Increased incidence and reduced mortality after first attack of acute pancreatitis over an 18-year period.

AIMS: To determine time trends in the incidence and etiology of acute pancreatitis and identify predictors for in-hospital mortality. PATIENTS AND METHODS: Retrospective study of 1722 patients with acute pancreatitis admitted to Akershus University Hospital between January 2000 and December 2017. Data were obtained from electronic patient files and computed tomography scans. We estimated a logistic regression model to assess differences in associations between patient characteristics and in-hospital mortality in two time periods, 2000-2009 (first period) and 2010-2018 (second period). RESULTS: First attack of acute pancreatitis (FAAP) was identified in 1579 patients (91.7%). The incidence of FAAP increased from 20.1/100,000 during the first period to 27.7/100,000 in the second period (p = .011). Etiology showed no differences between the two time periods. Gallstone was the most frequent etiology (47.2%). In total, 187 patients (11.8%) had necrotizing pancreatitis; more in the second period compared to the first (14.2 vs. 7.7%; p < .001). The overall mortality rate was 3.9%. Mortality rates decreased for both inflammatory and necrotizing pancreatitis during the study period. Age and comorbidity according to Charlson Comorbidity Index (CCI) were predictors of in-hospital mortality (OR 1.07, 95% CI 0.07; 0.40 and 13.58, 95% CI 3.88; 47.52), as were alcohol and organ failure (OR 7.20, 95% CI 2.02; 25.67 and OR 34.15, 95% CI 8.94; 130.53, respectively). CONCLUSIONS: The incidence of FAAP is increasing in southeast Norway. The etiology has remained unchanged over an 18-year period, with gallstones being the most frequent cause. The outcomes for both inflammatory and necrotic pancreatitis are improving.

Epidemiological and genetic clues for molecular mechanisms involved in uterine leiomyoma development and growth.

BACKGROUND: Uterine leiomyomas (fibroids) are highly prevalent benign smooth muscle tumors of the uterus. In the USA, the lifetime risk for women developing uterine leiomyomas is estimated as up to 75%. Except for hysterectomy, most therapies or treatments often provide only partial or temporary relief and are not successful in every patient. There is a clear racial disparity in the disease; African-American women are estimated to be three times more likely to develop uterine leiomyomas and generally develop more severe symptoms. There is also familial clustering between first-degree relatives and twins, and multiple inherited syndromes in which fibroid development occurs. Leiomyomas have been described as clonal and hormonally regulated, but despite the healthcare burden imposed by the disease, the etiology of uterine leiomyomas remains largely unknown. The mechanisms involved in their growth are also essentially unknown, which has contributed to the slow progress in development of effective treatment options. METHODS: A comprehensive PubMed search for and critical assessment of articles related to the epidemiological, biological and genetic clues for uterine leiomyoma development was performed. The individual functions of some of the best candidate genes are explained to provide more insight into their biological function and to interconnect and organize genes and pathways in one overarching figure that represents the current state of knowledge about uterine leiomyoma development and growth. RESULTS: In this review, the widely recognized roles of estrogen and progesterone in uterine leiomyoma pathobiology on the basis of clinical and experimental data are presented. This is followed by fundamental aspects and concepts including the possible cellular origin of uterine fibroids. The central themes in the subsequent parts are cytogenetic aberrations in leiomyomas and the racial/ethnic disparities in uterine fibroid biology. Then, the attributes of various in vitro and in vivo, human syndrome, rodent xenograft, naturally mutant, and genetically modified models used to study possible molecular mechanisms of leiomyoma development and growth are described. Particular emphasis is placed on known links to fibrosis, hypertrophy, and hyperplasia and genes that are potentially important in these processes. CONCLUSIONS: Menstrual cycle-related injury and repair and coinciding hormonal cycling appears to affect myometrial stem cells that, at a certain stage of fibroid development, often obtain cytogenetic aberrations and mutations of Mediator complex subunit 12 (MED12). Mammalian target of rapamycin (mTOR), a master regulator of proliferation, is activated in many of these tumors, possibly by mechanisms that are similar to some human fibrosis syndromes and/or by mutation of upstream tumor suppressor genes. Animal models of the disease support some of these dysregulated pathways in fibroid etiology or pathogenesis, but none are definitive. All of this suggests that there are likely several key mechanisms involved in the disease that, in addition to increasing the complexity of uterine fibroid pathobiology, offer possible approaches for patient-specific therapies. A final model that incorporates many of these reported mechanisms is presented with a discussion of their implications for leiomyoma clinical practice.

Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in Müllerian duct mesenchyme-derived myometria.

Uterine leiomyomata are the most common tumors found in the female reproductive tract. Despite the high prevalence and associated morbidities of these benign tumors, little is known about the molecular basis of uterine leiomyoma development and progression. Loss of the Tuberous Sclerosis 2 (TSC2) tumor suppressor has been proposed as a mechanism important for the etiology of uterine leiomyomata based on the Eker rat model. However, conflicting evidence showing increased TSC2 expression has been reported in human uterine leiomyomata, suggesting that TSC2 might not be involved in the pathogenesis of this disorder. We have produced mice with conditional deletion of the Tsc2 gene in the myometria to determine whether loss of TSC2 leads to leiomyoma development in murine uteri. Myometrial hyperplasia and increased collagen deposition was observed in Tsc2(cKO) mice compared with control mice, but no leiomyomata were detected by post-natal week 24. Increased signaling activity of mammalian target of rapamycin complex 1, which is normally repressed by TSC2, was also detected in the myometria of Tsc2(cKO) mice. Treatment of the mutant mice with rapamycin significantly inhibited myometrial expansion, but treatment with the progesterone receptor modulator, mifepristone, did not. The ovaries of the Tsc2(cKO) mice appeared normal, but half the mice were infertile and most of the other half became infertile after a single litter, which was likely due to oviductal blockage. Our study shows that although TSC2 loss alone does not lead to leiomyoma development, it does lead to myometrial hyperplasia and fibrosis.

The Müllerian inhibiting substance type 2 receptor suppresses tumorigenesis in testes with sustained ß-catenin signaling.

Dysregulated WNT/ß-catenin signaling in murine testes results in a phenotype with complete germ cell loss that resembles human Sertoli cell-only syndrome. In other systems, including the ovary, dysregulated WNT/ß-catenin induces tumorigenesis but no tumors are observed in the mutant testes without deletion of a tumor suppressor, such as phosphatase and tensin homolog (PTEN). Müllerian inhibiting substance (MIS, also known as AMH), a member of the transforming growth factor-ß family of growth factors responsible for Müllerian duct regression in fetal males, has been shown to inhibit tumor growth in vitro and in vivo but its role as an endogenous tumor suppressor has never been reported. We have deleted the MIS type 2 receptor (MISR2), and thus MIS signaling, in mice with dysregulated WNT/ß-catenin and show that these mice develop testicular stromal tumors with 100% penetrance within a few months postnatal. The tumors are highly proliferative and have characteristics of either Sertoli cell tumors or progenitor Leydig cell tumors based on their marker profiles and histology. Phosphorylated Sma and mothers against decapentaplegic-related homolog 1/5/8 is absent in the tumors and ß-catenin target genes are induced. The tumor suppressor TP53 is also highly expressed in the tumors, as is phosphorylated γH2AX, which is indicative of DNA damage. The phenotype of these tumors closely resembles those observed when PTEN is also deleted in mice with dysregulated WNT/ß-catenin. Tumorigenesis in these mice provides conclusive evidence that physiological MIS signaling is a tumor suppressor mechanism and suggests that targeted treatment of MISR2-expressing cancers with therapeutic MIS should have a beneficial effect on tumor progression.

Simulated effect of pneumococcal vaccination in the Netherlands on existing rules constructed in a non-vaccinated cohort predicting sequelae after bacterial meningitis.

BACKGROUND: Previously two prediction rules identifying children at risk of hearing loss and academic or behavioral limitations after bacterial meningitis were developed. Streptococcus pneumoniae as causative pathogen was an important risk factor in both. Since 2006 Dutch children receive seven-valent conjugate vaccination against S. pneumoniae. The presumed effect of vaccination was simulated by excluding all children infected by S. pneumoniae with the serotypes included in the vaccine, from both previous collected cohorts (between 1990-1995). METHODS: Children infected by one of the vaccine serotypes were excluded from both original cohorts (hearing loss: 70 of 628 children; academic or behavioral limitations: 26 of 182 children). All identified risk factors were included in multivariate logistic regression models. The discriminative ability of both new models was calculated. RESULTS: The same risk factors as in the original models were significant. The discriminative ability of the original hearing loss model was 0.84 and of the new model 0.87. In the academic or behavioral limitations model it was 0.83 and 0.84 respectively. CONCLUSION: It can be assumed that the prediction rules will also be applicable on a vaccinated population. However, vaccination does not provide 100% coverage and evidence is available that serotype replacement will occur. The impact of vaccination on serotype replacement needs to be investigated, and the prediction rules must be validated externally.

Atividade antimicrobiana dos extratos de folhas e ramos da Ilex paraguariensis A. St.-Hil., Aquifoliaceae / Antimicrobial activity of extracts of the leaves and branches of Ilex paraguariensis (erva-mate)

Para avaliação da atividade antimicrobiana de Ilex paraguariensis foram utilizados seis microrganismos: Candida albicans, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus e Staphylococcus epidermidis. O método utilizado foi de difusão do disco. Foram adicionados em discos de papel filtro 10 µl de extratos hidro-alcoólicos das folhas e ramos coletados de dois ambientes distintos, com e sem exposição ao sol. As placas foram incubadas a 35- 37 ºC por 24 h. Os extratos inibiram levedura, bacilos gram-negativos e cocos gram-positivos, não mostrando atividade frente à Escherichia coli.

For the evaluation of the antimicrobial activity of Ilex paraguariensis six microorganisms were used: Candida albicans, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. In disks of filter paper 10 µl of hydro-alcoholic extracts of the leaves and branches from two distinct environments were added, with and without sun exposure. The extracts have inhibited levedura, gram-negative bacillus and gram-positive cocos, with no activity to Escherichia coli.

Immunological reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation for advanced ovarian cancer.

We evaluated the immunological reconstitution of patients who underwent high-dose chemotherapy and autologous blood stem cell transplantation (ABSCT) for advanced ovarian cancer. Sixty days after transplantation a complete reconstitution of lymphocytes and of the CD3, CD4, CD8, CD19, and CD16/56 subsets was observed in this series. A significant increase in the count of interleukin-2 receptor expressing lymphocyte (CD25) was found on day +60 after transplantation compared to that obtained at diagnosis and before transplantation. A significantly higher lymphokine-activated killer (LAK) precursor activity was seen on day +60 compared to the values obtained at diagnosis and before transplantation while natural killer activity did not show any significant variation. We conclude that ABSCT gives prompt and complete immunohaematopoietic reconstitution after high-dose treatment. Moreover, our data support the feasibility of interleukin-2/LAK therapy as consolidative therapy after ABSCT.

Measurement of a breast cancer associated antigen detected by monoclonal antibody SP-2 in sera of cancer patients.

An enzyme-linked immuno-absorbent assay has been developed for the detection of a circulating tumor-associated antigen, 90K, recognized by murine monoclonal antibody SP-2 (Iacobelli et al., Cancer Res 46: 3005-3010, 1986). This assay was found to be simple and reproducible. Using this method, 6% of 165 apparently healthy individuals and 15% of 91 patients with benign breast disease showed 90K levels above 1.7 units/ml. Approximately 50% of 129 patients with advanced breast cancer demonstrated serum antigen levels above 1.7 units/ml. All histological types of breast cancer were positive, and no association between the incidence of elevated 90K levels and other prognostic variables could be detected. The titers of 90K were significantly higher in sera from advanced-stage (3 and 4) patients than in those from patients with limited-stage (1 and 2) disease. Elevated 90K levels were also observed in patients with carcinomas of other sites, including gastrointestinal, gynecological, and lung tumors. By means of the immune blotting technique, the antigenic components carrying the determinants in serum and extracts of breast cancer cells have been identified. The levels of 90K did not correlate with those of CA 15-3 or CEA. The measurement of 90K in sera appears to be a useful adjunct to other available assays for the detection and monitoring of breast cancer and other malignant tumors.

An antiestrogenic action of interferons in human breast cancer cells.

The antiproliferative and antiestrogenic effects of human interferon on estrogen-dependent CG-5 human breast cancer cells in vitro are reported. Fibroblast beta - interferon as well as recombinant alpha - and gamma -interferon inhibited proliferation of CG-5 cells in a dose and time - dependent fashion. In addition, they completely suppressed the two-fold increase in cell number induced by estradiol and showed an additive antiproliferative effect when used in combination with the antiestrogen tamoxifen. These antiestrogenic effects of interferons were accompanied by a reduced receptor binding of estradiol to the cells.

Detection of antigens recognized by a novel monoclonal antibody in tissue and serum from patients with breast cancer.

Monoclonal antibodies were produced in mice immunized with proteins released into tissue culture fluid of human breast cancer cells maintained in vitro. One monoclonal antibody (SP-2) identified a Mr 90,000 antigen which appears to be a proteolipid. In immunoperoxidase assays, SP-2 reacted with 81 of 90 specimens of human breast cancer. It also reacted with 12 of 23 cancers of nonbreast origin but was unreactive with all normal tissues tested. The Mr 90,000 antigen, purified by immunoaffinity chromatography using SP-2, was used in an indirect binding inhibition assay for the detection of antigen in human serum. With this assay, 35 of 69 patients with breast cancer and 11 of 37 patients with benign breast lesions showed serum antigen levels above 6 units/ml. Patients with nonbreast cancers also demonstrated elevated levels of antigen in 32% of cases. The SP-2 defined Mr 90,000 antigen appeared to be distinct from carcinoembryonic antigen and other monoclonal antibody-defined breast cancer antigens of similar molecular weight. SP-2 may prove useful as a serum and/or tissue marker in breast pathology.