Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.

BackgroundEndometriosis has been described to impair fertility through various mechanisms. However, studies evaluating the reproductive outcomes of women undergoing assisted reproductive technologies show controversial results. The aim of this study is to assess whether the reproductive outcome is impaired among women with endometriosis-associated infertility undergoing IVF.MethodsA retrospective cohort study was performed, including women undergoing IVF reported by the Red Latinoamericana de Reproduccion Asistida (Redlara) registry, between January 2010 and December 2012. The study group included women with endometriosis-associated infertility, and the control group women with tubal factor, endocrine disorders or unexplained infertility. Women above 40 years, severe male factor and premature ovarian failure were excluded. The reproductive outcomes of between both groups were compared. The primary outcome was live birth. Secondary outcomes included clinical pregnancy, miscarriage, number of oocytes retrieved and number of fertilized oocytes. Outcomes were assessed after the first fresh IVF cycle, and were adjusted for age and number of embryos transferred.ResultsA total of 22.416 women were included (3.583 with endometriosis and 18.833 in the control group). Mean age of patients in the endometriosis group and control group was 34.86 (3.47) and 34.61 (3.91) respectively, p = 0.000. The mean number of oocytes retrieved were 8.89 (6.23) and 9.86 (7.02) respectively, p = 0.000. No significant differences were observed between groups in terms of live birth (odds ratio (OR) 1.032, p = 0.556), clinical pregnancy (OR 1.044, p = 0.428) and miscarriage rates (OR 1.049, p = 0.623). Women with endometriosis had significantly lower number of oocytes retrieved (incidence risk ratio (IRR) 0.917, 95% CI 0.895–0.940), however, the number of fertilized oocytes did not differ among the two groups when adjusting for the number of oocytes retrieved (IRR 1.003, p = 0.794). An age-stratified analysis was performed, and no differences were observed in the reproductive outcomes between groups for women aged under 35 and 35 to 40.ConclusionsReproductive outcomes among women undergoing IVF and diagnosed with endometriosis-associated infertility do not differ significantly from women without the disease. Although women with endometriosis generate fewer oocytes, fertilization rate is not impaired and the likelihood of achieving a live birth is also not affected.

Using cDNA microarray methodology, we have shown previously that transcripts of progranulin gene (Grn, also known as acrogranin), a recently identified autocrine growth factor, were upregulated in mouse blastocysts adhered to the filter membrane in an in vitro-culture system. In the present study, we investigated the expression and effects of progranulin on blastocyst hatching, adhesion, and embryo outgrowth during the peri-implantation period in the mouse. During this period, substantial amounts of Grn mRNA were present in both inner cell mass (ICM) and trophectoderm. Progranulin was localized exclusively to the surface of the trophectoderm in early and pre- and postadhesion blastocysts as well as in trophoblast cells and ICM of outgrowth embryos, being secreted as a single, 88-kDa form into the surrounding medium. NIH3T3 cells that had been transfected with a progranulin expression construct secreted the 88-kDa form of the protein, from which a 68-kDa form could be generated by deglycosylation. In vitro treatment of blastocysts with recombinant progranulin promoted blastocyst hatching, adhesion, and outgrowth, whereas rabbit anti-mouse progranulin immunoglobulin G reduced the incidence of blastocyst hatching, adhesion, and outgrowth. Studies of bromodeoxyuridine incorporation and immunodissection of the ICM revealed that progranulin was effective on the trophectoderm but not on the ICM. These results indicate that progranulin is an important factor for the processes of blastocyst hatching, adhesion, and outgrowth, and they suggest that the effects of progranulin on blastocyst adhesion and outgrowth may have been triggered by the previous action of progranulin to induce hatching of the blastocysts.

ObjectiveThe main objective of this study was to assess the prevalence of overweight and obesity among patients undergoing assisted reproductive technology (ART) in Latin America and its consequences on treatment outcomes.MethodsWe used the Latin American Registry of ART to obtain women's age and body mass index (BMI), cancellation rate, number of oocytes retrieved and embryos transferred, clinical pregnancy, live birth and miscarriage rates from 107.313 patients undergoing autologous IVF and ICSI during four years; a multivariable analysis was performed to determine the effect of BMI on cancellation, oocytes retrieved, pregnancy, live birth and miscarriage, adjusting for age, number of embryos transferred and embryo developmental stage upon embryo transfer, when appropriate.ResultsThe prevalence of overweight and obesity was 16.1% and 42.4%, respectively; correcting for age of female partner, overweight and obesity were associated to an increase in the odds of cancellation and to a lower mean number of oocytes retrieved; after adjusting for age, number of embryos transferred and stage of embryo development at transfer, we found that the BMI category was not associated to a change in the likelihoods of pregnancy, live birth and miscarriage.ConclusionsThe prevalence of obesity among women seeking ART in Latin America is surprisingly high; however, BMI does not influence the outcome of ART performed in these women.

Study question Does the use of ICSI offer any outcome advantage over IVF in patients with non-male factor infertility? Summary answer We did not find any outcome improvement that justifies the routine use of ICSI over IVF in non-male factor ART cycles. What is already known Since its introduction in Latin America, the use of ICSI has increased substantially, even among patients without male factor infertility. However, it is not clear whether ICSI provides an advantage over IVF in non-male factor infertility. Study design size, duration A retrospective cohort study of fresh cycles performed in 155 ART clinics located in 15 Latin American countries between 2012 and 2014. Records were assessed for 49,813 ART cycles (39,564 ICSI and 10,249 IVF) performed in infertile couples who did not have male factor infertility. Student’s t -test was used to analyze normally distributed data, Wilcoxon test to analyze non-normally distributed data, and Fisher’s exact test for categorical data. Logistic regression was used to quantify the effect of ICSI on delivery rate, adjusting for age of female partner, number of oocytes inseminated, number of embryos transferred, and transfer at blastocyst stage as possible confounding factors. Poisson regression analysis was used to quantify the effect of ICSI on fertilization rate, adjusting for age of female partner. Participants/materials, setting, method Cycles with the diagnosis of male factor and use of cryopreserved semen and with a freeze-all strategy were excluded. Main results and the role of chance After correcting for age of female partner, number of oocytes inseminated, number of embryos transferred and transfer at blastocyst stage, we found that the use of ICSI was associated with a significant decrease in the odds of delivery compared to IVF (odds ratio 0.88, 95% CI 0.84 to 0.93; P < 0.0001). Limitations reasons for caution An important limitation of this study is the lack of randomization owing to its retrospective nature. This could result in selection bias, i.e. couples with the worst prognosis undergoing ICSI, or patients with a history of fertilization failure in IVF cycles undergoing ICSI. More than one cycle from the same couple may be included in the study. Wider implications of the findings The lack of an outcome benefit—and, indeed, a reduced likelihood of delivery—following ICSI in non-male factor infertile couples suggests that ICSI may not be the most appropriate clinical approach in these patients. Study funding/competing interest(s) None.