Scaling-Up of Dental Pulp Stem Cells Isolated from Multiple Niches

Dental pulp (DP) can be extracted from child’s primary teeth (deciduous), whose loss occurs spontaneously by about 5 to 12 years. Thus, DP presents an easy accessible source of stem cells without ethical concerns. Substantial quantities of stem cells of an excellent quality and at early (2–5) passages are necessary for clinical use, which currently is a problem for use of adult stem cells. Herein, DPs were cultured generating stem cells at least during six months through multiple mechanical transfers into a new culture dish every 3–4 days. We compared stem cells isolated from the same DP before (early population, EP) and six months after several mechanical transfers (late population, LP). No changes, in both EP and LP, were observed in morphology, expression of stem cells markers (nestin, vimentin, fibronectin, SH2, SH3 and Oct3/4), chondrogenic and myogenic differentiation potential, even after cryopreservation. Six hours after DP extraction and in vitro plating, rare 5-bromo-2′-deoxyuridine (BrdU) positive cells were observed in pulp central part. After 72 hours, BrdU positive cells increased in number and were found in DP periphery, thus originating a multicellular population of stem cells of high purity. Multiple stem cell niches were identified in different zones of DP, because abundant expression of nestin, vimentin and Oct3/4 proteins was observed, while STRO-1 protein localization was restricted to perivascular niche. Our finding is of importance for the future of stem cell therapies, providing scaling-up of stem cells at early passages with minimum risk of losing their “stemness”

Tumor miofibroblástico inflamatório do pulmão : Inflammatory myofibroblastic tumor of the lung

Introdução: Os tumores miofibroblásticos inflamatórios pulmonares são achados patológicos, de apresentação clínica, evolução e prognósticos controversos. Representam de 0,04% -1,2% de todos os tumores pulmonares, sendo mais comuns em crianças e rara sua forma primária em adultos. Possui diagnóstico difícil, pois é fundamentalmente anátomo-patológico. A apresentação clínica e radiográfica são muito variáveis.  Apresentação do caso: sexo masculino, 49 anos de idade, admitido no hospital das clínicas da UFG (Go) com história cronica de 6 meses de dispnea progressiva, com tosse produtiva e sibilos, paciente tinha história de tabagismo (1 maço por dia há 20 anos) hipertensão e asma. Discussão: O tumor miofibroblasto inflamatório de pulmão geralmente é assintomático e descoberto incidentalmente ou apresenta sintomas respiratórios inespecíficos, como tosse, dor torácica , dispneia, hemoptise e sintomas sistêmicos inespecíficos, como febre, mal-estar e perda de peso. Podem estar associados a distúrbios imunológicos e infecções crônicas e podem ocorrer em cicatrizes pulmonares cirúrgicas.  Conclusão: É uma causa rara de tumor primário em adultos, em contrapartida, frequente na população pediátrica e, tem no anatomopatológico seu melhor diagnóstico e tratamento após ressecção cirúrgica completa, o qual indica, de forma usual, um bom prognóstico

Proteinose alveolar pulmonar: Pulmonary alveolar proteinosis

INTRODUÇÃO: A Proteinose Alveolar Pulmonar (PAP) é uma síndrome rara causada pelo acúmulo de surfactante no espaço alveolar, mais comumente encontrada em homens com idade média de 20 a 50 anos. É uma patologia com apresentação clínica variável e de difícil diagnóstico, que pode cursar com dispneia, tosse e dor torácica. APRESENTAÇÃO DO CASO: RSM, sexo masculino, 39 anos,  ex-tabagista de um maço por dia, durante 8 anos, com queixa de dispneia, dor torácica, ventilatório dependente, febre não aferida esporadicamente, tosse seca, raramente produtiva durante a manhã, e cianose de extremidades aos esforços há 4 meses. Após 6 meses, evoluiu com piora do quadro. Prosseguiu a investigação de pneumopatia extensa bilateral, com realização de biópsia pulmonar, confirmando o diagnóstico de PAP. DISCUSSÃO: A tomografia de tórax é o exame inicial a ser solicitado na investigação de PAP, seguido da confirmação com líquido do lavado broncoalveolar. Embora não seja um exame obrigatório, o padrão-ouro é a biópsia pulmonar cirúrgica. O principal tratamento é a lavagem pulmonar, além de fisioterapia e suporte pulmonar. CONCLUSÃO: Ainda que seja uma doença rara, é essencial o diagnóstico diferencial de PAP com quadros de dispneia crônica e progressiva, não explicadas por outras patologias mais prevalentes

AVALIAÇÃO NEUROBIOLOGICA DO USO DA RITALINA EM PACIENTES NÃO PORTADORES DE TDHA

The non-therapeutic use of Ritalin, or methylphenidate, among individuals without Attention Deficit Hyperactivity Disorder (ADHD) has increased, especially in academic settings, due to its potential to improve attention and cognitive performance. This study reviews the neurobiological effects of this use in individuals without ADHD. Changes in brain activity, especially in the prefrontal cortex and limbic system, were compared, alterations in dopaminergic neurotransmission were investigated, and differences in neuropsychological performance before and after the use of Ritalin were assessed. The review included articles published between 2011 and 2024 in the PubMed, SciELO, LILACS, and Google Scholar databases, focusing on the neurobiological effects of Ritalin in individuals without ADHD. Results indicate that, despite temporary improvements in concentration and working memory, prolonged use may cause anxiety, tachycardia, changes in appetite, and dependence, as well as reduce the effectiveness of the medication due to tolerance. It is concluded that the risks to physical and mental health outweigh the short-term cognitive benefits. It is essential to raise awareness about the dangers of non-prescribed use of Ritalin and to promote healthy alternatives for cognitive enhancement, as well as to develop evidence-based guidelines to minimize the risks of unsupervised stimulant use.O uso não terapêutico da Ritalina, ou metilfenidato, entre indivíduos sem Transtorno de Déficit de Atenção e Hiperatividade (TDAH) tem aumentado, principalmente em ambientes acadêmicos, devido ao seu potencial para melhorar a atenção e o desempenho cognitivo. Este estudo revisa os efeitos neurobiológicos desse uso em indivíduos sem TDAH. Foram comparadas as alterações na atividade cerebral, especialmente no córtex pré-frontal e sistema límbico, investigadas mudanças na neurotransmissão dopaminérgica e avaliadas as diferenças no desempenho neuropsicológico antes e após o uso da Ritalina.    A revisão incluiu artigos publicados entre 2011 e 2024 nas bases PubMed, SciELO, LILACS e Google Scholar, focando nos efeitos neurobiológicos da Ritalina em indivíduos sem TDAH. Resultados indicam que, apesar de melhorias temporárias na concentração e memória de trabalho, o uso prolongado pode causar ansiedade, taquicardia, alterações no apetite e dependência, além de reduzir a eficácia do medicamento devido à tolerância.    Conclui-se que os riscos à saúde física e mental superam os benefícios cognitivos de curto prazo. É essencial conscientizar sobre os perigos do uso não prescrito da Ritalina e promover alternativas saudáveis para o aprimoramento cognitivo, além de desenvolver diretrizes baseadas em evidências para minimizar os riscos do uso não supervisionado de estimulantes

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference