Uso do prontuário eletrônico na assistência pré-natal às portadoras de diabetes na gestação

Objetivo Apresentar e validar um registro eletrônico de saúde (RES) multifuncional para atendimento ambulatorial a portadoras de endocrinopatias na gestação e comparar a taxa de preenchimento de informações de saúde com o prontuário convencional. Métodos Desenvolvemos um RES denominado Ambulatório de Endocrinopatias na Gestação eletrônico (AMBEG) para registro sistematizado das informações de saúde. O AMBEG foi utilizado para atendimento obstétrico e endocrinológico de gestantes acompanhadas no ambulatório de endocrinopatias na gestação na maternidade referência em gestação de alto risco na Bahia, no período de janeiro de 2010 a dezembro de 2013. Aleatoriamente foramselecionadas 100 pacientes atendidas como AMBEG e 100 pacientes atendidas comprontuário convencional comregistro em papel e comparou-se a taxa de preenchimento de informações clínicas. Resultados Foram realizados 1461 atendimentos com o AMBEG: 253, 963 e 245 respectivamente, admissões, consultas de seguimento e puerpério. Eram portadoras de diabetes 77,2% e sendo 60,1% portadoras de diabetes pré-gestacional. O AMBEG substituiu, satisfatoriamente, o prontuário convencional. O percentual de informações clínicas registradas em ambos os prontuários foi significativamente maior no AMBEG: queixas clínicas (100 versus 87%, p < 0,01), altura uterina (89 versus 75%, p = 0,01), ganho de peso total (91 versus 40%, p < 0,01) e dados específicos sobre o diabetes (dieta, esquema de insulina, controle glicêmico e manejo de hipoglicemias) revelando diferença significativa (p < 0,01). A possibilidade de exportar dados clínicos para planilhas facilitou e agilizou a análise estatística de dados. Conclusões O AMBEG é uma ferramenta útil no atendimento clínico a mulheres portadoras de endocrinopatias na gestação. A taxa de preenchimento de informações clínicas foi superior à do prontuário convencional.

Correlação das dosagens de frutosamina e de hemoglobina glicosilada com o perfil glicêmico em gestantes com diabetes mellitus

Objetivo Avaliar se há correlação das dosagens de frutosamina e de hemoglobina glicosilada (HbA1c) com as frequências de desvios de glicemia capilar em gestantes com diabetes mellitus. Métodos estudo observacional, retrospectivo, de corte transversal, incluindo todas as gestantes comdiabetes que iniciaram o pré-natal emhospital terciário de ensino durante o ano de 2014 e que apresentavam pelo menos 20 dias de auto monitoramento glicêmico previamente às dosagens séricas de frutosamina e de HbA1c. Os desvios de glicemia capilar foram considerados "hipoglicemias" quando menores que 70mg/dL ou "hiperglicemias" quando acima do alvo glicêmico terapêutico para o horário. Foram testadas as correlações lineares par a par das dosagens de frutosamina e de HbA1c com as frequências de hipoglicemias e de hiperglicemias capilares pelo teste Tau-b de Kendall. Na sequência, foi avaliada a regressão linear entre as dosagens de HbA1c e de frutosamina e as frequências de hipoglicemias e de hiperglicemias. Resultados Foram incluídas 158 gestantes que contribuíram com 266 amostras para dosagem sérica de frutosamina e HbA1c. As dosagens de frutosamina e de HbA1c apresentaram, respectivamente, coeficientes τ de Kendall de 0,29 (p < 0,001) e 0,5 (p < 0,001) com a frequência de hiperglicemias, e de 0,09 (p = 0,04) e 0,25 (p < 0,001) com a frequência de hipoglicemias capilares. No modelo de regressão linear, as dosagens de frutosamina e de HbA1c apresentaram, respectivamente, coeficientes de determinação R2 = 0,26 (p < 0,001) e R2 = 0,51 (p < 0,001) para a predição de hiperglicemias, e R2 = 0,03 (p = 0,003) e R2 = 0,059 (p < 0,001) para a predição de hipoglicemias. Conclusão As dosagens de frutosamina e de HbA1c apresentam correlação fraca a moderada com as frequências de hiperglicemias e hipoglicemias capilares no auto monitoramento glicêmico e não são capazes de traduzir com precisão os desvios da meta glicêmica no tratamento de gestantes com diabetes.

Estudo comparativo das estruturas do segmento anterior de olhos de cães normais e com catarata, portadores ou não de Diabetes mellitus, avaliados por biomicroscopia ultrassônica

A catarata representa uma das principais causas de cegueira em cães, sendo que as alterações metabólicas provocadas pelo Diabetes mellitus (DM), constituem a segunda causa mais comum de catarata nesta espécie. A biomicroscopia ultrassônica (UBM) é um método ultrassonográfico de alta frequência (50 MHz) que permite a obtenção de imagens do modo B de qualidade microscópica. Este estudo objetivou, por meio do uso da UBM, comparar as estruturas do segmento anterior de olhos de cães com catarata, diabética e não-diabética, às de cães normais, para verificar possíveis alterações decorrentes do DM. Os parâmetros avaliados foram espessura da córnea, profundidade da câmara anterior, aumento de celularidade no interior da câmara anterior e medida do ângulo iridocorneal. Foram realizados exames de 87 olhos de 47 animais da espécie canina, divididos em 3 grupos: grupo controle (GCO), grupo de portadores de catarata não-diabéticos (GCAT) e o grupo dos diabéticos (GDM). Os resultados revelam que o grupo dos diabéticos apresentou maiores espessuras de córnea que os demais grupos enquanto o grupo controle apresentou maiores câmaras anteriores. Encontrou-se aumento de celularidade em câmara anterior apenas nos grupos com catarata. Quando analisadas as medidas do ângulo iridocorneal, não houve diferença entre os 3 grupos. Com base no que foi aferido, permite-se concluir que olhos de cães diabéticos com catarata apresentam maior espessura de córnea central que olhos de cães com catarata de outras etiologias e de cães normais, que há diminuição da câmara anterior, com aumento de celularidade, em olhos de cães com catarata, quando comparados a cães normais e que não há diferença na medida do ângulo iridocorneal em olhos de cães com catarata, diabética ou não, e de cães normais.

Herpes simplex virus type 1 (HSV-1) pathogenesis and HSV gene therapy of experimental autoimmune encephalomyelitis

The aim of this thesis was to develop new herpes simplex virus (HSV) vectors for gene therapy of experimental autoimmune encephalomyelitis (EAE), the principal model of multiple sclerosis (MS), and to study the pathogenesis of wild-type HSV-1 and HSV-1 vectors in vivo. By introducing potential immunomodulatory factors into mice with EAE we strived to develop therapies and possibly find molecules improving recovery from EAE. We aimed at altering the immune response by inducing favorable Th2-type cytokines, thus shifting the immune response from a Th1- or a Th17-response. Our HSV vector expressing interleukin (IL)-5 modulated the cytokine responses, decreased inflammation and alleviated EAE. The use of a novel method, bacterial artificial chromosome (BAC), for engineering recombinant HSV facilitated the construction of a new vector expressing leukemia inhibitory factor (LIF). LIF is a neurotropic cytokine with broad functions in the central nervous system (CNS). LIF promotes oligodendrocyte maturation and decreases demyelination and oligodendrocyte loss. The BAC-derived HSV-LIF vector alleviated the clinical symptoms, induced a higher number of oligodendrocytes and modulated T cell responses. By administering HSV via different infection routes, e.g. peripherally via the nose or eye, or intracranially to the brain, the effect of the immune response on HSV spread at different points of the natural infection route was studied. The intranasal infection was an effective delivery route of HSV to the trigeminal ganglion and CNS, whereas corneal infection displayed limited spread. The corneal and intranasal infections induced different peripheral immune responses, which might explain the observed differences in viral spread.

Regulation of lymphocyte response in vitro and in vivo

CD4+ T helper (Th) cells have an important role in the defence against diverse pathogens. Th cells can differentiate into several functionally distinct subtypes including Th1 and Th2 cells. Th1 cells are important for eradicating intracellular pathogens, whereas Th2 cells pro¬tect our body against extracellular parasites. However if uncontrolled, Th cells can mediate immunopathology such as asthma or allergies, but inappropriate Th response can also lead to autoimmune diseases such as multiple sclerosis or type 1 diabetes. Deeper knowledge of the regulation of the lymphocyte response both in vitro and in vivo is important for un¬derstanding the pathogenesis of immune-mediated diseases and microbe-host interactions. In the work presented in this thesis, the first goal was to elucidate the role of novel factors, PIM kinases and c-FLIP in the regulation of human Th cell differentiation. The oncogenic serine-threonine kinases of the PIM family were shown to be preferentially expressed in Th1 cells and in addition, by using RNA interference, they were also shown to be positive regulators of Th1 differentiation. The PIM depletion experiments suggest that PIM kinases promote the expression of the hallmark cytokine of Th1 cells, IFNγ, and influence the IL12/STAT4 pathway during the early Th1 cell differentiation. In addition to cytokine and T cell receptor (TCR) induced pathways, caspase activity has been shown to regulate Th cell proliferation. In the work presented in this thesis, the two isoforms of the caspase regulator protein, c-FLIP, were shown to be differentially ex¬pressed in Th1 and Th2 cells. Both of the isoforms were up-regulated in response to TCR activation, but the expression of the short isoform was selectively induced by IL4, the Th2 inducing cytokine. Furthermore, the c-FLIP isoforms had distinct and opposite roles during the early differentiation of Th1 and Th2 cells. The knockdown of the long isoform of c-FLIP led to the induction of Th1 marker genes, such as IFNγ and TBET, whereas the depletion of c-FLIP short down-regulated Th2 marker genes IL-4 and GATA3. The third goal was to elucidate the gene expression profiles characterizing the T- and B-lymphocyte responses in vivo during experimental infection by intracellular bacte¬rium Chlamydia pneumoniae. Previously, it has been shown that CD8+ and CD4+ T cells are important for the protection against Chlamydia pneumoniae. In this study, the analysis revealed up-regulation of interferon induced genes during recurrent infection underlining the importance of IFNγ secreted by Th1 and CD8+ T cells in the protection against this pathogen. Taken together, in this study novel regulators of Th cell differ¬entiation were discovered and in addition the gene expression profiles of lymphocytes induced by Chlamydia pneumoniae infection were characterized.

Factors predicting mortality in type 2 diabetes. With special reference to physical exercise, blood pressure, proteinuria, inflammation and P wave duration

Background: Type 2 diabetes patients have a 2-4 fold risk of cardiovascular disease (CVD) compared to the general population. In type 2 diabetes, several CVD risk factors have been identified, including obesity, hypertension, hyperglycemia, proteinuria, sedentary lifestyle and dyslipidemia. Although much of the excess CVD risk can be attributed to these risk factors, a significant proportion is still unknown. Aims: To assess in middle-aged type 2 diabetic subjects the joint relations of several conventional and non-conventional CVD risk factors with respect to cardiovascular and total mortality. Subjects and methods: This thesis is part of a large prospective, population based East-West type 2 diabetes study that was launched in 1982-1984. It includes 1,059 middle-aged (45-64 years old) participants. At baseline, a thorough clinical examination and laboratory measurements were performed and an ECG was recorded. The latest follow-up study was performed 18 years later in January 2001 (when the subjects were 63-81 years old). The study endpoints were total mortality and mortality due to CVD, coronary heart disease (CHD) and stroke. Results: Physically more active patients had significantly reduced total, CVD and CHD mortality independent of high-sensitivity C-reactive protein (hs-CRP) levels unless proteinuria was present. Among physically active patients with a hs-CRP level >3 mg/L, the prognosis of CVD mortality was similar to patients with hs-CRP levels ≤3 mg/L. The worst prognosis was among physically inactive patients with hs-CRP levels >3 mg/L. Physically active patients with proteinuria had significantly increased total and CVD mortality by multivariate analyses. After adjustment for confounding factors, patients with proteinuria and a systolic BP <130 mmHg had a significant increase in total and CVD mortality compared to those with a systolic BP between 130 and 160 mmHg. The prognosis was similar in patients with a systolic BP <130 mmHg and ≥160 mmHg. Among patients without proteinuria, a systolic BP <130 mmHg was associated with a non-significant reduction in mortality. A P wave duration ≥114 ms was associated with a 2.5-fold increase in stroke mortality among patients with prevalent CHD or claudication. This finding persisted in multivariable analyses. Among patients with no comorbidities, there was no relationship between P wave duration and stroke mortality. Conclusions: Physical activity reduces total and CVD mortality in patients with type 2 diabetes without proteinuria or with elevated levels of hs-CRP, suggesting that the anti-inflammatory effect of physical activity can counteract increased CVD morbidity and mortality associated with a high CRP level. In patients with proteinuria the protective effect was not, however, present. Among patients with proteinuria, systolic BP <130 mmHg may increase mortality due to CVD. These results demonstrate the importance of early intervention to prevent CVD and to control all-cause mortality among patients with type 2 diabetes. The presence of proteinuria should be taken into account when defining the target systolic BP level for prevention of CVD deaths. A prolongation of the duration of the P wave was associated with increased stroke mortality among high-risk patients with type 2 diabetes. P wave duration is easy to measure and merits further examination to evaluate its importance for estimation of the risk of stroke among patients with type 2 diabetes.

Metformin in gestational diabetes mellitus

METFORMIININ KÄYTTÖ RASKAUSDIABETEKSESSA Raskausdiabeteksella tarkoitetaan sokeriaineenvaihdunnan häiriötä, joka todetaan ensimmäisen kerran raskauden aikana. Hoidolla voidaan vähentää raskausdiabetekseen liittyviä äidin ja vastasyntyneen haittoja. Lääkitystä tarvitaan, jos ruokavaliohoidolla ei saavuteta hyvää sokeritasapainoa. Perinteisesti lääkityksenä on käytetty insuliinia, mutta metformii¬nin käyttöä insuliinin vaihtoehtona on ehdotettu. Metformiini läpäisee istukan, mutta sen läpäisymekanismi ei ole selvillä. Tämän tutkimuskokonaisuuden pääasiallisin tarkoitus oli verrata metformiinin tehokkuutta ja turvallisuutta insuliiniin raskausdiabeteksen hoidossa selvittämällä lääkkeen vaiku¬tusta äitiin ja vastasyntyneeseen. Lisäksi haluttiin tutkia, mitkä tekijät ennustavat insulii¬nin tarvetta metformiinin lisänä, jotta saavutettaisiin hyvä sokeritasapaino. Metformiinin annoksen vaikutus äitiin ja vastasyntyneeseen arvioitiin mittaamalla metformiinin pitoisuus äidistä, ja sikiön puolelta napanuoran veressä. Tässä tutkimuksessa selvitettiin myös aktiivisen kuljetusproteiinin (OCT) merkitystä metformiinin kulkeutumiseen istukan läpi perfusiomalla istukkaa ex vivo . Ex vivo istukkaperfuusiotutkimuksen tulokset viittasivat siihen, että OCT-kuljetusproteiinilla ei ollut todennäköisesti merkittävää osuutta metformiinin kulkeutumisessa istukan läpi. Metformiinin pitoisuusmittaukset synnytyksen yhteydessä osoittivat metformiinin siirtyvän sikiöön istukan läpi suuressa määrin (96 %) kertymättä kuitenkaan sikiön verenkiertoon. Metformiinin pitoisuudella ei ollut vaikutusta vastasyntyneen hyvinvointiin. Maksi¬maalisella metformiinin annostuksella ja korkealla metformiinipitoisuudella todettiin olevan suotuisa vaikutus äidin painon nousuun raskauden aikana. Insuliiniin verrattuna metformiini ei lisännyt äidin, sikiön tai vastasyntyneen haittatapahtumia, eikä sillä ollut vaikutusta synnytystapaan. Sokeritasapaino insuliini- ja metformiinilääkityksen aikana oli yhtäläinen arvioitaessa sitä HbA1c- ja fruktosamiinimittauksilla, mutta 21 % metformiinin käyttäjistä tarvitsi lisäksi insuliinia hyvän sokeritasapainon saavuttamiseksi. Tutkimuksesssa todettiin, että mitä iäkkäämpi äiti oli, mitä varhaisemmassa raskauden vaiheessa sokerirasitus oli tehty ja lääkitys aloitettu, ja mitä korkeammat HbA1c ja fruktosamiinipitoisuudet olivat, sitä suuremmalla todennäköisyydellä metformiinin lisänä tarvittiin insuliinia.

Standardization of a computerized method for calculating autonomic function test responses in healthy subjects and patients with diabetes mellitus

The objectives of the present study were 1) to compare results obtained by the traditional manual method of measuring heart rate (HR) and heart rate response (HRR) to the Valsalva maneuver, standing and deep breathing, with those obtained using a computerized data analysis system attached to a standard electrocardiograph machine; 2) to standardize the responses of healthy subjects to cardiovascular tests, and 3) to evaluate the response to these tests in a group of patients with diabetes mellitus (DM). In all subjects (97 healthy and 143 with DM) we evaluated HRR to deep breathing, HRR to standing, HRR to the Valsalva maneuver, and blood pressure response (BPR) to standing up and to a sustained handgrip. Since there was a strong positive correlation between the results obtained with the computerized method and the traditional method, we conclude that the new method can replace the traditional manual method for evaluating cardiovascular responses with the advantages of speed and objectivity. HRR and BPR of men and women did not differ. A correlation between age and HRR was observed for standing (r = -0.48, P<0.001) and deep breathing (r = -0.41, P<0.002). Abnormal BPR to standing was usually observed only in diabetic patients with definite and severe degrees of autonomic neuropathy.

Pituitary-thyroid axis in short- and long-term experimental diabetes mellitus

Short-term experimental diabetes mellitus (DM) produces a significant decrease in serum thyroid hormones, a decreased or normal serum thyroid-stimulating hormone (TSH) and a reduction in hepatic and renal T4-5'-deiodination. However, little is known about the effects of chronic diabetes mellitus on the pituitary-thyroid axis function. We evaluated the changes induced by very short-term (6 days), short-term (15 days) and chronic (6 months) streptozotocin-induced diabetes mellitus in 3-month old female Dutch-Miranda rat serum T4, serum TSH and T4-5'-deiodinase activity in the thyroid and pituitary glands. Serum hormones were determined by specific radioimmunoassays. Iodothyronine-5'-deiodinase activities were assayed in the thyroid and pituitary microsomal fractions using 2 µM T4 as substrate. Mean serum T4 was significantly decreased from 3.3 to 2.0 µg/dl 6 days after diabetes mellitus induction, and from 2.2 to 1.5 µg/dl after 15 days of DM, with no significant changes in serum TSH, indicating a decreased pituitary TSH responsiveness to the diminished suppression by T4, even though pituitary T4-5'-deiodinase activity was unchanged. Thyroid T4-5'-deiodinase was unchanged after 6 days of diabetes mellitus, but was significantly increased from 20.6 to 37.0 pmol T3/mg protein after 15 days. Six months after diabetes mellitus induction, both serum T4 and thyroid T4-5'-deiodinase returned to normal ranges and serum TSH was unchanged, although pituitary T4-5'-deiodinase was now significantly decreased from 2.7 to 1.7 pmol T3/mg protein. These findings indicate that some kind of adaptation to chronic insulinopenia may occur at the thyroid level, but this does not seem to be true for the pituitary

Factors associated with the development of renal complications of diabetes mellitus in São Paulo city

The incidence of diabetic end-stage renal failure (ESRF) varies worldwide and risk factors have been demonstrated in several populations. The objective of the present study was to identify possible factors associated with the risk of development of ESRF in patients with diabetes mellitus (DM). Two groups of diabetic subjects were included in a case-control study: 1) one group was submitted to renal replacement therapies, attending dialysis centers in São Paulo city and 2) the same number of controls without clinical nephropathy (two negative dipstick tests for urine protein), matched for duration of DM, were obtained from an outpatient clinic. A standardized questionnaire was used by a single investigator and additional data were obtained from the medical records of the patients. A total of 290 diabetic patients from 33 dialysis centers were identified, and 266 questionnaires were considered to contain reliable information. Male/female ratios were 1.13 for ESRF and 0.49 for the control group. A higher frequency of men was observed in the ESRF group when compared with controls (53 vs 33%, P<0.00001), although logistic regression analysis did not confirm an association of gender and diabetic nephropathy (DN). Similar proportions of non-white individuals were found for both groups. Patients with insulin-dependent diabetes mellitus (IDDM) were less common than patients with non-insulin-dependent diabetes mellitus (NIDDM), particularly in the control group (3.4 vs 26.3%, P<0.00001, for controls and ESRF patients, respectively); this type of DM was associated with a higher risk of ESRF than NIDDM, as determined by univariate analysis or logistic regression (OR = 4.1). Hypertension by the time of the DM diagnosis conferred a 1.4-fold higher risk of ESRF (P = 0.04), but no difference was observed concerning the presence of a family history. Association between smoking and alcohol habits and increased risk was observed (OR = 4.5 and 5.9, respectively, P<0.001). A 2.4-fold higher risk of ESRF was demonstrated in patients with multiple hospitalizations due to DM decompensation, which suggested poor metabolic control. Photocoagulation and neuropathy were found to be strongly associated with ESRF but not with macrovascular disease. Data collected in our country reinforce the higher risk attributable to IDDM and the association between hypertension and the progression of DN. Indirect evidence for an association with metabolic control is also suggested