Effects of trying to conceive using an every-other-day strategy versus fertile window monitoring on stress: a 12-month randomized controlled trial.

STUDY QUESTION: Can animation videos on how to optimize the chances of pregnancy influence stress, anxiety, depression and sexual functioning of individuals trying to conceive (TTC)? SUMMARY ANSWER: There were no differences between those educated to have intercourse every other day, on the fertile window and a control group (CG), and depression and sexual dysfunction significantly increased over time for all arms. WHAT IS KNOWN ALREADY: Recent findings indicate that time to pregnancy can be significantly shortened by targeting the fertile period, but some reproductive care guidelines recommend instead the practice of intercourse every other day on the basis that it is less stressful to the couple. Evidence to support guidelines on how to preserve well-being and psychosocial adjustment and optimize pregnancy chances is lacking. STUDY DESIGN, SIZE, DURATION: We conducted a prospective, double-blinded, three-arm randomized controlled trial between July 2016 and November 2019. Participants were randomized to either not having any stimulus (CG) or visualizing a short animated video explaining how to improve chances of pregnancy by having intercourse every other day (EOD group), or by monitoring the fertile window (FWM group). Assessments were made before the intervention (T0), and 6 weeks (T1), 6 months (T2) and 12 months after (T3), with follow-ups censored in case of pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were childless individuals of reproductive age actively TTC and not diagnosed or unaware of a condition that could prevent spontaneous pregnancy. Individuals were excluded from recruitment if they had previous children or had a condition preventing spontaneous pregnancy. Our primary outcome was stress and secondary outcomes included anxiety, depression, sexual functioning and pregnancy. Primary analyses were performed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 450 randomized participants 127 were educated to use an every-other-day strategy, 135 to monitor the fertile window, and 134 received no intervention. Groups were similar regarding demographics and months TTC. Repeated measures analysis revealed that there were no significant interaction effects of psychological and sexual well-being between groups over time (P > 0.05). Significant time effects were revealed for stress (F(3,855) = 4.94, P < 0.01), depression (F(3,855) = 14.22, P < 0.01) and sexual functioning (time effects P values <0.001 for female sexual functioning dimensions and <0.002 for male dimensions), but not for anxiety (F(2,299) = 0.51, P > 0.05). Stress levels lowered after 6 months (P < 0.001) and returned to baseline levels at the 1-year follow-up. Depressive symptomatology significantly increased at 6 weeks (P = 0.023), and again 1 year after (P = 0.001). There were also significant decreases in all female sexual functioning dimensions (desire, satisfaction, arousal, pain, orgasm and lubrication). In men, there were significant variations in orgasm, intercourse satisfaction and erectile function, but not desire and sexual satisfaction. Revealed pregnancy rates were 16% for participants in the EOD group, 30% for the FWM group and 20% for the CG. Pregnancies were not significantly different between arms: EOD vs FWM (odds ratio (OR) 2.32; 95% CI 0.92-5.83); EOD vs CG (OR 0.74; 95% CI 0.30-1.87); and FWM vs CG (OR 1.71; 95% CI 0.70-4.18). LIMITATIONS, REASONS FOR CAUTION: Participants were recruited after transitioning to procreative sex. The study might be prone to bias as almost 30% of our sample fulfilled the chronological criterion for infertility, and other reproductive strategies could have been tried over time before recruitment. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that stress does not arise from feeling pressured on the fertile period and that advice on timing of intercourse might have to be personalized. The increasing levels of depression and sexual dysfunction over a year emphasize the crucial role of preconception care and fertility counseling in promoting psychological and sexual well-being. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Programme) and by national funds (FCT-Portuguese Foundation for Science and Technology) under the projects PTDC/MHC-PSC/4195/2012 and SFRH/BPD/85789/2012. TRIAL REGISTRATION NUMBER: NCT02814006. TRIAL REGISTRATION DATE: 27 June 2016. DATE OF FIRST PATIENT'S ENROLLMENT: 19 July 2016.

Perceived Threat of Infertility and Women's Intention to Anticipate Childbearing: The Mediating Role of Personally Perceived Barriers and Facilitators.

To study the role of perceived threat of infertility, barriers, and facilitators in intention to anticipate childbearing, a cross-sectional study was conducted with 240 women desiring to have children and committed in a heterosexual relationship. Participants answered an online survey between July 2016 and February 2018. Results showed that perceiving infertility as a strong barrier and being willing to use fertility treatment as a facilitator fully mediated the effect of perceived threat on intention to anticipate childbearing. In conclusion, women who perceive themselves at risk of being infertile will consider, to a higher degree, infertility as a strong barrier to achieve their reproductive life plan or will report higher willingness to use fertility treatments, which in turn would increase intentions to anticipate childbearing. Since evidence showed lack of fertility awareness, intervention initiatives should target these mediators.

COMPI Fertility Problem Stress Scales is a brief, valid and reliable tool for assessing stress in patients seeking treatment.

STUDY QUESTION: Are the Copenhagen Multi-Centre Psychosocial Infertility research program Fertility Problem Stress Scales (COMPI-FPSS) a reliable and valid measure across gender and culture? SUMMARY ANSWER: The COMPI-FPSS is a valid and reliable measure, presenting excellent or good fit in the majority of the analyzed countries, and demonstrating full invariance across genders and partial invariance across cultures. WHAT IS KNOWN ALREADY: Cross-cultural and gender validation is needed to consider a measure as standard care within fertility. The present study is the first attempting to establish comparability of fertility-related stress across genders and countries. STUDY DESIGN SIZE, DURATION: Cross-sectional study. First, we tested the structure of the COMPI-FPSS. Then, reliability and validity (convergent and discriminant) were examined for the final model. Finally, measurement invariance both across genders and cultures was tested. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our final sample had 3923 fertility patients (1691 men and 2232 women) recruited in clinical settings from seven different countries: Denmark, China, Croatia, Germany, Greece, Hungary and Sweden. Participants had a mean age of 34 years and the majority (84%) were childless. MAIN RESULTS AND THE ROLE OF CHANCE: Findings confirmed the original three-factor structure of the COMPI-FPSS, although suggesting a shortened measurement model using less items that fitted the data better than the full version model. While data from the Chinese and Croatian subsamples did not fit, all other counties presented good fit (χ2/df ≤ 5.4; comparative fit index ≥ 0.94; root-mean-square error of approximation ≤ 0.07; modified expected cross-validation index ≤ 0.77). In general, reliability, convergent validity, and discriminant validity were observed in all subscales from each country (composite reliability ≥ 0.63; average variance extracted ≥ 0.38; squared correlation ≥ 0.13). Full invariance was established across genders, and partial invariance was demonstrated across countries. LIMITATIONS REASONS FOR CAUTION: Generalizability regarding the validation of the COMPI-FPSS cannot be made regarding infertile individuals not seeking treatment, or non-European patients. This study did not investigate predictive validity, and hence the capability of this instrument in detecting changes in fertility-specific adjustment over time and predicting the psychological impact needs to be established in future research. WIDER IMPLICATIONS OF THE FINDINGS: Besides extending knowledge on the psychometric properties of one of the most used fertility stress questionnaire, this study demonstrates both research and clinical usefulness of the COMPI-FPSS. STUDY FUNDING/COMPETING INTERESTS: This study was supported by European Union Funds (FEDER/COMPETE-Operational Competitiveness Program, and by national funds (FCT-Portuguese Foundation for Science and Technology) under the projects PTDC/MHC-PSC/4195/2012 and SFRH/BPD/85789/2012). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Couples' discontinuation of fertility treatments: a longitudinal study on demographic, biomedical, and psychosocial risk factors.

PURPOSE: This study aims to explore the role of infertility-psychosocial variables on treatment discontinuation after controlling for demographic and biomedical variables in couples seeking reimbursed fertility treatment. METHODS: A prospective study was conducted in 139 couples seeking fertility treatment. Between February 2010 and March 2011, participants completed measures of anxiety (STAI-State), depression (BDI-II), infertility-stress (FPI), and infertility coping strategies (COMPI-CSS). Medical data related to diagnosis, treatment, and discontinuation were collected in December 2013. A multiple logistic regression was performed to identify the predictors of discontinuation. RESULTS: The discontinuation rate was 29.5%. Female education level, engagement in ART procedures, and female causation decreased the likelihood of treatment discontinuation, whereas female age and depression increased the likelihood of discontinuation. Female depression was the strongest predictor in this model. The model correctly identified 75.5% of cases. CONCLUSIONS: Female age and female depression are associated with a higher likelihood of treatment discontinuation in couples seeking treatment. Reproductive health professionals should therefore inform couples about the link between the fertility treatment discontinuation and both female age and female depression. Couples in which female partners present clinically relevant depression should be referred to a mental health professional to prevent premature abandonment of fertility treatments and thus increase success rates.

Use of maggot therapy for treating a diabetic foot ulcer colonized by multidrug resistant bacteria in Brazil.

This study reports the efficacy of maggot therapy in the treatment of diabetic foot ulcer infected with multidrug resistant microorganisms. A 74 year old female patient with diabetes for over 30 years, was treated with maggot therapy using larvae of Chrysomya megacephala. The microbiological samples were collected to evaluate aetiology of the infection. The therapy done for 43 days resulted in a reduction of necrosis and the ulcer's retraction of 0.7 cm [2] in area. Analysis of the bacteriological swabs revealed the presence of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Further studies need to be done to confirm the role of maggot therapy in wound healing using a large sample and a proper study design.

Hemorrhagic colitis associated with Salmonella enterica serotype Infantis infection in a captive western lowland gorilla (Gorilla gorilla gorilla) in Brazil.

BACKGROUND: Enteric diseases are among the most common causes of morbidity and mortality in gorillas, and it is often caused by bacteria. METHODS: A thirteen-year-old captive female western lowland gorilla (Gorilla gorilla gorilla) developed hemorrhagic diarrhea. Despite the treatment, the animal died 7 days after the onset of clinical signs. The animal was submitted to a thorough pathological and microbiological evaluation. RESULTS: Pathologic examination revealed a severe acute hemorrhagic colitis, neutrophilic splenitis, glomerulitis, and interstitial pneumonia. Salmonella enterica serotype Infantis was isolated from a mesenteric lymph node. CONCLUSION: A diagnosis of hemorrhagic colitis associated with Salmonella enterica serotype Infantis was established.

Connecting Clinical Capacity and Intervention Sustainability in Resource-Variable Pediatric Oncology Centers in Latin America.

Clinical capacity for sustainability, or the clinical resources needed to sustain an evidence-based practice, represent proximal determinants that contribute to intervention sustainment. We examine the relationship between clinical capacity for sustainability and sustainment of PEWS, an evidence-based intervention to improve outcomes for pediatric oncology patients in resource-variable hospitals. We conducted a cross-sectional survey among Latin American pediatric oncology centers participating in Proyecto Escala de Valoración de Alerta Temprana (EVAT), an improvement collaborative to implement Pediatric Early Warning Systems (PEWS). Hospitals were eligible if they had completed PEWS implementation. Clinicians were eligible to participate if they were involved in PEWS implementation or used PEWS in clinical work. The Spanish language survey consisted of 56 close and open-ended questions about the respondent, hospital, participants' assessment of clinical capacity to sustain PEWS using the clinical sustainability assessment tool (CSAT), and perceptions about PEWS and its use as an intervention. Results were analyzed using a multi-level modeling approach to examine the relationship between individual, hospital, intervention, and clinical capacity determinants to PEWS sustainment. A total of 797 responses from 37 centers in 13 countries were included in the analysis. Eighty-seven percent of participants reported PEWS sustainment. After controlling for individual, hospital, and intervention factors, clinical capacity was significantly associated with PEWS sustainment (OR 3.27, p < .01). Marginal effects from the final model indicate that an increasing capacity score has a positive influence (11% for every additional CSAT point) of predicting PEWS sustainment. PEWS is a sustainable intervention and clinical capacity to sustain PEWS contributes meaningfully to PEWS sustainment.

"Death is a sensitive topic when you are surrounded by life": Nurses experiences with pregnancy loss.

OBJECTIVE: Although there is increasing evidence on the psychosocial adjustment and experiencing pregnancy loss from the patient's perspective, few studies have investigated the nurses' experience perceptions. This study aimed to understand the experience of nurses involved in pregnancy loss care based on the self-fulfillment model of communication. METHODS: A qualitative approach was developed through semi-structured interviews to 16 nurses working in an Obstetrics and Maternal-Fetal Department of a local hospital. Based on grounded theory approach, data was analyzed with NVivo 12 software. RESULTS: The analysis revealed three major themes and 11 sub-themes: i) stressful work conditions, comprising care management and institutional practices; ii) personal characteristics, including discomfort with loss, communication skills, work experience and empathy; and iii) the patient's journey, containing the partner's ambiguous role, timing, respect for the patient's individuality, viewing the fetus and facilitating grief rituals. CONCLUSION: Nurses daily involved in providing care to patients suffering pregnancy loses have a demanding challenge in trying to assure that patients get the appropriate and better care and ensuring they keep their level of engagement in their profession. Interventions to improve communications skills with patients and with other health professionals are needed to enhance professional realization.

Mapping intentions to adopt fertility protective behaviours: the role of couple congruence and the importance of relationship and fertility awareness.

Several studies worldwide have shown that reproductive-aged people often have inadequate fertility awareness (FA). Since attitudes and health behaviours are influenced by the partner, there is a need for studies exploring the role of these influences on the individuals' adoption of fertility protective behaviours (FPB). This study explores the role of FA and relationship quality on couples' intention to adopt FPB. One hundred and twelve childless couples answered an online questionnaire about reproductive life plan, FA and intentions to adopt FPB. The results showed that couples were moderately congruent on their reproductive life plan. The female partners who reported higher female relationship quality and higher female willingness to undergo fertility treatments were more willing to adopt FPB. The male partners who had heightened FA also reported higher intention to adopt FPB. The influences of male and female FA, relationship quality and congruence on reproductive life plan were neither associated with couples' congruence on the intention to adopt FPB. Although the cross-sectional design restricts our ability to draw causal conclusions, these findings emphasize that future interventions should be targeted at couples and designed according to their expectations and reproductive desires.

Effectiveness of a video-based education on fertility awareness: a randomized controlled trial with partnered women.

Fertility awareness (FA) among young people is low. Fertility awareness interventions have been found to contribute to increase FA in the short-term. The long-term effectiveness of FA interventions on childless and presumed fertile people, committed in a heterosexual relationship and wishing to have children in the near future is not known. In a double-blind parallel randomized controlled trial conducted between 2016 and 2018, 652 childless partnered women were randomized to either watch a 5-min video about fertility (IG: 'Intervention Group') or to not receive any intervention (CG: 'Control Group'). Participants filled out an online questionnaire at the start of the study (and in the IG group immediately before intervention). They then completed the questionnaire after 1 month, 6 months and 1 year. The questionnaire assessed FA and intentions to adopt fertility-protective behaviours. In the IG, FA levels were found to increase at 1 month post-intervention. However, significant interaction effects between group and time were only found for four out of the seven FA variables at the 6-month and 1-year follow-up. No effects were found for: (i) intentions to adopt fertility-protective behaviours; or (ii) desired timing of pregnancy. These results suggest that the fertility video intervention seems to partially increase FA in the long term. Future studies should investigate the effectiveness of different intervention formats with a focus on overcoming high attrition rates.

Estrogen-dependent transcription of the NEL-like 2 (NELL2) gene and its role in protection from cell death.

NELL2 (neural tissue-specific epidermal growth factor-like repeat domain-containing protein) is a secreted glycoprotein that is predominantly expressed in neural tissues. We reported previously that NELL2 mRNA abundance in brain is increased by estrogen (E2) treatment and that NELL2 is involved in the E2-dependent organization of a sexually dimorphic nucleus in the preoptic area. In this study we cloned the mouse NELL2 promoter and found it to contain two half-E2 response elements. Electrophoretic mobility shift assays and promoter assays showed that E2 and its receptors (ERalpha and ERbeta) stimulated NELL2 transcription by binding to the two half-E2 response elements. Hippocampal neuroprogenitor HiB5 cells expressing recombinant NELL2 showed increased cell survival under cell death-inducing conditions. Blockade of endogenous synthesis of NELL2 in HiB5 cells abolished the cell survival effect of E2 and resulted in a decrease in phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). These data suggest that the NELL2 gene is trans-activated by E2 and contributes to mediating the survival promoting effects of E2 via intracellular signaling pathway of ERK.

Direct and indirect effects of perceived social support on women's infertility-related stress.

BACKGROUND: Social support can be a critical component of how a woman adjusts to infertility, yet few studies have investigated its impact on infertility-related coping and stress. We examined relationships between social support contexts and infertility stress domains, and tested if they were mediated by infertility-related coping strategies in a sample of infertile women. METHODS: The Multidimensional Scale of Perceived Social Support, the Copenhagen Multi-centre Psychosocial Infertility coping scales and the Fertility Problem Inventory were completed by 252 women seeking treatment. Structural equation modeling analysis was used to test the hypothesized multiple mediation model. RESULTS: The final model revealed negative effects from perceived partner support to relationship concern (ß = -0.47), sexual concern (ß = -0.20) and rejection of childfree lifestyle through meaning-based coping (ß = -0.04). Perceived friend support had a negative effect on social concern through active-confronting coping (ß = -0.04). Finally, besides a direct negative association with social concern (ß = -0.30), perceived family support was indirectly and negatively related with all infertility stress domains (ß from -0.04 to -0.13) through a positive effect of active-avoidance coping. The model explained between 12 and 66% of the variance of outcomes. CONCLUSIONS: Despite being limited by a convenience sampling and cross-sectional design, results highlight the importance of social support contexts in helping women deal with infertility treatment. Health professionals should explore the quality of social networks and encourage seeking positive support from family and partners. Findings suggest it might prove useful for counselors to use coping skills training interventions, by retraining active-avoidance coping into meaning-based and active-confronting strategies.

Glutaraldehyde-crosslinking chitosan scaffolds reinforced with calcium phosphate spray-dried granules for bone tissue applications.

The clinical demand for bone scaffolds as an alternative strategy for bone grafting has increased exponentially and, up to date, numerous formulations have been proposed to regenerate the bone tissue. However, most of these structures lack at least one of the fundamental/ideal properties of these materials (e.g., mechanical resistance, interconnected porosity, bioactivity, biodegradability, etc.). In this work, we developed innovative composite scaffolds, based on crosslinked chitosan with glutaraldehyde (GA), combined with different atomized calcium phosphates (CaP) granules - hydroxyapatite (HA) or biphasic mixtures of HA and ß - tricalcium phosphate (ß-TCP), with improved biomechanical behavior and enhanced biological response. This innovative combination was designed to improve the scaffolds' functionality, in which GA improved chitosan mechanical strength and stability, whereas CaP granules enhanced the scaffolds' bioactivity and osteoblastic response, further reinforcing the scaffolds' structure. The biological assessment of the composite scaffolds showed that the specimens with 0.2% crosslinking were the ones with the best biological performance. In addition, the inclusion of biphasic granules induced a trend for increase osteogenic activation, as compared to the addition of HA granules. In conclusion, scaffolds produced in the present work, both with HA granules or the biphasic ones, and with low concentrations of GA, have shown adequate properties and enhanced biological performance, being potential candidates for application in bone tissue engineering.

Kinesin superfamily-associated protein 3 is preferentially expressed in glutamatergic neurons and contributes to the excitatory control of female puberty.

It was earlier shown that expression of kinesin superfamily-associated protein 3 (KAP3), involved in the neuronal anterograde, microtubule-dependent transport of membrane organelles, increases in the hypothalamus of female rats during the juvenile phase of sexual development. KAP3 mRNA is abundant in the hypothalamus, suggesting that it might be expressed in broadly disseminated neuronal systems controlling neuroendocrine function. The present study identifies one of these systems and provides evidence for an involvement of KAP3 in the excitatory control of female puberty. In situ hybridization and immunohistofluorescence studies revealed that the KAP3 gene is expressed in glutamatergic neurons but not in GABAergic or GnRH neurons. Hypothalamic KAP3 mRNA levels increase during the juvenile period of female prepubertal development, remaining elevated throughout puberty. These changes appear to be, at least in part, estradiol dependent because ovariectomy decreases and estradiol increases KAP3 mRNA abundance. Lowering hypothalamic KAP3 protein levels via intraventricular administration of an antisense oligodeoxynucleotide resulted in reduced release of both glutamate and GnRH from the median eminence and delayed the onset of puberty. The median eminence content of vesicular glutamate transporter 2, a glutamate neuron-selective synaptic protein, and synaptophysin, a synaptic vesicle marker, were also reduced, suggesting that the loss of KAP3 diminishes the anterograde transport of these proteins. Altogether, these results support the view that decreased KAP3 synthesis diminishes GnRH output and delays female sexual development by compromising hypothalamic release of glutamate.

NELL2, a neuron-specific EGF-like protein, is selectively expressed in glutamatergic neurons and contributes to the glutamatergic control of GnRH neurons at puberty.

NELL2, a protein containing EGF-like repeats, is almost exclusively expressed in the nervous system. In the mammalian brain, NELL2 expression is mostly neuronal. NELL2 was previously found to be a secreted protein that functions during embryonic development as a neuronal differentiation and survival factor. We now show that the Nell2 gene is selectively expressed in the two major subtypes of glutamatergic neurons described in the postnatal brain: those containing the vesicular glutamate transporter 1 and those expressing vesicular glutamate transporter 2. No Nell2 mRNA is detected in GABAergic neurons. Likewise, GnRH neurons are devoid of NELL2. During prepubertal development of the female rat, Nell2 mRNA abundance increases selectively in the medial basal hypothalamus, reaching maximal values at the end of the juvenile period, to decline at the time of puberty to intermediate levels. Similar, but less pronounced changes are observed in the preoptic area, but they are absent in the cerebral cortex. A well-established glutamatergic function in the neuroendocrine brain is to enhance release of GnRH, the neurohormone controlling sexual development and the time of puberty. In vivo disruption of NELL2 synthesis via intraventricular administration of antisense oligodeoxynucleotides reduced GnRH release from the medial basal hypothalamus and delayed the initiation of female puberty. These results identify NELL2 as a new component of glutamatergic neurons and provide evidence for its physiological involvement in a major, glutamate-dependent, process of neuroendocrine regulation.

Multicentric squamous cell carcinona in a paca (Agouti paca) resembling Bowen's disease.

An 8-yr-old female paca (Agouti paca) was admitted at the Veterinary Hospital of the Belo Horizonte Zoo (Brazil) with an ulcerated cutaneous nodule of approximately 1.5 cm in diameter in the left ear. One week later, other cutaneous nodules were detected in various body locations. The animal died during a surgical procedure to remove the tumors. All cutaneous nodules were histologically similar with features of squamous cell carcinoma. Considering the predominant in situ nature of the lesion as well as its multicentric localization, the disease reported here closely resembles Bowen's disease, which has been described in humans and which has been identified as a rare neoplastic disease of cats, with one single report in a dog. This is the first report of a neoplastic disease in Agouti

What do people know about fertility? A systematic review on fertility awareness and its associated factors.

INTRODUCTION: Recent evidence indicates that reproductive-age people have inadequate fertility awareness (FA) concerning fertility, infertility risk factors, and consequences of delaying childbearing. However, no study has tried to summarize these studies and to clarify the variables associated with FA, namely the role of gender, age, education, and reproductive status on FA. METHODS: A literature search up to February 2017 was conducted using the EBSCO, Web of Science, Scielo, and Scopus electronic databases with combinations of keywords and MeSH terms (e.g. 'awareness' OR 'health knowledge, attitudes, practice' AND 'fertility'; 'fertile period'; 'assisted reprod*'). RESULTS: Seventy-one articles met the eligibility criteria and were included. The main results showed that participants report low-to-moderate FA. Higher levels of FA were shown by women, highly educated individuals, people who reported difficulties with conceiving, and those who had planned their pregnancies. Having or desiring to have children was not related to FA level. An inconsistent association between study participant age and FA was observed, with some studies indicating that older participants had higher FA, but others found an opposite result or did not find any association. CONCLUSION: The current findings suggest that interventions to increase FA are warranted, especially those targeting men, people with low education, and in family planning settings. Interventions and campaigns should be customized to meet individuals' needs regarding FA. Because of the high heterogeneity regarding the assessment of FA, these conclusions must be interpreted with caution.

Hypothalamic tumor necrosis factor-alpha converting enzyme mediates excitatory amino acid-dependent neuron-to-glia signaling in the neuroendocrine brain.

Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor alpha (TGFalpha) results in production of prostaglandin E2, which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-to-neuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs). Because the metalloproteinase tumor necrosis factor alpha converting enzyme (TACE) releases TGFalpha from its transmembrane precursor before TGFalpha can bind to erbB1 receptors, we sought to determine whether TACE is required for excitatory amino acids to activate the TGFalpha-erbB1 signaling module in hypothalamic astrocytes, and thus facilitate the advent of puberty. Coactivation of astrocytic AMPARs and mGluRs caused extracellular Ca2+ influx, a Ca2+/protein kinase C-dependent increase in TACE-like activity, and enhanced release of TGFalpha. Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence (ME), and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. ME explants respond to stimulation of AMPARs and mGluRs with LHRH release, and this response is prevented by blocking TACE activity. In vivo inhibition of TACE activity targeted to the ME delayed the age at first ovulation, indicating that ME-specific changes in TACE activity are required for the normal timing of puberty. These results suggest that TACE is a component of the neuron-to-glia signaling process used by glutamatergic neurons to control female sexual development.

Development of hydroxyapatite nanoparticles loaded with folic acid to induce osteoblastic differentiation.

Recently it has been shown that folic acid can have an important role in bone regeneration. For this reason, combining a classic bone regeneration system as, hydroxyapatite, loaded with folic acid, may be an important issue to be developed. To address this issue, hydroxyapatite nanoparticles loaded with folic acid were designed as an effective bone regenerative system, to induce osteoblast differentiation and improve the bone regeneration. HapNP were prepared by a hydrothermal method that used citric acid as a tailoring agent of particles morphology and, simultaneously, had the particularly to let carboxylic pendant groups in the particle surface, which provided a platform for the immobilization of folic acid (FA), producing HapNP-FA. A comparative study among hydroxyapatite nanoparticles loaded and unloaded with folic acid in presence of human mesenchymal stem cells was performed. The results demonstrate, that nanoparticles were able to be internalized by human mesenchymal stem cells. In addition, cell proliferation and viability were not affected in a wide concentration range. Both particles induced the expression of Runx2 and the expression and activity of alkaline phosphatase. However, HapNP-FA caused a significantly higher overexpression of Runx2. The osteoblastic differentiation confirms the potential applicability of HapNP-FA in the local bone regeneration.