Lane Medical Library

Protective effect of indoor residual spraying of insecticide on preterm birth among pregnant women with HIV in Uganda: A secondary data analysis.

J Infect Dis. 2017 Oct 06;:

Authors: Roh ME, Shiboski S, Natureeba P, Kakuru A, Muhindo M, Ochieng T, Plenty A, Koss CA, Clark TD, Awori P, Nakalambe M, Cohan D, Jagannathan P, Gosling R, Havlir DV, Kamya MR, Dorsey G

Abstract
Background: Recent evidence demonstrated improved birth outcomes among HIV-uninfected pregnant women protected by indoor residual spraying of insecticide (IRS). Evidence regarding its impact on HIV-infected pregnant women is lacking.
Methods: Data were pooled from two studies conducted before-and-after an IRS campaign in Tororo, Uganda among HIV-infected pregnant women who received bednets, daily trimethoprim-sulfamethoxazole (TMP-SMX), and combination antiretroviral therapy (c-ART) at enrollment. Exposure was the proportion of pregnancy protected by IRS. Adverse birth outcomes included preterm birth, low birthweight, and fetal/neonatal death. Multivariate Poisson regression with robust standard errors was used to estimate risk ratios (RR).
Results: Of 565 women in our analysis, 380 (67%), 88 (16%), and 97 (17%) women were protected by IRS for 0%, >0-90%, and >90% of their pregnancy, respectively. Any IRS protection significantly reduced malaria incidence during pregnancy and placental malaria risk. Compared to no IRS protection, >90% IRS protection reduced preterm birth risk (RR=0.35; 95% CI: 0.15-0.84), with non-significant decreases in the risk of low birthweight (RR=0.68; 95% CI: 0.29-1.57) and fetal/neonatal death (RR=0.24; 95% CI: 0.04-1.52).
Discussion: Our exploratory analyses support the hypothesis that IRS may significantly reduce malaria and preterm birth risk among pregnant women with HIV receiving bednets, daily TMP-SMX, and c-ART.

PMID: 29029337 [PubMed - as supplied by publisher]

Letter: Electric Beats Open New Frontiers for Deep Brain Stimulation.

Neurosurgery. 2017 Sep 27;:

Authors: Halpern CH, Miller KJ, Wu H, Tass PA

PMID: 29029326 [PubMed - as supplied by publisher]

Breathing disturbances without hypoxia are associated with objective sleepiness in sleep apnea.

Sleep. 2017 Sep 26;:

Authors: Koch H, Schneider LD, Finn LA, Leary EB, Peppard PE, Hagen E, Sorensen HBD, Jennum P, Mignot E

Abstract
Study Objectives: Determine if defining two subtypes of sleep-disordered breathing (SDB) events - with or without hypoxia - results in measures that are more strongly associated with hypertension and sleepiness.
Methods: A total of 1,022 subjects with 2,112 nocturnal polysomnograms (PSGs) from the Wisconsin Sleep Cohort were analyzed with our automated algorithm, developed to detect breathing disturbances and desaturations. Breathing events were time-locked to desaturations, resulting in 2 indices - desaturating (H-BDI) and non-desaturating (NH-BDI) events - regardless of arousals. Measures of subjective (Epworth Sleepiness Scale) and objective (2,981 multiple sleep latency tests from a subset of 865 subjects) sleepiness were analyzed, in addition to clinically relevant clinicodemographic variables. Hypertension was defined as BP ≥140/90 or antihypertensive use.
Results: H-BDI, but not NH-BDI, correlated strongly with SDB severity indices that included hypoxia (r≥0.89, p≤0.001 with 3% ODI and AHI with 4%-desaturations). A doubling of desaturation-associated events was associated with hypertension prevalence, which was significant for ODI but not H-BDI (3% ODI OR=1.06, 95% CI=1.00-1.12, p<0.05; H-BDI OR 1.04, 95% CI=0.98-1.10) and daytime sleepiness (β=0.20 ESS score, p<0.0001; β=-0.20 min in MSL on MSLT, p<0.01). Independently, non-desaturating event doubling was associated with more objective sleepiness (β=-0.52 min in MSL on MSLT, p<0.001), but had less association with subjective sleepiness (β=0.12 ESS score, p=0.10). In longitudinal analyses, baseline non-desaturating events were associated with worsening of H-BDI over a 4-year follow up, suggesting evolution in severity.
Conclusions: In SDB, non-desaturating events are independently associated with objective daytime sleepiness, beyond the effect of desaturating events.

PMID: 29029253 [PubMed - as supplied by publisher]

Early diagnosis of acute coronary syndrome.

Eur Heart J. 2017 Oct 03;:

Authors: Katus H, Ziegler A, Ekinci O, Giannitsis E, Stough WG, Achenbach S, Blankenberg S, Brueckmann M, Collinson P, Comaniciu D, Crea F, Dinh W, Ducrocq G, Flachskampf FA, Fox KAA, Friedrich MG, Hebert KA, Himmelmann A, Hlatky M, Lautsch D, Lindahl B, Lindholm D, Mills NL, Minotti G, Möckel M, Omland T, Semjonow V

Abstract
The diagnostic evaluation of acute chest pain has been augmented in recent years by advances in the sensitivity and precision of cardiac troponin assays, new biomarkers, improvements in imaging modalities, and release of new clinical decision algorithms. This progress has enabled physicians to diagnose or rule-out acute myocardial infarction earlier after the initial patient presentation, usually in emergency department settings, which may facilitate prompt initiation of evidence-based treatments, investigation of alternative diagnoses for chest pain, or discharge, and permit better utilization of healthcare resources. A non-trivial proportion of patients fall in an indeterminate category according to rule-out algorithms, and minimal evidence-based guidance exists for the optimal evaluation, monitoring, and treatment of these patients. The Cardiovascular Round Table of the ESC proposes approaches for the optimal application of early strategies in clinical practice to improve patient care following the review of recent advances in the early diagnosis of acute coronary syndrome. The following specific 'indeterminate' patient categories were considered: (i) patients with symptoms and high-sensitivity cardiac troponin <99th percentile; (ii) patients with symptoms and high-sensitivity troponin <99th percentile but above the limit of detection; (iii) patients with symptoms and high-sensitivity troponin >99th percentile but without dynamic change; and (iv) patients with symptoms and high-sensitivity troponin >99th percentile and dynamic change but without coronary plaque rupture/erosion/dissection. Definitive evidence is currently lacking to manage these patients whose early diagnosis is 'indeterminate' and these areas of uncertainty should be assigned a high priority for research.

PMID: 29029109 [PubMed - as supplied by publisher]

Validation of a theoretically motivated approach to measuring childhood socioeconomic circumstances in the Health and Retirement Study.

PLoS One. 2017;12(10):e0185898

Authors: Vable AM, Gilsanz P, Nguyen TT, Kawachi I, Glymour MM

Abstract
Childhood socioeconomic status (cSES) is a powerful predictor of adult health, but its operationalization and measurement varies across studies. Using Health and Retirement Study data (HRS, which is nationally representative of community-residing United States adults aged 50+ years), we specified theoretically-motivated cSES measures, evaluated their reliability and validity, and compared their performance to other cSES indices. HRS respondent data (N = 31,169, interviewed 1992-2010) were used to construct a cSES index reflecting childhood social capital (cSC), childhood financial capital (cFC), and childhood human capital (cHC), using retrospective reports from when the respondent was <16 years (at least 34 years prior). We assessed internal consistency reliability (Cronbach's alpha) for the scales (cSC and cFC), and construct validity, and predictive validity for all measures. Validity was assessed with hypothesized correlates of cSES (educational attainment, measured adult height, self-reported childhood health, childhood learning problems, childhood drug and alcohol problems). We then compared the performance of our validated measures with other indices used in HRS in predicting self-rated health and number of depressive symptoms, measured in 2010. Internal consistency reliability was acceptable (cSC = 0.63, cFC = 0.61). Most measures were associated with hypothesized correlates (for example, the association between educational attainment and cSC was 0.01, p < 0.0001), with the exception that measured height was not associated with cFC (p = 0.19) and childhood drug and alcohol problems (p = 0.41), and childhood learning problems (p = 0.12) were not associated with cHC. Our measures explained slightly more variability in self-rated health (adjusted R2 = 0.07 vs. <0.06) and number of depressive symptoms (adjusted R2 > 0.05 vs. < 0.04) than alternative indices. Our cSES measures use latent variable models to handle item-missingness, thereby increasing the sample size available for analysis compared to complete case approaches (N = 15,345 vs. 8,248). Adopting this type of theoretically motivated operationalization of cSES may strengthen the quality of research on the effects of cSES on health outcomes.

PMID: 29028834 [PubMed - in process]

Nervous system delivery of antilysophosphatidic acid antibody by nasal application attenuates mechanical allodynia after traumatic brain injury in rats.

Pain. 2017 Nov;158(11):2181-2188

Authors: Eisenried A, Meidahl ACN, Klukinov M, Tzabazis AZ, Sabbadini RA, Clark JD, Yeomans DC

Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood-brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI. However, poor brain penetration after systemic application of the antibody makes access to the central nervous system (CNS) problematic in situations where the BBB is intact. Our experiments investigated whether intranasal delivery of the anti-LPA mAb could bypass the BBB, allowing for direct entry of the antibody to certain areas of the CNS. When the humanized anti-LPA mAb, LT3114, was intranasally applied to injured rats within 30 minutes after mild TBI using the central lateral percussion model, enzyme-linked immunospecific assay and immunohistochemistry demonstrated antibody uptake to several areas in the CNS, including the area of cortical injury, the corpus callosum, cerebellum, and the subventricular region. Compared with control rats that received LT3114 but no TBI, TBI rats demonstrated significantly higher concentrations of intranasally administered LT3114 antibody in some tissues. In behavioral studies, a significant attenuation of mechanical allodynia after TBI was observed in the anti-LPA treatment group (P = 0.0079), when compared with vehicle controls within 14 days after TBI. These results suggest that intranasal application of the anti-LPA antibody directly accesses CNS sites involved in TBI-related pain and that this access attenuates pain sequelae to the neurotrauma.

PMID: 29028747 [PubMed - in process]

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

Crit Care Med. 2017 Nov;45(11):1907-1914

Authors: Okonkwo DO, Shutter LA, Moore C, Temkin NR, Puccio AM, Madden CJ, Andaluz N, Chesnut RM, Bullock MR, Grant GA, McGregor J, Weaver M, Jallo J, LeRoux PD, Moberg D, Barber J, Lazaridis C, Diaz-Arrastia RR

Abstract
OBJECTIVES: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.
DESIGN: Randomized prospective clinical trial.
SETTING: Ten ICUs in the United States.
PATIENTS: One hundred nineteen severe traumatic brain injury patients.
INTERVENTIONS: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended.
MEASUREMENTS AND MAIN RESULTS: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy.
CONCLUSIONS: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

PMID: 29028696 [PubMed - in process]

Acute kidney injury in congenital heart disease.

Curr Opin Cardiol. 2017 Oct 11;:

Authors: Gist KM, Kwiatkowski DM, Cooper DS

Abstract
PURPOSE OF REVIEW: Acute kidney injury (AKI) is associated with significant morbidity and mortality in patients with congenital heart disease undergoing cardiac surgery or in pediatric patients with congestive heart failure.
RECENT FINDINGS: This review describes the definition and various manifestations of AKI, the impact of biomarkers on the diagnosis of AKI, the importance of fluid overload as a consequence of AKI and its long-term impact.
SUMMARY: There are novel biomarkers for AKI detection that should facilitate early recognition and intervention to prevent or attenuate the effects of AKI and fluid overload. Previous conventional wisdom that survivors of AKI fully recover renal function without subsequent consequences is flawed.

PMID: 29028633 [PubMed - as supplied by publisher]

Diagnosis and treatment options for sequelae following radiation treatment of brain tumors.

Clin Neurol Neurosurg. 2017 Oct 07;163:1-8

Authors: Mehta S, Shah A, Jung H

Abstract
Radiation serves an important role in the treatment of metastatic and primary brain tumors. Radiation carries a risk of post radiation treatment effects, such as pseudoprogression and radiation necrosis. The ability to differentiate between radiation necrosis, pseudoprogression, and tumor recurrence remains a diagnostic conundrum with varying treatment options. In this review, we will discuss the pathophysiology, diagnostic imaging modalities, and treatments of these post-radiation treatment effects. We focus on the latest developments in magnetic resonance imaging (MRI) modalities including imaging biomarkers and the newest therapeutics such as VEGF inhibitors, Hyperbaric Oxygen Therapy, sensitized cytotoxic T cells, and Laser Interstitial Thermal Therapy (LITT).

PMID: 29028584 [PubMed - as supplied by publisher]

Assessing Adult Attention Deficit Hyperactivity Disorder (ADHD) in the University Setting.

J Am Coll Health. 2017 Oct 13;:0

Authors: Tinklenberg J, Patel B, Gelman K, Albucher R

Abstract
OBJECTIVE: To address the increasing demand for assessments of Adult Attention Deficit Hyperactivity Disorder (ADHD), the primary author developed a protocol for Counseling and Psychological Services (CAPS) at Stanford University's Vaden Student Health Center to improve the efficiency of such evaluations.
PARTICIPANTS: As part of quality assurance, we reviewed the charts of Stanford students who sought assessment for ADHD before the protocol was implemented (September 2011- June 2013) and after the protocol was established (October 2013 - August 2014). An IRB exemption was obtained.
METHODS: The protocol includes questionnaires that solicit detailed clinical information from a variety of sources prior to the student's initial visit.
RESULTS: A peer chart review of 35 randomly selected charts showed that students completing the protocol are receiving a more thorough assessment.
CONCLUSION: The new Stanford ADHD protocol, designed to improve clinic efficiency, also increases the availability of relevant clinical information.

PMID: 29028463 [PubMed - as supplied by publisher]

Optimizing the Nutritional Support of Adult Patients in the Setting of Cirrhosis.

Nutrients. 2017 Oct 13;9(10):

Authors: Perumpail BJ, Li AA, Cholankeril G, Kumari R, Ahmed A

Abstract
AIM: The aim of this work is to develop a pragmatic approach in the assessment and management strategies of patients with cirrhosis in order to optimize the outcomes in this patient population.
METHOD: A systematic review of literature was conducted through 8 July 2017 on the PubMed Database looking for key terms, such as malnutrition, nutrition, assessment, treatment, and cirrhosis. Articles and studies looking at associations between nutrition and cirrhosis were reviewed.
RESULTS: An assessment of malnutrition should be conducted in two stages: the first, to identify patients at risk for malnutrition based on the severity of liver disease, and the second, to perform a complete multidisciplinary nutritional evaluation of these patients. Optimal management of malnutrition should focus on meeting recommended daily goals for caloric intake and inclusion of various nutrients in the diet. The nutritional goals should be pursued by encouraging and increasing oral intake or using other measures, such as oral supplementation, enteral nutrition, or parenteral nutrition.
CONCLUSIONS: Although these strategies to improve nutritional support have been well established, current literature on the topic is limited in scope. Further research should be implemented to test if this enhanced approach is effective.

PMID: 29027963 [PubMed - in process]

Male factor infertility and risk of multiple sclerosis: A register-based cohort study.

Mult Scler. 2017 Oct 01;:1352458517734069

Authors: Glazer CH, Tøttenborg SS, Giwercman A, Bräuner EV, Eisenberg ML, Vassard D, Magyari M, Pinborg A, Schmidt L, Bonde JP

Abstract
BACKGROUND: Gender, possibly due to the influence of gonadal hormones, is presumed to play a role in the pathogenesis of multiple sclerosis (MS), but no studies have evaluated whether male infertility is associated with MS.
OBJECTIVE: To study the association between male factor infertility and prevalent as well as incident MS.
METHOD: Our cohort was established by linkage of the Danish National in vitro fertilization (IVF) registry to The Danish Multiple Sclerosis Registry and consisted of 51,063 men whose partners had undergone fertility treatment in all public and private fertility clinics in Denmark between 1994 and 2015.
RESULTS: With a median age of 34 years at baseline, 24,011 men were diagnosed with male factor infertility and 27,052 did not have male factor infertility and made up the reference group. Men diagnosed with male factor infertility had a higher risk of prevalent (odds ratio (OR) = 1.61, 95% confidence interval (95% CI) 1.04-2.51) and incident MS (hazard ratio (HR) = 1.28, 95% CI 0.76-2.17) when compared to the reference group.
CONCLUSION: This nationwide cohort study has shown, for the first time, an association between male infertility and MS which may be due to underlying common etiologies such as hypogonadism, shared genetics, or a joint autoimmune component.

PMID: 29027840 [PubMed - as supplied by publisher]

Wednesday's Meeting Really Is on Friday: A Meta-Analysis and Evaluation of Ambiguous Spatiotemporal Language.

Cogn Sci. 2017 Oct 13;:

Authors: Stickles E, Lewis TN

Abstract
Experimental work has shown that spatial experiences influence spatiotemporal metaphor use. In these studies, participants are asked a question that yields different responses depending on the metaphor participants use. It has been claimed that English speakers are equally likely to respond with either variant in the absence of priming. Related studies testing non-spatial experiences demonstrate varied results with a wide range of primes. Here, the effects of eye movement and stimuli presentation modality on comprehension of this question are investigated in different formats. In addition, the results of prior reported controls are re-analyzed in a meta-analysis to verify reliable ambiguity of the test question. Results suggest that English speakers have a baseline preference for the Moving Ego metaphor variant, with a stronger preference in verbal rather than written presentation. The findings have implications both for (re)interpretation of prior studies' results and future study designs.

PMID: 29027247 [PubMed - as supplied by publisher]

Multiplexed ChIP-Seq Using Direct Nucleosome Barcoding: A Tool for High-Throughput Chromatin Analysis.

Methods Mol Biol. 2018;1689:177-194

Authors: Chabbert CD, Adjalley SH, Steinmetz LM, Pelechano V

Abstract
Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) or microarray hybridization (ChIP-on-chip) are standard methods for the study of transcription factor binding sites and histone chemical modifications. However, these approaches only allow profiling of a single factor or protein modification at a time.In this chapter, we present Bar-ChIP, a higher throughput version of ChIP-Seq that relies on the direct ligation of molecular barcodes to chromatin fragments. Bar-ChIP enables the concurrent profiling of multiple DNA-protein interactions and is therefore amenable to experimental scale-up, without the need for any robotic instrumentation.

PMID: 29027175 [PubMed - in process]

Laser interstitial thermal therapy for the treatment of epilepsy: evidence to date.

Neuropsychiatr Dis Treat. 2017;13:2469-2475

Authors: Shukla ND, Ho AL, Pendharkar AV, Sussman ES, Halpern CH

Abstract
Medically intractable epilepsy is associated with increased morbidity and mortality. For those with focal epilepsy and correlated electrophysiological or radiographic features, open surgical resection can achieve high rates of seizure control, but can be associated with neurologic deficits and cognitive effects. Recent innovations have allowed for more minimally invasive methods of surgical seizure control such as magnetic resonance-guided laser interstitial therapy (MRgLITT). MRgLITT achieves the goal of ablating seizure foci while preserving neuropsycho-logical function and offering real-time feedback and monitoring of tissue ablation. This review summarizes the utilization of MRgLITT for mesial temporal lobe epilepsy and other seizure disorders. Overall, the efficacy of MRgLITT is comparable to that of open surgery and offers a less invasive approach in patients with significantly less morbidity.

PMID: 29026310 [PubMed]

Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV.

Science. 2017 Oct 13;358(6360):218-223

Authors: Wender PA, Hardman CT, Ho S, Jeffreys MS, Maclaren JK, Quiroz RV, Ryckbosch SM, Shimizu AJ, Sloane JL, Stevens MC

Abstract
Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.

PMID: 29026042 [PubMed - in process]

Marijuana as a 'concept' flavour for cigar products: availability and price near California schools.

Tob Control. 2017 Oct 12;:

Authors: Henriksen L, Schleicher NC, Ababseh K, Johnson TO, Fortmann SP

Abstract
OBJECTIVES: To assess the retail availability of cigar products that refer to marijuana and the largest package size of cigarillos available for ≤$1.
METHODS: Trained data collectors conducted marketing surveillance in a random sample of licensed tobacco retailers that sold little cigars/cigarillos (LCCs) (n=530) near a statewide sample of middle and high schools (n=132) in California. Multilevel models examined the presence of marijuana co-marketing and cigarillo pack size as a function of school/neighbourhood characteristics and adjusted for store type.
RESULTS: Of stores that sold LCCs, approximately 62% contained at least one form of marijuana co-marketing: 53.2% sold cigar wraps marketed as blunt wraps, 27.2% sold cigarillos marketed as blunts and 26.0% sold at least one LCC with a marijuana-related 'concept' flavour. Controlling for store type, marijuana co-marketing was more prevalent in school neighbourhoods with a higher proportion of young residents (ages 5-17 years) and with lower median household income. Nearly all stores that sold LCCs (87.9%) offered the products for ≤$1. However, significantly larger packs at similarly low prices were available near schools in lower-income neighbourhoods and with a lower percentage of Hispanic students.
CONCLUSIONS: Understanding how the tobacco industry manipulates cigar products and marketing to capitalise on the appeal of marijuana to youth and other priority populations is important to inform regulation, particularly for flavoured tobacco products. In addition, the retail availability of five and six packs of LCCs for ≤$1 near California schools underscores policy recommendations to establish minimum prices for multipacks.

PMID: 29025999 [PubMed - as supplied by publisher]

Appropriate Use Criteria for (18)F-FDG PET/CT in Restaging and Treatment Response Assessment of Malignant Disease.

J Nucl Med. 2017 Oct 12;:

Authors: Jadvar H, Colletti P, Delgado-Bolton R, Esposito G, Krause B, Iagaru A, Nadel H, Quinn D, Rohren E, Subramaniam R, Zukotynski K, Kauffman J, Ahuja S, Griffeth LK

PMID: 29025980 [PubMed - as supplied by publisher]

A germ-line deletion of APOBEC3B does not contribute to subtype-specific childhood acute lymphoblastic leukemia etiology.

Haematologica. 2017 Oct 12;:

Authors: Wallace AD, Francis SS, Shao X, de Smith AJ, Walsh KM, Mckean-Cowdin R, Ma X, Dahl G, Barcellos LF, Wiemels JL, Metayer C

PMID: 29025908 [PubMed - as supplied by publisher]

Higher Risk of Vascular Dementia in Myocardial Infarction Survivors.

Circulation. 2017 Oct 12;:

Authors: Sundbøll J, Hováth-Puhó E, Adelborg K, Schmidt M, Pedersen L, Bøtker HE, Henderson VW, Sørensen HT

Abstract
Background -Increased risk of dementia after myocardial infarction (MI) may be mediated by shared risk factors (e.g., atherosclerosis) and post-MI stroke. We examined risk of dementia in 1-year survivors of MI. Methods -Using Danish medical registries, we conducted a nationwide population-based cohort study of all patients with first-time MI and a sex-, birth year-, and calendar year-matched general population comparison cohort without MI (1980-2012). Cox regression analysis was used to compute 1-35 year adjusted hazard ratios (aHRs) for dementia, controlled for matching factors and adjusted for comorbidities and socioeconomic status. Results -We identified 314,911 patients with MI and 1,573,193 matched comparison cohort members randomly sampled from the general population (median age 70 years, 63% male). After 35 years of follow-up, the cumulative incidence of all-cause dementia in the MI cohort was 9% (2.8% for Alzheimer's disease, 1.6% for vascular dementia, and 4.5% for other dementias). Compared with the general population cohort, MI was not associated with all-cause dementia (aHR = 1.01, 95% confidence interval (CI): 0.98-1.03). Risk of Alzheimer's disease (aHR = 0.92, 95% CI: 0.88-0.95) and other dementias (aHR = 0.98, 95% CI: 0.95-1.01) also approximated unity. However, MI was associated with higher risk of vascular dementia (aHR = 1.35, 95% CI: 1.28-1.43), which was substantially strengthened for patients experiencing stroke after MI (aHR = 4.48, 95% CI: 3.29-6.12). Conclusions -MI was associated with higher risk of vascular dementia throughout follow-up and this asssociation was stronger in patients suffering stroke. The risk of Alzheimer's disease and other dementias was not higher in MI patients.

PMID: 29025764 [PubMed - as supplied by publisher]

Rack1 maintains intestinal homeostasis by protecting the integrity of the epithelial barrier.

Am J Physiol Gastrointest Liver Physiol. 2017 Oct 12;:ajpgi.00241.2017

Authors: Cheng ZF, Cartwright CA

Abstract
Previously we generated mouse models of Rack1 deficiency to identify key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. However, other than low body weight, we did not detect an overt phenotype in mice constitutively deleted of Rack1 in intestinal epithelia (vil-Cre:Rack1(fl/fl) mice), presumably because Rack1 was deleted in < 10% of the total surface area of the epithelia. To assess the effect of Rack1 loss throughout the entire intestinal epithelia, we generated another mouse model of Rack1 deficiency, vil-Cre-ER(T2):Rack1(fl/fl) Within 5-10 days of the initial tamoxifen treatment, the mice lost over 20% of their body weight, developed severe diarrhea that for some was bloody, became critically ill and died, if not euthanized. Necropsies revealed mildly distended, fluid-, gas- and sometimes blood-filled loops of small and large bowel, inguinal lymphadenopathy and thrombocytosis. Rack1 was deleted in nearly 100% of the epithelia in both the small intestine and colon when assessed by immunofluorescent or immunoblot analyses. Rack1 expression in other tissues and organs was not different than in control mice, indicating tissue specificity of the recombination. Histopathology revealed a patchy, erosive, hemorrhagic, inflammatory enterocolitis with denuded, sloughed off surface epithelium and crypt hyperplasia. These results suggest a protective function for Rack1 in maintaining the integrity of intestinal epithelia and for survival.

PMID: 29025732 [PubMed - as supplied by publisher]

A novel TRIP11-FLT3 fusion in a patient with a myeloid/lymphoid neoplasm with eosinophilia.

Cancer Genet. 2017 Oct;216-217:10-15

Authors: Chung A, Hou Y, Ohgami RS, Von Gehr A, Fisk DG, Roskin KM, Li X, Gojenola L, Bangs CD, Arber DA, Fire AZ, Cherry AM, Zehnder JL, Gotlib J, Merker JD

Abstract
FLT3 fusions are associated with myeloid and lymphoid neoplasms with eosinophilia. We describe a patient presenting with clinicopathologic features of both chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) and systemic mastocytosis (SM). The bone marrow demonstrated a myeloproliferative neoplasm with eosinophilia and aggregates of atypical mast cells. Cytogenetic analysis revealed a t(13;14)(q12;q32), which was subsequently molecularly characterized as a novel TRIP11-FLT3 rearrangement. A KIT D816V mutation was also identified. The patient rapidly transformed to T-lymphoblastic leukemia/lymphoma and expired shortly after diagnosis. This is the fifth FLT3 fusion gene described in the literature; the presence of both myeloid and lymphoid neoplasms implicates involvement of an early hematopoietic progenitor by rearranged FLT3. We suggest that leukemias and lymphomas with FLT3 fusion genes exhibit similar clinicopathologic features to, and should be included in, the WHO category of "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2."

PMID: 29025582 [PubMed - in process]

Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension.

JACC Cardiovasc Imaging. 2017 Oct;10(10 Pt B):1278-1280

Authors: Haddad F, Amsallem M

PMID: 29025578 [PubMed - in process]

Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus.

PLoS One. 2017;12(9):e0184816

Authors: Zhao X, Ouyang W, Chester C, Long S, Wang N, He Z

Abstract
Oncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy.

PMID: 28922411 [PubMed - indexed for MEDLINE]

Guide-bound structures of an RNA-targeting A-cleaving CRISPR-Cas13a enzyme.

Nat Struct Mol Biol. 2017 Oct;24(10):825-833

Authors: Knott GJ, East-Seletsky A, Cofsky JC, Holton JM, Charles E, O'Connell MR, Doudna JA

Abstract
CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR-Cas systems include the Cas13a enzyme, an RNA-activated RNase capable of crRNA processing and single-stranded RNA degradation upon target-transcript binding. Here we present the 2.0-Å resolution crystal structure of a crRNA-bound Lachnospiraceae bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define the Cas13a catalytic residues that are directly responsible for crRNA maturation. In addition, the orientation of the foreign-derived target-RNA-specifying sequence in the protein interior explains the conformational gating of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked before target-RNA recognition, with implications for both bacterial immunity and diagnostic applications.

PMID: 28892041 [PubMed - indexed for MEDLINE]

Semen quality and pregnancy loss in a contemporary cohort of couples recruited before conception: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study.

Fertil Steril. 2017 Oct;108(4):613-619

Authors: Eisenberg ML, Sapra KJ, Kim SD, Chen Z, Buck Louis GM

Abstract
OBJECTIVE: To study the relationship between semen quality and pregnancy loss in a cohort of couples attempting to conceive.
DESIGN: Observational prospective cohort.
SETTING: Not applicable.
PATIENT(S): Three hundred and forty-four couples with a singleton pregnancy observed daily through 7 postconception weeks of gestation.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Association between semen quality and pregnancy loss.
RESULT(S): Ninety-eight (28%) of the couples experienced a pregnancy loss after singleton pregnancy. No differences were observed in semen volume, sperm concentration, total sperm count, sperm viability, or sperm morphology (World Health Organization [WHO] and strict criteria) by couple's pregnancy loss status irrespective of whether they were analyzed continuously or as dichotomous variables per the WHO 5th edition semen criteria. A dichotomous DNA fragmentation measure of ≥30% was statistically significantly associated with pregnancy loss. No association was identified with other sperm morphometric or movement measures. Of the 70 couples who re-enrolled after a pregnancy loss, 14 experienced a second loss. Similar findings were identified when examining semen quality from couples with recurrent pregnancy loss.
CONCLUSION(S): Although a few trends were identified (e.g., DNA fragmentation), general semen parameters seemed to have little relation with risk of pregnancy loss or recurrent pregnancy loss at the population level. However, given that 30% of pregnancies end in miscarriage and half the fetal genome is paternal in origin, the findings await corroboration.

PMID: 28863939 [PubMed - indexed for MEDLINE]

Window of implantation transcriptomic stratification reveals different endometrial subsignatures associated with live birth and biochemical pregnancy.

Fertil Steril. 2017 Oct;108(4):703-710.e3

Authors: Díaz-Gimeno P, Ruiz-Alonso M, Sebastian-Leon P, Pellicer A, Valbuena D, Simón C

Abstract
OBJECTIVE: To refine the endometrial window of implantation (WOI) transcriptomic signature by defining new subsignatures associated to live birth and biochemical pregnancy.
DESIGN: Retrospective cohort study.
SETTING: University-affiliated in vitro fertilization clinic and reproductive genetics laboratory.
PATIENT(S): Healthy fertile oocyte donors (n = 79) and patients with infertility diagnosed by Endometrial Receptivity Analysis (n = 771).
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): WOI transcriptomic signatures associated with specific reproductive outcomes.
RESULT(S): The retrospective cohort study was designed to perform a prediction model based on transcriptomic clusters for endometrial classification (training set, n = 529). The clinical follow-up set in the expected WOI (n = 321) was tested with the transcriptomic predictor to detect WOI variability and the pregnancy outcomes associated with these subsignatures (n = 228). The endometrial receptivity signature was redefined into four WOI transcriptomic profiles. This stratification identified an optimal endometrial receptivity (RR) signature resulting in an ongoing pregnancy rate (OPR) of 80% in terms of live birth, as well as a late receptive-stage (LR) signature with a potential high risk of 50% biochemical pregnancy. Abnormal down-regulation of the cell cycle was the main dysregulated function among the 22 genes associated with biochemical pregnancy.
CONCLUSION(S): The major differences between the WOI transcriptomic stratification were in the OPR and biochemical pregnancy rate. The OPR ranged from 76.9% and 80% in the late prereceptive (LPR) and RR signatures, respectively, versus 33.3% in the LR. The biochemical pregnancy rate was 7.7% and 6.6% in LPR and RR, respectively, but 50% in LR, which highlights the relevance of endometrial status in the progression of embryonic implantation.

PMID: 28863933 [PubMed - indexed for MEDLINE]

Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients.

PLoS One. 2017;12(8):e0182585

Authors: Moss EL, Falconer SB, Tkachenko E, Wang M, Systrom H, Mahabamunuge J, Relman DA, Hohmann EL, Bhatt AS

Abstract
Immunocompromised individuals are at high risk of developing Clostridium difficile-associated disease (CDAD). Fecal microbiota transplantation (FMT) is a highly effective therapy for refractory or recurrent CDAD and, despite safety concerns, has recently been offered to immunocompromised patients. We investigated the genomics of bacterial composition following FMT in immunocompromised patients over a 1-year period. Metagenomic, strain and gene-level bacterial dynamics were characterized in two CDAD-affected hematopoietic stem cell (HCT) recipients following FMT. We found alterations in gene content, including loss of virulence and antibiotic resistance genes. These alterations were accompanied by long-term bacterial divergence at the species and strain levels. Our findings suggest limited durability of the specific bacterial consortium introduced with FMT and indicate that alterations of the functional potential of the microbiome are more complex than can be inferred by taxonomic information alone. Our observation that FMT alone cannot induce long-term donor-like alterations of the microbiota of HCT recipients suggests that FMT cannot indefinitely supersede environmental and/or host factors in shaping bacterial composition.

PMID: 28827811 [PubMed - indexed for MEDLINE]

Dose of physical activity, physical functioning and disability risk in mobility-limited older adults: Results from the LIFE study randomized trial.

PLoS One. 2017;12(8):e0182155

Authors: Fielding RA, Guralnik JM, King AC, Pahor M, McDermott MM, Tudor-Locke C, Manini TM, Glynn NW, Marsh AP, Axtell RS, Hsu FC, Rejeski WJ, LIFE study group

Abstract
Understanding the minimal dose of physical activity required to achieve improvement in physical functioning and reductions in disability risk is necessary to inform public health recommendations. To examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability in The Lifestyle Interventions and Independence for Elders (LIFE) Study. We conducted a multicenter single masked randomized controlled trial that enrolled participants in 2010 and 2011 and followed them for an average of 2.6 years. 1,635 sedentary men and women aged 70-89 years who had functional limitations were randomized to a structured moderate intensity walking, resistance, and flexibility physical activity program or a health education program. Physical activity dose was assessed by 7-day accelerometry and self-report at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery (SPPB), assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and SPPB from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability (overall P < 0.001) (highest versus the lowest quartile of physical activity change HR 0.23 ((95% CI:0.10-0.52) P = 0.001) in the physical activity arm. We observed a dose-dependent effect of objectively monitored physical activity on physical functioning and onset of major mobility disability. Relatively small increases (> 48 minutes per week) in regular physical activity participation had significant and clinically meaningful effects on these outcomes.
TRIAL REGISTRATION: ClinicalsTrials.gov NCT00116194.

PMID: 28820909 [PubMed - indexed for MEDLINE]

Use of phosphodiesterase inhibitors and prevalence of self-reported glaucoma in the United States.

PLoS One. 2017;12(8):e0183388

Authors: Chen SP, Singh K, Lin SC

Abstract
OBJECTIVE: While decreased ocular blood flow is thought to be a possible contributor to glaucoma pathogenesis, it is unclear what role systemic phosphodiesterase inhibitors (PDEi) play. We performed a cross-sectional study of a nationally representative sample of the U.S. population to investigate the relationship between the most commonly used PDEi, sildenafil and theophylline, and self-reported glaucoma.
METHODS: We used the National Health and Nutrition Examination Survey 2005-2008 cycles for this observational study. 7,042 participants, aged 40 years and over, responded to a survey item on glaucoma status and were included in the analysis. Multivariable logistic regression models were constructed to evaluate the association between at least 1 year of self-reported PDEi use and prevalent glaucoma. Regressions were adjusted for potential confounding variables, including demographics, socioeconomic status, and general health conditions, and accounted for the complex design of the survey. Sample weights were constructed and used to ensure the generalizability of results.
RESULTS: 482 respondents self-reported a diagnosis of glaucoma, of which 11 used sildenafil and 20 used theophylline for at least 1 year. Covariates significantly associated with higher odds of glaucoma prevalence in univariable analyses included older age, black race, former smoking status, diabetes, hyperlipidemia, myocardial infarction, and stroke. Conversely, higher education and income were significantly associated with lower odds of glaucoma prevalence. In regression analyses adjusted for demographic and socioeconomic variables, sildenafil (OR = 4.90, CI: 1.24-19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46-6.80, p = 0.005) were significantly associated with higher odds of self-reported glaucoma. These associations held after further adjustment with general health behaviors and conditions for both sildenafil and theophylline.
CONCLUSIONS: Use of sildenafil and theophylline for one or more years was associated with greater prevalence of self-reported glaucoma, a finding which requires further prospective study to assess causality and possible mechanisms of action.

PMID: 28817686 [PubMed - indexed for MEDLINE]

Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis.

EMBO J. 2017 Oct 02;36(19):2829-2843

Authors: García-Nieto PE, Schwartz EK, King DA, Paulsen J, Collas P, Herrera RE, Morrison AJ

Abstract
The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer.

PMID: 28814448 [PubMed - indexed for MEDLINE]

Regulated and unregulated halogenated disinfection byproduct formation from chlorination of saline groundwater.

Water Res. 2017 Oct 01;122:633-644

Authors: Szczuka A, Parker KM, Harvey C, Hayes E, Vengosh A, Mitch WA

Abstract
Coastal utilities exploiting mildly saline groundwater (<150 mg/L chloride) may be challenged by disinfection byproduct (DBP) formation, a concern likely to increase with sea-level rise. Groundwater from North Carolina coastal aquifers is characterized by large variations in concentrations of halides (bromide up to 10,600 μg/L) and dissolved organic carbon (up to 5.7 mg-C/L). Formation of 33 regulated and unregulated halogenated DBPs, including trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles, haloacetamides, and haloacetaldehydes, was measured after simulated chlorination of 24 coastal North Carolina groundwater samples under typical chlorination conditions. Results of chlorination simulation show that THM levels exceeded the Primary Maximum Contaminant Levels in half of the chlorinated samples. Addition of halides to a low salinity groundwater (110 mg/L chloride) indicated that elevated bromide triggered DBP formation, but chloride was not a critical factor for their formation. DBP speciation, but not overall molar formation, was strongly correlated with bromide variations in the groundwater. THMs and HAAs dominated the measured halogenated DBPs on a mass concentration basis. When measured concentrations were weighted by metrics of toxic potency, haloacetonitriles, and to a lesser degree, haloacetaldehydes and HAAs, were the predominant contributors to calculated DBP-associated toxicity. For some samples exhibiting elevated ammonia concentrations, the addition of chlorine to form chloramines in situ significantly reduced halogenated DBP concentrations and calculated toxicity. HAAs dominated the calculated toxicity of chloraminated waters. Reverse osmosis treatment of saline groundwater (chloride >250 mg/L) can reduce DBP formation by removing halides and organic precursors. However, we show that in a case where reverse osmosis permeate is blended with a separate raw groundwater, the residual bromide level in the permeate could still exceed that in the raw groundwater, and thereby induce DBP formation in the blend. DBP-associated calculated toxicity increased for certain blends in this system due to the DBPs resulting from the combination of the elevated bromide concentration in the permeate and the organic precursors from the raw coastal groundwater.

PMID: 28646800 [PubMed - indexed for MEDLINE]

Equilibria model for pH variations and ion adsorption in capacitive deionization electrodes.

Water Res. 2017 Oct 01;122:387-397

Authors: Hemmatifar A, Oyarzun DI, Palko JW, Hawks SA, Stadermann M, Santiago JG

Abstract
Ion adsorption and equilibrium between electrolyte and microstructure of porous electrodes are at the heart of capacitive deionization (CDI) research. Surface functional groups are among the factors which fundamentally affect adsorption characteristics of the material and hence CDI system performance in general. Current CDI-based models for surface charge are mainly based on a fixed (constant) charge density, and do not treat acid-base equilibria of electrode microstructure including so-called micropores. We here expand current models by coupling the modified Donnan (mD) model with weak electrolyte acid-base equilibria theory. In our model, surface charge density can vary based on equilibrium constants (pK's) of individual surface groups as well as micropore and electrolyte pH environments. In this initial paper, we consider this equilibrium in the absence of Faradaic reactions. The model shows the preferential adsorption of cations versus anions to surfaces with respectively acidic or basic surface functional groups. We introduce a new parameter we term "chemical charge efficiency" to quantify efficiency of salt removal due to surface functional groups. We validate our model using well controlled titration experiments for an activated carbon cloth (ACC), and quantify initial and final pH of solution after adding the ACC sample. We also leverage inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography (IC) to quantify the final background concentrations of individual ionic species. Our results show a very good agreement between experiments and model. The model is extendable to a wide variety of porous electrode systems and CDI systems with applied potential.

PMID: 28622631 [PubMed - indexed for MEDLINE]

Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia.

Am J Clin Pathol. 2017 Jun 01;147(6):596-603

Authors: Kunder C, Cascio MJ, Bakke A, Venkataraman G, O'Malley DP, Ohgami RS

Abstract
Objectives: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized.
Methods: Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016.
Results: In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia.
Conclusions: Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation.

PMID: 28575178 [PubMed - indexed for MEDLINE]

Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.

FASEB J. 2017 Sep;31(9):4187-4202

Authors: Oskolkova O, Gawlak G, Tian Y, Ke Y, Sarich N, Son S, Andreasson K, Bochkov VN, Birukova AA, Birukov KG

Abstract
Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) oxidation that contain cyclopenthenone groups, which recapitulate prostaglandin-like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by oxidized PAPC (OxPAPC) remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-α. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti-inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.

PMID: 28572443 [PubMed - indexed for MEDLINE]

Toolset for assessment of natural recovery from legacy contaminated sediment: Case study of Pallanza Bay, Lake Maggiore, Italy.

Water Res. 2017 Sep 15;121:109-119

Authors: Lin D, Cho YM, Oen A, Eek E, Tommerdahl JP, Luthy RG

Abstract
The aim of this study was to develop a toolset that can be used by site managers to assess and monitor natural attenuation processes in sediments contaminated with legacy hydrophobic organic contaminants. The toolset is composed of sediment traps to measure quality and deposition rate of incoming sediment under different hydrodynamic conditions, sediment cores to show trends in sediment bed concentrations over time, and passive samplers attached to a porewater probe frame to assess the mobility of buried contaminants and possible contaminant flux from sediment. These three tools were used together for the first time to assess the mobility of dichlorodiphenyltrichloroethane (DDT) contaminants in sediment in Pallanza Bay, Lake Maggiore, Italy. Depositing sediment and sediment cores were consistent in showing that DDT-contaminated sediment is undergoing burial by cleaner sediment. Elevated DDT concentrations from historical contamination seemed to be effectively buried and immobilized by ongoing deposition by cleaner sediment, because the positive flux from the elevated DDT concentration in the sediment porewater should not advance towards the sediment surface. The monitoring toolset introduced in this study enabled us to more effectively assess ongoing natural attenuation processes and provide more risk relevant data than traditional methods used in monitored natural recovery projects, such as bulk sediment concentrations from sediment cores. Our field assessment results suggest that incoming sediment from the Toce River have reduced DDT concentrations in the sediment compared to historic levels, and will continue to do so in locations where higher DDT concentrations are found within the bioactive layer.

PMID: 28525783 [PubMed - indexed for MEDLINE]

Maternal Stressors and Social Support and Risks of Delivering Babies With Gastroschisis or Hypospadias.

Am J Epidemiol. 2017 Jun 15;185(12):1240-1246

Authors: Carmichael SL, Ma C, Tinker S, Shaw GM, National Birth Defects Prevention Study

Abstract
We examined the association of maternal stressful life events and social support with risks of gastroschisis and hypospadias, using data from the National Birth Defects Prevention Study, a population-based case-control study of US births taking place in 2006-2011. We examined maternal self-reports of 7 life events and 3 sources of social support during the periconceptional period among mothers of 593 gastroschisis cases, 1,142 male hypospadias cases, and 4,399 nonmalformed controls. Responses to the questions on stressful life events were summed to form an index (higher is worse), as were responses to questions on social support (higher is better). We used logistic regression to estimate adjusted odds ratios and 95% confidence intervals. The adjusted odds ratios for gastroschisis for a 4-point increase in the stress index were 3.5 (95% confidence interval (CI): 2.6, 4.8) among nonteenage mothers (age ≥20 years) and 1.0 (95% CI: 0.5, 1.7) among teenage mothers (age <20 years). The odds ratio for hypospadias (among all mothers) was 0.8 (95% CI: 0.7, 1.1). Adjusted odds ratios for a social support score of 3 (versus 0) in the 3 respective groups were 0.6 (95% CI: 0.4, 1.0), 1.0 (95% CI: 0.5, 2.3), and 0.6 (95% CI: 0.4, 0.9). Given the lack of prior research on these outcomes and stress, results should be interpreted with caution.

PMID: 28505275 [PubMed - indexed for MEDLINE]

Active and Passive Smoking and Risk of Nasopharyngeal Carcinoma: A Population-Based Case-Control Study in Southern China.

Am J Epidemiol. 2017 Jun 15;185(12):1272-1280

Authors: Chang ET, Liu Z, Hildesheim A, Liu Q, Cai Y, Zhang Z, Chen G, Xie SH, Cao SM, Shao JY, Jia WH, Zheng Y, Liao J, Chen Y, Lin L, Ernberg I, Vaughan TL, Adami HO, Huang G, Zeng Y, Zeng YX, Ye W

Abstract
The magnitude and patterns of associations between smoking and risk of nasopharyngeal carcinoma (NPC) in high-incidence regions remain uncertain. Associations with active and passive tobacco smoking were estimated using multivariate logistic regression in a population-based case-control study of 2,530 NPC cases and 2,595 controls in Guangdong and Guangxi, southern China, in 2010-2014. Among men, risk of NPC was significantly higher in current smokers compared with never smokers (odds ratio (OR) = 1.32, 95% confidence interval (CI): 1.14, 1.53) but not in former smokers (OR = 0.92, 95% CI: 0.73, 1.17). Risk increased with smoking intensity (per 10 cigarettes/day, OR = 1.09, 95% CI: 1.03, 1.16), smoking duration (per 10 years, OR = 1.11, 95% CI: 1.06, 1.16), and cumulative smoking (per 10 pack-years, OR = 1.08, 95% CI: 1.04, 1.12). Risk decreased with later age at smoking initiation (per year, OR = 0.97, 95% CI: 0.96, 0.98) but not greater time since smoking cessation. Exposures to passive smoking during childhood (OR = 1.24, 95% CI: 1.03, 1.48) and from a spouse during adulthood (OR = 1.30, 95% CI: 1.03, 1.63) were independently associated with increased NPC risk in never-smoking men and women, but exposure-response trends were not observed. In conclusion, active and passive tobacco smoking are associated with modestly increased risk of NPC in southern China; risk is highest among long-term smokers.

PMID: 28459936 [PubMed - indexed for MEDLINE]

Longitudinal trends in self-reported anxiety. Effects of age and birth cohort during 25 years.

BMC Psychiatry. 2017 Apr 26;17(1):119

Authors: Calling S, Midlöv P, Johansson SE, Sundquist K, Sundquist J

Abstract
BACKGROUND: Anxiety has been suggested to increase among young individuals, but previous studies on longitudinal trends are inconclusive. The aim of this study was to analyze longitudinally, the changes over time of prevalence of self-reported anxiety in the Swedish population between 1980/1981 and 2004/2005, in different birth cohorts and age groups.
METHODS: A random sample of non-institutionalized persons aged 16-71 years was interviewed every eighth year. Self-reported anxiety was assessed using the question" Do you suffer from nervousness, uneasiness, or anxiety?" (no; yes, mild; yes, severe). Mixed models with random intercepts were used to estimate changes in rates of anxiety (mild or severe) within different age groups and birth cohorts and in males and females separately. In addition to three time-related variables - year of interview, age at the time of the interview, and year of birth -the following explanatory variables were included: education, urbanization, marital status, smoking, leisure time physical activity and body mass index.
RESULTS: Overall prevalence of self-reported anxiety increased from 8.0 to 12.4% in males and from 17.8% to 23.6% in females, during the 25-year follow-up period. The increasing trend was found in all age groups except in the oldest age groups, and the highest increase was found in young adults 16-23 years, with more than a three-fold increase in females, and a 2.5-fold increase in males, after adjustments for covariates.
CONCLUSIONS: Between 1980/81 and 2004/05, there was an increasing prevalence of self-reported anxiety in all age groups except in the oldest, which indicates increased suffering for a large part of the population, and probably an increased burden on the health care system. Clinical efforts should focus particularly on young females (16-23 years), where the increase was particularly large; almost one third experienced anxiety at the end of the 25-year follow-up.

PMID: 28441931 [PubMed - indexed for MEDLINE]

Phase-plate cryo-EM structure of a class B GPCR-G-protein complex.

Nature. 2017 06 01;546(7656):118-123

Authors: Liang YL, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J, Thal DM, Furness SGB, Christopoulos G, Coudrat T, Danev R, Baumeister W, Miller LJ, Christopoulos A, Kobilka BK, Wootten D, Skiniotis G, Sexton PM

Abstract
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαsβγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gβ subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.

PMID: 28437792 [PubMed - indexed for MEDLINE]

Racial and Ethnic Differences in Socioeconomic Position and Risk of Childhood Acute Lymphoblastic Leukemia.

Am J Epidemiol. 2017 Jun 15;185(12):1263-1271

Authors: Wang L, Gomez SL, Yasui Y

Abstract
Racial and ethnic differences in associations between socioeconomic position (SEP) and risk of childhood acute lymphoblastic leukemia (ALL) were investigated using data from population-based cancer registries in the Surveillance, Epidemiology, and End Results Program in the United States. The study included 8,383 ALL cases diagnosed at age ≤19 years in 2000-2010. Census tract-level composite SEP index in quintiles was assigned based on residence at the time of diagnosis. Incidence rate ratios and 95% confidence intervals associated with SEP and race/ethnicity, adjusted for sex, age, and year of diagnosis, were estimated using Poisson regression models. The incidence rate of childhood ALL was negatively associated with SEP among Hispanics but was positively associated among children of other races/ethnicities. As compared with the lowest SEP, the adjusted incidence rate ratios for children with the highest SEP were 1.29 (95% confidence interval (CI): 1.15, 1.44) for non-Hispanic whites, 1.67 (95% CI: 1.20, 2.34) for non-Hispanic blacks, 1.57 (95% CI: 1.17, 2.09) for Asians/Pacific Islanders, 2.33 (95% CI: 0.93, 5.83) for American Indians/Alaska Natives, and 0.70 (95% CI: 0.60, 0.81) for Hispanics. The findings of a reverse association in Hispanics need to be confirmed and further explained in future studies using different measures of SEP.

PMID: 28369160 [PubMed - indexed for MEDLINE]

Desire for predictive testing for Alzheimer's disease and impact on advance care planning: a cross-sectional study.

Alzheimers Res Ther. 2016 Dec 13;8(1):55

Authors: Sheffrin M, Stijacic Cenzer I, Steinman MA

Abstract
BACKGROUND: It is unknown whether older adults in the United States would be willing to take a test predictive of future Alzheimer's disease, or whether testing would change behavior. Using a nationally representative sample, we explored who would take a free and definitive test predictive of Alzheimer's disease, and examined how using such a test may impact advance care planning.
METHODS: A cross-sectional study within the 2012 Health and Retirement Study of adults aged 65 years or older asked questions about a test predictive of Alzheimer's disease (N = 874). Subjects were asked whether they would want to take a hypothetical free and definitive test predictive of future Alzheimer's disease. Then, imagining they knew they would develop Alzheimer's disease, subjects rated the chance of completing advance care planning activities from 0 to 100. We classified a score > 50 as being likely to complete that activity. We evaluated characteristics associated with willingness to take a test for Alzheimer's disease, and how such a test would impact completing an advance directive and discussing health plans with loved ones.
RESULTS: Overall, 75% (N = 648) of the sample would take a free and definitive test predictive of Alzheimer's disease. Older adults willing to take the test had similar race and educational levels to those who would not, but were more likely to be ≤75 years old (odds ratio 0.71 (95% CI 0.53-0.94)). Imagining they knew they would develop Alzheimer's, 81% would be likely to complete an advance directive, although only 15% had done so already.
CONCLUSIONS: In this nationally representative sample, 75% of older adults would take a free and definitive test predictive of Alzheimer's disease. Many participants expressed intent to increase activities of advance care planning with this knowledge. This confirms high public interest in predictive testing for Alzheimer's disease and suggests this may be an opportunity to engage patients in advance care planning discussions.

PMID: 27955707 [PubMed - indexed for MEDLINE]

Building proteomic tool boxes to monitor MHC class I and class II peptides.

Proteomics. 2017 Jan;17(1-2):

Authors: Schumacher FR, Delamarre L, Jhunjhunwala S, Modrusan Z, Phung QT, Elias JE, Lill JR

Abstract
Major histocompatibility complex Class I (MHCI) and Class II (MHCII) presented peptides powerfully modulate T cell immunity and play a vital role in generating effective anti-tumor and anti-viral immune responses in mammals. Characterizing these MHCI or MHCII presented peptides can help generate therapeutic treatments, afford information on T cell mediated biomarkers, provide insight into disease progression, and reduce adverse anti-drug side effects from engineered biotherapeutics. Here, we explore the tools and techniques commonly employed to discover both MHCI- and MHCII-presented peptides. We describe complementary strategies that enhance the characterization of these peptides and the informatics tools employed for both predicting and characterizing MHCI- and MHCII-presented epitopes. The evolution of methodologies for isolating MHC-presented peptides is discussed, as are the mass spectrometric workflows that can be employed for their characterization. We provide a perspective on where this field is headed, and how these tools may be applicable to the discovery and monitoring of epitopes in a variety of scenarios.

PMID: 27928884 [PubMed - indexed for MEDLINE]

[Historical review on obstructive sleep apnea in children].

Arch Pediatr. 2017 Feb;24 Suppl 1:S2-S6

Authors: Chien YH, Guilleminault C

Abstract
An historical review on the discoveries on pediatric obstructive sleep apnea syndrome and sleep-disordered breathing is outlined. Starting with the description by Dickens of "Joe" the obese, snoring and sleepy individual, the authors trace more than 50 years of questions and research starting with the lean adult to the child and from the recognition of obstructive sleep apnea syndrome to the outline of upper-airway resistance syndrome. The pathophysiological knowledge on sleep-disordered breathing has evolved over time, as have treatment approaches in children, from tracheostomy to positive-airway-pressure therapy, to adenotonsillectomy with and without orthodontic treatments to oral-facial myofunctional therapy. Co-morbidities of sleep-disordered breathing are multiple, involving cognition, behavioral, and mood disorders, cardiovascular impairment, etc. There have been many advances in a short time due to the investigation of OSAS, but many questions still need responses.

PMID: 27908527 [PubMed - indexed for MEDLINE]

Nuisance Regression of High-Frequency Functional Magnetic Resonance Imaging Data: Denoising Can Be Noisy.

Brain Connect. 2017 Feb;7(1):13-24

Authors: Chen JE, Jahanian H, Glover GH

Abstract
Recently, emerging studies have demonstrated the existence of brain resting-state spontaneous activity at frequencies higher than the conventional 0.1 Hz. A few groups utilizing accelerated acquisitions have reported persisting signals beyond 1 Hz, which seems too high to be accommodated by the sluggish hemodynamic process underpinning blood oxygen level-dependent contrasts (the upper limit of the canonical model is ∼0.3 Hz). It is thus questionable whether the observed high-frequency (HF) functional connectivity originates from alternative mechanisms (e.g., inflow effects, proton density changes in or near activated neural tissue) or rather is artificially introduced by improper preprocessing operations. In this study, we examined the influence of a common preprocessing step-whole-band linear nuisance regression (WB-LNR)-on resting-state functional connectivity (RSFC) and demonstrated through both simulation and analysis of real dataset that WB-LNR can introduce spurious network structures into the HF bands of functional magnetic resonance imaging (fMRI) signals. Findings of present study call into question whether published observations on HF-RSFC are partly attributable to improper data preprocessing instead of actual neural activities.

PMID: 27875902 [PubMed - indexed for MEDLINE]

The light-driven sodium ion pump: A new player in rhodopsin research.

Bioessays. 2016 Dec;38(12):1274-1282

Authors: Kato HE, Inoue K, Kandori H, Nureki O

Abstract
Rhodopsins are one of the most studied photoreceptor protein families, and ion-translocating rhodopsins, both pumps and channels, have recently attracted broad attention because of the development of optogenetics. Recently, a new functional class of ion-pumping rhodopsins, an outward Na(+) pump, was discovered, and following structural and functional studies enable us to compare three functionally different ion-pumping rhodopsins: outward proton pump, inward Cl(-) pump, and outward Na(+) pump. Here, we review the current knowledge on structure-function relationships in these three light-driven pumps, mainly focusing on Na(+) pumps. A structural and functional comparison reveals both unique and conserved features of these ion pumps, and enhances our understanding about how the structurally similar microbial rhodopsins acquired such diverse functions. We also discuss some unresolved questions and future perspectives in research of ion-pumping rhodopsins, including optogenetics application and engineering of novel rhodopsins.

PMID: 27859420 [PubMed - indexed for MEDLINE]

A Clinical Wide-Field Fluorescence Endoscopic Device for Molecular Imaging Demonstrating Cathepsin Protease Activity in Colon Cancer.

Mol Imaging Biol. 2016 Dec;18(6):820-829

Authors: Sensarn S, Zavaleta CL, Segal E, Rogalla S, Lee W, Gambhir SS, Bogyo M, Contag CH

Abstract
PURPOSE: Early and effective detection of cancers of the gastrointestinal tract will require novel molecular probes and advances in instrumentation that can reveal functional changes in dysplastic and malignant tissues. Here, we describe adaptation of a wide-field clinical fiberscope to perform wide-field fluorescence imaging while preserving its white-light capability for the purpose of providing wide-field fluorescence imaging capability to point-of-care microscopes.
PROCEDURES: We developed and used a fluorescent fiberscope to detect signals from a quenched probe, BMV109, that becomes fluorescent when cleaved by, and covalently bound to, active cathepsin proteases. Cathepsins are expressed in inflammation- and tumor-associated macrophages as well as directly from tumor cells and are a promising target for cancer imaging. The fiberscope has a 1-mm outer diameter enabling validation via endoscopic exams in mice, and therefore we evaluated topically applied BMV109 for the ability to detect colon polyps in an azoxymethane-induced colon tumor model in mice.
RESULTS: This wide-field endoscopic imaging device revealed consistent and clear fluorescence signals from BMV109 that specifically localized to the polypoid regions as opposed to the normal adjacent colon tissue (p < 0.004) in the murine colon carcinoma model.
CONCLUSIONS: The sensitivity of detection of BMV109 with the fluorescence fiberscope suggested utility of these tools for early detection at hard-to-reach sites. The fiberscope was designed to be used in conjunction with miniature, endoscope-compatible fluorescence microscopes for dual wide-field and microscopic cancer detection.

PMID: 27154508 [PubMed - indexed for MEDLINE]

Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export.

Elife. 2016 Sep 24;5:

Authors: Li J, Pfeffer SR

Abstract
LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X-linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone-mediated autophagy, and its expression improves tissue function in models of aging. We show here that human LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.

PMID: 27664420 [PubMed - indexed for MEDLINE]

Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location.

Mol Imaging Biol. 2017 Apr;19(2):215-224

Authors: Vilalta M, Hughes NP, Von Eyben R, Giaccia AJ, Graves EE

Abstract
PURPOSE: Preclinical studies of hypoxia are generally done using ectopic xenograft tumors, which behave differently from human tumors. Our previous findings have shown that subcutaneously implanted lung tumors exhibit more hypoxia than their orthotopic implanted or spontaneous K-ras-induced counterparts. We hypothesize that differences in hypoxia are due to site-specific differences in vascularity and perfusion.
PROCEDURES: To compare the presence and functionality of vessels in these tumor models, we studied vascular perfusion in vivo in real time.
RESULTS: Orthotopically implanted and spontaneous K-ras-induced lung tumors showed elevated perfusion, demonstrating vasculature functionality. Little contrast agent uptake was observed within the subcutaneously implanted tumors, indicating vascular dysfunction. These findings were corroborated at the microscopic level with Hoechst 33342 and Meca-32 staining.
CONCLUSIONS: From these observations, we concluded that differences in hypoxia in experimental models is related to vessel perfusion. Thus, appropriate selection of preclinical lung tumor models is essential for the study of hypoxia, angiogenesis and therapies targeting these phenomena.

PMID: 27709411 [PubMed - indexed for MEDLINE]

The impact of body mass index on treatment outcomes for patients with low-intermediate risk prostate cancer.

BMC Cancer. 2016 Jul 29;16:557

Authors: Yamoah K, Zeigler-Johnson CM, Jeffers A, Malkowicz B, Spangler E, Park JY, Whittemore A, Rebbeck TR

Abstract
BACKGROUND: Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa).
METHODS: We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or χ(2) for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model.
RESULTS: Patients with elevated body mass index (defined as body mass index ≥25 kg/m(2)) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index <30 kg/m(2)), obese patients (body mass index ≥30 kg/m(2)) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low- and intermediate- risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with ≥2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001).
CONCLUSIONS: Body mass index of ≥30 kg/m(2) is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa.

PMID: 27473687 [PubMed - indexed for MEDLINE]

The Intracellular Effect of Relaxin on Female Anterior Cruciate Ligament Cells.

Am J Sports Med. 2016 Sep;44(9):2384-92

Authors: Konopka JA, DeBaun MR, Chang W, Dragoo JL

Abstract
BACKGROUND: Female collegiate athletes with serum relaxin concentrations above 6.0 pg/mL have been shown to have more than 4 times increased risk for anterior cruciate ligament (ACL) tears. However, the intracellular effect of relaxin on ACL cells has not been elucidated.
HYPOTHESES: The hypotheses were that relaxin binding to receptors on female ACL cells will result in (1) an increase in matrix metalloproteinase (MMP) and decrease in tissue inhibitor of metalloproteinase (TIMP) gene expression, (2) a decrease in collagen and alpha smooth muscle actin (αSMA) expression, (3) inhibition of transforming growth factor β1 (TGFβ1)-induced fibrosis, and (4) an increase in cyclic adenosine 3',5'-monophosphate (cAMP) production and that these changes will not be observed in male ACL cells.
STUDY DESIGN: Controlled laboratory study.
METHODS: Ligament cells from ACL tissue were isolated from 7 male and 7 female human donors and expanded in vitro. The cells were incubated with escalating concentrations of relaxin-2, as well as with TGFβ1 or 17β-estradiol in certain groups. Cells were then lysed and analyzed for MMP1 (collagenase-1), MMP3 (stromelysin-1), MMP13 (collagenase-3), TIMP1, type I collagen, type III collagen, and/or αSMA mRNA expression using quantitative real-time polymerase chain reaction. Intracellular cAMP levels were assessed via an enzyme-linked immunoassay.
RESULTS: ACL cells primed with estrogen and treated with 10 ng/mL and 100 ng/mL relaxin illustrated increased MMP1 expression (P = .012 and .006, respectively) and MMP3 expression (P = .005 and .001, respectively). Treatment with 100 ng/mL relaxin decreased αSMA expression (P = .001). When ACL tissue isolated from female donors with a history of oral contraceptive use was excluded from the analysis, 100 ng/mL of relaxin decreased type I collagen (P = .005) and type III collagen (P = .028) expression in cells primed with estrogen. Relaxin exhibited no significant effect on male-derived ACL cells.
CONCLUSION: Relaxin-2 significantly upregulated intracellular processes in human female ACL cells, but no effect was observed in male cells. Relaxin increased MMP (MMP1 and MMP3) and decreased αSMA and type I and III collagen expression, which may act to alter the structural integrity of the ACL tissue over time.
CLINICAL RELEVANCE: Female athletes with higher circulating relaxin levels may be more susceptible to ACL injury.

PMID: 27245459 [PubMed - indexed for MEDLINE]

Effect of Oral JZP-110 (ADX-N05) on Wakefulness and Sleepiness in Adults with Narcolepsy: A Phase 2b Study.

Sleep. 2016 Jul 01;39(7):1379-87

Authors: Ruoff C, Swick TJ, Doekel R, Emsellem HA, Feldman NT, Rosenberg R, Bream G, Khayrallah MA, Lu Y, Black J

Abstract
STUDY OBJECTIVES: To evaluate the efficacy and safety of oral JZP-110, a second-generation wake-promoting agent with dopaminergic and noradrenergic activity, for treatment of impaired wakefulness and excessive sleepiness in adults with narcolepsy.
METHODS: This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 28 centers in the United States. Patients were adults with narcolepsy who had baseline scores ≥ 10 on the Epworth Sleepiness Scale (ESS) and baseline sleep latency ≤ 10 min on the Maintenance of Wakefulness Test (MWT). Patients received a daily placebo (n = 49) or JZP-110 (n = 44) 150 mg/day weeks 1-4 and 300 mg/day weeks 5-12. Primary efficacy endpoints were change from baseline in average MWT sleep latency, and the Clinical Global Impression-Change (CGI-C); secondary endpoints were change from baseline in ESS score and Patient Global Impression-Change.
RESULTS: Improvements were significantly greater with JZP-110 versus placebo on mean MWT sleep latency (4 w, 9.5 versus 1.4 min, P < 0.0001; 12 w, 12.8 versus 2.1 min, P < 0.0001), percentage of patients with CGI-C improvement (4 w, 80% versus 51%, P = 0.0066; 12 w, 86% versus 38%, P < 0.0001), and mean change in ESS (4 w, -5.6 versus -2.4, P = 0.0038; 12 w, -8.5 versus -2.5, P < 0.0001). Three JZP-110-treated patients (6.8%) discontinued due to adverse events (AEs). The most common AEs with JZP-110 versus placebo were insomnia (23% versus 8%), headache (16% versus 10%), nausea (14% versus 6%), diarrhea (11% versus 6%), decreased appetite (14% versus 0%), and anxiety (11% versus 0%).
CONCLUSIONS: At doses of 150-300 mg/day, JZP-110 was well tolerated and significantly improved the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy.
CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier NCT01681121.

PMID: 27166238 [PubMed - indexed for MEDLINE]

The efficacy of Focused Acceptance and Commitment Therapy in VA primary care.

Psychol Serv. 2016 May;13(2):156-161

Authors: Glover NG, Sylvers PD, Shearer EM, Kane MC, Clasen PC, Epler AJ, Plumb-Vilardaga JC, Bonow JT, Jakupcak M

Abstract
Focused Acceptance & Commitment Therapy (FACT) is a brief intervention based on traditional Acceptance and Commitment Therapy (ACT). Although there is a growing body of research on the efficacy of ACT for a variety of populations and disorders, there is little research to date on the use of FACT in group settings. This project is 1 of the first of its kind, as it examines data on psychological flexibility, health and mental health status, and symptom reduction from a 4-week FACT group. Participants in this study were 51 patients who attended this group as part of routine clinical care in a VA integrated primary care and mental health setting. They completed pre- and posttreatment measures of well-being, depression, anxiety, stress, psychological flexibility, and perceptions of physical and mental health functioning. Pre- to posttreatment analyses of variance demonstrated large effects for quality of life, F(1, 51) = 21.29, p < .001, η2 = 0.30, moderate effects for depressive symptoms, F(1, 51) = 11.47, p < .001, η2 = 0.08, and perceptions of mental health functioning (MCS scale), F(1, 51) = 9.67, p = .003, η2 = 0.11, and small effects for perceptions of perceived stress, F(1, 51) = 4.08, p = .04, η2 = 0.03, and physical health functioning (PCS scale), F(1, 51) = 6.60, p = .01, η2 = 0.08. There was a statistical trend for reductions in anxiety, F(1, 51) = 3.29, p = .07, η2 = 0.01, and a nonsignificant effect for psychological flexibility, F(1, 51) = 2.05, p = .16, η2 = 0.04. These data provide initial support for the implementation of a group-based FACT protocol within a VA primary care setting and help to lay a foundation for further, more controlled studies on Group FACT in future research. (PsycINFO Database Record

PMID: 27148950 [PubMed - indexed for MEDLINE]

Maternal Depression and Childhood Overweight in the CHAMACOS Study of Mexican-American Children.

Matern Child Health J. 2016 Jul;20(7):1405-14

Authors: Audelo J, Kogut K, Harley KG, Rosas LG, Stein L, Eskenazi B

Abstract
Objective Although previous studies have examined the impact of maternal depression on child overweight and obesity, little is known about the relationship in Latino families, who suffer from high risks of depression and obesity. We prospectively investigated the association between depressive symptoms in women with young children and child overweight and obesity (overweight/obesity) at age 7 years among Latino families. Methods Participants included 332 singletons with anthropometric measures obtained at 7 years from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a birth cohort study. Maternal depression was assessed using the Center for Epidemiologic Studies-Depression (CES-D) scale when the children were 1, 3.5, and 7 years. Overweight and obesity was measured by body mass index (kg/m(2)) at age 7 years. Results 63 % of women had CES-D scores consistent with depression in at least one of the 3 given assessments. Compared to children whose mothers were never depressed, children whose mothers were depressed at all three assessments had 2.4 times the adjusted odds of overweight/obesity at age 7 years (95 % CI 1.1-5.6). However, a single positive maternal depression screen was not associated with child overweight/obesity and there was no difference in the odds of overweight/obesity by the age of the child when maternal depression occurred. Conclusion Chronic maternal depression during a child's early life was associated with child overweight/obesity at 7 years. Addressing maternal depression is a critical component of comprehensive obesity prevention and treatment strategies for Latino children.

PMID: 27007986 [PubMed - indexed for MEDLINE]

Small-for-Gestational-Age Births are Associated with Maternal Relationship Status: A Population-Wide Analysis.

Matern Child Health J. 2016 Aug;20(8):1651-61

Authors: Steinberg JR, Sanders L, Cousens S

Abstract
Objectives To examine the association between maternal relationship status during pregnancy and infant birth outcomes. Methods Observational study of the National Longitudinal Survey of Youth 1979, a nationally representative sample of 12,686 men and women between the ages of 14 and 21. We used data from surveys of women reporting childbirth between 1979 and 2004. Relationship status was defined as relationship with an opposite-sex partner in the child's birth year. Relationship stability was defined as the consistency in relationship status in the 1 year before, of, and after the child's birth. Childbirth outcome included small-for-gestational age (SGA) infant. We applied random effects logistic regression models to assess the association between relationship status and stability and childbirth outcome-adjusting for maternal race, infant sex, history of miscarriage, employment, maternal age, multiparity, cohort-entry year, household poverty status, and tobacco use. Results The study included 4439 women with 8348 live births. In fully adjusted models, term SGA infants were more commonly born to partnered women (AOR 1.81; 95 % CI 1.20-2.73) and unmarried women (AOR 1.82; CI 1.34-2.47; LRT p value 0.0001), compared to married women. SGA infants were also more commonly born in unstable relationships (AOR 1.72; 95 % CI 1.14-2.63; LRT p value 0.01) compared to stable relationships. Conclusions for Practice Maternal relationship status and stability during pregnancy is independently associated with risk of SGA infant birth.

PMID: 27007984 [PubMed - indexed for MEDLINE]

Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information.

Dev Neurobiol. 2017 Apr;77(4):419-437

Authors: Trakhtenberg EF, Pita-Thomas W, Fernandez SG, Patel KH, Venugopalan P, Shechter JM, Morkin MI, Galvao J, Liu X, Dombrowski SM, Goldberg JL

Abstract
Serotonin (5HT) is present in a subpopulation of amacrine cells, which form synapses with retinal ganglion cells (RGCs), but little is known about the physiological role of retinal serotonergic circuitry. We found that the 5HT receptor 2C (5HTR2C) is upregulated in RGCs after birth. Amacrine cells generate 5HT and about half of RGCs respond to 5HTR2C agonism with calcium elevation. We found that there are on average 83 5HT+ amacrine cells randomly distributed across the adult mouse retina, all negative for choline acetyltransferase and 90% positive for tyrosine hydroxylase. We also investigated whether 5HTR2C and 5HTR5A affect RGC neurite growth. We found that both suppress neurite growth, and that RGCs from the 5HTR2C knockout (KO) mice grow longer neurites. Furthermore, 5HTR2C is subject to post-transcriptional editing, and we found that only the edited isoform's suppressive effect on neurite growth could be reversed by a 5HTR2C inverse agonist. Next, we investigated the physiological role of 5HTR2C in the retina, and found that 5HTR2C KO mice showed increased amplitude on pattern electroretinogram. Finally, RGC transcriptional profiling and pathways analysis suggested partial developmental compensation for 5HTR2C absence. Taken together, our findings demonstrate that 5HTR2C regulates neurite growth and RGC activity and is necessary for normal amplitude of RGC response to physiologic stimuli, and raise the hypothesis that these functions are modulated by a subset of 5HT+/ChAT-/TH+ amacrine cells as part of retinal serotonergic circuitry. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.

PMID: 26999672 [PubMed - indexed for MEDLINE]

Modification of Knee Flexion Angle Has Patient-Specific Effects on Anterior Cruciate Ligament Injury Risk Factors During Jump Landing.

Am J Sports Med. 2016 Jun;44(6):1540-6

Authors: Favre J, Clancy C, Dowling AV, Andriacchi TP

Abstract
BACKGROUND: The incidence of anterior cruciate ligament (ACL) injuries may be decreased through the use of intervention programs that focus on increasing the knee flexion angle during jump landing, which decreases strain on the ACL.
PURPOSE: To investigate whether intervention training designed to change the knee flexion angle during landing causes secondary changes in other known measures associated with the risk of ACL injuries and to examine the time points when these secondary measures change.
STUDY DESIGN: Controlled laboratory study.
METHODS: A total of 39 healthy recreational athletes performed a volleyball block jump task in an instrumented gait laboratory. The participants first completed the jumps without any modification to their normal landing technique. They were then given oral instruction to land softly and to increase their knee flexion angle during landing. Lower body kinematics and kinetics were measured before and after the modification using an optoelectronic motion capture system.
RESULTS: The knee flexion angle after the modification significantly increased from 11.2° to 15.2° at initial contact and from 67.8° to 100.7° at maximum flexion, and the time between initial contact and maximum flexion increased from 177.4 to 399.4 milliseconds. The flexion modification produced a substantial reduction in vertical ground-reaction force (243.1 to 187.8 %BW) with a concomitant reduction in the maximum flexion moment. Interestingly, the flexion modification only affected the abduction angle and abduction moment for the group of participants that landed in an initial adducted position before the modification and had no significant effect on the group that landed in an abducted position.
CONCLUSION: Increasing the knee flexion angle during jump landing may be an effective intervention to improve knee biomechanical risk factors associated with an ACL injury. However, the fact that the flexion modification only influenced critical risk factors (the abduction angle and abduction moment) in participants who initially landed in an adducted position suggests that the selection of interventions to prevent ACL injuries should account for patient-specific characteristics.
CLINICAL RELEVANCE: The study helps elucidate how increasing the knee flexion angle affects lower body biomechanics and provided evidence for the need to introduce patient-specific strategies for preventing ACL injuries.

PMID: 26983457 [PubMed - indexed for MEDLINE]

Nomogram to Predict Risk of Lymph Node Metastases in Patients With Endometrioid Endometrial Cancer.

Int J Gynecol Pathol. 2016 Sep;35(5):395-401

Authors: Pollom EL, Conklin CM, von Eyben R, Folkins AK, Kidd EA

Abstract
Pelvic lymphadenectomy in early-stage endometrial cancer is controversial, but the findings influence prognosis and treatment decisions. Noninvasive tools to identify women at high risk of lymph node metastasis can assist in determining the need for lymph node dissection and adjuvant treatment for patients who do not have a lymph node dissection performed initially. A retrospective review of surgical pathology was conducted for endometrioid endometrial adenocarcinoma at our institution. Univariate and multivariate logistic regression analysis of selected pathologic features were performed. A nomogram to predict for lymph node metastasis was constructed. From August 1996 to October 2013, 296 patients underwent total abdominal or laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and selective lymphadenectomy for endometrioid endometrial adenocarcinoma. Median age at surgery was 62.7 yr (range, 24.9-93.6 yr). Median number of lymph nodes removed was 13 (range, 1-72). Of all patients, 38 (12.8%) had lymph node metastases. On univariate analysis, tumor size ≥4 cm, grade, lymphovascular space involvement, cervical stromal involvement, adnexal or serosal or parametrial involvement, positive pelvic washings, and deep (more than one half) myometrial invasion were all significantly associated with lymph node involvement. In a multivariate model, lymphovascular space involvement, deep myometrial invasion, and cervical stromal involvement remained significant predictors of nodal involvement, whereas tumor size of ≥4 cm was borderline significant. A lymph node predictive nomogram was constructed using these factors. Our nomogram can help estimate risk of nodal disease and aid in directing the need for additional surgery or adjuvant therapy in patients without lymph node surgery. Lymphovascular space involvement is the most important predictor for lymph node metastases, regardless of grade, and should be consistently assessed.

PMID: 26598977 [PubMed - indexed for MEDLINE]