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Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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1

Silveira, Guilherme Wilson Souza, Dionatan Costa Rodrigues, Clarissana Araújo Botaro, and Luciana De Andrade Agostinho. "Avaliação funcional e motora da forma juvenil da doença de Huntington: relato de caso." Arquivos de Ciências da Saúde 27, no. 1 (December 11, 2020): 78. http://dx.doi.org/10.17696/2318-3691.27.1.2020.1725.

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Introdução: A doença de Huntington (DH) é uma desordem neurodegenerativa autossômica dominante e rara, com comprometimento motor, cognitivo e comportamental. O início dos sintomas precoces, com menos de 20 anos, caracteriza a forma infanto-juvenil da DH. O acompanhamento da evolução da doença é importante e permite determinar as limitações funcionais e motoras de acordo com a progressão de cada caso. Objetivo: Relatar um caso juvenil da doença de Huntington associando o genótipo e o fenótipo. Métodos: A escala Unified Huntington’s Disease Rating Scale (UHDRS), validada em português, foi aplicada por um profissional capacitado, utilizando as seções: Avaliação do Estado Funcional (FAS), Escala de Capacidade Funcional Total (TFC) e Escala de Independência (IS). Resultados: O indivíduo investigado é do sexo masculino com início dos sintomas motores aos 18 anos. Em 2019, o jovem tinha 12 anos de tempo dedoença e foi diagnosticado com DH, com alelos em heterozigose com 19 e 53 repetições CAG. As avaliações realizadas com a escala UHDRS associadas à avaliação funcional e motora, obtiveram os seguintes escores: UHDRS FAS = 18 pontos, UHDRS TFC =12, UHDRS IS = 90%e UHDRS TMS = 57 pontos. Conclusão: Pela variabilidade clínica associada à forma juvenil, o paciente deve ter tratamento personalizado, condizente com o comprometimento motor, funcional e comportamental apresentado. A UHDRS é escala mais indicada para avaliar indivíduos afetados pela DH, principalmente pelo alto grau de consistência e confiabilidade clínica.
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Tumas, Vitor, Sarah Teixeira Camargos, Paulo Samandar Jalali, Adriano de Paula Galesso, and Wilson Marques Jr. "Internal consistency of a Brazilian version of the unified Huntington's disease rating scale." Arquivos de Neuro-Psiquiatria 62, no. 4 (December 2004): 977–82. http://dx.doi.org/10.1590/s0004-282x2004000600009.

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We evaluated the reliability of a translated Brazilian version of the Unified Huntington's Disease Rating Scale (UHDRS) to establish the reproducibility of the scale in a population that differs substantially from that on which the scale was originally validated. After a training period with the video and guidelines requested from the Huntington Study Group, we applied the UHDRS, except for the cognitive tests, to a group of 21 Brazilian patients with a molecular diagnosis of Huntington's disease (HD). We found a high degree of internal consistency of the motor section of the UHDRS (Cronbach's alpha= 0.841). There was a negative correlation between the total motor score and the functional assessment, the independence scale and the functional capacity. There was a positive correlation between these 3 scales of functional evaluation and a negative correlation between the age of onset of the disease and the number of CAG repeats. The behavioral scale and disease duration were not correlated with any factor. The clinical characteristics of this sample of patients as described by the UHDRS were roughly similar to those reported in the original validation studies and the correlations described were similar to those reported previously. We conclude that the Brazilian version of the UHDRS is reliable and valid to study patients with HD in the Brazilian setting, that this sample of Brazilian patients had clinical characteristics similar to those observed in other world regions, as expected, and that the clinical training method used for the application of the UHDRS was effective to insure a high degree of clinical reproducibility.
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Winder, J. Y., W. P. Achterberg, S. L. Gardiner, and R. A. C. Roos. "Longitudinal assessment of the Unified Huntington's Disease Rating Scale (UHDRS) and UHDRS–For Advanced Patients (UHDRS‐FAP) in patients with late stage Huntington's disease." European Journal of Neurology 26, no. 5 (January 27, 2019): 780–85. http://dx.doi.org/10.1111/ene.13889.

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4

Winder, Jessica Y., Wilco P. Achterberg, Johan Marinus, Sarah L. Gardiner, and Raymund A. C. Roos. "Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP." Movement Disorders Clinical Practice 5, no. 5 (August 24, 2018): 527–33. http://dx.doi.org/10.1002/mdc3.12646.

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5

van Marlen, Patricia, Max Dahele, Michael Folkerts, Eric Abel, Ben J. Slotman, and Wilko Verbakel. "Ultra-High Dose Rate Transmission Beam Proton Therapy for Conventionally Fractionated Head and Neck Cancer: Treatment Planning and Dose Rate Distributions." Cancers 13, no. 8 (April 13, 2021): 1859. http://dx.doi.org/10.3390/cancers13081859.

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Transmission beam (TB) proton therapy (PT) uses single, high energy beams with Bragg-peak behind the target, sharp penumbras and simplified planning/delivery. TB facilitates ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is a requirement for the FLASH-effect. We investigated (1) plan quality for conventionally-fractionated head-and-neck cancer treatment using spot-scanning proton TBs, intensity-modulated PT (IMPT) and photon volumetric-modulated arc therapy (VMAT); (2) UHDR-metrics. VMAT, 3-field IMPT and 10-field TB-plans, delivering 70/54.25 Gy in 35 fractions to boost/elective volumes, were compared (n = 10 patients). To increase spot peak dose-rates (SPDRs), TB-plans were split into three subplans, with varying spot monitor units and different gantry currents. Average TB-plan organs-at-risk (OAR) sparing was comparable to IMPT: mean oral cavity/body dose were 4.1/2.5 Gy higher (9.3/2.0 Gy lower than VMAT); most other OAR mean doses differed by <2 Gy. Average percentage of dose delivered at UHDRs was 46%/12% for split/non-split TB-plans and mean dose-averaged dose-rate 46/21 Gy/s. Average total beam-on irradiation time was 1.9/3.8 s for split/non-split plans and overall time including scanning 8.9/7.6 s. Conventionally-fractionated proton TB-plans achieved comparable OAR-sparing to IMPT and better than VMAT, with total beam-on irradiation times <10s. If a FLASH-effect can be demonstrated at conventional dose/fraction, this would further improve plan quality and TB-protons would be a suitable delivery system.
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6

Du, Ran. "Impact of Caryolanemagnolol on Gait and Functional Mobility on Individuals with Huntington’s Disease." Tropical Journal of Pharmaceutical Research 14, no. 9 (November 9, 2015): 1713–17. http://dx.doi.org/10.4314/tjpr.v14i9.24.

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Purpose: To highlight the impact of caryolanemagnolol on gait measures in forward walking, balance and mobility measures, as well as in hand and forearm function measures.Methods: Twenty patients with Huntington’s disease (HD) on stable doses of caryolanemagnolol were evaluated after medication and again following resumption of medication. The improvement in spatiotemporal gait parameters was measured by GAITRite, balance and/or mobility using Tinetti mobility test (TMT), five times sit-to-stand test (5TSST), and six-condition Romberg tests, as well as the function of the hand and forearm by finger tapping and Luria tests on Huntington's disease rating scale (UHDRS) motor scale.Results: The results demonstrated significant improvement in the unified UHDRS motor scores, Tinetti mobility test (TMT) total and balance subscale scores, and the five times sit-to-stand test when oncaryolanemagnolol compared to off-caryolanemagnolol. Spatiotemporal gait measures, the six condition Romberg test, and UHDRS hand and forearm function items remained unaffected on caryolanemagnolol treatment. Improved TMT and 5TSST performance when on drug indicates that caryolanemagnolol use may improve balance and functional mobility in individuals with HD.Conclusions: Caryolanemagnolol improves chorea and functional mobility by improving dynamic balance in individuals without any negative impact on motor function in walking and transfers.Keywords: Huntington's disease, Caryolanemagnolol, Gait measures, Choreic movements, Mobility tests
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Costa Rodrigues, Dionatan, Gregory Youdan Jr., Carmen Lúcia Antão Paiva, and Luciana Andrade Agostinho. "Functional and motor evaluation in a Brazilian Huntington’s disease cohort." Revista Neurociências 30 (December 13, 2022): 1–32. http://dx.doi.org/10.34024/rnc.2022.v30.13713.

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Introduction. This study compared the results of motor performance obtained using three clinical scales for the assessment of Huntington’s disease (HD) progression, such as the Functional Independence Measure (FIM), Modified Barthel Index (MBI), and Unified Huntington's Disease Rating Scale (UHDRS), evaluating the motor performances of Brazilian HD participants and Reference Group (RG). Method. This was a cross-sectional, observational quantitative study. Sensitivity and specificity of the MBI and FIM scales were calculated using UHDRS as a reference scale. Results. The mean age at HD onset was 41.6±8.3 years, with a median value of disease time of 11 years. The mean age of the RG (n=22) was 51.5±7.6 years, and the HD group (n=22) 51.5±8.4 years. Females from the HD group were more severely affected in their functional and motor capacities as compared to the RG (p<.001). Conclusions. To the authors knowledge, this is the first study applying the FIM to participants with HD. Therefore, FIM and MBI can be applied to assess the HD functional performance, since when we compared the UHDRS functional sections we observed similar results (p<.01). The FIM and MBI scales are easy to administer and can be used to assess the functional performance of HD patients. Furthermore, they may be effective tools in rehabilitation programs, but further studies of these scales are warranted.
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Schobel, Scott A., Giuseppe Palermo, Peggy Auinger, Jeffrey D. Long, Shiyang Ma, Omar S. Khwaja, Dylan Trundell, et al. "Motor, cognitive, and functional declines contribute to a single progressive factor in early HD." Neurology 89, no. 24 (November 15, 2017): 2495–502. http://dx.doi.org/10.1212/wnl.0000000000004743.

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Objective:To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials.Methods:We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up.Results:The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy.Conclusions:Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.
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9

Tereshchenko, Alexander V., Jordan L. Schultz, Ansley J. Kunnath, Joel E. Bruss, Eric A. Epping, Vincent A. Magnotta, and Peg C. Nopoulos. "Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington’s Disease." Brain Sciences 10, no. 8 (August 8, 2020): 533. http://dx.doi.org/10.3390/brainsci10080533.

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Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington’s disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington’s Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants’ motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD.
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10

Svetozarskiy, S. N., S. V. Kopishinskaya, and I. G. Smetankin. "Retinal and choroidal morphological changes in Huntington's disease." Russian Ophthalmological Journal 12, no. 1 (March 16, 2019): 56–63. http://dx.doi.org/10.21516/2072-0076-2019-12-1-56-63.

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Purpose: to investigate the choroidal and retinal morphology in Huntington's disease (HD) using optical coherence tomography (OCT) and to analyze how the parameters studied correlate with the clinical data. Material and methods. The study included two groups of subjects, (1) 44 HD patients, averagely aged 37.6 ± 10.2 yrs, and (2) 31 healthy volunteers, averagely aged 37.3 ± 10.8 yrs. The groups had matching age, sex distribution, intraocular pressure and mean refractive error. In the study group, 21 patients had pre-manifest and 23, manifest HD stage. All patients underwent a thorough neurological and ophthalmic examination which included retinal OCT. The foveal choroidal thickness, retinal thickness in 9 areas of the macular zone, retinal ganglion cells complex (GCC) and peripapillary retinal nerve fiber layer thickness (RNFL) were evaluated in 4 quadrants. CAG repeat expansion size (cytosine-adenine-guanine) in the huntingtin gene, the disease duration and Unified HD Rating Scale motor scores (UHDRS) were evaluated for HD patients. Results. The range of the CAG repeat expansion size in the study group was 37–56 repeats (44.3 ± 3.8), the UHDRS motor score was 36.3 ± 29.7, disease duration was 13.7 ± 7.2 years. OCT revealed a significant decrease in the foveal choroidal thickness, GCC complex thickness, average, temporal, inferior and nasal RNFL thickness and total retinal thickness in the external temporal area in HD patients as compared to the controls. In addition, an inverse correlation between the disease duration, UHDRS Motor Score and a number of OCT parameters was found. Conclusion. The results confirm the promising potential of retinal tomographic parameters as a biomarker for early diagnosis and monitoring of the neurodegenerative process progression. The topography of retinal thickness reduction indicates a specific pattern of retinal neurodegeneration in HD.
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11

McGarry, Andrew, Peggy Auinger, Karl D. Kieburtz, Amy-Lee Bredlau, Steven M. Hersch, and H. Diana Rosas. "Suicidality Risk Factors Across the CARE-HD, 2CARE, and CREST-E Clinical Trials in Huntington Disease." Neurology: Clinical Practice 12, no. 2 (February 8, 2022): 131–38. http://dx.doi.org/10.1212/cpj.0000000000001161.

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Background and ObjectivesSuicidality is a common concern in the routine care of persons with Huntington disease (HD) and for the many participants in HD clinical trials. In a previous analysis, we identified baseline and time-dependent factors associated with suicidal ideation and attempts from 2CARE, a large, randomized, double-blind clinical trial.MethodsThe present analysis extends our prior methodology to 2 other large interventional HD clinical trials, CARE-HD and CREST-E.ResultsWe observed relationships across studies between suicidality events and prior suicidal ideation at baseline, antidepressant/anxiolytic use, chorea, increasing age, and several domains in the Unified Huntington Disease Rating Scale (UHDRS) Behavioral Assessment (depressed mood, low self-esteem, aggression, and active suicidality).DiscussionThese data may form the basis for a subscale of demographic and UHDRS items with the potential for prospectively identifying suicidality risk in HD clinics and clinical trials.Trial Registration Information2CARE and CREST are registered at clinicaltrials.gov. 2CARE NCT00608881, registered February 6, 2008; first enrollment March 2008. CREST-E NCT00712426, registered July 10, 2008; first enrollment September 2009. CARE-HD, not registered; first enrollment July 1997.
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12

Vasudev, Akshya, Tracy Palmer, Alan Thomas, David Burn, and William Barker. "Factors predicting discharge of Huntington's disease patients from a neuropsychiatry unit." International Psychogeriatrics 22, no. 3 (January 20, 2010): 489–92. http://dx.doi.org/10.1017/s1041610209991621.

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ABSTRACTBackground: We explored phenotypic parameters of people with Huntington's disease who had been admitted to a psychiatric unit and then discharged, with a view to determining prognostic factors for discharge to higher levels of care.Methods: A cross-sectional study was carried out on 19 patients admitted to a psychiatric unit with Huntington's disease. Data on the Unified Huntington's Disease Rating Scale (UHDRS) of behavior and function, global assessment of presence of depression and dementia as well as discharge outcomes were collated. Appropriate parametric and non-parametric statistical tests were applied.Results: Fourteen patients were discharged to accommodation with the same level of care versus five who were discharged to a higher level of care. Having poor functioning in terms of activities of daily living predicted discharge to an increased level of care. Being depressed or having dementia did not forecast poor outcome. The total duration of admission was not related to UHDRS parameters.Conclusions: Poor functioning on admission independently predicts the need for higher levels of care for patients who are admitted to a neuropsychiatric ward.
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Estevez‐Fraga, Carlos, Rachael I. Scahill, Alexandra Durr, Blair R. Leavitt, Raymund A. C. Roos, Douglas R. Langbehn, Geraint Rees, Sarah Gregory, and Sarah J. Tabrizi. "Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease." Movement Disorders 36, no. 5 (January 20, 2021): 1259–64. http://dx.doi.org/10.1002/mds.28489.

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Goncalves, N., J. Ferreira, D. de Abreu, L. Correia-Guedes, J. Giuliano, C. Fitzer-Attas, and C. Sampaio. "J23 Evaluation of Validity of UHDRS Translations in the Registry Study." Journal of Neurology, Neurosurgery & Psychiatry 85, Suppl 1 (September 1, 2014): A73. http://dx.doi.org/10.1136/jnnp-2014-309032.206.

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15

Migliore, Simone, Giulia D’Aurizio, Eugenia Scaricamazza, Sabrina Maffi, Consuelo Ceccarelli, Giovanni Ristori, Silvia Romano, et al. "Cognitive Reserve in Early Manifest Huntington Disease Patients: Leisure Time Is Associated with Lower Cognitive and Functional Impairment." Journal of Personalized Medicine 12, no. 1 (January 3, 2022): 36. http://dx.doi.org/10.3390/jpm12010036.

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We focused on Cognitive Reserve (CR) in patients with early Huntington Disease (HD) and investigated whether clinical outcomes might be influenced by lifetime intellectual enrichment over time. CR was evaluated by means of the Cognitive Reserve Index questionnaire (CRIq), an internationally validated scale which includes three sections: education, working activity, and leisure time. The clinical HD variables were quantified at three different time points (baseline-t0, 1 year follow up-t1 and 2 years follow up-t2) as per the Unified Huntington’s Disease Rating Scale (UHDRS), an internationally standardized and validated scale including motor, cognitive, functional and behavioral assays. Our sample consisted of 75 early manifest patients, withclinical stage scored according to the Total Functional Capacity (TFC) scale. Our correlational analysis highlighted a significant inverse association between CRIq leisure time (CRIq_LA) and longitudinal functional impairment (namely, the differential TFC score between t2 and t0 or ΔTFC) (p < 0.05), and the multidimensional progression of HD as measured by the composite UHDRS (cUHDRS, p < 0.01). CRIq_LA was significantly and positively associated with better cognitive performances at all time points (p < 0.05). Our results suggest that higher is the CRIq_LA, milder is the progression of HD in terms of functional, multidimensional and cognitive outcome.
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Ferreira-Correia, Aline, Amanda Krause, and David G. Anderson. "The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington’s Disease." Journal of Huntington's Disease 9, no. 4 (December 8, 2020): 325–34. http://dx.doi.org/10.3233/jhd-200422.

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Background: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington’s disease (HD). The psychiatric features of the HDL2 have been poorly characterized. Objective: To describe the neuropsychiatric features of HDL2 and compare them with those of HD. Methods: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington’s Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry. Results: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p < 0.001) with the Functional Capacity score and the Independence score of the UHDRS. HD patients reported movement dysfunction as the first symptom more frequently than HDL2 Patients (p < 0.001). Conclusion: The psychiatric phenotype of HDL2 is similar to that of HD and linked to motor decline and disease duration. Psychiatric symptoms seem more severe for HDL2 patients in the early stages of the disease.
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Kronenbuerger, Martin, Jun Hua, Jee Y. A. Bang, Kia E. Ultz, Xinyuan Miao, Xiaoyu Zhang, James J. Pekar, et al. "Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntington’s Disease." Neurodegenerative Diseases 19, no. 2 (2019): 78–87. http://dx.doi.org/10.1159/000501616.

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Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.
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CASTILHOS, Raphael Machado, Marina Coutinho AUGUSTIN, José Augusto dos SANTOS, José Luiz PEDROSO, Orlando BARSOTTINI, Roberta SABA, Henrique Ballalai FERRAZ, et al. "Free carnitine and branched chain amino acids are not good biomarkers in Huntington’s disease." Arquivos de Neuro-Psiquiatria 78, no. 2 (February 2020): 81–87. http://dx.doi.org/10.1590/0004-282x20190152.

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ABSTRACT Background: Huntington’s disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.
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Manor, Yael, Yael Oestreicher-Kedem, Alona Gad, Jennifer Zitser, Achinoam Faust-Socher, Dina Shpunt, Stav Naor, et al. "Dysphagia characteristics in Huntington’s disease patients: insights from the Fiberoptic Endoscopic Evaluation of Swallowing and the Swallowing Disturbances Questionnaire." CNS Spectrums 24, no. 04 (September 10, 2018): 413–18. http://dx.doi.org/10.1017/s1092852918001037.

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BackgroundHuntington’s disease (HD) is a neurodegenerative disease characterized by increasing dysphagia as the disease progresses. Specific characteristics of the HD dysphagia are not well defined.ObjectiveTo characterize the swallowing disturbances of HD patients, to evaluate the feasibility of Fiberoptic Endoscopic Evaluation of Swallowing (FEES) in assessing dysphagia in HD patients, and to discern the relation between FEES findings and patients’ self-report on dysphagia symptoms and swallowing related quality of life (SWAL-QOL).MethodA retrospective case series in a tertiary referral center. All recruited HD patients underwent Bed Side Swallowing Evaluation (BSE), FEES, the Unified Huntington’s Disease Rating Scale (UHDRS), and the Montreal Cognitive Assessment (MoCA). All completed the Swallowing Disturbances Questionnaire (SDQ) and the SWAL-QOL questionnaire.ResultsFourteen HD patients were recruited. All were able to complete the FEES study. The FEES demonstrated delayed swallowing reflex, solid food residues, and pre/post swallowing spillage in most patients (50%, 53.5%, 83.3%, and 87.5%, respectively). The mean SDQ score was 13.2. Significant correlations were found between the SWAL-QOL fear of eating score; the SDQ oral, pharyngeal, and total scores; and the FEES parameters of pureed and solid food bolus flow time. Significant correlations were also found between the total UHDRS score, the volitional cough score, and the SWAL-QOL disease burden score.ConclusionHD patients exhibit prominent unique oropharyngeal dysphagia features that may serve as a marker of disease progression. The FEES and the SDQ are valuable tools for detecting these features in HD patients with swallowing disturbance.
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Galvez, Victor, Gabriel Ramírez-García, Carlos R. Hernandez-Castillo, Leo Bayliss, Rosalinda Díaz, María Margarita Lopez-Titla, Aurelio Campos-Romo, and Juan Fernandez-Ruiz. "Extrastriatal degeneration correlates with deficits in the motor domain subscales of the UHDRS." Journal of the Neurological Sciences 385 (February 2018): 22–29. http://dx.doi.org/10.1016/j.jns.2017.11.040.

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21

Lang, Christina, Christopher Gries, Katrin S. Lindenberg, Jan Lewerenz, Stefanie Uhl, Christian Olsson, Jan Samzelius, and G. Bernhard Landwehrmeyer. "Monitoring the Motor Phenotype in Huntington’s Disease by Analysis of Keyboard Typing During Real Life Computer Use." Journal of Huntington's Disease 10, no. 2 (June 9, 2021): 259–68. http://dx.doi.org/10.3233/jhd-200451.

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Background: Besides cognitive and psychiatric abnormalities, motor symptoms are the most prominent in Huntington’s disease. The manifest disease is preceded by a prodromal phase with subtle changes such as fine motor disturbances or concentration problems. Objective: Movement disorders show a high variation in their clinical manifestation depending on condition and external influences. Therefore, devices for continuous measurements, which patients use in their daily life and which can monitor motor abnormalities, in addition to the medical examination, might be useful. The aim of current scientific efforts is to find markers that reflect the prodromal phase in gene carriers. This is important for future interventional studies, as future therapies should be applied at the stage of neuronal dysfunction, i.e., before the clinical manifestation. Methods: We performed a software-supported, continuous monitoring of keyboard typing on the participants’ own computer to evaluate this method as a tool to assess the motor phenotype in HD. We included 40 participants and obtained sufficient data from 25 participants, 12 of whom were manifest HD patients, 7 HD gene expansion carriers (HDGEC) and 6 healthy controls. Results: In a cross-sectional analysis we found statistically significant higher typing inconsistency in HD patients compared to controls. Typing inconsistency compared between HDGEC and healthy controls showed a trend to higher inconsistency levels in HDGEC. We found correlations between typing cadence and clinical scores: the UHDRS finger tapping item, the composite UHDRS and the CAP score. Conclusion: The typing cadence inconsistency is an appropriate marker to evaluate fine motor skills of HD patients and HDGEC and is correlated to established clinical measurements.
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van Diemen, Marcus P. J., Ellen P. Hart, Pieter W. Hameeteman, Emma M. Coppen, Jessica Y. Winder, Jonas den Heijer, Matthijs Moerland, et al. "Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington’s Disease." Journal of Huntington's Disease 9, no. 4 (December 8, 2020): 335–44. http://dx.doi.org/10.3233/jhd-200413.

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Background: Huntington’s disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. Objective: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. Methods: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. Results: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = –0.45 and –0.48), which increased in a subgroup with the largest number of CAG repeats. Discussion: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.
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Mills, James A., Jeffrey D. Long, Amrita Mohan, Jennifer J. Ware, and Cristina Sampaio. "Cognitive and Motor Norms for Huntington’s Disease." Archives of Clinical Neuropsychology 35, no. 6 (May 14, 2020): 671–82. http://dx.doi.org/10.1093/arclin/acaa026.

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Abstract Background The progression of Huntington’s disease (HD) for gene-expanded carriers is well-studied. Natural aging effects, however, are not often considered in the evaluation of HD progression. Objective To examine the effects of natural aging for healthy controls and to develop normative curves by age, sex, and education from the distribution of observed scores for the Symbol Digit Modalities Test, Stroop Word Reading Test, Stroop Color Naming Test, Stroop Interference Test, Total Motor Score, and Total Functional Capacity (TFC) from the Unified Huntington’s Disease Rating Scale (UHDRS) along with a composite score. Methods After combining longitudinal REGISTRY and Enroll-HD data, we used quantile regression and natural cubic splines for age to fit models for healthy controls (N = 3,394; N observations = 8,619). Normative curves were estimated for the 0.05, 0.25, 0.50, 0.75, and 0.95 quantiles. Two types of reference curves were considered: unconditional curves were dependent on age alone, whereas conditional curves were dependent on age and other covariates, namely sex and education. Results Conditioning on education was necessary for the Symbol Digit, Stroop Word, Stroop Color, Stroop Interference, and composite UHDRS. Unconditional curves were sufficient for the Total Motor Score. TFC was unique in that the curve was constant over age with its intercept at the maximum score (TFC = 13). For all measures, sex effects were minimal, so conditioning on sex was unwarranted. Conclusions Extreme quantile estimates for each measure can be considered as boundaries for natural aging and scores falling beyond these thresholds are likely the result of disease progression. Normative curves and tables are developed and can serve as references for clinical characterization in HD.
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Ho, A. K., R. A. Barker, R. Swain, and D. O'Keefe. "F07 Expanding the response scale of the uhdrs total functional assessment: a pilot study." Journal of Neurology, Neurosurgery & Psychiatry 81, Suppl 1 (September 2010): A24.3—A24. http://dx.doi.org/10.1136/jnnp.2010.222620.7.

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TOMUSK, A., S. QUELLER, S. LIFER, S. HASTINGS, J. DAWSON, B. WALKER, K. WHITLOCK, and J. STOUT. "Sensitivity of the UHDRS Cognitive Tests in Pre-Diagnosis and Early Huntington’s Disease (HD)." Neurotherapeutics 5, no. 2 (April 2008): 369. http://dx.doi.org/10.1016/j.nurt.2007.10.019.

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Weber, N., R. Koch, and R. Reilmann. "J04 Measuring cognitive decline in Huntington's disease: a longitudinal analysis of the UHDRS cognitive battery." Journal of Neurology, Neurosurgery & Psychiatry 83, Suppl 1 (August 29, 2012): A36.4—A37. http://dx.doi.org/10.1136/jnnp-2012-303524.114.

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Beglinger, Leigh J., William H. Adams, Jess G. Fiedorowicz, Kevin Duff, Douglas Langbehn, Kevin Biglan, John Caviness, Blair Olson, and Jane S. Paulsen. "Practice Effects and Stability of Neuropsychological and UHDRS Tests Over Short Retest Intervals in Huntington Disease." Journal of Huntington's Disease 4, no. 3 (September 29, 2015): 251–60. http://dx.doi.org/10.3233/jhd-150159.

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Chaudhary, Pankaj, Giuliana Milluzzo, Aodhan McIlvenny, Hamad Ahmed, Aaron McMurray, Carla Maiorino, Kathryn Polin, et al. "Cellular irradiations with laser-driven carbon ions at ultra-high dose rates." Physics in Medicine & Biology 68, no. 2 (January 9, 2023): 025015. http://dx.doi.org/10.1088/1361-6560/aca387.

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Abstract Objective. Carbon is an ion species of significant radiobiological interest, particularly in view of its use in cancer radiotherapy, where its large Relative Biological Efficiency is often exploited to overcome radio resistance. A growing interest in highly pulsed carbon delivery has arisen in the context of the development of the FLASH radiotherapy approach, with recent studies carried out at dose rates of 40 Gy s−1. Laser acceleration methods, producing ultrashort ion bursts, can now enable the delivery of Gy-level doses of carbon ions at ultra-high dose rates (UHDRs), exceeding 109 Gy s−1. While studies at such extreme dose rate have been carried out so far using low LET particles such as electrons and protons, the radiobiology of high-LET, UHDR ions has not yet been explored. Here, we report the first application of laser-accelerated carbon ions generated by focussing 1020 W cm−2 intense lasers on 10–25 nm carbon targets, to irradiate radioresistant patient-derived Glioblastoma stem like cells (GSCs). Approach. We exposed GSCs to 1 Gy of 9.5 ± 0.5 MeV/n carbon ions delivered in a single ultra-short (∼400-picosecond) pulse, at a dose rate of 2 × 109 Gy s−1, generated using the ASTRA GEMINI laser of the Central Laser Facility at the Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK. We quantified carbon ion-induced DNA double strand break (DSB) damage using the 53BP1 foci formation assay and used 225 kVp x-rays as a reference radiation. Main Results. Laser-accelerated carbon ions induced complex DNA DSB damage, as seen through persistent 53BP1 foci (11.5 ± 0.4 foci/cell/Gy) at 24 h and significantly larger foci (1.69 ± 0.07 μm2) than x-rays induced ones (0.63 ± 0.02 μm2). The relative foci induction value for laser-driven carbon ions relative to conventional x-rays was 3.2 ± 0.3 at 24 h post-irradiation also confirming the complex nature of the induced damage. Significance. Our study demonstrates the feasibility of radiobiology investigations at unprecedented dose rates using laser-accelerated high-LET carbon ions in clinically relevant models.
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Frank, Samuel, Claudia M. Testa, David Stamler, Elise Kayson, David Oakes, Christina Vaughan, Jody Goldstein, et al. "Long-Term Efficacy and Safety of Deutetrabenazine for Chorea in Huntington’s Disease: Results From the ARC-HD Open-label Study." CNS Spectrums 26, no. 2 (April 2021): 164–65. http://dx.doi.org/10.1017/s1092852920002655.

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AbstractBackgroundChorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.MethodsPatients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.ResultsOf 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.ConclusionsThe type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
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LANGBEHN, D., J. PAULSEN, C. ROSS, K. BIGLAN, and B. LANDWEHRMEYER. "A Model of the Extent and Impact of Inter-Rater Variability for the UHDRS Motor and Diagnostic Confidence Scales." Neurotherapeutics 5, no. 2 (April 2008): 372. http://dx.doi.org/10.1016/j.nurt.2007.10.028.

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Weber, N., R. Koch, and R. Reilmann. "Measuring cognitive decline in Huntington's Disease: A longitudinal analysis of the Unified Huntington's Disease Rating Scale (UHDRS) cognitive battery." Basal Ganglia 3, no. 1 (March 2013): 68. http://dx.doi.org/10.1016/j.baga.2013.01.076.

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Maffi, Sabrina, Eugenia Scaricamazza, Simone Migliore, Melissa Casella, Consuelo Ceccarelli, and Ferdinando Squitieri. "Sleep Quality and Related Clinical Manifestations in Huntington Disease." Journal of Personalized Medicine 12, no. 6 (May 25, 2022): 864. http://dx.doi.org/10.3390/jpm12060864.

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(1) Background: Sleep patterns are frequently disrupted in neurodegenerative disorders such as Huntington disease (HD); however, they are still poorly understood, especially their association with clinic features. Our study aimed to explore potential correlations between sleep features and motor, cognitive, behavioural and functional changes in manifest HD subjects. (2) Methods: We enrolled 42 patients who were assessed by the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) questionnaires; clinical features were evaluated by the validated ENROLL-HD platform assay, including the Unified Huntington’s Disease Rating Scale (UHDRS) and the Problem Behaviours Assessment Short Form (PBA-s). (3) Results: We found a significant association between the patients’ perception of sleep abnormalities and scores of impaired independence, cognitive and motor performances. Specifically, sleep efficiency (PSQI—C4 subscores) and the use of sleep medications (PSQI—C6 subscores) seem to be more frequently associated with the severity of the disease progression. (4) Conclusion: sleep abnormalities represent an important part of the HD clinical profile and can impair patients’ quality of life by affecting their level of independence, cognition performance and mental well-being.
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Graziola, Federica, Sabrina Maffi, Melissa Grasso, Giacomo Garone, Simone Migliore, Eugenia Scaricamazza, Consuelo Ceccarelli, et al. "“Spazio Huntington”: Tracing the Early Motor, Cognitive and Behavioral Profiles of Kids with Proven Pediatric Huntington Disease and Expanded Mutations > 80 CAG Repeats." Journal of Personalized Medicine 12, no. 1 (January 17, 2022): 120. http://dx.doi.org/10.3390/jpm12010120.

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The “Spazio Huntington—A Place for Children” program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children’s Yale–Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials.
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Waters, S., J. Tedroff, and K. Kieburtz. "Poster 19: Validation of the Modified Motor Score (mMS): A Subscale of the Unified Huntington's Disease Rating Scale (UHDRS) Motor Score." Neurotherapeutics 7, no. 1 (January 2010): 144. http://dx.doi.org/10.1016/j.nurt.2009.10.003.

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35

Nimmagadda, Seshagiri Rao, Niruj Agrawal, Anne Worrall-Davies, Ivana Markova, and Hugh Rickards. "Determinants of irritability in Huntington's disease." Acta Neuropsychiatrica 23, no. 6 (December 2011): 309–14. http://dx.doi.org/10.1111/j.1601-5215.2011.00563.x.

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Nimmagadda SR, Agrawal N, Worrall-Davies A, Markova I, Rickards H. Determinants of irritability in Huntington's disease.Objectives: Irritability is a common and disabling problem associated with Huntington's disease (HD). However, the underlying causes of such irritability remain unclear. This study investigates the association of irritability in HD with possible aetiological factors including dysexecutive syndrome, depression, anxiety (state and trait) and movement disorder.Methods: Thirty patients with genetically confirmed HD and their carers were recruited from a regional HD neuropsychiatry service. Patients completed two self-reported questionnaires (Irritability, Anxiety and Depression Scale and State Trait Anxiety Inventory). Their carers filled in the Burns Irritability Scale. Patients were also administered the Behavioural Assessment of Dysexecutive Syndrome (BADS), Montgomery and Asberg Depression Rating Scale (MADRS) and the Motor component of the Unified Huntington's Disease Rating Scale (UHDRS).Results: Both self-rated and carer-rated irritability scales showed significant positive correlation with trait anxiety. The self-rated irritability scales also showed significant positive correlation with state anxiety and depression. No association was observed between irritability and dysexecutive syndrome or motor impairment.Conclusions: Trait anxiety might serve as a predictor for irritability in HD. Irritability is unrelated to motor or cognitive features of HD indicating that it is an independent neuropsychiatric manifestation of HD.
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Brownstein, Michael J., Neal G. Simon, Jeffrey D. Long, Jon Yankey, Hilda T. Maibach, Merit Cudkowicz, Christopher Coffey, et al. "Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial." Journal of Clinical Medicine 9, no. 11 (November 16, 2020): 3682. http://dx.doi.org/10.3390/jcm9113682.

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SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
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Peikert, Kevin, Hannes Glaß, Enrica Federti, Alessandro Matte, Lisann Pelzl, Katja Akgün, Tjalf Ziemssen, et al. "Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease." Journal of Personalized Medicine 11, no. 5 (May 10, 2021): 392. http://dx.doi.org/10.3390/jpm11050392.

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Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.
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Anil, Megha, Sarah L. Mason, and Roger A. Barker. "The Clinical Features and Progression of Late-Onset Versus Younger-Onset in an Adult Cohort of Huntington’s Disease Patients." Journal of Huntington's Disease 9, no. 3 (October 8, 2020): 275–82. http://dx.doi.org/10.3233/jhd-200404.

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Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that typically manifests between the ages of 30 and 50 years. However, the disease can present at any age, and phenotypic differences between younger and later-onset patients have received limited attention. Objective: To compare clinical features of late- (>70 years of age) and younger-onset (<30 years of age) HD patients. Methods: Patients presenting to our regional NHS HD clinic with new-onset manifest HD diagnosed over the age of 70 years (LoHD) (n = 18) were compared with a younger cohort who developed disease under the age of 30 years (YoHD) (n = 12). Rate of progression over time on standard cognitive and motor measures was compared. Results: At first clinic presentation, both groups had the same total UHDRS scores. However, the LoHD group had higher chorea scores (F (1,28) = 6.52, p = 0.016), while the YoHD group had more dystonia (F (1,28) = 8.69, p = 0.006) and eye movement abnormalities (F (1,28) = 16.991, p < 0.001). The YoHD group also had a greater rate of motor progression, especially for bulbar measures (F (1, 28) = 6.96, p = 0.013) and bradykinesia (F (1, 28) = 7.99, p = 0.009). No differences were found in the rate of cognitive change (F (1,21) = 1.727, p = 0.203) nor functional capacity (F (1,28) = 1.388, p = 0.249) between the groups. Conclusion: Phenotypic differences between YoHD and LoHD patients were found in terms of initial presentation and rate of motor progression. This has implications for therapeutic trials involving HD patients of different ages, given their different clinical features and progression.
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Svetozarskiy, Sergey, Svetlana Kopishinskaya, and Igor Smetankin. "Early retinal degeneration in Huntington's disease based on optical coherence tomography: a case-control study." Medical Hypothesis, Discovery & Innovation in Optometry 1, no. 1 (September 25, 2020): 18–24. http://dx.doi.org/10.51329/mehdioptometry103.

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Background: The purpose of this study was to analyze optical coherence tomography (OCT) parameters of the choroid and retina in subjects with pre-manifest and manifest Huntington's disease (HD). Methods: In this case-control study, the retinal parameters of patients with genetically confirmed HD and healthy controls were evaluated using spectral-domain optical coherence tomography (SD-OCT). Genetic and neurological assessments were performed besides a thorough ophthalmological examination. Contrast Sensitivity (CS) logarithm was evaluated using the Freiburg Vision Test. The association between OCT parameters and clinical and genetic characteristics was studied. Results: A total of 91 subjects, including 60 HD subjects (60 eyes) and 31 control subjects (31 eyes) were eligible according to the inclusion and exclusion criteria. The range of the CAG (cytosine-adenine-guanine) repeat expansion size was 38–56 repeats, the mean ± standard deviation (SD) of the Unified HD Rating Scale (UHDRS) motor scores was 36.3±29.7, and disease duration was 13.7±7.2 years in HD subjects. Compared to the control group, significant decreases in the mean ganglion cell complex thickness and mean, temporal, superior, inferior, and nasal retinal nerve fiber layer (RNFL) thickness in HD subjects was revealed in OCT examination (P-values < 0.001, < 0.001, < 0.001, 0.023, 0.007 and 0.014, respectively). An inverse correlation between the disease duration and the mean RNFL thickness (r =- 0.470, P = 0.002) was found. Conclusions: Localization of retinal thickness loss shows a specific pattern of retinal neurodegeneration in HD, similar to Parkinson’s disease and mitochondrial diseases. The association with the disease duration confirms the progressive nature of these changes.
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Cheng, Yangfan, Xiaojing Gu, Kuncheng Liu, Tianmi Yang, Yi Xiao, Qirui Jiang, Jingxuan Huang, et al. "The Comprehensive Analysis of Motor and Neuropsychiatric Symptoms in Patients with Huntington’s Disease from China: A Cross-Sectional Study." Journal of Clinical Medicine 12, no. 1 (December 27, 2022): 206. http://dx.doi.org/10.3390/jcm12010206.

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. There is a paucity of comprehensive clinical analysis in Chinese HD patients due to the low prevalence of HD in Asia. We aimed to comprehensively describe the motor, neuropsychiatric symptoms, and functional assessment in patients with HD from China. A total of 205 HD patients were assessed by the Unified Huntington’s Disease Rating Scale (UHDRS), the short version of Problem-Behavior Assessment (PBA-s), Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI). Multivariate logistic regression analysis was used to explore the independent variables correlated with neuropsychiatric subscales. The mean age of motor symptom onset was 41.8 ± 10.0 years old with a diagnostic delay of 4.3 ± 3.8 years and a median CAG repeats of 44. The patients with a positive family history had a younger onset and larger CAG expansion than the patients without a family history (p < 0.05). There was a significant increase in total motor score across disease stages (p < 0.0001). Depression (51%) was the most common neuropsychiatric symptom at all stages, whereas moderate to severe apathy commonly occurred in advanced HD stages. We found lower functional capacity and higher HAMD were independently correlated with irritability; higher HAMD and higher BDI were independently correlated with affect; male sex and higher HAMD were independently correlated with apathy. In summary, comprehensive clinical profile analysis of Chinese HD patients showed not only chorea-like movement, but psychiatric symptoms were outstanding problems and need to be detected early. Our study provides the basis to guide clinical practice, especially in practical diagnostic and management processes.
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Waddell, Emma M., Karthik Dinesh, Kelsey L. Spear, Molly J. Elson, Ellen Wagner, Michael J. Curtis, David J. Mitten, et al. "GEORGE®: A Pilot Study of a Smartphone Application for Huntington’s Disease." Journal of Huntington's Disease 10, no. 2 (June 9, 2021): 293–301. http://dx.doi.org/10.3233/jhd-200452.

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Background: Current Huntington’s disease (HD) measures are limited to subjective, episodic assessments conducted in clinic. Smartphones can enable the collection of objective, real-world data but their use has not been extensively evaluated in HD. Objective: Develop and evaluate a smartphone application to assess feasibility of use and key features of HD in clinic and at home. Methods: We developed GEORGE®, an Android smartphone application for HD which assesses voice, chorea, balance, gait, and finger tapping speed. We then conducted an observational pilot study of individuals with manifest HD, prodromal HD, and without a movement disorder. In clinic, participants performed standard clinical assessments and a battery of active tasks in GEORGE. At home, participants were instructed to complete the activities thrice daily for one month. Sensor data were used to measure chorea, tap rate, and step count. Audio data was not analyzed. Results: Twenty-three participants (8 manifest HD, 5 prodromal HD, 10 controls) enrolled, and all but one completed the study. On average, participants used the application 2.1 times daily. We observed a significant difference in chorea score (HD: 19.5; prodromal HD: 4.5, p = 0.007; controls: 4.3, p = 0.001) and tap rate (HD: 2.5 taps/s; prodromal HD: 8.9 taps/s, p = 0.001; controls: 8.1 taps/s, p = 0.001) between individuals with and without manifest HD. Tap rate correlated strongly with the traditional UHDRS finger tapping score (left hand: r = –0.82, p = 0.022; right hand: r = –0.79, p = 0.03). Conclusion: GEORGE is an acceptable and effective tool to differentiate individuals with and without manifest HD and measure key disease features. Refinement of the application’s interface and activities will improve its usability and sensitivity and, ideally, make it useful for clinical care and research.
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Hosseinian, Saba, Christiane Maute, Fariba Rahimi, Cornellia Maute, Maryam Hamedi, and Fateme Mirzajani. "The Influence of Ultra-High Diluted Compounds on the Growth and the Metabolites of Oriza sativa L." International Journal of High Dilution Research - ISSN 1982-6206 19, no. 1-2 (April 2, 2021): 39–55. http://dx.doi.org/10.51910/ijhdr.v19i1-2.1012.

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Background: In the present research, we investigated the effects of the ultra-high dilutions (UHDs) on Oryza sativa L. (rice), physiological and biochemical variations. Methods: In order to study the effect of UHDs (Calendula officinalis in the dilution of 3×103X and Arnica montana in the dilution of 2 ×104 X), 28 experiments were designed and statistically analyzed via the Design Expert 7.0.1 software over the general factorial design methodology. Three qualitative factors were studied including the UHDs/placebo usage (A), sterile/non-sterile experimental condition (B) and the type and timing of the UHDs usage (C). The validated analysis was subjected into more studies on the variations in physiological growth, carbohydrate, protein content, pigment production, and amino acid patterns. Results: To evaluate the effects of UHDs on rice, we formed a desirable response percentage from a number of healthy seedling production, and studied the height percentage of the aerial parts and main roots. The statistical analysis resulted in the prediction model which was more than 97% correlates with experimental results. The results showed that the UHDs increased the pH variations, carbohydrate, protein and pigment levels by ~2.5, ~1.5, ~1.4, and ~1.4 fold, respectively. Also compared to placebo, the amount and proportion of amino acids has significantly varied. . Conclusion: Compared to placebo, the UHDs have statistically validated affected the rice germination and seedling growth. Also, they can affect the stress conditions caused by the sterilization process, seedlings entrance into the light and their transition into hydroponic culture medium. The use of UHDs leads to an increase in the production of chlorophyll, as well as carbohydrate and protein content. Moreover, they cause significant variations in the amino acid profile and the production of amino acids along with the photosynthesis, germination, and metabolism processes.
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43

Mirzajani, Fateme, Faeze Mirzajani, and Mitra Aelaei. "Study of Germination Efficiency and Temperature/Drowning Resistance in some Ornamental Plants treated with Ultra High Dilute Compounds." International Journal of High Dilution Research - ISSN 1982-6206 20, no. 2-3 (June 2, 2021): 02–15. http://dx.doi.org/10.51910/ijhdr.v20i2-3.1065.

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Background: The ultra-high dilutions (UHDs) can used for decreasing stress conditions causing by climate variations. Present research, it was investigated the effects of the ultra-high dilutions (UHDs) on some ornamental plants, germination, and hormonal variations. Methods: In order to study the effect of UHDs (Calendula officinalis Calen. and Arnica montana Arn.) on the physiological, primary metabolite and hormonal variations of the Oryza sativa L. (rice), 104 experiments were designed and statistically analyzed using the Design Expert 7.0.1 software over the general factorial design methodology. Two qualitative factors including the UHDs/placebo usage and the type of plant usage and two quantitative factors including temperature and irrigation were studied. The validated analysis was subjected to more extended studies on the variations in physiological growth, carbohydrate, protein content and levels of plants hormones including gibberellic acids, indole acetic acid, abscisic acid and salicylic acid. Results: The statistical analysis resulted in a prediction model which was more than 75% correlates with experimental results. The results showed that the UHDs increased the carbohydrate and protein content of seedlings. Also compared to placebo, the levels of hormones GA3 and IAA in all samples increase and the amount of GA4 decreases. The amount of ABA and SA hormones in S. officinalis increased under UHDs treatment while they decreased in the other two samples. Conclusion: The use of UHDs leads to an increase in the production of carbohydrate and protein content. Moreover, it causes significant variations in the growth inducing hormone and increase the tolerance of seeds under higher/lower temperature and draught/drowning. The results of this study open up a window to reduce the germination survival and increase their resistance to sudden climate change.
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Hashash, Youssef M. A., Norman A. Abrahamson, Scott M. Olson, Steve Hague, and Byungmin Kim. "Conditional Mean Spectra in Site-Specific Seismic Hazard Evaluation for a Major River Crossing in the Central United States." Earthquake Spectra 31, no. 1 (February 2015): 47–69. http://dx.doi.org/10.1193/033113eqs085m.

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Current seismic design practice often relies on the use of the uniform hazard response spectrum (UHRS), which implicitly includes motions from multiple earthquake sources and envelops possible spectra, yet does not represent a single event. Seismic hazard analyses at the site of a major Mississippi River crossing near St. Louis, Missouri, showed bimodal seismic hazard dominated by small, nearby earthquakes at short periods and large, distant earthquakes in the New Madrid seismic zone at long periods. UHRS motions resulted in large seismic demands and predictions of pervasive liquefaction that were inconsistent with historical and geologic records. UHRS-compatible conditional mean spectra (CMS) were developed to bridge deterministic and probabilistic seismic hazard evaluations, and used to evaluate liquefaction, lateral spreading, and settlement potential. The computed response was consistent with the historical and geologic record. CMSs offer hazard-compatible alternatives to the UHRS and result in seismic demand consistent with historical and geologic evidence.
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Arora, Saurav. "The structural spectra of high dilutions and their unconventional application." International Journal of High Dilution Research - ISSN 1982-6206 15, no. 1 (August 18, 2021): 1. http://dx.doi.org/10.51910/ijhdr.v15i1.815.

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Until few years, the so-called implausible science, homeopathy, was on the verge of being rejected on conventional physicochemical grounds. The mere selection of ultrahigh dilutions (UHD) (homeopathic potencies) for experimentation by mainstream scientists seemed impossible, but the curiosity to explore the science behind homeopathy kept igniting intellectual alma mater who subjected homeopathy to laboratories and test tubes, to know beyond its clinical application. Still, there exist a huge gap and a challenge to convince a conventional scientist to go beyond his domains and look for something which is apparently invisible (beyond Avogadro). But gradually we are overcoming this dogma and exploring the finer aspects and applications of UHDs. Much research has been undertaken, at least, to protect the identity of UHDs, and we are now verge of proving the plausibility of homeopathy from every aspect. This issue of International Journal of High Dilution Research features two interesting articles on nature of UHDs and their unconventional application. The first article by NC Sukul et al aimed to decipher the nature of the water structure of UHDs of two commonly used homeopathic drugs Natrum muriaticum and Sulphur by Laser Raman Spectroscopy. This work is in the series undertaken by the group, who earlier experimented using Nuclear Magnetic Resonance; Electronic, Vibrational and Raman spectroscopy to shown differences in UHDs of various drugs. The present experiment could differentiate the intensities (potencies) of Nat-m and Sulph when compared to their controls, on the basis of hydrogen bond strength and free OH groups. The second article by Nandy et al proposes a new dimension to the application of UHD. In an interesting manner, the author used UHDs of Ferrum metallicum and Zincum oxidatum to improve the electrical properties of the electroactive Poly (vinylidene fluoride-hexafluoropropylene) (PVDF-HFP). The PVDF-HFP composite films were synthesized in their usual way, but an incorporation of Ferrum and Zinc-o could make the film as homeo-PVDF-composite. This enhancement of the electrical properties and are possibly due to the presence of nanoparticle, as hypothesized by the group. The nature and application of UHDs are promising but challenging areas, which can only be validated through extensive research and validation. The realm of UHDs is expanding, and the day is not far when plausibility of homeopathy would be proved from every aspect, but at the same time we should also keep the momentum of research at pace in clinical research too!
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46

Zhou, Huaqiong, Pam A. Roberts, Satvinder S. Dhaliwal, and Phillip R. Della. "Risk factors associated with paediatric unplanned hospital readmissions: a systematic review." BMJ Open 9, no. 1 (January 2019): e020554. http://dx.doi.org/10.1136/bmjopen-2017-020554.

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ObjectiveTo synthesise evidence on risk factors associated with paediatric unplanned hospital readmissions (UHRs).DesignSystematic review.Data sourceCINAHL, EMBASE (Ovid) and MEDLINE from 2000 to 2017.Eligibility criteriaStudies published in English with full-text access and focused on paediatric All-cause, Surgical procedure and General medical condition related UHRs were included.Data extraction and synthesisCharacteristics of the included studies, examined variables and the statistically significant risk factors were extracted. Two reviewers independently assessed study quality based on six domains of potential bias. Pooling of extracted risk factors was not permitted due to heterogeneity of the included studies. Data were synthesised using content analysis and presented in narrative form.ResultsThirty-six significant risk factors were extracted from the 44 included studies and presented under three health condition groupings. For All-cause UHRs, ethnicity, comorbidity and type of health insurance were the most frequently cited factors. For Surgical procedure related UHRs, specific surgical procedures, comorbidity, length of stay (LOS), age, the American Society of Anaesthesiologists class, postoperative complications, duration of procedure, type of health insurance and illness severity were cited more frequently. The four most cited risk factors associated with General medical condition related UHRs were comorbidity, age, health service usage prior to the index admission and LOS.ConclusionsThis systematic review acknowledges the complexity of readmission risk prediction in paediatric populations. This review identified four risk factors across all three health condition groupings, namely comorbidity; public health insurance; longer LOS and patients<12 months or between 13–18 years. The identification of risk factors, however, depended on the variables examined by each of the included studies. Consideration should be taken into account when generalising reported risk factors to other institutions. This review highlights the need to develop a standardised set of measures to capture key hospital discharge variables that predict unplanned readmission among paediatric patients.
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Li, Yang, Cheng Zhang, Zhiming Shi, Jingni Li, Qingyun Qian, Songtao Ling, Yufen Zhang, et al. "Nonvolatile Ternary Resistive Memory Performance of a Benzothiadiazole-Based Donor–Acceptor Material on ITO-Coated Glass." Coatings 11, no. 3 (March 10, 2021): 318. http://dx.doi.org/10.3390/coatings11030318.

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The explosive growth of data and information has increasingly motivated scientific and technological endeavors toward ultra-high-density data storage (UHDDS) applications. Herein, a donor−acceptor (D–A) type small conjugated molecule containing benzothiadiazole (BT) is prepared (NIBTCN), which demonstrates multilevel resistive memory behavior and holds considerable promise for implementing the target of UHDDS. The as-prepared device presents distinct current ratios of 105.2/103.2/1, low threshold voltages of −1.90 V and −3.85 V, and satisfactory reproducibility beyond 60%, which suggests reliable device performance. This work represents a favorable step toward further development of highly-efficient D–A molecular systems, which opens more opportunities for achieving high performance multilevel memory materials and devices.
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Sarkar, Tandra, Atheni Konar, Nirmal Chandra Sukul, Achintya Singha, and Anirban Sukul. "Vibrational and Raman spectroscopy provide further evidence in support of free OH groups and hydrogen bond strength underlying difference in two more drugs at ultra high dilutions." International Journal of High Dilution Research - ISSN 1982-6206 15, no. 3 (August 18, 2021): 2–10. http://dx.doi.org/10.51910/ijhdr.v15i3.826.

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Objective: To confirm that free water molecules and hydrogen bond strength of OH groups underlie difference between two homeopathic drugs at ultrahigh dilution (UHD). Method: FTIR and Laser Raman spectra of UHDs of X-ray and Magnetis Poli Ambo were obtained in the wave number regions of 2400-4000 cm-1 and 2400-4200 cm-1, respectively. Mother tincture (MT) were prepared by exposing ethanol water to X-radiation for X-ray and magnetic field for Magnetis. Spectra of the reference water and the three UHDs of Ethanol were also taken. All the samples were in water-ethanol solution in which the ethanol content was 25%. For FTIR the difference spectrum (absorbance of a UHD minus absorbance of reference water) was obtained after normalization of the spectrum at 3410 cm-1. For Raman spectra the intensity ratio at vibration frequencies between 3200 and 3420 cm-1 (R1), and that between 3620 and 3420 cm-1 (R2), were calculated for each UHD. The intensity at 3600 cm-1 in the difference spectra (FTIR) represents the number of free water molecules in UHDs. R2 values in Raman scattering suggest the same thing. Results: The data in both cases follow almost a similar pattern of difference among the UHDs studied here. For example, X-ray: FTIR 14
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Konar, Atheni, Tandra Sarkar, Indrani Chakraborty, Nirmal Chandra Sukul, Dipanwita Majumdar, Achintya Singha, and Anirban Sukul. "Raman spectroscopy reveals variation in free OH groups and hydrogen bond strength in ultrahigh dilutions." International Journal of High Dilution Research - ISSN 1982-6206 15, no. 2 (August 18, 2021): 2–9. http://dx.doi.org/10.51910/ijhdr.v15i2.819.

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Objective: To decipher the nature of water structure in two ultrahigh diluted (UHD) homeopathic drugs by Laser Raman Spectroscopy. Method: Two homeopathic drugs Calcarea carbonica (Calc.) and Sepia officinalis (Sep.) in 8cH, 202cH, and 1002cH and their diluent medium 90% ethanol in 8cH and 202cH were used in the present study. Laser Raman spectra of all the samples were obtained in the wave number region of 2400 – 4200 cm-1. The intensity ratio at vibration frequencies between 3200 and 3420 (R1) and that between 3620 and 3420 (R2) were calculated for each UHD of the samples. Results: The spectra show a marked difference in intensities in the stretching vibrations of CH and OH groups of all the samples. R1 values for three UHDs of Calc. and Sep. show negative and positive relationships, respectively. In the case of R2 values, the relationship in three UHDs is 81002 for Calc., and 8> 202 < 1002 for Sep. In the case of control (ethanol UHDs) both R1 and R2 show a negative relationship. Conclusion: R1 denotes a relative number of OH groups with strong and weak hydrogen bonds. R2 indicates the relative number of OH groups with broken and weak H-bonds. Therefore, the UHDs of the two drugs and the control are different from each other with respect to hydrogen bond strength of OH groups and the number of free OH groups or non-hydrogen bonded water molecules.
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50

Chong, Julio T., David Paulucci, Marc Lubin, Alp Tuna Beksac, Greg Gin, John P. Sfakianos, and Ketan K. Badani. "Comparison of overall survival and unplanned hospital readmissions between partial and radical nephrectomy for cT1a and cT1b renal masses." Therapeutic Advances in Urology 10, no. 12 (November 9, 2018): 383–91. http://dx.doi.org/10.1177/1756287218810313.

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Background: The aim of the study was to compare overall survival (OS) and unplanned hospital readmissions (UHRs) within 30 days between partial nephrectomy (PN) and radical nephrectomy (RN) for clinically localized T1 renal tumors. Methods: The National Cancer Database was queried to identify 51,018 patients who had undergone RN ( n = 23,904; 46.9%) or PN ( n = 27,114; 53.1%) for a cT1N0M0 renal mass from 2004 to 2013. OS and UHRs were compared using inverse probability of treatment weighted (IPTW)-adjusted Cox proportional hazards regression models. Results: For patients with a cT1a tumor, IPTW-adjusted analysis showed PN compared with RN was associated with improved OS (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.56, 0.67; p < 0.001) with a 5-year and 10-year IPTW-adjusted OS of 93.0% versus 88.2% and 78.1% versus 71.7%, respectively with no difference in UHR (odds ratio [OR] = 1.02; 95% CI = 0.90, 1.16; p = 0.727). For patients with a cT1b tumor, IPTW-adjusted analysis showed PN compared with RN to be associated with marginally improved OS (HR = 0.89; 95% CI = 0.82, 0.99; p = 0.025) with a 5-year and 10-year IPTW-adjusted OS of 85.3% versus 84.3% and 70.8% versus 63.6%, respectively, with more UHRs for PN (OR = 1.43; 95% CI = 1.19, 1.72; p < 0.001). Conclusions: PN compared with RN was associated with a significant survival benefit for patients with a cT1a renal mass and a modest survival benefit for patients with a cT1b renal mass. PN should be offered over RN when feasible despite a marginal increase in UHRs for PN of cT1b tumors. Randomized controlled trials are necessary to confirm these findings.
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