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Novianti Qurnia Putri,1 Tiara Bunga Mayang Permata,1 Ni Ayu Wulandari,1 Handoko,1 Endang Nuryadi,1 Gatot Purwoto,2 Soehartati Argadikoesoema Gondhowiardjo1 1Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 2Department of Obstetrics and Gynecology, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine universitas Indonesia, Jakarta, IndonesiaCorrespondence: Soehartati Argadikoesoema Gondhowiardjo Tel/Fax +62 21-3926288Email gondhow@gmail.comAbstract: Cervical cancer is the one of the most common gynecology malignancies in the world. National Comprehensive Cancer Network (NCCN) guidelines on cervical cancer are widely adopted as national guidelines and clinical practice guidelines. These guidelines are constantly being updated but their effectiveness has not been questioned. Therefore, we conducted a systematic review to assess outcomes with/without guideline adherence in the published studies. This systematic review was conducted according to PRISMA statement. Searching with strategy on PubMed, ProQuest, Scopus, and Wiley databases resulted in three studies that met all criteria, thus assessed further with Newcastle-Ottawa scale, and assessed qualitatively. All three studies adopt NCCN guidelines. We found that the proportion of adherence to cervical cancer treatment guidelines was low, ranging from 42% to 54%, with violations occurring at various clinical stages. One study stated that early stage cervical cancer was more likely to receive guideline adherence (adjusted OR=5.48; 95%CI: 1.94– 15.5; p=0.001) than advanced stage. There was a higher five-year survival of cervical cancer patients in the guideline-adhering group than in the nonadhering group. In all three studies, survival in the adherent group was reported as big as 88%, 79%, and 93%, respectively, compared to nonadherent group with 56%, 78%, and 88.1%respectively (p< 0.05). One study stated that adherence to guidelines could reduce cervical cancer mortality on stage I and II by 0.22 times (p< 0.05). As the conclusion, adherence to guidelines increases survival rates. In the early stages, there are differences in survival.Keywords: intraepithelial, neoplasia, squamous, cell, recommendation

Cervical cancer is the one of the most common gynecology malignancies in the world. National Comprehensive Cancer Network (NCCN) guidelines on cervical cancer are widely adopted as national guidelines and clinical practice guidelines. These guidelines are constantly being updated but their effectiveness has not been questioned. Therefore, we conducted a systematic review to assess outcomes with/without guideline adherence in the published studies. This systematic review was conducted according to PRISMA statement. Searching with strategy on PubMed, ProQuest, Scopus, and Wiley databases resulted in three studies that met all criteria, thus assessed further with Newcastle-Ottawa scale, and assessed qualitatively. All three studies adopt NCCN guidelines. We found that the proportion of adherence to cervical cancer treatment guidelines was low, ranging from 42% to 54%, with violations occurring at various clinical stages. One study stated that early stage cervical cancer was more likely to receive guideline adherence (adjusted OR=5.48; 95%CI: 1.94–15.5; p=0.001) than advanced stage. There was a higher five-year survival of cervical cancer patients in the guideline-adhering group than in the nonadhering group. In all three studies, survival in the adherent group was reported as big as 88%, 79%, and 93%, respectively, compared to nonadherent group with 56%, 78%, and 88.1%respectively (p

Background and Objective: Primary fallopian tube carcinomas (PFTC) are rare tumors with non-specific clinical presentations. The current case was unique since the tumor was first detected on endometrial curettage and clinicoradiologically was misdiagnosed as endometrial carcinoma.Case Report: A 48-year-old, post-menopausal female presented with one episode of vaginal bleeding. Endometrial curettage showed poorly differentiated carcinoma, while cervico-vaginal Papanicolaou (Pap) smear was negative for malignant cells. Right sided fallopian tube carcinoma in-situ was diagnosed on histopathological examination of surgical hysterectomy with B/L salpingo-oophorectomy specimen. Conclusion: As observed in the current case, unusual tumor histology with broad papillary fronds lined by pleomorphic cells showing nuclear stratification and focal involvement of endometrial curettage specimen may be considered a useful pointer for tubal malignancy.

Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

Adequate adaptation by immune cells to the surrounding milieu is especially important in the intestine, a chronically stimulated barrier tissue where immune cells encounter stimulation from food, the commensal microbiota and potential pathogenic organisms. A main population of uniquely adapted immune cells in the intestine are a type of T cells called intraepithelial lymphocytes (IEL or IET). In this thesis, we first describe the key characteristics of these cells. Next, we investigate the tissue adaptation of intestinal IETs by studying their development and gene expression profiles, behavior and adaptation to anatomical localization as well as their metabolism. Our studies focused both on peripherally induced IELs (especially addressing CD4+populations, CD4IELs) as well as “natural” TCRgd+IELs. For CD4IELs,we show that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4+T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8aahomodimers. We found that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes. In addition, using intravital microscopy and fate mapping experiments, we showed that upon migration to the epithelium, regulatory T cells (Tregs)lose Foxp3 and convert to CD4IELsin a microbiota-dependent fashion. We demonstrate that pTregsand CD4IELsperform complementary roles in the regulation of intestinal inflammation. In studies using human colon tissue samples, we show that the frequency and type of CD4+T cells in the human colon differs between the intraepithelial (IE) and the lamina propria (LP) compartment. We observed that while CD4+in the IE follow a surface marker expression pattern of CD8+tissue resident memory cells (Trm), their transcriptome profile follows a different pattern, with an enrichment for regulatory pathways, suggesting that IE CD4+T cells may represent a presently unrecognized tissue resident state. We found a complete loss of these IE versus LP differences in T cell composition in patients with active Crohn’s Disease. Additionally, we observed a specific subset of CD69loCD4+and CD69loCD8ab+cells that is especially increased in the IE and LP at areas of local inflammation. Using high-resolution microscopy techniques and intersectional genetic tools, we investigated the nature of natural IEL responses to luminal microbes. We observed that TCRgdIELs exhibit distinct location and movement patterns in the epithelial compartment that were microbiota-dependent and quickly altered upon enteric infections. These infection-induced changes included increased inter-epithelial cell (EC) scanning, anti-microbial gene expression and glycolysis. Both gd IEL behavioral and metabolic changes were dependent on EC pathogen sensing. In conclusion, this thesis presents evidence of T cell adaptation to the intestinal tissue in terms of gene expression and function, migration, movement behavior and metabolism. These adaptations were influenced by the microbiome and diet, as well as by epithelial cell communication. Interfering with intestinal T cell tissue adaptation led to early invasion by diverse pathogens, inflammation triggered by a dietary antigen, and is associated with inflammatory bowel disease.

Impact of the chromatin remodeller SMARCAD1 on murine intestinal intraepithelial lymphocyte and white adipose tissue biology. Chromatin remodelling factors use the energy of ATP hydrolysis to drive the movement of and/or affect molecular changes to the nucleosome. One such factor, SMARCAD1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1), has been previously shown to restore heterochromatin at the replication fork in vitro. This project aimed to assess the impact of SMARCAD1 on mammalian biology, utilising an animal model in which the catalytic ATPase domain of murine SMARCAD1 had been deleted using Cre/lox technology. Preliminary results had implicated SMARCAD1 in adaptive-immunity and white adipose tissue biology, and SMARCAD1 expression in these tissues/cells was confirmed by tissue-panel western blot. This project therefore aimed to build on these results to understand better the impact of SMARCAD1 on adaptive immune development and white adipose tissue biology. In addition, fewer than expected viable Smarcad1-/- homozygous offspring were produced during Smarcad1+/- x +/- matings, which both confirmed the observation from a previous knockout model of Smarcad1, and limited the number of knockout animals available for this study. Investigation of systemic B- and T-cells in the bone marrow, thymus and spleen had previously suggested there was no significant defect in adaptive immune development in Smarcad1-/- mice, however a tissue-specific and age-related loss of intra-epithelial (IEL) T-lymphocytes was found in the small intestine by flow cytometry. Analysis by qPCR of duodenal RNA suggested that differentiation rather than inflammation may underpin any loss-of-IEL phenotype, although further examination of cell-proliferation and crypt/villus anatomy by EdU incorporation and immunofluorescence revealed no overt cell-anatomical or proliferative difference in the knockout mice. The requirement for large numbers of aged mice made further investigation of the intestinal IEL phenotype logistically prohibitive. The reduction of epididymal white adipose tissue (eWAT) size had also been observed in male Smarcad1-/- mice, and serum from these mice showed elevated triglyceride (TG) and free fatty acids (FFA) levels. Transcriptomic analysis by RNA-seq of whole-WAT revealed an elevation in macrophage-related markers in knockout mice, which was confirmed by flow cytometry. As a number of reports have implicated SMARCAD1 in stem cell biology, putative adipose stem cells were isolated from +/+ and -/- mice by FACS and used for adipogenic differentiation assays ex-vivo In parallel, mouse embryonic fibroblasts from +/- and -/- mice were also assayed for adipogenic differentiation. While no significant differences in adipogenesis were observed, Smarcad1-/- mice challenged with a (60%) high fat diet did show increased weight gain over +/+ mice, and measurements of adipocyte size and cell cycle/cell proliferation analysis suggested hyperplasia rather than defects in adipogenesis may drive any WAT-related pathology in these mice., MRC-DTP

CILJ ISTRAŽIVANJA: Utvrditi udio abnormalnih Papa nalaza, njihovu raspodjelu po dobi žene i Bethesda kategorijama te analizirati sukladnost nalaza citološke analize s konačnom patohistološkom dijagnozom. ISPITANICI I METODE: U istraživnje su uključene 652 ispitanice s abnormalnim nalazom Papa testa. Uzorci su obrađeni i citomorfološki analizirani na Odjelu za kliničku citologiju Kliničkog zavoda za patologiju, sudsku medicinu i citologiju KBC Split od 01. siječnja 2015. do 31. prosinca 2015. godine. Uvidom u medicinsku dokumentaciju prikupljeni su klinički podaci o dobi ispitanica, citološkoj dijagnozi te dostupnom patohistološkom nalazu. REZULTATI: Abnormalan nalaz Papa testa nađen je u 3,6% uzoraka. Intraepitelne lezije činile su 98% abnormalnih nalaza. Najveća zastupljenost abnormalnih Papa nalaza je u dobnoj skupini 30 do 39 godina. Najbrojniju skupinu čini ASC-US (38%) i LSIL (32%). ASC-H je dijagnosticiran u 6% ispitanica, dok je 12% uzoraka zadovoljilo citomorfološke kriterije za HSIL. U 55% uzoraka patohistološka analiza potvrdila je citomorfološku dijagnozu. Negativan patohistološki nalaz nakon pozitivnog nalaza Papa testa nađen je u 20% ispitanica. U ovoj kategoriji, LSIL je dijagnosticiran u 37%, a HSIL u 44% slučajeva. Među patohistološkom uzorcima, LSIL je dijagnosticiran u 15%, a HSIL u 48% ispitanica. U 32% slučajeva nakon citološke dijagnoze LSIL, patološkom analizom nađen je HSIL. U 13% slučajeva neslaganja, kod citološke dijagnoze HSIL-a, patohistološka dijagnoza odgovarala je LSIL leziji, dok je u 11% slučajeva, konačna patohistološka analiza utvrdila invazivni karcinom. Abnormalne žljezdane stanice nađene su u 11% Papa uzoraka. Najčešća patohistološka dijagnoza u ovoj kategoriji je polip. ZAKLJUČAK: Citološko-histološka korelacija mora biti „zlatni standard“ sa slojevitim pristupom. Rezultati analize „dvosmjerne“ korelacije, potaknute bilo rezultatom citološke analize Papa testa ili analize bioptičkog uzorka moraju se integrirati s ciljem kontinuiranog poboljšanja kvalitete laboratorija. OBJECTIVES: The aim of the study was to analyse the distribution of abnormal Pap smears according to the age and Bethesda categories, as well as to determine validity of cytological analysis in relation to final pathohistological diagnosis. PATIENTS AND METHODS: The study included 652 patients with abnormal Pap smears. The samples were analysed at the Department of Clinical Cytology Clinical Hospital Centre Split, from January 1st 2015 till December 31st 2015. Clinical data with cytological and pathohistological diagnoses were collected from the medical records of the Department. RESULTS: Abnormal Pap smears were found in 3,6% samples. Intraepithelial lesions were found in 98% abnormal smears. The highest incidence were in the age group of 30-39 years. The most common category of the abnormal report were ASC-US (38%) and LSIL (32%). ASC-H was diagnosed in 6% and HSIL in 12% of Pap samples. Cytomorphological diagnosis was pathohistologicaly confirmed in 55% cases. Negative patohistological report was found in 20% of cases with abnormal Pap smears. In this group, LSIL was reported in 37% and HSIL in 44% cases. LSIL was found in 15 % and HSIL in 48% of biopsy samples. In 32% of cases following cytological diagnosis of LSIL, pathological analysis showed HSIL. In 13% of HSIL cases in cytological reports, pathohistological report was corresponded to LSIL, while in 11% of cases, final pathohistological report established invasive cancer. AGC was found in 11% of Pap smears. The most common pathohistological diagnosis in this category was polyp. CONCLUSION: Cytological- histologic correlation must be the “gold standard“ with multi-layered approach. “Bidirectional“ correlation, initiated by either a Pap test result or a cervical biopsy result, must be integrated and used for continuous quality improvement.

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα(+) T lymphocytes, and CD49a(+) liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46(-)CD8αα(-)Ly49E(+) cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity. publisher: Elsevier articletitle: A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties journaltitle: Cell Reports articlelink: http://dx.doi.org/10.1016/j.celrep.2017.04.068 content_type: article copyright: © 2017 The Author(s). ispartof: Cell Reports vol:19 issue:7 pages:1431-1443 ispartof: location:United States status: published

Objetivos: Determinar la distribución de los genotipos de VPH en mujeres de Bogotá con citología cervicouterina anormal. Métodos: Se colectaron muestras cervicales de 191 mujeres con ASCUS, 236 con lesiones intraepiteliales escamosas de bajo grado (LIEBG) y 116 de alto grado (LIEAG). La tipificación de VPH se realizó usando PCR con iniciadores consenso GP5+/GP6+ y reverse line blot. Resultados: La prevalencia de VPH fue 76,1%. Se observaron infecciones únicas en el 41,4% de las participantes, y coinfecciones en el 34,6%. La frecuencia de VPH según diagnóstico fue: 60,2%, 84,7% y 84,5% en ASCUS, LIEBG y LIEAG. Los VPH-16 y 58 fueron los tipos más frecuentes en los tres grupos, con frecuencias para VPH-16 de 20,4%, 33,9% y 38,8%, y para VPH-58 de 7,3%, 13,6%, 18,1% para ASCUS, LIEBG y LIEAG. En ASCUS y LSIL el tercer tipo en frecuencia fue VPH-56 (6,8% y 11,0%), mientras que en LIEAG fue VPH-18 (10,3%). Las infecciones con tipos virales probablemente oncogénicos y con tipos de bajo riesgo fueron mucho menos frecuentes y en general se presentaron como coinfecciones con tipos de alto riesgo. Conclusiones: Las infecciones con tipos de VPH de alto riesgo fueron las más frecuentes en todas las lesiones estudiadas, el VPH-58 ocupo el segundo lugar en frecuencia, como ha sido reportado en México y en general en Suramérica. El cambio hacia nuevas vacunas profilácticas que incluyan más tipos virales como el VPH-58 puede tener un mayor impacto en la disminución de la incidencia de lesiones preneoplásicas en nuestra región. Objective: To determine the distribution of HPV genotypes in women from Bogotá with abnormal cervical smear. Methods: Cervical samples were collected from 191 women with ASCUS, 236 with low-grade (LSIL) and 116 with high-grade squamous intraepithelial lesions (HSIL). HPV typing was performed using consensus PCR primers GP5+/GP6 + and reverse line blot. Results: The prevalence of HPV was 76.1%. Unique infections were observed in 41.4% of the participants and co-infections in 34.6%. The frequency of HPV according to diagnosis was: 60.2%, 84.7% and 84.5% in ASCUS, LSIL and HSIL respectively. HPV16 and 58 were the more frequent types in the three groups, HPV16 frequencies were 20.4%, 33.9% and 38.8%, and HPV58 frequencies were 7.3%, 13.6%, and 18,1% for ASCUS, LSIL and HSIL respectively. The third type in frequency in ASCUS and LSIL was HPV56 (6.8% and 11.0%), while in HSIL was HPV18 (10.3%). Infections with probably oncogenic types or with low risk types were much less frequent and generally were observed as co-infections with high-risk types. Conclusions: Infections with high risk HPV types were the most frequent in all studied lesions, VPH-58 ranked second in frequency as has been reported in Mexico and in general in South America. The change to new prophylactic vaccines including more viral types as HPV58 could have a higher impact in reducing the incidence of pre-neoplastic lesions in our region.

Background Non-erosive reflux disease (NERD) is a variant of gastroesophageal reflux disease (GERD) in which patients with typical reflux symptoms have no evidence of erosive esophagitis at endoscopy. An objective diagnostic tool for NERD remains an unmet need for clinicians and researchers. This study was designed to determine the types of histological alterations seen in Nigerian patients with NERD. Methods This was a prospective cross-sectional study in which mucosal biopsy was taken from the lower esophagus in patients with NERD. Similar biopsy was also taken from patients with nonulcer dyspepsia who served as controls. The materials were processed and examined histologically. Results There were 68 patients with NERD and 60 patients with nonulcer dyspepsia. Intraepithelial neutrophil infiltration was significantly more frequent in patients with NERD compared to those with nonulcer dyspepsia (47.1% vs 13.3%, P = 0.0326). Epithelial proliferative chnges in the form of basal cell hyperplasia and papilla elongation were minimal (11.8% and 3.3% respectively). Conclusions Nigerian patients with NERD have a high degree of esophageal intraepithelial neutrophil infiltration and a low prevalence of epithelial proliferative changes. This may be related to the relative rarity of Barrett's esophagus in Nigerians.

Minimally invasive therapy of cervical intraepithelial neoplasia for fertility preservation

Objectives/Hypothesis: Studies on the morphology and location of the sensory receptors in the laryngeal mucosa have resulted in insufficient and sometimes conflicting data. In the present study the authors analyzed the distribution and morphology of sensory nerve plexuses and terminal fibers in the laryngeal mucosa of the rat. Study Design: Two groups of Male Wistar rats were used in this laboratory study; the larynx of the first group were used to analyse the sensitive innervation of its epithelium, whereas the larynx of the second group (controls) were tested for the specificity of the antibodies used. Methods: The larynges of the animals were entirely removed after perfusion, and coronal or horizontal sections were immunoprocessed for further randomized analysis of the mucosa. Primary afferents were detected by immunoreaction to two widely recognized markers of sensory nerves, calcitonin generelated peptide and substance P, and visualized using diaminobenzidine as a chromogen. Results: The nerve plexuses were more densely distributed in the dorsal half of the vocal folds and in the laryngeal aspect of the epiglottis. Dense networks of fine fibers with many varicosities en passant, immunoreactive for both calcitonin gene-related peptide and substance P, occurred in the lamina propria and along the epithelial thickness. Calcitonin gene-related peptide– immunoreactive and substance P–immunoreactive fibers extended across the epithelium and projected to the laryngeal lumen itself, reaching the space between the cilia. Conclusion: The projection of intraepithelial nerve fibers into the lumen of the larynx indicates that in the absence of mucus, nerve endings may be exposed and thus receive direct stimulation from airborne substances. Furthermore, it suggests that the laryngeal mucosa of the rat may constitute an experimental model for studying the direct activation or manipulation of primary afferents at the periphery and neurogenic inflammation., União Europeia (UE). Fundo Europeu de Desenvolvimento Regional (FEDER)., Fundação para a Ciência e a Tecnologia (FCT) – Programa Operacional “Ciência, Tecnologia, Inovação” (POCTI) - POCTI/NSE/46399/2002., Grunenthal Foundation.

Intraepithelial lymphocytes (IEL) are specialized T cells found between the epithelial cells of the small intestine. Because of their location, IEL are the first lymphocytes to contact intestinal bacteria and food antigens. In the neonate, IEL may be the first cells of the immune system to interact with milk-borne hormones including prolactin (PRL). PRL, an endocrine hormone abundant in breast milk, interacts with cells through surface receptors. PRL has been shown to function as an immunoregulator and may affect the development of the newborn's immune system. To determine if PRL plays a role in IEL development, small intestine IEL from rats of various ages were examined for the presence of surface prolactin receptor (PRL-R) and several lymphoid markers by flow cytometry. Between birth and 96 days of age about 80% of IEL were found to express PRL-R. These same cells also expressed the mRNA for PRL. Additionally, all of the IEL subpopulations examined were found to express PRL-R. Analysis of the normal development of rat IEL revealed an age related increase in total IEL, CD4 positive cells as well as a peak in interleukin-2 receptor (IL-2R) expression at weaning. In summary, the results indicate that IEL express PRL and PRL-R. In addition, an activation marker, IL-2R, changes in expression during neonatal development.

The Hedgehog signaling pathway regulates embryo patterning and progenitor cell homeostasis in adult tissues, including epidermal appendages. A role for the Hh pathway in mammary biology and breast cancer has also been suggested. The aim of this study was to analyze Hh signaling in the mouse mammary gland through the generation of transgenic mice that express Sonic Hedgehog (Shh) under the control of the mammary-specific WAP promoter (WAP-Shh mice). To identify mammary cells capable of activating the Hh pathway we bred WAP-Shh mice to Ptch1-lacZ knock-in mice, in which the expression of a nuclear-targeted β-galactosidase reporter protein (β-gal) is driven by the endogenous Patched 1 gene regulatory region. After two cycles of induction of transgenic Shh expression, we detected areas of X-gal reactivity. Immunohistochemical analysis showed nuclear β-gal staining in clusters of mammary cells in WAP-Shh/Ptch1-lacZ bitransgenic mice. These were epithelial cells present in a basal location of displastic ducts and alveoli, adjacent to Shh-expressing luminal cells, and overexpressed epithelial basal markers keratin 5, 14 and 17 and transcription factor p63. Absence of smooth muscle actin expression and a cuboidal morphology differentiated Hh-responding cells from flat-shaped mature myoepithelial cells. Groups of cells expressing stem cell markers integrin β3 and keratins 6 and 15 were also detected within Hh-responding areas. In addition, we found that Hh-responding cells in the mammary glands of WAP-Shh/Ptch1-lacZ mice were ciliated and exhibited a low proliferation rate. Our data show the paracrine nature of hedgehog signaling in the epithelial compartment of the mouse mammary gland, where a subset of basal cells that express mammary progenitor cell markers and exhibit primary cilia is expanded in response to secretory epithelium-derived Shh. This work was supported by MCINN Grant no. SAF2006 03244, Fundación Marcelino Botín and Federación Española Cáncer de Mama (FECMA).

Aim. To evaluate clinical peculiarities and prognostic value of abdominal syndrome in adult patients with systemic vascular purpura (SVP). Material and methods. Incidence, clinical picture, complications of abdominal syndrome, its relations with principal extraintestinal manifestations of SVP were studied in 125 SVP patients. Absorption and barrier functions of the small intestine, their correlations with clinical activity of the disease were investigated in 32 SVP patients with no clinical signs of intestinal affection. Computer-assisted morphometry of duodenal mucosa biopsies was conducted and the results were compared to those of intestinal permiability and clinical activity of SVP. Results. Negative correlation was found between the occurrence of abdominal syndrome and the patients' age. The gastrointestinal tract suffered more frequently in men. 21% patients had abdominal complications, association of abdominal syndrome with higher frequency of glomerulonephritis. In the absence of abdominal symptoms, the barrier function of the small intestine for protein macromolecules was impaired. This correlated with exacerbations of skin purpura. Increased intestinal permeability and activity of skin purpura correlated with severity of inflammation in the duodenal mucosa. Conclusion. Abdominal syndrome in SVP is an unfavourable prognostic factor indicating possible severe complications and high risk of glomerulonephritis. Subclinical intestinal involvement presenting as barrier dysfunction may contribute to aggravation of skin vasculitis.