O diabetes mellitus (DM) é uma doença crônica com alto índice de morbidade e mortalidade, sendo considerado um dos maiores problemas de saúde pública do século 21, afetando aproximadamente 415 milhões de pessoas. As complicações em longo prazo do DM incluem a doença renal, a qual pode levar à falência renal, a retinopatia com perda potencial da visão e neuropatia, bem como o risco de amputações. A hemoglobina glicada (A1c) é considerada o parâmetro de referência na avaliação do controle glicêmico de pacientes com DM. No entanto, a mensuração da A1c pode não ser adequada para avaliar as variações em curto prazo do controle glicêmico, devido ao longo tempo de vida dos eritrócitos (120 dias). Existem ainda algumas limitações do uso deste teste, como em pacientes com hemoglobinas variantes, persistência hereditária à hemoglobina fetal, anemia hemolítica, anemia renal, entre outros. A avaliação da glicação da albumina é considerada, por alguns autores, como um melhor marcador para o controle glicêmico do que a A1c, em situações onde a A1c é de difícil interpretação devido à presença de interferentes, uma vez que a glicação da albumina não é afetada pela alteração no tempo de sobrevida das hemácias, como ocorre com a A1c. Atualmente, não há nenhum teste de albumina glicada (AG) disponível na rotina prática no Brasil, sendo um método limitado à pesquisa. No entanto, vários estudos mostram dados promissores em relação à AG e o controle do DM em situações específicas. Assim, a AG tem sido considerada um marcador alternativo no controle glicêmico e há necessidade de maior investigação sobre a utilização deste teste na prática clínica. / Diabetes mellitus (DM) is a chronic disease with high morbidity and mortality, being considered one of the biggest public health problems of the 21st century, affecting approximately 415 million people. Long-term complications of DM include renal disease, which can lead to kidney failure, retinopathy with potential loss of vision and neuropathy, as well as the risk of amputations. Glycated hemoglobin (A1c) is considered the reference in the assessment of glycemic control in patients with diabetes mellitus (DM). However, A1c measurement may not be adequate to evaluate the short-term variations of glycemic control due to the long lifespan of erythrocytes (120 days). There are also some limitations of using this test, such as in patients with variant hemoglobins, hereditary persistence to fetal hemoglobin, hemolytic anemia, renal anemia, among others. The evaluation of albumin glycation is considered by some authors to be a better marker for glycemic control than A1c in situations where A1c is difficult to interpret due to the presence of interferents, since albumin glycation is not affected by alteration in the survival time of red blood cells, as occurs with A1c. Currently, there is no glycated albumin (GA) test available in routine practice in Brazil, being a method limited to the research. However, several studies show promising data about GA in DM control in specific situations. Therefore, GA has been considered an alternative marker in glycemic control and there is a need of further investigation into the use of this test in clinical practice.

Thesis. 1976. Ph.D.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science. / Microfiche copy available in Archives and Engineering. / Vita. / Includes bibliographical references. / Ph.D.

Introdução: a doença falciforme (DF) é uma condição crônica e de caráter hereditário que, devido a sua importância clínica e epidemiológica, constitui-se em um grave problema de saúde pública. As famílias de crianças com esta condição alteram suas rotinas e manejam os cuidados buscando adaptarem-se às frequentes crises e hospitalizações. Objetivos: este estudo visou conhecer a experiência de manejo familiar da criança com doença falciforme e, especificamente, procurou identificar como as famílias definem a situação, buscando compreender os comportamentos de manejo adquiridos na experiência do cuidado, além de conhecer as consequências percebidas pela família e geradas pela doença falciforme da criança. Método: trata-se de uma pesquisa qualitativa que utilizou o Family Management Style Framework como referencial teórico e, como método, o estudo de caso sendo os dados analisados segundo o modelo híbrido de análise temática. A amostra foi composta por oito famílias de crianças com DF que fazem os acompanhamentos em um Hemonúcleo da Fundação Centro de Hematologia e Hemoterapia de Minas Gerais, as quais participaram de três entrevistas em profundidade, avaliadas por meio da composição de hemograma, ecomapa, linha do tempo da doença e análise de documentos, como exames, receituários e sumários de alta hospitalar. Resultados: as famílias definiram a situação da doença falciforme como um evento Assustador e de difícil Entendimento; a identidade das crianças oscilou entres as características de Vulnerável a Normal entendido como qualquer outra criança. Os comportamentos de manejo incidem sobre a responsabilidade que as famílias sentem em manterem a criança por perto, sendo vigilantes no controle da doença e buscando a manutenção da vida e do bem-estar desta criança. Assim, as famílias procuram adaptar-se às novas situações impostas pela doença. As consequências percebidas refletem que o foco destas famílias está na criança doente e no estímulo para que as crianças gerenciem os seus próprios cuidados preparando-as para a fase adulta. As expectativas familiares sobre o futuro estão na possibilidade de cura e de uma vida dentro da normalidade, embora relatem o medo da morte diante do curso incerto da doença. Considerações finais: a compreensão do manejo familiar das crianças com doença falciforme subsidiou propostas de intervenções, para estas famílias, com o intuito de orientá-las e apoiá-las na experiência do manejo; além de encorajar os profissionais de saúde que atuam com estas famílias a utilizarem este modelo de avaliação teórica para a execução de suas intervenções em todos os níveis de assistência à saúde. / Introduction: Sickle cell disease (SCD) is a chronic and hereditary condition that, due to its clinical and epidemiological importance, is a serious public health problem. The families of children with this condition alter their routines and manage the care seeking to adapt to frequent crises and hospitalizations. Objectives: This study aimed to know the experience of family management of the child with sickle cell disease and, specifically, sought to identify how families define the seeking to understand the management behaviors acquired in the care experience, as well as to understand the consequences perceived by the family and generated by the sickle cell disease of the child. Method: this is a qualitative research that used the Family Management Style Framework as a theoretical reference and, as a method, the case study - being the data analyzed according to the hybrid model of thematic analysis. The sample consisted of eight families of children with SCD who follow the follow-up in a Hemodynamic and Haemotherapy Center Foundation Hemodynamic of Minas Gerais, who participated in three in-depth interviews, evaluated through the composition of genogram, ecomapa, line time of disease and document analysis, such as exams, prescriptions and hospital discharge summaries. Results: Families defined sickle cell disease as a \"scary\" event and difficult to understand. Children\'s identities ranged from \"Vulnerable\" to \"Normal\" - understood as \"any other child\". Management behaviors focus on the responsibility that families feel in keeping the child close, being vigilant in controlling the disease and seeking to maintain the life and well-being of this child. Thus, families seek to adapt to the new situations imposed by the disease. The perceived consequences reflect that the focus of these families is on the sick child and the encouragement for children to manage their own care - preparing them for adulthood. Family expectations about the future lie in the possibility of healing and living within normality, even though they report the fear of death in the face of the uncertain course of illness. Final considerations: understanding the family management of children with sickle-cell disease subsidized intervention proposals for these families, with the aim of guiding them and supporting them in the management experience; in addition to encouraging health professionals working with these families to use this theoretical evaluation model for the execution of their interventions at all levels of health care.

Different cucurbitacin derivatives have been compared for the gamma globin induction potential. Cucurbitacin D turned out to be the most potential inducer among the derivatives had been tested. Later I had screened more herbs for the gamma globin induction activities. One of the herbs showed a higher activity than Fructus Trichosanthis, which could be the potential candidate to isolate more potent inducer. In the toxicity study, cucurbitacin D only have a mild toxic effect on the normal cell lines and transgenic mice. Finally, the efficacy of cucurbitacin D was tested on a sickle cell anemia mouse model and demonstrated a significant induction of fetal haemoglobin production. Cucurbitacin D may be a potential drug candidate for treating beta globinopathies. / Thalassemia is a global disease. It was report in 2001 that there were 270 million people who carried the severe disease. Most of the cases were found in Africa and south-east Asia. China has a high incidence rate of 0.66% in 2001. In the past, the treatments of the disease were blood transfusion and bone marrow transplantation. However, many defects in such kinds of treatments were reported. The balance of relieving the syndrome of the disease and the adverse effects of the drugs was the consideration to the physician. The drug, hydroxyurea, can activate the gamma globin gene and produce hemoglobin F to replace the beta globin as an oxygen transporter is considered as an better treatment to ameliorate the syndrome. Safety and effectiveness in the long-term treatment using hydroxyurea are questionable. Cucurbatacin D purified from a Chinese herb demonstrates 2000 folds more potent than hydroxyurea. It can activate the gamma globin gene and produce hemoglobin F shown in ELISA and confocal microscopy. The fundamental work for drug development is carrying out through this project. In this project the biological property and toxicity were studied. / Liu, Shuk Ming. / Adviser: M.C. Tung. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 245-270). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2016-03-16T16:33:05Z No. of bitstreams: 1 PDF - Natane Daiana Silva Sousa.pdf: 1503620 bytes, checksum: b35393e08e0ecf2db48eaff10e1ef855 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-07-22T13:22:12Z (GMT) No. of bitstreams: 1 PDF - Natane Daiana Silva Sousa.pdf: 1503620 bytes, checksum: b35393e08e0ecf2db48eaff10e1ef855 (MD5) / Made available in DSpace on 2016-07-22T13:22:25Z (GMT). No. of bitstreams: 1 PDF - Natane Daiana Silva Sousa.pdf: 1503620 bytes, checksum: b35393e08e0ecf2db48eaff10e1ef855 (MD5) Previous issue date: 2015-12-02 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Aim: To determine the prevalence of anemia and correlated factors to the hemoglobin level in the elderly population living in Campina Grande, Paraiba, Brazil. Methods: This is a crosssectional study conducted with individuals aged 60 years or older. Blood was collected for later determination of plasma hemoglobin. Male individuals who had hemoglobin levels <13 g / dL and females who had hemoglobin levels <12 g / dL were considered anemic. Demographic and socioeconomic variables, cognitive status, functional capacity, nutritional status and number of self-reported chronic diseases were analyzed. Simple and multiple linear regression analyses were performed using SPSS 22.0 software. Results: A total of 360 older individuals (67.2% women) were evaluated, and the prevalence of anemia was 12.5%. The average hemoglobin level was 13.5 g / dL and was correlated with variables sex (β = -0.44; CI 95%: -1.35-0.85), age (β = -0 14; CI 95%: -0.03 -0.01), nutritional status (β = 0.16; CI 95%: 0.01; 0.06), memory impairment (β = 0.12; CI 95% : -0.06; -0.01), and dementia (β = -0.13; CI 95%: -0.06, -0.01). Conclusion: The results of this study indicated influence of sex, age, nutritional status, memory impairment and dementia on anemia in the elderly. This study can assist in planning specific actions for prevention, early diagnosis and treatment of this disease, thus improving the health and quality of life of the elderly population. / Objetivo: Verificar a prevalência de anemia e os fatores correlacionados ao nível de hemoglobina em população idosa residente em Campina Grande, Paraíba, Brasil. Material e Métodos: Estudo transversal com indivíduos de 60 anos de idade ou mais. Realizou-se coleta sanguínea dos idosos para posterior dosagem da hemoglobina plasmática. Foram considerados anêmicos os indivíduos do sexo masculino que apresentaram níveis de hemoglobina <13 g/dL e do sexo feminino que apresentaram níveis <12 g/dL. Foram analisadas variáveis demográficas, socioeconômicas, condição cognitiva, capacidade funcional, estado nutricional e número de doenças crônicas referidas. As análises de regressão linear simples e múltipla, foram realizadas por meio do SPSS 22.0. Resultados: Foram avaliados 360 idosos (67,2% mulheres), cuja prevalência de anemia foi de 12,5%. O nível médio de hemoglobina verificado foi de 13,5 g/dL e esteve correlacionado às variáveis sexo (β = -0,44; IC95%: -1,35;-0,85), idade (β= -0,14; IC95%: -0,03;-0,01), estado nutricional (β= 0,16; IC95%: 0,01;0,06), comprometimento de memória (β= 0,12; IC95%: -0,06;-0,01), e demência (β = -0,13; IC95%: -0,06;0,01). Conclusão: Os resultados deste estudo indicaram influência do sexo, da idade, do estado nutricional, do comprometimento de memória e da demência sobre o nível de hemoglobina em idosos. Este estudo pode auxiliar no planejamento de ações específicas voltadas para a prevenção, diagnóstico precoce e tratamento adequado da anemia, melhorando, assim, a saúde e qualidade de vida da população idosa.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A anemia falciforme (AF) à uma hemoglobinopatia hereditÃria autossÃmica causada por uma mutaÃÃo pontual no gene da beta globina gerando uma hemoglobina anormal denominada de hemoglobina S (HbS), em homozigose. A doenÃa se caracteriza por apresentar uma variabilidade do quadro clÃnico, que se deve à mÃltiplos fatores, dentre eles a concentraÃÃo de hemoglobina fetal (HbF), os haplÃtipos do gene da beta globina e os polimorfismos do gene BCL11A, entre outros. A avaliaÃÃo dos moduladores genÃticos na AF tem sido desenvolvida com a finalidade de melhorar o entendimento da sua fisiopatologia e direcionar a abordagem terapÃutica objetivando sua individualizaÃÃo. A pesquisa se propÃs a determinar a modulaÃÃo genÃtica dos polimorfismos do gene BCL11A (rs4671393, rs7557939 e rs1186868) sobre o perfil inflamatÃrio, hemolÃtico, no estresse oxidativo e nas concentraÃÃes das HbF, HbS nos pacientes portadores de AF, em estado estacionÃrio. O estudo foi do tipo transversal e analÃtico com 42 pacientes adultos, em acompanhamento ambulatorial no Hospital UniversitÃrio Walter CantÃdio (HUWC), com diagnÃstico molecular e haplÃtipos do gene da beta globina S previamente realizados. Os pacientes estavam em uso de HidroxiurÃia (HU), em mÃdia, 20mg/kg de peso corporal. Amostras biolÃgicas de sangue perifÃrico foram obtidas para a realizaÃÃo dos exames laboratoriais: as dosagens das citocinas prà inflamatÃrias IL-6, IL-17, TNF-alpha e das antiinflamatÃrias IL-10 e TGF-beta, por Elisa; contagem de reticulÃcitos por metodologia manual, dosagem de metemoglobina (MetHb) e lactato desidrogenase (LDH), por espectrofotometria; do nitrito (NOx), malonaldeÃdo (MDA) sÃricos, as enzimas antioxidantes eritrocitÃrias, catalase (CAT) e da glutationa peroxidase (GPx) por kits e espectrofotometria. Os polimorfismos genÃticos do gene BCL11A nas regiÃes, rs4671393, rs7557939 e rs1186868 foram determinados por Real Time PCR. As dosagens da HbF e HbS foram realizadas por HPLC (High Performance Liquid Chromatography). Os dados idade, sexo e eventos clÃnicos foram obtidos dos prontuÃrios. Toda a anÃlise estatÃstica foi realizada usando o software livre R, na versÃo 3.1.2. Para anÃlise da frequÃncia do sexo e dos genÃtipos, por regiÃo e das associaÃÃes entre o tipo de haplÃtipo e dos eventos clÃnicos com as regiÃes do BCL11A, foram usados os testes de Qui-quadrado e o exato de Fisher. Realizou-se o teste paramÃtrico de ANOVA (obtido sob suposiÃÃes distribucionais), bem como o teste nÃo-paramÃtrico de Kruskal-Wallis para a anÃlise da associaÃÃo dos genÃtipos do gene BCL11A com a idade, os nÃveis de HbS, HbF, perfil inflamatÃrio, hemolÃtico e do estresse oxidativo. Foi considerado significante ao nÃvel de 5%. A maioria dos pacientes (57,14%) era do sexo feminino. A idade dos pacientes incluÃdos foi de 18 a 65 anos, com valor mÃdio e mediano de 35,1 e 33 anos, respectivamente. Somente a rs7557939 do BCL11A, o genÃtipo A/G foi o mais prevalente e a prevalÃncia do genÃtipo A/G foi maior nas mulheres , enquanto nos homens a prevalÃncia maior foi do genÃtipo A/A. No entanto, a rs1186868 do BCL11A, a maioria (56,52%) das mulheres apresentaram o genÃtipo C/T e a metade dos homens apresentaram o genÃtipo T/T. Nenhuma regiÃo do gene BCL11A apresentou associaÃÃo significativa com os haplÃtipos do gene da beta globina S. Em relaÃÃo a moduÃÃo do gene BCL11A com os nÃveis de HbS e HbF, verificou-se que na rs1186868 houve resultado significativo do genÃtipo mutante T/T, que apresentou maiores nÃveis de HbS e menores nÃveis de HbF. Na rs7557939 houve uma diminuiÃÃo significante de HbF no alelo mutante A/A, porÃm, nÃo houve relaÃÃo com a HbS. NÃo houve associaÃÃo entre os SNPs, nas trÃs regiÃes estudadas, com relaÃÃo ao nÃmero mÃdio/mediano dos moduladores inflamatÃrios, marcadores de hemÃlise, do estresse oxidativo e dos eventos clÃnicos, ao nÃvel de 5%.Os achados reforÃam a hipÃtese da moduÃÃo genÃtica dos polimorfismos do gene BCL11A em relaÃÃo aos nÃveis de HbF, onde os alelos selvagens, nas regiÃes rs7557939 e rs1186868 apresentaram um carÃter protetor no prognÃstico em decorÃncia de terem apresentado aumento dos nÃveis de HbF, nos pacientes com AF do estudo.

Introdução- A hiperglicemia (HG), durante o infarto agudo do miocárdio (IAM), está associada com aumento de mortalidade hospitalar em pacientes diabéticos e não diabéticos. Entretanto, não é conhecido o mecanismo responsável por esta associação. Assim estudou-se, simultaneamente, a correlação entre a glicemia e marcadores bioquímicos relacionados ao sistema neuro-humoral de estresse, metabolismo glicídico e lipídico, sistema de coagulação e inflamatório. Métodos- 80 pacientes foram incluídos consecutiva e prospectivamente. Foram realizadas duas coletas de sangue, a primeira com 24h a 48h do início dos sintomas do IAM (fase aguda) e a segunda após 3 meses do IAM (fase crônica), sempre com 12h de jejum. Foram analisados os seguintes parâmetros: glicose, cortisol, noradrenalina, hemoglobina glicada (HbA1c), insulina, LDL minimamente modificada eletronegativa, ácidos graxos livres (AGL), adiponectina, factor VII da coagulação, fibrinogênio, inibidor do ativação do plasminogênio tipo 1, proteína C reativa ultra-sensível (PCRus), colesterol total (c) e frações e triglicérides. Nas correlações univariadas entre glicemia e as variáveis contínuas empregou-se o teste de correlação de Pearson. As análises multivariadas foram feitas através de regressão logística (variáveis qualitativas) e modelo linear generalizado (quando as variáveis independentes incluídas foram quantitativas e nominais). Resultados- Na fase aguda, a glicemia correlacionou-se significativamente com HbA1c (r=0,75, p<0,001), insulina (r=0,25, p<0,001), AGL (r=0,3, p=0,01), adiponectina (r=-0,22, p=0,05), LDL-c (r=-0,25, p=0,03), VLDL-c (r=0,24, p=0,03) e triglicérides (r=0,27, p=0,01). No modelo multivariado, as variáveis correlacionadas de forma independente com a glicemia, na fase aguda, foram: HbA1c (p<0,001), insulina (p<0,001), e AGL (p=0,013). Para analisar uma variável de confusão, a história de diabetes mellitus (DM), incluiu-se esta variável num modelo, juntamente com as variáveis acima e todas mostraram associação significativas com glicose: HbA1c (p<0,001), insulina (p=0,001), AGL (p=0,013) e história de DM (p=0,027). Na fase crônica, glicose correlacionou-se com: cortisol (r=0,31, p=0,01), noradrenalina (r=0,54, p<0,001), HbA1c (r=0,78, p<0,001) e PCRus (r=0,46, p<0,001). Na análise multivariada, somente HbA1c (p<0,001) e noradrenalina (p<0,001) mantiveram correlação independente. Conclusão- A HbA1c foi a única variável que correlacionou-se de forma significativa e independente com a glicemia, tanto na fase aguda, quanto na crônica, mostrando que a hiperglicemia, durante o IAM, pode representar uma alteração crônica, sub-diagnosticada, do metabolismo glicídico. / Introduction- Hyperglycemia (HG) is an important prognostic factor in acute myocardial infarction (AMI). However, the pathophysiology is poorly understood. So we proposed a simultaneous correlation between glycemia and biochemical markers of stress, glucose and lipid metabolism, coagulation and inflammation system. Methods- Eighty AMI patients were included prospectively. Blood were collected between 24h and 48h from the pain (acute phase), and 3 months post AMI (chronic phase), with 12-h fasting. These parameters were analyzed: glucose, cortisol, norepinephrine, hemoglobin glycated (HbA1c), insulin, minimally modified electronegative LDL, free fatty acids (FFA), adiponectin, factor VII coagulant, fibrinogen, plasminogen activator inhibitor-1, high sensitive C reaction protein (hsCRP), total cholesterol (c) and fractions and triglyceride. The relationships between glucose and continuous variables were assessed by Pearsons correlation coefficient (r) and multivariate analysis with linear regression. Results- At acute phase, glucose correlated significantly with HbA1c (r=0.75, p<0.001), insulin (r=0.25, p<0.001), FFA (r=0.3, p=0.01), adiponectin (r=-0.22, p=0.05), LDL-c (r=-0.25, p=0.03), VLDL-c (r=0.24, p=0.03) and triglyceride (r=0.27, p=0.01). In a multivariate model, variables correlated were: HbA1c (p<0.001), insulin (p<0.001), and FFA (p=0.013). At the chronic phase, glucose correlated significantly with cortisol (r=0.31, p=0.01), norepinephrine (r=0.54, p<0.001), HbA1c (r=0.78, p<0.001) and hsCRP (r=0.46, p<0,001). By multivariable analysis, only HbA1c (p<0.001) and norepinephrine (p<0.001) remained correlated. Conclusion- HbA1c was the main variable that correlated significantly and independently with glycemia at acute and chronic phases, suggesting that HG during AMI can represent an exacerbation of abnormal glucose metabolism previously not diagnosed.

Inpatient falls are the most reported incidents in the acute care setting. Symptoms associated with a diagnosis of cancer and treatment may increase risk for falls. The objectives of this study were to identify the risk factors, and the most common risk factors, of adult patients with cancer who fell while hospitalized. A retrospective, matched, case-control audit of electronic medical records and occurrence reports was conducted for 30 patients who fell and 30 patients who did not fall while under the care of the inpatient oncology unit in a community hospital. Fall subjects and controls were matched by cancer diagnosis and age. Results of the study (N = 30) revealed altered cognition (p = .010), muscular weakness (p = .037), and a history of a fall in the past six months (p = .045) as statistically significant fall risk factors. The audit of the electronic medical records revealed variations in the nursing documentation of fall risk factors that could increase the chance of assessments being omitted or communicated inaccurately to other members of the care team. Additional studies are needed to examine risk factors for falls in hospitalized oncology patient populations.

The study investigated the association between body mass index (BMI) and depression based upon glycated hemoglobin levels (HBA1C) among United States veterans. Based on Bandura's social cognitive theory, a cross-sectional analysis examined the association between BMI and depression on HBA1C regulation, and if the interaction between BMI and depression affects HBAIC regulation among veterans. Multiple regression analysis was used to test the multivariate associations between depression and BMI on the outcome variable of HBA1C. Linearity, normality, and homoscedasticity were assessed using normal probability plots and residual analysis. Durbin-Watson statistics were used to test for autocorrelations, and variance inflation factor was used to check for multicollinearity. There was not a statistically significant difference between those who were depressed (Mdn = 32.76, IQR = 7.8) and those who were not depressed (Mdn = 33.27, IQR = 5.0) in terms of BMI (U = 774.0, p = 0.47). When depression, BMI, an interaction term for depression*BMI, and other predictor variables were entered into the regression model, these variables did not account for a significant increase in shared variance in HBA1C (Î?R2 = 0.17, F (14, 74) = 0.17, p = 0.37). Social change implications generated from this study include better resource utilization, improved quality of care, increased veteran satisfaction and improved veteran experience across the healthcare system. The findings from the study can be used to expand access to specialized services for chronically ill veterans, coordinate resources, better outcomes and facilitate seamless care coordination between mental health and primary care providers

Intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) remains the principal cause of the pathophysiology associated with sickle cell disease (SCD). Naturally occurring and synthetic allosteric effectors of hemoglobin (AEH) have been investigated as potential therapeutic agents for the treatment of SCD. Several aromatic aldehydes, including vanillin, have been studied previously as AEHs for their antisickling activities. Specifically, these compounds form Schiff- base adduct with Hb to stabilize the oxygenated (R) state, increase Hb affinity for O2 and concomitantly prevent the hypoxia-induced primary pathophysiology of Hb S polymerization and RBC sickling, in turn, ameliorating several of the cascading secondary adverse effects. These compounds, however, undergo significant metabolism leading to suboptimal pharmacokinetic properties, e.g. short duration of pharmacologic action and low bioavailability. These drawbacks have severely hampered the use of aromatic aldehydes as AEHs to treat SCD. To counter these challenges, we designed and synthesized 14 novel compounds (PP- compounds) based on previously studied pyridyl derivative of vanillin. These modifications were expected to increase binding interactions with the protein and thus stabilize the Schiff-base adduct, as well as lead to perturbation of the surface-located F-helix that would stereospecifically destabilize polymer contacts. We investigated the in vitro pharmacokinetic/pharmacodynamic properties of these newly synthesized compounds to ascertain sustained binding and modification of normal human Hb. Subsequently, we conducted in vitro screening assays to test for inhibition of sickling, modification of Hb to the high-affinity form, as well as for a direct left-shift in oxygen equilibrium curves (OEC). Three selected compounds, PP6, PP10, and PP14, that demonstrated not only high antisickling activity but also showed sustained pharmacologic action were chosen for preliminary in vivo studies. Our results showed maximal levels of Hb modification, which were sustained for the entire 24 h experimental period. In contrast, TD-7 after reaching maximum effect at 1 h gradually decreased in potency and at 24 h has lost 45% of its activity, consistent with the low bioavailability of this compound. These findings suggested that our modifications appeared to successfully limit drug metabolism in red blood cells. Most of these compounds showed almost complete inhibition of sickling at 2 mM concentration; with significant modification of Hb to a higher affinity Hb as well as an increase in O2 affinity of Hb. Interestingly, while TD-7 demonstrated a clear linear correlation between its ability to increase Hb-O2 affinity and antisickling activity, PP2, PP3, PP6, PP9, PP10, and PP14, showed a weak correlation between these parameters. In fact, these compounds demonstrated high antisickling effect despite only marginally increasing Hb affinity for O2. This observation indicated that these compounds possibly exhibit the dual mechanism of antisickling activity. We hypothesize that their secondary mechanism of action is due to interactions with the surface located αF-helix that would lead to direct or stereospecific inhibition of polymer formation. To establish the mode of interaction with Hb, we further conducted x-ray crystallography studies and co-crystallized PP2, PP6, PP9 and PP11 with CO-liganded Hb. Our studies showed that these compounds bind in symmetry-related fashion at the α-cleft of Hb to form Schiff-base adducts with the N-terminal Val1 and showed direct interactions with the F-helix which overall enhanced interactions with Hb. PP6, PP10, and PP14 demonstrated significant in vivo modification of intracellular Hb in mice after IP administration, with increasing levels from 1 h to the 6 h experimental period. They also showed corresponding changes in O2 affinity observed at 3 h and 6 h, compared to 0 h pre-treatment samples in vivo. Thus, our results establish these compounds as a novel, promising group of potent anti-sickling agents, demonstrate their proposed mechanism of action and provide proof-of-concept justifications for our structure-based approach to developing potent therapeutics for SCD.