Lane Medical Library

Hedgehog signaling regulates gene expression in planarian glia.

Elife. 2016 Sep 9;5

Authors: Wang IE, Lapan SW, Scimone ML, Clandinin TR, Reddien PW

Abstract
Hedgehog signaling is critical for vertebrate central nervous system (CNS) development, but its role in CNS biology in other organisms is poorly characterized. In the planarian Schmidtea mediterranea, hedgehog (hh) is expressed in medial cephalic ganglia neurons, suggesting a possible role in CNS maintenance or regeneration. We performed RNA sequencing of planarian brain tissue following RNAi of hh and patched (ptc), which encodes the Hh receptor. Two misregulated genes, intermediate filament-1 (if-1) and calamari (cali), were expressed in a previously unidentified non-neural CNS cell type. These cells expressed orthologs of astrocyte-associated genes involved in neurotransmitter uptake and metabolism, and extended processes enveloping regions of high synapse concentration. We propose that these cells are planarian glia. Planarian glia were distributed broadly, but only expressed if-1 and cali in the neuropil near hh(+) neurons. Planarian glia and their regulation by Hedgehog signaling present a novel tractable system for dissection of glia biology.

PMID: 27612382 [PubMed - as supplied by publisher]

Heart failure and risk of dementia: a Danish nationwide population-based cohort study.

Eur J Heart Fail. 2016 Sep 9;

Authors: Adelborg K, Horváth-Puhó E, Ording A, Pedersen L, Toft Sørensen H, Henderson VW

Abstract
AIMS: The association between heart failure and dementia remains unclear. We assessed the risk of dementia among patients with heart failure and members of a general population comparison cohort.
METHODS AND RESULTS: Individual-level data from Danish medical registries were linked in this nationwide population-based cohort study comparing patients with a first-time hospitalization for heart failure between 1980 and 2012 and a year of birth-, sex-, and calendar year-matched comparison cohort from the general population. Stratified Cox regression analysis was used to compute 1-35-year hazard ratios (HRs) for the risk of all-cause dementia and, secondarily, Alzheimer's disease, vascular dementia, and other dementias. Analyses included 324 418 heart failure patients and 1 622 079 individuals from the general population (median age 77 years, 52% male). Compared with the general population cohort, risk of all-cause dementia was increased among heart failure patients [adjusted HR 1.21, 95% confidence interval (CI) 1.18-1.24]. The associations were stronger in men and in heart failure patients under age 70. Heart failure patients had higher risks of vascular dementia (adjusted HR 1.49, 95% CI 1.40-1.59) and other dementias (adjusted HR 1.30, 95% CI 1.26-1.34) than members of the general population cohort. Heart failure was not associated with Alzheimer's disease (adjusted HR 1.00, 95% CI 0.96-1.04).
CONCLUSION: Heart failure was associated with an increased risk of all-cause dementia. Heart failure may represent a risk factor for dementia, but not necessarily for Alzheimer's disease.

PMID: 27612177 [PubMed - as supplied by publisher]

Surgical outcomes of Majewski osteodysplastic primordial dwarfism Type II with intracranial vascular anomalies.

J Neurosurg Pediatr. 2016 Sep 9;:1-7

Authors: Teo M, Johnson JN, Bell-Stephens TE, Marks MP, Do HM, Dodd RL, Bober MB, Steinberg GK

Abstract
OBJECTIVE Majewski osteodysplastic primordial dwarfism Type II (MOPD II) is a rare genetic disorder. Features of it include extremely small stature, severe microcephaly, and normal or near-normal intelligence. Previous studies have found that more than 50% of patients with MOPD II have intracranial vascular anomalies, but few successful surgical revascularization or aneurysm-clipping cases have been reported because of the diminutive arteries and narrow surgical corridors in these patients. Here, the authors report on a large series of patients with MOPD II who underwent surgery for an intracranial vascular anomaly. METHODS In conjunction with an approved prospective registry of patients with MOPD II, a prospectively collected institutional surgical database of children with MOPD II and intracranial vascular anomalies who underwent surgery was analyzed retrospectively to establish long-term outcomes. RESULTS Ten patients with MOPD II underwent surgery between 2005 and 2012; 5 patients had moyamoya disease (MMD), 2 had intracranial aneurysms, and 3 had both MMD and aneurysms. Patients presented with transient ischemic attack (TIA) (n = 2), ischemic stroke (n = 2), intraparenchymal hemorrhage from MMD (n = 1), and aneurysmal subarachnoid hemorrhage (n = 1), and 4 were diagnosed on screening. The mean age of the 8 patients with MMD, all of whom underwent extracranial-intracranial revascularization (14 indirect, 1 direct) was 9 years (range 1-17 years). The mean age of the 5 patients with aneurysms was 15.5 years (range 9-18 years). Two patients experienced postoperative complications (1 transient weakness after clipping, 1 femoral thrombosis that required surgical repair). During a mean follow-up of 5.9 years (range 3-10 years), 3 patients died (1 of subarachnoid hemorrhage, 1 of myocardial infarct, and 1 of respiratory failure), and 1 patient had continued TIAs. All of the surviving patients recovered to their neurological baseline. CONCLUSIONS Patients with MMD presented at a younger age than those in whom aneurysms were more prevalent. Microneurosurgery with either intracranial bypass or aneurysm clipping is extremely challenging but feasible at expert centers in patients with MOPD II, and good long-term outcomes are possible.

PMID: 27611897 [PubMed - as supplied by publisher]

Additive value of nicorandil on ATP for further inducing hyperemia in patients with an intermediate coronary artery stenosis.

Coron Artery Dis. 2016 Sep 8;

Authors: Kobayashi Y, Okura H, Neishi Y, Higa T, Kobayashi Y, Uemura S, Yoshida K

Abstract
BACKGROUND: The induction of hyperemia is of importance to precisely assess the functional significance of coronary artery lesions with fractional flow reserve (FFR). Adenosine or ATP alone is used widely in this setting; however, little is known about the additive value of nicorandil, which acts as a nitrate and a K-ATP channel opener, to induce further hyperemia.
PATIENTS AND METHODS: A total of 183 intermediate native coronary artery lesions from 112 patients were prospectively enrolled into this study. FFR was measured using a coronary pressure wire during an intravenous ATP infusion alone (150 mcg/kg/min) (FFRATP) and repeated after an adjunctive intracoronary nicorandil injection (2.0 mg) (FFRATP+Nico).
RESULTS: Physiologic measurements were completed without any severe adverse effects from ATP and nicorandil in all patients. FFRATP and FFRATP+Nico had a strong linear correlation (R=0.79, P<0.001). The FFR value became significantly lower with an adjunctive intracoronary nicorandil injection compared with ATP alone [FFRATP vs. FFRATP+Nico, 0.87 (interquartile range: 0.81-0.92) vs. 0.85 (0.79-0.90), P<0.001]. A total of 18 lesions out of 183 (9.8%) were reclassified after a nicorandil injection (12 from FFR>0.80 to ≤0.80 vs. six from FFR≤0.80 to >0.80, P=0.26). The adjunctive effect of nicorandil was accentuated with each increment of FFRATP strata (per 0.05 increase, P for trend<0.001), but with minimal effect around the borderline FFR zone.
CONCLUSION: An adjunctive intracoronary nicorandil injection is safe, but appears to have little effect in inducing further hyperemia. Therefore, its effect on the clinical scenario is limited.

PMID: 27611876 [PubMed - as supplied by publisher]

Rising Bilateral Mastectomy Rates Among Neoadjuvant Chemotherapy Recipients in California From 1998 to 2012.

Ann Surg. 2016 Sep 8;

Authors: Wapnir IL, Kurian AW, Lichtensztajn DY, Clarke CA, Gomez SL

Abstract
OBJECTIVE: To study the impact of rising bilateral mastectomy rates among neoadjuvant chemotherapy (NAC) recipients in California.
BACKGROUND: NAC for operable breast cancer (BC) can downstage disease and facilitate breast conservation. We assessed trends in NAC use and surgical procedures in California from January 1, 1998 to December 31, 2012 using statewide population-based cancer registry data.
METHODS: A total of 236,797 females diagnosed with stage I-III BC were studied. Information regarding NAC, adjuvant chemotherapy (aCT), breast conserving surgery (BCS), bilateral mastectomy (BLM), and unilateral mastectomy (ULM) was abstracted from the medical records. Multivariable polytomous logistic regression was used to estimate odds ratios (OR) of receiving NAC and of type of surgery after NAC.
RESULTS: Approximately, 40.1% (94,980) of patients received chemotherapy: 87% (82,588) aCT and 13.0% (12,392) NAC. NAC use more than doubled over time and increased with stage (Stage I, 0.7%; Stage III, 29.9%). Multivariable predictors of NAC treatment were stage (III), younger age (<40 yrs), Black or Hispanic race/ethnicity versus non-Hispanic White (OR 1.10, 95% confidence interval (CI) 1.05-1.16), and care at a National Cancer Institute (NCI)-designated center (OR 1.70, CI 1.58-1.82). Most NAC recipients (68.4%) had mastectomies, and 14.3% of them underwent BLM. In contrast, 47.9% aCT patients had mastectomies with 7.3% BLM. The only independent predictor of BCS after NAC was care at a NCI-designated center (OR 1.28, CI 1.10-1.49), and of BLM, age <40 years versus 50 to 64 years (OR 2.59, CI 2.21-3.03), or residence in the highest socioeconomic neighborhood quintile versus lowest (OR 2.10, CI 1.67-2.64).
CONCLUSIONS: NAC use remains low. Predictors of surgery type after NAC were sociodemographic rather than clinical, raising concern for disparities in care access.

PMID: 27611617 [PubMed - as supplied by publisher]

Diversity in a Polymicrobial Community Revealed by Analysis of Viromes, Endolysins and CRISPR Spacers.

PLoS One. 2016;11(9):e0160574

Authors: Davison M, Treangen TJ, Koren S, Pop M, Bhaya D

Abstract
The polymicrobial biofilm communities in Mushroom and Octopus Spring in Yellowstone National Park (YNP) are well characterized, yet little is known about the phage populations. Dominant species, Synechococcus sp. JA-2-3B'a(2-13), Synechococcus sp. JA-3-3Ab, Chloroflexus sp. Y-400-fl, and Roseiflexus sp. RS-1, contain multiple CRISPR-Cas arrays, suggesting complex interactions with phage predators. To analyze phage populations from Octopus Spring biofilms, we sequenced a viral enriched fraction. To assemble and analyze phage metagenomic data, we developed a custom module, VIRITAS, implemented within the MetAMOS framework. This module bins contigs into groups based on tetranucleotide frequencies and CRISPR spacer-protospacer matching and ORF calling. Using this pipeline we were able to assemble phage sequences into contigs and bin them into three clusters that corroborated with their potential host range. The virome contained 52,348 predicted ORFs; some were clearly phage-like; 9319 ORFs had a recognizable Pfam domain while the rest were hypothetical. Of the recognized domains with CRISPR spacer matches, was the phage endolysin used by lytic phage to disrupt cells. Analysis of the endolysins present in the thermophilic cyanophage contigs revealed a subset of characterized endolysins as well as a Glyco_hydro_108 (PF05838) domain not previously associated with sequenced cyanophages. A search for CRISPR spacer matches to all identified phage endolysins demonstrated that a majority of endolysin domains were targets. This strategy provides a general way to link host and phage as endolysins are known to be widely distributed in bacteriophage. Endolysins can also provide information about host cell wall composition and have the additional potential to be used as targets for novel therapeutics.

PMID: 27611571 [PubMed - as supplied by publisher]

Utility of electroencephalography: Experience from a U.S. tertiary care medical center.

Clin Neurophysiol. 2016 Aug 24;127(10):3335-3340

Authors: Gururangan K, Razavi B, Parvizi J

Abstract
OBJECTIVE: To investigate the utility of electroencephalography (EEG) for evaluation of patients with altered mental status (AMS).
METHODS: We retrospectively reviewed 200 continuous EEGs (cEEGs) obtained in ICU and non-ICU wards and 100 spot EEGs (sEEGs) obtained from the emergency department (ED) of a large tertiary medical center. Main outcomes were access time (from study request to hookup), and diagnostic yield (percentage of studies revealing significant abnormality).
RESULTS: Access time, mean±SD (maximum), was 3.5±3.2 (20.8) hours in ICU, 4.8±5.0 (25.6) hours in non-ICU, and 2.7±3.6 (23.9) hours in ED. Access time was not significantly different for stat requests or EEGs with seizure activity. While the primary indication for EEG monitoring was to evaluate for seizures as the cause of AMS, only 8% of cEEGs and 1% of sEEGs revealed seizures. Epileptiform discharges were detected in 45% of ICU, 24% of non-ICU, and 9% of ED cases, while 2% of ICU, 15% of non-ICU, and 45% of ED cases were normal.
CONCLUSIONS: Access to EEG is hampered by significant delays, and in emergency settings, the conventional EEG system detects seizures only in a minority of cases.
SIGNIFICANCE: Our findings underscore the inefficiencies of current EEG infrastructure for accessing diagnostically important information, as well as the need for more prospective data describing the relationship between EEG access time and EEG findings, clinical outcomes, and cost considerations.

PMID: 27611442 [PubMed - as supplied by publisher]

Sleep Duration and Cancer in the NIH-AARP Diet and Health Study Cohort.

PLoS One. 2016;11(9):e0161561

Authors: Gu F, Xiao Q, Chu LW, Yu K, Matthews CE, Hsing AW, Caporaso NE

Abstract
BACKGROUND: Very few studies have examined sleep duration in relation to cancer incidence with the exception of breast cancer.
METHODS: We assessed the associations between sleep duration and incidences of total and 18 site-specific cancers in the NIH-AARP Health and Diet Study cohort, with 173,327 men and 123,858 women aged 51-72 years at baseline. Self-reported sleep duration categories were assessed via questionnaire. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), using 7-8 hours/night as the reference.
RESULTS: We observed a significantly increased risk of stomach cancer among male short sleepers (multivariable HR5-6 vs. 7-8 hours = 1.29; 95%CI: 1.05, 1.59; Ptrend = 0.03). We also observed suggestive associations in either short or long sleepers, which did not reach overall significance (Ptrend >0.05), including increased risks in male short sleepers for cancers of head and neck (HR<5vs.7-8 hours = 1.39; 95%CI:1.00-1.95), bladder (HR5-6vs.7-8 hours = 1.10; 95%CI:1.00-1.20), thyroid (HR<5 vs. 7-8 hours = 2.30; 95%CI:1.06, 5.02), Non-Hodgkin Lymphoma (NHL) (HR5-6vs.7-8 hours = 1.17; 95%CI:1.02-1.33), and myeloma (HR<5vs.7-8 hours = 2.06; 95%CI:1.20-3.51). In women, the suggestive associations include a decreased total cancer risk (HR<5vs.7-8 hours = 0.9; 95%CI:0.83-0.99) and breast cancer risk (HR<5vs.7-8 hours = 0.84; 95%CI:0.71-0.98) among short sleepers. A decreased ovarian cancer risk (HR≥ 9 vs. 7-8 hours = 0.50; 95%CI:0.26-0.97) and an increased NHL risk (HR≥ 9 vs. 7-8 hours = 1.45; 95%CI:1.00-2.11) were observed among long sleepers.
CONCLUSION: In an older population, we observed an increased stomach cancer risk in male short sleepers and suggestive associations with short or long sleep duration for many cancer risks in both genders.

PMID: 27611440 [PubMed - as supplied by publisher]

Assessment of sex differences in bone deficits among adolescents with anorexia nervosa.

Int J Eat Disord. 2016 Sep 9;

Authors: Nagata JM, Golden NH, Peebles R, Long J, Leonard MB, Chang AO, Carlson JL

Abstract
OBJECTIVE: The objective of this study was to compare sex differences in bone deficits among adolescents with anorexia nervosa (AN) and to identify other correlates of bone health.
METHOD: Electronic medical records of all patients 9-20 years of age with a DSM-5 diagnosis of AN who were evaluated by the eating disorders program at Stanford with dual-energy X-ray absorptiometry (DXA) between March 1997 and February 2011 were retrospectively reviewed. Whole body bone mineral content Z-scores and bone mineral density (BMD) Z-scores at multiple sites were recorded using the Bone Mineral Density in Childhood Study (BMDCS) reference data.
RESULTS: A total of 25 males and 253 females with AN were included, with median age 15 years (interquartile range [IQR] 14-17) and median duration of illness 9 months (IQR 5-13). Using linear regression analyses, no significant sex differences in bone deficits were found at the lumbar spine, total hip, femoral neck, or whole body when controlling for age, %mBMI, and duration of illness. Lower %mBMI was significantly associated with bone deficits at all sites in adjusted models.
DISCUSSION: This is the first study to evaluate sex differences in bone health among adolescents with AN, using novel DSM-5 criteria for AN and robust BMDCS reference data. We find no significant sex differences in bone deficits among adolescents with AN except for a higher proportion of females with femoral neck BMD Z-scores <-1. Degree of malnutrition was correlated with bone deficits at all sites. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016).

PMID: 27611361 [PubMed - as supplied by publisher]

The Role of Executive Function in Independent Living Skills in Female Adolescents and Young Adults With Fragile X Syndrome.

Am J Intellect Dev Disabil. 2016 Sep;121(5):448-460

Authors: Martin A, Quintin EM, Hall SS, Reiss AL

Abstract
Fragile X syndrome (FXS) is associated with executive function (EF) and independent living skills (ILS) deficits. We examined the role of childhood EF in ILS during adolescence/early adulthood in females with FXS and two comparison groups in the same age range (matched for IQ [IQ/Age group] and with another genetic condition, Turner syndrome [TS group]). EF and ILS were significantly higher for the FXS group than the IQ/Age group but did not differ from the TS group. For the FXS group, age and EF were significant predictors of ILS during adolescence/early adulthood, but there were no statistically significant longitudinal associations between EF and ILS. Our findings suggest that impairments in EF may have a significant effect on ILS in FXS.

PMID: 27611354 [PubMed - as supplied by publisher]

Spatial and Temporal Dynamics and Value of Nature-Based Recreation, Estimated via Social Media.

PLoS One. 2016;11(9):e0162372

Authors: Sonter LJ, Watson KB, Wood SA, Ricketts TH

Abstract
Conserved lands provide multiple ecosystem services, including opportunities for nature-based recreation. Managing this service requires understanding the landscape attributes underpinning its provision, and how changes in land management affect its contribution to human wellbeing over time. However, evidence from both spatially explicit and temporally dynamic analyses is scarce, often due to data limitations. In this study, we investigated nature-based recreation within conserved lands in Vermont, USA. We used geotagged photographs uploaded to the photo-sharing website Flickr to quantify visits by in-state and out-of-state visitors, and we multiplied visits by mean trip expenditures to show that conserved lands contributed US $1.8 billion (US $0.18-20.2 at 95% confidence) to Vermont's tourism industry between 2007 and 2014. We found eight landscape attributes explained the pattern of visits to conserved lands; visits were higher in larger conserved lands, with less forest cover, greater trail density and more opportunities for snow sports. Some of these attributes differed from those found in other locations, but all aligned with our understanding of recreation in Vermont. We also found that using temporally static models to inform conservation decisions may have perverse outcomes for nature-based recreation. For example, static models suggest conserved land with less forest cover receive more visits, but temporally dynamic models suggest clearing forests decreases, rather than increases, visits to these sites. Our results illustrate the importance of understanding both the spatial and temporal dynamics of ecosystem services for conservation decision-making.

PMID: 27611325 [PubMed - as supplied by publisher]

Actigraphy in Patients With Major Depressive Disorder Undergoing Repetitive Transcranial Magnetic Stimulation: An Open Label Pilot Study.

J ECT. 2016 Sep 8;

Authors: Nishida M, Kikuchi S, Nisijima K, Suda S

Abstract
BACKGROUND: The effects of repetitive transcranial magnetic stimulation (rTMS) on physical activity and sleep patterns in individuals with major depressive disorder (MDD) remain unclear.
METHOD: We examined the effects of rTMS treatment on the rest-activity cycle and sleep disturbances in MDD. In this open-label pilot study, 14 patients with medication-resistant MDD underwent 10 rTMS sessions over the bilateral dorsolateral prefrontal cortex. In addition to Hamilton Depression Rating Scale and Pittsburgh Sleep Quality Index scores, waist actigraphy was used to evaluate alterations in the rest-activity cycle over the course of rTMS treatments. Actigraphic data were evaluated at baseline and in the first (rTMS sessions 1-3), second (rTMS sessions 4-7), and third (rTMS sessions 8-10) sections.
RESULTS: Although Hamilton Depression Rating Scale and Pittsburgh Sleep Quality Index scores were significantly improved by rTMS, sleep variables assessed by actigraphy did not show significant changes. However, post hoc tests indicated a significant increase in mean steps per day between the baseline and first section time points (P = 0.014; t13 = -2.316).
CONCLUSIONS: Our data indicated that a daytime physical activity response to rTMS occurred in early sessions, whereas subjective symptom improvements were consistent across all sessions. Future double-blind placebo-controlled studies assessing the effects of rTMS on the rest-activity cycle and sleep disturbances in MDD are warranted.

PMID: 27611301 [PubMed - as supplied by publisher]

Empirically derived personality subtyping for predicting clinical symptoms and treatment response in bulimia nervosa.

Int J Eat Disord. 2016 Sep 9;

Authors: Haynos AF, Pearson CM, Utzinger LM, Wonderlich SA, Crosby RD, Mitchell JE, Crow SJ, Peterson CB

Abstract
OBJECTIVE: Evidence suggests that eating disorder subtypes reflecting under-controlled, over-controlled, and low psychopathology personality traits constitute reliable phenotypes that differentiate treatment response. This study is the first to use statistical analyses to identify these subtypes within treatment-seeking individuals with bulimia nervosa (BN) and to use these statistically derived clusters to predict clinical outcomes.
METHODS: Using variables from the Dimensional Assessment of Personality Pathology-Basic Questionnaire, K-means cluster analyses identified under-controlled, over-controlled, and low psychopathology subtypes within BN patients (n = 80) enrolled in a treatment trial. Generalized linear models examined the impact of personality subtypes on Eating Disorder Examination global score, binge eating frequency, and purging frequency cross-sectionally at baseline and longitudinally at end of treatment (EOT) and follow-up. In the longitudinal models, secondary analyses were conducted to examine personality subtype as a potential moderator of response to Cognitive Behavioral Therapy-Enhanced (CBT-E) or Integrative Cognitive-Affective Therapy for BN (ICAT-BN).
RESULTS: There were no baseline clinical differences between groups. In the longitudinal models, personality subtype predicted binge eating (P = 0.03) and purging (P = 0.01) frequency at EOT and binge eating frequency at follow-up (p = 0.045). The over-controlled group demonstrated the best outcomes on these variables. In secondary analyses, there was a treatment by subtype interaction for purging at follow-up (P = 0.04), which indicated a superiority of CBT-E over ICAT-BN for reducing purging among the over-controlled group.
DISCUSSION: Empirically derived personality subtyping appears to be a valid classification system with potential to guide eating disorder treatment decisions. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016).

PMID: 27611235 [PubMed - as supplied by publisher]

Lieb-Robinson Bound and the Butterfly Effect in Quantum Field Theories.

Phys Rev Lett. 2016 Aug 26;117(9):091602

Authors: Roberts DA, Swingle B

Abstract
As experiments are increasingly able to probe the quantum dynamics of systems with many degrees of freedom, it is interesting to probe fundamental bounds on the dynamics of quantum information. We elaborate on the relationship between one such bound-the Lieb-Robinson bound-and the butterfly effect in strongly coupled quantum systems. The butterfly effect implies the ballistic growth of local operators in time, which can be quantified with the "butterfly" velocity v_{B}. Similarly, the Lieb-Robinson velocity places a state-independent ballistic upper bound on the size of time evolved operators in nonrelativistic lattice models. Here, we argue that v_{B} is a state-dependent effective Lieb-Robinson velocity. We study the butterfly velocity in a wide variety of quantum field theories using holography and compare with free-particle computations to understand the role of strong coupling. We find that v_{B} remains constant or decreases with decreasing temperature. We also comment on experimental prospects and on the relationship between the butterfly velocity and signaling.

PMID: 27610843 [PubMed - as supplied by publisher]

Structure of a Complete Mediator-RNA Polymerase II Pre-Initiation Complex.

Cell. 2016 Sep 8;166(6):1411-1422.e16

Authors: Robinson PJ, Trnka MJ, Bushnell DA, Davis RE, Mattei PJ, Burlingame AL, Kornberg RD

Abstract
A complete, 52-protein, 2.5 million dalton, Mediator-RNA polymerase II pre-initiation complex (Med-PIC) was assembled and analyzed by cryo-electron microscopy and by chemical cross-linking and mass spectrometry. The resulting complete Med-PIC structure reveals two components of functional significance, absent from previous structures, a protein kinase complex and the Mediator-activator interaction region. It thereby shows how the kinase and its target, the C-terminal domain of the polymerase, control Med-PIC interaction and transcription.

PMID: 27610567 [PubMed - as supplied by publisher]

Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist: Naproxen with Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo to Treating Acute Low Back Pain: A Randomized Clinical Trial.

Am J Phys Med Rehabil. 2016 Sep 8;

Authors: Schneider BJ, Kennedy DJ, Kumbhare D

PMID: 27610552 [PubMed - as supplied by publisher]

Protonation State of MnFe and FeFe Cofactors in a Ligand-Binding Oxidase Revealed by X-ray Absorption, Emission, and Vibrational Spectroscopy and QM/MM Calculations.

Inorg Chem. 2016 Sep 9;

Authors: Kositzki R, Mebs S, Marx J, Griese JJ, Schuth N, Högbom M, Schünemann V, Haumann M

Abstract
Enzymes with a dimetal-carboxylate cofactor catalyze reactions among the top challenges in chemistry such as methane and dioxygen (O2) activation. Recently described proteins bind a manganese-iron cofactor (MnFe) instead of the classical diiron cofactor (FeFe). Determination of atomic-level differences of homo- versus hetero-bimetallic cofactors is crucial to understand their diverse redox reactions. We studied a ligand-binding oxidase from the bacterium Geobacillus kaustophilus (R2lox) loaded with a FeFe or MnFe cofactor, which catalyzes O2 reduction and an unusual tyrosine-valine ether cross-link formation, as revealed by X-ray crystallography. Advanced X-ray absorption, emission, and vibrational spectroscopy methods and quantum chemical and molecular mechanics calculations provided relative Mn/Fe contents, X-ray photoreduction kinetics, metal-ligand bond lengths, metal-metal distances, metal oxidation states, spin configurations, valence-level degeneracy, molecular orbital composition, nuclear quadrupole splitting energies, and vibrational normal modes for both cofactors. A protonation state with an axial water (H2O) ligand at Mn or Fe in binding site 1 and a metal-bridging hydroxo group (μOH) in a hydrogen-bonded network is assigned. Our comprehensive picture of the molecular, electronic, and dynamic properties of the cofactors highlights reorientation of the unique axis along the Mn-OH2 bond for the Mn1(III) Jahn-Teller ion but along the Fe-μOH bond for the octahedral Fe1(III). This likely corresponds to a more positive redox potential of the Mn(III)Fe(III) cofactor and higher proton affinity of its μOH group. Refined model structures for the Mn(III)Fe(III) and Fe(III)Fe(III) cofactors are presented. Implications of our findings for the site-specific metalation of R2lox and performance of the O2 reduction and cross-link formation reactions are discussed.

PMID: 27610479 [PubMed - as supplied by publisher]

Solving Logistic Regression with Group Cardinality Constraints for Time Series Analysis.

Med Image Comput Comput Assist Interv. 2015 Oct;9351:459-466

Authors: Zhang Y, Pohl KM

Abstract
We propose an algorithm to distinguish 3D+t images of healthy from diseased subjects by solving logistic regression based on cardinality constrained, group sparsity. This method reduces the risk of overfitting by providing an elegant solution to identifying anatomical regions most impacted by disease. It also ensures that consistent identification across the time series by grouping each image feature across time and counting the number of non-zero groupings. While popular in medical imaging, group cardinality constrained problems are generally solved by relaxing counting with summing over the groupings. We instead solve the original problem by generalizing a penalty decomposition algorithm, which alternates between minimizing a logistic regression function with a regularizer based on the Frobenius norm and enforcing sparsity. Applied to 86 cine MRIs of healthy cases and subjects with Tetralogy of Fallot (TOF), our method correctly identifies regions impacted by TOF and obtains a statistically significant higher classification accuracy than logistic regression without and relaxed grouped sparsity constraint.

PMID: 27610425 [PubMed - as supplied by publisher]

Back to the Lecture.

ACS Cent Sci. 2016 Aug 24;2(8):483-5

Authors: Bertozzi CR

PMID: 27610405 [PubMed]

Minimally Invasive Lumbar Pedicle Screw Fixation Using Cortical Bone Trajectory - A Prospective Cohort Study on Postoperative Pain Outcomes.

Cureus. 2016;8(7):e714

Authors: Chen YR, Deb S, Pham L, Singh H

Abstract
OBJECTIVE: Our study aims to evaluate the clinical outcomes of cortical screws in regards to postoperative pain.
BACKGROUND: Pedicle screw fixation is the current mainstay technique for posterior spinal fusion. Over the past decade, a new technique called cortical screw fixation has been developed, which allows for medialized screw placement through stronger cortical bone. There have been several studies that showed either biomechanical equivalence or superiority of cortical screws. However, there is currently only a single study in the literature looking at clinical outcomes of cortical screw fixation in patients who have had no prior spine surgery.
METHODS: We prospectively looked at the senior author's patients who underwent cortical versus pedicle lumbar screw fixation surgeries between 2013 and 2015 for lumbar degenerative disease. Eighteen patients underwent cortical screw fixation, and 15 patients underwent traditional pedicle screw fixation. We looked at immediate postoperative pain, changes in short-term pain (six to 12 weeks post-surgery), and changes in long-term pain (six to eight months). All pain outcomes were measured using a visual analog scale ranging from 1 to 10. Mann-Whitney or Kruskal-Wallis tests were used to measure continuous data, and the Fisher Exact test was used to measure categorical data as appropriate.
RESULTS: Our results showed that the cortical screw cohort showed a trend towards having less peak postoperative pain (p = 0.09). The average postoperative pain was similar between the two cohorts (p = 0.93). There was also no difference in pain six to 12 weeks after surgery (p = 0.8). However, at six to eight months, the cortical screw cohort had worse pain compared to the pedicle screw cohort (p = 0.02).
CONCLUSIONS: The cortical screw patients showed a trend towards less peak pain in the short-term (one to three days post-surgery) and more pain in the long-term (six to eight months post-surgery) compared to pedicle screw patients. Both cohorts had a statistically significant reduction in pain levels compared to preoperative pain. More studies are needed to further evaluate postoperative pain, long-term functional outcomes, and fusion rates in patients who undergo cortical screw fixation.

PMID: 27610286 [PubMed]

The rise and fall of infectious disease in a warmer world.

F1000Res. 2016;5

Authors: Lafferty KD, Mordecai EA

Abstract
Now-outdated estimates proposed that climate change should have increased the number of people at risk of malaria, yet malaria and several other infectious diseases have declined. Although some diseases have increased as the climate has warmed, evidence for widespread climate-driven disease expansion has not materialized, despite increased research attention. Biological responses to warming depend on the non-linear relationships between physiological performance and temperature, called the thermal response curve. This leads performance to rise and fall with temperature. Under climate change, host species and their associated parasites face extinction if they cannot either thermoregulate or adapt by shifting phenology or geographic range. Climate change might also affect disease transmission through increases or decreases in host susceptibility and infective stage (and vector) production, longevity, and pathology. Many other factors drive disease transmission, especially economics, and some change in time along with temperature, making it hard to distinguish whether temperature drives disease or just correlates with disease drivers. Although it is difficult to predict how climate change will affect infectious disease, an ecological approach can help meet the challenge.

PMID: 27610227 [PubMed]

Aberrant Development of Speech Processing in Young Children with Autism: New Insights from Neuroimaging Biomarkers.

Front Neurosci. 2016;10:393

Authors: Sperdin HF, Schaer M

Abstract
From the time of birth, a newborn is continuously exposed and naturally attracted to human voices, and as he grows, he becomes increasingly responsive to these speech stimuli, which are strong drivers for his language development and knowledge acquisition about the world. In contrast, young children with autism spectrum disorder (ASD) are often insensitive to human voices, failing to orient and respond to them. Failure to attend to speech in turn results in altered development of language and social-communication skills. Here, we review the critical role of orienting to speech in ASD, as well as the neural substrates of human voice processing. Recent functional neuroimaging and electroencephalography studies demonstrate that aberrant voice processing could be a promising marker to identify ASD very early on. With the advent of refined brain imaging methods, coupled with the possibility of screening infants and toddlers, predictive brain function biomarkers are actively being examined and are starting to emerge. Their timely identification might not only help to differentiate between phenotypes, but also guide the clinicians in setting up appropriate therapies, and better predicting or quantifying long-term outcome.

PMID: 27610073 [PubMed]

Sex differences in obesity, dietary habits, and physical activity among urban middle-class Bangladeshis.

Int J Health Sci (Qassim). 2016 Jul;10(3):363-72

Authors: Saquib J, Saquib N, Stefanick ML, Khanam MA, Anand S, Rahman M, Chertow GM, Barry M, Ahmed T, Cullen MR

Abstract
BACKGROUND: The sustained economic growth in Bangladesh during the previous decade has created a substantial middle-class population, who have adequate income to spend on food, clothing, and lifestyle management. Along with the improvements in living standards, has also come negative impact on health for the middle class. The study objective was to assess sex differences in obesity prevalence, diet, and physical activity among urban middle-class Bangladeshi.
METHODS: In this cross-sectional study, conducted in 2012, we randomly selected 402 adults from Mohammedpur, Dhaka. The sampling technique was multi-stage random sampling. We used standardized questionnaires for data collection and measured height, weight, and waist circumference.
RESULTS: Mean age (standard deviation) was 49.4 (12.7) years. The prevalence of both generalized (79% vs. 53%) and central obesity (85% vs. 42%) were significantly higher in women than men. Women reported spending more time watching TV and spending less time walking than men (p<.05); however, men reported a higher intake of unhealthy foods such as fast food and soft drinks.
CONCLUSIONS: We conclude that the prevalence of obesity is significantly higher in urban middle-class Bangladeshis than previous urban estimates, and the burden of obesity disproportionately affects women. Future research and public health efforts are needed to address this severe obesity problem and to promote active lifestyles.

PMID: 27610059 [PubMed]

The Bilirubin Binding Panel: A Henderson-Hasselbalch Approach to Neonatal Hyperbilirubinemia.

Pediatrics. 2016 Sep 8;

Authors: Ahlfors CE

Abstract
Poor plasma bilirubin binding increases the risk of bilirubin neurotoxicity in newborns with hyperbilirubinemia. New laboratory tests may soon make it possible to obtain a complete bilirubin binding panel when evaluating these babies. The 3 measured components of the panel are the plasma total bilirubin concentration (BTotal), which is currently used to guide clinical care; the bilirubin binding capacity (BBC); and the concentration of non-albumin bound or free bilirubin (BFree). The fourth component is the bilirubin-albumin equilibrium dissociation constant, KD, which is calculated from BTotal, BBC, and BFree The bilirubin binding panel is comparable to the panel of components used in the Henderson-Hasselbalch approach to acid-base assessment. Bilirubin binding population parameters (not prospective studies to determine whether the new bilirubin binding panel components are better predictors of bilirubin neurotoxicity than BTotal) are needed to expedite the clinical use of bilirubin binding. At any BTotal, the BFree and the relative risk of bilirubin neurotoxicity increase as the KD/BBC ratio increases (ie, bilirubin binding worsens). Comparing the KD/BBC ratio of newborns with BTotal of concern with that typical for the population helps determine whether the risk of bilirubin neurotoxicity varies significantly from the inherent risk at that BTotal Furthermore, the bilirubin binding panel individualizes care because it helps to determine how aggressive intervention should be at any BTotal, irrespective of whether it is above or below established BTotal guidelines. The bilirubin binding panel may reduce anxiety, costs, unnecessary treatment, and the likelihood of undetected bilirubin neurotoxicity.

PMID: 27609825 [PubMed - as supplied by publisher]

Disparities in Liver Transplantation resulting from Variations in Regional Donor Supply and Multiple Listing Practices.

Clin Gastroenterol Hepatol. 2016 Sep 5;

Authors: Cholankeril G, Yoo ER, Perumpail RB, Younossi ZM, Ahmed A

PMID: 27609705 [PubMed - as supplied by publisher]

Fractional Flow Reserve in Acute Coronary Syndromes.

J Am Coll Cardiol. 2016 Sep 13;68(11):1192-4

Authors: Fearon WF, De Bruyne B, Pijls NH

PMID: 27609681 [PubMed - in process]

Differential activation of vasotocin neurons in contexts that elicit aggression and courtship.

Behav Brain Res. 2016 Sep 5;

Authors: Loveland JL, Fernald RD

Abstract
Despite continued study on the neurobiological bases of aggressive and sexual behaviors, it is still not well understood how the brain integrates social information with physiological and neural states to produce context-specific behavioral outcomes. In fishes, manipulation of endogenous levels of arginine vasotocin (AVT) through peripheral and intracerebroventricular pharmacological injections results in significant changes in social behaviors, including aggressive and reproduction-related behaviors. In addition, many features of AVT neurons have been shown to correlate with social status and associated behavioral phenotypes. In this study, we used the immediate early gene egr-1 as a marker for neuronal activity and quantified the number of AVT neurons that were positive for egr-1 mRNA by in situ hybridization in Astatotilapia burtoni males that were exposed to either a social context that would elicit aggression or to one that would elicit courtship. In these social settings, focal males readily displayed context-appropriate bouts of aggression (towards the opponent) or bouts of courting (towards females). We found that males that fought had higher levels of egr-1 expression in the POA compared to courting males. A greater proportion of AVT cells was positive for egr-1 after a fight than after a bout of courting. We mapped mRNA distribution of AVT V1a receptor subtypes v1a1 and v1a2 in the brain and identified overlapping areas of expression in nuclei in the ventral telencephalon, hypothalamus and thalamus as key areas for AVT signaling in males.

PMID: 27609648 [PubMed - as supplied by publisher]

Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms.

J Neuroinflammation. 2016;13(1):241

Authors: Xiong X, Gu L, Wang Y, Luo Y, Zhang H, Lee J, Krams S, Zhu S, Zhao H

Abstract
BACKGROUND: Glycyrrhizin (Gly) protects against brain injury induced by stroke. We studied whether Gly achieves its protection by inhibiting T cell activity and high-mobility group box 1 (HMGB1) release in the ischemic brain.
METHODS: Stroke was induced by transient middle cerebral artery occlusion in rats and mice. Gly was injected intraperitoneally before or after stroke. We measured infarction, neuroinflammatory cells, gene expressions of interferon-γ (IFNγ), IL-4, and IL-10 in CD4 T cells, HMGB1 release, and T cell proliferation in cultured splenocytes.
RESULTS: Gly treatment reduced infarctions and neuroinflammation characterized by the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils, which corresponds to a reduction in the number of T cells and their subsets, CD4 and CD8 T cells, in the ischemic brain, as measured by flow cytometry. Unlike in wild-type animals, Gly did not offer protection in nude rats and severe combined immunodeficient (SCID) mice who had no T cells, while Gly reduced infarction in both nude rats and SCID mice whose T cells were reconstituted, suggesting that T cells should be the target of Gly. In addition, Gly administration inhibited T cell proliferation stimulated by ConA in in vitro assays and inhibited HMGB1 release from the ischemic brain. Furthermore, Gly attenuated gene expression of IFNγ, but not IL-4 and IL-10 in CD4 T cells. Lastly, HMGB1 promoted T cell proliferation stimulated by ConA, which was inhibited by the addition of Gly.
CONCLUSIONS: Gly blocks infarction by inhibiting IFNγ-mediated T cell activity, which is at least partly modulated by HMGB1 activity.

PMID: 27609334 [PubMed - in process]

Genetic background modulates outcome of therapeutic amyloid peptides in treatment of neuroinflammation.

J Neuroimmunol. 2016 Sep 15;298:42-50

Authors: Kraus A, Race B, Phillips K, Winkler C, Saturday G, Kurnellas M, Rothbard JB, Groveman BR, Steinman L, Caughey B

Abstract
Amyloid hexapeptide molecules are effective in the treatment of the murine model of neuroinflammation, known as experimental autoimmune encephalomyelitis (EAE). Efficacy however differs between two inbred mouse strains, C57BL/6J (B6) and C57BL/10SnJ (B10). Amyloid hexapeptide treatments improved the clinical outcomes of B6, but not B10 mice, indicating that genetic background influences therapeutic efficacy. Moreover, although previous studies indicated that prion protein deficiency results in more severe EAE in B6 mice, we observed no such effect in B10 mice. In addition, we found that amyloid hexapeptide treatments of B10 and B6 mice elicited differential IL4 responses. Thus, the modulatory potential of prion protein and related treatments with other amyloid hexapeptides in EAE depends on mouse strain.

PMID: 27609274 [PubMed - in process]

Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood.

Am J Psychiatry. 2016 Sep 9;:appiajp201616040454

Authors: Bergink V, Rasgon N, Wisner KL

Abstract
OBJECTIVE: Psychosis or mania after childbirth is a psychiatric emergency with risk for suicide and infanticide.
METHOD: The authors reviewed the epidemiologic and genetic research and physiological postpartum triggers (endocrine, immunological, circadian) of psychosis. They also summarized all systematic reviews and synthesized the sparse clinical studies to provide diagnostic recommendations, treatment options, and strategies for prevention.
RESULTS: The incidence of first-lifetime onset postpartum psychosis/mania from population-based register studies of psychiatric admissions varies from 0.25 to 0.6 per 1,000 births. After an incipient episode, 20%-50% of women have isolated postpartum psychosis. The remaining women have episodes outside the perinatal period, usually within the bipolar spectrum. Presumably, the mechanism of onset is related to physiological changes after birth (e.g., hormonal, immunological, circadian), which precipitate disease in genetically vulnerable women. Some women have treatable causes and comorbidities, such as autoimmune thyroiditis or infections. N-methyl-d-aspartate-encephalitis or inborn errors of metabolism may present after birth with psychosis. Fewer than 30 publications have focused on the treatment of postpartum psychosis. The largest study (N=64) provided evidence that lithium is highly efficacious for both acute and maintenance treatment. Another report (N=34) described successful ECT treatment. Inpatient care is usually required to ensure safety, complete the diagnostic evaluation, and initiate treatment. The relapse risk after a subsequent pregnancy for women with isolated postpartum psychoses is 31% (95% CI=22-42). Strategies for prevention of postpartum psychosis include lithium prophylaxis immediately postpartum and proactive safety monitoring.
CONCLUSIONS: Postpartum psychosis offers an intriguing model to explore etiologic contributions to the neurobiology of affective psychosis.

PMID: 27609245 [PubMed - as supplied by publisher]

Exosomal proteome analysis of cerebrospinal fluid detects biosignatures of neuromyelitis optica and multiple sclerosis.

Clin Chim Acta. 2016 Sep 5;

Authors: Lee J, McKinney KQ, Pavlopoulos AJ, Han MH, Kim SH, Kim HJ, Hwang S

Abstract
Quantitative proteomic analysis of exosomes isolated from cerebrospinal fluid (CSF) of neuromyelitis optica (NMO) patients detected signature proteins differentiating NMO from multiple sclerosis (MS) and idiopathic longitudinally extensive transverse myelitis.Exosomes with good yields were obtained using ultracentrifugation from pooled CSF assisted by chemokine-based clustering strategy, which improved target molecule identification by providing amplified fold change values.442 significant proteins generated a list of signature molecules of diseases validated primarily by the identification of known markers such as glial fibrillary acidic protein (GFAP) and fibronectin specific to NMO and MS respectively.MetaCore pathway analysis of significant proteins supported the involvement of these proteins in disease progression via neurological pathway.Expression levels of target molecules from orthogonal label-free quantification employing quadrupole-Orbitrap hybrid mass spectrometry were in good agreement with those from Western blotting.Additional investigation of GFAP and fibronectin as representative disease molecules revealed their presence in intact exosomes as detected by flow cytometry.This comprehensive study suggests that the exosomal proteomic analysis of CSF can be applied to the identification and characterization of inflammatory disorders of the central nervous system.

PMID: 27609124 [PubMed - as supplied by publisher]

Generation of Functional Cardiomyocytes from the Synoviocytes of Patients with Rheumatoid Arthritis via Induced Pluripotent Stem Cells.

Sci Rep. 2016;6:32669

Authors: Lee J, Jung SM, Ebert AD, Wu H, Diecke S, Kim Y, Yi H, Park SH, Ju JH

Abstract
Cardiovascular disease is a leading cause of morbidity in rheumatoid arthritis (RA) patients. This study aimed to generate and characterise cardiomyocytes from induced pluripotent stem cells (iPSCs) of RA patients. Fibroblast-like synoviocytes (FLSs) from patients with RA and osteoarthritis (OA) were successfully reprogrammed into RA-iPSCs and OA-iPSCs, respectively. The pluripotency of iPSCs was confirmed by quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining. Established iPSCs were differentiated into cardiomyocytes using a small molecule-based monolayer differentiation protocol. Within 12 days of cardiac differentiation from patient-specific and control-iPSCs, spontaneously beating cardiomyocytes (iPSC-CMs) were observed. All iPSC-CMs exhibited a reliable sarcomeric structure stained with antibodies against cardiac markers and similar expression profiles of cardiac-specific genes. Intracellular calcium signalling was recorded to compare calcium-handling properties among cardiomyocytes differentiated from the three groups of iPSCs. RA-iPSC-CMs had a lower amplitude and a shorter duration of calcium transients than the control groups. Peak tangential stress and the maximum contractile rate were also decreased in RA-iPSC-CMs, suggesting that contractility was reduced. This study demonstrates the successful generation of functional cardiomyocytes from pathogenic synovial cells in RA patients through iPSC reprogramming. Research using RA-iPSC-CMs might provide an opportunity to investigate the pathophysiology of cardiac involvement in RA.

PMID: 27609119 [PubMed - in process]

Development of a Mobile Tool That Semiautomatically Screens Patients for Stroke Clinical Trials.

Stroke. 2016 Sep 8;

Authors: Spokoyny I, Lansberg M, Thiessen R, Kemp SM, Aksoy D, Lee Y, Mlynash M, Hirsch KG

Abstract
BACKGROUND AND PURPOSE: Despite several national coordinated research networks, enrollment in many cerebrovascular trials remains challenging. An electronic tool was needed that would improve the efficiency and efficacy of screening for multiple simultaneous acute clinical stroke trials by automating the evaluation of inclusion and exclusion criteria, improving screening procedures and streamlining the communication process between the stroke research coordinators and the stroke clinicians.
METHODS: A multidisciplinary group consisting of physicians, study coordinators, and biostatisticians designed and developed an electronic clinical trial screening tool on a HIPAA (Health Insurance Portability and Accountability Act)-compliant platform.
RESULTS: A web-based tool was developed that uses branch logic to determine eligibility for simultaneously enrolling clinical trials and automatically notifies the study coordinator teams about eligible patients. After 12 weeks of use, 225 surveys were completed, and 51 patients were enrolled in acute stroke clinical trials. Compared with the 12 weeks before implementation of the tool, there was an increase in enrollment from 16.5% of patients screened to 23.4% of patients screened (P<0.05). Clinicians and coordinators reported increased satisfaction with the process and improved ease of screening.
CONCLUSIONS: We created a semiautomated electronic screening tool that uses branch logic to screen patients for stroke clinical trials. The tool has improved efficiency and efficacy of screening, and it could be adapted for use at other sites and in other medical fields.

PMID: 27608822 [PubMed - as supplied by publisher]

Nutritional Deficiencies, the Absence of Information and Caregiver Shortcomings: A Qualitative Analysis of Infant Feeding Practices in Rural China.

PLoS One. 2016;11(4):e0153385

Authors: Yue A, Marsh L, Zhou H, Medina A, Luo R, Shi Y, Zhang L, Kenny K, Rozelle S

Abstract
BACKGROUND AND OBJECTIVES: Development during the first two years of life is critical and has a lasting impact on a child's health. Poor infant and child nutrition can lead to deficiencies in essential micronutrients, which may cause a weakened immune system and lasting effects on children's growth and development. Recent studies in rural Shaanxi Province found an anemia prevalence of 54.3% among rural children aged six to twelve months. While new large-scale, quantitative research has begun to catalogue the extent of child malnutrition and anemia, no effort has yet been made to look more closely at the potential reasons for rural children's nutritional deficiencies through qualitative analysis. This study aims to elucidate some of the fundamental causes of poor complementary feeding practices that may lead to anemia among children in rural Shaanxi Province, China.
METHODOLOGY: We interviewed sixty caregivers participating in a large survey on child health and nutrition. We conducted three waves of interviews with children's primary caregivers in seventeen rural villages within four nationally-designated poverty counties in the southern part of Shaanxi Province.
RESULTS: The qualitative analysis reveals that poor complementary feeding practices are common across our sample. Information gathered from our interviews suggests that complementary feeding practices are impeded by two constraints: absence of understanding topics related to infant health and nutrition under caregivers, as well as inadequate sources of information on these topics. Poverty does not appear to constrain child feeding practices.
CONCLUSION: Our results uncover lack of proper knowledge on infant and child nutrition among rural caregivers in China. This situation causes them to fail incorporating micronutrient rich foods in their children's diet. Age-appropriate complementary feeding can stimulate children's physical and cognitive development, but in its absence it leads to iron-deficiency anemia. We suggest that steps be taken to educate caregivers to improve complementary feeding of their infants and children.

PMID: 27073864 [PubMed - indexed for MEDLINE]

Perfusion Computed Tomography for the Evaluation of Acute Ischemic Stroke: Strengths and Pitfalls.

Stroke. 2016 Apr;47(4):1153-8

Authors: Heit JJ, Wintermark M

PMID: 26965849 [PubMed - indexed for MEDLINE]

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke: Motor and Cognitive Assessments.

Stroke. 2016 Apr;47(4):1109-16

Authors: McEntire CR, Choudhury GR, Torres A, Steinberg GK, Redmond DE, Daadi MM

Abstract
BACKGROUND AND PURPOSE: Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements.
METHODS: Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery. Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct.
RESULTS: The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results suggest that this species has less collateralization, which closely resembles humans.
CONCLUSIONS: The reported nonhuman primate model produces a defined and reproducible syndrome relevant to our understanding of ischemic stroke, cortical representation, and sensorimotor integration controlling dexterous movements. This model will be useful in basic and translational research addressing loss of arm function and dexterity.

PMID: 26956259 [PubMed - indexed for MEDLINE]

Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty.

Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3353-8

Authors: Zhou X, Zhu D, King SG, Lees CJ, Bennett AJ, Salinas E, Stanford TR, Constantinidis C

Abstract
Executive functions including behavioral response inhibition mature after puberty, in tandem with structural changes in the prefrontal cortex. Little is known about how activity of prefrontal neurons relates to this profound cognitive development. To examine this, we tracked neuronal responses of the prefrontal cortex in monkeys as they transitioned from puberty into adulthood and compared activity at different developmental stages. Performance of the antisaccade task greatly improved in this period. Among neural mechanisms that could facilitate it, reduction of stimulus-driven activity, increased saccadic activity, or enhanced representation of the opposing goal location, only the latter was evident in adulthood. Greatly accentuated in adults, this neural correlate of vector inversion may be a prerequisite to the formation of a motor plan to look away from the stimulus. Our results suggest that the prefrontal mechanisms that underlie mature performance on the antisaccade task are more strongly associated with forming an alternative plan of action than with suppressing the neural impact of the prepotent stimulus.

PMID: 26951656 [PubMed - indexed for MEDLINE]

Characterizing Cathepsin Activity and Macrophage Subtypes in Excised Human Carotid Plaques.

Stroke. 2016 Apr;47(4):1101-8

Authors: Abd-Elrahman I, Meir K, Kosuge H, Ben-Nun Y, Weiss Sadan T, Rubinstein C, Samet Y, McConnell MV, Blum G

Abstract
BACKGROUND AND PURPOSE: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo.
METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes.
RESULTS: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU).
CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease.

PMID: 26941255 [PubMed - indexed for MEDLINE]

Association Between Time From Stroke Onset and Fluid-Attenuated Inversion Recovery Lesion Intensity Is Modified by Status of Collateral Circulation.

Stroke. 2016 Apr;47(4):1018-22

Authors: Wouters A, Dupont P, Christensen S, Norrving B, Laage R, Thomalla G, Albers G, Thijs V, Lemmens R

Abstract
BACKGROUND AND PURPOSE: In patients with acute stroke, the intensity of a fluid-attenuated inversion recovery (FLAIR) lesion in the region of diffusion restriction is associated with time from symptom onset. We hypothesized that collateral status as assessed by the hypoperfusion intensity ratio could modify the association between time from stroke onset and FLAIR lesion intensity.
METHODS: From the AX200 for ischemic stroke trial, 141 patients had appropriate FLAIR, diffusion-weighted imaging, and perfusion-weighted imaging. In the region of nonreperfused core, we calculated voxel-based relative FLAIR (rFLAIR) signal intensity. The hypoperfusion intensity ratio was defined as the ratio of the Tmax >10 s lesion over the Tmax >6 s lesion volume. A hypoperfusion intensity ratio threshold of ≤0.4 was used to dichotomize good versus poor collaterals. We studied the interaction between collateral status on the association between time from symptom onset and FLAIR intensity.
RESULTS: Time from symptom onset was associated with the rFLAIR intensity in the region of nonreperfused core (B=1.05; 95% confidence interval, 1.0-1.1). We identified an interaction between this association and collateral status; an association was present between time and rFLAIR intensity in patients with poor collaterals (r=0.53), but absent in patients with good collaterals (r=0.17; P=0.04).
CONCLUSIONS: Our findings show that the relationship between time from symptom onset and rFLAIR lesion intensity depends on collateral status. In patients with good collaterals, the development of an rFLAIR-positive lesion is less dependent on time from symptom onset compared with patients with poor collaterals.

PMID: 26917566 [PubMed - indexed for MEDLINE]

Intrinsic differences between males and females determine sex-specific consequences of inbreeding.

BMC Evol Biol. 2016;16:36

Authors: Ebel ER, Phillips PC

Abstract
BACKGROUND: Inbreeding increases homozygosity and exposes deleterious recessive alleles, generally decreasing the fitness of inbred individuals. Interestingly, males and females are usually affected differently by inbreeding, though the more vulnerable sex depends on the species and trait measured.
RESULTS: We used the soil-dwelling nematode Caenorhabditis remanei to examine sex-specific inbreeding depression across nine lineages, five levels of inbreeding, and hundreds of thousands of progeny. Female nematodes consistently suffered greater fitness losses than their male counterparts, especially at high levels of inbreeding.
CONCLUSIONS: These results suggest that females experience stronger selection on genes contributing to reproductive traits. Inbreeding depression in males may be further reduced by sex chromosome hemizygosity, which affects the dominance of some mutations, as well as by the absence of sexual selection. Determining the relative contributions of sex-specific expression, genes on the sex chromosomes, and the environment they are filtered through-including opportunities for sexual selection-may explain the frequent though inconsistent records of sex differences in inbreeding depression, along with their implications for conservation and the evolution of mating systems.

PMID: 26860745 [PubMed - indexed for MEDLINE]

In Vivo Reprogramming for Brain and Spinal Cord Repair.

eNeuro. 2015 Sep-Oct;2(5)

Authors: Chen G, Wernig M, Berninger B, Nakafuku M, Parmar M, Zhang CL

Abstract
Cell reprogramming technologies have enabled the generation of various specific cell types including neurons from readily accessible patient cells, such as skin fibroblasts, providing an intriguing novel cell source for autologous cell transplantation. However, cell transplantation faces several difficult hurdles such as cell production and purification, long-term survival, and functional integration after transplantation. Recently, in vivo reprogramming, which makes use of endogenous cells for regeneration purpose, emerged as a new approach to circumvent cell transplantation. There has been evidence for in vivo reprogramming in the mouse pancreas, heart, and brain and spinal cord with various degrees of success. This mini review summarizes the latest developments presented in the first symposium on in vivo reprogramming glial cells into functional neurons in the brain and spinal cord, held at the 2014 annual meeting of the Society for Neuroscience in Washington, DC.

PMID: 26730402 [PubMed - indexed for MEDLINE]

Finesse of transparent tissue cutting by ultrafast lasers at various wavelengths.

J Biomed Opt. 2015;20(12):125004

Authors: Wang J, Schuele G, Palanker D

Abstract
Transparent ocular tissues, such as the cornea and crystalline lens, can be ablated or dissected using short-pulse lasers. In refractive and cataract surgeries, the cornea, lens, and lens capsule can be cut by producing dielectric breakdown in the focus of a near-infrared (IR) femtosecond laser, which results in explosive vaporization of the interstitial water, causing mechanical rupture of the surrounding tissue. Here, we compare the texture of edges of lens capsule cut by femtosecond lasers with IR and ultraviolet (UV) wavelengths and explore differences in interactions of these lasers with biological molecules. Scanning electron microscopy indicates that a 400-nm laser is capable of producing very smooth cut edges compared to 800 or 1030 nm at a similar focusing angle. Using gel electrophoresis and liquid chromatography/mass spectrometry, we observe laser-induced nonlinear breakdown of proteins and polypeptides by 400-nm femtosecond pulses above and below the dielectric breakdown threshold. On the other hand, 800-nm femtosecond lasers do not produce significant dissociation even above the threshold of dielectric breakdown. However, despite this additional interaction of UV femtosecond laser with proteins, we determine that efficient cutting requires plasma-mediated bubble formation and that remarkably smooth edges are the result of reduced thresholds and smaller focal volume.

PMID: 26720869 [PubMed - indexed for MEDLINE]

Do CSF Biomarkers Predict Progression to Cognitive Impairment in Parkinson's disease patients? A Systematic Review.

Neuropsychol Rev. 2015 Dec;25(4):411-23

Authors: Leaver K, Poston KL

Abstract
Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as α-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious.

PMID: 26626621 [PubMed - indexed for MEDLINE]

Manipulation of host plant cells and tissues by gall-inducing insects and adaptive strategies used by different feeding guilds.

J Insect Physiol. 2016 Jan;84:103-13

Authors: Oliveira DC, Isaias RM, Fernandes GW, Ferreira BG, Carneiro RG, Fuzaro L

Abstract
Biologists who study insect-induced plant galls are faced with the overwhelming diversity of plant forms and insect species. A challenge is to find common themes amidst this diversity. We discuss common themes that have emerged from our cytological and histochemical studies of diverse neotropical insect-induced galls. Gall initiation begins with recognition of reactive plant tissues by gall inducers, with subsequent feeding and/or oviposition triggering a cascade of events. Besides, to induce the gall structure insects have to synchronize their life cycle with plant host phenology. We predict that reactive oxygen species (ROS) play a role in gall induction, development and histochemical gradient formation. Controlled levels of ROS mediate the accumulation of (poly)phenols, and phytohormones (such as auxin) at gall sites, which contributes to the new cell developmental pathways and biochemical alterations that lead to gall formation. The classical idea of an insect-induced gall is a chamber lined with a nutritive tissue that is occupied by an insect that directly harvests nutrients from nutritive cells via its mouthparts, which function mechanically and/or as a delivery system for salivary secretions. By studying diverse gall-inducing insects we have discovered that insects with needle-like sucking mouthparts may also induce a nutritive tissue, whose nutrients are indirectly harvested as the gall-inducing insects feeds on adjacent vascular tissues. Activity of carbohydrate-related enzymes across diverse galls corroborates this hypothesis. Our research points to the importance of cytological and histochemical studies for elucidating mechanisms of induced susceptibility and induced resistance.

PMID: 26620152 [PubMed - indexed for MEDLINE]

Responsive Direct Brain Stimulation for Epilepsy.

Neurosurg Clin N Am. 2016 Jan;27(1):111-21

Authors: Morrell MJ, Halpern C

Abstract
Closed-loop, responsive focal brain stimulation provides a new treatment option for patients with refractory partial onset seizures who are not good candidates for potentially curative epilepsy surgery. The first responsive brain neurostimulator (RNS® System, NeuroPace), provides stimulation directly to the seizure focus when abnormal electrocorticographic is detected. Seizure reductions of 44% at one year increase to 60 to 66% at years 3 to 6 of treatment. There is no negative impact on cognition and mood. Risks are similar to other implanted medical devices and therapeutic stimulation is not perceived.

PMID: 26615113 [PubMed - indexed for MEDLINE]

High Frequency Deep Brain Stimulation and Neural Rhythms in Parkinson's Disease.

Neuropsychol Rev. 2015 Dec;25(4):384-97

Authors: Blumenfeld Z, Brontë-Stewart H

Abstract
High frequency (HF) deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD). It effectively treats the cardinal motor signs of PD, including tremor, bradykinesia, and rigidity. The most common neural target is the subthalamic nucleus, located within the basal ganglia, the region most acutely affected by PD pathology. Using chronically-implanted DBS electrodes, researchers have been able to record underlying neural rhythms from several nodes in the PD network as well as perturb it using DBS to measure the ensuing neural and behavioral effects, both acutely and over time. In this review, we provide an overview of the PD neural network, focusing on the pathophysiological signals that have been recorded from PD patients as well as the mechanisms underlying the therapeutic benefits of HF DBS. We then discuss evidence for the relationship between specific neural oscillations and symptoms of PD, including the aberrant relationships potentially underlying functional connectivity in PD as well as the use of different frequencies of stimulation to more specifically target certain symptoms. Finally, we briefly describe several current areas of investigation and how the ability to record neural data in ecologically-valid settings may allow researchers to explore the relationship between brain and behavior in an unprecedented manner, culminating in the future automation of neurostimulation therapy for the treatment of a variety of neuropsychiatric diseases.

PMID: 26608605 [PubMed - indexed for MEDLINE]

Editorial Comments to the Special Issue of Neuropsychology Review on the Basic Neuroscience and Neuropsychology of Selective Movement Disorders.

Neuropsychol Rev. 2015 Dec;25(4):369-70

Authors: Schulte T, Brontë-Stewart H

PMID: 26590835 [PubMed - indexed for MEDLINE]

Aging with HIV-1 Infection: Motor Functions, Cognition, and Attention--A Comparison with Parkinson's Disease.

Neuropsychol Rev. 2015 Dec;25(4):424-38

Authors: DeVaughn S, Müller-Oehring EM, Markey B, Brontë-Stewart HM, Schulte T

Abstract
Recent advances in highly active anti-retroviral therapy (HAART) in their various combinations have dramatically increased the life expectancies of HIV-infected persons. People diagnosed with HIV are living beyond the age of 50 but are experiencing the cumulative effects of HIV infection and aging on brain function. In HIV-infected aging individuals, the potential synergy between immunosenescence and HIV viral loads increases susceptibility to HIV-related brain injury and functional brain network degradation similar to that seen in Parkinson's disease (PD), the second most common neurodegenerative disorder in the aging population. Although there are clear diagnostic differences in the primary pathology of both diseases, i.e., death of dopamine-generating cells in the substantia nigra in PD and neuroinflammation in HIV, neurotoxicity to dopaminergic terminals in the basal ganglia (BG) has been implied in the pathogenesis of HIV and neuroinflammation in the pathogenesis of PD. Similar to PD, HIV infection affects structures of the BG, which are part of interconnected circuits including mesocorticolimbic pathways linking brainstem nuclei to BG and cortices subserving attention, cognitive control, and motor functions. The present review discusses the combined effects of aging and neuroinflammation in HIV individuals on cognition and motor function in comparison with age-related neurodegenerative processes in PD. Despite the many challenges, some HIV patients manage to age successfully, most likely by redistribution of neural network resources to enhance function, as occurs in healthy elderly; such compensation could be curtailed by emerging PD.

PMID: 26577508 [PubMed - indexed for MEDLINE]

New Diseases and New Treatments--Head and Neck Cancer Updates.

Hematol Oncol Clin North Am. 2015 Dec;29(6):xiii-xiv

Authors: Colevas AD

PMID: 26568555 [PubMed - indexed for MEDLINE]

Transoral Endoscopic Head and Neck Surgery: The Contemporary Treatment of Head and Neck Cancer.

Hematol Oncol Clin North Am. 2015 Dec;29(6):1075-92

Authors: Lim GC, Holsinger FC, Li RJ

Abstract
Traditional open surgical approaches are indicated for treatment of select tumor subsites of head and neck cancer, but can also result in major cosmetic and functional morbidity. Transoral surgical approaches have been used for head and neck cancer since the 1960s, with their application continuing to evolve with the changing landscape of this disease and recent innovations in surgical instrumentation. The potential to further reduce treatment morbidity with transoral surgery, while optimizing oncologic outcomes, continues to be investigated. This review examines current literature evaluating oncologic and quality-of-life outcomes achieved through transoral head and neck surgery.

PMID: 26568549 [PubMed - indexed for MEDLINE]

Immunotherapy for Head and Neck Squamous Cell Carcinoma.

Hematol Oncol Clin North Am. 2015 Dec;29(6):1033-43

Authors: Schoppy DW, Sunwoo JB

Abstract
Although head and neck squamous cell carcinoma has traditionally been considered to be a very immunosuppressive, or at least nonimmunogenic, tumor type, recent results from clinical studies of immune checkpoint blockade strategies have led to resurgence in the enthusiasm for immunotherapeutic approaches. Additional strategies for immunotherapy that are under active investigation include enhancement of cetuximab-mediated antibody-dependent cell-mediated cytotoxicity, tumor vaccines, and engineered T cells for adoptive therapy. All of these studies have early-phase clinical trials under way, and the next several years will be exciting as the results of these studies are reported.

PMID: 26568546 [PubMed - indexed for MEDLINE]

Risk of breast cancer among patients with bioprosthetic or mechanical valve replacement: a population-based study in Sweden.

Breast Cancer Res Treat. 2015 Nov;154(2):369-75

Authors: Ji J, Zöller B, Giaccia A, Haile R, Sundquist J, Sundquist K

Abstract
The association between breast cancer and warfarin is inconclusive as most previous studies examined their association using patients with thromboembolism, whereas thromboembolism itself is a risk factor for cancer. We explored this issue using patients received mechanical heart valves replacement as a proxy for warfarin exposure as these patients need a lifelong warfarin treatment, and compared them with patients received bioprosthesis valves replacement (short-term warfarin treatment) in Sweden between 1987 and 2010. Patients who were operated on for valve replacement were identified from the Swedish Hospital Discharge Registry and linked to the Swedish Cancer Registry to examine the hazard ratios of subsequent breast cancer. A total of 12,242 women were operated on for valve replacement (5481 with mechanical valve and 6401 with bioprosthetic valve). For the entire cohort, the HR of breast cancer was 1.49 (95 % CI 1.09-2.02) among patients with mechanical valve replacement compared to those with bioprosthetic valve replacement. After controlling for a number of confounding factors using propensity score weighting, the HR was 1.69 (95 % CI 1.15-2.47). Our study found that patients with mechanical valve replacement have an increased risk of breast cancer compared to those with bioprosthetic valve replacement. If confirmed, this increased risk should be considered when recommending breast cancer screening for women with mechanical valve replacement. Long-term use of warfarin may explain the observed increase. If so, patients who have used warfarin long-term for other reasons should be studied for a possible increased risk of breast cancer.

PMID: 26476725 [PubMed - indexed for MEDLINE]

A Survey to Assess Perceived Differences in Referral Pathways to Board-Certified Pediatric Dermatologists.

Pediatr Dermatol. 2015 Nov-Dec;32(6):e314-315

Authors: Fogel AL, Teng JM

Abstract
This study surveyed all U.S. board-certified pediatric dermatologists to determine referral pathways to the specialty; we obtained a 48% (108/226) response rate. Significantly higher self-referral rates were found in private practice than in academic settings, and higher referral rates from specialist and generalist physicians were observed in academic practice. The substantial differences found in this preliminary study indicate that triage inefficiency may be occurring, and further study to investigate the causes for referral differences and their effect on clinical outcomes is needed.

PMID: 26446294 [PubMed - indexed for MEDLINE]

Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California.

Paediatr Perinat Epidemiol. 2015 Nov;29(6):536-45

Authors: Padula AM, Yang W, Carmichael SL, Tager IB, Lurmann F, Hammond SK, Shaw GM

Abstract
BACKGROUND: Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood.
METHODS: We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997-2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race-ethnicity, education, and multivitamin use.
RESULTS: We present below odds ratios (ORs) that exclude 1 and a chi-square test of homogeneity P-value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 μm (PM10 ) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods.
CONCLUSIONS: Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California.

PMID: 26443985 [PubMed - indexed for MEDLINE]

Pneumocystis jiroveci pneumonia (PCP) in patients receiving neoadjuvant and adjuvant anthracycline-based chemotherapy for breast cancer: incidence and risk factors.

Breast Cancer Res Treat. 2015 Nov;154(2):359-67

Authors: Waks AG, Tolaney SM, Galar A, Arnaout A, Porter JB, Marty FM, Winer EP, Hammond SP, Baden LR

Abstract
Opportunistic infection with Pneumocystis jiroveci pneumonia (PCP) has not been recognized as a significant complication of early-stage breast cancer treatment. However, we have observed an increase in PCP incidence among patients receiving chemotherapy for early-stage breast cancer. Herein we identify risk factors for and calculate incidence of PCP in this population. We identified all cases of PCP at Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) from 1/1/2000 to 12/31/2013 in patients with stage I-III breast cancer treated with an adriamycin/cyclophosphamide (AC)-containing regimen. Nineteen cases of PCP in non-metastatic breast cancer patients were identified. All patients with PCP were diagnosed after receipt of either three or four cycles of AC chemotherapy on a dose-dense schedule. Patients who developed PCP were treated with median 16.4 mg prednisone equivalents/day as nausea prophylaxis for a median 64 days. The overall incidence of PCP among 2057 patients treated with neoadjuvant or adjuvant dose-dense AC for three or more cycles was 0.6 % (95 % confidence interval 0.3-1.0 %). No PCP was diagnosed in 1001 patients treated with non-dose-dense AC. There was one death from PCP. Women receiving dose-dense AC chemotherapy for early-stage breast cancer are at risk for PCP. Administering the same chemotherapy and corticosteroid dose over an 8-week versus 12-week non-dose-dense schedule appears to have created a novel infectious vulnerability. Replacing dexamethasone with alternative anti-emetics may mitigate this risk.

PMID: 26420402 [PubMed - indexed for MEDLINE]

The U.S. Pediatric Dermatology Workforce: An Assessment of Productivity and Practice Patterns.

Pediatr Dermatol. 2015 Nov-Dec;32(6):825-9

Authors: Fogel AL, Teng JM

Abstract
BACKGROUND: Pediatric dermatology has always played an important role in children's healthcare, but there has been a shortage of pediatric dermatologists nationwide for more than a decade, and few metrics of productivity and practice patterns exist. This study sought to provide insight into these and other factors of the pediatric dermatology workforce.
METHODS: Electronic surveys were distributed to all 226 U.S. board-certified pediatric dermatologists.
RESULTS: A total of 108/226 (48%) of the electronic surveys were returned. Sixty percent of respondents were employed full- or part-time in academic environments and 81% were salaried. Respondents reported that children constituted 79.5% of their practice, and the average respondent spent 3.8 days/week treating 92.6 patients, considerably lower than the 136.3 patients/week that the average general dermatologist sees. The academic practice environment was associated with children constituting a larger proportion of the practice (p < 0.001), fewer patients seen per week (85.9, p < 0.001), and longer median new patient wait times (60 vs 15 days) than in other practice environments. Private practitioners saw significantly more patients per week than those in academic environments (112.7, p = 0.005). Male and female practitioners reported approximately equal patient care days per week, similar wait times, and similar proportions of children in their practices.
CONCLUSIONS: This assessment revealed productivity and practice pattern differences between the various pediatric dermatology practice environments and between pediatric and general dermatology. This study provides important information for workforce planning and care availability assessments and baseline information for future studies.

PMID: 26391633 [PubMed - indexed for MEDLINE]

Generalized motor inhibitory deficit in Parkinson's disease patients who freeze.

J Neural Transm (Vienna). 2015 Dec;122(12):1693-701

Authors: Bissett PG, Logan GD, van Wouwe NC, Tolleson CM, Phibbs FT, Claassen DO, Wylie SA

Abstract
Freezing of gait is a disabling symptom of Parkinson's disease (PD) that involves failure to initiate and continue motor activity appropriately. PD disrupts fronto-basal ganglia circuitries that also implement the inhibition of responses, leading to the hypothesis that freezing of gait may involve fundamental changes in both initiation and inhibition of motor actions. We asked whether PD patients who show freezing of gait show selective deficits in their ability to inhibit upper and lower extremity reactions. We compared older healthy controls, older PD controls without freezing of gait, and older PD participants with freezing of gait, in stop-signal tasks that measured the initiation (go trials) and inhibition (stop trials) of both hand and foot responses. When only go trials were presented, all three groups showed similar initiation speeds across lower and upper extremity responses. When stop-signal trials were introduced, both PD groups slowed their reactions nearly twice as much as healthy controls. While this adjustment helped PD controls stop their actions as quickly as healthy controls, PD patients with freezing showed significantly delayed inhibitory control of both upper and lower extremities. When anticipating the need to stop their actions urgently, PD patients show greater adjustments (i.e., slowing) to reaction speed than healthy controls. Despite these proactive adjustments, PD patients who freeze show marked impairments in inhibiting both upper and lower extremity responses, suggesting that freezing may involve a fundamental disruption to the brain's inhibitory control system.

PMID: 26354102 [PubMed - indexed for MEDLINE]

Multigenerational Positive Family History of Psychiatric Disorders Is Associated With a Poor Prognosis in Bipolar Disorder.

J Neuropsychiatry Clin Neurosci. 2015;27(4):304-10

Authors: Post RM, Altshuler L, Kupka R, McElroy SL, Frye MA, Rowe M, Grunze H, Suppes T, Keck PE, Leverich GS, Nolen WA

Abstract
The authors assessed how family history loading affected the course of illness in patients from the United States. A total of 676 outpatients with bipolar disorder from the United States rated their illness and provided a parental and grandparental history of mood disorder, substance abuse, and other clinical conditions. A positive family history for each illness was associated with almost all of the seven poor prognosis factors established in the study (abuse in childhood, early onset, anxiety and substance abuse comorbidity, rapid cycling, multiple episodes, and worsening of severity or frequency of episodes). Family history for psychiatric difficulties in parents and grandparents was associated with a more complex and difficult course of bipolar illness.

PMID: 26258489 [PubMed - indexed for MEDLINE]

Clinical Features of Lysosomal Acid Lipase Deficiency.

J Pediatr Gastroenterol Nutr. 2015 Dec;61(6):619-25

Authors: Burton BK, Deegan PB, Enns GM, Guardamagna O, Horslen S, Hovingh GK, Lobritto SJ, Malinova V, McLin VA, Raiman J, Di Rocco M, Santra S, Sharma R, Sykut-Cegielska J, Whitley CB, Eckert S, Valayannopoulos V, Quinn AG

Abstract
OBJECTIVE: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.
METHODS: Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.
RESULTS: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years).
CONCLUSION: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

PMID: 26252914 [PubMed - indexed for MEDLINE]

Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease.

Am J Geriatr Psychiatry. 2015 Nov;23(11):1127-33

Authors: Weintraub D, Drye LT, Porsteinsson AP, Rosenberg PB, Pollock BG, Devanand DP, Frangakis C, Ismail Z, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Rabins PV, Schneider LS, Shade DM, Yesavage J, Lyketsos CG, CitAD Research Group

Abstract
OBJECTIVE: Agitation is a common and significant problem in Alzheimer disease (AD). In the recent Citalopram for Agitation in Alzheimer's Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment.
METHODS: Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study Clinical Global Impression of Change (CGIC) score of 1 or 2 or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction ≥ 50% from baseline. "Stable early response" was defined as meeting the aforementioned criteria at both weeks 3 and 9, "late response" was response at week 9 but not at week 3, and "unstable response" was response at week 3 but not at week 9.
RESULTS: In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. Little between-group differences were found in response rates in the first 3 weeks of the study (21% versus 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% versus 8% on CGIC, Fisher's exact p = 0.09; 31% versus 15% on NBRS-A, Fisher's exact p = 0.02). Approximately half of citalopram responders (45%-56%) at end of study achieved response later in the study compared with 30%-44% of placebo responders.
CONCLUSION: Treatment with citalopram for agitation in AD needs to be at least 9 weeks in duration to allow sufficient time for full response. Study duration is an important factor to consider in the design of clinical trials for agitation in AD.

PMID: 26238225 [PubMed - indexed for MEDLINE]

Survival in systemic sclerosis-pulmonary arterial hypertension by serum autoantibody status in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry.

Semin Arthritis Rheum. 2015 Dec;45(3):309-14

Authors: Hinchcliff M, Khanna S, Hsu VM, Lee J, Almagor O, Chang RW, Steen V, Chung L, PHAROS Investigators

Abstract
OBJECTIVE: To determine the association between serum autoantibodies and survival in patients with incident systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry.
METHODS: Patients with definite PAH diagnosed by right heart catheterization within 6 months of registry enrollment were studied. Serum autoantibodies were assayed at each participating institution's clinical laboratory. Mortality data were collected from electronic medical records and/or the Social Security Death Index. Kaplan-Meier survival estimates were reported for five autoantibody groups (anticentromere/AC, nucleolar ANA/NUC, anti-topoisomerase/Scl-70, overlapping or non-specific autoantibodies/other, and a combined group with similar survival consisting of RNA polymerase III, U1RNP, and autoantibody-negative patients). Cox proportional hazards models permitted examination of the association between autoantibody groups and overall survival, controlling for age, sex, race, and SSc disease duration.
RESULTS: In all, 162 subjects had PAH, and serum autoantibody and survival information; 60 (37%) had AC, 39 (24%) NUC, 11 (7%) Scl-70, 28 (17%) had other, 9 (6%) RNA pol, 8 (5%) U1RNP autoantibodies, and 7 (4%) had negative antibodies; 32 (20%) subjects died over a median follow-up time of 2.1 years (range: 0.01-6.8); 1- and 3-year survival estimates were, respectively, 94% and 78% for AC, 94% and 72% for NUC, 89% and 63% for Scl-70, 92% and 79% for the other group, and 100% and 93% for the combined group. Unadjusted and adjusted hazard ratios revealed no statistically significant association between risk of death and autoantibodies.
CONCLUSION: Anticentromere and NUC autoantibodies are prevalent in SSc-PAH patients. An association between serum autoantibodies and survival in patients with SSc-PAH was not identified in the PHAROS cohort.

PMID: 26210782 [PubMed - indexed for MEDLINE]

Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease.

Am J Geriatr Psychiatry. 2015 Nov;23(11):1117-26

Authors: Wroolie TE, Kenna HA, Williams KE, Rasgon NL

Abstract
OBJECTIVE: Use of estrogen-based hormone therapy (HT) as a protection from cognitive decline and Alzheimer disease (AD) is controversial, although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17β-estradiol preferable to conjugated equine estrogen formulations. Little is known regarding specific populations of women who may derive benefit from HT.
METHODS: Women with heightened risk for AD (aged 49-69), all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset, underwent cognitive assessment followed by randomization to continue or discontinue HT. Assessments were repeated at 2 years after randomization.
RESULTS: Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention, working memory, and processing speed measures. Women who used 17β-estradiol versus conjugated equine estrogen, whether randomized to continue or discontinue HT, showed better verbal memory performance at the 2-year follow-up assessment. An interaction was also found with HT randomization and family history of AD in a first-degree relative. All female offspring of patients with AD declined in verbal memory; however, women who continued HT declined less than women who discontinued HT. Women without a first-degree relative with AD showed verbal memory improvement (likely because of practice effects) with continuance and declined with discontinuance of HT.
CONCLUSION: Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset.

PMID: 26209223 [PubMed - indexed for MEDLINE]

De novo production of the key branch point benzylisoquinoline alkaloid reticuline in yeast.

Metab Eng. 2015 Sep;31:74-83

Authors: Trenchard IJ, Siddiqui MS, Thodey K, Smolke CD

Abstract
Microbial biosynthesis for plant-based natural products, such as the benzylisoquinoline alkaloids (BIAs), has the potential to address limitations in plant-based supply of established drugs and make new molecules available for drug discovery. While yeast strains have been engineered to produce a variety of downstream BIAs including the opioids, these strains have relied on feeding an early BIA substrate. We describe the de novo synthesis of the major BIA branch point intermediate reticuline via norcoclaurine in Saccharomyces cerevisiae. Modifications were introduced into yeast central metabolism to increase supply of the BIA precursor tyrosine, allowing us to achieve a 60-fold increase in production of the early benzylisoquinoline scaffold from fed dopamine with no supply of exogenous tyrosine. Yeast strains further engineered to express a mammalian tyrosine hydroxylase, four mammalian tetrahydrobiopterin biosynthesis and recycling enzymes, and a bacterial DOPA decarboxylase produced norcoclaurine de novo. We further increased production of early benzylisoquinoline scaffolds by 160-fold through introducing mutant tyrosine hydroxylase enzymes, an optimized plant norcoclaurine synthase variant, and optimizing culture conditions. Finally, we incorporated five additional plant enzymes--three methyltransferases, a cytochrome P450, and its reductase partner--to achieve de novo production of the key branch point molecule reticuline with a titer of 19.2 μg/L. These strains and reconstructed pathways will serve as a platform for the biosynthesis of diverse natural and novel BIAs.

PMID: 26166409 [PubMed - indexed for MEDLINE]

Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale.

J Neuropsychiatry Clin Neurosci. 2015;27(4):365-70

Authors: Sher Y, Miller AC, Lolak S, Ament A, Maldonado JR

Abstract
Patients with delirium may fail to respond to standard therapies. Sixteen patients with management-refractory hyperactive delirium responded to adjunctive valproic acid, with complete resolution of hyperactive delirium in 13 cases. A rationale for using valproic acid in such circumstances is discussed.

PMID: 25803136 [PubMed - indexed for MEDLINE]

Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma.

Leuk Lymphoma. 2015;56(10):2847-54

Authors: Kim EJ, Kim YH, Rook AH, Lerner A, Duvic M, Reddy S, Robak T, Becker JC, Samtsov A, McCulloch W, Waksman J, Whittaker S

Abstract
Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.

PMID: 25791237 [PubMed - indexed for MEDLINE]

Management of adverse events associated with idelalisib treatment: expert panel opinion.

Leuk Lymphoma. 2015;56(10):2779-86

Authors: Coutré SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, Li D, O'Brien SM, Pagel JM, Poleski MH, Sharman JP, Yao NS, Zelenetz AD

Abstract
Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.

PMID: 25726955 [PubMed - indexed for MEDLINE]