Lane Medical Library

Nicotinic modulation of cortical circuits.

Front Neural Circuits. 2014;8:30

Authors: Arroyo S, Bennett C, Hestrin S

Abstract
The ascending cholinergic neuromodulatory system sends projections throughout cortex and has been shown to play an important role in a number of cognitive functions including arousal, working memory, and attention. However, despite a wealth of behavioral and anatomical data, understanding how cholinergic synapses modulate cortical function has been limited by the inability to selectively activate cholinergic axons. Now, with the development of optogenetic tools and cell-type specific Cre-driver mouse lines, it has become possible to stimulate cholinergic axons from the basal forebrain (BF) and probe cholinergic synapses in the cortex for the first time. Here we review recent work studying the cell-type specificity of nicotinic signaling in the cortex, synaptic mechanisms mediating cholinergic transmission, and the potential functional role of nicotinic modulation.

PMID: 24734005 [PubMed - as supplied by publisher]

Transcription factors TFIIF and TFIIS promote transcript elongation by RNA polymerase II by synergistic and independent mechanisms.

Proc Natl Acad Sci U S A. 2014 Apr 14;

Authors: Schweikhard V, Meng C, Murakami K, Kaplan CD, Kornberg RD, Block SM

Abstract
Recent evidence suggests that transcript elongation by RNA polymerase II (RNAPII) is regulated by mechanical cues affecting the entry into, and exit from, transcriptionally inactive states, including pausing and arrest. We present a single-molecule optical-trapping study of the interactions of RNAPII with transcription elongation factors TFIIS and TFIIF, which affect these processes. By monitoring the response of elongation complexes containing RNAPII and combinations of TFIIF and TFIIS to controlled mechanical loads, we find that both transcription factors are independently capable of restoring arrested RNAPII to productive elongation. TFIIS, in addition to its established role in promoting transcript cleavage, is found to relieve arrest by a second, cleavage-independent mechanism. TFIIF synergistically enhances some, but not all, of the activities of TFIIS. These studies also uncovered unexpected insights into the mechanisms underlying transient pauses. The direct visualization of pauses at near-base-pair resolution, together with the load dependence of the pause-entry phase, suggests that two distinct mechanisms may be at play: backtracking under forces that hinder transcription and a backtrack-independent activity under assisting loads. The measured pause lifetime distributions are inconsistent with prevailing views of backtracking as a purely diffusive process, suggesting instead that the extent of backtracking may be modulated by mechanisms intrinsic to RNAPII. Pauses triggered by inosine triphosphate misincorporation led to backtracking, even under assisting loads, and their lifetimes were reduced by TFIIS, particularly when aided by TFIIF. Overall, these experiments provide additional insights into how obstacles to transcription may be overcome by the concerted actions of multiple accessory factors.

PMID: 24733897 [PubMed - as supplied by publisher]

Endemism and functional convergence across the North American soil mycobiome.

Proc Natl Acad Sci U S A. 2014 Apr 14;

Authors: Talbot JM, Bruns TD, Taylor JW, Smith DP, Branco S, Glassman SI, Erlandson S, Vilgalys R, Liao HL, Smith ME, Peay KG

Abstract
Identifying the ecological processes that structure communities and the consequences for ecosystem function is a central goal of ecology. The recognition that fungi, bacteria, and viruses control key ecosystem functions has made microbial communities a major focus of this field. Because many ecological processes are apparent only at particular spatial or temporal scales, a complete understanding of the linkages between microbial community, environment, and function requires analysis across a wide range of scales. Here, we map the biological and functional geography of soil fungi from local to continental scales and show that the principal ecological processes controlling community structure and function operate at different scales. Similar to plants or animals, most soil fungi are endemic to particular bioregions, suggesting that factors operating at large spatial scales, like dispersal limitation or climate, are the first-order determinants of fungal community structure in nature. By contrast, soil extracellular enzyme activity is highly convergent across bioregions and widely differing fungal communities. Instead, soil enzyme activity is correlated with local soil environment and distribution of fungal traits within the community. The lack of structure-function relationships for soil fungal communities at continental scales indicates a high degree of functional redundancy among fungal communities in global biogeochemical cycles.

PMID: 24733885 [PubMed - as supplied by publisher]

Rape Prevention Through Empowerment of Adolescent Girls.

Pediatrics. 2014 Apr 14;

Authors: Sarnquist C, Omondi B, Sinclair J, Gitau C, Paiva L, Mulinge M, Cornfield DN, Maldonado Y

Abstract
BACKGROUND AND OBJECTIVE: Sexual assault is a major cause of injury, unplanned pregnancy, HIV infection, and mental health problems worldwide. In parts of sub-Saharan Africa, sexual assault has reached epidemic proportions. This study evaluated the efficacy of an empowerment and self-defense intervention for adolescent girls to decrease the incidence of sexual assault and harassment in Nairobi's large informal settlements.
METHODS: A prospective cohort of 1978 adolescents from 4 neighborhoods near Nairobi were taught empowerment, deescalation, and self-defense skills in six 2-hour sessions. The standard-of-care (SOC) group (n = 428) received a life skills class. Self-reported, anonymous survey data were collected at baseline and 10.5 months after intervention.
RESULTS: Annual sexual assault rates decreased from 17.9/100 person-years at baseline to 11.1 at follow-up (rate ratio = 1.61; 95% confidence interval [CI], 1.26-1.86; P < .001); there was no significant change in the SOC group (14.3 to 14.0, rate ratio = 1.02; 95% CI, 0.67-1.57, P = .92). Sexual assault disclosure in the intervention group increased from 56% to 75% (P = .006), compared with a constant incidence of disclosure (53%) in the SOC group. The majority (52.3%) of adolescents in the intervention group reported using skills learned to stop an assault.
CONCLUSIONS: This intervention decreased sexual assault rates among adolescent girls in Kenya. The intervention was also associated with an increase in the disclosure of assaults, thereby enabling survivors to seek care and support and possibly leading to the identification and prosecution of perpetrators. This model should be adaptable to other settings both in Africa and globally.

PMID: 24733880 [PubMed - as supplied by publisher]

Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment.

J Clin Oncol. 2014 Apr 14;

Authors: Kurian AW, Hare EE, Mills MA, Kingham KE, McPherson L, Whittemore AS, McGuire V, Ladabaum U, Kobayashi Y, Lincoln SE, Cargill M, Ford JM

Abstract
PURPOSE: Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.
METHODS: Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.
RESULTS: In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.
CONCLUSION: Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

PMID: 24733792 [PubMed - as supplied by publisher]

Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice.

Glia. 2014 Apr 15;

Authors: Cekanaviciute E, Fathali N, Doyle KP, Williams AM, Han J, Buckwalter MS

Abstract
Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered "Ast-Tbr2DN" mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60% more activated CD11b(+) monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 2 days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex and preserve brain function during the subacute period after stroke. GLIA 2014.

PMID: 24733756 [PubMed - as supplied by publisher]

Pharmacokinetics of Prophylactic Cefazolin in Parturients undergoing Cesarean Delivery.

Antimicrob Agents Chemother. 2014 Apr 14;

Authors: Elkomy MH, Sultan P, Drover DR, Epshtein E, Galinkin JL, Carvalho B

Abstract
The objectives of this work were (1) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (2) to assess cefazolin transplacental transmission; (3) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (4) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 L/h. Pre- and post-delivery clearance was 7.18 and 4.12 L/h, respectively. Computer simulations revealed that the probability of maintaining free plasma concentrations above 8 mg/L during scheduled caesarean surgery was < 50% in the cord blood when cefazolin was administered in doses < 2 g or when it was administered < 1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates > 5 h after birth. Cefazolin clearance increases during pregnancy and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates as compared with adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates.

PMID: 24733461 [PubMed - as supplied by publisher]

Arthroscopic Repair of Full-Thickness Rotator Cuff Tears With and Without Acromioplasty: Randomized Prospective Trial With 2-Year Follow-up.

Am J Sports Med. 2014 Apr 14;

Authors: Abrams GD, Gupta AK, Hussey KE, Tetteh ES, Karas V, Bach BR, Cole BJ, Romeo AA, Verma NN

Abstract
BACKGROUND:Acromioplasty is commonly performed during arthroscopic rotator cuff repair, but its effect on short-term outcomes is debated. PURPOSE:To report the short-term clinical outcomes of patients undergoing arthroscopic repair of full-thickness rotator cuff tears with and without acromioplasty. STUDY DESIGN:Randomized controlled trial; Level of evidence, 2. METHODS:Patients undergoing arthroscopic repair of full-thickness rotator cuff tears were randomized into acromioplasty or nonacromioplasty groups. The Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES) score, Constant score, University of California-Los Angeles (UCLA) score, and Short Form-12 (SF-12) health assessment were collected along with physical examination including range of motion and dynamometer strength testing. Intraoperative data including tear size, repair configuration, and concomitant procedures were recorded. Follow-up examination was performed at regular intervals up to 2 years. Preoperative imaging was reviewed to classify the acromial morphologic type, acromial angle, and lateral acromial angulation. RESULTS:A total of 114 patients were initially enrolled in the study, and 95 (83%; 43 nonacromioplasty, 52 acromioplasty) were available for a minimum 2-year follow-up. There were no significant differences in baseline characteristics, including number of tendons torn, repair configuration, concomitant procedures, and acromion type and angles. Within groups, there was a significant (P < .001) improvement in all functional outcome scores from preoperatively to all follow-up time points, including 2 years, for the nonacromioplasty and acromioplasty groups (ASES score: 55.1-91.5, 48.8-89.0; Constant score: 48.3-75.0, 51.9-78.7, respectively). There were no significant differences in functional outcomes between nonacromioplasty and acromioplasty groups or between subjects with different acromial features at any time point. CONCLUSION:The results of this study demonstrate no difference in clinical outcomes after rotator cuff repair with or without acromioplasty at 2 years postoperatively.

PMID: 24733157 [PubMed - as supplied by publisher]

Positive reinforcement mediated by midbrain dopamine neurons requires d1 and d2 receptor activation in the nucleus accumbens.

PLoS One. 2014;9(4):e94771

Authors: Steinberg EE, Boivin JR, Saunders BT, Witten IB, Deisseroth K, Janak PH

Abstract
The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

PMID: 24733061 [PubMed - in process]

Association of CHRNA5-A3-B4 SNP rs2036527 with smoking cessation therapy response in African American smokers.

Clin Pharmacol Ther. 2014 Apr 14;

Authors: Zhu AZ, Zhou Q, Cox LS, David SP, Ahluwalia JS, Benowitz NL, Tyndale RF

Abstract
Associations between CHRNA5-A3-B4 variants and smoking behaviors exist, however the association with smoking abstinence is less understood, particularly among African Americans. In 1295 African Americans enrolled in two clinical trials, we investigated the association between CHRNA5-A3-B4 and smoking abstinence. Rs2056527[A] was associated with lower abstinence with active pharmacotherapy (during-treatment: OR=0.42&P<0.001; end of treatment (EOT): OR=0.55&P=0.004), or with nicotine gum alone (during-treatment: OR=0.31&P<0.001; EOT: OR=0.51&P=0.02), but not significantly with bupropion, although similar directions and magnitudes were observed (during-treatment: OR=0.54&P=0.05; EOT: OR=0.59&P=0.08). Additionally, rs588765[T] was associated with abstinence with gum during treatment (OR=2.31&P<0.01). Rs16969968 occurred at a low frequency and was not consistently associated with abstinence. CHRNA5-A3-B4 variants were not associated with tobacco consumption and adjustments for smoking behaviors did not alter the associations with smoking abstinence. Together, our data suggest that in African Americans CHRNA5-A3-B4 variants are not associated with baseline smoking, but can influence smoking abstinence during active pharmacotherapy.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 14 April 2014; doi:10.1038/clpt.2014.88.

PMID: 24733007 [PubMed - as supplied by publisher]

Mechanisms for Photoinactivation of Enterococcus faecalis in Seawater.

Appl Environ Microbiol. 2014 May;80(9):2964

Authors: Sassoubre LM, Nelson KL, Boehm AB

PMID: 24732731 [PubMed - in process]

The Role of Stem Cells in Aesthetic Surgery: Fact or Fiction?

Plast Reconstr Surg. 2014 Apr 11;

Authors: McArdle A, Senarath-Yapa K, Walmsley GG, Hu M, Atashroo DA, Tevlin R, Zielins E, Gurtner GC, Wan DC, Longaker MT

Abstract
Stem cells are attractive candidates for the development of novel therapies, targeting indications that involve functional restoration of defective tissue. Although most stem cell therapies are new and highly experimental, there are clinics around the world that exploit vulnerable patients with the hope of offering supposed stem cell therapies, many of which operate without credible scientific merit, oversight, or other patient protection.We review the potential, as well as drawbacks, for incorporation of stem cells in cosmetic procedures. A review of FDA-approved indications and ongoing clinical trials with adipose stem cells is provided. Furthermore, a "snapshot" analysis of websites using the search terms "stem cell therapy" or "stem cell treatment" or "stem cell facelift" was performed.Despite the protective net cast by regulatory agencies such as the FDA and professional societies such as the American Society of Plastic Surgeons, we are witnessing worrying advertisements for procedures such as stem cell facelifts, stem cell breast augmentations, and even stem cell vaginal rejuvenation. The marketing and promotion of stem cell procedures in aesthetic surgery is not adequately supported by clinical evidence in the majority of cases.Stem cells offer tremendous potential, but the marketplace is saturated with unsubstantiated and sometimes fraudulent claims that may place patients at risk. With plastic surgeons at the forefront of stem cell-based regenerative medicine, it is critically important that we provide an example of a rigorous approach to research, data collection, and advertising of stem cell therapies.

PMID: 24732654 [PubMed - as supplied by publisher]

Pediatric lung transplantation: promise being realized.

Curr Opin Pediatr. 2014 Apr 12;

Authors: Conrad C, Cornfield DN

Abstract
PURPOSE OF REVIEW: Lung transplantation for infants and children is an accepted but rarely exercised option for the treatment of end-stage lung disease, with outcomes equivalent to those for adults. However, widespread misconceptions regarding pediatric outcomes often confound timely and appropriate referral to specialty centers. We present the updated information for primary pediatricians to utilize when counseling families with children confronted by progressive end-stage pulmonary or cardiovascular disease.
RECENT FINDINGS: We provide general guidelines to consider for referral, and discuss allocation of organs in children, information regarding standard treatment protocols, and survival outcomes.
SUMMARY: Lung transplantation is a worthwhile treatment option to consider in children with end-stage lung disease. The treatment is complex, but lung transplant provides substantial survival benefit and markedly improved quality of life for children and their families. This timely review provides comprehensive information for pediatricians who are considering options for treatment of children with end-stage lung disease.

PMID: 24732565 [PubMed - as supplied by publisher]

Optimizing Care of Adults With Congenital Heart Disease in a Pediatric Cardiovascular ICU Using Electronic Clinical Decision Support.

Pediatr Crit Care Med. 2014 Apr 11;

Authors: May LJ, Longhurst CA, Pageler NM, Wood MS, Sharek PJ, Zebrack CM

Abstract
OBJECTIVES:: The optimal location for postoperative cardiac care of adults with congenital heart disease is controversial. Some congenital heart surgeons operate on these adults in children's hospitals with postoperative care provided by pediatric critical care teams who may be unfamiliar with adult national performance measures. This study tested the hypothesis that Clinical Decision Support tools integrated into the clinical workflow would facilitate improved compliance with The Joint Commission Surgical Care Improvement Project performance measures in adults recovering from cardiac surgery in a children's hospital.
DESIGN:: Retrospective chart review comparing compliance pre- and post-Clinical Decision Support intervention for Surgical Care Improvement Project measures addressed in the critical care unit: appropriate cessation of prophylactic antibiotics; controlled blood glucose; urinary catheter removal; and reinitiation of preoperative β-blocker when indicated.
SETTING:: Cardiovascular ICU in a quaternary care freestanding children's hospital.
PATIENTS:: The cohort included 114 adults 18-70 years old recovering from cardiac surgery in our pediatric cardiovascular ICU.
INTERVENTIONS:: Clinical Decision Support tools including data-triggered alerts, smart documentation forms, and order sets with conditional logic were integrated into the workflow.
MEASUREMENTS AND MAIN RESULTS:: Compliance with antibiotic discontinuation was 100% pre- and postintervention. Compliance rates improved for glucose control (p = 0.007) and urinary catheter removal (p = 0.05). Documentation of β-blocker therapy (nonexistent preintervention) was 100% postintervention. Composite compliance for all measures increased from 53% to 84% (p = 0.002). There were no complications related to institution of the Surgical Care Improvement Project measures. There was no in-hospital mortality.
CONCLUSIONS:: Compliance with the national adult postoperative performance measures can be excellent in a children's hospital with the help of Clinical Decision Support tools. This represents an important step toward providing high-quality care to a growing population of adults with congenital heart disease who may receive care in a pediatric center.

PMID: 24732291 [PubMed - as supplied by publisher]

Comment on Hurley, J.C. Towards Clinical Application of Anti-endotoxin Antibodies; A Re-Appraisal of the Disconnect. Toxins 2013, 5, 2589-2620.

Toxins (Basel). 2014;6(4):1362-3

Authors: Brock-Utne JG

Abstract
I have read with interest James C. Hurley's very good review [1].

PMID: 24732205 [PubMed - in process]

Congenital Anomalies of the Aortic Arch in Acute Type-A Aortic Dissection: Implications for Monitoring, Perfusion Strategy, and Surgical Repair.

J Cardiothorac Vasc Anesth. 2014 Apr 11;

Authors: Maxwell BG, Harrington KB, Beygui RE, Oakes DA

Abstract
OBJECTIVE: To assess whether management of acute Stanford type-A aortic dissection differs in patients with congenital anomalies of the aortic arch compared with standard institutional practice.
DESIGN: Retrospective analysis of all consecutive patients from 2001 through 2011.
SETTING: Quaternary referral center for surgical management of thoracic aortic disease.
PARTICIPANTS: All patients with arch anomalies who underwent surgery for acute Stanford type-A aortic dissection during the study period (n = 43).
INTERVENTIONS: Surgical management, anesthetic monitoring, and perfusion strategy were analyzed in a retrospective fashion. No new interventions were undertaken as part of this study.
MEASUREMENTS AND MAIN RESULTS: Management differed most in patients with an aberrant right subclavian artery (n = 5), because the institutional standard of right axillary artery cannulation with left upper extremity arterial pressure monitoring was not possible. In patients with one of two "bovine" arch patterns (n = 32), management differed in the conduct of selective antegrade cerebral perfusion, which could include clamping above or below the takeoff of the left common carotid artery (and, therefore, produced unilateral or bilateral antegrade cerebral perfusion). All patients with a connective tissue disorder exhibited a bovine arch pattern. Management of patients with a right arch (n = 3) reflected the opposite of management for normal anatomy (for patients with traditional mirror-image branching) or opposite that of the aberrant right subclavian group (for patients who had a corresponding aberrant left subclavian artery).
CONCLUSIONS: Rational management reflected the anatomic variations observed. These results support the importance of interdisciplinary planning, especially in an emergency, to optimize outcome.

PMID: 24731741 [PubMed - as supplied by publisher]

Refinements and Secondary Surgery After Flap Reconstruction of the Traumatized Hand.

Hand Clin. 2014 May;30(2):211-223

Authors: Chiou GJ, Chang J

Abstract
The traumatized hand often has soft tissue loss requiring flap reconstruction. Before proceeding with flap selection, the need for future refinement and secondary surgery should be taken into consideration. Although muscle flaps may offer better contour, fasciocutaneous flaps allow easier secondary flap elevation. After the initial flap reconstruction, indications for secondary procedures may be managed according to tissue type: bone, joint, tendon, nerve, and soft tissue.

PMID: 24731611 [PubMed - as supplied by publisher]

The Implications of Hyponitroxia in Cancer.

Transl Oncol. 2014 Mar 4;

Authors: Oronsky B, Fanger GR, Oronsky N, Knox S, Scicinski J

Abstract
Tumors are spatially heterogeneous, with regions of relative hypoxia and normoxia. The tumor microenvironment is an important determinant of both tumor growth and response to a variety of cytotoxic and targeted therapies. In the tumor microenvironment, reactive oxygen species and nitric oxide (NO) are important mediators of the level of expression of many transcription factors and signaling cascades that affect tumor growth and responses to therapy. The primary objective of this review is to explore and discuss the seemingly dichotomous actions of NO in cancer biology as both a tumor promoter and suppressor with an emphasis on understanding the role of persistently low NO concentrations or hyponitroxia as a key mediator in tumor progression. This review will also discuss the potential role of hyponitroxia as a novel therapeutic target to treat cancer and outline an approach that provides new opportunities for pharmacological intervention.

PMID: 24731473 [PubMed - as supplied by publisher]

A practical clinical definition of epilepsy.

Epilepsia. 2014 Apr 14;

Authors: Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S

Abstract
Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

PMID: 24730690 [PubMed - as supplied by publisher]

Identification of Desulfobacterales as primary hydrogenotrophs in a complex microbial mat community.

Geobiology. 2014 May;12(3):221-230

Authors: Burow LC, Woebken D, Marshall IP, Singer SW, Pett-Ridge J, Prufert-Bebout L, Spormann AM, Bebout BM, Weber PK, Hoehler TM

Abstract
Hypersaline microbial mats have been shown to produce significant quantities of H2 under dark, anoxic conditions via cyanobacterial fermentation. This flux of a widely accessible microbial substrate has potential to significantly influence the ecology of the mat, and any consumption will affect the net efflux of H2 that might otherwise be captured as a resource. Here, we focus on H2 consumption in a microbial mat from Elkhorn Slough, California, USA, for which H2 production has been previously characterized. Active biologic H2 consumption in this mat is indicated by a significant time-dependent decrease in added H2 compared with a killed control. Inhibition of sulfate reduction, as indicated by a decrease in hydrogen sulfide production relative to controls, resulted in a significant increase in H2 efflux, suggesting that sulfate-reducing bacteria (SRB) are important hydrogenotrophs. Low methane efflux under these same conditions indicated that methanogens are likely not important hydrogenotrophs. Analyses of genes and transcripts that encode for rRNA or dissimilatory sulfite reductase, using both PCR-dependent and PCR-independent metatranscriptomic sequencing methods, demonstrated that Desulfobacterales are the dominant, active SRB in the upper, H2 -producing layer of the mat (0-2 mm). This hypothesis was further supported by the identification of transcripts encoding hydrogenases derived from Desulfobacterales capable of H2 oxidation. Analysis of molecular data provided no evidence for the activity of hydrogenotrophic methanogens. The combined biogeochemical and molecular data strongly indicate that SRB belonging to the Desulfobacterales are the quantitatively important hydrogenotrophs in the Elkhorn Slough mat.

PMID: 24730641 [PubMed - as supplied by publisher]

Open-label extension studies: are they really research?

Am J Bioeth. 2014 Apr;14(4):60-1

Authors: Cho MK

PMID: 24730503 [PubMed - in process]

Research: increasing value, reducing waste - Authors' reply.

Lancet. 2014 Mar 29;383(9923):1126-7

Authors: Glasziou P, Macleod M, Chalmers I, Ioannidis JP, Al-Shahi Salman R, Chan AW

PMID: 24679627 [PubMed - indexed for MEDLINE]

Reperfusion times and in-hospital outcomes among patients with an isolated posterior myocardial infarction: insights from the National Cardiovascular Data Registry (NCDR).

Am Heart J. 2014 Mar;167(3):350-4

Authors: Waldo SW, Brenner DA, Li S, Alexander K, Ganz P

Abstract
BACKGROUND: A posterior myocardial infarction (PMI) is associated with significant morbidity and delays in recognition may prevent the timely revascularization of these patients. The present study sought to evaluate the reperfusion times and in-hospital outcomes among patients with an isolated PMI.
METHODS: Clinical characteristics and reperfusion times were compared between those with an isolated PMI and those with all other ST-elevation myocardial infarctions (STEMI) in the NCDR ACTION-GWTG Registry from 2007 to 2012. Logistic generalized estimating equations were used to examine risk-adjusted mortality.
RESULTS: Among 117,739 subjects with a STEMI, 824 (0.7%) had evidence of an isolated PMI. The median time between patient arrival and initial electrocardiogram was similar between those with an isolated PMI and those with a non-PMI STEMI (6 vs. 6 minutes, P = .48). However, the median time from initial electrocardiogram to percutaneous coronary intervention was significantly longer among subjects with a PMI (69 vs 61 minutes, P < .01) and fewer patients achieved a door-to-balloon time less than 90 minutes (83% vs 89%, P < .01). After multivariable adjustment, in-hospital mortality was similar for PMI patients compared to those with a non-PMI STEMI (AOR: 1.11, 95% CI: 0.83-1.50).
CONCLUSION: The door-to-balloon times are significantly longer for those with an isolated PMI resulting in fewer patients receiving reperfusion within the guideline recommended time period. Ongoing educational initiatives to increase recognition of a PMI are needed to improve the reperfusion times and outcomes associated with this condition.

PMID: 24576519 [PubMed - indexed for MEDLINE]

Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.

Am Heart J. 2014 Mar;167(3):342-349.e17

Authors: O'Brien EC, Roe MT, Fraulo ES, Peterson ED, Ballantyne CM, Genest J, Gidding SS, Hammond E, Hemphill LC, Hudgins LC, Kindt I, Moriarty PM, Ross J, Underberg JA, Watson K, Pickhardt D, Rader DJ, Wilemon K, Knowles JW

Abstract
BACKGROUND: Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.
DESIGN: The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.
SUMMARY: The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

PMID: 24576518 [PubMed - indexed for MEDLINE]

The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study.

Am Heart J. 2014 Mar;167(3):335-41

Authors: Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF, Kitt MM, Lorenz TJ

Abstract
Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35-42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of "normal", or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE.

PMID: 24576517 [PubMed - indexed for MEDLINE]

Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium.

Am Heart J. 2014 Mar;167(3):292-300

Authors: Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N

Abstract
This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.

PMID: 24576511 [PubMed - indexed for MEDLINE]

Early-stage non-small cell lung cancer: surgery, stereotactic radiosurgery, and individualized adjuvant therapy.

Semin Oncol. 2014 Feb;41(1):40-56

Authors: Padda SK, Burt BM, Trakul N, Wakelee HA

Abstract
Despite cures in early stage (IA-IIB) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 36%-73%. Surgical resection via lobectomy is the treatment of choice in early-stage NSCLC, with the goal being complete anatomic resection of the tumor and mediastinal lymph node evaluation. Newer technologies, including the minimally invasive thoracoscopic approach and the many techniques available to stage the mediastinum, have introduced advantages over traditional approaches in achieving this goal. The advent of stereotactic ablative radiotherapy (SABR) has changed how we treat those patients who cannot undergo surgery secondary to comorbidities or patient preference. SABR allows for precise radiation delivery in a short course and at high doses. Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected high-risk stage IB and stage II NSCLC based on a ~5% improvement in 5-year overall survival. The concept of customized adjuvant chemotherapy is emerging, and we will explore the potential value of targeting tumor mutations with available drugs (ie, epidermal growth factor receptor [EGFR] mutations with erlotinib), a strategy that for the moment should be restricted to clinical trials.

PMID: 24565580 [PubMed - indexed for MEDLINE]

Cognitive and neurological aspects of sex chromosome aneuploidies.

Lancet Neurol. 2014 Mar;13(3):306-18

Authors: Hong DS, Reiss AL

Abstract
Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.

PMID: 24556008 [PubMed - indexed for MEDLINE]

Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission.

Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2548-53

Authors: Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R

Abstract
Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in "proliferative" genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.

PMID: 24550281 [PubMed - indexed for MEDLINE]

Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging.

Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2436-41

Authors: Eberlin LS, Tibshirani RJ, Zhang J, Longacre TA, Berry GJ, Bingham DB, Norton JA, Zare RN, Poultsides GA

Abstract
Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastric-tissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastric-cancer surgery.

PMID: 24550265 [PubMed - indexed for MEDLINE]

A new leadership curriculum: the multiplication of intelligence.

Acad Med. 2014 Mar;89(3):376-9

Authors: Wiseman L, Bradwejn J, Westbroek EM

Abstract
The authors propose a new model of leadership for the clinical setting. The authors' research suggests that there is latent intelligence inside business and educational organizations because many leaders operate in a way that shuts down the intelligence of others. Such leaders are classified as "Diminishers." In the clinical setting this behavior creates a hidden curriculum in medical education, passing on unprofessional patterns of behavior to future physicians. Other leaders, however, amplify intelligence, produce better outcomes, and grow talent. These leaders are classified as "Multipliers." The authors suggest that Multiplier leadership should become the standard leadership practice in medical schools. Case studies of a Multiplier and a Diminisher are presented and illustrate the positive effect these leaders can have on medical education and health organizations.

PMID: 24448054 [PubMed - indexed for MEDLINE]

Role-modeling and medical error disclosure: a national survey of trainees.

Acad Med. 2014 Mar;89(3):482-9

Authors: Martinez W, Hickson GB, Miller BM, Doukas DJ, Buckley JD, Song J, Sehgal NL, Deitz J, Braddock CH, Lehmann LS

Abstract
PURPOSE: To measure trainees' exposure to negative and positive role-modeling for responding to medical errors and to examine the association between that exposure and trainees' attitudes and behaviors regarding error disclosure.
METHOD: Between May 2011 and June 2012, 435 residents at two large academic medical centers and 1,187 medical students from seven U.S. medical schools received anonymous, electronic questionnaires. The questionnaire asked respondents about (1) experiences with errors, (2) training for responding to errors, (3) behaviors related to error disclosure, (4) exposure to role-modeling for responding to errors, and (5) attitudes regarding disclosure. Using multivariate regression, the authors analyzed whether frequency of exposure to negative and positive role-modeling independently predicted two primary outcomes: (1) attitudes regarding disclosure and (2) nontransparent behavior in response to a harmful error.
RESULTS: The response rate was 55% (884/1,622). Training on how to respond to errors had the largest independent, positive effect on attitudes (standardized effect estimate, 0.32, P < .001); negative role-modeling had the largest independent, negative effect (standardized effect estimate, -0.26, P < .001). Positive role-modeling had a positive effect on attitudes (standardized effect estimate, 0.26, P < .001). Exposure to negative role-modeling was independently associated with an increased likelihood of trainees' nontransparent behavior in response to an error (OR 1.37, 95% CI 1.15-1.64; P < .001).
CONCLUSIONS: Exposure to role-modeling predicts trainees' attitudes and behavior regarding the disclosure of harmful errors. Negative role models may be a significant impediment to disclosure among trainees.

PMID: 24448052 [PubMed - indexed for MEDLINE]

Visual categorization is automatic and obligatory: evidence from Stroop-like paradigm.

J Vis. 2014;14(1)

Authors: Greene MR, Fei-Fei L

Abstract
Human observers categorize visual stimuli with remarkable efficiency--a result that has led to the suggestion that object and scene categorization may be automatic processes. We tested this hypothesis by presenting observers with a modified Stroop paradigm in which object or scene words were presented over images of objects or scenes. Terms were either congruent or incongruent with the images. Observers classified the words as being object or scene terms while ignoring images. Classifying a word on an incongruent image came at a cost for both objects and scenes. Furthermore, automatic processing was observed for entry-level scene categories, but not superordinate-level categories, suggesting that not all rapid categorizations are automatic. Taken together, we have demonstrated that entry-level visual categorization is an automatic and obligatory process.

PMID: 24434626 [PubMed - indexed for MEDLINE]

Structural studies show energy transfer within stabilized phycobilisomes independent of the mode of rod-core assembly.

Biochim Biophys Acta. 2014 Mar;1837(3):385-95

Authors: David L, Prado M, Arteni AA, Elmlund DA, Blankenship RE, Adir N

Abstract
The major light harvesting complex in cyanobacteria and red algae is the phycobilisome (PBS), comprised of hundreds of seemingly similar chromophores, which are protein bound and assembled in a fashion that enables highly efficient uni-directional energy transfer to reaction centers. The PBS is comprised of a core containing 2-5 cylinders surrounded by 6-8 rods, and a number of models have been proposed describing the PBS structure. One of the most critical steps in the functionality of the PBS is energy transfer from the rod substructures to the core substructure. In this study we compare the structural and functional characteristics of high-phosphate stabilized PBS (the standard fashion of stabilization of isolated complexes) with cross-linked PBS in low ionic strength buffer from two cyanobacterial species, Thermosynechococcus vulcanus and Acaryochloris marina. We show that chemical cross-linking preserves efficient energy transfer from the phycocyanin containing rods to the allophycocyanin containing cores with fluorescent emission from the terminal emitters. However, this energy transfer is shown to exist in PBS complexes of different structures as characterized by determination of a 2.4Å structure by X-ray crystallography, single crystal confocal microscopy, mass spectrometry and transmission electron microscopy of negatively stained and cryogenically preserved complexes. We conclude that the PBS has intrinsic structural properties that enable efficient energy transfer from rod substructures to the core substructures without requiring a single unique structure. We discuss the significance of our observations on the functionality of the PBS in vivo.

PMID: 24407142 [PubMed - indexed for MEDLINE]

Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

Cancer Res. 2014 Feb 1;74(3):852-61

Authors: Charbonneau B, Block MS, Bamlet WR, Vierkant RA, Kalli KR, Fogarty Z, Rider DN, Sellers TA, Tworoger SS, Poole E, Risch HA, Salvesen HB, Kiemeney LA, Baglietto L, Giles GG, Severi G, Trabert B, Wentzensen N, Chenevix-Trench G, for AOCS/ACS group, Whittemore AS, Sieh W, Chang-Claude J, Bandera EV, Orlow I, Terry K, Goodman MT, Thompson PJ, Cook LS, Rossing MA, Ness RB, Narod SA, Kupryjanczyk J, Lu K, Butzow R, Dörk T, Pejovic T, Campbell I, Le ND, Bunker CH, Bogdanova N, Runnebaum IB, Eccles D, Paul J, Wu AH, Gayther SA, Hogdall E, Heitz F, Kaye SB, Karlan BY, Anton-Culver H, Gronwald J, Hogdall CK, Lambrechts D, Fasching PA, Menon U, Schildkraut J, Pearce CL, Levine DA, Kjaer SK, Cramer D, Flanagan JM, Phelan CM, Brown R, Massuger LF, Song H, Doherty JA, Krakstad C, Liang D, Odunsi K, Berchuck A, Jensen A, Lubinski J, Nevanlinna H, Bean YT, Lurie G, Ziogas A, Walsh C, Despierre E, Brinton L, Hein A, Rudolph A, Dansonka-Mieszkowska A, Olson SH, Harter P, Tyrer J, Vitonis AF, Brooks-Wilson A, Aben KK, Pike MC, Ramus SJ, Wik E, Cybulski C, Lin J, Sucheston L, Edwards R, McGuire V, Lester J, du Bois A, Lundvall L, Wang-Gohrke S, Szafron LM, Lambrechts S, Yang H, Beckmann MW, Pelttari LM, Van Altena AM, van den Berg D, Halle MK, Gentry-Maharaj A, Schwaab I, Chandran U, Menkiszak J, Ekici AB, Wilkens LR, Leminen A, Modugno F, Friel G, Rothstein JH, Vergote I, Garcia-Closas M, Hildebrandt MA, Sobiczewski P, Kelemen LE, Pharoah PD, Moysich K, Knutson KL, Cunningham JM, Fridley BL, Goode EL

Abstract
A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

PMID: 24272484 [PubMed - indexed for MEDLINE]

Urgent-start peritoneal dialysis: a chance for a new beginning.

Am J Kidney Dis. 2014 Mar;63(3):390-5

Authors: Arramreddy R, Zheng S, Saxena AB, Liebman SE, Wong L

Abstract
Peritoneal dialysis (PD) remains greatly underutilized in the United States despite the widespread preference of home modalities among nephrologists and patients. A hemodialysis-centric model of end-stage renal disease care has perpetuated for decades due to a complex set of factors, including late end-stage renal disease referrals and patients who present to the hospital requiring urgent renal replacement therapy. In such situations, PD rarely is a consideration and patients are dialyzed through a central venous catheter, a practice associated with high infection and mortality rates. Recently, the term urgent-start PD has gained momentum across the nephrology community and has begun to change this status quo. It allows for expedited placement of a PD catheter and initiation of PD therapy within days. Several published case reports, abstracts, and poster presentations at national meetings have documented the initial success of urgent-start PD programs. From a wide experiential base, we discuss the multifaceted issues related to urgent-start PD implementation, methods to overcome barriers to therapy, and the potential impact of this technique to change the existing dialysis paradigm.

PMID: 24246221 [PubMed - indexed for MEDLINE]

Prospective identification of parasitic sequences in phage display screens.

Nucleic Acids Res. 2014 Feb;42(3):1784-98

Authors: Matochko WL, Cory Li S, Tang SK, Derda R

Abstract
Phage display empowered the development of proteins with new function and ligands for clinically relevant targets. In this report, we use next-generation sequencing to analyze phage-displayed libraries and uncover a strong bias induced by amplification preferences of phage in bacteria. This bias favors fast-growing sequences that collectively constitute <0.01% of the available diversity. Specifically, a library of 10(9) random 7-mer peptides (Ph.D.-7) includes a few thousand sequences that grow quickly (the 'parasites'), which are the sequences that are typically identified in phage display screens published to date. A similar collapse was observed in other libraries. Using Illumina and Ion Torrent sequencing and multiple biological replicates of amplification of Ph.D.-7 library, we identified a focused population of 770 'parasites'. In all, 197 sequences from this population have been identified in literature reports that used Ph.D.-7 library. Many of these enriched sequences have confirmed function (e.g. target binding capacity). The bias in the literature, thus, can be viewed as a selection with two different selection pressures: (i) target-binding selection, and (ii) amplification-induced selection. Enrichment of parasitic sequences could be minimized if amplification bias is removed. Here, we demonstrate that emulsion amplification in libraries of ∼ 10(6) diverse clones prevents the biased selection of parasitic clones.

PMID: 24217917 [PubMed - indexed for MEDLINE]

Impact of intraprocedural stent thrombosis during percutaneous coronary intervention: insights from the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention).

J Am Coll Cardiol. 2014 Feb 25;63(7):619-29

Authors: Généreux P, Stone GW, Harrington RA, Gibson CM, Steg PG, Brener SJ, Angiolillo DJ, Price MJ, Prats J, Lasalle L, Liu T, Todd M, Skerjanec S, Hamm CW, Mahaffey KW, White HD, Bhatt DL, CHAMPION PHOENIX Investigators

Abstract
OBJECTIVES: This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.
BACKGROUND: In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.
METHODS: An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.
RESULTS: IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.
CONCLUSIONS: In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

PMID: 24184169 [PubMed - indexed for MEDLINE]

Indefatigable: an erect coralline alga is highly resistant to fatigue.

J Exp Biol. 2013 Oct 15;216(Pt 20):3772-80

Authors: Denny M, Mach K, Tepler S, Martone P

Abstract
Intertidal organisms are subjected to intense hydrodynamic forces as waves break on the shore. These repeated insults can cause a plant or animal's structural materials to fatigue and fail, even though no single force would be sufficient to break the organism. Indeed, the survivorship and maximum size of at least one species of seaweed is set by the accumulated effects of small forces rather than the catastrophic imposition of a single lethal force. One might suppose that fatigue would be especially potent in articulated coralline algae, in which the strain of the entire structure is concentrated in localized joints, the genicula. However, previous studies of joint morphology suggest an alternative hypothesis. Each geniculum is composed of a single tier of cells, which are attached at their ends to the calcified segments of the plant (the intergenicula) but have minimal connection to each other along their lengths. This lack of neighborly attachment potentially allows the weak interfaces between cells to act as 'crack stoppers', inhibiting the growth of fatigue cracks. We tested this possibility by repeatedly loading fronds of Calliarthron cheilosporioides, a coralline alga common on wave-washed shores in California. When repeatedly loaded to 50-80% of its breaking strength, C. cheilosporioides commonly survives more than a million stress cycles, with a record of 51 million. We show how this extraordinary fatigue resistance interacts with the distribution of wave-induced water velocities to set the limits to size in this species.

PMID: 24068348 [PubMed - indexed for MEDLINE]

The gap between estimated incidence of end-stage renal disease and use of therapy.

PLoS One. 2013;8(8):e72860

Authors: Anand S, Bitton A, Gaziano T

Abstract
BACKGROUND: Relatively few data exist on the burden of end-stage renal disease (ESRD) and use of renal replacement therapy (RRT)-a life-saving therapy-in developing regions. No study has quantified the proportion of patients who develop ESRD but are unable to access RRT.
METHODS: We performed a comprehensive literature search to estimate use and annual initiation of RRT worldwide, and present these estimates according to World Bank regions. We also present estimates of survival and of etiology of diseases in patients undergoing RRT. Using data on prevalence of diabetes and hypertension, we modeled the incidence of ESRD related to these risk factors in order to quantify the gap between ESRD and use of RRT in developing regions.
RESULTS: We find that 1.9 million patients are undergoing RRT worldwide, with continued use and annual initiation at 316 and 73 per million population respectively. RRT use correlates directly (Pearson's r = 0.94) with regional income. Hemodialysis remains the dominant form of RRT but there is wide regional variation in its use. With the exception of the Latin American and Caribbean region, it appears that initiation of RRT in developing regions is restricted to fewer than a quarter of patients projected to develop ESRD. This results in at least 1.2 million premature deaths each year due to lack of access to RRT as a result of diabetes and elevated blood pressure and as many as 3.2 million premature deaths due to all causes of ESRD.
CONCLUSION: Thus, the majority of patients projected to reach ESRD due to diabetes or hypertension in developing regions are unable to access RRT; this gap will increase with rising prevalence of these risk factors worldwide.

PMID: 24023651 [PubMed - indexed for MEDLINE]

Prevalence of abnormal patellofemoral congruence in elite American football players and association with quadriceps isokinetic testing.

J Knee Surg. 2014 Feb;27(1):47-52

Authors: Brown CA, Carragee C, Sox-Harris A, Merchant AC, Mcadams TR

Abstract
Abnormal patellofemoral joint alignment has been discussed as a potential risk factor for patellofemoral disorders and can impact the longevity of any elite athlete's career. The prevalence of abnormal patellofemoral congruence in elite American football athletes is similar to the general population and does not have a relationship with quadriceps isokinetic testing. A total of 125 athletes (220 knees) from the 2011 National Football League (NFL) Combine database who had radiographic and isokinetic studies were reviewed. Congruence angles (CA) and lateral patellofemoral angles (LPA) were calculated on a Merchant radiographic view. Isokinetic testing was used to determine quadriceps-to-hamstring strength (Q/H) ratio and side-to-side deficits. The relationships between abnormal CA and LPA with Q/H ratios, side-to-side deficits, and body mass index (BMI) were examined in separate logistic regression models. A Chi-square test was used to examine the association between CA and player position. Of all, 26.8% of the knees (95% CI: 21.1-33.2%) had an abnormal CA. Knees with normal CA (n = 161) did not significantly differ from those with an abnormal CA (n  = 59) in Q/H ratios (mean: 0.699 vs. 0.728, p = 0.19) or side-to-side quadriceps deficits (mean: 4.0 vs. 1.24, p  = 0.45). For each point increase in BMI, the odds ratio (OR) of abnormal congruence increased by 11.4% (p = 0.002). Of all the knees, 4.1% (95% CI: 1.9-7.6%) had an abnormal LPA, and this was not associated with Q/H ratios (p  =  0.13). For each point increase in BMI, the odds of abnormal LPA increased by 16% (p  = 0.036). CA abnormality had much higher odds of having an abnormal LPA (OR: 5.96, p = 0.014). We found that abnormal patellofemoral radiographic alignment in elite American football players is relatively common and there was no association with isokinetic testing.

PMID: 23925950 [PubMed - indexed for MEDLINE]

Diurnal patterns of productivity of arbuscular mycorrhizal fungi revealed with the Soil Ecosystem Observatory.

New Phytol. 2013 Oct;200(2):547-57

Authors: Hernandez RR, Allen MF

Abstract
Arbuscular mycorrhizal (AM) fungi are the most abundant plant symbiont and a major pathway of carbon sequestration in soils. However, their basic biology, including their activity throughout a 24-h day : night cycle, remains unknown. We employed the in situ Soil Ecosystem Observatory to quantify the rates of diurnal growth, dieback and net productivity of extra-radical AM fungi. AM fungal hyphae showed significantly different rates of growth and dieback over a period of 24 h and paralleled the circadian-driven photosynthetic oscillations observed in plants. The greatest rates (and incidences) of growth and dieback occurred between noon and 18:00 h. Growth and dieback events often occurred simultaneously and were tightly coupled with soil temperature and moisture, suggesting a rapid acclimation of the external phase of AM fungi to the immediate environment. Changes in the environmental conditions and variability of the mycorrhizosphere may alter the diurnal patterns of productivity of AM fungi, thereby modifying soil carbon sequestration, nutrient cycling and host plant success.

PMID: 23844990 [PubMed - indexed for MEDLINE]

Nutritional policy changes in the supplemental nutrition assistance program: a microsimulation and cost-effectiveness analysis.

Med Decis Making. 2013 Oct;33(7):937-48

Authors: Basu S, Seligman H, Bhattacharya J

Abstract
BACKGROUND: Some experts have proposed limiting the use of Supplemental Nutrition Assistance Program (SNAP) benefits, for calorie-dense foods or subsidizing SNAP purchases of healthier foods.
OBJECTIVE: To estimate health effects and cost-effectiveness of banning or taxing sugar-sweetened beverages (SSBs) or subsidizing fruits and vegetables purchased with SNAP.
DESIGN: . Microsimulation. Data Sources. National Health and Nutrition Examination Survey, US Department of Agriculture Quarterly Food-at-Home Price Database, and SNAP program data. Target Population: US adults aged 25 to 64 y. Time Horizon. 10 y. Perspective. Governmental. Outcome
MEASURES: Incremental costs, quality-adjusted life-years (QALYs), body mass index, Alternative Healthy Eating Index, Food Security Score, diabetes person-years, and deaths from myocardial infarctions (MIs) and strokes.
RESULTS: of Base-Case Analysis. Banning SSB purchases using SNAP benefits would be expected to avert 510,000 diabetes person-years and 52,000 deaths from MIs and strokes over the next decade, with a savings of $2900 per QALY saved. A penny-per-ounce tax on SSBs purchased with SNAP dollars would produce higher cost savings due to tax revenues but avert fewer chronic disease deaths. However, some SNAP participants are likely to preferentially purchase SSBs through their disposable income, indirectly reducing their food security. A 30% produce subsidy would be expected to avert 39,000 diabetes person-years and 4600 cardiovascular deaths over 10 y without effects on food security. Results of Sensitivity Analysis. Results are sensitive to the intake elasticities of SSBs and produce. Limitations. Input data did not provide information on heterogeneity in response to price changes within the SNAP-using
POPULATION:
CONCLUSIONS: SNAP restrictions on SSBs could lower chronic disease mortality, but further testing should examine indirect effects on disposable income and food security. Subsidizing produce could confer fewer benefits or risks but at higher cost.

PMID: 23811757 [PubMed - indexed for MEDLINE]

Estimation of resting-state functional connectivity using random subspace based partial correlation: a novel method for reducing global artifacts.

Neuroimage. 2013 Nov 15;82:87-100

Authors: Chen T, Ryali S, Qin S, Menon V

Abstract
Intrinsic functional connectivity analysis using resting-state functional magnetic resonance imaging (rsfMRI) has become a powerful tool for examining brain functional organization. Global artifacts such as physiological noise pose a significant problem in estimation of intrinsic functional connectivity. Here we develop and test a novel random subspace method for functional connectivity (RSMFC) that effectively removes global artifacts in rsfMRI data. RSMFC estimates the partial correlation between a seed region and each target brain voxel using multiple subsets of voxels sampled randomly across the whole brain. We evaluated RSMFC on both simulated and experimental rsfMRI data and compared its performance with standard methods that rely on global mean regression (GSReg) which are widely used to remove global artifacts. Using extensive simulations we demonstrate that RSMFC is effective in removing global artifacts in rsfMRI data. Critically, using a novel simulated dataset we demonstrate that, unlike GSReg, RSMFC does not artificially introduce anti-correlations between inherently uncorrelated networks, a result of paramount importance for reliably estimating functional connectivity. Furthermore, we show that the overall sensitivity, specificity and accuracy of RSMFC are superior to GSReg. Analysis of posterior cingulate cortex connectivity in experimental rsfMRI data from 22 healthy adults revealed strong functional connectivity in the default mode network, including more reliable identification of connectivity with left and right medial temporal lobe regions that were missed by GSReg. Notably, compared to GSReg, negative correlations with lateral fronto-parietal regions were significantly weaker in RSMFC. Our results suggest that RSMFC is an effective method for minimizing the effects of global artifacts and artificial negative correlations, while accurately recovering intrinsic functional brain networks.

PMID: 23747287 [PubMed - indexed for MEDLINE]

The decision to continue a pregnancy affected by Down syndrome: timing of decision and satisfaction with receiving a prenatal diagnosis.

J Genet Couns. 2013 Oct;22(5):587-93

Authors: Hurford E, Hawkins A, Hudgins L, Taylor J

Abstract
In order to provide the best genetic counseling possible for women who learn of a diagnosis of Down syndrome prenatally, we sought to assess the timing of the decision to continue a pregnancy and the satisfaction these women had with learning this information. Fifty-six mothers of children with Down syndrome diagnosed prenatally between 2007 and 2010 completed a survey regarding their experience with decision-making after prenatal diagnosis. Approximately one third (17/56) of participants reported they knew before getting pregnant that they would not terminate for any reason, and almost half of the participants (24/56) reported they did not decide to continue their pregnancy until after the diagnosis. Many participants (82 %; 42/56) stated that learning the diagnosis during pregnancy increased their anxiety. The majority (88 %; 45/56) also reported that if they could do it over again, they would undergo prenatal testing for preparation purposes, despite increased anxiety. Religious and spiritual beliefs as well as feeling attached to the baby were the personal factors that had the greatest impact on most women's decision-making. Despite increased anxiety caused by learning the diagnosis prenatally, most women favored prenatal diagnosis as it allowed them time to process the information and prepare for the birth of their child.

PMID: 23604903 [PubMed - indexed for MEDLINE]

Radiotherapy for nonadenoid cystic carcinomas of major salivary glands.

Am J Otolaryngol. 2013 Sep-Oct;34(5):425-30

Authors: Chung MP, Tang C, Chan C, Hara WY, Loo BW, Kaplan MJ, Fischbein N, Le QT, Chang DT

Abstract
PURPOSE: To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.
MATERIALS AND METHODS: From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).
RESULTS: Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients ≥65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed ≥grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.
CONCLUSIONS: Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

PMID: 23583094 [PubMed - indexed for MEDLINE]