Atrofia prostatica : contribuição a etiopatogenese de uma lesão que se confunde com adenocarcinoma

Orientador: Athanase BillisTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: A atrofia prostática (AP) é uma das lesões que mais se confunde com carcinoma. AP aumenta com a idade e sua etiopatogênese é desconhecida. Isquemia local é um fator que pode ter papel na patogênese da lesão. O presente trabalho teve como objetivos estudar o fluxo sangüíneo, pelo Doppler colorido, de nódulos e/ou áreas suspeitas cujas biópsias tenham mostrado AP como única lesão e comparar a expressão imunoistoquímica dos marcadores de hipóxia tecidual HIF-1a e VEGF entre áreas com AP e áreas de infarto agudo da próstata. O material obtido corresponde a biópsias prostáticas por agulha de 33 pacientes entre 43 e 86 anos (média: 69) com lesões suspeitas ao ultra-som, correspondendo a 40 áreas nodulares. Estudaram-se também 8 pacientes com áreas de infarto agudo em hiperplasia nodular da próstata. A expressão imunoistoquímica do HIF-1a e do VEGF foi quantificada e comparada entre os grupos. AP foi a única lesão presente nas 40 áreas biopsiadas. O fluxo estava ausente em 24/40 (60%), presente em 12/40 (30%) e aumentado em 4/40 (10%). A quantidade de células expressando o HIF-1a e o VEGF foi significativamente maior nas áreas de infarto agudo (p<0,001). Concluímos que a ausência de fluxo em 60% das lesões estudadas e a menor expressão dos marcadores de isquemia tecidual (HIF-1a e VEGF) nas áreas de AP parecem apoiar a isquemia local crônica como um dos importantes fatores na etiopatogênese desta lesãoAbstract: Prostatic atrophy (PA) is one of the most frequent mimics of prostatic adenocarcinoma. The frequency of PA increases with age and its etiopathogenesis is unknown. Local ischemia seems to be a potential factor for its pathogenesis. The aims of this study were to study prostatic blood flow on color Doppler transrectal ultrasound examination of nodules and / or suspicious areas that showed prostatic atrophy as the only diagnosis on biopsy and compare the imunnohistochemical expression of hypoxia induced factors such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF). between areas of prostatic atrophy and areas of prostatic infarcts. The material was obtained from transrectal prostatic core biopsies of 33 men whose age ranged from 43 to 86 (average 69) years with suspicious lesions on transrectal ultrasound, corresponding to 40 areas. We have also studied 8 patients with prostatic nodular hyperplasia and areas of acute ischemia on biopsy. The expression of HIF-1a and VEGF was analysed and compared between the groups. PA was the only lesion present in all 40 suspicious lesions biopsied at ultrasound. On color Doppler the suspicious areas showed absent flow in 24/40 (60%), present flow in 12/40 (30%), and increased flow in 4/40 (10%) of the lesions. HIF-1a and VEGF were strongly expressed in areas of prostatic infarcts. In contrast, less frequently staining was observed in areas of PA (p<0,001). Absent flow in the majority of the lesions studied (60%) and the weaker expression of HIF-1a and VEGF in atrophic areas may be a further evidence for a possible role of local chronic ischemia in the etiopathogenesis of prostatic atrophyDoutoradoAnatomia PatologicaDoutor em Ciências Médica

Glomus tumor of digital artery of thumb: case report

We report on a case of glomus tumor in the branch of the radial artery of the right thumb. The tumor had a 4-year clinical history. The patient reported the development of a 2.0-cm tumor in the interdigital region between the first and second fingers of the right hand on the short flexor muscle of thumb. The patient also complained of severe and progressive pain. Tests using bidirectional Doppler and echo-color-Doppler revealed a presumptive diagnosis of arteriovenous malformation based on the turbulence of the flow and absence of stenosis. The tumor was removed by open surgery and sent for histopathological examination, which showed a diagnosis of glomangioma. The present report describes a rare arterial disease causing extreme discomfort to the patient, which may be treated with surgical resection without sequelae.Os autores relatam um caso de tumor glômico em ramo da artéria radial que irriga o polegar direito, com história clínica de 4 meses. O doente referia o aparecimento de tumoração de aproximadamente 2,0 centímetros na região interdigital, entre o primeiro e o segundo quirodactilos da mão direita, sobre o músculo flexor curto do polegar, extremamente dolorosa e com dor em progressão. Os exames com aparelho de Doppler bidirecional e o eco-color-Doppler apresentaram, como diagnóstico presuntivo, malformação arteriovenosa, pelo turbilhonamento do fluxo e ausência de estenoses. A tumoração foi retirada por cirurgia aberta e encaminhada para exame histopatológico, com diagnóstico de glomangioma. Este relato descreve uma doença arterial pouco frequente, que causa extremo desconforto ao seu portador, mas que é solucionada pela exerese cirúrgica, sem sequelas.32032

Expression of CDX2 and mucins (MUC1, MUC2, MUC5AC and MUC6) in Barrett's esophagus before and after Nissen fundoplication

INTRODUCTION: Barrett´s esophagus (BE) is characterized by the exchange of esophageal squamous epithelium for intestinal type in response to chronic reflux in patients with gastroesophageal reflux disease (GERD).It is an important precursor of esophageal adenocarcinoma. Nissen fundoplication (NF) is an antireflux surgery which aims to reduce esophageal mucosa inflammation. Changes in the immunohistochemical expression patterns of mucins (MUC1, MUC2, MUC5AC and MUC6) and CDX2 in BE before and after NF may be useful to identify the expression patterns of these markers and, possibly, to detect cases with risks of malignancy. OBJECTIVES: To investigate and compare mucin and CDX2 immunoexpression in BE patients with GERD before and after NF. MATERIAL AND METHODS: This retrospective study comprised 25 patients with GERD and BE who had been submitted to NF. The patients had a 3-year minimum follow up. Histological and immunohistochemical analyses of endoscopic biopsies were performed before and after the surgery, comparing inflammation and MUC1, MUC2, MUC5AC, MUC6 and CDX2 immunoexpression. The percentage of Barrett mucosa cells with expression to the studied markers was estimated at 0%-25%, 25%-75% and 75%-100%. McNemar and Stuart-William tests were used and the significance level of <0.05 was applied. RESULTS AND CONCLUSION: Concerning the presence or the intensity of inflammation and mucin and CDX2 expression in BE, there were no significant differences before and after NF. The surgical procedure did not promote any changes in the expression of these glycoproteins in BE.INTRODUÇÃO: O esôfago de Barrett (EB) corresponde à substituição do epitélio escamoso por um do tipo intestinal, em resposta ao refluxo crônico nos pacientes com doença do refluxo gastroesofágico (DRGE). É um importante precursor do adenocarcinoma esofágico. A fundoplicatura de Nissen (FN) é uma cirurgia antirrefluxo que visa a reduzir a agressão à mucosa esofágica. Alterações no padrão de expressão imuno-histoquímica de mucinas e de CDX2 no EB antes e depois da FN podem ser úteis na identificação de um padrão de expressão desses marcadores e, eventualmente, na identificação de casos com risco de evolução para malignidade. OBJETIVOS: Avaliar e comparar a imunoexpressão de CDX2 e mucinas no EB de pacientes com DRGE submetidos à FN antes e após a cirurgia. MATERIAIS E MÉTODOS: Estudo retrospectivo de 25 pacientes com diagnóstico de DRGE e EB submetidos à FN, acompanhados por, pelo menos, três anos. Foram feitos análise histológica e estudo imuno-histoquímico das biópsias endoscópicas antes e após a cirurgia, comparando-se a inflamação e a imunoexpressão de MUC1, MUC2, MUC5AC, MUC6 e CDX2. Estimou-se a porcentagem de células com expressão para os marcadores estudados na mucosa de Barrett: 0%-25%, 25%-75% e 75%-100% das células positivas. Foram utilizados os testes de McNemar e Stuart-William e adotou-se o nível de 5% de significância estatística. RESULTADOS E CONCLUSÃO: Não houve diferenças significativas quanto a presença ou intensidade de inflamação, nem da imunoexpressão de mucinas e CDX2 no EB antes e após a FN. O tratamento cirúrgico não influenciou a mudança da expressão dessas glicoproteínas no EB.36136

Rare Gastric Inflammatory Myofibroblastic Tumor in an Adult Woman: A Case Report with Review of the Literature

Inflammatory myofibroblastic tumor (IMT) of the stomach is extremely rare and its prognosis is unpredictable. We present a 37-year-old woman with a gastric IMT. She presented epigastric pain since 2 months, anemia and weight loss associated. Physical examination showed cutaneous pallor and mild abdominal tenderness in the epigastrium. Abdominal ultrasonography showed a tumor near the pancreas and the CT scan revealed that the lesion was arising from the stomach. Upper endoscopy showed a submucosal lesion of approximately 7.5 cm located in the posterior wall of the gastric body such as a gastrointestinal stromal tumor (GIST). The patient underwent a subtotal gastrectomy and Billroth I reconstruction. The histopathological and immunohistochemical analysis revealed an IMT that originated from the gastric wall

Eficácia do balonete do tubo endotraqueal sobre a traqueia: aspectos físicos e mecânicos

Introduction: The inflation pressure of the endotracheal tube cuff can cause ischemia of the tracheal mucosa at high pressures; thus, it can cause important tracheal morbidity and tracheal microaspiration of the oropharyngeal secretion, or it can even cause pneumonia associated with mechanical ventilation if the pressure of the cuff is insufficient. Objective: In order to investigate the effectiveness of the RUSCH® 7.5 mm endotracheal tube cuff, this study was designed to investigate the physical and mechanical aspects of the cuff in contact with the trachea. Methods: For this end, we developed an in vitro experimental model to assess the flow of dye (methylene blue) by the inflated cuff on the wall of the artificial material. We also designed an in vivo study with 12 Large White pigs under endotracheal intubation. We instilled the same dye in the oral cavity of the animals, and we analyzed the presence or not of leakage in the trachea after the region of the cuff after their deaths (animal sacrifice). All cuffs were inflated at the pressure of 30 cmH2O. Results: We observed the passage of fluids through the cuff in all in vitro and in vivo experimental models. Conclusion: We conclude that, as well as several other cuff models in the literature, the RUSCH® 7.5 mm tube cuffs are also not able to completely seal the trachea and thus prevent aspiration of oropharyngeal secretions. Other prevention measures should be taken.The inflation pressure of the endotracheal tube cuff can cause ischemia of the tracheal mucosa at high pressures, thus, it can cause important tracheal morbidity and tracheal microaspiration of the oropharyngeal secretion, or it can even cause pneumonia a294552558SEM INFORMAÇÃOSEM INFORMAÇÃODobell, A.R., The origins of endotracheal ventilation (1994) Ann Thorac Surg, 58 (2), pp. 578-584Mehta, S., Tracheal tube cuff pressure (1989) Anaesthesia, 44 (12), pp. 1001-1002Mehta, S., Mickiewicz, M., Pressure in large volume, low pressure cuffs: Its significance, measurement and regulation (1985) Intensive Care Med, 11 (5), pp. 267-272Luna, C.M., Legarreta, G., Esteva, H., Laffaire, E., Jolly, E.C., Effect of tracheal dilatation and rupture on mechanical ventilation using a low-pressure cuff tube (1993) Chest, 104 (2), pp. 639-640Bernhard, W.N., Yost, L., Turndorf, H., Danziger, F., Cuffed tracheal tubes--physical and behavioral characteristics (1982) Anesth Analg, 61 (1), pp. 36-41Nordin, U., The trachea and cuff-induced tracheal injury. An experimental study on causative factors and prevention (1977) Acta Otolaryngol Suppl, 345, pp. 1-71Sole, M.L., Su, X., Talbert, S., Penoyer, D.A., Kalita, S., Jimenez, E., Evaluation of an intervention to maintain endotracheal tube cuff pressure within therapeutic range (2011) Am J Crit Care, 20 (2), pp. 109-117Benumof, J.L., Cooper, S.D., Quantitative improvement in laryngoscopic view by optimal external laryngeal manipulation (1996) J Clin Anesth, 8 (2), pp. 136-140Keller, C., Brimacombe, J., Boehler, M., Loeckinger, A., Puehringer, F., The influence of cuff volume and anatomic location on pharyngeal, esophageal, and tracheal mucosal pressures with the esophageal tracheal combitube (2002) Anesthesiology, 96 (5), pp. 1074-1077Cooper, J.D., Grillo, H.C., The evolution of tracheal injury due to ventilatory assistance through cuffed tubes: A pathologic study (1969) Ann Surg, 169 (3), pp. 334-348Seegobin, R.D., Van Hasselt, G.L., Endotracheal cuff pressure and tracheal mucosal blood flow: Endoscopic study of effects of four large volume cuffs (1984) Br Med J (Clin Res Ed), 288 (6422), pp. 965-968Joseph, N.M., Sistla, S., Dutta, T.K., Badhe, A.S., Parija, S.C., Ventilator-associated pneumonia: A review (2010) Eur J Intern Med, 21 (5), pp. 360-368Dave, M.H., Koepfer, N., Madjdpour, C., Frotzler, A., Weiss, M., Tracheal fluid leakage in benchtop trials: Comparison of static versus dynamic ventilation model with and without lubrication (2010) J Anesth, 24 (2), pp. 247-252Lucangelo, U., Zin, W.A., Antonaglia, V., Petrucci, L., Viviani, M., Buscema, G., Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit (2008) Crit Care Med, 36 (2), pp. 409-413Young, P.J., Burchett, K., Harvey, I., Blunt, M.C., The prevention of pulmonary aspiration with control of tracheal wall pressure using a silicone cuff (2000) Anaesth Intensive Care, 28 (6), pp. 660-665Dave, M.H., Frotzler, A., Spielmann, N., Madjdpour, C., Weiss, M., Effect of tracheal tube cuff shape on fluid leakage across the cuff: An in vitro study (2010) Br J Anaesth, 105 (4), pp. 538-543Pavlin, E.G., Vannimwegan, D., Hornbein, T.F., Failure of a high-compliance low-pressure cuff to prevent aspiration (1975) Anesthesiology, 42 (2), pp. 216-219Macrae, W., Wallace, P., Aspiration around high-volume, low-pressure endotracheal cuff (1981) Br Med J (Clin Res Ed), 283 (6301), p. 1220Windsor, H.M., Shanahan, M.X., Cherian, K., Chang, V.P., Tracheal injury following prolonged intubation (1976) Aust N Z J Surg, 46 (1), pp. 18-25Lewis, F.R., Jr., Schiobohm, R.M., Thomas, A.N., Prevention of complications from prolonged tracheal intubation (1978) Am J Surg, 135 (3), pp. 452-457Servin, S.O., Barreto, G., Martins, L.C., Moreira, M.M., Meirelles, L., Neto, J.A., Atraumatic endotracheal tube for mechanical ventilation (2011) Rev Bras Anestesiol, 61 (3), pp. 311-319Lima, L.C., Avelar, S.F., Westphal, F.L., Lima, I., Lung nodule, tracheal stenoses and coronary disease: How to approach when are all associated to? (2007) Rev Bras Cir Cardiovasc, 22 (3), pp. 359-361Conti, M., Pougeoise, M., Wurtz, A., Porte, H., Fourrier, F., Ramon, P., Management of postintubation tracheobronchial ruptures (2006) Chest, 130 (2), pp. 412-418Marjot, R., Pressure exerted by the laryngeal mask airway cuff upon the pharyngeal mucosa (1993) Br J Anaesth, 70 (1), pp. 25-29. , Erratum in: Br J Anaesth. 1993;70(6):711Peták, F., Janosi, T.Z., Myers, C., Fontao, F., Habre, W., Impact of elevated pulmonary blood flow and capillary pressure on lung responsiveness (2009) J Appl Physiol (1985), 107 (3), pp. 780-786Iglesias, J.L., Lanoue, J.L., Rogers, T.E., Inman, L., Turnage, R.H., Physiologic basis of pulmonary edema during intestinal reperfusion (1998) J Surg Res, 80 (2), pp. 156-163Dullenkopf, A., Gerber, A., Weiss, M., Fluid leakage past tracheal tube cuffs: Evaluation of the new Microcuff endotracheal tube (2003) Intensive Care Med, 29 (10), pp. 1849-1853Lomholt, N., A device for measuring the lateral wall cuff pressure of endotracheal tubes (1992) Acta Anaesthesiol Scand, 36 (8), pp. 775-778Young, P.J., Pakeerathan, S., Blunt, M.C., Subramanya, S., A low-volume, low-pressure tracheal tube cuff reduces pulmonary aspiration (2006) Crit Care Med, 34 (3), pp. 632-639Blunt, M.C., Young, P.J., Patil, A., Haddock, A., Gel lubrication of the tracheal tube cuff reduces pulmonary aspiration (2001) Anesthesiology, 95 (2), pp. 377-381Sanjay, P.S., Miller, S.A., Corry, P.R., Russell, G.N., Pennefather, S.H., The effect of gel lubrication on cuff leakage of double lumen tubes during thoracic surgery (2006) Anaesthesia, 61 (2), pp. 133-137A pressão de insuflação do balonete (cuff) do tubo endotraqueal tanto pode causar isquemia de mucosa traqueal em pressões elevadas, e assim ocasionar morbidade traqueal importante, quanto pode causar microaspiração traqueal de secreção de orofaringe ou,

Prevalence of cutaneous neoplasms in dogs from the metropolitan area of Porto Alegre, RS, Brazil : 1,017 cases (2002-2007)

O objetivo deste trabalho foi realizar um estudo retrospectivo sobre neoplasias cutâneas diagnosticadas em cães. A avaliação foi realizada pela análise dos arquivos diagnósticos do Setor de Patologia Veterinária (SPV) da Universidade Federal do Rio Grande do Sul (UFRGS), Brasil, considerando-se um intervalo de seis anos (2002 a 2007). Neste intervalo, um total de 1.869 (37,3%) amostras de pele canina foram obtidas de 5.016 amostras variadas de tecidos de cães encaminhadas ao SPV. Dentre as amostras cutâneas, 1.002 pertenciam a cães diagnosticados com um tipo de neoplasia cutânea e 15 animais apresentaram mais de uma neoplasia de pele, totalizando 1.017 (20,3%) amostras. Os resultados revelaram que 50,5% (514/1017) das neoplasias cutâneas apresentaram origem mesenquimal, 45,1% (459/1017) para epitelial e 3,9% (40/1017) para melanocítica. Mastocitoma foi o tipo neoplásico cutâneo mais frequente, diagnosticado em 228 casos (22,4%), seguido por carcinoma de células escamosas (7,5%), lipoma (7,3%), adenoma de glândula perianal (7,1%) e tricoblastoma (5,8%). Cocker Spaniel, Boxer, Poodle e Pastor Alemão foram as raças mais representadas em diversos neoplasmas. Os dados obtidos, comparados aos estudos prévios, ressaltam as variáveis raças, idade e sexo, relacionadas a alguns tumores cutâneos e salientam a importância e prevalência dos diferentes tipos de neoplasia cutânea em cães. __________________________________________________________________________________________ ABSTRACTThe aim of this study was to perform a retrospective study of cutaneous neoplasms diagnosed in dogs. The evaluation was established by analyzing the diagnostic files at the Veterinary Pathology Sector, UFRGS, Brazil, over a 6-year period (2002 to 2007). During this period a total of 1869 (37.3%) skin samples were obtained from 5016 different tissue samples of dogs submitted for examination. Among the referred skin samples, 1002 were from dogs with the diagnosis of cutaneous neoplasia and 15 dogs exhibited more than one type of skin tumor, what amounted to a total of 1017 (20.3%) cutaneous tumor samples. Results confirmed 50.5% (514/1017), 45.1% (459/1017), and 3.9% (40/1017) of respectively mesenquimal, epithelial, and melanocytic origin. Mast cell tumor was the most frequent neoplasia, diagnosed in 228 cases (22.4%), and was followed by squamous cell carcinoma (7.5%), lipoma (7.3%), perianal gland adenoma (7.1%), and trichoblastoma (5.8%). Purebred dogs such as Cocker Spaniel, Boxer, Poodle and German Sheepdog were the most representative breeds affected by various neoplasms. The data obtained, compared to data from previous studies, emphasize the variables breed, age and sex related to some skin tumors, and reinforce the importance and prevalence of different types of skin tumors in dogs

Synchronous adenocarcinoma and stromal tumor (GIST) in the stomach: a rare occurrence

A concomitant epithelial and stromal tumor in stomach is unusual in the literature. The purpose of this paper is to report the case and it's therapeutic management. A 72 year old black male patient , which upper digestive endoscopy showed a gastric neoplasm (Borrmann III) at incisura angularis and the biopsy revealed adenocarcinoma. A subtotal gastrectomy with D2 limphadenectomy and Roux-en-Y reconstruction was performed. The histopathology studies confirmed an adenocarcinoma and a gastric stromal tumor, whose immunohistochemical exam was compatible to GIST. Seventeen months after surgery, a computadorized tomography revealed a retrogastric tumor and laparotomy was indicated to remove the lesion.616

Defective Apoptosis In Intestinal And Mesenteric Adipose Tissue Of Crohn's Disease Patients.

Crohn's disease (CD) is associated with complex pathogenic pathways involving defects in apoptosis mechanisms. Recently, mesenteric adipose tissue (MAT) has been associated with CD ethiopathology, since adipose thickening is detected close to the affected intestinal area. However, the potential role of altered apoptosis in MAT of CD has not been addressed. To evaluate apoptosis in the intestinal mucosa and MAT of patients with CD. Samples of intestinal mucosa and MAT from patients with ileocecal CD and from non-inflammatory bowel diseases patients (controls) were studied. Apoptosis was assessed by TUNEL assay and correlated with the adipocytes histological morphometric analysis. The transcriptional and protein analysis of selected genes and proteins related to apoptosis were determined. TUNEL assay showed fewer apoptotic cells in CD, when compared to the control groups, both in the intestinal mucosa and in MAT. In addition, the number of apoptotic cells (TUNEL) correlated significantly with the area and perimeter of the adipose cells in MAT. Transcriptomic and proteomic analysis reveal a significantly lower transcript and protein levels of Bax in the intestinal mucosa of CD, compared to the controls; low protein levels of Bax were found localized in the lamina propria and not in the epithelium of this tissue. Furthermore, higher level of Bcl-2 and low level of Caspase 3 were seen in the MAT of CD patients. The defective apoptosis in MAT may explain the singular morphological characteristics of this tissue in CD, which may be implicated in the pathophysiology of the disease.9e9854

Redução da gestação gemelar em éguas puro sangue de corrida antes ou após a fixação uterina da vesícula embrionária

A gestação gemelar é um sério problema devido às perdas econômicas geradas pelos altos índices de abortos, natimortos, mortalidade perinatal e queda de fertilidade da égua. Diversos métodos têm sido utilizados para realizar a redução de um dos gêmeos, como o esmagamento precoce de uma das vesículas sob controle ultra-sonográfico. O experimento teve como objetivo verificar a eficácia da redução de uma das vesículas embrionárias no 16 o dia pós-ovulação, antes ou depois de sua fixação no útero. Foram analisados os registros de 1337 éguas, da raça Puro Sangue de Corrida (PSC), pertencentes a três criatórios da região Sul do Brasil, num período de 10 anos. O diagnóstico de gestação foi realizado através de ultra-sonografia a partir do 10o dia após a ovulação e repetido semanalmente até os 45 dias de gestação. Uma vez diagnosticadas gestações gemelares procedeu-se a eliminação de uma das vesículas embrionárias pelos seguintes métodos: (a) diagnóstico antes da fixação no 16o dia pós-ovulação - esmagamento de uma das vesículas, (b) diagnóstico após o 16o dia com vesículas não justapostas - esmagamento de uma das vesículas ou (c) diagnóstico após o 16o dia com vesículas justapostas - restrição alimentar de concentrado durante duas semanas. A técnica foi bem sucedida quando ocorreu a redução de apenas uma das vesículas embrionárias. Naquelas gestações em que as vesículas se encontravam justapostas após os 30 dias optou-se pela administração de prostaglandina. A taxa geral de prenhez observada foi de 68,3% (914/1337) e a porcentagem de gestação gemelar foi de 11,5% (105/914). Diagnosticaram-se 38 gestações gemelares após a fixação, no 16o e 62 o dia antes da fixação. Houve cinco perdas de dados. A redução embrionária realizada antes da fixação foi significativamente (p=0,0317) mais bem sucedida do que quando o procedimento ocorreu após a fixação embrionária. Conclui-se, que o esmagamento de uma das vesículas é um procedimento eficaz na redução da gestação gemelar, principalmente quando realizado antes do 15o dia de gestação