Obstetric antiphospholipid syndrome: A recent classification for an old defined disorder

Obstetric antiphospholipid syndrome (APS) is nowbeing recognized as a distinct entity fromvascular APS. Pregnancy morbidity includes N3 consecutive and spontaneous early miscarriages before 10 weeks of gestation; at least one unexplained fetal death after the 10thweek of gestation of a morphologically normal fetus; a premature birth before the 34thweek of gestation of a normal neonate due to eclampsia or severe pre-eclampsia or placental insufficiency. It is not well understood how antiphospholipid antibodies (aPLs), beyond their diagnostic and prognostic role, contribute to pregnancy manifestations. Indeed aPL-mediated thrombotic events cannot explain the obstetric manifestations and additional pathogenic mechanisms, such as a placental aPL mediated complement activation and a direct effect of aPLs on placental development, have been reported. Still debated is the possible association between aPLs and infertility and the effect of maternal autoantibodies on non-vascular manifestations in the babies. Combination of low dose aspirin and unfractionated or low molecular weight heparin is the effective treatment in most of the cases. However, pregnancy complications, in spite of this therapy, can occur in up to 20% of the patients. Novel alternative therapies able to abrogate the aPL pathogenic action either by interfering with aPL binding at the placental level or by inhibiting the aPL-mediated detrimental effect are under active investigation

Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women

OBJECTIVE: Over the last few years, medical scholars have reported the significant association between recurrent pregnancy loss (RPL) and celiac disease (CD). Various pathogenic mechanisms underlying the pregnancy failure in CD have been suggested: among them the ability of anti-transglutaminase antibodies to impair the trophoblast invasiveness and endometrial endothelial cells differentiation and disrupt early placentation. CD shows a complex non-Mendelian pattern of inheritance, involving major histocompatibility complex (MHC) genes. The strongest effects are mapped to the classical human leukocyte antigen (HLA)-DQA1 and HLA-DQB1 genes. Specifically, the common haplotypes DQ2.5, DQ2.2, and DQ8 have been shown to increase CD risk by six-fold on average. MHC region contains genes with immunological functions and is responsible for the strongest association signals observed in most immune-mediated diseases. The aim of our study was to investigate the prevalence of the HLA-DQ2/DQ8 haplotypes in RPL, outside of CD. METHODS: The study population included women with history of RPL (≥3 spontaneous pregnancy losses) and women with at least two previous uncomplicated term pregnancies (control group, CTR). All women gave their informed consent to use their data for research purposes. RESULTS: 97 RPL women and 55 CTR were considered in the study. Mean age of the RPL sample was 37.7 (standard deviation, SD, 3.0; min 27; max 39). Mean age of the control group was 35.6 (SD 3.0; min 26years; m, max 38). A significantly increased prevalence of HLA-DQ2/DQ8 haplotype positivity was found in RPL population compared to control women (52.6% vs 23.6%; p<0.01). CONCLUSIONS: Our observations show for the first time a higher proportion of individuals HLA DQ2/DQ8 positive in women with RPL as compared to controls (and to general population estimates). Further studies are needed to better understand (i) the possible pathogenic mechanism to this observation; (ii) the clinical and therapeutic implications of our observation in order to provide a new approach to RPL couples. Copyright © 2016. Published by Elsevier B.V. KEYWORDS: Celiac disease; Genetic susceptibility; Human leukocyte antigen (HLA)-DQ2/DQ8; Intestinal permeabylity; Recurrent pregnancy los

Recent Insights on the Maternal Microbiota: Impact on Pregnancy Outcomes

Abstract Hormonal changes during and after pregnancy are linked with modifications in the maternal microbiota. We describe the importance of the maternal microbiota in pregnancy and examine whether changes in maternal microbiotic composition at different body sites (gut, vagina, endometrium) are associated with pregnancy complications. We analyze the likely interactions between microbiota and the immune system. During pregnancy, the gastrointestinal (gut) microbiota undergoes profound changes that lead to an increase in lactic acid-producing bacteria and a reduction in butyrate-producing bacteria. The meaning of such changes needs clarification. Additionally, several studies have indicated a possible involvement of the maternal gut microbiota in autoimmune and lifelong diseases. The human vagina has its own microbiota, and changes in vaginal microbiota are related to several pregnancy-related complications. Recent studies show reduced lactobacilli, increased bacterial diversity, and low vaginal levels of beta-defensin 2 in women with preterm births. In contrast, early and healthy pregnancies are characterized by low diversity and low numbers of bacterial communities dominated by Lactobacillus. These observations suggest that early vaginal cultures that show an absence of Lactobacillus and polymicrobial vaginal colonization are risk factors for preterm birth. The endometrium is not a sterile site. Resident endometrial microbiota has only been defined recently. However, questions remain regarding the main components of the endometrial microbiota and their impact on the reproductive tract concerning both fertility and pregnancy outcomes. A classification based on endometrial bacterial patterns could help develop a microbiota-based diagnosis as well as personalized therapies for the prevention of obstetric complications and personalized treatments through nutritional, microbiotic, or pharmaceutical interventions. Keywords: endometrium; gut; immunity; inflammasome; microbiota; pregnancy; vagina

Effect of alpha‐lipoic acid and myoinositol on endometrial inflammasome from recurrent pregnancy loss women

Problem: A significant increased expression/activation of one of the most well‐characterized inflammasomes, the NAcht leucine‐rich‐repeat protein‐3 (NALP‐3), in the endometrium from idiopathic recurrent pregnancy loss women (RPL) has been previously found by our research group. We therefore, suggested this event as being one of the molecular mechanisms altering endometrial inflammatory status during early pregnancy. In the present research, we attempt to investigate whether molecules with anti‐inflammatory activity, alpha‐lipoic acid (ALA), and/or myoinositol affect the endometrial NALP‐3 expression and activation. Method of study: Women with a history of idiopathic RPL (n = 30) were included in the study and compared to a control group (n = 15). Endometrial tissues were collected by hysteroscopy during the mid‐luteal phase. RPL women underwent a three‐month prescription of tablets containing ALA plus myoinositol (Sinopol®). After treatment, hysteroscopic biopsies were repeated in RPL patients. Inflammasome expression was evaluated by immunohistochemical and Western blot analysis. NALP‐3 activation was studied by quantifying the secretion of both caspase‐1 and interleukin IL)‐1ß and IL‐18 through ELISA. In ex vivo experiments, the effects of each molecule on endometrial inflammasome were studied. Results: Sinopol® significantly reduced the RPL endometrial inflammasome expression and activation. ALA, but not myoinositol, significantly reduced the endometrial inflammasome expression and activity. Conclusion: Our data suggest a role for ALA on RPL inflammasome. Understanding the mechanisms involved in RPL and the observation that specific molecules are able to interfere with such complex at the endometrium might provide new rational design approaches to a personalized evaluation of endometrial status and, ultimately, a targeted medicine

The chromosome analysis of the miscarriage tissue. Miscarried embryo/fetal crown rump length (CRL) measurement: A practical use

Objective To investigate whether miscarried embryo/fetal crown rump length (CRL) measurement may yield a practical application for predicting a conclusive result at the cytogenetic analysis of miscarriage tissue. Our study might help in improving the cytogenetic method, the results of which may be affected by maternal cell contamination (MCC). In particular, we aimed at establishing whether the miscarried embryo/fetal CRL measurement shows accuracy in predicting the possibility of MCC and the scan cut-off value useful to this purpose and, as a result, suggest a multi-step procedure for the genetic ascertainment. Methods Women experiencing at least two miscarriages of less than 20 weeks size at the Pregnancy Loss Unit at Fondazione Policlinico A. Gemelli underwent a scan before surgery. The CRL value was recorded. After the dilatation and courettage (D&C) procedure, miscarriage tissue was processed through the proposed multi-step procedure before performing oligo-nucleotide- based and SNP (single nucleotide polymorphisms)-based comparative genomic hybridization (CGH+SNP) microarray analysis. Results 63 women and 63 miscarriages met the criteria. By using the Receiving Operator Characteristic (ROC) curves, CRL showed an AUC of 0.816 (95%CI:0.703\ub10.928,p<0.001). A CRL24.5 mm cut-off value showed a higher positive likelihood ratio (5.27) but, conversely, a higher negative likelihood ratio (0.64) in predicting the possibility of MCC. Microarray analysis was successful in the totality of cases in which the embryo/fetal origin of miscarriage tissues was proven

Psychological treatments and psychotherapies in the neurorehabilitation of pain. Evidences and recommendations from the italian consensus conference on pain in neurorehabilitation

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the pape

Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL)-mediated inhibition of endometrial angiogenesis

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with \u3b22-glycoprotein I (\u3b22GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. \u3b22GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind \u3b22GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-\u3baB (NF-\u3baB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-\u3baB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in AP

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns