Immunomodulation for unexplained recurrent implantation failure: where are we now?

In brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

No. 354-Canadian HIV Pregnancy Planning Guidelines.

OBJECTIVE: The objective of the Canadian HIV Pregnancy Planning Guidelines is to provide clinical information and recommendations for health care providers to assist Canadians affected by HIV with their fertility, preconception, and pregnancy planning decisions. These guidelines are evidence- and community-based and flexible and take into account diverse and intersecting local/population needs based on the social determinants of health. INTENDED OUTCOMES: EVIDENCE: Literature searches were conducted by a librarian using the Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases for published articles in English and French related to HIV and pregnancy and HIV and pregnancy planning for each section of the guidelines. The full search strategy is available upon request. VALUES: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the SOGC under the leadership of the principal authors, and recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care and through use of the Appraisal of Guidelines Research and Evaluation instrument for the development of clinical guidelines. BENEFITS, HARMS, AND COSTS: Guideline implementation should assist the practitioner in developing an evidence-based approach for the prevention of unplanned pregnancy, preconception, fertility, and pregnancy planning counselling in the context of HIV infection. VALIDATION: These guidelines have been reviewed and approved by the Infectious Disease Committee and the Executive and Council of the SOGC. SPONSOR: Canadian Institutes of Health Research Grant Planning and Dissemination grant (Funding Reference # 137186), which funded a Development Team meeting in 2016.

Women infected with human immunodeficiency virus type 1 have poorer assisted reproduction outcomes: a case-control study.

OBJECTIVE: To compare the efficacy of assisted reproductive technology (ART) in women infected with human immunodeficiency virus type 1 (HIV-1) versus HIV-negative controls. DESIGN: Retrospective case-control study. SETTING: University hospital ART unit. PATIENT(S): Eighty-two women infected with HIV-1 and 82 women as seronegative controls. INTERVENTION(S): Ovarian stimulation, oocytes retrieval, standard in vitro fertilization (IVF) or intracytoplasmic sperm injection, embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancies and live-birth rates. RESULT(S): After oocyte retrieval, all women infected with HIV-1 infected were matched 1:1 to HIV-negative controls according to the following criteria: date of ART attempt, age, parity, main cause of infertility, ART technique, and rank of attempt. Only the first IVF cycle during the study period was considered for each couple. We found no statistically significant differences between the two groups for ovarian stimulation data, fertilization rate, or average number of embryos transferred. The clinical pregnancy rate per transfer was statistically significantly lower for the cases compared with the controls (12% vs. 32%), as were the implantation rate (10% vs. 21%) and the live-birth rate (7% vs. 19%). CONCLUSION(S): In one of the largest studies to pair six factors that influence the results of ART, HIV infection in women was associated with poorer outcomes after ART. These results suggest that women with controlled HIV-1-infection should be counseled not to delay ART in cases of self-insemination failure or other causes of infertility. Fertility preservation by vitrification of oocytes in women whose pregnancy should be delayed may be an important future consideration.

Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases.

Tristetraprolin (TTP) is an mRNA-binding protein, but studies of this interaction have been difficult due to problems with the purification of recombinant TTP. In the present study, we expressed human and mouse TTP as glutathione S-transferase and maltose-binding protein (MBP) fusion proteins in Escherichia coli, and purified them by affinity resins and Mono Q chromatography. TTP cleaved from the fusion protein was identified by immunoblotting, MALDI-MS, and protein sequencing, and was further purified to homogeneity by continuous-elution SDS-gel electrophoresis. Purified recombinant TTP bound to the AU-rich element of tumor necrosis factor-alpha (TNFalpha) mRNA and this binding was dependent on Zn(2+). Results from sizing columns suggested that the active species might be in the form of an oligomer of MBP-TTP. Recombinant TTP was phosphorylated by three members of the mitogen-activated protein (MAP) kinase family, p42, p38, and JNK, with half-maximal phosphorylation occurring at approximately 0.5, 0.25, and 0.25 microM protein, respectively. Phosphorylation by these kinases did not appear to affect the ability of TTP to bind to TNFalpha mRNA under the assay conditions. This study describes a procedure for purifying nonfusion protein TTP to homogeneity, demonstrates that TTP's RNA-binding activity is zinc dependent, and that TTP can be phosphorylated by JNK as well as by the other members of the greater MAP kinase family.