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- Abscisic acid dynamics in roots detected with genetically encoded FRET sensors.Jones AM, Danielson JA, Manojkumar SN, Lanquar V, Grossmann G, Frommer WBElife
- Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome.Romano D, Nicolau M, Quintin EM, Mazaika PK, Lightbody AA, Cody Hazlett H, Piven J, Carlsson G, Reiss ALHum Brain Mapp
- Hearing evaluation of head and neck cancer patients (HNCP): Comparison of CTCAE, Brock and Chang adverse event (AE) criteria in patients receiving cisplatin (CDDP).Colevas AD, Lira RR, Colevas EA, Lavori PW, Chan C, Shultz DB, Chang KWHead Neck
- Parental inconsistency, impulsive choice and neural value representations in healthy adolescents.Schneider S, Peters J, Peth JM, Büchel CTransl Psychiatry
- Forensic genomics as a novel tool for identifying the causes of mass mortality events.De Wit P, Rogers-Bennett L, Kudela RM, Palumbi SRNat Commun
- One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films.Giri G, Li R, Smilgies DM, Li EQ, Diao Y, Lenn KM, Chiu M, Lin DW, Allen R, Reinspach J, Mannsfeld SC, Thoroddsen ST, Clancy P, Bao Z, Amassian ANat Commun
- Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing.Xu D, Nishimura T, Nishimura S, Zhang H, Zheng M, Guo YY, Masek M, Michie SA, Glenn J, Peltz GPLoS Med
- Vitamin D levels and menopause-related symptoms.Leblanc ES, Desai M, Perrin N, Wactawski-Wende J, Manson JE, Cauley JA, Michael YL, Tang J, Womack C, Song Y, Johnson KC, O'Sullivan MJ, Woods N, Stefanick MLMenopause
- Facility characteristics and quality of lung cancer care in an integrated health care system.Ryoo JJ, Malin JL, Ordin DL, Oishi SM, Kim B, Asch SM, He R, Gould MKJ Thorac Oncol
- Psychosocial predictors of salivary cortisol among older adults with depression.Holland JM, Rengifo J, Currier JM, O'Hara R, Sudheimer K, Gallagher-Thompson DInt Psychogeriatr
- Novel nitric oxide generating compound glycidyl nitrate enhances the therapeutic efficacy of chemotherapy and radiotherapy.Ning S, Bednarski M, Oronsky B, Scicinski J, Knox SJBiochem Biophys Res Commun
- Theory of third-order spectroscopic methods to extract detailed molecular orientational dynamics for planar surfaces and other uniaxial systems.Nishida J, Fayer MDJ Chem Phys
- The learning curve for hip arthroscopy: a systematic review.Hoppe DJ, de Sa D, Simunovic N, Bhandari M, Safran MR, Larson CM, Ayeni ORArthroscopy
- Deep brain stimulation for epilepsy.Fisher RSHandb Clin Neurol
- Deep brain stimulation surgical techniques.Khan FR, Henderson JMHandb Clin Neurol
- Modulating polymer chemistry to enhance non-viral gene delivery inside hydrogels with tunable matrix stiffness.Keeney M, Onyiah S, Zhang Z, Tong X, Han LH, Yang FBiomaterials
- Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.Ruby NF, Fernandez F, Garrett A, Klima J, Zhang P, Sapolsky R, Heller HCPLoS One
- Do end of treatment assessments predict outcome at follow-up in eating disorders?Lock J, Agras WS, Le Grange D, Couturier J, Safer D, Bryson SWInt J Eat Disord
- Photo-induced conformational flexibility in single solution-phase peridinin-chlorophyll-proteins.Bockenhauer SD, Moerner WEJ Phys Chem A
- Exudative retinal detachment following photocoagulation in older premature infants for retinopathy of prematurity: description and management.Moshfeghi DM, Silva RA, Berrocal AMRetina
- Subvisible retinal laser therapy: titration algorithm and tissue response.Lavinsky D, Sramek C, Wang J, Huie P, Dalal R, Mandel Y, Palanker DRetina
- The autoimmune basis of narcolepsy.Mahlios J, De la Herrán-Arita AK, Mignot ECurr Opin Neurobiol
- Aggregate health data in the United States: steps toward a public good.Rolnick JHealth Informatics J
- Multifocal choroiditis without panuveitis: clinical characteristics and progression.Fung AT, Pal S, Yannuzzi NA, Christos P, Cooney M, Slakter JS, Klancnik JM, Freund KB, Cunningham ET, Yannuzzi LARetina
- Adaptive enrichment designs for clinical trials.Simon N, Simon RBiostatistics
Abscisic acid dynamics in roots detected with genetically encoded FRET sensors.
Authors: Jones AM, Danielson JA, Manojkumar SN, Lanquar V, Grossmann G, Frommer WB
Cytosolic hormone levels must be tightly controlled at the level of influx, efflux, synthesis, degradation and compartmentation. To determine ABA dynamics at the single cell level, FRET sensors (ABACUS) covering a range ∼0.2-800 µM were engineered using structure-guided design and a high-throughput screening platform. When expressed in yeast, ABACUS1 detected concentrative ABA uptake mediated by the AIT1/NRT1.2 transporter. Arabidopsis roots expressing ABACUS1-2µ (Kd∼2 µM) and ABACUS1-80µ (Kd∼80 µM) respond to perfusion with ABA in a concentration-dependent manner. The properties of the observed ABA accumulation in roots appear incompatible with the activity of known ABA transporters (AIT1, ABCG40). ABACUS reveals effects of external ABA on homeostasis, that is, ABA-triggered induction of ABA degradation, modification, or compartmentation. ABACUS can be used to study ABA responses in mutants and quantitatively monitor ABA translocation and regulation, and identify missing components. The sensor screening platform promises to enable rapid fine-tuning of the ABA sensors and engineering of plant and animal hormone sensors to advance our understanding of hormone signaling. DOI: http://dx.doi.org/10.7554/eLife.01741.001.
PMID: 24737862 [PubMed]
Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome.
Hum Brain Mapp. 2014 Apr 15;
Authors: Romano D, Nicolau M, Quintin EM, Mazaika PK, Lightbody AA, Cody Hazlett H, Piven J, Carlsson G, Reiss AL
Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability as well as the most common single-gene risk factor for autism. Our goal was to examine variation in brain structure in FXS with topological data analysis (TDA), and to assess how such variation is associated with measures of IQ and autism-related behaviors. To this end, we analyzed imaging and behavioral data from young boys (n = 52; aged 1.57-4.15 years) diagnosed with FXS. Application of topological methods to structural MRI data revealed two large subgroups within the study population. Comparison of these subgroups showed significant between-subgroup neuroanatomical differences similar to those previously reported to distinguish children with FXS from typically developing controls (e.g., enlarged caudate). In addition to neuroanatomy, the groups showed significant differences in IQ and autism severity scores. These results suggest that despite arising from a single gene mutation, FXS may encompass two biologically, and clinically separable phenotypes. In addition, these findings underscore the potential of TDA as a powerful tool in the search for biological phenotypes of neuropsychiatric disorders. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
PMID: 24737721 [PubMed - as supplied by publisher]
Hearing evaluation of head and neck cancer patients (HNCP): Comparison of CTCAE, Brock and Chang adverse event (AE) criteria in patients receiving cisplatin (CDDP).
Head Neck. 2014 Apr 15;
Authors: Colevas AD, Lira RR, Colevas EA, Lavori PW, Chan C, Shultz DB, Chang KW
Purpose: To compare CTCAE, Brock and Chang hearing loss (HL) grading in HNCP receiving CDDP. Endpoints were baseline distribution of HL, inter-observer consistency, and sensitivity to HL following CDDP treatment. Methods: 460 single ear audiograms in 110 HNCP were graded. HL at baseline, inter-observer agreement rates, and changes in HL following CDDP were evaluated. Results: The Chang and Brock tools' baseline HL distribution was concentrated at grade 0 (57 and 41%, respectively), whereas 47% per the CTCAE had grade 3 baseline HL. Inter-observer agreement was highest for the Brock scale (≥ 90%) followed by the Chang (≥89%) and CTCAE (≥75%) scales. Detection of change following CDDP was highest for Chang (48%) followed by Brock (45%) and the CTCAE (32%). Conclusion: The Brock and Chang tools may be superior to the CTCAE in HNCP receiving CDDP using baseline HL distribution, inter-observer agreement and detection of HL grade change as performance indicators. Head Neck, 2014.
PMID: 24737682 [PubMed - as supplied by publisher]
Parental inconsistency, impulsive choice and neural value representations in healthy adolescents.
Transl Psychiatry. 2014;4:e382
Authors: Schneider S, Peters J, Peth JM, Büchel C
A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13-15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention.
PMID: 24736798 [PubMed - as supplied by publisher]
Forensic genomics as a novel tool for identifying the causes of mass mortality events.
Nat Commun. 2014;5:3652
Authors: De Wit P, Rogers-Bennett L, Kudela RM, Palumbi SR
Toxic spills, hypoxia, disease outbreaks and toxin-producing algal blooms are all possible causes of mass mortality events, but in many cases it can be difficult to pinpoint the cause of death. Here we present a new approach that we name 'forensic genomics', combining field surveys, toxin testing and genomic scans. Forensic genomics queries allele frequencies of surviving animals for signatures of agents causing mass mortality and, where genetic diversity is high, is uniquely suited to identify natural selection in action. As a proof of concept, we use this approach to investigate the causes of an invertebrate mass mortality event, and its genetic effects on an abalone population. Our results support that a harmful algal bloom producing a yessotoxin was a major causative agent to the event.
PMID: 24736548 [PubMed - as supplied by publisher]
One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films.
Nat Commun. 2014;5:3573
Authors: Giri G, Li R, Smilgies DM, Li EQ, Diao Y, Lenn KM, Chiu M, Lin DW, Allen R, Reinspach J, Mannsfeld SC, Thoroddsen ST, Clancy P, Bao Z, Amassian A
A crystal's structure has significant impact on its resulting biological, physical, optical and electronic properties. In organic electronics, 6,13(bis-triisopropylsilylethynyl)pentacene (TIPS-pentacene), a small-molecule organic semiconductor, adopts metastable polymorphs possessing significantly faster charge transport than the equilibrium crystal when deposited using the solution-shearing method. Here, we use a combination of high-speed polarized optical microscopy, in situ microbeam grazing incidence wide-angle X-ray-scattering and molecular simulations to understand the mechanism behind formation of metastable TIPS-pentacene polymorphs. We observe that thin-film crystallization occurs first at the air-solution interface, and nanoscale vertical spatial confinement of the solution results in formation of metastable polymorphs, a one-dimensional and large-area analogy to crystallization of polymorphs in nanoporous matrices. We demonstrate that metastable polymorphism can be tuned with unprecedented control and produced over large areas by either varying physical confinement conditions or by tuning energetic conditions during crystallization through use of solvent molecules of various sizes.
PMID: 24736391 [PubMed - as supplied by publisher]
Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing.
PLoS Med. 2014 Apr;11(4):e1001628
Authors: Xu D, Nishimura T, Nishimura S, Zhang H, Zheng M, Guo YY, Masek M, Michie SA, Glenn J, Peltz G
BACKGROUND: Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.
METHODS AND FINDINGS: Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.
CONCLUSIONS: FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.
PMID: 24736310 [PubMed - as supplied by publisher]
Vitamin D levels and menopause-related symptoms.
Menopause. 2014 Apr 14;
Authors: Leblanc ES, Desai M, Perrin N, Wactawski-Wende J, Manson JE, Cauley JA, Michael YL, Tang J, Womack C, Song Y, Johnson KC, O'Sullivan MJ, Woods N, Stefanick ML
OBJECTIVE: This study aims to determine whether vitamin D levels are associated with menopause-related symptoms in older women.
METHODS: A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women's Health Initiative Calcium and Vitamin D trial of postmenopausal women aged 51 to 80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the Women's Health Initiative Calcium and Vitamin D trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women (mean [SD] age, 66.2 [6.8] y) were included in these analyses.
RESULTS: Borderline significant associations between 25(OH)D levels and total number of menopausal symptoms were observed (with P values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. No associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue were observed (P's > 0.10 for fully adjusted models).
CONCLUSIONS: There is no evidence for a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women.
PMID: 24736200 [PubMed - as supplied by publisher]
Facility characteristics and quality of lung cancer care in an integrated health care system.
J Thorac Oncol. 2014 Apr;9(4):447-55
Authors: Ryoo JJ, Malin JL, Ordin DL, Oishi SM, Kim B, Asch SM, He R, Gould MK
INTRODUCTION: In a national, integrated health care system, we sought to identify facility-level attributes associated with better quality of lung cancer care.
METHODS: Adherence to 23 quality indicators across four domains (Diagnosis and Staging, Treatment, Supportive Care, End-of-Life Care) was assessed through abstraction of electronic records from 4804 lung cancer patients diagnosed in 2007 at 131 Veterans Health Administration facilities. Performance was reported as proportions of eligible patients fulfilling adherence criteria. With stratification of patients by stage, generalized estimating equations identified facility-level characteristics associated with performance by domain.
RESULTS: Overall performance was high for the older (mean age 67.7 years, SD 9.4 years), predominantly male (98%) veterans. However, no facility did well on every measure, and range of adherence across facilities was large; 9% of facilities were in the highest quartile for one or more domain of care, more than 30% for two, and 65% for three. No facility performed consistently well across all domains. Less than 1% performed in the lowest quartile for all. Few facility-level characteristics were associated with care quality. For End-of-Life Care, diagnosis and treatment within the same facility, availability of cancer psychiatry/psychology consultation services, and availability of both inpatient and outpatient palliative care consultation services were associated with better adherence.
CONCLUSIONS: Quality of Veterans Health Administration lung cancer care is generally high, though substantial variation exists across facilities. With the exception of the salutary impact of palliative care consultation services on end-of-life quality of care, observed facility-level characteristics did not consistently predict adherence to indicators, suggesting quality may be determined by complex local factors that are difficult to measure.
PMID: 24736065 [PubMed - in process]
Psychosocial predictors of salivary cortisol among older adults with depression.
Int Psychogeriatr. 2014 Apr 15;:1-9
Authors: Holland JM, Rengifo J, Currier JM, O'Hara R, Sudheimer K, Gallagher-Thompson D
ABSTRACT Background: Previous studies have identified a number of psychosocial risk factors of dysregulated cortisol (frequently referred to as the "stress hormone") among older adults with depression. However, these studies have typically only examined a handful of risk factors at a time and have sometimes yielded inconsistent results. Method: This study aims to address this gap in the literature by simultaneously examining a range of relevant psychosocial predictors of diurnal cortisol among 54 older adults with a depressive disorder. Salivary cortisol was assessed upon awakening, at 5 PM, and at 9 PM across two consecutive days. Participants also completed measures of global psychosocial stress, current psychiatric symptomatology, pervasive distress (e.g. history of past depression), and protective factors (e.g. social support, resiliency, extent to which one has "made sense" of a significant stressor). Results: High levels of current depressive symptoms, psychiatric comorbidities, past depressive episodes, trait anxiety, and poorer ability to make sense of one's stress were found to be associated with flatter (more abnormal) cortisol slopes. However, when all of these variables were entered simultaneously in a multiple regression analysis, only history of past depression and the degree of sense made of stress emerged as unique predictors of cortisol in the model. Conclusions: These findings have important implications for identifying depressed elderly individuals with dysregulated cortisol patterns who may be most at risk for health complications. Treatments that aim to limit the chronicity of depression and help to increase the sense made of stress could potentially have a positive impact on health.
PMID: 24735686 [PubMed - as supplied by publisher]
Novel nitric oxide generating compound glycidyl nitrate enhances the therapeutic efficacy of chemotherapy and radiotherapy.
Biochem Biophys Res Commun. 2014 Apr 12;
Authors: Ning S, Bednarski M, Oronsky B, Scicinski J, Knox SJ
Selective release of nitric oxide (NO) in tumors could improve the tumor blood flow and drug delivery for chemotherapeutic agents and radiotherapy, thereby increasing the therapeutic index. Glycidyl nitrate (GLYN) is a NO generating small molecule, and has ability to release NO on bioactivation in SCC VII tumor cells. GLYN-induced intracellular NO generation was significantly attenuated by NO scavenger carboxy-PTIO (cPTIO) and NAC. GLYN significantly increases tumor blood flow, but has no effect on the blood flow of normal tissues in tumor-bearing mice. When used with cisplatin, GLYN significantly increased the tumor growth inhibition effect of cisplatin. GLYN also had a modest radiosensitizing effect in vitro and in vivo. GLYN was well tolerated and there were no acute toxicities found at its effective therapeutic doses in preclinical studies. These results suggest that GLYN is a promising new drug for use with chemotherapy and radiotherapy, and provide a compelling rationale for future studies of GLYN and related compounds.
PMID: 24735538 [PubMed - as supplied by publisher]
Theory of third-order spectroscopic methods to extract detailed molecular orientational dynamics for planar surfaces and other uniaxial systems.
J Chem Phys. 2014 Apr 14;140(14):144702
Authors: Nishida J, Fayer MD
Functionalized organic monolayers deposited on planar two-dimensional surfaces are important systems for studying ultrafast orientational motions and structures of interfacial molecules. Several studies have successfully observed the orientational relaxation of functionalized monolayers by fluorescence depolarization experiments and recently by polarization-resolved heterodyne detected vibrational transient grating (HDTG) experiments. In this article we provide a model-independent theory to extract orientational correlation functions unique to interfacial molecules and other uniaxial systems based on polarization-resolved resonant third-order spectroscopies, such as pump-probe spectroscopy, HDTG spectroscopy, and fluorescence depolarization experiment. It will be shown (in the small beam-crossing angle limit) that five measurements are necessary to completely characterize the monolayer's motions: I∥(t) and I⊥(t) with the incident beams normal to the surface, I∥(t) and I⊥(t) with a non-zero incident angle, and a time averaged linear dichroism measurement. Once these measurements are performed, two orientational correlation functions corresponding to in-plane and out-of-plane motions are obtained. The procedure is applicable not only for monolayers on flat surfaces, but any samples with uniaxial symmetry such as uniaxial liquid crystals and aligned planar bilayers. The theory is valid regardless of the nature of the actual molecular motions on interface. We then apply the general results to wobbling-in-a-cone model, in which molecular motions are restricted to a limited range of angles. Within the context of the model, the cone angle, the tilt of the cone relative to the surface normal, and the orientational diffusion constant can be determined. The results are extended to describe analysis of experiments where the beams are not crossing in the small angle limit.
PMID: 24735308 [PubMed - in process]
The learning curve for hip arthroscopy: a systematic review.
Arthroscopy. 2014 Mar;30(3):389-97
Authors: Hoppe DJ, de Sa D, Simunovic N, Bhandari M, Safran MR, Larson CM, Ayeni OR
PURPOSE: The learning curve for hip arthroscopy is consistently characterized as "steep." The purpose of this systematic review was to (1) identify the various learning curves reported in the literature, (2) examine the evidence supporting these curves, and (3) determine whether this evidence supports an accepted number of cases needed to achieve proficiency.
METHODS: The electronic databases Embase and Medline were screened for any clinical studies reporting learning curves in hip arthroscopy. Two reviewers conducted a full-text review of eligible studies and a hand search of conference proceedings and reference sections of the included articles. Inclusion/exclusion criteria were applied, and a quality assessment was completed for each included article. Descriptive statistics were compiled.
RESULTS: We identified 6 studies with a total of 1,063 patients. Studies grouped surgical cases into "early" versus "late" in a surgeon's experience, with 30 cases being the most common cutoff used. Most of these studies used descriptive statistics and operative time and complication rates as measures of competence. Five of 6 studies showed improvement in these measures between early and late experience, but only one study proposed a bona fide curve.
CONCLUSIONS: This review shows that when 30 cases was used as the cutoff point to differentiate between early and late cases in a surgeon's experience, there were significant reductions in operative time and complication rates. However, there was insufficient evidence to quantify the learning curve and validate 30, or any number of cases, as the point at which the learning curve plateaus. As a result, this number should be interpreted with caution.
LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.
PMID: 24461140 [PubMed - indexed for MEDLINE]
Deep brain stimulation for epilepsy.
Handb Clin Neurol. 2013;116:217-34
Authors: Fisher RS
Deep brain stimulation for seizures has been applied to cerebellum, caudate, locus coeruleus, subthalamic nucleus, mammillary bodies, centromedian thalamus, anterior nucleus of thalamus, hippocampus and amygdala, hippocampal commissure, corpus callosum, neocortex, and occasionally to other sites. Animal and clinical studies have primarily investigated seizure prevention and, to a lessersmaller extent, seizure interruption. No studies have yet shown stimulation able to cure epilepsy. A wide variety of stimulation parameters have been employed in multiple different combinations of frequencies, amplitudes, and durations. Literature review identifies at least 52 clinical studies of brain stimulation for epilepsy in 817 patients. Two studies were large, randomized, and controlled, one in the anterior nucleus of thalamus and another at the cortical or hippocampal seizure focus; both of these studies showed efficacy and tolerability of stimulation. Many questions remain. We do not know the mechanisms, the best stimulation parameters, the best patient population, or how to predict benefit in advance. We do not know why benefit of neurostimulation for epilepsy seems to increase over time or whether there are long-term deleterious effects. All of these questions may be answerable with a combination of laboratory research and clinical experience.
PMID: 24112896 [PubMed - indexed for MEDLINE]
Deep brain stimulation surgical techniques.
Handb Clin Neurol. 2013;116:27-37
Authors: Khan FR, Henderson JM
Stereotactic techniques for placement of deep brain stimulation (DBS) electrodes have undergone continuous refinement since the introduction of human stereotaxis in the 1940s. Volumetric imaging techniques, including magnetic resonance imaging and computed tomography, have replaced ventriculography, and increasingly sophisticated computer systems now allow highly refined targeting of subcortical structures. This chapter reviews the underlying principles of stereotactic surgery, including imaging, targeting, and registration, and describes the surgical approach to DBS placement using both framed and frameless techniques.
PMID: 24112882 [PubMed - indexed for MEDLINE]
Modulating polymer chemistry to enhance non-viral gene delivery inside hydrogels with tunable matrix stiffness.
Biomaterials. 2013 Dec;34(37):9657-65
Authors: Keeney M, Onyiah S, Zhang Z, Tong X, Han LH, Yang F
Non-viral gene delivery holds great promise for promoting tissue regeneration, and offers a potentially safer alternative than viral vectors. Great progress has been made to develop biodegradable polymeric vectors for non-viral gene delivery in 2D culture, which generally involves isolating and modifying cells in vitro, followed by subsequent transplantation in vivo. Scaffold-mediated gene delivery may eliminate the need for the multiple-step process in vitro, and allows sustained release of nucleic acids in situ. Hydrogels are widely used tissue engineering scaffolds given their tissue-like water content, injectability and tunable biochemical and biophysical properties. However, previous attempts on developing hydrogel-mediated non-viral gene delivery have generally resulted in low levels of transgene expression inside 3D hydrogels, and increasing hydrogel stiffness further decreased such transfection efficiency. Here we report the development of biodegradable polymeric vectors that led to efficient gene delivery inside poly(ethylene glycol) (PEG)-based hydrogels with tunable matrix stiffness. Photocrosslinkable gelatin was maintained constant in the hydrogel network to allow cell adhesion. We identified a lead biodegradable polymeric vector, E6, which resulted in increased polyplex stability, DNA protection and achieved sustained high levels of transgene expression inside 3D PEG-DMA hydrogels for at least 12 days. Furthermore, we demonstrated that E6-based polyplexes allowed efficient gene delivery inside hydrogels with tunable stiffness ranging from 2 to 175 kPa, with the peak transfection efficiency observed in hydrogels with intermediate stiffness (28 kPa). The reported hydrogel-mediated gene delivery platform using biodegradable polyplexes may serve as a local depot for sustained transgene expression in situ to enhance tissue engineering across broad tissue types.
PMID: 24011715 [PubMed - indexed for MEDLINE]
Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.
PLoS One. 2013;8(8):e72433
Authors: Ruby NF, Fernandez F, Garrett A, Klima J, Zhang P, Sapolsky R, Heller HC
Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopussungorus) so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.
PMID: 24009680 [PubMed - indexed for MEDLINE]
Do end of treatment assessments predict outcome at follow-up in eating disorders?
Int J Eat Disord. 2013 Dec;46(8):771-8
Authors: Lock J, Agras WS, Le Grange D, Couturier J, Safer D, Bryson SW
OBJECTIVE: To examine the predictive value of end of treatment (EOT) outcomes for longer term recovery status.
METHOD: We used signal detection analysis to identify the best predictors of recovery based on outcome at EOT using five different eating disorder samples from randomized clinical treatment trials. We utilized a transdiagnostic definition of recovery that included normalization of weight and eating related psychopathology.
RESULTS: Achieving a body weight of 95.2% of expected body weight by EOT is the best predictor of recovery for adolescents with anorexia nervosa (AN). For adults with AN, the most efficient predictor of weight recovery (BMI > 19) was weight gain to greater than 85.8% of ideal body weight. In addition, for adults with AN, the most efficient predictor of psychological recovery was achievement of an eating disorder examination (EDE) weight concerns score below 1.8. The best predictor of recovery for adults with Bulimia Nervosa (BN) was a frequency of compensatory behaviors less than two times a month. For adolescents with BN, abstinence from purging and reduction in the EDE restraint score of more than 3.4 from baseline to EOT were good predictors of recovery. For adults with binge eating disorder, reduction of the Global EDE score to within the normal range (<1.58) was the best predictor of recovery.
DISCUSSION: The relationship between EOT response and recovery remains understudied. Utilizing a transdiagnostic definition of recovery, no uniform predictors were identified across all eating disorder diagnostic groups.
PMID: 23946139 [PubMed - indexed for MEDLINE]
Photo-induced conformational flexibility in single solution-phase peridinin-chlorophyll-proteins.
J Phys Chem A. 2013 Sep 5;117(35):8399-406
Authors: Bockenhauer SD, Moerner WE
The peridinin-chlorophyll-protein (PCP) is an accessory light-harvesting complex found in red-tide dinoflagellates. PCP absorbs photons primarily in the blue-green spectral region via peridinin (Per) carotenoid pigments which then transfer excitations to chlorophyll (Chl) and ultimately downstream to photosystem II (PSII). Whereas the ultrafast dynamics of PCP are well-studied, much less is known about slower protein dynamics on time scales of milliseconds and seconds. Previous single-molecule studies of spectral emission and intensity have attached PCP to surfaces, but the native environment of PCP is in the lumen, meaning that a surface-attached environment could perturb its native conformations. To address this concern, we use the anti-Brownian electrokinetic (ABEL) trap to study single PCP monomers in solution for several seconds each. We measure, for the first time, simultaneous single-molecule intensity, lifetime, and spectral emission shifts for each trapped PCP monomer. The rate of reversible spectral redshifts depends linearly on irradiance over a factor of 30, indicating a light-induced mechanism which we attribute to a protein conformational change. Independent of these spectral shifts, our measurements of intensity and lifetime show reversible Chl quenching. In contrast to previous work, we show that this quenching cannot result from isolated photobleaching of Chl. These independent mechanisms arise from distinct conformational changes which maintain relatively stable fluorescence emission.
PMID: 23919352 [PubMed - indexed for MEDLINE]
Exudative retinal detachment following photocoagulation in older premature infants for retinopathy of prematurity: description and management.
Retina. 2014 Jan;34(1):83-6
Authors: Moshfeghi DM, Silva RA, Berrocal AM
PURPOSE: To describe exudative retinal detachment following laser photocoagulation after 40 weeks of postmenstrual age (PMA) for retinopathy of prematurity in premature infants, its medical management, and outcomes.
METHODS: Two pediatric vitreoretinal surgeons at 2 different quaternary care institutions retrospectively identified children who received laser photocoagulation after 40 weeks of PMA and subsequently developed exudative detachment. Hospital course, management, and outcomes were identified.
RESULTS: Three infants were identified that developed exudative retinal detachments following laser photocoagulation for retinopathy of prematurity after 40 weeks of PMA. The average gestational age was 25 weeks with an average birth weight of 650 g. All babies were Zone II at initial examination and developed Stage 3 with pre-plus or plus disease after 40 weeks of PMA (average 42 weeks of PMA). Therapy consisted of topical cyclogyl (0.5%) and topical prednisolone acetate (1%) to the affected eyes and intravenous dexamethasone in all cases. The exudative retinal detachments resolved by 50 weeks of PMA in all infants. Hard exudates following resolution were found in all eyes. Two eyes demonstrated temporal macular dragging.
CONCLUSION: Premature infants who require laser photocoagulation for retinopathy of prematurity at >40 weeks of PMA may be predisposed to develop exudative retinal detachments. In the absence of identifiable traction, systemic corticosteroid use can be considered to achieve favorable anatomic outcomes.
PMID: 23881225 [PubMed - indexed for MEDLINE]
Subvisible retinal laser therapy: titration algorithm and tissue response.
Retina. 2014 Jan;34(1):87-97
Authors: Lavinsky D, Sramek C, Wang J, Huie P, Dalal R, Mandel Y, Palanker D
PURPOSE: Laser therapy for diabetic macular edema and other retinal diseases has been used within a wide range of laser settings: from intense burns to nondamaging exposures. However, there has been no algorithm for laser dosimetry that could determine laser parameters yielding a predictable extent of tissue damage. This multimodal imaging and structural correlation study aimed to verify and calibrate a computational model-based titration algorithm for predictable laser dosimetry ranging from nondamaging to intense coagulative tissue effects.
METHODS: Endpoint Management, an algorithm based on a computational model of retinal photothermal damage, was used to set laser parameters for various levels of tissue effect. The algorithm adjusts both power and pulse duration to vary the expected level of thermal damage at different percentages of a reference titration energy dose. Experimental verification was conducted in Dutch Belted rabbits using a PASCAL Streamline 577 laser system. Titration was performed by adjusting laser power to produce a barely visible lesion at 20 ms pulse duration, which is defined as the nominal (100%) energy level. Tissue effects were then determined for energy levels of 170, 120, 100, 75, 50, and 30% of the nominal energy at 1 hour and 3, 7, 30, and 60 days after treatment. In vivo imaging included fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography. Morphologic changes in tissue were analyzed using light microscopy, as well as scanning and transmission electron microscopy.
RESULTS: One hundred and seventy percent and 120% levels corresponded to moderate and light burns, respectively, with damage to retinal pigment epithelium, photoreceptors, and at highest settings, to the inner retina. 50% to 75% lesions were typically subvisible ophthalmoscopically but detectable with fluorescein angiography and optical coherence tomography. Histology in these lesions demonstrated some selective damage to retinal pigment epithelium and photoreceptors. The 30% to 50% lesions were invisible with in vivo multimodal imaging, and damage was limited primarily to retinal pigment epithelium, visible best with scanning electron microscopy. Over time, photoreceptors shifted into the coagulated zone, reestablishing normal retinal anatomy in lesions ≤100%, as seen in optical coherence tomography and light microscopy. Transmission electron microscopy at 2 months demonstrated restoration of synapses between shifted-in photoreceptors and bipolar cells in these lesions. Retinal pigment epithelium monolayer restored its continuity after 1 week in all lesions. No damage could be seen <30% level.
CONCLUSION: A retinal laser dosimetry protocol based on the Endpoint Management algorithm provides reproducible changes in retinal morphology in animals with various levels of pigmentation. This algorithm opens doors to clinical trials of well-defined subvisible and nondestructive regimes of retinal therapy, especially important for treatment of macular disorders.
PMID: 23873164 [PubMed - indexed for MEDLINE]
The autoimmune basis of narcolepsy.
Curr Opin Neurobiol. 2013 Oct;23(5):767-73
Authors: Mahlios J, De la Herrán-Arita AK, Mignot E
Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections.
PMID: 23725858 [PubMed - indexed for MEDLINE]
Aggregate health data in the United States: steps toward a public good.
Health Informatics J. 2013 Jun;19(2):137-51
Authors: Rolnick J
The rise of electronic medical records promotes the collection and aggregation of medical data. These data have tremendous potential utility for health policy and public health; yet there are gaps in the scholarly literature. No articles in the medical or legal literature have mapped the "information flows" from patient to database, and commentary has focused more on privacy than on data's social value and incentives for production. Utilizing short case studies of data flows, I show that ample data exist, much of them are available online through government websites or hospital trade associations. However, available information comes from billing records rather than medical records. Turning to legal and policy recommendations for better provision, I note that weak intellectual property law has ironically led to stronger control over health data through private contracts and technological barriers, as these methods of protection lack any exceptions for noncommercial use. I conclude with a series of policy proposals to make data more available.
PMID: 23715213 [PubMed - indexed for MEDLINE]
Multifocal choroiditis without panuveitis: clinical characteristics and progression.
Retina. 2014 Jan;34(1):98-107
Authors: Fung AT, Pal S, Yannuzzi NA, Christos P, Cooney M, Slakter JS, Klancnik JM, Freund KB, Cunningham ET, Yannuzzi LA
PURPOSE: To describe the clinical characteristics and progression of patients with multifocal choroiditis lesions who had minimal or no evidence of anterior uveitis and/or vitritis.
METHODS: Retrospective, observational, single-center consecutive case series. Clinical histories, examination, and multimodal imaging findings were analyzed.
RESULTS: Sixty-five eyes of 41 patients were identified. The mean age at diagnosis was 38.4 years (median, 35 years; range, 15-81 years), and 70.7% of the patients were women. Involvement was bilateral in 21 patients (51.2%) at presentation. The 60-month bilateral event-free survival was 75.0% (95% confidence interval, 49.8-91.2%). The mean visual acuity was 20/46 (median, 20/25; range, 20/20 to count fingers at 2 feet) at presentation and 20/42 (median, 20/25; range, 20/20-5/400) at the last recorded visit. The 60-month "20/50 or worse" event-free survival was 100%. Between the first presentation and final follow-up (a mean duration of 92.6 months; range, 0-343 months), 46.7% of the eyes developed new or larger chorioretinal spots and 32.6% developed new or recurrent choroidal neovascularization. The 60-month choroidal neovascularization event-free survival was 68.1% (95% confidence interval, 39.2-85.4%).
CONCLUSION: Patients with multifocal choroiditis lesions, but with minimal or no anterior uveitis or vitritis, tended to be young women. Approximately half of the patients presented with bilateral involvement, which is less than has been reported in most case series of multifocal choroiditis with panuveitis. One quarter of all unilaterally affected patients will develop bilateral involvement by 60 months.
PMID: 23670288 [PubMed - indexed for MEDLINE]
Adaptive enrichment designs for clinical trials.
Biostatistics. 2013 Sep;14(4):613-25
Authors: Simon N, Simon R
Modern medicine has graduated from broad spectrum treatments to targeted therapeutics. New drugs recognize the recently discovered heterogeneity of many diseases previously considered to be fairly homogeneous. These treatments attack specific genetic pathways which are only dysregulated in some smaller subset of patients with the disease. Often this subset is only rudimentarily understood until well into large-scale clinical trials. As such, standard practice has been to enroll a broad range of patients and run post hoc subset analysis to determine those who may particularly benefit. This unnecessarily exposes many patients to hazardous side effects, and may vastly decrease the efficiency of the trial (especially if only a small subset of patients benefit). In this manuscript, we propose a class of adaptive enrichment designs that allow the eligibility criteria of a trial to be adaptively updated during the trial, restricting entry to patients likely to benefit from the new treatment. We show that our designs both preserve the type 1 error, and in a variety of cases provide a substantial increase in power.
PMID: 23525452 [PubMed - indexed for MEDLINE]