Keratin 7 expression in different anatomical parts of colonic epithelium in inflammatory bowel diseases and its prognostic value: a 3-year follow-up study.

The diagnosis of inflammatory bowel diseases (IBD) may be challenging and their clinical course, characterized by relapses and spontaneous or drug-induced remissions, is difficult to predict. Novel prognostic biomarkers are needed. Keratin 7 (K7) is a cytoskeletal intermediate filament protein which is not normally expressed in the colonic epithelium. It was recently shown that K7 expression in the colonic epithelium is associated with ulcerative colitis and Crohn's disease, the two main subtypes of IBD. Here we investigated IBD associated K7 neo-expression in different regions of colon and terminal ileum. The correlation of the K7 expression with the inflammatory activity of the epithelium was analyzed in each region. The prognostic value of K7 was estimated by comparing the clinical disease activity after 3 years with the K7 expression at the time of enrollment. Our data shows that the level of K7 expression in inflamed epithelium varies depending on the anatomical region and it is the most pronounced in ascending and descending colon, but it did not predict the severity of IBD for the following 3 years. These results warrant future studies focusing on the biological role of K7 in colon and its utilization as potential IBD biomarker.

Colonocyte keratin 7 is expressed de novo in inflammatory bowel diseases and associated with pathological changes and drug-resistance.

The clinical course of IBD, characterized by relapses and remissions, is difficult to predict. Initial diagnosis can be challenging, and novel disease markers are needed. Keratin 7 (K7) is a cytoskeletal intermediate filament protein not expressed in the colonic epithelium but has been reported in IBD-associated colorectal tumors. Our aim was to analyze whether K7 is expressed in chronic colonic inflammatory diseases and evaluate its potential as a novel biomarker. K7 was analyzed in two patient cohorts using immunohistochemistry-stained colon samples and single-cell quantitative digital pathology methods. K7 was correlated to pathological changes and clinical patient characteristics. Our data shows that K7 is expressed de novo in the colonic epithelium of ulcerative colitis and Crohn's disease IBD patients, but not in collagenous or lymphocytic colitis. K7 mRNA expression was significantly increased in colons of IBD patients compared to controls when assessed in publicly available datasets. While K7 increased in areas with inflammatory activity, it was not expressed in specific crypt compartments and did not correlate with neutrophils or stool calprotectin. K7 was increased in areas proximal to pathological alterations and was most pronounced in drug-resistant ulcerative colitis. In conclusion, colonic epithelial K7 is neo-expressed selectively in IBD patients and could be investigated for its potential as a disease biomarker.

The value of combined positron emission tomography/magnetic resonance imaging to diagnose inflammatory bowel disease: a prospective study.

BACKGROUND: The clinical utility of positron emission tomography/magnetic resonance imaging (PET/MRI) in comparison to standard work-up with patients with known or suspected inflammatory bowel disease (IBD) is unknown. PURPOSE: To evaluate the value of 18F-fluorodeoxyglucose (18F-FDG) PET/MRI in the diagnostics of IBD and further compare the data obtained using PET/MRI to histological findings. MATERIALS AND METHODS: Ten patients with relapse in IBD or with symptoms of suspected IBD were recruited either from a gastroenterology outpatient clinic or from a hospital ward. Intestinal inflammation was assessed with histology and 18F-FDG PET/MRI. Maximum standard uptake values (SUVmax) were calculated in six regions of the intestine (small bowel, ascending, transverse, descending and sigmoid colon, and rectum) and compared to histological analysis of inflammation activity. RESULTS: The study showed that both the inflammation activity (P = 0.008) and the region of the biopsy in the intestine (P = 0.015) had a significant effect on SUV. SUVs obtained from severe inflammation activity emerged significantly from the background (P = 0.006). In addition, the SUVs obtained from moderate inflammation raised from background, but the difference was not statistically significant (P = 0.083), while SUVs of mild inflammation were at the same level with SUVs of normal bowel wall (P = 0.988). CONCLUSION: 18F-FDG PET/MRI is a promising method of detecting especially severe inflammatory bowel lesions. More data are required to define its sensitivity and specificity.

A relational database to identify differentially expressed genes in the endometrium and endometriosis lesions.

Endometriosis is a common inflammatory estrogen-dependent gynecological disorder, associated with pelvic pain and reduced fertility in women. Several aspects of this disorder and its cellular and molecular etiology remain unresolved. We have analyzed the global gene expression patterns in the endometrium, peritoneum and in endometriosis lesions of endometriosis patients and in the endometrium and peritoneum of healthy women. In this report, we present the EndometDB, an interactive web-based user interface for browsing the gene expression database of collected samples without the need for computational skills. The EndometDB incorporates the expression data from 115 patients and 53 controls, with over 24000 genes and clinical features, such as their age, disease stages, hormonal medication, menstrual cycle phase, and the different endometriosis lesion types. Using the web-tool, the end-user can easily generate various plot outputs and projections, including boxplots, and heatmaps and the generated outputs can be downloaded in pdf-format.Availability and implementationThe web-based user interface is implemented using HTML5, JavaScript, CSS, Plotly and R. It is freely available from https://endometdb.utu.fi/ .

A Mayer-Rokitansky-Kuster-Hauser patient with leiomyoma and dysplasia of neovagina: a case report.

BACKGROUND: Most patients with congenital uterus and vaginal aplasia (i.e., Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome) have rudimentary pelvic uterine structures that contain smooth muscle. Although leiomyomas and dysplasia of vaginal mucosa are relatively common in the general population, they are rare in MRKH patients. Data on the vulnerability of neovaginas to HPV-associated dysplasia are limited. CASE PRESENTATION: A rare case of an MRKH patient with two gynaecological conditions detected during long-term gynaecological follow-up is presented. At the age of 21, the patient was treated for HPV-associated neovaginal dysplasia. At the age of 47, a pelvic leiomyoma was detected with transvaginal ultrasound and confirmed with magnetic resonance imaging. CONCLUSION: A Pap smear or human papillomavirus testing is indicated in sexually active MRKH women. Uterine rudiments contain smooth muscle, which facilitates the development of oestrogen-dependent diseases, such as leiomyomas and adenomyosis. Although magnetic resonance imaging is recommended in cases of a pelvic mass, easily attainable and cost-efficient transvaginal ultrasound offers high diagnostic accuracy in patients with a surgically created neovagina and is suitable for the patients' follow-up. Guidelines for the gynaecological follow-up of MRKH patients are warranted.

Chorioamnionitis and Five-Year Neurodevelopmental Outcome in Preterm Infants.

BACKGROUND: Chorioamnionitis, a risk factor for preterm delivery, has been suggested to be associated with suboptimal neurological development in premature infants. OBJECTIVE: To evaluate the association between chorioamnionitis and neurodevelopment in preterm infants at 5 years of age. Methods Very low birth weight and very low gestational age infants (n = 197) were recruited. Placental samples (n = 117) were evaluated for histological chorioamnionitis. Fetal histological chorioamnionitis was analyzed as a subgroup. The diagnosis of clinical chorioamnionitis was derived from medical records. Neurodevelopmental impairments were evaluated at 2 years of age, and cognitive development (n = 188) and neuropsychological performance (n = 193) were evaluated at 5 years of age. RESULTS: There were no associations between histological or clinical chorioamnionitis and neurodevelopmental impairments at 2 years of age. Clinical chorioamnionitis and fetal histological chorioamnionitis were not associated with cognitive development or neuropsychological performance, but histological chorioamnionitis was associated with poorer cognitive outcome (regression coefficient = -7.22, 95% CI: -14.31 to -0.13) and weaker memory and learning functions (regression coefficient = -1.29, 95% CI: -2.40 to -0.18) at 5 years of age. CONCLUSION: Our study findings do not support clinical chorioamnionitis having a major independent role in the pathogenesis of neurodevelopmental problems in very preterm infants. Histological chorioamnionitis was associated with slightly less optimal performance at 5 years of age, but further studies are needed to verify the clinical significance of these findings.

Intra-tissue steroid profiling indicates differential progesterone and testosterone metabolism in the endometrium and endometriosis lesions.

CONTEXT: Aberrant sex steroid signaling is suggested to promote endometriosis growth by several mechanisms, and the tissue concentrations of sex steroids are key determinants of the hormone action. However, their concentrations are only superficially known in the endometrium and endometriosis lesions. OBJECTIVE: This study sought to evaluate whether the tissue steroid hormone concentrations in endometriosis differ from the endometrium or serum. MAIN OUTCOME MEASURES: Steroid analysis of serum and tissue specimens of women with endometriosis (n = 60) and healthy controls (n=16) was measured, and supporting data from quantitative RT-PCR for steroidogenic enzymes and explant cultures of a subset of specimens is provided. RESULTS: Endometrial tissue progesterone (P4) concentrations reflected the serum P4 levels during the menstrual cycle, whereas in endometriosis lesions, the cycle-dependent change was missing. Remarkably high tissue T concentrations were measured in endometriosis lesions independent of the cycle phase, being 5-19 times higher than the corresponding serum levels. Tissue/serum ratio of T was further increased in patients with contraceptive medication. The altered tissue steroid concentrations in endometriosis were in line with the expression of various steroidogenic enzymes in the lesions, of which HSD3B2 showed constantly high expression, whereas CYP11A1 expression was low. Furthermore, the high concentration of sex steroids detected in the ovarian lesions involves their production by the lesion and by the adjacent ovarian tissue. CONCLUSIONS: Endometriosis lesions present with progestin and androgen metabolism, which are different from that of the endometrium, and the lesions are characterized by high tissue T and a loss of cyclical changes in tissue P4 concentration.

Characterization of hepatic tumors using [11C]metomidate through positron emission tomography: comparison with [11C]acetate.

BACKGROUND: Using positron emission tomography (PET), we compared two tracers, [11C]metomidate ([11C]MTO) and [11C]acetate ([11C]ACE), for the characterization of hepatic tumors. METHODS: Thirty-three patients underwent PET with [11C]MTO and [11C]ACE and magnetic resonance imaging (MRI). Based on the histology of the tumor biopsy, 14 patients had hepatocellular carcinoma (HCC), 9 patients had focal nodular hyperplasia (FNH), and 10 patients had other types of hepatic tumors. Tumor uptake was evaluated by calculating the maximum and mean standardized uptake value and tumor-to-liver ratio. RESULTS: Altogether, 120 hepatic lesions (59 HCC, 18 FNH, 30 metastases of different primaries, 9 adenomas, and 4 regenerating nodules of liver cirrhosis) were detected by MRI. The overall tumor detection rate was slightly higher for [11C]MTO (39%) than for [11C]ACE (33%). [11C]ACE was more sensitive for HCC detection (50% versus 43%, respectively), whereas [11C]MTO was more sensitive for FNH detection (78% versus 44%, respectively). In HCC patients, the tumor grade correlated with [11C]ACE, but not with [11C]MTO. All of the patients with liver metastases, from various primary tumors (n = 10), were negative for both tracers. CONCLUSIONS: Due to low sensitivity, [11C]MTO and [11C]ACE PET have only limited value in diagnosing hepatic tumors.

Protodynamic intracellular acidification by cis-urocanic acid promotes apoptosis of melanoma cells in vitro and in vivo.

The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30 m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30 mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo.

Low proportion of false-negative smears in the Finnish program for cervical cancer screening.

BACKGROUND: We assessed the performance and validity of cytology in the Finnish screening program by considering high-grade neoplasia and cervical cancer (CIN3+) rates as detected in the program and by reevaluating cases observed after a negative screening test. METHODS: This retrospective study included 915 screen-detected CIN3+ cases and 421 cases observed after a negative screen. Randomized and blinded reevaluation of potential false-negative screening tests covered 345 archival case smears from women without a referral to colposcopy, as well as 689 control smears for estimating performance and validity measures. RESULTS: The false-negative rate at the cutoff of low-grade squamous intraepithelial lesion or worse was 35% (95% confidence interval, 30-40%). In the subpopulation with original screening result of Pap I, the false-negative rate was 23% (18-28%). Sensitivity of screening laboratory rereading for detecting low-grade lesions or worse as atypical was 75% (67-82%) and specificity 93% (91-94%). Reproducibility of specific cytologic diagnoses was only fair. False negatives constituted 11% of all CIN3+ diagnoses in the screened population; those false negatives with an original Pap I screening result constituted 5%. CONCLUSIONS: Although screen failures in the form of diagnostic false negatives occur within the Finnish screening program, their effect on cancer incidence is fairly small and cannot be readily decreased without sacrificing the high specificity of screening or without high incremental costs. Feedback for the screening laboratories is needed, however, to improve the reproducibility of cytologic diagnoses to optimize the burden of intensified follow-up and treatment of precancerous lesions.

Novel hydroxysteroid (17beta) dehydrogenase 1 inhibitors reverse estrogen-induced endometrial hyperplasia in transgenic mice.

Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction, which triggers a rise in circulating progesterone levels, and in response to exogenous progestins. Strikingly, a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment, although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.

Acute dysphagia associated with aortic dissection: a case report and review of the literature.

Thoracic aortic aneurysm and dissection are rare causes of neurologic symptoms as well as of dysphagia. We report on a 58-year-old otherwise healthy male patient who presented with acute-onset intermittent dysphagia, mild dyspnea, and chest symptoms. He was referred to an emergency ENT unit for a suspected peritonsillar abscess but died of a massive aortic dissection and cardiac tamponation a few hours later. This rare condition is discussed in the differential diagnosis of adult acute-onset dysphagia.

Diffusion tensor imaging of the inferior colliculus and brainstem auditory-evoked potentials in preterm infants.

BACKGROUND: Preterm and low-birth-weight infants have an increased risk of sensorineural hearing loss. Brainstem auditory-evoked potentials (BAEP) are an effective method to detect subtle deficits in impulse conduction in the auditory pathway. Abnormalities on diffusion tensor imaging (DTI) have been shown to be associated with perinatal white-matter injury and reduced fractional anisotropy (FA) has been reported in patients with sensorineural hearing loss. OBJECTIVES: To evaluate the possibility of a correlation between BAEP and DTI of the inferior colliculus in preterm infants. MATERIALS AND METHODS: DTI at term age and BAEP measurements were performed on all very-low-birth-weight or very preterm study infants (n=56). FA and apparent diffusion coefficient (ADC) of the inferior colliculus were measured from the DTI. RESULTS: Shorter BAEP wave I, III, and V latencies and I-III and I-V intervals and higher wave V amplitude correlated with higher FA of the inferior colliculus. CONCLUSION: The association between the DTI findings of the inferior colliculus and BAEP responses suggests that DTI can be used to assess the integrity of the auditory pathway in preterm infants.

Interleukin-6 polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants.

OBJECTIVES: To evaluate whether genotypes of interleukin (IL)-6 gene promoter positions -174 and -572 are associated with histologic chorioamnionitis and neonatal inflammatory disease in preterm infants. STUDY DESIGN: DNA from very low birth weight or very preterm infants (n = 107) was genotyped for IL-6-174 and -572 polymorphisms (GG/GC/CC). The placentas were analyzed for histological inflammatory findings. Data on neonatal inflammatory diseases, including chronic lung disease (CLD), necrotizing enterocolitis (NEC), and septicemia, were collected using the definitions of the Vermont Oxford Network database. RESULTS: In univariate analyses, the IL-6-174 GG genotype was associated with a higher incidence of histologic chorioamnionitis. In multivariate analyses, the -174 GG and -572 GC genotypes were correlated with histologic chorioamnionitis (P = .039 and .009, respectively). Gestational age was not associated with genotype polymorphisms. IL-6-174 genotypes were not associated with CLD and/or NEC, but the CC genotype was correlated with septicemia in both univariate and multivariate analyses (P = .027). IL-6-572 genotypes were not associated with neonatal inflammatory disease. CONCLUSIONS: The IL-6-174 GG and -572 GC genotypes were associated with a higher incidence of histologic chorioamnionitis, and the IL-6-174 CC genotype was associated with septicemia in preterm infants. These findings suggest that the genetic composition of the IL-6 promoter area plays a significant role in the pathogenesis of chorioamnionitis and neonatal infections.

Does placental inflammation relate to brain lesions and volume in preterm infants?

OBJECTIVES: To evaluate the association between histologic inflammation of placenta and brain findings in ultrasound examinations and regional brain volumes in magnetic resonance imaging in very-low-birth-weight (VLBW) or in very preterm infants. STUDY DESIGN: VLBW or very preterm infants (n = 121) were categorized into 3 groups according to the most pathologic brain finding on ultrasound examinations until term. The brain magnetic resonance imaging performed at term was analyzed for regional brain volumes. The placentas were analyzed for histologic inflammatory findings. RESULTS: Histologic chorioamnionitis on the fetal side correlated to brain lesions in univariate but not in multivariate analyses. Low gestational age was the only significant risk factor for brain lesions in multivariate analysis (P < .0001). Histologic chorioamnionitis was not associated with brain volumes in multivariate analyses. Female sex, low gestational age, and low birth weight z score correlated to smaller volumes in total brain tissue (P = .001, P = .0002, P < .0001, respectively) and cerebellum (P = .047, P = .003, P = .001, respectively). In addition, low gestational age and low-birth-weight z score correlated to a smaller combined volume of basal ganglia and thalami (P = .0002). CONCLUSIONS: Placental inflammation does not appear to correlate to brain lesions or smaller regional brain volumes in VLBW or in very preterm infants at term age.

Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas.

Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) belong to the short-chain dehydrogenase/reductase family consisting of a diverse pool of enzymes with oxidoreductase activity. HSD17B enzymes catalyze the conversion between 17-keto and 17-hydroxy steroids, either activating or inactivating sex steroids. Previous studies have demonstrated a role for human HSD17B1 enzyme in estradiol (E2) biosynthesis both in gonads and extragonadal steroid target tissues and various estrogen-dependent diseases. In the present study, five transgenic (TG) mouse lines universally overexpressing human HSD17B1 were generated and characterized at fetal and adult ages, especially to study the enzyme function in vivo. Activity measurements in vivo indicated that in addition to activating estrone to E2, the enzyme is able to significantly reduce androstenedione to testosterone, and TG females presented increased testosterone concentration preceding birth. As a consequence, TG females suffered from several phenotypic features typical to enhanced fetal androgen exposure. Furthermore, the ovaries developed androgen-dependent ovarian benign serous cystadenomas at adulthood. Androgen dependency of the phenotypes was confirmed by rescuing them by antiandrogen treatment, or by transplanting wild-type ovaries to the TG females. In conclusion, the data evidently show that, in addition to activating estrone to E2, human HSD17B1 enhances androgen action in vivo. Thus, the relative amounts of androgenic and estrogenic substrates available partially determine the physiological function of the enzyme in vivo. The novel function observed for human HSD17B1 is likely to open new possibilities also for the use of HSD17B1-inhibitors as drugs against androgen-related dysfunctions in females.

Interstitial pneumonitis and coinfection of human herpesvirus 6 and Pneumocystis carinii in a patient with hypogammaglobulinemia.

Human herpesvirus 6 (HHV-6) has occasionally been associated with cases of interstitial pneumonitis, mainly in individuals with impaired cellular immunity. Here we report for the first time severe interstitial pneumonitis with simultaneous HHV-6 and Pneumocystis carinii infections in the lung tissue of a young patient with hypogammaglobulinemia.

Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages.

During the secretory phase of the menstrual cycle, the composition of extracellular matrix (ECM) in endometrium changes to favour implantation. In the present study, we have analysed whether some cases of unexplained infertility and recurrent abortions could be explained by abnormal production or turnover of endometrial ECM. Comparison of mRNA levels of a panel of collagens, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and cathepsins in the samples revealed higher levels of type I collagen, MMP-2 and cathepsin H and decreased levels of TIMP-3 mRNA in mid-secretory endometrium of patients with unexplained infertility and/or recurrent miscarriages when compared with normal mid-secretory endometrium. Furthermore, changes were also seen in the levels of type I collagen and TIMP-3 mRNA between the proliferative and mid-secretory phases of normal endometrium. The results suggest an altered ECM turnover in the endometrium of patients with fertility disorders prior to implantation.