion become tumour-initiating cells, although Shh expression is lost in subsequent carcinomas. We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.

PMID: 24747439 [PubMed - as supplied by publisher]

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Nature. 2014 Apr 20;

Authors: Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, Bolaños JP, Rakovic A, Spin JM, Stubbendorff M, Ikeno F, Länger F, Zeller T, Schulte-Uentrop L, Stoehr A, Itagaki R, Haddad F, Eschenhagen T, Blankenberg S, Kiefmann R, Reichenspurner H, Velden J, Klein C, Yeung A, Robbins RC, Tsao PS, Schrepfer S

Abstract
Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

PMID: 24747400 [PubMed - as supplied by publisher]

Fabrication, vascularization and osteogenic properties of a novel synthetic biomimetic induced membrane for the treatment of large bone defects.

Bone. 2014 Apr 16;

Authors: Ren L, Kang Y, Browne C, Bishop J, Yang Y

Abstract
The induced membrane has been widely used in the treatment of large bone defects but continues to be limited by a relatively lengthy healing process and a requisite two stage surgical procedure. Here we report the development and characterization of a synthetic biomimetic induced membrane (BIM) consisting of an inner highly pre-vascularized cell sheet and an outer osteogenic layer using cell sheet engineering. The pre-vascularized inner layer was formed by seeding human umbilical vein endothelial cells (HUVECs) on a cell sheet comprised of a layer of undifferentiated human bone marrow-derived mesenchymal stem cells (hMSCs). The outer osteogenic layer was formed by inducing osteogenic differentiation of hMSCs. In vitro results indicated the undifferentiated hMSCs cell sheet facilitated the alignment of HUVECs and significantly promoted the formation of vascular-like networks. Furthermore, seeded HUVECs rearranged the extracellular matrix produced by hMSCs sheet. After subcutaneously implantation, the composite constructs showed rapid vascularization and anastomosis with the host vascular system, forming functional blood vessels in vivo. Osteogenic potential of the BIM was evidenced by immunohistochemistry staining of osteocalcin, tartrate-resistant acid phosphatase (TRAP) staining, and alizarin red staining. In summary, the synthetic BIM showed rapid vascularization, significant anastomoses, and osteogenic potential in vivo. This synthetic BIM has the potential for treatment of large bone defects in the absence of infection.

PMID: 24747351 [PubMed - as supplied by publisher]

Sleep Disruption in Hematopoietic Cell Transplant Recipients: Prevalence, Severity, and Clinical Management.

Biol Blood Marrow Transplant. 2014 Apr 17;

Authors: Jim HS, Evans B, Jeong JM, Gonzalez BD, Johnston L, Nelson AM, Kesler S, Phillips KM, Barata A, Pidala J, Palesh O

Abstract
Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of patients experiencing sleep disruption pre-transplant, up to 82% experiencing moderate to severe sleep disruption during hospitalization for transplant, and up to 43% in the post-transplant period. These rates of sleep disruption are substantially higher than the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT in order to facilitate patient education, intervention, and research. The review opens with a discussion of sleep disruption measurement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemographic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as directions for future research.

PMID: 24747335 [PubMed - as supplied by publisher]

Contrasting changes in extracellular dopamine and glutamate along the rostrocaudal axis of the anterior cingulate cortex of the rat following an acute d-amphetamine or dopamine challenge.

Neuropharmacology. 2014 Apr 17;

Authors: Ash E, Heal DJ, Stanford SC

Abstract
There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral ('rACC: Cg1 and Cg3 (prelimbic area)) and caudal ('cACC': Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5 - 50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine into the cACC increased glutamate efflux. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC.

PMID: 24747182 [PubMed - as supplied by publisher]

An Affordable HIV-1 Drug Resistance Monitoring Method for Resource Limited Settings.

J Vis Exp. 2014;(85)

Authors: Manasa J, Danaviah S, Pillay S, Padayachee P, Mthiyane H, Mkhize C, Lessells RJ, Seebregts C, de Wit TF, Viljoen J, Katzenstein D, De Oliveira T

Abstract
HIV-1 drug resistance has the potential to seriously compromise the effectiveness and impact of antiretroviral therapy (ART). As ART programs in sub-Saharan Africa continue to expand, individuals on ART should be closely monitored for the emergence of drug resistance. Surveillance of transmitted drug resistance to track transmission of viral strains already resistant to ART is also critical. Unfortunately, drug resistance testing is still not readily accessible in resource limited settings, because genotyping is expensive and requires sophisticated laboratory and data management infrastructure. An open access genotypic drug resistance monitoring method to manage individuals and assess transmitted drug resistance is described. The method uses free open source software for the interpretation of drug resistance patterns and the generation of individual patient reports. The genotyping protocol has an amplification rate of greater than 95% for plasma samples with a viral load >1,000 HIV-1 RNA copies/ml. The sensitivity decreases significantly for viral loads <1,000 HIV-1 RNA copies/ml. The method described here was validated against a method of HIV-1 drug resistance testing approved by the United States Food and Drug Administration (FDA), the Viroseq genotyping method. Limitations of the method described here include the fact that it is not automated and that it also failed to amplify the circulating recombinant form CRF02_AG from a validation panel of samples, although it amplified subtypes A and B from the same panel.

PMID: 24747156 [PubMed - in process]

High prevalence of screen-detected prostate cancer in West Africans: implications for racial disparity of prostate cancer.

J Urol. 2014 Apr 17;

Authors: Hsing AW, Yeboah E, Biritwum R, Tettey Y, De Marzo AM, Adjei A, Netto GJ, Yu K, Li Y, Chokkalingam AP, Chu LW, Chia D, Partin A, Thompson IM, Quraishi SM, Niwa S, Tarone R, Hoover RN

Abstract
PURPOSE: Reasons for the high rates of prostate cancer in African Americans are unknown; both genetic and lifestyle factors have been implicated. A better understanding of prostate cancer rates in West Africans would help clarify why African Americans have such high rates, since African Americans share genetic ancestry with West Africans yet have very different lifestyles and screening practices. To estimate prostate cancer burden in West Africans, we conducted a population-based screening study with biopsy confirmation in Ghana.
MATERIALS AND METHODS: We randomly selected 1,037 healthy men aged 50-74 from Accra, Ghana for prostate cancer screening with prostate specific antigen (PSA) testing and digital rectal examination (DRE). Men who had a positive screen (DRE+ or PSA>2.5 ng/ml) underwent transrectal ultrasound (TRUS)-guided biopsies.
RESULTS: Of the 1,037 men, 154 (14.9%) had a positive DRE and 272 (26.2%) had a PSA>2.5 ng/ml (166 had a PSA>4.0 ng/ml). In total, 352 (33.9%) men had a positive screen by PSA or DRE, and 307 (87%) had a biopsy. Of these, 73 were confirmed to have prostate cancer, yielding a 7.0% screen-detected prevalence of prostate cancer (65 cases, 5.8% with a PSA>4.0 ng/ml).
CONCLUSIONS: In this relatively unscreened population in Africa, the screen-detected prostate cancer prevalence is high, suggesting a possible role of genetics in both prostate cancer etiology and the disparity in prostate cancer risk between African Americans and Caucasian Americans. Further studies are needed to confirm the high prostate cancer burden in Africans and the role of genetics in prostate cancer etiology.

PMID: 24747091 [PubMed - as supplied by publisher]

The contribution of co-transcriptional RNA:DNA hybrid structures to DNA damage and genome instability.

DNA Repair (Amst). 2014 Apr 17;

Authors: Hamperl S, Cimprich KA

Abstract
Accurate DNA replication and DNA repair are crucial for the maintenance of genome stability, and it is generally accepted that failure of these processes is a major source of DNA damage in cells. Intriguingly, recent evidence suggests that DNA damage is more likely to occur at genomic loci with high transcriptional activity. Furthermore, loss of certain RNA processing factors in eukaryotic cells is associated with increased formation of co-transcriptional RNA:DNA hybrid structures known as R-loops, resulting in double-strand breaks (DSBs) and DNA damage. However, the molecular mechanisms by which R-loop structures ultimately lead to DNA breaks and genome instability is not well understood. In this review, we summarize the current knowledge about the formation, recognition and processing of RNA:DNA hybrids, and discuss possible mechanisms by which these structures contribute to DNA damage and genome instability in the cell.

PMID: 24746923 [PubMed - as supplied by publisher]

Conjugated bisphenol A (BPA) in maternal serum in relation to miscarriage risk.

Fertil Steril. 2014 Apr 17;

Authors: Lathi RB, Liebert CA, Brookfield KF, Taylor JA, Vom Saal FS, Fujimoto VY, Baker VL

Abstract
OBJECTIVE: To examine the relationship between the maternal serum bisphenol A (BPA) concentration at the time of the missed menstrual cycle and miscarriage risk.
DESIGN: Retrospective cohort of prospectively collected serum samples.
SETTING: Academic fertility center.
PATIENT(S): Women presenting for early pregnancy monitoring with singleton pregnancies.
INTERVENTION(S): Stored serum samples from 4 to 5 weeks' gestation analyzed for conjugated serum BPA concentrations.
MAIN OUTCOME MEASURE(S): Live birth, miscarriage, and chromosome content of miscarriage.
RESULT(S): With the 115 women included in the study, there were 47 live births and 68 clinical miscarriages (46 aneuploid and 22 euploid). Median conjugated BPA concentrations were higher in the women who had miscarriages than in those who had live births (0.101 vs. 0.075 ng/mL). Women with the highest quartile of conjugated BPA had an increased relative risk of miscarriage (1.83; 95% CI, 1.14-2.96) compared with the women in the lowest quartile. We found a similar increase risk for both euploid and aneuploid miscarriages.
CONCLUSION(S): Maternal conjugated BPA was associated with a higher risk of aneuploid and euploid miscarriage in this cohort. The impact of reducing individual exposure on future pregnancy outcomes deserves further study.

PMID: 24746738 [PubMed - as supplied by publisher]

Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke.

Neuron. 2014 Apr 15;

Authors: Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, Steinberg GK, Barres BA, Nimmerjahn A, Agalliu D

Abstract
Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.

PMID: 24746419 [PubMed - as supplied by publisher]

Use of CD137 ligand expression in the detection of small B-cell lymphomas involving the bone marrow.

Hum Pathol. 2014 May;45(5):1024-30

Authors: Zhao S, Xing Y, Natkunam Y

Abstract
Staging for small B-cell lymphomas is important for prognostic and therapeutic decision making; however, the detection of lymphoid infiltrates in the bone marrow is often hampered by the lack of specific diagnostic markers. We recently described the hematopoietic tissue distribution patterns of CD137 and CD137 ligand (CD137L), which have shown promise as immunotherapeutic targets. CD137 expression was primarily confined to cells in the microenvironment, whereas CD137L was expressed in neoplastic cells in most B-cell lymphomas. Here we evaluate the use of CD137L in the detection of small B-cell lymphomas involving the bone marrow. To test the potential efficacy of CD137L in detecting bone marrow lymphoid infiltrates, 166 small B-cell lymphomas were evaluated by immunohistochemistry and double-immunofluorescence labeling on formalin-fixed, paraffin-embedded bone marrow core biopsies. CD137L was highly expressed in bone marrows involved by small B-cell lymphomas and included hairy cell leukemia, mantle cell lymphoma, follicular lymphoma, B-lymphoblastic leukemia, and chronic lymphocytic leukemia. In addition, a small subset of marginal zone lymphoma and most of lymphoplasmacytic lymphoma showed staining. Normal bone marrow cells including myeloid, erythroid and megakaryocytic precursors, and reactive lymphoid aggregates lacked staining. Our findings show that immunohistochemistry for CD137L is capable of reliably distinguishing small B-cell lymphomas from reactive lymphoid aggregates. These data also suggest that CD137L is useful in providing staging information for clinical diagnosis and is likely to furnish a potential target for minimal residual disease assessment as well as immunotherapy in patients with stage 4 disease.

PMID: 24746207 [PubMed - in process]

Health literacy and injury prevention behaviors among caregivers of infants.

Am J Prev Med. 2014 May;46(5):449-56

Authors: Heerman WJ, Perrin EM, Yin HS, Sanders LM, Eden SK, Shintani A, Coyne-Beasley T, Bronaugh AB, Barkin SL, Rothman RL

Abstract
BACKGROUND: Unintentional injury is a leading cause of infant mortality.
PURPOSE: To examine the role of caregiver health literacy in infant injury prevention behaviors.
METHODS: A cross-sectional analysis of data collected in 2010-2012 from a randomized trial at four pediatric clinics was performed in 2012-2013. Caregiver health literacy was assessed with the Short Test of Functional Health Literacy in Adults. Caregiver-reported adherence to American Academy of Pediatrics-recommended injury prevention behaviors was assessed across seven domains: (1) car seat position; (2) car seat use; (3) sleeping safety; (4) fire safety; (5) hot water safety; (6) fall prevention; and (7) firearm safety.
RESULTS: Data were analyzed from 844 English- and Spanish-speaking caregivers of 2-month-old children. Many caregivers were non-adherent with injury prevention guidelines, regardless of health literacy. Notably, 42.6% inappropriately placed their children in the prone position to sleep, and 88.6% did not have their hot water heater set <120°F. Eleven percent of caregivers were categorized as having low health literacy. Low caregiver health literacy, compared to adequate health literacy, was significantly associated with increased odds of caregiver non-adherence with recommended behaviors for car seat position (AOR=3.4, 95% CI=1.6, 7.1) and fire safety (AOR=2.0, 95% CI=1.02, 4.1) recommendations. Caregivers with low health literacy were less likely to be non-adherent to fall prevention recommendations (AOR=0.5, 95% CI=0.2, 0.9).
CONCLUSIONS: Non-adherence to injury prevention guidelines was common. Low caregiver health literacy was significantly associated with some injury prevention behaviors. Future interventions should consider the role of health literacy in promoting injury prevention.

PMID: 24745634 [PubMed - in process]

Orthogonal spectral coding of entangled photons.

Phys Rev Lett. 2014 Apr 4;112(13):133602

Authors: Lukens JM, Dezfooliyan A, Langrock C, Fejer MM, Leaird DE, Weiner AM

Abstract
We extend orthogonal optical coding, previously applied to multiuser classical communication networks, to entangled photons. Using a pulse shaper and sum-frequency generation for ultrafast coincidence detection, we demonstrate encoding and decoding of biphoton wave packets. Applying one code to the signal photon spreads the wave packet in time and creates a null at zero delay; filtering the idler with the matched code recovers a narrow correlation peak, whereas applying any other code leaves the wave packet spread. Our results could prove useful in the development of code-based quantum communication networks.

PMID: 24745415 [PubMed - in process]

Constraints on Cosmic Strings from the LIGO-Virgo Gravitational-Wave Detectors.

Phys Rev Lett. 2014 Apr 4;112(13):131101

Authors: Aasi J, Abadie J, Abbott BP, Abbott R, Abbott T, Abernathy MR, Accadia T, Acernese F, Adams C, Adams T, Adhikari RX, Affeldt C, Agathos M, Aggarwal N, Aguiar OD, Ajith P, Allen B, Allocca A, Amador Ceron E, Amariutei D, Anderson RA, Anderson SB, Anderson WG, Arai K, Araya MC, Arceneaux C, Areeda J, Ast S, Aston SM, Astone P, Aufmuth P, Aulbert C, Austin L, Aylott BE, Babak S, Baker PT, Ballardin G, Ballmer SW, Barayoga JC, Barker D, Barnum SH, Barone F, Barr B, Barsotti L, Barsuglia M, Barton MA, Bartos I, Bassiri R, Basti A, Batch J, Bauchrowitz J, Bauer TS, Bebronne M, Behnke B, Bejger M, Beker MG, Bell AS, Bell C, Belopolski I, Bergmann G, Berliner JM, Bersanetti D, Bertolini A, Bessis D, Betzwieser J, Beyersdorf PT, Bhadbhade T, Bilenko IA, Billingsley G, Birch J, Bitossi M, Bizouard MA, Black E, Blackburn JK, Blackburn L, Blair D, Blom M, Bock O, Bodiya TP, Boer M, Bogan C, Bond C, Bondu F, Bonelli L, Bonnand R, Bork R, Born M, Boschi V, Bose S, Bosi L, Bowers J, Bradaschia C, Brady PR, Braginsky VB, Branchesi M, Brannen CA, Brau JE, Breyer J, Briant T, Bridges DO, Brillet A, Brinkmann M, Brisson V, Britzger M, Brooks AF, Brown DA, Brown DD, Brückner F, Bulik T, Bulten HJ, Buonanno A, Buskulic D, Buy C, Byer RL, Cadonati L, Cagnoli G, Calderón Bustillo J, Calloni E, Camp JB, Campsie P, Cannon KC, Canuel B, Cao J, Capano CD, Carbognani F, Carbone L, Caride S, Castiglia A, Caudill S, Cavaglià M, Cavalier F, Cavalieri R, Cella G, Cepeda C, Cesarini E, Chakraborty R, Chalermsongsak T, Chao S, Charlton P, Chassande-Mottin E, Chen X, Chen Y, Chincarini A, Chiummo A, Cho HS, Chow J, Christensen N, Chu Q, Chua SS, Chung S, Ciani G, Clara F, Clark DE, Clark JA, Cleva F, Coccia E, Cohadon PF, Colla A, Colombini M, Constancio M, Conte A, Conte R, Cook D, Corbitt TR, Cordier M, Cornish N, Corsi A, Costa CA, Coughlin MW, Coulon JP, Countryman S, Couvares P, Coward DM, Cowart M, Coyne DC, Craig K, Creighton JD, Creighton TD, Crowder SG, Cumming A, Cunningham L, Cuoco E, Dahl K, Canton TD, Damjanic M, Danilishin SL, D'Antonio S, Danzmann K, Dattilo V, Daudert B, Daveloza H, Davier M, Davies GS, Daw EJ, Day R, Dayanga T, De Rosa R, Debreczeni G, Degallaix J, Del Pozzo W, Deleeuw E, Deléglise S, Denker T, Dent T, Dereli H, Dergachev V, Derosa R, Desalvo R, Dhurandhar S, Di Fiore L, Di Lieto A, Di Palma I, Di Virgilio A, Díaz M, Dietz A, Dmitry K, Donovan F, Dooley KL, Doravari S, Drago M, Drever RW, Driggers JC, Du Z, Dumas JC, Dwyer S, Eberle T, Edwards M, Effler A, Ehrens P, Eichholz J, Eikenberry SS, Endrőczi G, Essick R, Etzel T, Evans K, Evans M, Evans T, Factourovich M, Fafone V, Fairhurst S, Fang Q, Farinon S, Farr B, Farr W, Favata M, Fazi D, Fehrmann H, Feldbaum D, Ferrante I, Ferrini F, Fidecaro F, Finn LS, Fiori I, Fisher R, Flaminio R, Foley E, Foley S, Forsi E, Fotopoulos N, Fournier JD, Franco S, Frasca S, Frasconi F, Frede M, Frei M, Frei Z, Freise A, Frey R, Fricke TT, Fritschel P, Frolov VV, Fujimoto MK, Fulda P, Fyffe M, Gair J, Gammaitoni L, Garcia J, Garufi F, Gehrels N, Gemme G, Genin E, Gennai A, Gergely L, Ghosh S, Giaime JA, Giampanis S, Giardina KD, Giazotto A, Gil-Casanova S, Gill C, Gleason J, Goetz E, Goetz R, Gondan L, González G, Gordon N, Gorodetsky ML, Gossan S, Goßler S, Gouaty R, Graef C, Graff PB, Granata M, Grant A, Gras S, Gray C, Greenhalgh RJ, Gretarsson AM, Griffo C, Groot P, Grote H, Grover K, Grunewald S, Guidi GM, Guido C, Gushwa KE, Gustafson EK, Gustafson R, Hall B, Hall E, Hammer D, Hammond G, Hanke M, Hanks J, Hanna C, Hanson J, Harms J, Harry GM, Harry IW, Harstad ED, Hartman MT, Haughian K, Hayama K, Heefner J, Heidmann A, Heintze M, Heitmann H, Hello P, Hemming G, Hendry M, Heng IS, Heptonstall AW, Heurs M, Hild S, Hoak D, Hodge KA, Holt K, Holtrop M, Hong T, Hooper S, Horrom T, Hosken DJ, Hough J, Howell EJ, Hu Y, Hua Z, Huang V, Huerta EA, Hughey B, Husa S, Huttner SH, Huynh M, Huynh-Dinh T, Iafrate J, Ingram DR, Inta R, Isogai T, Ivanov A, Iyer BR, Izumi K, Jacobson M, James E, Jang H, Jang YJ, Jaranowski P, Jiménez-Forteza F, Johnson WW, Jones D, Jones DI, Jones R, Jonker RJ, Ju L, K H, Kalmus P, Kalogera V, Kandhasamy S, Kang G, Kanner JB, Kasprzack M, Kasturi R, Katsavounidis E, Katzman W, Kaufer H, Kaufman K, Kawabe K, Kawamura S, Kawazoe F, Kéfélian F, Keitel D, Kelley DB, Kells W, Keppel DG, Khalaidovski A, Khalili FY, Khazanov EA, Kim BK, Kim C, Kim K, Kim N, Kim W, Kim YM, King EJ, King PJ, Kinzel DL, Kissel JS, Klimenko S, Kline J, Koehlenbeck S, Kokeyama K, Kondrashov V, Koranda S, Korth WZ, Kowalska I, Kozak D, Kremin A, Kringel V, Królak A, Kucharczyk C, Kudla S, Kuehn G, Kumar A, Kumar P, Kumar R, Kurdyumov R, Kwee P, Landry M, Lantz B, Larson S, Lasky PD, Lawrie C, Lazzarini A, Le Roux A, Leaci P, Lebigot EO, Lee CH, Lee HK, Lee HM, Lee J, Lee J, Leonardi M, Leong JR, Leroy N, Letendre N, Levine B, Lewis JB, Lhuillier V, Li TG, Lin AC, Littenberg TB, Litvine V, Liu F, Liu H, Liu Y, Liu Z, Lloyd D, Lockerbie NA, Lockett V, Lodhia D, Loew K, Logue J, Lombardi AL, Lorenzini M, Loriette V, Lormand M, Losurdo G, Lough J, Luan J, Lubinski MJ, Lück H, Lundgren AP, Macarthur J, Macdonald E, Machenschalk B, Macinnis M, Macleod DM, Magana-Sandoval F, Mageswaran M, Mailand K, Majorana E, Maksimovic I, Malvezzi V, Man N, Manca GM, Mandel I, Mandic V, Mangano V, Mantovani M, Marchesoni F, Marion F, Márka S, Márka Z, Markosyan A, Maros E, Marque J, Martelli F, Martin IW, Martin RM, Martinelli L, Martynov D, Marx JN, Mason K, Masserot A, Massinger TJ, Matichard F, Matone L, Matzner RA, Mavalvala N, May G, Mazumder N, Mazzolo G, McCarthy R, McClelland DE, McGuire SC, McIntyre G, McIver J, Meacher D, Meadors GD, Mehmet M, Meidam J, Meier T, Melatos A, Mendell G, Mercer RA, Meshkov S, Messenger C, Meyer MS, Miao H, Michel C, Mikhailov EE, Milano L, Miller J, Minenkov Y, Mingarelli CM, Mitra S, Mitrofanov VP, Mitselmakher G, Mittleman R, Moe B, Mohan M, Mohapatra SR, Mokler F, Moraru D, Moreno G, Morgado N, Mori T, Morriss SR, Mossavi K, Mours B, Mow-Lowry CM, Mueller CL, Mueller G, Mukherjee S, Mullavey A, Munch J, Murphy D, Murray PG, Mytidis A, Nagy MF, Nanda Kumar D, Nardecchia I, Nash T, Naticchioni L, Nayak R, Necula V, Nelemans G, Neri I, Neri M, Newton G, Nguyen T, Nishida E, Nishizawa A, Nitz A, Nocera F, Nolting D, Normandin ME, Nuttall LK, Ochsner E, O'Dell J, Oelker E, Ogin GH, Oh JJ, Oh SH, Ohme F, Oppermann P, O'Reilly B, Ortega Larcher W, O'Shaughnessy R, Osthelder C, Ott CD, Ottaway DJ, Ottens RS, Ou J, Overmier H, Owen BJ, Padilla C, Pai A, Palomba C, Pan Y, Pankow C, Paoletti F, Paoletti R, Papa MA, Paris H, Pasqualetti A, Passaquieti R, Passuello D, Pedraza M, Peiris P, Penn S, Perreca A, Phelps M, Pichot M, Pickenpack M, Piergiovanni F, Pierro V, Pinard L, Pindor B, Pinto IM, Pitkin M, Poeld J, Poggiani R, Poole V, Poux C, Predoi V, Prestegard T, Price LR, Prijatelj M, Principe M, Privitera S, Prix R, Prodi GA, Prokhorov L, Puncken O, Punturo M, Puppo P, Quetschke V, Quintero E, Quitzow-James R, Raab FJ, Rabeling DS, Rácz I, Radkins H, Raffai P, Raja S, Rajalakshmi G, Rakhmanov M, Ramet C, Rapagnani P, Raymond V, Re V, Reed CM, Reed T, Regimbau T, Reid S, Reitze DH, Ricci F, Riesen R, Riles K, Robertson NA, Robinet F, Rocchi A, Roddy S, Rodriguez C, Rodruck M, Roever C, Rolland L, Rollins JG, Romano R, Romanov G, Romie JH, Rosińska D, Rowan S, Rüdiger A, Ruggi P, Ryan K, Salemi F, Sammut L, Sandberg V, Sanders J, Sannibale V, Santiago-Prieto I, Saracco E, Sassolas B, Sathyaprakash BS, Saulson PR, Savage R, Schilling R, Schnabel R, Schofield RM, Schreiber E, Schuette D, Schulz B, Schutz BF, Schwinberg P, Scott J, Scott SM, Seifert F, Sellers D, Sengupta AS, Sentenac D, Sergeev A, Shaddock D, Shah S, Shahriar MS, Shaltev M, Shapiro B, Shawhan P, Shoemaker DH, Sidery TL, Siellez K, Siemens X, Sigg D, Simakov D, Singer A, Singer L, Sintes AM, Skelton GR, Slagmolen BJ, Slutsky J, Smith JR, Smith MR, Smith RJ, Smith-Lefebvre ND, Soden K, Son EJ, Sorazu B, Souradeep T, Sperandio L, Staley A, Steinert E, Steinlechner J, Steinlechner S, Steplewski S, Stevens D, Stochino A, Stone R, Strain KA, Straniero N, Strigin S, Stroeer AS, Sturani R, Stuver AL, Summerscales TZ, Susmithan S, Sutton PJ, Swinkels B, Szeifert G, Tacca M, Talukder D, Tang L, Tanner DB, Tarabrin SP, Taylor R, Ter Braack AP, Thirugnanasambandam MP, Thomas M, Thomas P, Thorne KA, Thorne KS, Thrane E, Tiwari V, Tokmakov KV, Tomlinson C, Toncelli A, Tonelli M, Torre O, Torres CV, Torrie CI, Travasso F, Traylor G, Tse M, Ugolini D, Unnikrishnan CS, Vahlbruch H, Vajente G, Vallisneri M, van den Brand JF, Van Den Broeck C, van der Putten S, van der Sluys MV, van Heijningen J, van Veggel AA, Vass S, Vasúth M, Vaulin R, Vecchio A, Vedovato G, Veitch J, Veitch PJ, Venkateswara K, Verkindt D, Verma S, Vetrano F, Viceré A, Vincent-Finley R, Vinet JY, Vitale S, Vlcek B, Vo T, Vocca H, Vorvick C, Vousden WD, Vrinceanu D, Vyachanin SP, Wade A, Wade L, Wade M, Waldman SJ, Walker M, Wallace L, Wan Y, Wang J, Wang M, Wang X, Wanner A, Ward RL, Was M, Weaver B, Wei LW, Weinert M, Weinstein AJ, Weiss R, Welborn T, Wen L, Wessels P, West M, Westphal T, Wette K, Whelan JT, Whitcomb SE, White DJ, Whiting BF, Wibowo S, Wiesner K, Wilkinson C, Williams L, Williams R, Williams T, Willis JL, Willke B, Wimmer M, Winkelmann L, Winkler W, Wipf CC, Wittel H, Woan G, Worden J, Yablon J, Yakushin I, Yamamoto H, Yancey CC, Yang H, Yeaton-Massey D, Yoshida S, Yum H, Yvert M, Zadrożny A, Zanolin M, Zendri JP, Zhang F, Zhang L, Zhao C, Zhu H, Zhu XJ, Zotov N, Zucker ME, Zweizig J, (LIGO Scientific Collaboration and Virgo Collaboration)

Abstract
Cosmic strings can give rise to a large variety of interesting astrophysical phenomena. Among them, powerful bursts of gravitational waves (GWs) produced by cusps are a promising observational signature. In this Letter we present a search for GWs from cosmic string cusps in data collected by the LIGO and Virgo gravitational wave detectors between 2005 and 2010, with over 625 days of live time. We find no evidence of GW signals from cosmic strings. From this result, we derive new constraints on cosmic string parameters, which complement and improve existing limits from previous searches for a stochastic background of GWs from cosmic microwave background measurements and pulsar timing data. In particular, if the size of loops is given by the gravitational backreaction scale, we place upper limits on the string tension Gμ below 10-8 in some regions of the cosmic string parameter space.

PMID: 24745400 [PubMed - in process]

Neuroscience. Optogenetic regeneration.

Science. 2014 Apr 4;344(6179):44-5

Authors: Iyer SM, Delp SL

PMID: 24700845 [PubMed - indexed for MEDLINE]

Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial.

JAMA. 2014 Apr 2;311(13):1300-7

Authors: Pisansky TM, Pugh SL, Greenberg RE, Pervez N, Reed DR, Rosenthal SA, Mowat RB, Raben A, Buyyounouski MK, Kachnic LA, Bruner DW

Abstract
IMPORTANCE: Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined.
OBJECTIVES: To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected.
DESIGN, SETTING, AND PARTICIPANTS: Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013.
INTERVENTIONS: One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year.
MAIN OUTCOMES AND MEASURES: Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events.
RESULTS: Among 221 evaluable participants, 80 (79%; 95% CI, 70%-88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%-85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, -9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%-84% vs 71%; 95% CI, 59%-84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners.
CONCLUSIONS AND RELEVANCE: Among men undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00931528.

PMID: 24691606 [PubMed - indexed for MEDLINE]

Visual space is compressed in prefrontal cortex before eye movements.

Nature. 2014 Mar 27;507(7493):504-7

Authors: Zirnsak M, Steinmetz NA, Noudoost B, Xu KZ, Moore T

Abstract
We experience the visual world through a series of saccadic eye movements, each one shifting our gaze to bring objects of interest to the fovea for further processing. Although such movements lead to frequent and substantial displacements of the retinal image, these displacements go unnoticed. It is widely assumed that a primary mechanism underlying this apparent stability is an anticipatory shifting of visual receptive fields (RFs) from their presaccadic to their postsaccadic locations before movement onset. Evidence of this predictive 'remapping' of RFs has been particularly apparent within brain structures involved in gaze control. However, critically absent among that evidence are detailed measurements of visual RFs before movement onset. Here we show that during saccade preparation, rather than remap, RFs of neurons in a prefrontal gaze control area massively converge towards the saccadic target. We mapped the visual RFs of prefrontal neurons during stable fixation and immediately before the onset of eye movements, using multi-electrode recordings in monkeys. Following movements from an initial fixation point to a target, RFs remained stationary in retinocentric space. However, in the period immediately before movement onset, RFs shifted by as much as 18 degrees of visual angle, and converged towards the target location. This convergence resulted in a threefold increase in the proportion of RFs responding to stimuli near the target region. In addition, like in human observers, the population of prefrontal neurons grossly mislocalized presaccadic stimuli as being closer to the target. Our results show that RF shifts do not predict the retinal displacements due to saccades, but instead reflect the overriding perception of target space during eye movements.

PMID: 24670771 [PubMed - indexed for MEDLINE]

Costs associated with multimorbidity among VA patients.

Med Care. 2014 Mar;52 Suppl 3:S31-6

Authors: Yoon J, Zulman D, Scott JY, Maciejewski ML

Abstract
BACKGROUND: Multimorbidity (the presence of multiple chronic conditions) is associated with high levels of healthcare utilization and associated costs. We investigated the association between number of chronic conditions and costs of care for nonelderly and elderly Veterans Affairs (VA) patients, and estimated mean VA healthcare costs for the most prevalent and most costly combinations of 3 conditions (triads).
METHODS: We identified a cohort of 5,233,994 patients who received care within the VA system in fiscal year 2010. We estimated the costs of VA care for each patient using established methods and aggregated costs for inpatient care, outpatient care, prescription drugs, and contract care. Using ICD-9 diagnosis fields from all inpatient and outpatient records, we determined the prevalence of 28 chronic conditions and all condition triads. We then compared the condition-cost gradient, most prevalent triads, and most costly triads among nonelderly (below 65 y) and elderly (65 y and above) patients.
RESULTS: Almost one third of nonelderly and slightly more than a third of elderly VA patients had ≥3 conditions, but these patients accounted for 65% and 67% of total VA healthcare costs, respectively. The most common triad of chronic conditions for both nonelderly and elderly patients was diabetes, hyperlipidemia, and hypertension (24% and 29%, respectively). Conditions that were present in the most costly triads included spinal cord injury, heart failure, renal failure, ischemic heart disease, peripheral vascular disease, stroke, and depression. Although patients with the most costly triads had average costs that were 3 times higher than average costs among patients with ≥3 conditions, the prevalence of these costly triads was extremely low (0.1%-0.4%).
CONCLUSIONS: Patients with multiple chronic conditions account for a disproportionate share of VA healthcare expenditures. Interventions that aim to optimize care and contain costs for multimorbid patients need to incorporate strategies specific to the most prevalent and the most costly combinations of conditions.

PMID: 24561756 [PubMed - indexed for MEDLINE]

Molecular mechanisms of varicella zoster virus pathogenesis.

Nat Rev Microbiol. 2014 Mar;12(3):197-210

Authors: Zerboni L, Sen N, Oliver SL, Arvin AM

Abstract
Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV-host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.

PMID: 24509782 [PubMed - indexed for MEDLINE]

Let's talk about sex, baby: gendered innovations in orthopaedic science.

Clin Orthop Relat Res. 2014 Mar;472(3):793-5

Authors: Ladd AL

PMID: 24442840 [PubMed - indexed for MEDLINE]

Usefulness of the Seattle Heart Failure Model to identify adults with congenital heart disease at high risk of poor outcome.

Am J Cardiol. 2014 Mar 1;113(5):865-70

Authors: Stefanescu A, Macklin EA, Lin E, Dudzinski DM, Johnson J, Kennedy KF, Jacoby D, DeFaria Yeh D, Lewis GD, Yeh RW, Liberthson R, Lui G, Bhatt AB

Abstract
Our objective was to determine whether the Seattle Heart Failure Model (SHFM) differentiates patients with adult congenital heart disease (ACHD) at high versus low risk for cardiovascular outcomes and poor exercise capacity. The ACHD population is growing and presents increasingly for care in the community and at tertiary centers. Few strategies exist to identify the patients with ACHD at high risk for heart failure and mortality.We studied 153 adults with transposition of the great arteries, Ebstein anomaly, tetralogy of Fallot, double outlet right ventricle, and single ventricle from 2 ACHD centers. The primary outcome was cardiovascular death, with a secondary composite outcome of death, transplant, ventricular assist device, cardiovascular admission, and treatment for arrhythmia. We defined risk groups based on SHFM 5-year predicted survival: high (predicted survival <70%), intermediate (70% to 85%), and low risk (>85%). Ten patients had the primary outcome of death, and 46 the combined end point. The hazard of death in the SHFM high- versus the intermediate-risk group was 7.09 (95% confidence interval 1.5 to 33.4, p = 0.01; no deaths in the low-risk group) and the hazard of the composite outcome between the high- versus low-risk group was 6.64 (95% confidence interval 2.5 to 17.6, p = 0.0001). Kaplan-Meier survival analysis showed greater probability of all-cause mortality (p = 0.003) in the high-risk group. In conclusion, the SHFM can help identify subjects with ACHD at risk for adverse outcome and poor cardiopulmonary efficiency. This may add to the care of patients with ACHD in the community and streamline care at tertiary centers.

PMID: 24411285 [PubMed - indexed for MEDLINE]

Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

Circ Res. 2014 Feb 14;114(4):650-9

Authors: Macarthur JW, Cohen JE, McGarvey JR, Shudo Y, Patel JB, Trubelja A, Fairman AS, Edwards BB, Hung G, Hiesinger W, Goldstone AB, Atluri P, Wilensky RL, Pilla JJ, Gorman JH, Gorman RC, Woo YJ

Abstract
RATIONALE: After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.
OBJECTIVE: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.
METHODS AND RESULTS: Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).
CONCLUSIONS: The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

PMID: 24366171 [PubMed - indexed for MEDLINE]

Motility enhancement through surface modification is sufficient for cyanobacterial community organization during phototaxis.

PLoS Comput Biol. 2013;9(9):e1003205

Authors: Ursell T, Chau RM, Wisen S, Bhaya D, Huang KC

Abstract
The emergent behaviors of communities of genotypically identical cells cannot be easily predicted from the behaviors of individual cells. In many cases, it is thought that direct cell-cell communication plays a critical role in the transition from individual to community behaviors. In the unicellular photosynthetic cyanobacterium Synechocystis sp. PCC 6803, individual cells exhibit light-directed motility ("phototaxis") over surfaces, resulting in the emergence of dynamic spatial organization of multicellular communities. To probe this striking community behavior, we carried out time-lapse video microscopy coupled with quantitative analysis of single-cell dynamics under varying light conditions. These analyses suggest that cells secrete an extracellular substance that modifies the physical properties of the substrate, leading to enhanced motility and the ability for groups of cells to passively guide one another. We developed a biophysical model that demonstrates that this form of indirect, surface-based communication is sufficient to create distinct motile groups whose shape, velocity, and dynamics qualitatively match our experimental observations, even in the absence of direct cellular interactions or changes in single-cell behavior. Our computational analysis of the predicted community behavior, across a matrix of cellular concentrations and light biases, demonstrates that spatial patterning follows robust scaling laws and provides a useful resource for the generation of testable hypotheses regarding phototactic behavior. In addition, we predict that degradation of the surface modification may account for the secondary patterns occasionally observed after the initial formation of a community structure. Taken together, our modeling and experiments provide a framework to show that the emergent spatial organization of phototactic communities requires modification of the substrate, and this form of surface-based communication could provide insight into the behavior of a wide array of biological communities.

PMID: 24039562 [PubMed - indexed for MEDLINE]

25th anniversary article: Understanding the lithiation of silicon and other alloying anodes for lithium-ion batteries.

Adv Mater. 2013 Sep 25;25(36):4966-85

Authors: McDowell MT, Lee SW, Nix WD, Cui Y

Abstract
Alloying anodes such as silicon are promising electrode materials for next-generation high energy density lithium-ion batteries because of their ability to reversibly incorporate a high concentration of Li atoms. However, alloying anodes usually exhibit a short cycle life due to the extreme volumetric and structural changes that occur during lithium insertion/extraction; these transformations cause mechanical fracture and exacerbate side reactions. To solve these problems, there has recently been significant attention devoted to creating silicon nanostructures that can accommodate the lithiation-induced strain and thus exhibit high Coulombic efficiency and long cycle life. In parallel, many experiments and simulations have been conducted in an effort to understand the details of volumetric expansion, fracture, mechanical stress evolution, and structural changes in silicon nanostructures. The fundamental materials knowledge gained from these studies has provided guidance for designing optimized Si electrode structures and has also shed light on the factors that control large-volume change solid-state reactions. In this paper, we review various fundamental studies that have been conducted to understand structural and volumetric changes, stress evolution, mechanical properties, and fracture behavior of nanostructured Si anodes for lithium-ion batteries and compare the reaction process of Si to other novel anode materials.

PMID: 24038172 [PubMed - indexed for MEDLINE]

Improved quenched fluorescent probe for imaging of cysteine cathepsin activity.

J Am Chem Soc. 2013 Oct 2;135(39):14726-30

Authors: Verdoes M, Oresic Bender K, Segal E, van der Linden WA, Syed S, Withana NP, Sanman LE, Bogyo M

Abstract
The cysteine cathepsins are a family of proteases that play important roles in both normal cellular physiology and many human diseases. In cancer, the activity of many of the cysteine cathepsins is upregulated and can be exploited for tumor imaging. Here we present the design and synthesis of a new class of quenched fluorescent activity-based probes (qABPs) containing a phenoxymethyl ketone (PMK) electrophile. These reagents show enhanced in vivo properties and broad reactivity resulting in dramatically improved labeling and tumor imaging properties compared to those of previously reported ABPs.

PMID: 23971698 [PubMed - indexed for MEDLINE]

Direct oligonucleotide synthesis onto super-paramagnetic beads.

J Biotechnol. 2013 Sep 20;167(4):448-53

Authors: Jensen MA, Akhras MS, Fukushima M, Pourmand N, Davis RW

Abstract
Super-paramagnetic beads (SPMB)s used for a variety of molecular diagnostic assays are prepared by attaching pre-synthesized oligonucleotides to the surface via a cumbersome and low efficient method of carbodiimide-mediated amide bond formation. To mainstream the process, we describe a novel procedure of direct oligonucleotide synthesis onto the surface of SPMBs (e.g. MyOne Dynabeads). With the many challenges surrounding containment of paramagnetic beads (≤1 μm) during automated oligonucleotide synthesis, we show that by applying a magnetic force directly to the SPMBs we prevent their loss caused by high-pressure drain steps during synthesis. To date we have synthesized 40 mers using a Spacer 9 phosphoramidite (triethylene glycol) coupled to the surface of hydroxylated SPMBs. HPLC analysis shows successful product generation with an average yield of 200 pmol per sample. Furthermore, because of the versatility of this powerful research tool, we envision its use in any laboratory working with conventional synthesis automation, as employed for single columns and for multi-well titer plates. In addition to direct synthesis of oligodeoxynucleotides (DNA) onto SPMBs, this platform also has the potential for RNA and peptide nucleic acid synthesis.

PMID: 23942380 [PubMed - indexed for MEDLINE]

A smarter mouse with human astrocytes.

Bioessays. 2013 Oct;35(10):876-80

Authors: Zhang Y, Barres BA

Abstract
What is the biological basis for human cognition? Our understanding why human brains make us smarter than other animals is still in its infancy. In recent years, astrocytes have been shown to be indispensable for neuronal survival, growth, synapse formation, and synapse function. Now, in a new study from Maiken Nedergaard and Steven Goldman's groups (Han et al., 2013), human glia progenitor cells have been transplanted into mouse forebrains. These progenitors survived, migrated widely, and gave rise to astrocytes that displayed the characteristics of human astrocytes in the rodent host brains. Strikingly, the mice with transplanted human cells displayed improved long term potentiation (LTP) and learning, suggesting the potential importance of human astrocytes in the unique cognitive abilities of human brains. This landmark paper is an important first step toward future investigations of whether and how human astrocytes play a role in distinguishing the cognitive abilities of humans from those of other animals.

PMID: 23897758 [PubMed - indexed for MEDLINE]

Imaging for evaluation of cholesteatoma: current concepts and future directions.

Curr Opin Otolaryngol Head Neck Surg. 2013 Oct;21(5):461-7

Authors: Corrales CE, Blevins NH

Abstract
PURPOSE OF REVIEW: To examine the rationale and utility of imaging in patients with known or suspected cholesteatoma, with emphasis on high-resolution computed tomography (HRCT) and diffusion-weighted MRI (DW-MRI).
RECENT FINDINGS: The initial diagnosis of cholesteatoma is largely based on patient history and clinical findings. HRCT scan can be a useful adjunct to define the presence of pathologic soft tissue in the temporal bone, and the extent of bony erosion, and inform the otologic surgeon about expected findings at the time of surgery. Although MRI has not traditionally been used in the evaluation of cholesteatoma given its poor resolution of bone anatomy, recent advances in DW-MRI sequences allow for high sensitivity and specificity in identifying the presence of cholesteatoma. More specifically, non-echo-planar DW-MRI is superior in the detection of residual or recurrent cholesteatoma compared to delayed-contrast MRI and echo-planar DW-MRI.
SUMMARY: HRCT and DW-MRI offer complementary anatomic information that can be used effectively in the management of cholesteatoma. DW-MRI imaging has proven to be a reliable method for detecting residual or recurrent cholesteatomas down to 3 mm in size, and allows radiologic differentiation between cholesteatoma and other soft tissue. As more centers implement DW-MRI imaging for detecting residual or recurrent cholesteatoma, there will likely be less need for second-look surgery, thereby potentially decreasing associated morbidity and surgical costs.

PMID: 23880648 [PubMed - indexed for MEDLINE]

Retroviruses facilitate the rapid evolution of the mammalian placenta.

Bioessays. 2013 Oct;35(10):853-61

Authors: Chuong EB

Abstract
The mammalian placenta exhibits elevated expression of endogenous retroviruses (ERVs), but the evolutionary significance of this feature remains unclear. I propose that ERV-mediated regulatory evolution was, and continues to be, an important mechanism underlying the evolution of placental development. Many recent studies have focused on the co-option of ERV-derived genes for specific functional adaptations in the placenta. However, the co-option of ERV-derived regulatory elements could potentially lead to the incorporation of entire gene regulatory networks, which, I argue, would facilitate relatively rapid developmental evolution of the placenta. I suggest a model in which an ancient retroviral infection led to the establishment of the ancestral placental developmental gene network through the co-option of ERV-derived regulatory elements. Consequently, placental development would require elevated tolerance to ERV activity. This in turn would expose a continuous stream of novel ERV mutations that may have catalyzed the developmental diversification of the mammalian placenta.

PMID: 23873343 [PubMed - indexed for MEDLINE]

CO2 mitigation potential of mineral carbonation with industrial alkalinity sources in the United States.

Environ Sci Technol. 2013 Jul 2;47(13):7548-54

Authors: Kirchofer A, Becker A, Brandt A, Wilcox J

Abstract
The availability of industrial alkalinity sources is investigated to determine their potential for the simultaneous capture and sequestration of CO2 from point-source emissions in the United States. Industrial alkalinity sources investigated include fly ash, cement kiln dust, and iron and steel slag. Their feasibility for mineral carbonation is determined by their relative abundance for CO2 reactivity and their proximity to point-source CO2 emissions. In addition, the available aggregate markets are investigated as possible sinks for mineral carbonation products. We show that in the U.S., industrial alkaline byproducts have the potential to mitigate approximately 7.6 Mt CO2/yr, of which 7.0 Mt CO2/yr are CO2 captured through mineral carbonation and 0.6 Mt CO2/yr are CO2 emissions avoided through reuse as synthetic aggregate (replacing sand and gravel). The emission reductions represent a small share (i.e., 0.1%) of total U.S. CO2 emissions; however, industrial byproducts may represent comparatively low-cost methods for the advancement of mineral carbonation technologies, which may be extended to more abundant yet expensive natural alkalinity sources.

PMID: 23738892 [PubMed - indexed for MEDLINE]

Studying protein-reconstituted proteoliposome fusion with content indicators in vitro.

Bioessays. 2013 Jul;35(7):658-65

Authors: Diao J, Zhao M, Zhang Y, Kyoung M, Brunger AT

Abstract
In vitro reconstitution assays are commonly used to study biological membrane fusion. However, to date, most ensemble and single-vesicle experiments involving SNARE proteins have been performed only with lipid-mixing, but not content-mixing indicators. Through simultaneous detection of lipid and small content-mixing indicators, we found that lipid mixing often occurs seconds prior to content mixing, or without any content mixing at all, during a 50-seconds observation period, for Ca(2+) -triggered fusion with SNAREs, full-length synaptotagmin-1, and complexin. Our results illustrate the caveats of commonly used bulk lipid-mixing fusion experiments. We recommend that proteoliposome fusion experiments should always employ content-mixing indicators in addition to, or in place of, lipid-mixing indicators.

PMID: 23625805 [PubMed - indexed for MEDLINE]

Polyethylene-water partitioning coefficients for parent- and alkylated-polycyclic aromatic hydrocarbons and polychlorinated biphenyls.

Environ Sci Technol. 2013 Jul 2;47(13):6943-50

Authors: Choi Y, Cho YM, Luthy RG

Abstract
We report polyethylene (PE)-water partitioning coefficients (K(PE)) for 17 parent-polycyclic aromatic hydrocarbons (PAHs), 22 alkylated-PAHs, 3 perdeuterated parent-PAHs, and 100 polychlorinated biphenyl (PCB) congeners or coeluting congener groups. The K(PE) values for compounds in the same homologue group are within 0.2 log units for alkylated-PAHs but span up to an order of magnitude for PCBs, due to the greater contribution of the position of the substituents (i.e., chlorines for PCBs and alkyl groups for alkylated-PAHs) to the molecular structure. The K(PE) values in deionized water for parent- and alkylated-PAHs show a good correlation with a regression model employing the number of aromatic carbons (C(AR)) and aliphatic carbons (C(AL)) in each compound: log K(PE) = -0.241 + 0.313 C(AR) + 0.461 C(AL). The regression model is useful for the assessment of freely dissolved aqueous concentrations of alkylated-PAHs, which comprise a significant fraction of the total in petroleum-derived PAHs and in some pyrogenic PAH mixtures. For PCBs, experimentally determined octanol-water partitioning coefficients are the best predictor of the K(PE) values among the molecular parameters studied. The effect of salinity up to 20 or 30 parts per thousand is found to be relatively insignificant on K(PE) values for PAHs or PCBs, respectively.

PMID: 23488618 [PubMed - indexed for MEDLINE]

Impact of a multiple mice holder on quantitation of high-throughput MicroPET imaging with and without Ct attenuation correction.

Mol Imaging Biol. 2013 Oct;15(5):569-75

Authors: Habte F, Ren G, Doyle TC, Liu H, Cheng Z, Paik DS

Abstract
PURPOSE: The aim of this study is to evaluate the impact of scanning multiple mice simultaneously on image quantitation, relative to single mouse scans on both a micro-positron emission tomography/computed tomography (microPET/CT) scanner (which utilizes CT-based attenuation correction to the PET reconstruction) and a dedicated microPET scanner using an inexpensive mouse holder "hotel."
METHODS: We developed a simple mouse holder made from common laboratory items that allows scanning multiple mice simultaneously. It is also compatible with different imaging modalities to allow multiple mice and multi-modality imaging. For this study, we used a radiotracer ((64)Cu-GB170) with a relatively long half-life (12.7 h), selected to allow scanning at times after tracer uptake reaches steady state. This also reduces the effect of decay between sequential imaging studies, although the standard decay corrections were performed. The imaging was also performed using a common tracer, 2-deoxy-2-[(18) F]fluoro-D-glucose (FDG), although the faster decay and faster pharmacokinetics of FDG may introduce greater biological variations due to differences in injection-to-scan timing. We first scanned cylindrical mouse phantoms (50 ml tubes) both in a groups of four at a time (multiple mice mode) and then individually (single mouse mode), using microPET/CT and microPET scanners to validate the process. Then, we imaged a first set of four mice with subcutaneous tumors (C2C12Ras) in both single- and multiple-mice imaging modes. Later, a second set of four normal mice were injected with FDG and scanned 1 h post-injection. Immediately after completion of the scans, ex vivo biodistribution studies were performed on all animals to provide a "gold-standard" to compare quantitative values obtained from PET. A semi-automatic threshold-based region of interest tool was used to minimize operator variability during image analysis.
RESULTS: Phantom studies showed less than 4.5 % relative error difference between the single- and multiple-mice imaging modes of PET imaging with CT-based attenuation correction and 18.4 % without CT-based attenuation correction. In vivo animal studies (n = 4) showed <5 % (for (64)Cu, p > 0.686) and <15 % (for FDG, p > 0.4 except for brain image data p = 0.029) relative mean difference with respect to percent injected dose per gram (%ID/gram) between the single- and multiple-mice microPET imaging mode when CT-based attenuation correction is performed. Without CT-based attenuation correction, we observed relative mean differences of about 11 % for (64)Cu and 15 % for FDG.
CONCLUSION: Our results confirmed the potential use of a microPET/CT scanner for multiple mice simultaneous imaging without significant sacrifice in quantitative accuracy as well as in image quality. Thus, the use of the mouse "hotel" is an aid to increasing instrument throughput on small animal scanners with minimal loss of quantitative accuracy.

PMID: 23479323 [PubMed - indexed for MEDLINE]

Long-term results and costs of muscle flap coverage with Ilizarov bone transport in lower limb salvage.

J Orthop Trauma. 2013 Oct;27(10):576-81

Authors: Lowenberg DW, Buntic RF, Buncke GM, Parrett BM

Abstract
OBJECTIVES: To determine long-term outcomes and costs of Ilizarov bone transport and flap coverage for lower limb salvage.
DESIGN: Case series with retrospective review of outcomes with at least 6-year follow-up.
SETTING: Academic tertiary care medical center.
PATIENTS: Thirty-four consecutive patients with traumatic lower extremity wounds and tibial defects who were recommended amputation but instead underwent complex limb salvage from 1993 to 2005.
INTERVENTION: Flap reconstruction and Ilizarov bone transport.
MAIN OUTCOME MEASUREMENTS: Outcomes assessed were flap complications, infection, union, malunion, need for chronic narcotics, ambulation status, employment status, and need for reoperations. A cost analysis was performed comparing this treatment modality to amputation.
RESULTS: Thirty-four patients (mean age: 40 years) were included with 14 acute Gustilo IIIB/C defects and 20 chronic tibial defects (nonunion with osteomyelitis). Thirty-five muscle flaps were performed with 1 flap loss (2.9%). The mean tibial bone defect was 8.7 cm, mean duration of bone transport was 10.8 months, and mean follow-up was 11 years. Primary nonunion rate at the docking site was 8.8% and malunion rate was 5.9%. All patients achieved final union with no cases of recurrent osteomyelitis. No patients underwent future amputations, 29% required reoperations, 97% were ambulating without assistance, 85% were working full time, and only 5.9% required chronic narcotics. Mean lifetime cost per patient per year after limb salvage was significantly less than the published cost for amputation.
CONCLUSIONS: The long-term results and costs of bone transport and flap coverage strongly support complex limb salvage in this patient population.

PMID: 23412507 [PubMed - indexed for MEDLINE]

A comprehensive examination of delay discounting in a clinical sample of Cannabis-dependent military veterans making a self-guided quit attempt.

Exp Clin Psychopharmacol. 2013 Feb;21(1):55-65

Authors: Heinz AJ, Peters EN, Boden MT, Bonn-Miller MO

Abstract
Delay discounting (DD), an index of impulsivity, reflects individuals' preference for smaller immediate rewards to larger delayed rewards. The current study examined (a) relations between DD and quantity, frequency, and severity of Cannabis use, as well as several other measures of co-occurring substance use and clinical severity, and (b) whether DD predicted Cannabis-cessation outcomes. Cannabis-dependent United States (U.S.) veterans (N = 72; 95% male) who were interested in making serious self-quit attempts were evaluated prior to their cessation attempts, during which they completed a computerized DD task, and were followed throughout six months postattempt. Results indicated that higher DD was significantly correlated with higher compulsive craving for Cannabis (ρ = .29, p < .05), younger age of first Cannabis use (r = -.32, p < .01), earlier commencement of regular Cannabis smoking (r = -.25, p < .05), and seeking professional help for a previous Cannabis quit attempt (ρ = .27, p < .05). DD did not significantly predict any Cannabis-cessation outcomes in the first week postattempt or during the 6-month follow-up. These results add to the literature on DD, which has focused on users of tobacco, alcohol, opioids, and cocaine, by demonstrating that DD is sensitive to developmental trajectories of Cannabis dependence, but does not reliably predict cessation outcomes. Results also suggest that DD may carry less relevance for Cannabis than for other substances of abuse.

PMID: 23379614 [PubMed - indexed for MEDLINE]

Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression.

Psychiatry Res. 2013 Feb 28;211(2):119-26

Authors: Kelley R, Garrett A, Cohen J, Gomez R, Lembke A, Keller J, Reiss AL, Schatzberg A

Abstract
Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

PMID: 23149036 [PubMed - indexed for MEDLINE]

Modeling and experiments of magneto-nanosensors for diagnostics of radiation exposure and cancer.

Biomed Microdevices. 2013 Aug;15(4):665-71

Authors: Kim D, Lee JR, Shen E, Wang SX

Abstract
We present a resistive network model, protein assay data, and outlook of the giant magnetoresistive (GMR) spin-valve magneto-nanosensor platform ideal for multiplexed detection of protein biomarkers in solutions. The magneto-nanosensors are designed to have optimal performance considering several factors such as sensor dimension, shape anisotropy, and magnetic nanoparticle tags. The resistive network model indicates that thinner spin-valve sensors with narrower width lead to higher signals from magnetic nanoparticle tags. Standard curves and real-time measurements showed a sensitivity of ~10 pM for phosphorylated-structural maintenance of chromosome 1 (phosphor-SMC1), ~53 fM for granulocyte colony stimulation factor (GCSF), and ~460 fM for interleukin-6 (IL6), which are among the representative biomarkers for radiation exposure and cancer.

PMID: 22763391 [PubMed - indexed for MEDLINE]