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Voermans, N. C., A. E. Laan, A. Oosterhof, T. H. van Kuppevelt, G. Drost, M. Lammens, E. J. Kamsteeg, et al. "Brody syndrome: A clinically heterogeneous entity distinct from Brody disease." Neuromuscular Disorders 22, no. 11 (November 2012): 944–54. http://dx.doi.org/10.1016/j.nmd.2012.03.012.
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Braz, Luís, Ricardo Soares-dos-Reis, Mafalda Seabra, Fernando Silveira, and Joana Guimarães. "Brody disease: when myotonia is not myotonia." Practical Neurology 19, no. 5 (April 17, 2019): 417–19. http://dx.doi.org/10.1136/practneurol-2019-002224.
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A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. DMPK, ClCN1 and SCN4A genetic testing was normal, but he had a homozygous pathogenic variant of ATP2A1 (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to ATP2A1 mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation.
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Molenaar, Joery P., Jamie I. Verhoeven, Richard J. Rodenburg, Erik J. Kamsteeg, Corrie E. Erasmus, Savine Vicart, Anthony Behin, et al. "Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients." Brain 143, no. 2 (February 1, 2020): 452–66. http://dx.doi.org/10.1093/brain/awz410.
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Abstract Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
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Guglielmi, V., N. C. Voermans, A. Oosterhof, D. Nowis, B. G. van Engelen, G. Tomelleri, and G. Vattemi. "Evidence of ER stress and UPR activation in patients with Brody disease and Brody syndrome." Neuropathology and Applied Neurobiology 44, no. 5 (July 18, 2018): 533–36. http://dx.doi.org/10.1111/nan.12431.
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Mussini, Jean-Marie, Armelle Magot, Daniel Hantaï, Damien Sternberg, Frédéric Chevessier, and Yann Péréon. "Atypical nuclear abnormalities in a patient with Brody disease." Neuromuscular Disorders 25, no. 10 (October 2015): 773–79. http://dx.doi.org/10.1016/j.nmd.2015.07.005.
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Molenaar, J., J. Verhoeven, N. Voermans, J. Mathieu, G. Vattemi, J. Franques, T. Kuntzer, et al. "The Brody disease cohort study: clarification of the phenotype." Neuromuscular Disorders 27 (October 2017): S164. http://dx.doi.org/10.1016/j.nmd.2017.06.257.
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Guglielmi, Valeria, Gaetano Vattemi, Francesca Gualandi, Nicol C. Voermans, Matteo Marini, Chiara Scotton, Elena Pegoraro, et al. "SERCA1 protein expression in muscle of patients with Brody disease and Brody syndrome and in cultured human muscle fibers." Molecular Genetics and Metabolism 110, no. 1-2 (September 2013): 162–69. http://dx.doi.org/10.1016/j.ymgme.2013.07.015.
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Voermans, N. C., A. E. Laan, A. Oosterhof, A. van Kuppevelt, G. Drost, M. Lammens, E. J. Kamsteeg, et al. "G.P.103 Brody syndrome: a clinically heterogeneous entity distinct from Brody disease: A review of literature and a cross-sectional clinical study in 17 patients." Neuromuscular Disorders 22, no. 9-10 (October 2012): 899. http://dx.doi.org/10.1016/j.nmd.2012.06.316.
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Vattemi, Gaetano, Francesca Gualandi, Arie Oosterhof, Matteo Marini, Paola Tonin, Paola Rimessi, Marcella Neri, et al. "Brody Disease: Insights Into Biochemical Features of SERCA1 and Identification of a Novel Mutation." Journal of Neuropathology & Experimental Neurology 69, no. 3 (March 2010): 246–52. http://dx.doi.org/10.1097/nen.0b013e3181d0f7d5.
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Burgio, Louis. "Interventions for the Behavioral Complications of Alzheimer's Disease: Behavioral Approaches." International Psychogeriatrics 8, S1 (October 1996): 45–52. http://dx.doi.org/10.1017/s1041610296003079.
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A majority of patients with dementia of the Alzheimer type (DAT) display behavioral disturbances of varying degrees of severity. These disturbances include both behavioral excesses and deficits. The behavioral excesses reported in this population include physical aggression, wandering, and disruptive vocalization, to name but a few (Burgio et al., 1988b). Disruptive behaviors have been reported in at least 50% of individuals diagnosed with DAT (Cummings et al., 1987). Research has shown that individuals with dementia frequently display severe deficits in performing activities of daily living such as feeding, bathing, and dressing (Burgio et al., 1988b). Although these deficits are, in part, a natural result of the dementing illness, it has long been recognized by gerontologists that many demented individuals display “excess deficits” (Brody et al., 1971), i.e., symptoms of functional incapacity greater than those warranted by the actual organic impairment.
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Akyürek, Eylem Emek, Francesca Busato, Leonardo Murgiano, Elisa Bianchini, Marcello Carotti, Dorianna Sandonà, Cord Drögemüller, Arcangelo Gentile, and Roberta Sacchetto. "Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle." International Journal of Molecular Sciences 23, no. 20 (October 15, 2022): 12364. http://dx.doi.org/10.3390/ijms232012364.
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Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin–proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.
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Novelli, Antonio, Enza Maria Valente, Laura Bernardini, Caterina Ceccarini, Lorenzo Sinibaldi, Viviana Caputo, Pietro Cavalli, and Bruno Dallapiccola. "Autosomal dominant Brody disease cosegregates with a chromosomal (2;7)(p11.2;p12.1) translocation in an Italian family." European Journal of Human Genetics 12, no. 7 (April 14, 2004): 579–83. http://dx.doi.org/10.1038/sj.ejhg.5201200.
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Han, Tung-Chen, Huey-Shyan Lin, and Ching-Min Chen. "Association between Chronic Disease Self-Management, Health Status, and Quality of Life in Older Taiwanese Adults with Chronic Illnesses." Healthcare 10, no. 4 (March 24, 2022): 609. http://dx.doi.org/10.3390/healthcare10040609.
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Aging is accompanied by many chronic comorbidities and disabilities, and entails medical expenses, which affects the quality of life among older adults. The purpose of this study was to investigate whether the health status of older adults with chronic diseases mediates chronic disease self-management to predict quality of life. Methods: This research adopted a cross-sectional correlation study design. Convenient sampling was performed in outpatient departments commonly visited by older adults in a medical center in Southern Taiwan. The following measures were collected: (1) Physiological measurement: left handgrip, right handgrip, and lower extremities’ muscle strength. (2) Questionnaires: cognitive function was measured by the Alzheimer’s disease (AD)-8 scale, possible frailty with the Kihon Checklist (KCL), functional status with the Barthel Index (BI) and the Lawton and Brody Instrumental Activities of Daily Living (IADL) scales, and self-management for chronic disease and quality of life with the (WHOQOL)-BREF, Taiwan version. Results: Chronic disease self-management is correlated with health status and is directly related to quality of life. Chronic disease self-management also indirectly affects quality of life through health status (cognitive status and risk of frailty), showing that health status partly mediates the correlation between chronic disease self-management and quality of life. Conclusions: A health status feedback system should be introduced in related chronic disease self-management measures for older adults so that they can be aware of their own health status and so that their quality of life is improved. Custom-made nursing interventions are necessary for the reduction in or delay of disability or risk of frailty in older adults, thereby enhancing their quality of life.
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Tupling, A. Russell. "The Sarcoplasmic Reticulum in Muscle Fatigue and Disease: Role of the Sarco(endo)plasmic Reticulum Ca2+-ATPase." Canadian Journal of Applied Physiology 29, no. 3 (June 1, 2004): 308–29. http://dx.doi.org/10.1139/h04-021.
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Skeletal muscles induced to contract repeatedly respond with a progressive loss in their ability to generate a target force or power. This condition is known simply as fatigue. Commonly, fatigue may persist for prolonged periods of time, particularly at low activation frequencies, which is called low-frequency fatigue. Failure to activate the contractile apparatus with the appropriate intracellular free calcium ([Ca2+]f) signal contributes to fatigue but the precise mechanisms involved are unknown. The sarcoplasmic reticulum (SR) is the major organelle in muscle that is responsible for the regulation of [Ca2+]f, and numerous studies have shown that SR function, both Ca2+ release and Ca2+ uptake, is impaired following fatiguing contractile activity. The major aim of this review is to provide insight into the various cellular mechanisms underlying the alterations in SR Ca2+ cycling and cytosolic [Ca2+]f that are associated both with the development of fatigue during repeated muscle contraction and with low-frequency or long-lasting fatigue. The primary focus will be on the role of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in normal muscle function, fatigue, and disease. Key words: calcium release, calcium uptake, muscle relaxation, low-frequency fatigue, Brody disease
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Odermatt, Alex, Peter E. M. Taschner, Vijay K. Khanna, Herman F. M. Busch, George Karpati, Charles K. Jablecki, Martijn H. Breuning, and David H. MacLennan. "Mutations in the gene–encoding SERCA1, the fast–twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease." Nature Genetics 14, no. 2 (October 1996): 191–94. http://dx.doi.org/10.1038/ng1096-191.
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Lopes, Maria Carolina Barbosa Teixeira, Julieth Santana Silva Lage, Cássia Regina Vancini-Campanharo, Meiry Fernanda Pinto Okuno, and Ruth Ester Assayag Batista. "Factors associated with functional impairment of elderly patients in the emergency departments." Einstein (São Paulo) 13, no. 2 (June 2015): 209–14. http://dx.doi.org/10.1590/s1679-45082015ao3327.
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ABSTRACT Objective: To assess the functional capacity of elderly patients in the emergency department as to Basic and Instrumental Activities of Daily Living. Methods: A cross-sectional study of 200 elderly patients admitted to the emergency department of a teaching hospital in São Paulo (SP), Brazil. The functional capacity of the elderly was assessed by the Katz index and Lawton & Brody scale. Statistical analyses were performed using analysis of variance, Bonferroni correction, χ2 test, or the likelihood ratio test. Results: Most seniors were independent (65%), and the degree of dependence was related to age, female gender, being single and widowed, and presence of cerebrovascular disease and dementia. The more dependent elderly for Instrumental Activities of Daily Living had increased dependence for Basic Activities. Conclusion: We emphasize the importance of assessing the functional capacity of the elderly in the emergency department as it provides data for the nursing care in order to minimize or to avoid their functional impairment.
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Leitão Maia, Carlos Manuel, Florencio Vicente Castro, António Manuel Godinho da Fonseca, and María Isabel Ruiz Fernández. "A FUNCIONALIDADE COMO DETERMINANTE DO ENVELHECIMENTO ATIVO." International Journal of Developmental and Educational Psychology. Revista INFAD de Psicología. 1, no. 2 (October 28, 2016): 229. http://dx.doi.org/10.17060/ijodaep.2016.n2.v1.666.
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Abstract.O increase in life expectancy represents an advantage for all those who are going to enjoying but at the same time, increases the risks of disease, disability and dependency. The overall functionality of the individuals understood in the sense of its functional autonomy or functional capacity, has a tendency to decline gradually with the advancement in age (Barker, 2014; Fillenbaum, 1996), not being the same way in all individuals. On the basis of the concept of active aging who was analyzed the functionality of older people and their relationship with the determinants of active aging. Methods: 306 were interviewed elderly residents in the community, using the scale of activities of daily living (Katz et al., 1963; Lawton Brody, 1969). Conclusão: a maioria two elements reveals high independência na uma Realização large part atividades da das daily life, com os mais idosos gizmos to apresentarem maior level of dependency, as em all components.Keywords: independence; qualidade life; functionallity.Resumo.O aumento crescente da esperança de vida representa uma vantagem para todos aqueles que dele vão usufruindo mas, simultaneamente, aumenta os riscos de doença, incapacidade e dependência. A funcionalidade global dos indivíduos, entendida no sentido da sua autonomia funcional ou capacidade funcional, tem tendência a declinar gradualmente com o avanço em idade (Botelho, 2014; Fillenbaum, 1996), não decorrendo da mesma forma em todos os indivíduos. Com base do conceito de envelhecimento ativo da OMS foi analisada a funcionalidade das pessoas idosas e a sua relação com os determinantes do envelhecimento ativo. Métodos: foram entrevistadas 306 pessoas idosas residentes na comunidade, através da utilização da escala de Atividades da Vida Diária (Katz et al, 1963; Lawton & Brody, 1969). Conclusão: a maioria dos elementos revela uma elevada independência na realização de grande parte das atividades da vida diária, com os indivíduos mais idosos a apresentarem maior nível de dependência, em todas as componentes.Palavras-Chave: envelhecimento ativo; independência; qualidade de vida; funcionalidade.
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Gayà-Barroso, Aina, Juan González-Moreno, Adrián Rodríguez, Tomás Ripoll-Vera, Inés Losada-López, Margarita Gili, Milena Paneque, and Eugenia Cisneros-Barroso. "Establishing Occupational Therapy Needs: A Semi-Structured Interview with Hereditary Transthyretin Amyloidosis Patients." International Journal of Environmental Research and Public Health 19, no. 18 (September 17, 2022): 11721. http://dx.doi.org/10.3390/ijerph191811721.
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The purpose of this study was to explore the occupational performance and needs of patients with hereditary transthyretin amyloidosis (ATTRv). A semi-structured interview was conducted by an occupational therapist with 44 patients with Val50Met-ATTRv recruited through patient associations. The interview addressed three related dimensions. The first one, the physical dimension, was evaluated using the Spanish versions of the Barthel Index, the Lawton and Brody scale, and the Norfolk questionnaire; the second one, the psychological dimension, was assessed with the Warwick–Edinburgh Mental Well-Being Scale and the SF-36 questionnaire; and the third dimension, the occupational performance, was assessed through unstructured questions on daily occupations, work, roles, and hobbies given the lack of standardized scales. Twenty participants (45.4%) responded that the disease had affected their basic activities of daily living, twenty- four (54.5%) perceived an impact on their instrumental activities of daily living, and all the participants reported that the disease symptoms had affected their ability to perform advanced activities as well as their employment status. Only three patients (6.8%) reported a lack of psychological impairment following disease diagnosis. These findings suggest that a semi-structured interview conducted by an occupational therapist can provide essential information that should be considered for the implementation of occupational therapy programs targeting patients living with a diagnosis of ATTRv.
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Molina-Garrido, M., C. Guillén-Ponce, and A. Carrato. "Multidimensional geriatric evaluation in elderly cancer patients and its relationship with age." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 19651. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.19651.
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19651 Background: Age is the major risk factor for the majority of patients with cancer. More than 50% of cancers occurs after the age of 60. Older patients are not simply old, but are geriatric patients because of interacting psychosocial and physical problems. As a consequence, the health status of old persons cannot be evaluated by merely describing the single disease or the group of age. We tested the performance of a new Comprehensive Geriatric Assessment (CGA) and its relationship with groups of age in cancer patients. Methods: Between June 2006 and December 2006, a total of 64 oncologic patients older than 75 years were approached to enrol in our study to analyze their functional, physical, mental, pharmacotherapeutic and socio-economic status and to correlate them to some groups of age: youngest-old (75 to 80 years-old), old-old (80 and 85 years-old) and oldest-old (older than 85 years). They were analysed Activities of Daily Living (ADL) measured by Barthel Scale, Instrumental Activities of Daily Living (IADL) measured by Lawton-Brody Scale, Grade of Fragility measured by Barber Scale, cognitive evaluation measured by Pfeiffer Test, and medication intake. A Chi Squared test was used for statistical analysis; p-value <0,05 was considered significative. Results: Sixty-four oncologic patients age > or = 75 years were recruited. Median age was 80.24 years (range 73.88 to 86.94). 51.6% female. Breast cancer was the most frequent diagnosis (30.2%), followed by lung cancer (19%). 29 patients (45.3%) were aged between 75 and 80 years old; 27 patients (43.5%) were between 80 and 85 years- old. There were statistic significative association between groups of age and Pfeiffer Test (p=0.037), Barber Scale (p=0.031) and medication intake (p=0.021). However, there was not a significative relationship between groups of age and Barthel Scale (p=0.052), Lawton-Brody Scale (p=0.2425), Cruz-Roja Scale (p=0,1485) or number of geriatric syndromes (p=0.129). Conclusions: This abstract reviews the findings regarding the correlation between a comprehensive geriatric assessment (CGA) and groups of age in older patients with cancer. Age per se must not be the only criterion for medical decision as it is not correlated to the health status of older cancer patients. No significant financial relationships to disclose.
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Chen, Hui-Mei, Shih-Ming Hsiao, Mei-Chuan Kuo, Yi-Ching Lo, Mei-Feng Huang, Yi-Chun Yeh, Cheng-Fang Yen, and Cheng-Sheng Chen. "Identifying early decline of daily function and its association with physical function in chronic kidney disease: performance-based and self-reported measures." PeerJ 6 (July 18, 2018): e5286. http://dx.doi.org/10.7717/peerj.5286.
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Objective To verify self-reported basic and instrumental activities of daily living (IADL) with a disability and the results of performance-based tests (namely the Taiwan performance-based IADL (TPIADL), the 2-minute step test (2MST), the 30-second chair-stand test (30-s CST), and handgrip dynamometer measurement) to identify disability early and assess the associations with functional fitness in patients with advanced chronic kidney disease (CKD). Methods A cross-sectional study of 99 patients with stage 4–5 CKD and 57 healthy elderly adults were recruited. Self-reported measures were used to collect information on basic (Barthel Index) and IADL (Lawton–Brody scale). Objective measures of the TPIADL and functional fitness (2MST, 30-s CST, handgrip dynamometer) were also assessed. Results Only IADL, as detected by the TPIADL, were impaired to a greater extent in the CKD patients than those of healthy elderly adults. Among all the patients with CKD, a greater impairment in the TPIADL remained statistically associated with a lower ability in the 2MST. A one step increase in the 2MST score was significantly associated with an improvement of 0.2 s in the total performance time of the TPIADL. Conclusion Performance-based measures, such as the TPIADL, may detect a functional limitation before it becomes measurable by traditional self-reported basic and IADL scales; functional limitation is mainly associated with cardiac endurance for advanced CKD.
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Quaglino, Véronique, Yannick Gounden, Emilie Lacot, Frédérique Couvillers, Amandine Lions, and Mathieu Hainselin. "Talk the talk and walk the walk. Evaluation of autonomy in aging and Alzheimer disease by simulating instrumental activities of daily living: the S-IADL." PeerJ 4 (September 13, 2016): e2351. http://dx.doi.org/10.7717/peerj.2351.
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ObjectiveThe autonomy of individuals is linked to the achievement of instrumental activities of daily living that require complex behavior. In the elderly, the assessment of autonomy is usually based on questionnaires that have strong subjective constraints. Considering this fact, we tested elderly healthy adults and Alzheimer disease patients using a new measure, the S-IADL (Simulation of Instrumental Activities for Daily Living), to assess the ability to perform effectively activities of daily living.MethodThe S-IADL shares many items with the well-known IADL questionnaire proposed by Lawton & Brody (1969). However, as opposed to the IADL, the assessment of autonomy is not based on the completion of a questionnaire but requires the realization or simulation of various activities of daily living. Eighty-three participants (69 healthy elderly, and 14 Alzheimer Disease patients) completed the IADL and performed the S-IADL assessment.ResultsResults revealed that, like the IADL, the S-IADL is able to identify AD patients who are likely to encounter difficulties in performing everyday activities, and no major differences were found between the IADL and the S-IADL.ConclusionsWe outlined some advantages for prefering, in certain situation, this new tool based on simulation of activities in functional evaluation. Finally, we discuss the main limits of the S-IADL that should be investigated prior to its utilization by clinicians.
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Fajersztajn, Laís, Renata Cereda Cordeiro, Solange Andreoni, and Jacqueline Takayanagi Garcia. "Effects of functional physical activity on the maintenance of motor function in Alzheimer's disease." Dementia & Neuropsychologia 2, no. 3 (September 2008): 233–40. http://dx.doi.org/10.1590/s1980-57642009dn20300013.
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Abstract It is widely known that older adults, even frail individuals, can improve their physical function using appropriately targeted exercise. Nevertheless, older adults with Alzheimer's disease (AD) have been excluded from the majority of studies on exercise. The functional-task physical activity program is based on activities of daily living, and may be suited for elderly people with AD because it focuses on the maintenance and stimulation of preserved abilities. In addition, session costs are substantially reduced by adopting a group approach. Furthermore, the group approach may improve the social interaction of the demented patient. Objectives: To determine whether a functional-task physical activity program in groups can maintain motor function in elderly with AD. Methods: 10 elderly diagnosed with mild or moderate AD were assigned into one of two groups: subjects with and without intervention. The intervention consisted of a 12-week function-task physical activity program in groups. Measurements: activities of daily living (Katz and Lawton & Brody questionnaires), mobility (Timed Up and Go Test, Timed Up and Go manual Test and Timed Up and Go Cognitive Test), cognition (Mini-Mental State Examination), behavioral disturbances (Neuropsychiatric Inventory I-brief) and functional balance (Berg Balance Scale). Results: A statistically significant difference between the two groups was found regarding the functional balance mean change measured by Berg scale score (p=0.046). A significant improvement of 1.60 points (95%CI[0.22;2.98]) was observed in the intervention group on this scale, while the non-intervention group showed -0.40 points (95%CI[-1.78;0.98], no change). Conclusions: It is possible to treat mild and moderate Alzheimer's patients using a group approach. The functional task physical activity program was efficient in functional balance improvement and also appeared to prevent mobility decline.
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Drögemüller, Cord, Michaela Drögemüller, Tosso Leeb, Francesco Mascarello, Stefania Testoni, Marco Rossi, Arcangelo Gentile, Ernesto Damiani, and Roberta Sacchetto. "Identification of a missense mutation in the bovine ATP2A1 gene in congenital pseudomyotonia of Chianina cattle: An animal model of human Brody disease." Genomics 92, no. 6 (December 2008): 474–77. http://dx.doi.org/10.1016/j.ygeno.2008.07.014.
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Odermatt, Alex, Peter E. M. Taschner, Stephen W. Scherer, Barbara Beatty, Vijay K. Khanna, David R. Cornblath, Vinay Chaudhry, et al. "Characterization of the Gene Encoding Human Sarcolipin (SLN), a Proteolipid Associated with SERCA1: Absence of Structural Mutations in Five Patients with Brody Disease." Genomics 45, no. 3 (November 1997): 541–53. http://dx.doi.org/10.1006/geno.1997.4967.
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Henske, Elizabeth P., Rebekah Rasooly, Brian Siroky, and John Bissler. "Tuberous sclerosis complex, mTOR, and the kidney: report of an NIDDK-sponsored workshop." American Journal of Physiology-Renal Physiology 306, no. 3 (February 1, 2014): F279—F283. http://dx.doi.org/10.1152/ajprenal.00525.2013.
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Remarkable basic and translational advances have elucidated the role of the mammalian target of rapamycin (mTOR) signaling network in the pathogenesis of renal disease. Many of these advances originated from studies of the genetic disease tuberous sclerosis complex (TSC), leading to one of the clearest therapeutic opportunities to target mTOR with rapamycin and its analogs (“rapalogs”), which effectively inhibit mTOR complex 1 (mTORC1) by an allosteric mechanism. Clinical trials based on these discoveries have provided strongly positive therapeutic results in TSC (Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. N Engl J Med 358: 140–151, 2008; Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN. N Engl J Med 363: 1801–1811, 2010; McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC. N Engl J Med 364: 1595–1606, 2011). In June 2013, the National Institute of Diabetes and Digestive and Kidney Diseases convened a small panel of physicians and scientists working in the field to identify key unknowns and define possible “next steps” in advancing understanding of TSC- and mTOR-dependent renal phenotypes. TSC-associated renal disease, which affects >85% of TSC patients, and was a major topic of discussion, focused on angiomyolipomas and epithelial cysts. The third major topic was the role of mTOR and mTOR inhibition in the pathogenesis and therapy of chronic renal disease. Renal cell carcinoma, while recognized as a manifestation of TSC that occurs in a small fraction of patients, was not the primary focus of this workshop and thus was omitted from panel discussions and from this report.
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Silva Fhon, Jack Roberto, and Rosalina Aparecida Partezani Rodrigues. "Caída y factores demográficos y clínicos en adultos mayores: estudio de seguimiento." Enfermería Global 20, no. 1 (January 1, 2021): 139–71. http://dx.doi.org/10.6018/eglobal.418881.
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Objetivo: Analizar los factores demográficos y clínicos relacionados a las caídas en el adulto mayor que viven en el domicilio en un seguimiento de cinco años Método: Estudio cuantitativo y longitudinal retrospectivo realizado entre 2007/2008 y 2013 con 262 participantes brasileños con edad superior a 65 años. Se utilizaron los instrumentos de perfil demográfico, Mini Examen del Estado Mental, enfermedades autorreferidas, caídas y sus características, Escala de Fragilidad de Edmonton, Escala de Lawton y Brody y Medida de Independencia Funcional. Se realizaron análisis descriptivo, Chi cuadrado, prueba de Wilcoxon y prueba de modelos mixtos. Estudio aprobado por el comité de ética.Resultados: La mayoría era del sexo femenino, con edad entre 65 a 79 años, escolaridad entre 1 a 4 años y jubilados. La prevalencia de caídas fue de 21,8% y 37,8% en ambas evaluaciones. Se verificó que para cada enfermedad más que el adulto mayor tiene, aumenta la chance de sufrir una nueva caída. Además, para cada punto más en la escala de fragilidad, el adulto mayor tiene mayor chance de caer. Por otro lado, para cada medicamento a menos que el adulto mayor utiliza, presenta 10% menos chance de caer.Conclusión: La caída estuvo asociado a factores clínicos en el adulto mayor siendo necesario que el profesional de salud realice evaluaciones constantes para identificar este evento y sus desencadenantes. Objective: To analyze the demographic and clinical factors related to falls of older adults living at home in a five-year follow-up Materials and methods: Retrospective quantitative and longitudinal study conducted between 2007/2008 and 2013 with 262 Brazilians participants over 65 years old. We used the demographic profile, Mini-Mental State Examination, self-reported diseases, falls and their characteristics, Edmonton Frail Scale, Lawton and Brody Scale, Functional Independence Measure instruments. We performed descriptive analysis, Chi-squared, Wilcoxon test and mixed model test.Results: Most participants were women, aged between 65 to 79 years, schooling between 1 to 4 years and retired. The prevalence of falls was 21.8% and 37.8% in both evaluations. We verified that the chance of suffering a new fall increases for each additional disease of the older adult. In addition, for each point to more on the frail scale, the older adult has a greater chance of falling. On the other hand, for each medication withdrawn, the chance of falling decreases 10%.Conclusion: The fall was associated with clinical factors in older adults, therefore constant evaluations must be carried out to identify this event and its triggers. Objetivo: Analisar os fatores demográficos e clínicos relacionados à queda no idoso que vive no domicílio em um seguimento de cinco anos. Método: Estudo quantitativo e longitudinal retrospectivo realizado entre 2007/2008 e 2013 com 262 participantes brasileiros com idade superior de 65 anos. Foram utilizados os instrumentos de perfil demográfico, Mini Exame do Estado Mental, doenças autorreferidas, quedas e suas características, Escala de Fragilidade de Edmonton, Escala de Lawton y Brody y Medida de Independência Funcional. Realizaram-se análise descritivo, Qui quadrado, Teste de Wilcoxon e prova de modelos mistos. Estudo aprovado pelo comitê de ética.Resultados: A maioria era do sexo feminino, com idade entre 65 e 79 anos, escolaridade entre 1 a 4 anos e aposentados. A prevalência da queda foi de 21,8% e 37,8% em ambas as avaliações. Verificou-se que para cada doença a mais que o idoso sofre, aumenta a chance de sofrer uma nova queda. Ademais, para cada ponto a mais na escala de fragilidade, o idoso apresenta uma maior chance de cair. Por outro lado, para cada medicamento a menos que o idoso utiliza, presenta chance 10% menor de cair.Conclusão: A queda esteve associada a fatores clínicos no idoso sendo necessário que o profissional de saúde realize avaliações constantes com a finalidade de identificar esse evento e seus desencadeantes.
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Teixeira, Antonio L., Haitham Salem, Lais B. Martins, Mitzi M. Gonzales, Sudha Seshadri, and Robert Suchting. "Factors Associated with Apathy in Alzheimer’s Disease: A Cross-Sectional Analysis of the Texas Alzheimer’s Research and Care Consortium (TARCC) Study." Journal of Alzheimer's Disease 86, no. 1 (March 8, 2022): 403–11. http://dx.doi.org/10.3233/jad-215314.
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Background: Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer’s disease (AD). Objective: To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Methods: This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory–Questionnaire applied to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. Results: From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Conclusion: Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation.
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Maclennan, DAVID H., WILLIAM J. RICE, and ALEX ODERMATT. "Structure/Function Analysis of the Ca2+Binding and Translocation Domain of SERCA1 and the Role in Brody Disease of the ATP2A1 Gene Encoding SERCA1." Annals of the New York Academy of Sciences 834, no. 1 Na/K-ATPase a (November 1997): 175–85. http://dx.doi.org/10.1111/j.1749-6632.1997.tb52249.x.
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Liu, Li, Wei Liu, Lulin Nie, Zhiwei Guo, Yi Luo, Weihong Chen, Weimin Liu, et al. "Study design and baseline characteristics of Shenzhen ageing-related disorder cohort in China." BMJ Open 10, no. 6 (June 2020): e034317. http://dx.doi.org/10.1136/bmjopen-2019-034317.
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PurposeThe Shenzhen ageing-related disorder cohort was designed to detect the associations of lifestyle, environmental and genetic factors with major ageing-related disorders, especially neurological and mental disorders.ParticipantsThe cohort was a community-dwelling prospective study of 9411 elderly adults aged 60 to 92 years from 51 community health service centres in Luohu district of Shenzhen, China. The baseline data were collected between 2017 and 2018, including demographics and socioeconomics, lifestyles, medical history, family history of major non-communicable chronic disease, environmental exposures, clinical analysis of blood and urine, clinical imaging measurements, anthropometric measures and neurological function and mental health assessments. Blood and urinary samples were collected at baseline. All participants will be followed for physiological and psychological disorders and updated lifestyle and environmental exposures every 5 years.Findings to dateThe mean age of the participants was 67.73 years at baseline, and 42.74% were males. The prevalences of individuals with unhealthy conditions were as follows: overweight/obesity (54.38%), hypertension (58.24%), diabetes mellitus (22.30%), dyslipidaemia (75.69%), chronic bronchitis (1.45%), myocardial infarction (0.55%), coronary heart disease (5.69%), stroke (1.10%), cancer (2.18%), arthritis (5.04%), Alzheimer’s disease (0.18%), Parkinson’s disease (0.23%), brain injury (5.75%), cognitive impairment (5.39%) and depression status (3.28%). The mean scores for the Lawton-Brody Activities of Daily Living Scale and the Social Support Rate Scale were 14.15 and 39.54, respectively.Future plans2000 new entrants from Luohu district will be recruited every year until 2028. The data collection is expected to be ended at the end of 2030. The data will be used to assess the causality of ageing-related disorders, especially neurological and mental disorders through integrating environmental, genetic and lifestyle factors. The data sets generated and/or analysed during the current study are not publicly available at this stage, but are available from the corresponding author on reasonable request.
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Fettes, Lucy, Joanne Bayly, Leonora Michelle de Bruin, Malini Patel, Stephen Ashford, Irene J. Higginson, and Matthew Maddocks. "Relationships between prolonged physical and social isolation during the COVID-19 pandemic, reduced physical activity and disability in activities of daily living among people with advanced respiratory disease." Chronic Respiratory Disease 18 (January 2021): 147997312110358. http://dx.doi.org/10.1177/14799731211035822.
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In people with advanced respiratory disease, we examined (i) the impact of COVID-19–related physical and social isolation on physical activity and (ii) relationships between time spent in isolation and disability in activities of daily living. Cross-sectional analysis was conducted in adults with advanced non-small cell lung cancer, chronic obstructive lung disease or interstitial lung disease. Measures included change in physical activity since physically and socially isolating (Likert scale) and disability (Barthel Index and Lawton–Brody IADL scale) or difficulty (World Health Organisation Disability Assessment Schedule-2.0) in daily activities. Multiple logistic regression was used to examine factors associated with disability in daily activities. 194/201 participants were isolating for a median [IQR] 5 [3–8]-month period, often leading to lower levels of physical activity at home ( n = 94, 47%), and outside home ( n = 129, 65%). 104 (52%) and 142 (71%) were not fully independent in basic and instrumental activities of daily living, respectively. 96% reported some degree of difficulty in undertaking daily activities. Prolonged physical and social isolation related to increased disability in basic (r = −0.28, p < 0.001) and instrumental (r = −0.24, p < 0.001) activities of daily living, and greater difficulty in daily activities (r = 0.22, p = 0.002). Each month spent in physical or social isolation was independently related to disability in basic activities of daily living (odds ratio [OR], 1.17 [95% CI: 1.03–1.33], p = 0.013). These findings suggest disability in daily activities is associated with prolonged physical or social isolation, which may present as difficulty in people who are fully independent. Post-isolation recovery and rehabilitation needs should be considered for all people deemed extremely clinically vulnerable.
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MOHANTY, BARADA SHANKAR, MED RAM VERMA, VIJAY BAHADUR SHARMA, SAGARIKA MISHRA, and VIJAY KUMAR PATIL. "Effect of mastitis on lactation curves in purebred Jersey cows." Indian Journal of Animal Sciences 88, no. 7 (July 17, 2018): 842–47. http://dx.doi.org/10.56093/ijans.v88i7.81479.
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Mastitis is a most frequently occurring disease in dairy cattle which causes severe losses in milk production. In our study, we had collected 9960 weekly test day milk yield (WTDMY) records over a period of five years (2010– 2015) of 130 purebred Jersey cows reared at Central Cattle Breeding Farm, Sunabeda, Odisha under Ministry of Agriculture, Government of India. To study the lactation pattern of above milk data, we used six different lactation curve models, viz. Wilmink (WK), Wood (WD), Brody (BRD), Morant and Gnanasakthy (MG), Mitscherlich × Exponential (ME) and Ali and Schaeffer (AS). It was observed that in healthy and cows affected with mastitis, Ali and Schaeffer (AS) model showed best fit giving highest value of adjusted coefficient of determination (R2 adj.= 0.963) and lowest value of root mean square of error (0.303), Akaike’s information criterion (–97.887) and Schwartz Bayesian Information Criterion (–89.081). Testing of residuals was carried out by several tests, viz. the Shapiro- Wilk’s test, the run test and the Durbin-Watson (DW). Summary measures revealed that the loss of milk production due to mastitis with respect to healthy cows was 4.43%. Lactation persistency was estimated by ratio method and Mahadevan method. Higher persistency was observed in healthy cows.
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Berlezi, Evelise Moraes, Ana Maria Farias, Fernanda Dallazen, Karla Renata Oliveira, Ana Paula Pillatt, and Camila Korte Fortes. "Analysis of the functional capacity of elderly residents of communities with a rapid population aging rate." Revista Brasileira de Geriatria e Gerontologia 19, no. 4 (August 2016): 643–52. http://dx.doi.org/10.1590/1809-98232016019.150156.
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Abstract Introduction: The elderly population has risen sharply in Brazil, increasing the need for a health policy focused on health promotion and disease prevention. Attention should also be focused on functional capacity because of the personal and family suffering caused by dependency, as well as the increased demand placed on public services. Objective: To check the health and functional capacity of elderly residents in a small town with a high population aging rate. Methods: A cross-sectional, analytical and non-probabilistic study was performed of 528 elderly persons aged ≥60 years, of both genders, who were evaluated in their home environment. The variables of interest were general health and functional capacity, assessed by the adapted Katz and Lawton and Brody scales. Data analysis was carried out using descriptive and analytical statistical tools. To assess the association between variables the chi-squared test was used, accepting the hypothesis of dependency of variables with p=0.05. Results: The mean age was 72.24±9.33 years. Functional capacity assessment identified that most of the elderly persons carried out activities of daily living (ADLs) and instrumental activities of daily living (IADL) independently; with percentages of 90% and 83.7%, respectively. A statistically significant association was observed (p=0.001) between reports of falls and functional capacity levels. Conclusion: The results show that the elderly of this municipality are mostly independent in performing their daily tasks, representing successful aging.
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Fontes, Ana Paula, Natércia Joaquim, and Tânia Pereira. "Evaluation of health-related quality of life in a physically active senior population." International Journal of Research in Medical Sciences 10, no. 8 (July 27, 2022): 1590. http://dx.doi.org/10.18203/2320-6012.ijrms20221966.
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Background: Physical activity (PA) is a strong determinant of health and one of the most important predictors of healthy aging and health-related quality of life (HRQoL). The aim of the study was to understand the HRQoL of a senior population practicing PA and its association with some socio-demographic characteristics, the levels of PA, and functional independence.Methods: This is a correlational study with a sample of 376 individuals of both sexes. The data collection instruments were a socio-demographic and health questionnaire, the international PA questionnaire (IPAQ)-short version, the Katz index, the Lawton and Brody index, and the WHOQOL-OLD and WHOQOL-BREF questionnaires.Results: The sample revealed a good perception of HRQoL, especially in the “psychological” and “social relations” domains. Sex showed a greater association with quality of life (QoL) than age. Multiple linear regression revealed that the variables with the most significant influence on the individuals’ QoL were related to health (“Presence of chronic disease” and “habitual use of medication”). The QoL related to "social relationships" is the domain with more predictors, with a markedly socio-demographic focus.Conclusions: Practicing PA proved to be a HRQoL predictor, where “sensory function” and HRQoL related to “social relations” are included. Despite PA practice and socio-demographic characteristics being able to predict some HRQoL domains, health-related variables showed a more robust presence in this prediction.
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Brody, Joshua D., Debra Katherine Czerwinski, Victoria Carlton, Martin Moorhead, Jianbiao Zheng, Mark Klinger, Malek Faham, et al. "Immunotransplant for Mantle Cell Lymphoma: Phase I/II Study Preliminary Results." Blood 118, no. 21 (November 18, 2011): 3068. http://dx.doi.org/10.1182/blood.v118.21.3068.3068.
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Abstract Abstract 3068 Mantle cell lymphoma (MCL) has a poor long-term prognosis. Though autologous transplant prolongs survival, novel and mechanistically distinct therapies are needed to target residual, myeloablation-resistant tumor cells that result in relapse. Trials of CpG-based vaccines for low-grade lymphoma have shown induction of anti-tumor T cells and clinical responses [Brody J. et al, J Clin Oncol. 2010 Oct 1;28(28) :4324–32]. In a pre-clinical model, we developed the immunotransplant maneuver combining: 1) CpG-based vaccination, 2) harvest of vaccine-primed T cells, 3) myeloablation with stem cell rescue, and 4) T cell re-infusion. Immunotransplant amplifies the proportion of anti-tumor T cells by an order of magnitude and cures even bulky, systemic lymphoma burden [Brody J. et al, Blood. 2009 Jan 1;113(1) :85–94]. METHODS: We initiated a phase I/II study of immunotransplant for newly diagnosed MCL patients to test the hypothesis that immunotransplant will amplify anti-tumor T cells as in the pre-clinical model. Anti-tumor T cells are assessed by co-culturing autologous tumor with peripheral blood T cells and measuring their production of: IFNg, TNF, IL2, CD137, perforin and granzyme by multiplex surface and intracellular flow cytometry. A secondary endpoint is measurement of molecular residual disease (MRD) using both standard allele-specific oligonucleotide (ASO) qPCR as well as high-throughput sequencing (HTS) of the entire IgH repertoire. The study is powered to detect a 50% improvement in sustained molecular remission rate compared to recent trials of standard transplant [Pott C. et al, Blood 2010 Apr 22;115(16) :3215–23, Geisler C. et al, Blood 2008 Oct 1;112(7) :2687–93]. Using the same HTS technology, we have also initiated studies of the entire TCR β repertoire as an alternate approach of tracking the amplification of vaccine-induced T-cells. RESULTS: Accrual has been rapid with 25 patients enrolled in 22 months and 13 patients completing the complete protocol so far. Flow-cytometric immune response testing has demonstrated that immunotransplant amplifies the proportion of tumor-reactive T cells in 83% of patients thus far. Notably, we have observed some patients with primarily CD8 T cell responses, some with CD4 T cell responses, and some with a combination of the two. In some cases, tumor-reactive T cells have been tested for reactivity to autologous, non-malignant B cells and have demonstrated a significant proportion that are tumor-specific. TCR β repertoire sequencing has also demonstrated instances of significant clonal amplification after immunotransplantation, some exceeding three orders of magnitude. In extreme cases, these have yielded dominant clones comprising as much as 50% of a patient's entire peripheral blood T cell repertoire post-transplant. HTS of the IgH repertoire has been an effective measurement of MRD bypassing the assay individualization of ASO qPCR and has been shown to be more sensitive than conventional flow cytometry. CONCLUSIONS: Pre-clinically, amplification of anti-tumor T cells correlates with cure of even myeloablation-resistant disease. The reiteration of anti-tumor T cell amplification in our preliminary patient data raises the possibility that immunotransplant may improve clinical outcomes. Ongoing MRD testing should suggest whether certain patterns of T cell response –measured functionally per flow cytometry or clonally per HTS- correlate with clinical benefit and whether the cohort has a better-than-expected molecular remission rate. Disclosures: Moorhead: Sequenta, Inc.: Employment. Zheng:Sequenta, Inc.: Employment. Klinger:Sequenta, Inc.: Employment. Faham:Sequenta Inc: Employment, Equity Ownership. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Odermatt, Alex, Kimby Barton, Vijay K. Khanna, Jean Mathieu, Diana Escolar, Thierry Kuntzer, George Karpati, and David H. MacLennan. "The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease." Human Genetics 106, no. 5 (May 2000): 482–91. http://dx.doi.org/10.1007/s004390000297.
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Marabelle, Aurelien, Holbrook E. Kohrt, Joshua Brody, James Anthony Torchia, Gang Zhou, Richard Luong, Ranjani Rajapaksa, Victor Tse, and Ronald Levy. "Local Treg Immunomodulation Cures Metastatic Lymphoma Including CNS Sites." Blood 118, no. 21 (November 18, 2011): LBA—2—LBA—2. http://dx.doi.org/10.1182/blood.v118.21.lba-2.bld0076_p1_lba-2.
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Abstract LBA-2 Background: CD4+CD25+FOXP3+ regulatory T-cells (Tregs) protect cancers from the immune system. They express important functional molecules such as CTLA-4 and Ox40 on their surface. Anti-CTLA4 monoclonal antibody (mAb) is the first drug to improve survival of refractory metastatic melanoma. Its recent approval by the FDA/EMEA inaugurates a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself. Scientific question: Does local immunomodulation of tumor specific Tregs trigger a systemic anti-tumor immune response and cure disseminated lymphoma? Results: The Tregs that infiltrate the tumor site preferentially express CTLA4 and OX40 compared to their counterparts in the blood and other lymphoid organs, both in mice and in humans. Upon injection of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into the tumor, tumor-specific Tregs are depleted from the tumor-infiltrate. This immunomodulatory combination therapy triggers an anti-tumor immune response able to cure mice with established disseminated disease. The triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. The local Treg immunomodulation with anti-CTLA4+anti-OX40+CpG in a single sub-cutaneous tumor eradicates disease in mice with established CNS lymphoma, even with leptomeningeal and spinal cord metastases, whereas chemotherapies or mAb therapy directed against the tumor cells have little effect in the CNS site. Moreover, these cured mice have a long term intra-cranial anti-tumor immunity since they are protected against late intra-cranial re-challenge. Significance: Immunomodulatory antibodies are currently under clinical development for cancer treatment, and their major side effect is the triggering of auto-immune diseases. We show here that injecting very little doses of these antibodies in combination with CpG at one tumor site is sufficient to trigger a systemic anti-tumor response able to eradicate distant sites, including in the CNS which is usually considered a sanctuary site for conventional systemic therapies. Impact: We recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody,Levy, et al. JCO, 2010). Anti-CTLA4 has just been FDA approved in patients with metastatic melanoma, and anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma, even if they have CNS disease. Disclosures: No relevant conflicts of interest to declare.
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Marabelle, Aurelien, Holbrook E. Kohrt, Joshua Brody, James Anthony Torchia, Gang Zhou, Richard Luong, Ranjani Rajapaksa, Victor Tse, and Ronald Levy. "Local Treg Immunomodulation Cures Metastatic Lymphoma Including CNS Sites." Blood 118, no. 21 (November 18, 2011): LBA—2—LBA—2. http://dx.doi.org/10.1182/blood.v118.21.lba-2.lba-2.
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Abstract Abstract LBA-2 Background: CD4+CD25+FOXP3+ regulatory T-cells (Tregs) protect cancers from the immune system. They express important functional molecules such as CTLA-4 and Ox40 on their surface. Anti-CTLA4 monoclonal antibody (mAb) is the first drug to improve survival of refractory metastatic melanoma. Its recent approval by the FDA/EMEA inaugurates a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself. Scientific question: Does local immunomodulation of tumor specific Tregs trigger a systemic anti-tumor immune response and cure disseminated lymphoma? Results: The Tregs that infiltrate the tumor site preferentially express CTLA4 and OX40 compared to their counterparts in the blood and other lymphoid organs, both in mice and in humans. Upon injection of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into the tumor, tumor-specific Tregs are depleted from the tumor-infiltrate. This immunomodulatory combination therapy triggers an anti-tumor immune response able to cure mice with established disseminated disease. The triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. The local Treg immunomodulation with anti-CTLA4+anti-OX40+CpG in a single sub-cutaneous tumor eradicates disease in mice with established CNS lymphoma, even with leptomeningeal and spinal cord metastases, whereas chemotherapies or mAb therapy directed against the tumor cells have little effect in the CNS site. Moreover, these cured mice have a long term intra-cranial anti-tumor immunity since they are protected against late intra-cranial re-challenge. Significance: Immunomodulatory antibodies are currently under clinical development for cancer treatment, and their major side effect is the triggering of auto-immune diseases. We show here that injecting very little doses of these antibodies in combination with CpG at one tumor site is sufficient to trigger a systemic anti-tumor response able to eradicate distant sites, including in the CNS which is usually considered a sanctuary site for conventional systemic therapies. Impact: We recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody,Levy, et al. JCO, 2010). Anti-CTLA4 has just been FDA approved in patients with metastatic melanoma, and anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma, even if they have CNS disease. Disclosures: No relevant conflicts of interest to declare.
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Lau, Karen M., Mili Parikh, Danielle J. Harvey, Chun-Jung Huang, and Sarah Tomaszewski Farias. "Early Cognitively Based Functional Limitations Predict Loss of Independence in Instrumental Activities of Daily Living in Older Adults." Journal of the International Neuropsychological Society 21, no. 9 (September 22, 2015): 688–98. http://dx.doi.org/10.1017/s1355617715000818.
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AbstractOlder adults with early forms of neurodegenerative disease are at risk for functional disability, which is often defined by the loss of independence in instrumental activities of daily living (IADLs). The current study investigated the influence of mild changes in everyday functional abilities (referred to as functional limitations) on risk for development of incident functional disability. A total of 407 participants, who were considered cognitively normal or diagnosed with mild cognitive impairment (MCI) at baseline, were followed longitudinally over an average 4.1 years (range=0.8–9.2 years). Informant-based ratings from the Everyday Cognition (ECog; Farias et al., 2008) and the Instrumental Activities of Daily Living (Lawton & Brody, 1969) scales assessed the degree of functional limitations and incident IADL disability, respectively. Cox proportional hazards models revealed that more severe functional limitations (as measured by the Total ECog score) at baseline were associated with approximately a four-fold increased risk of developing IADL disability a few years later. Among the ECog domains, functional limitations in Everyday Planning, Everyday Memory, and Everyday Visuospatial domains were associated with the greatest risk of incident functional disability. These results remained robust even after controlling for participants’ neuropsychological functioning on tests of executive functions and episodic memory. Current findings indicate that early functional limitations have prognostic value in identifying older adults at risk for developing functional disability. Findings highlight the importance of developing interventions to support everyday abilities related to memory, executive function, and visuospatial skills in an effort to delay loss of independence in IADLs. (JINS, 2015,21, 688–698)
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Zhang, Yilin, Junichi Fujii, Michael S. Phillips, Hai-Shiene Chen, George Karpati, Won-Chee Yee, Bertold Schrank, David R. Cornblath, Kevin B. Boylan, and David H. MacLennan. "Characterization of cDNA and Genomic DNA Encoding SERCA1, the Ca2+-ATPase of Human Fast-Twitch Skeletal Muscle Sarcoplasmic Reticulum, and Its Elimination as a Candidate Gene for Brody Disease." Genomics 30, no. 3 (December 1995): 415–24. http://dx.doi.org/10.1006/geno.1995.1259.
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Buckstein, Rena, Richard A. Wells, Nancy Zhu, Thomas J. Nevill, Heather A. Leitch, Karen W. L. Yee, Brian Leber, et al. "Patient Related Factors Have an Indepedent Impact on Overall Survival in Myelodysplastic Syndrome Patients: A Report of the MDS-Can Registry." Blood 124, no. 21 (December 6, 2014): 165. http://dx.doi.org/10.1182/blood.v124.21.165.165.
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Abstract Introduction: MDS is a disease of the elderly; yet, the impact of clinical frailty (an age-related vulnerability state created by a multidimensional loss of reserves) and patient-reported outcomes on overall survival (OS) are unknown. Rockwood et al. have developed a simple 9-point clinical frailty scale (CFS) that correlated highly with the risk of death, institutionalization, worsening health and hospital use (Rockwood K., CMAJ 2005). In a prospective, national MDS registry, participants have undergone annual evaluations with the following: (a) 3 geriatric physical performance tests, (b) Charlson (CCI) and Della Porta comorbidity index (DP-CCI) scores, (c) graded frailty using the Rockwood CFS, (d) disability assessments with the Lawton Brody SIADL, and (e) QOL using the EORTC QLQ C-30 and the EQ-5D. The results of these frailty assessments and the effects of these patient-related factors and reported outcomes on OS, in addition to the IPSS/revised IPSS, will be presented. Methods: Overall survival was measured from time to enrollment. Results from physical performance tests were divided into quintiles with higher scores indicating better performance. We used univariate and multivariable Cox proportional hazard model to determine significant predictive factors of overall survival (OS). The variables considered included age, IPSS, R-IPSS, ferritin, LDH, transfusion dependence, hemoglobin (hgb), ECOG, frailty, CCI and DP-CCI, grip strength, 4 M walk test, stand-sit test, modified short physical performance battery (SPPB), Lawton Brody SIADL, time from diagnosis and selected QOL domains including the EQ-5D summary score, EORTC physical functioning, dyspnea and fatigue scores. Results: 453 MDS patients (pts) have been consented and enrolled locally since January 2008 (n=231) and nationally since January 2012 (n=222). Median time from diagnosis was 5.8 mos (IQR 1.4-21). Median age was 73 y (range, 26-95 y), 65% were male and the R-IPSS scores were very low (14%), low (46%), intermediate (24%), high (10%) and very high (6%). Thirty-three % of pts were transfusion dependent at enrollment. Median CCI and DP-CCI scores were 1 (0-12) and 0 (0-6) respectively with 18% and 24% falling into the highest category scores. Median frailty scale score (n=346) was 3 (1-9) with 25% having scores indicating moderate (4-5) or severe (6-9) frailty. The CCI and DP-CCI strongly correlated (r=0.6; p< .0001) with each other, while frailty significantly but modestly correlated with them (r=0.3-0.35, p<.0001). With a median follow up (from enrollment) of 15 mos (95% CI: 13-16), 159 (35%) pts have died and 28 pts lost to follow up. Actuarial survival was 41.0 mos (range, 33.6 - 48.5 mos). When considering patient related factors - age, frailty, comorbidity (both indices), sex, ECOG, the 10 x stand sit test, the SPPB, Lawton Brody SIADL, and all QOL domains considered above were significantly predictive of OS. The multivariable model with the highest R2 included R-IPSS (p=.0004), frailty (1-3 vs 4-9, p= .004), CCI (0-1 vs >2, p=.03) and EORTC fatigue (p=.01) as summarized in Table 1 below. A frailty score > 3 predicted for worse survival (figure 1: 2 year OS 68.5% vs. 83.8%) and further refined survival within the R-IPSS categories (Figure 2). Frailty was also the single most predictive factor for OS from the start of azacitidine therapy (not shown). Conclusions: Patient-related factors such as frailty and comorbidity (that evaluate physiologic reserve and global fitness) should be considered in addition to traditional MDS prognostic indices. Abstract 165. Table. Independent Covariate Predictive factors at baseline Coefficient SE p -value HR 95% CI of HR R2 (%) Time from diagnosis (months) * 0.0335 0.1076 0.7557 1.034 0.837 1.277 17.29% R-IPSS (5 categories) <.0001 Very high vs. very low 2.5701 0.7289 0.0004 13.066 3.131 54.524 High vs. very low 2.1156 0.6437 0.0010 8.294 2.349 29.285 Intermediate vs. very low 1.0466 0.6430 0.1036 2.848 0.808 10.043 Low vs. very low 0.6346 0.6181 0.3045 1.886 0.562 6.334 Frailty (1-3 vs. 4-9) -0.8323 0.2905 0.0042 0.435 0.246 0.769 Comorbidity Charlson (0-1 vs. ³2) -0.5915 0.2749 0.0314 0.553 0.323 0.949 EORTC fatigue * 0.3671 0.1546 0.0176 1.443 1.066 1.954 natural log-transformation was applied for normalizing distribution Figure 1 Overall survival by Frailty (n=346) Figure 1. Overall survival by Frailty (n=346) Figure 2 Overall Survival by Frailty and R-IPSS Figure 2. Overall Survival by Frailty and R-IPSS Disclosures Buckstein: Celgene Canada: Research Funding. Wells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Leitch:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Educational Grant Other, Honoraria, Research Funding. Shamy:Celgene: Honoraria, Other.
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Zinko, H. O. "Імунний статус телят, хворих на гастроентерит." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 19, no. 82 (October 6, 2017): 61–65. http://dx.doi.org/10.15421/nvlvet8213.
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It has been established that there is a violation of the immunocompetence of the macroorganism at diseases of the gastrointestinal tract which are accompanied by diarrhea. Since the immune system is one of the most important homeostatic systems in the body, these disorders play an important role in the pathogenesis of the disease. Thus, the purpose of the work was to study the indicators of natural resistance and immunological reactivity in calves with gastroenteritis. The research was carried out at the state enterprise «Milk Rinks»Pravda LTD in Brody district of Lviv region on 1.5–2-month-old-calves. 15 calves were selected for the study: 5 healthy ones and 10 patients with gastroenteritis. Blood for research was taken from the jugular vein before the early feeding.In the study of indicators of natural resistance, it was found that in calves with gastroenteritis, the content of circulating immune complexes in serum is authentically (P < 0.001) greater than 45.1%, bactericidal and lysozyme activity of serum is authentically (P < 0.01 ) lower at 15.1 and 26.3% and phagocytic activity of neutrophils – by 8.6% compared with healthy animals. In the study of lymphocytes and their subpopulations, it was found that the relative amount of T-total and T-active lymphocytes is authentically (P < 0.01) less by 8.6 and 11.7%, respectively, compared with healthy animals, the relative number of T-helper cells – less than 16.4% (P < 0.01). There is no probable difference in the relative number of T-suppressors between patients and healthy animals, but the immunoregulatory index in calves, patients with gastroenteritis, is 19.4% smaller, compared with healthy ones. The relative number of B-lymphocytes was authentically (P < 0.01) less in sick animals by 14.5% compared with clinically healthy ones, and the content of immunoglobulins in serum was lower by 16.3% (P < 0.01). Conclusion: in calves, patients with gastroenteritis, there are a number of violations of the immune system, characterized by a decrease in the parameters of cellular and humoral immunity, which require correction in the process of treatment.
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Levkivska, N., B. V. Gutyj, and D. Levkivskyj. "ПОРІВНЯЛЬНА ЕФЕКТИВНІСТЬ ЛІКУВАЛЬНО–ПРОФІЛАКТИЧНИХ ПРЕПАРАТІВ ПРИ ЗАСТОСУВАННІ 3% СПИРТОВО–ВОДНОЇ ЕМУЛЬСІЇ ПРОПОЛІСУ ТА АНТИБІОТИКІВ ЗА КАТАРАЛЬНОЇ БРОНХОПНЕВМОНІЇ ТЕЛЯТ." Scientific Messenger of LNU of Veterinary Medicine and Biotechnology 18, no. 2(66) (September 17, 2016): 116–22. http://dx.doi.org/10.15421/nvlvet6624.
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Catarrhal bronchopneumonia of calves appears on the background of adverse environmental factors, actions conditionally pathogenic microflora particularly Str.pneumoniae and their associations that cause immune deficiency of animals. Experimental research was carried out in the agricultural firm Ltd. «Pravda» Brody district, Lviv region. For research it was formed three groups of calves: first – control (healthy calves 5 goals); second and third groups – research (calves suffering from catarrhal bronchopneumonia caused by the causative agent Str. pneumoniae – 7 goals), as well as the a third research group – 7 goals, diseases caused by microorganisms association (isolated from nasal exudate).Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli. were isolated from the nasal passages of calves on catarrhal bronchopneumonia.Materials of antibiotic gramme showed the highest sensitivity cultures of bacteria isolated from nasal fluid holes of calves suffering from catarrhal bronchopneumonia to 3% of ethanol–water emulsion of propolis.The use of aerosols to 3% of ethanol–water emulsion of propolis with medicinal purposes for catarrhal bronchopneumonia of calves, 1 time a day, during 6 days contributed the stimulation of cellular and humoral factors of calves body protection and their recovery. After use of aerosols – 3% of ethanol–water emulsion of propolis in calves suffering from catarrhal bronchopneumonia, of both research groups in serum was increased the content: in calves of the first group Ig G to 8.18 mg/ml, Ig M to 0.7 mg/ml, and second, respectively, 6.85 mg/ml and 0.3 mg/ml.It was noted a level decrease of CIC 1.6 times compared with the data of sick animals. The use of 3% alcohol–water emulsion of propolis to the calves with catarrhal bronchopneumonia contributed to increased activity of bactericidal and lizocimic activity whereby these figures were higher in the first experimental group of calves, in which Str. pneumoniae was the causative agent, compared with calves from the second research group. Prophylactic use of aerosols of 3% ethanol – water emulsion of propolis prevented disease in calves with catarrhal bronchopneumonia.
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Macdonald, Jennifer J., Jennifer Rees, Gene H. Brody, Man-Kit Lei, Yi-fu Chen, Desiree A. White, and Allison A. King. "Maternal Depression Is Associated with Adaptive Skill Deficits of Children with Sickle Cell Disease through Parenting Practices." Blood 114, no. 22 (November 20, 2009): 1397. http://dx.doi.org/10.1182/blood.v114.22.1397.1397.
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Abstract Abstract 1397 Poster Board I-419 Background: Caregivers of children with sickle cell disease (SCD) have high levels of stress and depression. Students with SCD have a higher prevalence of behavioral and cognitive deficits compared to healthy students. Adaptive skills are particularly important for children with chronic disease because they are the skills needed to transition into independent adulthood. We hypothesize that (1) Maternal depressive symptoms are associated with decreased adaptive skills in children with SCD, and (2) This association will be mediated by the association between maternal depression and the provision of lower levels of competence promoting parenting. Methods: We completed a cross-sectional analysis of a single center prospective cohort study. Adaptive skills of children with SCD were assessed by parent report of the Behavior Assessment System for Children (BASC). The BASC reflects the child's adaptive skills by 5 key adaptive scales: adaptability, activities of daily living, functional communication, social skills, and leadership. Maternal risk for depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). We completed structured interviews of the mothers to assess parenting quality. Effective parenting was characterized by high levels of support, involvement, monitoring, and low levels of ongoing conflict. A path analysis using ordinary least squares was used for statistical analysis. Results: 48 children with SCD and their mothers were evaluated. 52% of the children were male; mean age was 12 yrs (Range 6-16). 25% of the children repeated a grade level in school. The mothers' mean age was 38 yrs (Range 27-59) and the average yearly household income per capita was $7,133 (Range 708- 22,800). 60% of the children received healthcare via Medicaid. 20% of the mothers were at risk for depression.12.5% of the children had clinically significant deficits in adaptive skills and18.8% of the children were considered “at risk.” There was a moderate correlation between maternal depression and child adaptive skills (r = .481, p=.01). A path analysis revealed that in the presence of parenting, the association between maternal depression and child adaptive skills is no longer significant. The effect of maternal depression is mediated by depression induced decrements in competence promoting parenting practices (Fig. 1). Medicaid was associated with higher maternal depressive symptoms. Conclusions: Our preliminary data provide direct evidence that maternal depression is associated with proximal parenting practices that are associated with child adaptive skills. Parenting practices can be modified through education and family support and serve as a potential intervention target for moderating the effects of maternal depression on child adaptive skills in this vulnerable population. Maternal depressive symptoms have a negative association with proximal parenting processes that are linked to adaptive skills in children with SCD. Stronger parenting indices are associated with better adaptive skills. In the presence of parenting, the direct association between maternal depression and adaptive skills is no longer significant. Disclosures: Brody: NIH: Research Funding. White: NIH: Research Funding. King: NIH-NHLBI: Research Funding; Doris Duke Charitable Foundation: Research Funding.
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Brody, Stuart. "Dr Brody replies:." International Journal of STD & AIDS 7, no. 4 (July 1, 1996): 302–6. http://dx.doi.org/10.1258/0956462961917889.
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Link, Jason M., Patrick J. Worth, Dove Keith, Sydney Owen, Alison Grossblatt-Wait, Carl Pelz, Hannah Holly, et al. "Abstract PR-007: Lung-tropic, liver-averse, primary PDAC tumors are associated with greater peripheral T cell diversity and have a unique, subtype-independent, gene-expression signature that significantly correlates with longer survival." Cancer Research 81, no. 22_Supplement (November 15, 2021): PR—007—PR—007. http://dx.doi.org/10.1158/1538-7445.panca21-pr-007.
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Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related death in the United States, and most patients who present with metastatic PDAC die within a year. However, we and others have found that patients with lung metastases in the absence of liver metastases survive significantly longer than patients who present with liver metastases. We analyzed an unpublished RNASeq dataset from ~300 tumor-enriched samples from primary and metastatic PDAC specimens. Consistent with many previous publications, we found that patients with basal/squamoid-subtype tumors had significantly worse outcomes than patients with classical/ductal-subtype tumors. Additionally, we identified that most primary tumors from patients who develop lung – but not liver – metastases are classical subtype. However, this association did not wholly account for the pro-survival effect of lung-tropic, liver-averse metastatic disease because patients with lung-tropic, liver-averse, classical-subtype, primary tumors had significantly better outcomes than patients with liver-tropic, classical-subtype tumors. To identify and parse metastatic organotropism from subtype, we used organotropism-independent and subtype-independent, primary-tumor training cohorts to generate two non-overlapping gene sets that were significantly enriched in test cohorts of either primary, basal-subtype or liver-tropic tumors over primary tumors that were classical-subtype or lung-tropic and liver-averse, respectively. When applied to all primary tumors in our dataset, both the subtype-specific and organotropism-specific gene sets significantly correlated with patient outcome. From an unpublished analysis of TCRbeta CDR3 sequences from ~250 paired blood and primary tumor samples, we identified significantly greater TCRbeta diversity in blood and primary tumors from patients with lung-tropic, liver-averse disease. Additionally, we found evidence that TCRbeta rearrangements from liver-tropic primary tumors were more likely to be found in autologous peripheral blood samples than TCRbeta rearrangements from lung-tropic, liver-averse primary tumors. We also found that TCRbeta sequences were often shared between samples from patients with liver-tropic disease but never shared between samples from patients with lung-tropic, liver-averse disease. Overall, our results point to a lung-tropic, liver-averse form of PDAC that – independent of tumor subtype – leads to positive outcomes, and that T cell diversity may have a causal relationship and/or may serve as a biomarker of long-term survival with lung-tropic, liver-averse disease. Citation Format: Jason M. Link, Patrick J. Worth, Dove Keith, Sydney Owen, Alison Grossblatt-Wait, Carl Pelz, Hannah Holly, Motoyuki Tsuda, Kevin MacPherson, Jonathan Brody, Charles Lopez, Brett C. Sheppard, Rosalie C. Sears. Lung-tropic, liver-averse, primary PDAC tumors are associated with greater peripheral T cell diversity and have a unique, subtype-independent, gene-expression signature that significantly correlates with longer survival [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-007.
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Eggar, J. M., C. S. Lea, L. S. Bellin, R. E. Raab, J. H. Wong, and L. P. Burke. "A pilot study of the decision-making process of seeking medical care in women diagnosed with large breast tumors." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 237. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.237.
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237 Background: Twelve percent of women diagnosed with invasive breast cancer in eastern NC present with large tumors (≥ 4 cm). The reasons for presentation with advanced cancer are not known and may include both social factors and tumor characteristics. Methods: The objective of this qualitative pilot study was to investigate the decision-making process of seeking medical care in women diagnosed with ≥ 4 cm breast tumors through in-depth interviews. Six female breast cancer patients treated at Brody School of Medicine completed in-depth qualitative semistructured interviews along with demographic questionnaires. The interviews, designed to uncover barriers and motivators to seeking breast cancer diagnosis and care, were recorded and transcribed verbatim. Results: Six women (aged 44-68) completed the interview process, three African Americans and three Caucasians. Mean tumor at diagnosis size was 11.2 cm (range 4-18 cm). Three women who lived alone hid breast cancer symptoms from their family; of these, two women had fungating tumors and one had nipple drainage for more than 1 year prior to diagnosis. Four women had health insurance. Two women reported being without insurance for more than 10 years and cited this as the primary reason for delaying care. Both insured and uninsured subjects delayed care due to fear of being a burden to family, financially or support wise. One woman delayed care due to fear of chemotherapy and radiation. Three women reported regular mammograms; two presented with fast-growing tumors, one had a chest wall tumor that was missed on mammography. Conclusions: Three of six patients presenting with locally advanced disease stated that they made a decision to delay medical care. Subjects’ lack of insurance, fear of cancer and cancer treatments, and concern for family were among reasons for delays. Qualitative approaches may be useful in studying factors that affect patient access to care. More research is needed on ways to improve access and empower women to seek care.
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Parmar, Ambica, Heather A. Leitch, Richard A. Wells, Thomas J. Nevill, Nancy Y. Zhu, Karen W. L. Yee, Brian Leber, et al. "Iron Chelation Is Associated with Improved Survival Adjusting for Disease and Patient Related Characteristics in Low/Int-1 Risk MDS at the Time of First Transfusion Dependence: A MDS-CAN Study." Blood 126, no. 23 (December 3, 2015): 1701. http://dx.doi.org/10.1182/blood.v126.23.1701.1701.
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Abstract Introduction: Transfusional hemosiderosis is common in myelodysplastic syndromes (MDS). There are multiple retrospective analyses demonstrating a survival benefit associated with iron chelation therapy (ICT) in lower risk, transfusion dependent (TD) MDS patients. However, these studies are limited by their retrospective nature, potential for bias and by the use of risk scores at diagnosis rather than at the onset of TD. Since January 2012 the Canadian MDS Registry has prospectively collected disease and patient-related data on MDS patients including comorbidity (Charlson and MDS-CI), frailty (Rockwood clinical frailty scale) and disability [Lawton Brody Instrumental Activities of Daily Living (sIADL)]. We compared characteristics and clinical outcomes of lower risk TD MDS patients who received ICT to non chelated TD patients, adjusting for MDS and patient-related factors. Methods: Only patients who remained International Prognostic Scoring System (IPSS) low or intermediate (int)-1 risk at the time of first TD were included with MDS and patient-related factors analyzed at first TD rather than at MDS diagnosis or registry enrollment. Univariate and multivariate Cox proportional hazard models were used to determine significant predictive factors for overall survival (OS) and the model with the highest R2 was selected. Results: 219 Low (n=69)/Int-1 (n=149) risk MDS patients at the time of first TD were included. Median age was 73 [interquartile range (IQR 65,80)] with a median time from diagnosis until TD of 7 months (IQR 1,28). 60% were male with a median ECOG of 1 and median blast of 3% (IQR 1,4). By WHO classification, 39% and 37% had unilineage and multilineage dysplasia respectively, 11% CMML and 13% had excess blasts. By IPSS-revised (R), very low, low, intermediate, high and very high risk groups were 12%, 34%, 38%, 15% and 0.5%, respectively. Seventy (32%) patients received ICT with desferrioxamine (n=6), deferasirox (n=56) or both (n=8). At the time of first TD, chelated patients were younger, had higher ferritins and had lower IPSS-R risk scores (Table 1). Importantly, frailty, comorbidity, and disability scores did not differ. At a median follow up of 2.7 (IQR 2.2-3.3) years from diagnosis, OS was 6.1(IQR 4.5-7.5) years. OS was significantly improved among MDS patients treated with ICT as compared to those without (median 8.62 vs. 4.38 years, respectively, p = 0.0005, Figure 1.) By univariate analysis, age, ICT, IPSS, IPSS-R, MDS-CI, frailty, karyotype, time from diagnosis until TD, and disability were associated with improved OS. By multivariate analysis, ICT, age at TD and IPSS-R at TD were independently predictive of OS (Table 2). Conclusions: Adjusting for patient and disease related factors at the time of TD, ICT remains predictive of improved OS in patients with low/int-1 risk MDS who become TD. The adjustment for patient-related factors and analysis from TD rather than MDS diagnosis, diminishes the impact of selection bias that may have favored ICT patients in past analyses and lends additional support to the role for ICT in lower risk MDS. Table 1. Comparing Clinical Factors at the time of First Transfusion Dependency (TD) between Chelated and Non-Chelated Patients Factors at Time of TDMedian (IQR) Without Iron Chelation (n=149) With Iron Chelation (n=70) p-value Age (y) 75 (67,81) 69 (62,75) 0.0008 Ferritin (ug/L) 664 (346,1118) n=92 1201 (883,1691) n=44 <0.0001 RA/RARS, del5q, MDS-U, RCUD [N(%)] RCMD+/-RS CMML/MDS/MPN RAEB1 RAEB2 51 (34) 56(38) 18 (12) 17 (11) 7 (4) 35 (50) 25 (36) 3 (4) 6(9) 1(1) 0.11 IPSS [N(%)] Low Int-1 42 (28) 106 (72) 27 (39) 43 (61) 0.16 IPSS-R [N(%)] Very Low Low Intermediate High Very High 15 (10) 48 (32) 54 (36) 30 (20) 1 (0) 12 (17) 26 (37) 29 (41) 3 (4) 0 (0) 0.01 Frailty N=96 3 (2,4) N=37 3 (2,4) 0.40 Charlson Comorbidity N=95 1 (0,2) N=37 0(0, 1) 0.06 MDS-CI N=95 1 (0,2) N=37 0 (0,2) 0.26 Lawton Brody Disability N=90 1 (0,2) N=36 0 (0,2) 0.68 Time from diagnosis until TD (mo) 6 (1,23) 14 (0,38) 0.19 Table 2. Predictive factors for Overall Survival by Multivariate Analysis Predictive Factors p-value HR 95% CI of HR R2 (%) Iron chelation (no vs. yes) 0.0152 1.821 1.122 2.953 14.76 Age at time of diagnosis (yr) 0.0125 1.025 1.005 1.045 IPSS-R at time of TD 0.0018 High/vHigh vs. Low 0.0004 2.866 1.601 5.132 Int. vs. Low/vLow 0.0775 1.523 0.955 2.429 High/vHigh vs. Low 0.0292 1.882 1.066 3.322 Figure 1. Kaplan-Meier Curve of Overall Survival of Chelated and Non-Chelated Patients Figure 1. Kaplan-Meier Curve of Overall Survival of Chelated and Non-Chelated Patients Disclosures Leitch: Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Exjade: Speakers Bureau. Wells:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Nevill:Celgene: Honoraria. Zhu:Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Yee:Oncoethix: Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leber:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Celgene: Honoraria. Kumar:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geddes:Celgene: Honoraria. Storring:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kew:Celgene: Honoraria. Shamy:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Elemary:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Buckstein:Celgene: Honoraria, Research Funding.
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DiNiro, Roberto, Alex O. Haber, Kang J. Jeong, Soon Y. Park, Gordon B. Mills, William H. Gmeiner, and Jonathan R. Brody. "Abstract 3935: The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3935. http://dx.doi.org/10.1158/1538-7445.am2022-3935.
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Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease that will soon become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits for this devastating disease, and in the majority of cases, only improve survival by a few months. Moreover, systemic toxicities are a harsh reality of these treatments. FOLFIRINOX is the drug regimen of choice, one component of which is 5-Fluorouracil (5-FU) which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance due, in part, to thymidylate synthase (TS) overexpression. The Gmeiner lab has pioneered the development of polymeric fluoropyrimidines, named F10 and CF10, which unlike 5-FU, are in principle completely converted to the TS inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities and while displaying much stronger anti-cancer activity. Here, we further confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors targeting replication stress, a hallmark of PDA cells. We show that, consistent with our previous studies in PDA cells, CF10 is much more potent as a single agent than 5-FU, by an average 308x fold, and was effective in the nM range (GI50 range 3.13 - 336 nM) in 5 PDA cell lines tested. We also found that CF10 induces increased replication stress as assessed by phosphorylation of ATR, which appears as early as 8 hours after treatment and increases in intensity over 48 hours, consistent with the kinetics of FdU being released from CF10 and incorporated into DNA, a process requiring several hours. Importantly, phosphorylation of ATR induced by CF10 was significantly higher than with 5-FU. This is especially striking because compounds for this assay were used at their IC50 concentrations, with for example MiaPaCA2 cells being exposed to 899 time more 5-FU than CF10, yet at this concentration 5-FU induced less ATR phosphorylation. Further, we find that the activity of CF10, but not 5-FU can be enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 damage checkpoints. Our results indicate CF10 has potential to supersede the established benefit of 5-FU in PDA treatment and indicate novel combination approaches that may be beneficial compared to well-established regimens used currently for 5-FU. Citation Format: Roberto DiNiro, Alex O. Haber, Kang J. Jeong, Soon Y. Park, Gordon B. Mills, William H. Gmeiner, Jonathan R. Brody. The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3935.
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Patterson, Marc C., and Steven U. Walkley. "Niemann-Pick disease, type C and Roscoe Brady." Molecular Genetics and Metabolism 120, no. 1-2 (January 2017): 34–37. http://dx.doi.org/10.1016/j.ymgme.2016.11.008.
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Branche, Angela, Evelyn Granieri, Edward Walsh, Lynn Finelli, William Greendyke, Ann R. Falsey, Angela Barrett, Celibell Vargas, and Lisa Saiman. "733. Incidence and Evaluation of the Change in Functional Status Associated with Respiratory Syncytial Virus Infection in Hospitalized Older Adults." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S263. http://dx.doi.org/10.1093/ofid/ofy210.740.
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Abstract Background Respiratory Syncytial Virus (RSV) causes severe respiratory illnesses in infants and older adults. Mortality disproportionately affects the elderly, can exacerbate chronic cardiopulmonary conditions and may result in loss of function. The purpose of this study was to determine the incidence of RSV infection in hospitalized adults and evaluate functional changes associated with RSV hospitalization in older adults ≥60 years. Methods Adults ≥18 years of age admitted with an acute respiratory infection (ARI) or exacerbation of chronic cardiopulmonary disease (e.g. CHF, COPD, asthma) preceded by an ARI within 14 days were screened. Subjects were included if hospitalized for ≥24 hours with laboratory confirmed RSV and residing in two catchment areas (Rochester, NY and New York, NY). Illness history, comorbidities and demographic characteristics were collected at enrollment. Enrolled subjects ≥60 years underwent functional status evaluation retrospectively 2 weeks prior to hospitalization, at enrollment, discharge and 2 months using the Lawton–Brody Instrumental Activity of Daily Living (IADL) Scale (0–8), Barthel (ADL) Index (0–100), MRC Breathlessness score (1–5) and Mini-Cog instrument. Results From October 2017 to March 2018, 2,883 adults hospitalized with ARI were tested and 322 (11%) positive for RSV. Seventy-two adults ≥60 years underwent functional assessment. Mean age was 75 years, 53% were female and 58% demonstrated impaired cognition on admission. Five subjects died during hospitalization and one prior to 2-month follow-up. Interim analysis of 2-month functional assessment was available for 39 subjects. RSV illness resulted in acute functional loss in almost all patients. Although there were no statistically significant differences between mean pre-hospitalization and 2-month functional scores, IADL (6.7 vs. 6.0, P = 0.27), ADL (90.4 vs. 88.5, P = 0.67) and MRC (2.96 vs. 2.7, P = 0.57), 23% of subjects required a higher level of care at discharge. Additionally, RSV hospitalization resulted in decreased ADL scores in 36% of subjects and worsening respiratory function in 18% assessed at 2 months (figure). Conclusion Older adults hospitalized with RSV infection demonstrate acute functional decline which may result in prolonged loss of function in some patients. Disclosures A. Branche, Merck: Investigator, Grant recipient and Research grant. E. Granieri, Merck: Investigator, Research grant. E. Walsh, Merck: Investigator, Research grant. L. Finelli, Merck: Employee, Salary. A. R. Falsey, sanofi pasteur: Consultant and Grant Investigator, Consulting fee and Research grant. Gilead: Consultant, Consulting fee. Merck Sharpe and Dome: Investigator, Grant recipient. Janssen Pharmacueticals: Investigator, Grant recipient. Pfizer: Consultant, Research grant. Novavax: Consultant, none. A. Barrett, Merck: Investigator, Research support. L. Saiman, Merck: Investigator, Research grant.