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- Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.Sokolove J, Johnson DS, Lahey LJ, Wagner CA, Cheng D, Thiele GM, Michaud K, Sayles H, Reimold AM, Caplan L, Cannon GW, Kerr G, Mikuls TR, Robinson WHArthritis Rheumatol
- Systemic Lupus Prevalence in Sweden in 2010: What do national registers say?Simard JF, Sjöwall C, Rönnblom L, Jönsen A, Svenungsson EArthritis Care Res (Hoboken)
- Pattern-based Detection of Toxic Metals in Surface Water with DNA Polyfluorophores.Yuen LH, Franzini RM, Wang S, Crisalli P, Singh V, Jiang W, Kool ETAngew Chem Int Ed Engl
- Divergence in Age Patterns of Mortality Change Drives International Divergence in Lifespan Inequality.Gillespie DO, Trotter MV, Tuljapurkar SDDemography
- The Relationship of Health Aid to Population Health Improvements.Bendavid E, Bhattacharya JJAMA Intern Med
- Radiation-induced heart disease: an under-recognized entity?Davis M, Witteles RMCurr Treat Options Cardiovasc Med
- Modulation of STAT3 Folding and Function by TRiC/CCT Chaperonin.Kasembeli M, Lau WC, Roh SH, Eckols TK, Frydman J, Chiu W, Tweardy DJPLoS Biol
- Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY study.Wu HC, Wang Q, Chung WK, Andrulis IL, Daly MB, John EM, Keegan TH, Knight J, Bradbury AR, Kappil MA, Gurvich I, Santella RM, Terry MBEpigenetics
- Curcumin Treatment Attenuates Pain and Enhances Functional Recovery after Incision.Sahbaie P, Sun Y, Liang DY, Shi XY, Clark JDAnesth Analg
- High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor.St-Pierre F, Marshall JD, Yang Y, Gong Y, Schnitzer MJ, Lin MZNat Neurosci
- Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors.Gong Y, Wagner MJ, Zhong Li J, Schnitzer MJNat Commun
- On the fate of pumice rafts formed during the 2012 Havre submarine eruption.Jutzeler M, Marsh R, Carey RJ, White JD, Talling PJ, Karlstrom LNat Commun
- Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents.Wender PA, Fournogerakis DN, Jeffreys MS, Quiroz RV, Inagaki F, Pfaffenbach MNat Chem
- Trainee involvement in transforaminal epidural steroid injections associated with increased incidence of vasovagal reactions.Schneider B, Kennedy DJ, Casey E, Smuck M, Conrad B, Plastaras CPM R
- Gating of neural error signals during motor learning.Kimpo RR, Rinaldi JM, Kim CK, Payne HL, Raymond JLElife
- Complementary assessments of executive function in preterm and full-term preschoolers.Loe IM, Chatav M, Alduncin NChild Neuropsychol
- A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release.Tani H, Dulla CG, Farzampour Z, Taylor-Weiner A, Huguenard JR, Reimer RJNeuron
- The deleterious mutation load is insensitive to recent population history.Simons YB, Turchin MC, Pritchard JK, Sella GNat Genet
- Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis.Özkan E, Chia PH, Wang RR, Goriatcheva N, Borek D, Otwinowski Z, Walz T, Shen K, Garcia KCCell
- APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory.Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC, Deutsch GK, Wyss-Coray T, Rutt BKNeurology
- Respiratory-mode display of echocardiographic images highlights effects of pericardial disease.McConnell MV, Wu HHJACC Cardiovasc Imaging
- Prevention of mother-to-child transmission of hepatitis B virus: is elective cesarean section in highly viremic mothers an appropriate adjunct to immunoprophylaxis?Nguyen LH, Nguyen MHClin Gastroenterol Hepatol
- Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-¹³C]pyruvate.Park JM, Josan S, Grafendorfer T, Yen YF, Hurd RE, Spielman DM, Mayer DNMR Biomed
- Use and misuse of small bowel video capsule endoscopy in clinical practice.Gerson LBClin Gastroenterol Hepatol
Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.
Arthritis Rheumatol. 2014 Apr;66(4):813-21
Authors: Sokolove J, Johnson DS, Lahey LJ, Wagner CA, Cheng D, Thiele GM, Michaud K, Sayles H, Reimold AM, Caplan L, Cannon GW, Kerr G, Mikuls TR, Robinson WH
OBJECTIVE: The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation.
METHODS: In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation.
RESULTS: Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone).
CONCLUSION: The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.
PMID: 24757134 [PubMed - in process]
Systemic Lupus Prevalence in Sweden in 2010: What do national registers say?
Arthritis Care Res (Hoboken). 2014 Apr 22;
Authors: Simard JF, Sjöwall C, Rönnblom L, Jönsen A, Svenungsson E
Objective: Worldwide prevalence estimates of systemic lupus erythematosus (SLE) range from 3-207 per 100,000 depending on region and population, SLE definition, case sources and other methodological considerations. We aimed to determine the prevalence of SLE in Sweden on January 1, 2010 using population-based registers. Methods: Linking multiple national registers we identified all possible inpatient and outpatient visits with SLE-specific discharge diagnoses and relevant prescription dispensations among living individuals registered in Sweden on January 1, 2010. SLE was defined from a lenient classification (requiring only a single visit) to stricter definitions, which required multiple visits with a history of relevant specialist care and a dispensation for common SLE medications. Prevalence was calculated overall, and by sex, age (0-14, 15-49, 50+yrs, as well as in 5-year age groups), and county of residence. Result: Overall prevalence ranged from 46 per 100,000 for the strictest definition to 85 per 100,000 for the least strict definition. As expected, SLE was more common among females (ranged from 79 to 144/100,000) than males (12-25/100,000) and varied by age. The up to four-fold variation by county was unexpected. Prevalence generally increased with age (2, 52, and 95 per 100,000 by increasing age group, 0-14/15-49/50+, using a moderately strict definition) and also varied by county. Conclusion: Variations of prevalence by age and sex were consistent with previous studies and overall ranged from 46 to 85 per 100,000. We observed a surprising geographical variation in the prevalence of SLE in Sweden on January 1, 2010 according to multiple definitions. © 2014 American College of Rheumatology.
PMID: 24757083 [PubMed - as supplied by publisher]
Pattern-based Detection of Toxic Metals in Surface Water with DNA Polyfluorophores.
Angew Chem Int Ed Engl. 2014 Apr 22;
Authors: Yuen LH, Franzini RM, Wang S, Crisalli P, Singh V, Jiang W, Kool ET
Heavy metal contamination of water can be toxic to humans and wildlife; thus the development of methods to detect this contamination is of high importance. Here we describe the design and application of DNA-based fluorescent chemosensors on microbeads to differentiate eight toxic metal ions in water. We developed and synthesized four fluorescent 2'-deoxyribosides of metal-binding ligands. A tetramer-length oligodeoxy-fluoroside (ODF) library of 6561 members was constructed and screened for sequences responsive to metal ions, of which seven sequences were selected. Statistical analysis of the response patterns showed successful differentiation of the analytes at concentrations as low as 100 nM. Sensors were able to classify water samples from 13 varied sites and quantify metal contamination in unknown specimens. The results demonstrate the practical potential of bead-based ODF chemosensors to analyze heavy metal contamination in water samples by a simple and inexpensive optical method.
PMID: 24756982 [PubMed - as supplied by publisher]
Divergence in Age Patterns of Mortality Change Drives International Divergence in Lifespan Inequality.
Demography. 2014 Apr 23;
Authors: Gillespie DO, Trotter MV, Tuljapurkar SD
In the past six decades, lifespan inequality has varied greatly within and among countries even while life expectancy has continued to increase. How and why does mortality change generate this diversity? We derive a precise link between changes in age-specific mortality and lifespan inequality, measured as the variance of age at death. Key to this relationship is a young-old threshold age, below and above which mortality decline respectively decreases and increases lifespan inequality. First, we show for Sweden that shifts in the threshold's location have modified the correlation between changes in life expectancy and lifespan inequality over the last two centuries. Second, we analyze the post-World War II (WWII) trajectories of lifespan inequality in a set of developed countries-Japan, Canada, and the United States-where thresholds centered on retirement age. Our method reveals how divergence in the age pattern of mortality change drives international divergence in lifespan inequality. Most strikingly, early in the 1980s, mortality increases in young U.S. males led to a continuation of high lifespan inequality in the United States; in Canada, however, the decline of inequality continued. In general, our wider international comparisons show that mortality change varied most at young working ages after WWII, particularly for males. We conclude that if mortality continues to stagnate at young ages yet declines steadily at old ages, increases in lifespan inequality will become a common feature of future demographic change.
PMID: 24756909 [PubMed - as supplied by publisher]
The Relationship of Health Aid to Population Health Improvements.
JAMA Intern Med. 2014 Apr 21;
Authors: Bendavid E, Bhattacharya J
IMPORTANCE International aid to the health sector is an important component of all health spending in many developing countries. The relationship between health aid and changes in population health among aid recipients remains unknown. OBJECTIVE To quantify the relationship between health aid and changes in life expectancy and mortality in children younger than 5 years (under-5 mortality) among aid recipient nations. DESIGN Cross-country panel data analysis of the relationship between measures of health aid, life expectancy, and under-5 mortality. Using difference models for longitudinal data with fixed effects for countries and years, we estimated the unique relationship between health aid and changes in life expectancy and under-5 mortality, controlling for gross domestic product per capita, urbanization, and total fertility rate. SETTING AND PARTICIPANTS A total of 140 aid-recipient countries between 1974 and 2010. EXPOSURE Annual amount of development assistance directed to the health sector in constant 2010 US dollars. MAIN OUTCOMES AND MEASURES Improvements in under-5 mortality and life expectancy in the period following aid receipt. RESULTS Between 1974 and 2010, each 1% increase in health aid was associated with 0.24 months greater increase in life expectancy (95% CI, 0.02-0.46) (P = .03) and a 0.14 per 1000 live births faster decline in the probability of under-5 deaths per 1000 live births (95% CI, 0.02-0.26) (P = .02). The association between health aid and health improvements has strengthened over time, with the closest association occurring between 2000 and 2010. Health improvements associated with health aid are measurable for 3 to 5 years after aid disbursement. These findings imply that an increase of $1 billion in health aid could be associated with 364 800 fewer under-5 deaths (95% CI, 98 400-630 000). CONCLUSIONS AND RELEVANCE International aid to the health sector is related to increasing life expectancy and declining under-5 mortality. The benefits from aid appear to last for several years and have been greatest between 2000 and 2010, possibly because of improving health technologies or effective targeting of aid.
PMID: 24756557 [PubMed - as supplied by publisher]
Radiation-induced heart disease: an under-recognized entity?
Curr Treat Options Cardiovasc Med. 2014 Jun;16(6):317
Authors: Davis M, Witteles RM
OPINION STATEMENT: Radiation-induced heart disease (RIHD) represents a spectrum of cardiovascular disease in patients who have undergone mediastinal, thoracic, or breast radiotherapy (RT). RIHD may involve any cardiac structure and is a major cause of morbidity and mortality in cancer survivors. While large cohort studies have demonstrated that symptomatic RIHD is a common late finding in this population, the incidence of asymptomatic disease is likely to be even higher. Long-term follow-up with regular screening for RIHD plays an important role in the management of cancer survivors who have undergone RT. Aggressive modification of traditional cardiovascular risk factors such as hypertension, dyslipidemia, and cigarette smoking is essential in patients at risk for RIHD, as these have been shown to potentiate the risks of radiation. In patients with symptomatic RIHD, medical and/or percutaneous therapies are often preferable to surgical interventions in view of the increased surgical risk associated with radiation damage to surrounding tissues. Percutaneous revascularization should generally be favored over surgical revascularization. Transcatheter valve replacements have not been widely used in this population but may offer an alternative to high-risk surgical valve procedures. Pericardiectomy is usually associated with extremely poor short-term and long-term outcomes in patients with RIHD and should be avoided in most cases. Heart transplantation is also higher risk in patients with RIHD than in patients with other etiologies of heart failure, but may be considered in young patients without other comorbidities.
PMID: 24756471 [PubMed]
Modulation of STAT3 Folding and Function by TRiC/CCT Chaperonin.
PLoS Biol. 2014 Apr;12(4):e1001844
Authors: Kasembeli M, Lau WC, Roh SH, Eckols TK, Frydman J, Chiu W, Tweardy DJ
Signal transducer and activator of transcription 3 (Stat3) transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD), at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC.
PMID: 24756126 [PubMed - in process]
Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY study.
Epigenetics. 2014 Apr 22;9(7)
Authors: Wu HC, Wang Q, Chung WK, Andrulis IL, Daly MB, John EM, Keegan TH, Knight J, Bradbury AR, Kappil MA, Gurvich I, Santella RM, Terry MB
Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.
PMID: 24756002 [PubMed - as supplied by publisher]
Curcumin Treatment Attenuates Pain and Enhances Functional Recovery after Incision.
Anesth Analg. 2014 Apr 21;
Authors: Sahbaie P, Sun Y, Liang DY, Shi XY, Clark JD
BACKGROUND:: Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs, and regional anesthesia. Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively, and there are no established methods for its prevention. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, antioxidant, anti-inflammatory, and analgesic agent. It may be effective for treating postoperative pain.
METHODS:: We used the hindpaw incision model with C57BL/6 mice. Sensitization to mechanical and thermal stimuli as well as effects on edema and temperature were measured up to 7 days after surgery. Spontaneous pain after incision was assessed by using conditioned place preference (CPP), and alterations in gait function were assessed using multiparameter digital gait analysis.
RESULTS:: Curcumin (50 mg/kg) significantly reduced the intensity of mechanical and heat sensitization after hindpaw incision in mice. No effects of curcumin on baseline nociceptive thresholds were observed. Curcumin also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. In addition, perioperative curcumin treatment attenuated hyperalgesic priming due to incision when mice were subsequently challenged with hindpaw prostaglandin E2 application. Furthermore, while vehicle-treated mice had evidence of spontaneous pain 48 hours after incision in the CPP paradigm, no evidence of ongoing pain was observed in the mice treated with curcumin. Likewise, hindpaw incision caused changes in several gait-related indices, but most of these were normalized in the curcumin-treated animals. The peri-incisional levels of several pronociceptive immune mediators including interleukin (IL)-1β, IL-6, tumor necrosis factor α, and macrophage inflammatory protein-1α were either not reduced or were even augmented 1 and 3 days after incision in curcumin-treated mice. The anti-inflammatory cytokine IL-10 was unchanged, while transforming growth factor-β levels were enhanced under the same conditions.
CONCLUSIONS:: Our studies suggest that curcumin treatment is effective in alleviating incision-induced inflammation, nociceptive sensitization, spontaneous pain, and functional gait abnormalities. Augmented transforming growth factor-β production provides one possible mechanism. These preclinical findings demonstrate curcumin's potential as a preventative strategy in postoperative pain treatment.
PMID: 24755847 [PubMed - as supplied by publisher]
High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor.
Nat Neurosci. 2014 Apr 22;
Authors: St-Pierre F, Marshall JD, Yang Y, Gong Y, Schnitzer MJ, Lin MZ
Accurate optical reporting of electrical activity in genetically defined neuronal populations is a long-standing goal in neuroscience. We developed Accelerated Sensor of Action Potentials 1 (ASAP1), a voltage sensor design in which a circularly permuted green fluorescent protein is inserted in an extracellular loop of a voltage-sensing domain, rendering fluorescence responsive to membrane potential. ASAP1 demonstrated on and off kinetics of ∼2 ms, reliably detected single action potentials and subthreshold potential changes, and tracked trains of action potential waveforms up to 200 Hz in single trials. With a favorable combination of brightness, dynamic range and speed, ASAP1 enables continuous monitoring of membrane potential in neurons at kilohertz frame rates using standard epifluorescence microscopy.
PMID: 24755780 [PubMed - as supplied by publisher]
Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors.
Nat Commun. 2014;5:3674
Authors: Gong Y, Wagner MJ, Zhong Li J, Schnitzer MJ
Genetically encoded fluorescence voltage sensors offer the possibility of directly visualizing neural spiking dynamics in cells targeted by their genetic class or connectivity. Sensors of this class have generally suffered performance-limiting tradeoffs between modest brightness, sluggish kinetics and limited signalling dynamic range in response to action potentials. Here we describe sensors that use fluorescence resonance energy transfer (FRET) to combine the rapid kinetics and substantial voltage-dependence of rhodopsin family voltage-sensing domains with the brightness of genetically engineered protein fluorophores. These FRET-opsin sensors significantly improve upon the spike detection fidelity offered by the genetically encoded voltage sensor, Arclight, while offering faster kinetics and higher brightness. Using FRET-opsin sensors we imaged neural spiking and sub-threshold membrane voltage dynamics in cultured neurons and in pyramidal cells within neocortical tissue slices. In live mice, rates and optical waveforms of cerebellar Purkinje neurons' dendritic voltage transients matched expectations for these cells' dendritic spikes.
PMID: 24755708 [PubMed - in process]
On the fate of pumice rafts formed during the 2012 Havre submarine eruption.
Nat Commun. 2014;5:3660
Authors: Jutzeler M, Marsh R, Carey RJ, White JD, Talling PJ, Karlstrom L
Pumice rafts are floating mobile accumulations of low-density pumice clasts generated by silicic volcanic eruptions. Pumice in rafts can drift for years, become waterlogged and sink, or become stranded on shorelines. Here we show that the pumice raft formed by the impressive, deep submarine eruption of the Havre caldera volcano (Southwest Pacific) in July 2012 can be mapped by satellite imagery augmented by sailing crew observations. Far from coastal interference, the eruption produced a single >400 km(2) raft in 1 day, thus initiating a gigantic, high-precision, natural experiment relevant to both modern and prehistoric oceanic surface dispersal dynamics. Observed raft dispersal can be accurately reproduced by simulating drift and dispersal patterns using currents from an eddy-resolving ocean model hindcast. For future eruptions that produce potentially hazardous pumice rafts, our technique allows real-time forecasts of dispersal routes, in addition to inference of ash/pumice deposit distribution in the deep ocean.
PMID: 24755668 [PubMed - in process]
Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents.
Nat Chem. 2014 May;6(5):448-52
Authors: Wender PA, Fournogerakis DN, Jeffreys MS, Quiroz RV, Inagaki F, Pfaffenbach M
Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions-the homologous Diels-Alder and Diels-Alder cycloadditions-through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.
PMID: 24755598 [PubMed - in process]
Trainee involvement in transforaminal epidural steroid injections associated with increased incidence of vasovagal reactions.
PM R. 2014 Apr 19;
Authors: Schneider B, Kennedy DJ, Casey E, Smuck M, Conrad B, Plastaras C
OBJECTIVES: To evaluate if trainee involvement (Resident and fellow) during transforaminal epidural steroid injections (TFESI) results in higher rates of vasovagal reactions.
DESIGN: Retrospective study on consecutive patients SETTING: Single Academic Medical Center with multiple attending physicians and trainees.
PARTICIPANTS: 2642 consecutive subjects undergoing 4482 TFESI were analyzed from 3/8/2004 to 1/30/2009 MAIN OUTCOME MEASURES: Pearsons chi square test was used to determine the relationship between vasovagal reactions and level of trainee involvement.
RESULTS: A total of 4482 TFESIs were performed, with 157 (3.5%) of procedures complicated by a vasovagal reaction. An attending physician performed 2884 (64.3%) procedures without trainee involvement, with only 79 (2.7%) vasovagal reaction noted. A fellow was involved in 723 (16.1%) procedures, with 30 (4.1%) noted to have a vasovagal reaction. A resident was involved in 875 (19.5%) procedures, with 48 (5.5%) having a vasovagal reaction. Overall, trainees were involved in 1598 (35.7%) cases, of which 78 (4.9%) were complicated by vasovagal reaction. When a trainee was involved in the case, there was a higher incidence of vasovagal episodes (p<.001, Χ(2) = 16.047). Although there was a trend towards higher vasovagal rates with residents over fellows, this did not reach statistical difference.
CONCLUSIONS: Vasovagal reactions can occur with spine injection procedures and may result in premature procedure termination or other adverse events. Although this retrospective study has significant potential for bias, it appears that trainee involvement in a TFESI is associated with a higher incidence of vasovagal reaction (p<.001, Χ(2) = 16.047).
PMID: 24755514 [PubMed - as supplied by publisher]
Gating of neural error signals during motor learning.
Authors: Kimpo RR, Rinaldi JM, Kim CK, Payne HL, Raymond JL
Cerebellar climbing fiber activity encodes performance errors during many motor learning tasks, but the role of these error signals in learning has been controversial. We compared two motor learning paradigms that elicited equally robust putative error signals in the same climbing fibers: learned increases and decreases in the gain of the vestibulo-ocular reflex (VOR). During VOR-increase training, climbing fiber activity on one trial predicted changes in cerebellar output on the next trial, and optogenetic activation of climbing fibers to mimic their encoding of performance errors was sufficient to implant a motor memory. In contrast, during VOR-decrease training, there was no trial-by-trial correlation between climbing fiber activity and changes in cerebellar output, and climbing fiber activation did not induce VOR-decrease learning. Our data suggest that the ability of climbing fibers to induce plasticity can be dynamically gated in vivo, even under conditions where climbing fibers are robustly activated by performance errors. DOI: http://dx.doi.org/10.7554/eLife.02076.001.
PMID: 24755290 [PubMed]
Complementary assessments of executive function in preterm and full-term preschoolers.
Child Neuropsychol. 2014 Apr 22;:1-23
Authors: Loe IM, Chatav M, Alduncin N
Executive functions (EFs) are interrelated cognitive processes that have been studied in relation to behavior, attention, academic achievement, and developmental disorders. Studies of EF skills assessed through parent report and performance-based measures show correlations between them ranging from none to modest. Few studies have examined the relationship between EF skills measured through parent report and performance-based measures in relation to adaptive function. The present study included preschool children born preterm as a population at high risk for EF impairments. Preschool children (N = 149) completed a battery of EF tasks that assess working memory, response inhibition, idea generation, and attention shifting or cognitive flexibility. Parents reported on children's EF and adaptive skills. Preterm children showed more parent-rated and performance-based EF impairments than did full-term children. The combined use of either parent report or performance-based measures resulted in the identification of a large number of children at risk for EF impairment, especially in the preterm group. Both parent report and performance-based EF measures were associated with children's adaptive function. EF skills are measurable in young child'ren, and we suggest that EF skills may serve as targets for intervention to improve functional outcomes. We recommend the use of both parent report and performance-based measures to characterize children's EF profiles and to customize treatment.
PMID: 24754400 [PubMed - as supplied by publisher]
A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release.
Neuron. 2014 Feb 19;81(4):888-900
Authors: Tani H, Dulla CG, Farzampour Z, Taylor-Weiner A, Huguenard JR, Reimer RJ
Biochemical studies suggest that excitatory neurons are metabolically coupled with astrocytes to generate glutamate for release. However, the extent to which glutamatergic neurotransmission depends on this process remains controversial because direct electrophysiological evidence is lacking. The distance between cell bodies and axon terminals predicts that glutamine-glutamate cycle is synaptically localized. Hence, we investigated isolated nerve terminals in brain slices by transecting hippocampal Schaffer collaterals and cortical layer I axons. Stimulating with alternating periods of high frequency (20 Hz) and rest (0.2 Hz), we identified an activity-dependent reduction in synaptic efficacy that correlated with reduced glutamate release. This was enhanced by inhibition of astrocytic glutamine synthetase and reversed or prevented by exogenous glutamine. Importantly, this activity dependence was also revealed with an in-vivo-derived natural stimulus both at network and cellular levels. These data provide direct electrophysiological evidence that an astrocyte-dependent glutamate-glutamine cycle is required to maintain active neurotransmission at excitatory terminals.
PMID: 24559677 [PubMed - indexed for MEDLINE]
The deleterious mutation load is insensitive to recent population history.
Nat Genet. 2014 Mar;46(3):220-4
Authors: Simons YB, Turchin MC, Pritchard JK, Sella G
Human populations have undergone major changes in population size in the past 100,000 years, including recent rapid growth. How these demographic events have affected the burden of deleterious mutations in individuals and the frequencies of disease mutations in populations remains unclear. We use population genetic models to show that recent human demography has probably had little impact on the average burden of deleterious mutations. This prediction is supported by two exome sequence data sets showing that individuals of west African and European ancestry carry very similar burdens of damaging mutations. We further show that for many diseases, rare alleles are unlikely to contribute a large fraction of the heritable variation, and therefore the impact of recent growth is likely to be modest. However, for those diseases that have a direct impact on fitness, strongly deleterious rare mutations probably do have an important role, and recent growth will have increased their impact.
PMID: 24509481 [PubMed - indexed for MEDLINE]
Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis.
Cell. 2014 Jan 30;156(3):482-94
Authors: Özkan E, Chia PH, Wang RR, Goriatcheva N, Borek D, Otwinowski Z, Walz T, Shen K, Garcia KC
SYG-1 and SYG-2 are multipurpose cell adhesion molecules (CAMs) that have evolved across all major animal taxa to participate in diverse physiological functions, ranging from synapse formation to formation of the kidney filtration barrier. In the crystal structures of several SYG-1 and SYG-2 orthologs and their complexes, we find that SYG-1 orthologs homodimerize through a common, bispecific interface that similarly mediates an unusual orthogonal docking geometry in the heterophilic SYG-1/SYG-2 complex. C. elegans SYG-1's specification of proper synapse formation in vivo closely correlates with the heterophilic complex affinity, which appears to be tuned for optimal function. Furthermore, replacement of the interacting domains of SYG-1 and SYG-2 with those from CAM complexes that assume alternative docking geometries or the introduction of segmental flexibility compromised synaptic function. These results suggest that SYG extracellular complexes do not simply act as "molecular velcro" and that their distinct structural features are important in instructing synaptogenesis. PAPERFLICK:
PMID: 24485456 [PubMed - indexed for MEDLINE]
APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory.
Neurology. 2014 Feb 25;82(8):691-7
Authors: Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC, Deutsch GK, Wyss-Coray T, Rutt BK
OBJECTIVES: Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.
METHODS: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.
RESULTS: We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.
CONCLUSIONS: The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.
PMID: 24453080 [PubMed - indexed for MEDLINE]
Respiratory-mode display of echocardiographic images highlights effects of pericardial disease.
JACC Cardiovasc Imaging. 2013 Aug;6(8):917-9
Authors: McConnell MV, Wu HH
PMID: 23769491 [PubMed - indexed for MEDLINE]
Prevention of mother-to-child transmission of hepatitis B virus: is elective cesarean section in highly viremic mothers an appropriate adjunct to immunoprophylaxis?
Clin Gastroenterol Hepatol. 2013 Oct;11(10):1356-7
Authors: Nguyen LH, Nguyen MH
PMID: 23639607 [PubMed - indexed for MEDLINE]
Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-¹³C]pyruvate.
NMR Biomed. 2013 Oct;26(10):1197-203
Authors: Park JM, Josan S, Grafendorfer T, Yen YF, Hurd RE, Spielman DM, Mayer D
Hyperpolarized [1-(13) C]pyruvate ([1-(13) C]Pyr) has been used to assess metabolism in healthy and diseased states, focusing on the downstream labeling of lactate (Lac), bicarbonate and alanine. Although hyperpolarized [2-(13) C]Pyr, which retains the labeled carbon when Pyr is converted to acetyl-coenzyme A, has been used successfully to assess mitochondrial metabolism in the heart, the application of [2-(13) C]Pyr in the study of brain metabolism has been limited to date, with Lac being the only downstream metabolic product reported previously. In this study, single-time-point chemical shift imaging data were acquired from rat brain in vivo. [5-(13) C]Glutamate, [1-(13) C]acetylcarnitine and [1-(13) C]citrate were detected in addition to resonances from [2-(13) C]Pyr and [2-(13) C]Lac. Brain metabolism was further investigated by infusing dichloroacetate, which upregulates Pyr flux to acetyl-coenzyme A. After dichloroacetate administration, a 40% increase in [5-(13) C]glutamate from 0.014 ± 0.004 to 0.020 ± 0.006 (p = 0.02), primarily from brain, and a trend to higher citrate (0.002 ± 0.001 to 0.004 ± 0.002) were detected, whereas [1-(13) C]acetylcarnitine was increased in peripheral tissues. This study demonstrates, for the first time, that hyperpolarized [2-(13) C]Pyr can be used for the in vivo investigation of mitochondrial function and tricarboxylic acid cycle metabolism in brain.
PMID: 23553852 [PubMed - indexed for MEDLINE]
Use and misuse of small bowel video capsule endoscopy in clinical practice.
Clin Gastroenterol Hepatol. 2013 Oct;11(10):1224-31
Authors: Gerson LB
PMID: 23524277 [PubMed - indexed for MEDLINE]