bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Genetic Variability and Correlation Studies on Fruit Yield and Its Component Characters in Okra (Abelmoschus esculentus L.)
Authors: Yadav Y. S. , Kaur Harmanpreet , Korake S. R.
Published: August 2024

A field experiment was carried out with 20 Okra genotypes with one check for analysis of genetic variability and correlation studies on fruit yield and its component characters in Okra (Abelmoschus esculentus L.) in a randomized block design with three replications. The material was planted 30 x 45cm, and genotype to genotype 45 cm on July 20, 2023. The experiment was carried out during the Kharif season of 2023-2024 at research farm, College of Agriculture Saralgaon, Murbad, Thane. The observations were recorded on thirteen traits viz., days to first flowering, plant height (cm), number of branches per plant, number of internodes, internodal length (cm), fruit length (cm), fruit diameter (cm), average fruit weight (cm), number of fruits per plant, number of seeds per fruit, seed index (%), and fruit yield per plant (g). The estimation of analysis of variance revealed mean sum of square due to genotypes were significant for all the characters indicating sufficient genetic variability among the genotypes. The present study revealed that the phenotypic coefficient of variation was higher than the corresponding genotypic coefficient of variation for all the traits which might be due to the interaction of the genotypes with the environment to some degree or other explaining environmental factors influencing the expression of these characters. Moderate phenotypic coefficient of variation (PCV) and genotypic coefficient of variation (GCV) were recorded in plant height (cm), number of branches per plant, average fruit weight (cm), number of fruits per plant, and fruit yield per plant (g). High estimation genetic advance as a percentage of the mean was recorded for average fruit weight (cm), and number of fruits per plant. Moderate genetic advance as a percentage of the mean was recorded for plant height (cm), number of branches per plant, internodal length (cm) and fruit yield per plant (g). Low genetic advance as a percentage of the mean was recorded for days to first flowering, number of internodes, fruit length (cm), fruit diameter (cm), and number of seeds per fruit.
Evaluation of Hybrids and Parents of Chilli (Capsicum annuum L.) for Yield and Resistance to Chilli Leaf Curl Virus
Authors: Palled Apoorva , Jawadagi Raveendra , Evoor Shashikanth , D Satish , Mudenur Vinaykumar M , Kumar Ravi
Published: August 2024

Chilli (Capsicum annuum L.) is the most important vegetable and spice crops that belonging to family Solanaceae. Leaf curl virus disease is a most destructive threat to chilli production which adversely affect yield. Twenty four F1 hybrids were developed by crossing eleven diverse parents in line x tester mating design and were screened for yield, yield related traits and for resistance to leaf curl virus under natural epiphytotic condition and artificial inoculation using viruliferous white flies at College of horticulture, Bagalkot (University of horticulture science, Bagalkot) during 2021-2023. The analysis of variance indicated the presence of significant variation among the chilli hybrids and parents for the characters observed and reaction to disease. Based on the per se performance, the hybrid Byadgi Dabbi x IC284628 recorded the highest individual fruit weight, hybrid Byadgi Kaddi x Punjab Sindhuri observed highest number of fruits per plant and hybrid Byadgi Kaddi x Punjab Lal recorded highest green fruit yield per plant among all the hybrids. The hybrids Byadgi Kaddi x Punjab Surkh, Byadgi Dabbi x Punjab Surkh, Byadgi Dabbi x Punjab Sindhuri and Byadgi Kaddi x Punjab Sindhuri were found to have higher tolerance to chilli leaf curl disease.
Temporal and spatial resolved SuperDARN line of sight velocity measurements corrected for plasma index of refraction using Bayesian inference
Authors: Spaleta J. , Bristow W. A. , Klein J.
Published: March 2015

Recent work by Gillies et al. (2012, 2009, 2010) has sought an explanation for the SuperDARN line‐of‐sight velocity underestimate of ionospheric plasma velocity. The reason for the underestimation is thought to be from the modification of the measured Doppler shift of the backscattered signal due to phase refractive index of the ionospheric plasma in the scattering region. Presented here is an analysis technique to estimate the plasma drift velocity, correcting for the index of the refraction of the scattering medium. The technique requires dual frequency SuperDARN observations and calculates velocity from the phase of the SuperDARN autocorrelation function (ACF). Both plasma velocity and plasma density are treated as independent unknowns, and self‐consistent error estimates are generated for each. This new technique was employed at the McMurdo radar, resulting in estimates of plasma velocity on scales relevant to existing SuperDARN data products. The McMurdo dual frequency analysis also provides a new SuperDARN data product, an estimate for the plasma density in the ionospheric region derived wholly from SuperDARN backscatter.
Reconciling viscoelastic models of postseismic and interseismic deformation: Effects of viscous shear zones and finite length ruptures
Authors: Hearn Elizabeth H. , Thatcher Wayne R.
Published: March 2015

We have developed a suite of earthquake cycle models for strike‐slip faults to investigate how finite ruptures and lithosphere‐scale viscous shear zones affect interseismic deformation. In particular, we assess whether localized and stationary interseismic deformation and large‐scale, rapidly decaying postseismic transients may be explained with models incorporating either or both of these features. Models incorporating viscous shear zones give more stationary interseismic deformation than layered half‐space, Maxwell viscoelastic models producing similar early postseismic deformation in the near field. This tendency is accentuated when the effective viscosity per unit width of the shear zone increases either with depth or with interseismic time. Models with finite (200 km long) ruptures produce time‐dependent deformation similar to that from models with infinitely long ruptures, though with smaller‐magnitude and somewhat more localized surface velocity fluctuations. Models incorporating a stiff lithosphere, a low‐viscosity mantle asthenosphere, and a crust‐ to lithosphere‐scale viscous shear zone can replicate postseismic and interseismic deformation typical of large, strike‐slip earthquakes. Such models require depth‐dependent, power law, or transient rheologies for the viscous shear zone material in the crust, as long as the effective viscosity per unit shear zone width is approximately 1015 Pa s/m at crustal depths during the postseismic interval. Below the Moho, the shear zone effective viscosity per unit width must be higher throughout the seismic cycle, at least over a short depth interval. For example, if shear zone viscosity per unit width is 5×1016 Pa s/m in the mantle lithosphere, a model with a 50 km thick lithosphere and asthenosphere effective viscosities of 1 to 5×1018 Pa s can reproduce reference velocity profiles for both postseismic and later interseismic deformation.
What do benthic δ13C and δ18O data tell us about Atlantic circulation during Heinrich Stadial 1?
Authors: Oppo Delia W. , Curry William B. , McManus Jerry F.
Published: March 2015

Approximately synchronous with the onset of Heinrich Stadial 1 (HS1), δ13C decreased throughout most of the upper (~1000–2500 m) Atlantic, and at some deeper North Atlantic sites. This early deglacial δ13C decrease has been alternatively attributed to a reduced fraction of high‐δ13C North Atlantic Deep Water (NADW) or to a decrease in the NADW δ13C source value. Here we present new benthic δ18O and δ13C records from three relatively shallow (~1450–1650 m) subpolar Northeast Atlantic cores. With published data from other cores, these data form a depth transect (~1200–3900 m) in the subpolar Northeast Atlantic. We compare Last Glacial Maximum (LGM) and HS1 data from this transect with data from a depth transect of cores from the Brazil Margin. The largest LGM‐to‐HS1 decreases in both benthic δ13C and δ18O occurred in upper waters containing the highest NADW fraction during the LGM. We show that the δ13C decrease can be explained entirely by a lower NADW δ13C source value, entirely by a decrease in the proportion of NADW relative to Southern Ocean Water, or by a combination of these mechanisms. However, building on insights from model simulations, we hypothesize that reduced ventilation due to a weakened but still active Atlantic Meridional Overturning Circulation also contributed to the low δ13C values in the upper North Atlantic. We suggest that the benthic δ18O gradients above ~2300 m at both core transects indicate the depth to which heat and North Atlantic deglacial freshwater had mixed into the subsurface ocean by early HS1.
Avalanching glacier instabilities: Review on processes and early warning perspectives
Authors: Faillettaz Jérome , Funk Martin , Vincent Christian
Published: March 2015

Avalanching glacier instabilities are gravity‐driven rupture phenomena that might cause major disasters, especially when they are at the origin of a chain of processes. Reliably forecasting such events combined with a timely evacuation of endangered inhabited areas often constitute the most efficient action. Recently, considerable efforts in monitoring, analyzing, and modeling such phenomena have led to significant advances in destabilization process understanding, improving early warning perspectives. The purpose of this paper is to review the recent progress in this domain. Three different types of instabilities can be identified depending on the thermal properties of the ice/bed interface. If cold (1), the maturation of the rupture is associated with a typical time evolution of surface velocities and passive seismic activity. A prediction of the final break off is possible using these precursory signs. For the two other types, water plays a key role in the development of the instability. If the ice/bed interface is partly temperate (2), the presence of meltwater may reduce the basal resistance, which promotes the instability. No clear and easily detectable precursory signs are known in this case, and the only way to infer any potential instability is to monitor the temporal evolution of the thermal regime. The last type of instability (3) concerns steep temperate glacier tongues switching for several days/weeks during the melting season into a so‐called “active phase” followed in rare cases by a major break‐off event. Although the prediction of such events is still far from being achievable, critical conditions promoting the final instability can be identified.
Introduction to Amorphous Solid Dispersions
Authors: Zografi George , Newman Ann
Published: March 2015

This chapter reviews some of the important physicochemical characteristics of amorphous solids as single components and as mixtures of active pharmaceutical ingredient (API) with other formulation components that might be used to enhance oral bioavailability in drug products. The structural arrangement of molecules in crystals, as determined by intermolecular interactions and molecular size and shape, can be described in terms of a specific local structure reflected by the geometric arrangement of molecules within the unit cell, and the long‐range symmetrical three‐dimensional extension of the repeating unit cells. From a thermodynamic perspective molecules in the amorphous state are in a higher free energy state than those in the corresponding crystal at all temperatures. In the case of amorphous solid dispersions, a miscible amorphous system is generally required to obtain appropriate levels of stability, enhanced dissolution, and oral absorption.
Polymers and Surfactants
Authors: Narayan Padma , Porter William W. , Brackhagen Meinolf , Tucker Christopher
Published: March 2015

This chapter focuses on the criteria for designing amorphous solid dispersions (ASDs) with combinations of various surfactant‐type molecules and polymers for stabilization of the supersaturated or high‐energy form, and to improve the bioavailability of poorly soluble drugs. The successful formulation of an ASD requires the generation of basic physical properties of both the drug substance and the carrier agent. In the case of the polymer or surfactant utilized as the carrier for the ASD, physical properties to be considered include molecular weight, glass transition temperature (Tg), solubility in organic solvents, thermal stability, melt viscosity, and the ability to process the polymer by various methods. The ability to utilize these important active pharmaceutical ingredient (API) and polymer properties combined with the critical parameters for the process used for creating the amorphous solid dispersion can guide a formulator to create a stable ASD.
Amorphous Solid Dispersion Screening
Authors: Newman Ann
Published: March 2015

Finding the optimal form for drug development can involve a number of different screening activities, including a search for polymorphs, salts, cocrystals, and/or amorphous solid dispersions. High‐risk compounds will require special formulations that include amorphous solid dispersions. An amorphous dispersion screen is performed to find a suitable amorphous dispersion that exhibits acceptable properties. The screening performed in early development may focus on parameters such as solubility, supersaturation, short‐term physical and chemical stability, and animal bioavailability to get into early‐phase clinical trials quickly and establish proof of concept. Before starting an amorphous dispersion screen project, information on the active pharmaceutical ingredient (API) is needed. This may include chemical structure, solid form, physical stability, chemical stability, log P, hydrogen bond donors/acceptors, calculated solubility parameters, and known solubilities of the solid in various solvents/biorelevant media.
Solid‐State Characterization of Amorphous Dispersions
Authors: Vogt Frederick G.
Published: March 2015

This chapter reviews established and emerging analytical and physical techniques for the characterization of amorphous solid dispersions. The thermal analysis methods used in most reported studies of amorphous solid dispersions include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and isothermal microcalorimetry (ITC). Many of the commonly used polymers in amorphous solid dispersions are hydrophilic in nature and contain polar functional groups, and can absorb moisture from the atmosphere. In the pharmaceutical sciences, vibrational spectroscopic methods are generally used to probe molecular vibrations and phonon modes in crystalline substances. Solid‐state nuclear magnetic resonance (SSNMR) analysis of mobility in amorphous solid dispersions is complementary to thermal analysis and dielectric spectroscopy techniques. Scanning electron microscopy (SEM) is widely used in the characterization of amorphous solid dispersions. Effective characterization plays a critical role in the development of pharmaceutical amorphous solid dispersions.
Solubility and Dissolution Considerations for Amorphous Solid Dispersions
Authors: Ilevbare Grace A. , Xu Wei , John Christopher T. , D. Ormes James , Kuiper Jesse L. , Templeton Allen C. , Bak Annette
Published: March 2015

This chapter presents differences between dispersions, amorphous materials, and crystalline forms, and discusses the impact of excipient selection, especially polymers. It provides guidance for solubility and dissolution testing of amorphous dispersions. Crystalline solids are mostly used in pharmaceutical drug formulations because of their physical and chemical stabilities. Amorphous solids are commonly described as condensed phases that lack the long‐range translational order typical of a crystalline solid, although the molecules may have short‐range order. The success of amorphous solids as a supersaturating dosage form depends on the choice of processing conditions to yield a pure amorphous solid with no or minimal crystallization of the amorphous drug during storage and upon dosing. The use of amorphous solid dispersions has become a well‐known strategy for inhibiting crystallization, as the amorphous solid dispersions can have increased physical stability over neat amorphous material.
Translational Development of Amorphous Dispersions
Authors: Connelly Patrick R. , Quinn Brian Patrick , Johnston Steve , Bransford Philip , Mudunuri Praveen , Peresypkin Andrey , Fawaz Majed , Roday Setu , Kuldipkumar Anuj , Wang Hong‐Ren , Snyder Phillip , Katstra Jeff , Sanghvi Tapan , Rowe Bill , Hurter Patricia
Published: March 2015

This chapter demonstrates that the personnel involved in translational drug development (TDD) are integrated into each stage of discovery and development, serving as regular members of working groups, projects teams, and major steering committees. The early development of amorphous dispersions is carried out using certain aspects of telaprevir as an example. TDD charges the pharmaceutical development division with understanding a broad range of physicochemical properties as early as possible in a compound's development. In developing a suspension formulation of an amorphous dispersion, a mathematical, biopharmaceutical model that predicts absorption is created to ensure that a preclinical study will not result in inadequate exposure
in vivo
. An advance in the pharmaceutical industry would move us away from much of the current
a posteriori
trial‐and‐error empiricism and into a level of rigor one can expect in other technically intensive sectors of the society.
Preclinical and Clinical Studies
Authors: Brewster Marcus E. , Verreck Geert , Bevernage Jan , Brouwers Joachim , Van den Mooter Guy , Augustijns Patrick
Published: March 2015

Contemporary drug pipelines are increasingly populated with difficult‐to‐formulate drug substances. Amorphous solid dispersions can increase drug dissolution rate by reducing the effective drug particle size through its dispersion in the matrix. Based on the theorized way of working of amorphous solid dispersions, one of the most important design elements is their ability to dissolve and supersaturate. This is initially assessedin vitrothrough the use of dissolution protocols especially set up for that purpose. A number ofin vivoassessments of the potential utility of amorphous solid dispersions have been completed using various animal models. Clinical assessments to investigate itraconazole supersaturation (indirectly) have also been completed. Itraconazole is a widely studied compound in this context with numerousin vitro,in vivo, and clinical evaluations completed. Useful preclinical and clinical models for assessing solid dispersion fitness will contribute to the drug development process.
Spray Drying and Scale‐Up
Authors: Dobry Daniel E. , Settell Dana M. , Baumann John M.
Published: March 2015

This chapter discusses amorphous dispersions manufactured using the spray drying process, which are referred to as spray‐dried dispersions (SDDs). It covers key aspects of spray drying equipment, process development, and scale‐up. The spray drying process can be broken down into the following five key steps or focus areas: spray solution preparation; atomization; drying; product collection; and secondary drying. Scalable spray drying process for SDDs is based on integrated consideration of formulation variables and process parameters that control atomization and drying thermodynamics. The chapter lists some of the key formulation selection considerations that have a significant impact on spray drying process development. The goal of scale‐up is often to ensure that the SDD particle attributes (e.g., particle size, density, physical state, and morphology) remain consistent while achieving the necessary throughput to meet clinical and/or commercial demands. This can be achieved by matching droplet size and drying rate during scale‐up.
Hot Melt Extrusion of Amorphous Solid Dispersions
Authors: Crowley Kieran , Gryczke Andreas
Published: March 2015

Hot melt extrusion (HME) is a frontline manufacturing solution for pharmaceutical amorphous solid dispersions. The status of HME technology is validated by the presence of successful commercial solid dispersion products, and is seeing widespread use in early‐stage R&D laboratories that are formulating poorly soluble compounds. This chapter describes a number of important factors that justify HME suitability for solid dispersion applications, ranging from materials performance and quality, equipment performance and versatility, and the proven ability generate to robust finished dosage forms that provide enhanced and controlled solubility behavior leading to improved bioavailability. Solid dispersion development using hot melt extrusion typically includes
in vitro
and/or
in vivo
assessment of early formulation prototypes before any process development has occurred. Screening of early prototypes is common because demonstration of a solubility or bioavailability increase will be a critical selection criterion for a solid dispersion.
Formulation Development of Amorphous Dispersions
Authors: Sanghvi Tapan , Katstra Jeff , Quinn Brian Patrick , Thomas Hayden , Hurter Patricia
Published: March 2015

This chapter examines the development of clinical and commercial formulations of amorphous dispersions. It considers the various means available to render a crystalline drug amorphous. The chapter explores the downstream ramifications of each technique, such as on the dosage forms available, and special processing and handling. It gives the high‐level strategic picture of amorphous formulation development, a process that best fits the framework of quality by design (QbD) advocated for by the FDA. The chapter reviews a detailed case study of the first amorphous dispersion‐based drugs developed and commercialized inhouse, the hepatitis C protease inhibitor VX‐950 or telaprevir (Incivek). It focuses on developing a drug product manufacturing process, including defining parameters, developing the design space, modeling, and applying the QbD framework to manufacture. The chapter examines the analytical methods used to discriminate dispersion attributes and tablet properties that could affect performance of the product in the clinic.
Scientific and Regulatory Considerations in Product Development
Authors: Gupta Abhay , Rahman Ziyaur , Khan Mansoor A.
Published: March 2015

This chapter focuses on the scientific and regulatory considerations for developing amorphous solid dispersions (ASDs) of small‐molecule drugs with poor aqueous solubility for oral administration. Drug development is a multistep and multidisciplinary process involving discovery, development, Food and Drug Administration (FDA) review and approval, and postapproval, postmarketing safety surveillance to ensure continued safety and efficacy of the drug. The approval process includes a comprehensive review of all data, similar to the FDA approval process, or a limited review if the drug has already been approved in one of the major foreign markets (the United States, Europe, and/or Japan). The harmonized aspects, that is, the International Conference on Harmonisation (ICH) guidelines, are adopted as law in several countries. Quality‐by‐design (QbD) is a systematic approach toward product development that begins with predefined objectives and emphasizes the use of sound science and quality risk management principles in product and process understanding and control.
Patenting Amorphous Solid Dispersions of Pharmaceuticals
Authors: Lindeman Jeffrey A.
Published: March 2015

This chapter considers some key aspects of patenting amorphous solid dispersions of pharmaceuticals by surveying the information to be included in a patent (or patent application) to support and present robust patent claims to amorphous solid dispersions. Under U.S. law, the patent specification must provide a written description of the invention, the manner of making and using the invention, and the best mode contemplated for carrying out the invention. The chapter describes the patent examination process and three common types of patent applications. To obtain a patent, an inventor files a patent application with a patent office, for example, the U.S. Patent and Trademark Office. There are three “;common” types of patent applications that one sees in the patenting of amorphous solid dispersions of pharmaceutical. These common patent applications include a U.S. provisional patent application, a nonprovisional application, and a Patent Cooperation Treaty (PCT) application.
Monographs on Polymers and Surfactants
Authors: Lu Xia , Wenslow Robert , Newman Ann
Published: March 2015

This chapter highlights common polymers and surfactants that have been used in various studies. Most polymers exhibit a range of molecular weights. Where possible, the grade, molecular weight, and glass transition temperature (T
g
) are given in the chapter. The glass transition temperature (T
g
) and melting temperature (T
m
) are given as a range since different molecular weights change these properties. Some semicrystalline polymers exhibit both temperatures and these are listed in the chapter. Many enteric polymers are only soluble near neutral pH (5–7), while others are soluble over a larger pH range. The chapter considers melt extrusion and spray drying as the primary production methods. The methods are based on studies and products that employ the various polymers.
DNA mismatch repair deficiency accelerates lung neoplasm development in K‐rasLA1/+ mice: a brief report
Authors: Downey Charlene M. , Jirik Frank R.
Published: March 2015

Inherited as well as acquired deficiencies in specific DNA mismatch repair (MMR) components are associated with the development of a wide range of benign and malignant neoplasms. Loss of key members such as MSH2 and MLH1 severely cripples the ability of the cell to recognize and correct such lesions as base:base mismatches and replicative DNA polymerase errors such as slippages at repetitive sequences. Genomic instability resulting from MMR deficiency not only predisposes cells to malignant transformation but may also promote tumor progression. To test the latter, we interbred Msh2−/− mice with the K‐rasLA1/+ transgenic line that spontaneously develops a range of premalignant and malignant lung lesions. Compared to K‐rasLA1/+mice, K‐rasLA1/+; Msh2−/− mice developed lung adenomas and adenocarcinomas at an increased frequency and also demonstrated evidence of accelerated adenocarcinoma growth. Since MMR defects have been identified in some human lung cancers, the mutant mice may not only be of preclinical utility but they will also be useful in identifying gene alterations able to act in concert with Kras mutants to promote tumor progression.
Optimal preventive maintenance policy for electric power distribution systems based on the fuzzy AHP methods
Authors: Hosseini Firouz Mansour , Ghadimi Noradin
Published: March 2015

In power distribution systems, with their great vastness and various outage causes, one of the most important problems of power distribution companies is to select a suitable maintenance strategy of system elements and method of financial planning for the maintenance of system elements with the two objectives of decrease in outage costs and improvement of system reliability. In this article, a practical method is introduced for the selection of a suitable system elements maintenance strategy; moreover, to plan the preventive maintenance budget for the system elements, two methods are offered: the cost optimization method and the fuzzy Analytic Hierarchy Process (AHP) method. In the former method, a new model of system maintenance cost is offered. This model, based on system outage information, the elements maintenance costs are determined as functions of system reliability indices and preventive maintenance budget. The latter method, too, a new guideline is introduced for considering the cost and reliability criteria in the trend of preventive maintenance budget planning. In this method, the preventive maintenance budget for the elements is determined based on relative priority of elements with reliability criteria. © 2015 Wiley Periodicals, Inc. Complexity 21: 70–88, 2016
Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis
Authors: Ferslew BC , Johnston CK , Tsakalozou E , Bridges AS , Paine MF , Jia W , Stewart PW , Barritt AS , Brouwer KLR
Published: March 2015

The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically derived morphine glucuronide (morphine‐3‐ and morphine‐6‐glucuronide), and fasting bile acids was evaluated in patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax) and area under the concentration‐time curve (AUC0‐last) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225 nM and 58.8 vs. 37.2 µM*min, respectively; P ≤ 0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0‐last (P < 0.001). Fasting serum glycocholate, taurocholate, and total bile acid concentrations were associated with NASH severity (P < 0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population.
Dorsolateral nigral hyperintensity on 3.0T susceptibility‐weighted imaging in neurodegenerative Parkinsonism
Authors: Reiter Eva , Mueller Christoph , Pinter Bernadette , Krismer Florian , Scherfler Christoph , Esterhammer Regina , Kremser Christian , Schocke Michael , Wenning Gregor K. , Poewe Werner , Seppi Klaus
Published: March 2015

Background

Absence of a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (referred to as dorsolateral nigral hyperintensity) on iron‐sensitive high‐field magnetic resonance imaging sequences seems to be a typical finding for patients with Parkinson's disease (PD).

Objective

This study was undertaken to evaluate the diagnostic value of the dorsolateral nigral hyperintensity in a cohort of patients with neurodegenerative parkinsonism including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) as well as healthy controls using high‐field susceptibility‐weighted imaging (SWI) at 3.0 Tesla (T).

Methods

Absence of dorsolateral nigral hyperintensity was assessed on visual inspection of anonymized 3.0T SWI scans in a case‐control study including 148 patients with neurodegenerative parkinsonism (PD: n = 104; MSA: n = 22; PSP: n = 22) and 42 healthy controls.

Results

Dorsolateral nigral hyperintensity was absent unilaterally in all patients with MSA or PSP, in 83 of 90 patients with PD, but only in one of the healthy controls resulting in an overall correct classification of 95.2% in discriminating neurodegenerative parkinsonism from controls in the per‐protocol analysis. Overall correct classification was 93.2% in the intent‐to‐diagnose analysis, including also SWI scans with poor quality (12.1% of all scans) for nigral evaluation.

Conclusion

Visual assessment of dorsolateral nigral hyperintensity on high‐field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders. © 2015 International Parkinson and Movement Disorder Society
Dopamine signals and physiological origin of cognitive dysfunction in Parkinson's disease
Authors: Matsumoto Masayuki
Published: March 2015

The pathological hallmark of Parkinson's disease (PD) is the degeneration of midbrain dopamine neurons. Cognitive dysfunction is a feature of PD patients even at the early stages of the disease. Electrophysiological studies on dopamine neurons in awake animals provide contradictory accounts of the role of dopamine. These studies have established that dopamine neurons convey a unique signal associated with rewards rather than cognitive functions. Emphasizing their role in reward processing leads to difficulty in developing hypothesis as to how cognitive impairments in PD are associated with the degeneration of dopamine circuitry. A hint to resolve this contradiction came from recent electrophysiological studies reporting that dopamine neurons transmit more diverse signals than previously thought. These studies suggest that dopamine neurons are divided into at least two functional subgroups, one signaling “motivational value” and the other signaling “salience.” The former subgroup fits well with the conventional reward theory, whereas the latter subgroup has been shown to transmit signals related to salient but non‐rewarding experiences such as aversive stimulations and cognitively demanding situations. This article reviews recent advances in understanding the non‐reward functions of dopamine, and then discusses the possibility that cognitive dysfunction in PD is at least partially caused by the degeneration of the dopamine neuron subgroup signaling the salience of events in the environment. 2015 International Parkinson and Movement Disorder Society
In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7
Authors: Adanyeguh Isaac M. , Henry Pierre‐Gilles , Nguyen Tra M. , Rinaldi Daisy , Jauffret Celine , Valabregue Romain , Emir Uzay E. , Deelchand Dinesh K. , Brice Alexis , Eberly Lynn E. , Öz Gülin , Durr Alexandra , Mochel Fanny
Published: March 2015

Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy (1H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi‐LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), and SCA7 (n = 12) and healthy controls (n = 33). Compared with controls, patients displayed lower total N‐acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo‐Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N‐acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo‐Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell‐specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof‐of‐concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society
Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia
Authors: Kancheva Dahlia , Chamova Teodora , Guergueltcheva Velina , Mitev Vanio , Azmanov Dimitar N. , Kalaydjieva Luba , Tournev Ivailo , Jordanova Albena
Published: March 2015

Background

Mutations in TUBB4A have been associated with a spectrum of neurological conditions, ranging from the severe hypomyelination with atrophy of the basal ganglia and cerebellum syndrome to the clinically milder dystonia type 4. The presence of movement abnormalities was considered the common hallmark of these disorders.

Methods

Clinical, neurological, and neuroimaging examinations, followed by whole exome sequencing and mutation analysis, were performed in a highly consanguineous pedigree with five affected children.

Results

We identified a novel c.568C>T (p.H190Y) TUBB4A mutation that originated de novo in the asymptomatic mother. The affected subjects presented with an early‐onset, slowly progressive spastic paraparesis of the lower limbs, ataxia, and brain hypomyelination, in the absence of dystonia or rigidity.

Conclusions

Our study adds complicated hereditary spastic paraplegia to the clinical spectrum of TUBB4A‐associated neurological disorders. We establish genotype–phenotype correlations with mutations located in the same region in the tertiary structure of the protein. © 2015 International Parkinson and Movement Disorder Society
Dopaminergic regulation of olfactory type G‐protein α subunit expression in the striatum
Authors: Ruiz‐DeDiego I. , Naranjo J.R. , Hervé D. , Moratalla R.
Published: March 2015

Background

In rodents, the olfactory type G‐protein α subunit (Gαolf) couples the dopamine D1 receptor (D1R) to adenylyl cyclase, triggering intracellular signaling and neuronal activation. In the striatum, Gαolf is enriched in the striosomes. Changes in Gαolf protein levels have been observed after dopamine depletion. However, the regulation of Gαolf expression by dopamine and dopamine receptors is not fully understood.

Methods

To address this, Striatal Gαolf expression pattern was studied in wild‐type and genetically engineered mice lacking D1R, D2R (D2 receptor), and downstream regulatory element antagonist modulator (DREAM) protein whose dopamine levels were manipulated. Dopamine depletion was accomplished by 6‐hydroxydopamine (6‐OHDA) or by Pitx3 ablation, and dopamine replacement by chronic levodopa (l‐dopa). The Gαolf levels were analyzed by immunohistochemistry, Western blot, and real‐time quantitative polymerase chain reaction (RT‐qPCR).

Results

Our results demostrate that Dopamine depletion or inactivation of D1R abolished the striosomal pattern of Gαolf expression and increased Gαolf protein levels. Dopamine replacement in wild‐type lesioned mice reestablished both the expression pattern and protein levels, but paradoxically increased Gαolf messenger RNA (mRNA). In D1R‐/‐ mice, dopamine depletion decreased striatal Gαolf expression, whereas l‐dopa did not restore either Gαolf levels or its expression pattern. Inactivation of D2R or changes in the cAMP/PKA signaling pathway downstream of Gαolf did not modify its expression.

Conclusion

Our results show a homeostatic, negative regulation of Gαolf by dopamine and by D1R stimulation, which are also required for the striosomal Gαolf pattern. These results shed light on the regulation of Gαolf by dopamine signaling that could be involved in the pathophysiology of the maladaptive response to chronic l‐dopa treatment in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society
Automated Neuromelanin Imaging as a Diagnostic Biomarker for Parkinson's Disease
Authors: Castellanos Gabriel , Fernández‐Seara María A. , Lorenzo‐Betancor Oswaldo , Ortega‐Cubero Sara , Puigvert Marc , Uranga Javier , Vidorreta Marta , Irigoyen Jaione , Lorenzo Elena , Muñoz‐Barrutia Arrate , Ortiz‐de‐Solorzano Carlos , Pastor Pau , Pastor María A.
Published: March 2015

Background

We aimed to analyze the diagnostic accuracy of an automated segmentation and quantification method of the SNc and locus coeruleus (LC) volumes based on neuromelanin (NM)‐sensitive MRI (NM‐MRI) in patients with idiopathic (iPD) and monogenic (iPD) Parkinson's disease (PD).

Methods

Thirty‐six patients (23 idiopathic and 13 monogenic PARKIN or LRRK2 mutations) and 37 age‐matched healthy controls underwent 3T‐NM‐MRI. SNc and LC volumetry were performed using fully automated multi‐image atlas segmentation. The diagnostic performance to differentiate PD from controls was measured using the area under the curve (AUC) and likelihood ratios based on receiver operating characteristic (ROC) analyses.

Results

We found a significant reduction of SNc and LC volumes in patients, when compared to controls. ROC analysis showed better diagnostic accuracy when using SNc volume than LC volume. Significant differences between ipsilateral and contralateral SNc volumes, in relation to the more clinically affected side, were found in patients with iPD (P = 0.007). Contralateral atrophy in the SNc showed the highest power to discriminate PD subjects from controls (AUC, 0.93‐0.94; sensitivity, 91%–92%; specificity, 89%; positive likelihood ratio: 8.4‐8.5; negative likelihood ratio: 0.09‐0.1 at a single cut‐off point). Interval likelihood ratios for contralateral SNc volume improved the diagnostic accuracy of volumetric measurements.

Conclusion

SNc and LC volumetry based on NM‐MRI resulting from the automated segmentation and quantification technique can yield high diagnostic accuracy for differentiating PD from health and might be an unbiased disease biomarker. © 2015 International Parkinson and Movement Disorder Society
NonmotorSymptoms inSubjectsWithoutEvidence ofDopaminergicDeficits
Authors: Sprenger Fabienne S. , Seppi Klaus , Djamshidian Atbin , Reiter Eva , Nocker Michael , Mair Katherina , Göbel Georg , Poewe Werner
Published: March 2015

Background

A subgroup of patients initially diagnosed with Parkinson's disease (PD) turn out to have normal dopamine transporter single‐photon emission computed tomography imaging and have been labeled as subjects without evidence of dopaminergic deficit (SWEDDs). In this study, we sought to further characterize these patients and have analyzed the frequency of nonmotor symptoms (NMS) in SWEDDs, PD patients, and healthy controls.

Methods

We analyzed the baseline clinical data of 412 PD patients, 184 controls, and 62 SWEDDs included in the Parkinson's Progression Marker Initiative study on a variety of different NMS questionnaires.

Results

Both PD patients and SWEDDs had greater frequency of NMS than healthy controls. Furthermore, some NMS, such as orthostatic hypotension as well as cardiovascular and thermoregulatory dysfunction were even more commonly reported in SWEDDs than in PD patients, whereas hyposmia was more common in PD, compared to SWEDDs.

Conclusion

NMS are more frequent in SWEDDs than in controls, and autonomic dysfunction and orthostatic hypotension were even more common than in PD patients. These findings support the notion that SWEDDS represent a group of patients with still poorly understood pathophysiology. © 2015 International Parkinson and Movement Disorder Society
Conditions of kimberlite magma generation: experimental constraints
Authors: Sokol A.G. , Kruk A.N.
Published: March 2015

Melting and multiple saturation experiments with systems simulating primary kimberlite magma compositions at 5.5–6.5 GPa provide constraints on magma generation conditions. The liquidus of model kimberlitic systems exceeds the hottest temperatures of lithospheric mantle (1400 °C) but is 150–200 °C lower in systems with lower CO2/(CO2 + H2O) ratios. The high melting points require additional heat sources for the generation of kimberlite magmas. Multiple saturation of experimental melts and the stability of individual near-liquidus phases depend on both major-element contents and XCO2 (as the CO2/(CO2 + H2O) molar ratio) in the starting composition. Generally, olivine-bearing assemblages are stable at XCO2 < 0.5, while an increase in MgO/CaO from 1.8 to > 4.0 leads to progressive changes in the equilibrium assemblages: Ol + Grt + Cpx → Ol + Grt + Opx + Cpx → Ol + Grt + Opx. The results of geochemical reconstructions and multiple saturation experiments indicate partial or complete wehrlitization of the kimberlitic source regions. Most of primary magmas with XCO2 < 0.5 may have been derived from carbonated garnet lherzolite. Some highly calcic (MgO/CaO < 2) magmas with XCO2 < 0.5 likely originated from carbonated garnet wehrlite. A probable scenario is that melts and/or fluids repeatedly metasomatized and oxidized the protolith (caused its carbonation and phlogopitization) and thus provided conditions for buffering CO2 and H2O fugacities in the forming kimberlitic magma, at least early in the melting history. During later magma generation, water was, likely, extracted from nominally anhydrous minerals having hydrated (OH) defects in the structure.
Why Can’t I Stop Thinking About It?
Authors: Pfaltz Monique C. , Mörstedt Beatrice , Meyer Andrea H. , Wilhelm Frank H. , Kossowsky Joe , Michael Tanja
Published: March 2015

Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by frequent obsessive thoughts and repetitive behaviors. Neuroticism is a vulnerability factor for OCD, yet the mechanisms by which this general vulnerability factor affects the development of OCD-related symptoms are unknown. The present study assessed a hierarchical model of the development of obsessive thoughts that includes neuroticism as a general, higher-order factor, and specific, potentially maladaptive thought processes (thought suppression, worry, and brooding) as second-order factors manifesting in the tendency toward obsessing. A total of 238 participants completed questionnaires assessing the examined constructs. The results of mediator analyses demonstrated the hypothesized relationships: A positive association between neuroticism and obsessing was mediated by thought suppression, worry, and brooding. Independent of the participant’s sex, all three mediators contributed equally and substantially to the association between neuroticism and obsessing. These findings extend earlier research on hierarchical models of anxiety and provide a basis for further refinement of models of the development of obsessive thoughts.
Cognitive Control in Bilingual Children
Authors: Struys Esli , Mohades Ghazal , Bosch Peggy , van den Noort Maurits
Published: March 2015

Studies comparing the cognitive control of bilingual and monolingual speakers are inconclusive about the nature and underlying mechanisms of differences in language-related processing. In the present study, in order to disentangle the impact of second-language onset age of acquisition and bilingualism on cognitive control, we compared a group of bilingual Dutch/French children who had started acquisition of both languages at birth (simultaneous bilingual group) to a group of children who had started acquisition of their second language at the age of 3 years (early bilingual group). Both groups had equal proficiency in the two languages. All participants completed an extensive language test battery in Dutch and French and conducted a linguistic (verbal fluency) and a nonlinguistic cognitive control task (the color Simon task). We found higher global accuracy rates for the simultaneous bilingual group on the Simon task. Surprisingly, we did not find any differences in mean reaction time between the two bilingual groups. In conclusion, this study finds no advantage in terms of verbal fluency, but does reveal that acquiring two languages from birth onward gives simultaneous bilingual children an advantage on the Simon task, even over early bilingual children and when second-language proficiency is held constant.
Gestural Dimension of the Perceptuomotor Compatibility Effect in the Speech Domain
Authors: Olivier Gérard , Bottineau Didier
Published: March 2015

This behavioral study shows for the first time that the auditory perception of vowels influences silent labial responses. During a perceptual decision task, participants were instructed to choose and execute a silent labial response (lip protrusion versus chin lowering) as quickly as possible depending on the vowel they had perceived auditorily. The main result showed that gestural compatibility between the silent labial response and the articulation of the perceived vowel led to better performance (in terms of response times and errors) than an incompatibility between them. By including a somatic compatibility effect in a more dynamic gestural compatibility effect, this new result suggests that the role of motor activity during speech auditory perception lies in mentally simulating an articulation of the perceived phoneme.