Advances in the medical management of bowel endometriosis

Endometriosis infiltrating the bowel can be treated medically in accurately selected women not seeking conception and without overt obstructive symptomatology. When the rectosigmoid junction is involved, the probabilities of intestinal symptoms relief, undergoing surgery after treatment failure, and developing bowel obstruction during hormonal treatment are around 70%, 10%, and 1-2%, respectively. When the lesion infiltrates exclusively the mid-rectum, thus in cases of true rectovaginal endometriosis, the probabilities of intestinal symptoms relief and undergoing surgery are about 80% and 3%, respectively. Endometriotic obstructions of the rectal ampulla have not been reported. A rectosigmoidoscopy or colonoscopy should be performed systematically before starting medical therapies, also to rule out malignant tumours arising from the intestinal mucosa. Progestogens are safe, generally effective, well-tolerated, inexpensive, and should be considered as first-line medications for bowel endometriosis. Independently of symptom relief, intestinal lesions should be checked periodically to exclude nodule progression during hormonal treatment

Red Blood Cell Distribution Width, Hematology, and Serum Biochemistry in Dogs with Echocardiographically Estimated Precapillary and Postcapillary Pulmonary Arterial Hypertension

Background: Red blood cell distribution width (RDW) is a quantitative measurement of anisocytosis. RDW has prognostic value in humans with different cardiovascular and systemic disorders, but few studies have investigated this biomarker in dogs. Objectives: To compare the RDW in dogs with precapillary and postcapillary pulmonary hypertension (PH) and a control population of dogs and to correlate RDW with demographic, echocardiographic, and laboratory variables. Animals: One hundred and twenty-seven client-owned dogs including 19 healthy dogs, 82 dogs with myxomatous mitral valve disease (50 dogs without PH and 32 dogs with postcapillary PH), and 26 dogs with precapillary PH. Methods: Prospective study. Dogs were allocated to groups according to clinical and echocardiographic evaluation. RDW and selected laboratory and echocardiographic variables were compared among dog groups. Associations between RDW and demographic, laboratory, and echocardiographic variables were analyzed using correlation and multiple regression analysis. Results: Median RDW in dogs with precapillary PH (13.8%, interquartile range 13.2\ue2\u80\u9314.9%) and postcapillary PH (13.7, 13.2\ue2\u80\u9314.7%) was significantly increased compared to healthy dogs (13.3, 12.3\ue2\u80\u9313.7%; P <.05 for both comparisons), but only dogs with severe PH had significantly increased RDW compared to dogs without PH (P <.05). Peak tricuspid regurgitation pressure gradient was significantly associated with increased RDW (rho = 0.263, P =.007). Serum urea concentration, hematocrit, age, and white blood cell number were significantly associated with RDW in the multivariate analysis. Conclusions and Clinical Importance: Underlying pathophysiologic processes associated with PH instead of severity of PH are likely responsible for increased RDW in dogs with PH

"Per vaginam" topical use of hormonal drugs in women with symptomatic deep endometriosis : a narrative literature review

PURPOSE: We aim to provide a comprehensive overview of the role of the vagina as a route for drug delivery and absorption, with a particular focus on the use of vaginal hormonal compounds for the treatment of deep infiltrating symptomatic endometriosis. METHODS: A MEDLINE search through PubMed was performed to identify all published studies in English language on vaginal hormonal treatments for symptomatic endometriosis. RESULTS: Main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic dosages, and the reduction of side effects compared with the oral administration. Studies on endometriosis treatment mainly focused on the use of vaginal danazol (n = 6) and the contraceptive vaginal ring (n = 2). One pilot study evaluated the efficacy of vaginal anastrozole in women with rectovaginal endometriosis. Most investigations evaluated the vaginal use of hormonal agents in women with deep infiltrating endometriosis/rectovaginal endometriosis. Overall, a substantial amelioration of pelvic pain symptoms associated with endometriosis was observed, particularly of dysmenorrhea. A significant reduction in rectovaginal endometriotic nodule dimensions measured at ultrasound examination was detected by some but not all authors. CONCLUSIONS: The vaginal route represents a scarcely explored modality for drug administration. High local hormonal concentrations might achieve a greater effect on endometriotic lesions compared with alternative routes. Future studies should focus on the use of the vagina for delivering target therapies particularly in patients with deeply infiltrating rectovaginal lesions

When love hurts : A systematic review on the effects of endometriosis surgical and pharmacological treatments on female sexual functioning

INTRODUCTION: Endometriosis is associated with an increased risk of dyspareunia, therefore this chronic gynaecologic disease should be considered as a major cause of sexual dysfunctions. The aims of this study were to review the literature on the effects of endometriosis surgical and pharmacological treatments on female sexual functioning, and to provide suggestions for future treatment strategies. MATERIAL AND METHODS: We followed the PRISMA guidelines to conduct this systematic review, which involved an electronic database search of studies on the association between endometriosis and sexuality published between 2000 and 2016. RESULTS: As a result of the screening process, 22 studies were included in this systematic review. The 22 studies included were divided in 2 categories: 1) surgical intervention studies (n = 17), examining postoperative sexual outcomes of surgery for endometriosis; 2) pharmacological intervention studies (n = 5), evaluating the effects of pharmacological endometriosis treatments on sexual functioning. The studies considered showed that overall surgical and pharmacological interventions for endometriosis can lead to medium-/long-term improvement, but not necessarily to a definitive resolution of female sexual dysfunctions due to endometriosis. CONCLUSIONS: Sexual functioning is a multidimensional phenomenon and the ideal treatment for endometriosis related sexual dysfunctions should be conducted by a multidisciplinary team that involves not only gynaecologists, but also sexologists and psychologists/psychotherapists. Improving global sexual functioning, and not just reducing pain at intercourse, should be considered as a major clinical goal of endometriosis treatment

Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies

<p>Abstract</p> <p>Background</p> <p>Ki67 labeling index (Ki67 LI), the percentage Ki67 immunoreactive cells, is a measure of tumor proliferation, with important clinical relevance in breast cancer, and it is extremely important to standardize its evaluation.</p> <p>Aim</p> <p>To test the efficacy of computer assisted image analysis (CAIA) applied to completely digitized slides and to assess its feasibility in routine practice and compare the results obtained using two different Ki67 monoclonal antibodies.</p> <p>Materials and methods</p> <p>315 consecutive breast cancer routinely immunostained for Ki-67 (223 with SP6 and 92 with MM1 antibodies previously examined by an experienced pathologist, have been re-evaluated using Aperio Scanscope Xs.</p> <p>Results</p> <p>Mean human Ki67 LI values were 36%± 14.% and 28% ± 18% respectively for SP6 and MM1 antibodies; mean CAM Ki67 LI values were 31%± 19% and 22% ± 18% respectively for SP6 and MM1. Human and CAIA evaluation are statistically highly correlated (Pearson: 0.859, p<0.0001), although human LI are systematically higher. An interobserver variation study on CAIA performed on 84 cases showed that the correlation between the two evaluations was linear to an excellent degree.</p> <p>Discussion</p> <p>Our study shows that a) CAIA can be easily adopted in routine practice, b) human and CAIA Ki67 LI are highly correlated, although human LI are systematically higher, c) Ki67 LI using different evaluation methods and different antibodies shows important differences in cut-off values.</p

Impact of endometriosis on obstetric outcome after natural conception: a multicenter Italian study

Purpose To evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy. Methods Cases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis. Results Three hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery &lt; 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery &lt; 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery &lt; 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09). Conclusion Women with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery. Trial registration Clinical trial registration number: NCT03354793

High Yield Production Process for Shigella Outer Membrane Particles

Gram-negative bacteria naturally shed particles that consist of outer membrane lipids, outer membrane proteins, and soluble periplasmic components. These particles have been proposed for use as vaccines but the yield has been problematic. We developed a high yielding production process of genetically derived outer membrane particles from the human pathogen Shigella sonnei. Yields of approximately 100 milligrams of membrane-associated proteins per liter of fermentation were obtained from cultures of S. sonnei ΔtolR ΔgalU at optical densities of 30–45 in a 5 L fermenter. Proteomic analysis of the purified particles showed the preparation to primarily contain predicted outer membrane and periplasmic proteins. These were highly immunogenic in mice. The production of these outer membrane particles from high density cultivation of bacteria supports the feasibility of scaling up this approach as an affordable manufacturing process. Furthermore, we demonstrate the feasibility of using this process with other genetic manipulations e.g. abolition of O antigen synthesis and modification of the lipopolysaccharide structure in order to modify the immunogenicity or reactogenicity of the particles. This work provides the basis for a large scale manufacturing process of Generalized Modules of Membrane Antigens (GMMA) for production of vaccines from Gram-negative bacteria

Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BackgroundInfluenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses.MethodsWe did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050.FindingsBetween Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis.InterpretationThe tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed.FundingBill &amp; Melinda Gates Foundation

Mining unexpected patterns using decision trees and interestingness measures: a case study of endometriosis

[[abstract]]Because clinical research is carried out in complex environments, prior domain knowledge, constraints, and expert knowledge can enhance the capabilities and performance of data mining. In this paper we propose an unexpected pattern mining model that uses decision trees to compare recovery rates of two different treatments, and to find patterns that contrast with the prior knowledge of domain users. In the proposed model we define interestingness measures to determine whether the patterns found are interesting to the domain. By applying the concept of domain-driven data mining, we repeatedly utilize decision trees and interestingness measures in a closed-loop, in-depth mining process to find unexpected and interesting patterns. We use retrospective data from transvaginal ultrasound-guided aspirations to show that the proposed model can successfully compare different treatments using a decision tree, which is a new usage of that tool. We believe that unexpected, interesting patterns may provide clinical researchers with different perspectives for future research.[[incitationindex]]SCI[[incitationindex]]EI[[booktype]]紙本[[booktype]]電子

A Novel Phase Variation Mechanism in the Meningococcus Driven by a Ligand-Responsive Repressor and Differential Spacing of Distal Promoter Elements

Phase variable expression, mediated by high frequency reversible changes in the length of simple sequence repeats, facilitates adaptation of bacterial populations to changing environments and is frequently important in bacterial virulence. Here we elucidate a novel phase variable mechanism for NadA, an adhesin and invasin of Neisseria meningitidis. The NadR repressor protein binds to operators flanking the phase variable tract and contributes to the differential expression levels of phase variant promoters with different numbers of repeats likely due to different spacing between operators. We show that IHF binds between these operators, and may permit looping of the promoter, allowing interaction of NadR at operators located distally or overlapping the promoter. The 4-hydroxyphenylacetic acid, a metabolite of aromatic amino acid catabolism that is secreted in saliva, induces NadA expression by inhibiting the DNA binding activity of the repressor. When induced, only minor differences are evident between NadR-independent transcription levels of promoter phase variants and are likely due to differential RNA polymerase contacts leading to altered promoter activity. Our results suggest that NadA expression is under both stochastic and tight environmental-sensing regulatory control, both mediated by the NadR repressor, and may be induced during colonization of the oropharynx where it plays a major role in the successful adhesion and invasion of the mucosa. Hence, simple sequence repeats in promoter regions may be a strategy used by host-adapted bacterial pathogens to randomly switch between expression states that may nonetheless still be induced by appropriate niche-specific signals