segunda-feira, 26 de outubro de 2015

Minha História de vida e minha História vivida na EPM/UNIFESP (35)

Minha trajetória na carreira Acadêmica na Escola Paulista de Medicina (EPM) – Parte 1

1- A evolução funcional dentro da carreira acadêmica

Quando decidi ir para Buenos-Aires fazer meu 3º ano de Residência Médica, foi um salto no escuro, não tinha qualquer tipo de promessa de que no meu retorno poderia vir a ser contratado pelo Departamento de Pediatria, fato que muito desejava, posto que tinha todo interesse em seguir a carreira acadêmica. Porém, foi uma decisão unilateral, tinha entendido que para atingir meu objetivo seria necessário fazer algo distinto do rotineiro, era preciso criar uma mudança de paradigma, pois com este tipo de atitude teria a oportunidade de me tornar um agregador de valores, o que se constituiria em um diferencial em relação aos meus pares da mesma geração, e assim, quem sabe, despertar o interesse pela minha contratação. O Departamento de Pediatria estava com sua lotação praticamente completa dentro do quadro de docentes da EPM. Naquela época não havia uma perspectiva definida para a abertura de novo concurso para ingresso no magistério federal a médio prazo, portanto, além de querer diferenciar-me profissionalmente, qualificando-me na busca da excelência na especialidade ainda totalmente incipiente no nosso meio, valia a pena correr o risco na expectativa de que algo de positivo viesse a ocorrer. De fato, foi o que se sucedeu, pois quando Prof. Azarias foi me visitar em Buenos-Aires durante minha estada, já mais para o final da mesma, ouviu referências muito elogias do Dr. Toccalino a meu respeito, o que aplainou o terreno para convencer Prof. Azarias sobre a importância da minha contratação, a qual ocorreu imediatamente após o meu retorno em 1974, pelo Centro de Estudos de Pediatria da Escola Paulista. Para minha felicidade já em 1975 foi aberto concurso público para Professor Auxiliar ao qual me apresentei, fui aprovado, e assim começava a tornar realidade o almejado sonho de seguir a carreira de professor universitário. A partir deste ponto inicial fui gradualmente ascendendo, sempre por meio de concursos públicos, na progressão funcional, inicialmente para Professor Assistente, posteriormente para Professor Adjunto, e, para finalmente alcançar o topo da carreira, em 1988, aos 44 anos de idade, como Professor Titular. Vale assinalar que esta era a segunda vez que eu havia prestado concurso para Professor Titular, na primeira delas, em 1982, aos 38 anos de idade, concorri com meu colega e amigo Calil Kairalla Farharat, que venceu o concurso com nota 9,92, enquanto eu obtive nota 9,88 (Figura 1).


Figura 1- Calil ladeado à sua direita pela sua mulher René e à esquerda por minha mulher  Eurídice. Logo após o concurso para Professor Titular, do qual ele sagrou-se vencedor, nós fomos convidados a participar de um evento da Sociedade Brasileira de Pediatria para dar cursos de atualização em Pediatria em várias cidades do Nordeste do país durante 2 semanas seguidas, ministrando palestras cada um em sua respectiva especialidade.

No segundo concurso fui aprovado com nota 10,0 por todos os 5 examinadores da banca constituída exclusivamente por Professores Titulares, sendo que 3 deles pertenciam a outras prestigiosas instituições universitárias (Figuras 2-3).



Figuras 2-3- Cerimônia de posse de Professor Titular, em 1988. Acima Prof. Benjamin Kopelman faz o discurso de saudação a mim e abaixo Professor Nader Wafae, então Diretor da EPM, faz a colocação do símbolo da titularidade.

2- A formação da Disciplina de Gastroenterologia Pediátrica: sua progressiva e sólida expansão

Logo após meu retorno de Buenos-Aires contando com o entusiasmo incontido e apoio incondicional do Prof. Jamal Wehba, e com a autorização do Departamento de Pediatria, criamos inicialmente o Setor de Gastroenterologia Pediátrica, que alguns anos mais tarde, pelo reconhecimento da instituição quanto à nossa excelente qualidade, fez jus a ser promovido a Disciplina. Ato seguinte, tratamos de colocar em prática, sempre de comum acordo, e após amplas discussões, todos os planos elaborados para a consolidação de um Setor cujo eixo fundamental de apoio deveria estar centrado em um trabalho de equipe. Foi, então, celebrado entre nós um modo de vida baseado acima de tudo no respeito recíproco das opiniões emitidas e que todos os pontos de possíveis divergências seriam discutidos à exaustão até o surgimento de um consenso, para que as soluções dos problemas resultassem de comum acordo. Assumimos naquela oportunidade um compromisso formal quanto ao nosso porvir, as responsabilidades pelo sucesso ou pelo fracasso seriam, pois, igualmente repartidas. Caso conseguíssemos levar adiante nossos ideais, ambos triunfaríamos, caso contrário teríamos também que dividir com a mesma responsabilidade o ônus do fracasso. Movidos por estes princípios que nortearam nosso comportamento desde os primórdios tratamos de forjar algo palpável do qual pudéssemos nos orgulhar no futuro. Estaríamos, assim, contribuindo de maneira altamente positiva para uma melhor formação dos nossos alunos, construindo bases para adquirir tradição em pesquisa e criando condições para oferecer assistência de alta qualidade. Na verdade, nosso primeiro investimento foi com a assistência, a partir da criação de um Ambulatório de Gastroenterologia que oferecia atendimento clínico e investigação laboratorial especializada, por meio da realização dos principais testes diagnósticos disponíveis à época, os quais rapidamente tratamos de colocar em prática com a inestimável colaboração do Prof. Nelson Machado, inclusive procedimentos de biópsia do intestino delgado, retal e hepática, cuja análise anatomopatológica sempre esteve a cargo da Profa. Francy Reis Patrício. Semanalmente eu me reunia com a Profa. Francy para fazer a revisão das lâminas das biópsias realizadas e buscar estabelecer uma relação clínico-patológica dos pacientes atendidos. Vale ressaltar que esta associação perdurou por mais de 30 anos, sendo muito profícua e que serviu como fonte inesgotável de produção científica de excelente qualidade. Além disso, também se constituiu em material de ensino de altíssima valia para nossos médicos residentes e especializandos, posto que nos reuníamos em sessões semanais para discussões anátomo-clínicas extremamente proveitosas.  

Seguindo nossos preceitos básicos as atividades de pesquisa e ensino, além da assistencial, receberam cuidado especial desde os primórdios. Inicialmente o ensino esteve mais dirigido para nossos alunos de graduação do 4º e 6º anos, e para os médicos residentes da EPM. No plano da pesquisa, no princípio, nossos interesses se voltaram para a investigação clínica, a partir da experiência acumulada e devidamente analisada dos pacientes por nós atendidos no Ambulatório da especialidade e daqueles internados no Setor de Gastroenterologia Pediátrica do Hospital São Paulo (Figura 4).


Figura 4- Jamal ao centro, Elisabete Kawakami recém incorporada ao grupo e eu nos primórdios da nossa Disciplina.
 
A comprovação definitiva de que as linhas mestras traçadas, que serviram de orientação para o funcionamento do nosso Setor, haviam sido, acertadas foi selada durante a realização dos Congressos Pediátricos, em 1975, em São Paulo. Naquele evento tivemos a oportunidade de apresentar alguns trabalhos nas sessões de Temas Livres, e que representavam os primeiros frutos colhidos em prazo de tempo inferior a 2 anos do início das nossas atividades no Setor recém constituído (Figura 5).


Figura 5- O Congresso Internacional de Pediatria de 1975, realizado no Pavilhão do Anhembi foi o marco inicial da nossa produção científica. Da esquerda para a direita, a Silvana, Eurídice, eu, Jorge Ortiz, Mairon Lima, Ricardo Licastro, Horácio Toccalino e Sérgio Reppeto.

O primeiro marco havia sido alcançado, mas era apenas o começo de uma longa caminhada, era necessário seguir avançando. As prioridades básicas haviam sido supridas, podíamos, assim, partir agora para alçar outros voos mais ambiciosos. Tornava-se imperioso expandir nossas fronteiras, isto significava a abertura do nosso Setor para o treinamento na especialidade, estávamos escalando o primeiro degrau da excelência ao admitirmos especializandos, ao oferecer um programa de especialização para médicos que haviam completado a residência em Pediatria Geral. Pouco a pouco foram chegando os primeiros interessados em aprimorar seus conhecimentos, e em curto espaço de tempo já se fazia necessário realizar um verdadeiro concurso para limitar o corpo de especializandos, porque a grande afluência de candidatos começou a suplantar nossa capacidade de oferecer um programa de ótima qualidade. Passamos a reservar uma parte das vagas aos interessados que eram oriundos da nossa própria instituição e uma outra parte para aqueles que se apresentavam de outras instituições fossem de São Paulo ou de outros Estados do país (Figuras 6-7-8-9-10-11).



Figuras 6-7-8- Nossos diversos Especializandos ao longo dos anos na sede da nossa Disciplina.
 

Figuras 9-10- Nossos Especializandos e amigos do Brasil e de Portugal em um dos churrascos de confraternização que costumeiramente organizávamos em nossa Clínica.


Figura 11- Nossos especializandos e amigos ao participar de um dos Congressos da LASPGHAN em Buenos Aires em 1984.

Com o decorrer dos anos, médicos de praticamente todas as regiões do país vieram a se formar no nosso programa de especialização, e, inclusive, muitos deles aqui permaneceram por tempo mais prolongado para realizar os cursos de Mestrado e Doutorado, antes de retornarem aos seus locais de origem (Figuras 12-13-14).


Figura 12- Dras. Maria Ceci (Fortaleza) e Rosa Helena (Belém) que fizeram a especialização conosco e aqui permaneceram para realizar os cursos de Mestrado e Doutorado antes de retornar às suas origens. 


Figura 13- Dra. Arelis LLeras à minha direita oriunda de Maracaibo, Venezuela, com sua família em visita a São Paulo depois de muitos anos de aqui ter vivido para realizar conosco seu curso de Mestrado e Doutorado. Trabalhou comigo na Favela Cidade Leonor coletando amostras de fezes de crianças com e sem diarreia para pesquisa de agentes enteropatogênicos. Foi uma pesquisa extremamente importante que fez parte de um capítulo para desvendarmos a história natural da Enteropatia Ambiental.

Figura 14- Dra. Fátima Lindoso, natural de Recife, fez o curso de especialização e em seguida realizou os cursos de Mestrado e Doutorado sob minha orientação. Seus trabalhos na Favela Cidade Leonor promovendo o aleitamento natural exclusivo por tempo prolongado demonstraram cabalmente a excepcional importância dessa prática em populações socialmente vulneráveis. Atualmente Fátima é Professora Titular do Departamento de Pediatria e Diretora da Faculdade de Medicina da Universidade Federal de Goiás.

sexta-feira, 9 de outubro de 2015

Persistent Diarrhea: Still a Serious Public Health Problem in Developing Countries (Part 3)

Diagnosis

In order to establish an accurate diagnosis of the respective etiology and potential complications, detailed information must be obtained on the following topics: a comprehensive clinical history extending as far back as the onset of the diarrheal illness; prior dietary history; breastfeeding history; socioeconomic status and living conditions; and prior medical history, including prior infectious diseases and family history. History and physical examination can provide an outline of the profile of a patient’s nutritional status and other consequences of the diarrheal illness. The laboratory investigation should include a stool culture and a search for ova and parasites in fresh stool specimens, a detection of fecal pH and reducing substances search in the stools, a search for leukocytes and occult blood in the stools, and a determination of fecal α1 anti-trypsin and steatocrit.

Considering the high prevalence of carbohydrate intolerance in the diet reported in PD patients as a perpetuating factor of diarrhea, the approach should include overload tests with the various carbohydrates commonly used in the diet, such as lactose, glucose, and fructose. The lactulose load test should also be carried out in order to detect a possible bacterial overgrowth in the small intestine. All these tests should preferably be carried out by the technique of the H2 breath test, because this is a noninvasive method with high sensitivity and specificity [47].

If possible, the determination of fecal electrolytes should also be done, which will distinguish osmotic from secretory diarrhea [48]. In many cases, a small bowel biopsy should be performed to evaluate the mucosal architecture and the inflammatory infiltrate in the lamina propria, to investigate specific causes, and to demonstrate the extent of intestinal damage [49]. The knowledge of the intensity and extension of morphological damage enables the appropriate dietary management approach. When concurrent rectal bleeding occurs, it may be necessary to perform a rectal biopsy to evaluate the degree and type of inflammation [50].

Management

The importance of proper rehydration and dietary management during the acute diarrheic episode for preventing the progression to PD is well-known [51]. Antibiotic treatment is recommended only for prolonged infection caused by Salmonella, Giardia, Cyclospora, and EAEC (the latter especially if the infant is less than 3 months old or malnourished, immunodeppressed, or shows signs of systemic disease) [52] and in the presence of bloody diarrhea when Shigella is isolated in the stools [53]. The decision to prescribe antibiotics is limited to laboratory evidence of the enteropathogen and type of microbial resistance [54, 55].

Although ready-to-use therapeutic food (RUTF) has greatly improved the capacity for rapid catch-up growth in both the hospital and community, it is necessary to focus more on the initial diets of unwell children with nutritional aggravation, due to the persistence of diarrhea and malabsorption of the nutrients. Fasting is clearly deleterious for such children, as the practice of resuscitation on children’s wards with IV fluids, minerals, vitamins, and antibiotics (without milk or equivalent) has shown. Small, frequent feeding is crucial, but volumes may need to be individualized, which makes it very difficult for pediatric wards with a scarcity of nursing resources, especially during evening and night shifts. WHO guidelines recommend the use of F75 formula, following research done >30 years ago [56]. But now there is a clearer concept of the gut in malnutrition due to the persistence of diarrhea, so better diets are available in the market. Osmolality, in particular, may be important. F75 has an osmolality of 333 mOsmol/L, while there are commercial lactose-free formulas with 160 mOsmol/L [57].

The use of an extensive hydrolyzed protein formula or even a mixture of amino acids based formula is indicated in the following clinical circumstances: (1) acute diarrhea in infants under 6 months or less than 1 year of age with severe malnutrition, associated with dehydration and/or metabolic disorders; (2) PD with aggravation of the nutritional status or frequent recurrence of dehydration and/or metabolic acidosis [58].

The prescription of zinc and vitamin A seems to have a positive impact over the cellular immune system, helping in the treatment of acute and persistent diarrhea [59–61]. It is necessary to prescribe a daily supplementation of zinc at a dose of 10 mg/day for a period of 2–3 months after the diarrhea episode has ceased.

Prophylaxis

In conclusion, UNICEF and WHO propose seven strategic measures to be implemented around the world for diarrheal disease control: (1) fluid replacement to prevent dehydration; (2) zinc treatments, which decrease the severity and duration of the attack; (3) immunization against rotavirus and measles; (4) early and exclusive breastfeeding and vitamin A supplementation; (5) hand washing with soap; (6) improved water supply quantity and quality, including safe storage of water in homes; and (7) promoting community-wide sanitation [16]. Other proposals for reducing the incidence of PD include prolonged and exclusive breastfeeding and strategies to ensure a safe food supply for adequate weight and height development, considering that protein-energy malnutrition is a risk factor for this syndrome [16]. Gut infections lead to malnutrition, and malnutrition increases the risk for further intestinal infections. Ending the vicious cycle of diarrhea–malnutrition should be assigned priority as a goal for pediatricians concerned with the safe development of children [48].

Compliance with Ethics Guidelines

Conflict of Interest Ulysses Fagundes-Neto declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

References

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sexta-feira, 2 de outubro de 2015

Persistent Diarrhea: Still a Serious Public Health Problem in Developing Countries (Part 2)

Pathophysiology
There are multiple and complex pathophysiological mechanisms that may be involved in and determine the perpetuation of an acute diarrheic episode. Small bowel injury has been incriminated as the central mechanism in PD [2728]. The status of the mucosal permeability barrier and the ability of the host in the clearance of the enteropathogenic agent have a direct influence on the persistence of these lesions [25].

It is well known that some enteropathogenic agents cause diarrhea by damaging the small bowel mucosa and/or through the secretion of enterotoxins that act on the enterocytes triggering the secretion of water and electrolytes, and even by the production of some cytotoxins that induce cell damage [2930].

EAEC and EPEC, among the several other agents, are usually the most frequent enteropathogenic agents isolated in the stools of infants with PD. The mechanisms of EAEC and EPEC infections are also the ones known and studied in most detail in the medical literature [2931].

EAEC infection represents an important cause of PD in developing countries [30]. The investigation of the role of the EAEC strains in the persistence of diarrhea has shown the ability of this microorganism to adhere to both the small bowel and the colonic mucosa.

Hicks et al. [
31] examined the interaction between EAEC and the human intestine using the in vitro organ culture model from biopsies obtained from infants with diarrhea. The EAEC strains were able to adhere to the jejunal, ileal, and colonic mucosa; most of the bacteria were associated with the mucus layer above the intestinal mucosa, and few of them were found in close association with the mucosal surface. Andrade et al. [32] studied the interaction of EAEC strains that were isolated from the stools of infants with PD, with the human fragments of ileal and colonic mucosa in vitro, utilizing the transmission electron microscopy, and showed the occurrence of bacterial aggregates colonizing and provoking cytotoxic effects in the ileal and colonic mucosa.

Aggregative adherent fimbriae that are encoded on a 60 mda virulence plasmid called paa create a mucus biofilm that seems responsible for the small bowel damage leading to malabsorption of nutrients and persistence of diarrhea [33].

In contrast to the limited importance of EPEC in developed countries, EPEC is a major cause of infantile diarrhea in developing countries [12] and, in many cases, is responsible for PD [34]. Proximal small intestinal mucosal biopsy specimens show, but not always, intimately adherent bacteria and the classic attaching and effacing (A/E) histopathology [35]. Cantey and Blake [36] were the first authors to describe this new pattern of adherence of an EPEC strain in rabbits, which was characterized by adherence of bacteria to the apical portion of the enterocyte, with cuplike pedestal formation and subsequent effacement of the brush border. This effect was designated by Moon et al. as attaching and effacing (A/E) [37]. Rothbaum et al. [38] reported on the adherence of EPEC O119:B14 associated with effacement of microvilli, leading to the formation of a cuplike pedestal on the enterocytes of infants with PD. The determinants of the A/E lesion have been localized to a large island of pathogenicity on EPEC chromosomes, termed the locus of enterocyte effacement, or LEE [39]. Fagundes-Neto et al. [40] reported the presence of bacteria within the enterocytes from an infant with acute diarrhea that evolved into PD caused by EPEC O111:H2. Fagundes-Neto et al. [28] studied patients with PD in whom EPEC strains were isolated in the jejunal fluid secretion and in the stools, utilizing the scanning electron microscopy. At low magnification (150×), most of the villi showed mild to moderate stunting, but on several occasions, there was subtotal villous atrophy. At higher magnification (7,500×), photomicrographs showed derangement of the enterocytes; on several occasions, cell borders were not clearly defined, and very often microvilli decreased in number and height; in some areas there was complete disappearance of the microvilli. Moreover, several baciliform microorganisms tightly adhering to the enterocytes were seen, and lymphocytes and fat droplets overlay the surface of the enterocytes as well. In half of the patients, a mucous-fibrinoid pseudomembrane partially coating the enterocytes was observed. This mucus coating may hamper absorption of nutrients of a diet due to mechanical block, thus leading to osmotic diarrhea and nutritional aggravation. This hypothesis may be supported by the finding off at droplets accumulated on the apical surfaces of the enterocytes. These ultrastructural changes may arise from a combined interaction of the enteropathogenic agent that causes the A/E lesion associated with disarrangement of the digestive–absorptive enzyme system, leading to malabsorption of nutrients [29]. These pathophysiological events determine the onset of food intolerance that is responsible for the perpetuation of diarrhea and nutritional aggravation.

Bacterial overgrowth in the small bowel lumen of the colonic microflora may occur in up to 68 % of patients with PD, and it is another factor that will perpetuate the damage of the intestinal mucosa [28]. It is particularly associated with anaerobic bacteria, suchas Veillonella and Bacteroides species, and predisposes to intestinal mucosal injury [41]. Pathologic changes occur due to the ability of the anaerobic bacteria to induce deconjugation and 7α-dehydroxylation of the primary bile acids cholic and chenodeoxycholic acid, converting them into their respective secondary bile acids (deoxycholic and lithocholic acid), which are highly damaging to the jejunal mucosa, provoking a decrease in the absorption surface and functional lesions with a deficiency of enterokinase [42] and of the ATPase (Na+K+) enzyme [43]. When present in the intestinal lumen, these secondary, unconjugated bile acids induce water and sodium secretion and glucose malabsorption and can also lead to a breakdown of the intestinal permeability barrier, facilitating the penetration of potentially allergenic macromolecules (food proteins, intact or partially hydrolyzed), leading, as a consequence, to an allergy to the proteins of the diet (cow milk, soybean protein) [44].

The presence of secondary and unconjugated bile salts in the small bowel prevents the formation of the mixed micelles, which play an essential role in ensuring solubilization of dietary fats. The consequent decrease of bile salts pool will lead, first, to malabsorption of fats in a diet, having as a result steatorrhea, which will deprive the patient of an important caloric offer [45]. Second, the excretion of bile salts will induce the appearance of cholereic diarrhea, due to the direct toxic action of the bile salts on the colonic mucosa [46].

Finally, the synergistic effects of these pathophysiologic events become responsible for the perpetuation of the diarrheal process and for the aggravation of the nutritional status, with a high risk of death.

Diagnosis

In order to establish an accurate diagnosis of the respective etiology and potential complications, detailed information must be obtained on the following topics: a comprehensive clinical history extending as far back as the onset of the diarrheal illness; prior dietary history; breastfeeding history; socioeconomic status and living conditions; and prior medical history, including prior infectious diseases and family history. History and physical examination can provide an outline of the profile of a patient’s nutritional status and other consequences of the diarrheal illness. The laboratory investigation should include a stool culture and a search for ova and parasites in fresh stool specimens, a detection of fecal pH and reducing substances search in the stools, a search for leukocytes and occult blood in the stools, and a determination of fecal α1 anti-trypsin and steatocrit.

Considering the high prevalence of carbohydrate intolerance in the diet reported in PD patients as a perpetuating factor of diarrhea, the approach should include overload tests with the various carbohydrates commonly used in the diet, such as lactose, glucose, and fructose. The lactulose load test should also be carried out in order to detect a possible bacterial overgrowth in the small intestine. All these tests should preferably be carried out by the technique of the H2 breath test, because this is a noninvasive method with high sensitivity and specificity [47].

If possible, the determination of fecal electrolytes should also be done, which will distinguish osmotic from secretory diarrhea [48]. In many cases, a small bowel biopsy should be performed to evaluate the mucosal architecture and the inflammatory infiltrate in the lamina propria, to investigate specific causes, and to demonstrate the extent of intestinal damage [49]. The knowledge of the intensity and extension of morphological damage enables the appropriate dietary management approach. When concurrent rectal bleeding occurs, it may be necessary to perform a rectal biopsy to evaluate the degree and type of inflammation [50].