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Polycystic ovary syndrome (PCOS) is one of the most prevalent female endocrine reproductive disorders, affecting between 4 to 18% of the women in their reproductive age. It is generally characterized by several clinical aspects, among which anovulation, inflammation and infertility. Moreover, PCOS has several health implications, including increased metabolic, reproductive, and psychological risks. Previously, metformin and to some extent thiazolidinediones were considered as drug of choice for PCOS management, but they had several side-effects, and controversial results were obtained about their efficiency, especially in non-insulin-resistant non-obese patients. Thus, alternative treatment options are now being studied for PCOS, including different natural molecules and complementary medicines (CM) for the improvement of their health, wellbeing and fertility. Recently, treatment of PCOS patients with different natural molecules, coming from nutritional supplements and herbal medicines, has attained satisfactory results with the absence of any side effects. In this review, four natural molecules, curcumin, vitamin D, inositol and CoQ10 are discussed for their therapeutic ability. These molecules proved to decrease insulin sensitivity and inflammation, to improve the restoration of ovarian function, and they could restore hormonal balance and regulate the menstrual cycle, all of which are the main features and major concerns for women suffering from PCOS., Journal of Preventive Medicine and Hygiene, Vol. 63 No. 2S3 (2022): The secret of Mediterranean food: How “omic” sciences, biochemistry and human physiology can be applied to exploit the secrets of Mediterranean foods

The gut microbiota (GM) is a complex and dynamic population of microorganisms living in the human gastrointestinal tract that play an important role in human health and diseases. Recent evidence suggests a strong direct or indirect correlation between GM and both male and female fertility: on the one hand, GM is involved in the regulation of sex hormone levels and in the preservation of the blood–testis barrier integrity; on the other hand, a dysbiotic GM is linked to the onset of pro-inflammatory conditions such as endometriosis or PCOS, which are often associated with infertility. Exposure to endocrine-disrupting chemicals (EDCs) is one of the main causes of GM dysbiosis, with important consequences to the host health and potential transgenerational effects. This perspective article aims to show that the negative effects of EDCs on reproduction are in part due to a dysbiotic GM. We will highlight (i) the link between GM and male and female fertility; (ii) the mechanisms of interaction between EDCs and GM; and (iii) the importance of the maternal–fetal GM axis for offspring growth and development.

Aims Gestational diabetes mellitus (GDM) can lead to short- and long-term complications for the child. Epigenetic alterations could contribute to explaining the metabolic disturbances associated with foetal programming. Although the role of the FTO gene remains unclear, it affects metabolic phenotypes probably mediated by epigenetic mechanisms. The aim of this study was to assess whether placental DNA epigenetic modifications at FTO promoter-associated cysteine–phosphate–guanine (CpG) sites are correlated with GDM. A secondary aim was to evaluate the association between the placental FTO DNA methylation and the maternal metabolic traits in women with and without GDM. Methods Socio-demographic characteristics, clinical parameters at the third trimester of pregnancy, Mediterranean diet adherence, and physical activity were assessed in 33 GDM women and 27 controls. Clinical information about the newborns was registered at birth. The FTO rs9939609 (T > A) was genotyped. Results No association between FTO DNA methylation and GDM was found. DNA methylation on the maternal side at the CpG1 was associated with maternal smoking in GDM (p = 0.034), and DNA methylation at the CpG3 was correlated with smoking or former smoking in controls (p = 0.023). A higher level of TGs was correlated with higher foetal placental DNA methylation at the CpG2 (p = 0.036) in GDM. An inverse association between HDL-C and maternal placental DNA methylation at the CpG3 in controls (p = 0.045) was found. An association between FTO rs9939609 and neonatal birthweight (p = 0.033) was detected. Conclusions In the awareness that the obesity pathophysiology is complex, the study adds a piece to this intricate mosaic.

There is growing interest in the potential role of different stereoisomers of inositol or their combination as well as probiotics supplementation in healthy glucose metabolism during pregnancy and in promoting offspring health. The aim of this review is to clarify the effects of several inositol and probiotics-based supplements in the prevention and treatment of gestational diabetes (GDM). Moreover, we will discuss the epigenetic aspects and their short- and long-term effects in response to probiotic intervention as well as the possible implications of these findings in guiding appropriate supplementation regimens in pregnancy.

Diabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA’s loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism.

SHOX haploinsufficiency causes 70–90% of Léri-Weill dyschondrosteosis (LWD) and 2–10% of idiopathic short stature (ISS). Deletions removing the entire gene or enhancers and point mutations in the coding region represent a well-established cause of haploinsufficiency. During diagnostic genetic testing on ISS/LWD patients, in addition to classic SHOX defects, five 5′UTR variants (c.-58G > T, c.-55C > T, c.-51G > A, c.-19G > A, and c.-9del), were detected whose pathogenetic role was unclear and were thus classified as VUS (Variants of Uncertain Significance). The purpose of the present study was to investigate the role of these noncoding variations in SHOX haploinsufficiency. The variants were tested for their ability to interfere with correct gene expression of a regulated reporter gene (luciferase assay). The negative effect on the mRNA splicing predicted in silico for c.-19G > A was assayed in vitro through a minigene splicing assay. The luciferase assay showed that c.-51G > A, c.-19G > A, and c.-9del significantly reduce luciferase activity by 60, 35, and 40% at the homozygous state. Quantification of the luciferase mRNA showed that c.-51G > A and c.-9del might interfere with the correct SHOX expression mainly at the post-transcriptional level. The exon trapping assay demonstrated that c.-19G > A determines the creation of a new branch site causing an aberrant mRNA splicing. In conclusion, this study allowed us to reclassify two of the 5′UTR variants identified during SHOX diagnostic screening as likely pathogenic, one remains as a VUS, and two as likely benign variants. This analysis for the first time expands the spectrum of the genetic causes of SHOX haploinsufficiency to noncoding variations in the 5′UTR.

Female reproduction focuses mainly on achieving fully grown follicles and competent oocytes to be successfully fertilized, as well as on nourishing the developing offspring once pregnancy occurs. Current evidence demonstrates that obesity and/or high-fat diet regimes can perturbate these processes, leading to female infertility and transgenerational disorders. Since the mechanisms and reproductive processes involved are not yet fully clarified, the present review is designed as a systematic and comparative survey of the available literature. The available data demonstrate the adverse influences of obesity on diverse reproductive processes, such as folliculogenesis, oogenesis, and embryo development/implant. The negative reproductive impact may be attributed to a direct action on reproductive somatic and germinal compartments and/or to an indirect influence mediated by the endocrine, metabolic, and immune axis control systems. Overall, the present review highlights the fragmentation of the current information limiting the comprehension of the reproductive impact of a high-fat diet. Based on the incidence and prevalence of obesity in the Western countries, this topic becomes a research challenge to increase self-awareness of dietary reproductive risk to propose solid and rigorous preventive dietary regimes, as well as to develop targeted pharmacological interventions.

Dietary factors can regulate epigenetic processes during life, modulating the intracellular pools of metabolites necessary for epigenetic reactions and regulating the activity of epigenetic enzymes. Their effects are strong during the prenatal life, when epigenetic patterns are written, allowing organogenesis. However, interactions between diet and the epigenome continue throughout life and likely contribute to the onset and progression of various complex diseases. Here, we review the contribution of dietary factors to the epigenetic changes observed in complex diseases and suggest future steps to better address this issue, focusing on neurobehavioral, neuropsychiatric and neurodegenerative disorders, cardiovascular diseases, obesity and Type 2 diabetes, cancer and inflammatory skin diseases.

Purpose Axillary management remains unclear when sentinel lymph node (SLN) results are positive in cN0 patients with breast cancer (BC). The trial ACOSOG Z0011 represented a revolution with axillary lymph node dissection (ALND) omission in SLN+ patients, despite critiques regarding non-uniformity of radiation fields. We conducted an observational study (LISEN) where whole breast radiotherapy (WBRT) was planned with tangential fields without nodal irradiation in patients eligible for the Z0011 trial. Methods Inclusion criteria were female patients with histologically proven BC, cT1-2cN0, planned conservative surgery, no neoadjuvant therapy. Patients were stratified into two groups: micrometastatic (pN1mic, group 1) and macrometastatic (pN1a, group 2) lymph nodes. Tangential field WBRT was mandatory. Clinical outcomes were analysed, measured from surgery until the first event. Results In all, 199 patients underwent conservative surgery and SLN biopsy; 133 patients meeting criteria were analysed: 41 patients (30.8%) pN1mic and 92 (69.2%) pN1a. The 5‑year disease-free survival (DFS) was 95.0% (85.9–100%) in group 1 and 93.0% (86.3–100.0%) in group 2 (p = 0.78). Overall survival (OS) was 100% (100–100%) in group 1 and 97.4% (92.4–100%) in group 2 (p = 0.74). For the whole cohort DFS and OS were 93.6% (88.2–99.4%) and 96.9% (91.5–100.0%), respectively. For groups 1 and 2, the 5‑year outcomes were 5.0% (0.0–14.4%) and 2.3% (0.0–6.1%) for local recurrence (p = 0.51), and 6.2% (0.0–17.4%) and 7.0% (0.0–13.7%) for distant metastasis (p = 0.61), respectively. In group 1, regional recurrence (RR) and local regional recurrence (LRR) were 5.0% (0.0–14.1%; p = 0.13). In group 2, RR and LRR were 0.0% (0.0–0.0%). Conclusion Our results showed good regional control in patients who met the Z0011 trial criteria. WBRT, without nodal surgery or RT, avoiding axillary morbidity, seems to be a good choice.

Background: The real impact of genetic factors on personality is still unknown, even if in literature about 50% of variance in personality traits are considered genetically determined. The determination of the genetic variance in personality traits could promote psychological well-being and the prevention of psychopathologies, because there are many experimental evidences showing that mental illness is associated to personality. Numerous studies have showed that Catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF) and serotonin transporter (5-HTT) are genes whose variants are associated with personality traits. This aim of this study is the investigation of the association between personality traits and 5-HTTLPR/rs255315-HTT promoter variant, COMT Val158Met and BDNF Val66Met gene polymorphisms. Methods: The sample was composed by 132 healthy female students. Genomic DNA was extracted from buccal swab, while personality was assessed with Cloninger's Temperament and Character Inventory-Revised (TCI-R). Linear discriminant analysis was used to analyze how personality characteristics can differentiate individuals in relation to their genetic polymorphisms. Results: Data showed that the temperament trait Reward Dependence discriminated individuals with different BDNF variants; Novelty Seeking and Harm Avoidance discriminated individuals with different 5HTTLPR variants; Persistence discriminated individuals with different COMT variants. Conclusions: Since these traits are connected to psychological diseases as depression, social anxiety, anorexia and obsessive-compulsive disorders of personality, the study of their genetic component can be used as intermediary issue to better define the connection between genes and predisposition toward maladaptive behavior and mental illness.

Cyclophosphamide (CPM), an agent widely used in breast cancer therapy, has strong gonadotoxic effects. Female reproductive potential after therapy relies on ovulated oocytes deriving from primordial follicles surviving CPM toxic insult. In this study, we investigated in the mouse model whether pre-conceptional maternal exposure to CPM has epigenetic effects on offspring oocytes and if they are inherited. Adult female mice mated following CPM exposure, generated an offspring (F1) with delayed growth, normal fertility and altered methylation of three imprinted genes (H19, Igf2r and Peg3) in their oocytes. These alterations were present in oocytes generated by F2 mice. Pre-conceptional maternal exposure to fertoprotective agents AS101 and crocetin prior to CPM was not able to fully counteract alterations in offspring oocyte imprinting. For the first time, current study evidences that pre-conceptional CPM maternal exposure can affect the competence of offspring’s oocytes and warns on possible long-term effects on the health of next generations.

Gestational Diabetes Mellitus (GDM) is the most common metabolic condition during pregnancy and may result in short- and long-term complications for both mother and offspring. The complexity of phenotypic outcomes seems influenced by genetic susceptibility, nutrient-gene interactions and lifestyle interacting with clinical factors. There is strong evidence that not only the adverse genetic background but also the epigenetic modifications in response to nutritional and environmental factors could influence the maternal hyperglycemia in pregnancy and the foetal metabolic programming. In this view, the correlation between epigenetic modifications and their transgenerational effects represents a very interesting field of study. The present review gives insight into the role of gene variants and their interactions with nutrients in GDM. In addition, we provide an overview of the epigenetic changes and their role in the maternal-foetal transmission of chronic diseases. Overall, the knowledge of epigenetic modifications induced by an adverse intrauterine and perinatal environment could shed light on the potential pathophysiological mechanisms of long-term disease development in the offspring and provide useful tools for their prevention.

Worldwide, infertility affects between 10 and 15% of reproductive-aged couples. Female infertility represents an increasing health issue, principally in developing countries, as the current inclinations of delaying pregnancy beyond 35 years of age significantly decrease fertility rates. Female infertility, commonly imputable to ovulation disorders, can be influenced by several factors, including congenital malformations, hormonal dysfunction, and individual lifestyle choices, such as smoking cigarettes, stress, drug use and physical activity. Moreover, diet-related elements play an important role in the regulation of ovulation. Modern types of diet that encourage a high fat intake exert a particularly negative effect on ovulation, affecting the safety of gametes and the implantation of a healthy embryo. Identifying and understanding the cellular and molecular mechanisms responsible for diet-associated infertility might help clarify the confounding multifaceted elements of infertility and uncover novel, potentially curative treatments. In this view, this systematic revision of literature will summarize the current body of knowledge of the potential effect of high-fat diet (HFD) exposure on oocyte and follicular quality and consequent female reproductive function, with particular reference to molecular mechanisms and pathways. Inflammation, oxidative stress, gene expression and epigenetics represent the main mechanisms associated with mammal folliculogenesis and oogenesis.

The aim of the current study was to investigate if and to what extent depression and emotional regulation strategies (namely, cognitive reappraisal and expressive suppression) might lead to parenting stress in a sample of mothers with cancer and in a sample of healthy mothers. A sample of mothers with cancer (clinical group; n = 64) and a sample of healthy mothers (control group; n = 80) were administered self-report questionnaires investigating parenting stress (the parenting stress index), depressive symptoms (the Zung depression self-rating scale) and emotion regulation strategies (the emotion regulation questionnaire). Depressive levels represented the most significant predictor of maternal parenting stress in both groups (p

Background The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. Methods We used next‐generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Results Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants—p.(Leu590His) and p.(Gly106Asp)—indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema., Background: The PROX1 gene is a specific marker expressed in a subpopulation of endothelial cells that by budding and sprouting give rise to the murine lymphatic system. It plays a critical role in embryo development and functions as a key regulatory protein in neurogenesis and the development of many organs, including the lymphatic system. Methods and Results: We used NGS to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then tested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Two of 235 probands were found to carry rare missense heterozygous variants in PROX1. In silico analysis suggested that the overall protein structure was somehow altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions: Our results suggest that PROX1 is a possible candidate for predisposition to lymphedema.

Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy, with increasing prevalence worldwide and still unclear pathogenic mechanisms. Extracellular vesicles (EVs) are emerging as potential biomarkers of disease-specific pathways in metabolic disorders, but their potential role in GDM is not fully understood. Therefore, the main aim of this study was to evaluate the link between EVs and hyperglycaemia during pregnancy. We assessed 50 GDM women and 50 controls at the third trimester of pregnancy in whom we collected demographic characteristics and clinical and anthropometric parameters. In addition, the circulating total EVs (tEVs) and their subpopulations were assessed using flow cytometry. The levels of tEVs and EVs subtypes, expressed as median and interquartile range, were not significantly different between two groups; however, adipocyte-derived EVs (aEVs) concentration, expressed as percentage, was higher in controls than in GDM women (p = 0.045). In addition, a significant correlation was observed between aEVs (%) and third trimester total cholesterol (p = 0.022) within the GDM group. Furthermore, a significant correlation between endothelial-derived EVs (eEVs) and platelet-derived EVs (pEVs) within both groups was found, as well as a significant relation between aEVs and pEVs. These data, although preliminary, represent the starting point for further studies to determine the role of circulating EVs in GDM.

Aim Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy and it can be considered a silent risk associated to T2DM and CVD later in life. The aim of this study was to investigate the association of clinical parameters with nine single nucleotide polymorphisms (SNPs) involved with nutrients and metabolism in women with or without GDM in order to identify potential routine clinical markers for early prevention. Methods Nine gene variants associated with nutrients and metabolism, namely PPARG2 rs1801282 (C > G); PPARGC1A rs8192678 (C > T); TCF7L2 rs7903146 (C > T); LDLR rs2228671 (C > T); MTHFR rs1801133 (C > T); APOA5 rs662799 (T > C); GCKR rs1260326 (C > T); FTO rs9939609 (T > A); MC4R rs17782313 (T > C) were genotyped in 104 GDM cases and 124 controls using High Resolution Melting (HRM) analysis. Results The genetic variant rs7903146 (C > T) in TCF7L2 gene showed a strong association with GDM risk (OR: 2.56; 95% CI: [1.24–5.29]). Moreover, a significant correlation was observed between lipid parameters and polymorphisms in other genes, namely PPARG2 [p = 0,03], APOA5 [p = 0,02], MC4R [p = 0,03], LDLR [p = 0,04] and FTO [p = 0,03]. In addition, rs17782313 variant, mapped close to MC4R gene, was associated to BMI in pre-pregnancy [p = 0,02] and at the end of pregnancy [p = 0,03] in GDM group. Conclusion In our study, we found significant associations between routine clinical parameters and some gene variants connected with nutrients and metabolism in women with GDM. These results can provide useful information to develop effective tools and possible personalized intervention strategies in a timely manner.

The female reproductive system represents a sensitive target of the harmful effects of cigarette smoke, with folliculogenesis as one of the ovarian processes most affected by this exposure. The aim of this study was to analyze the impact of tobacco smoking on expression of oxidative stress-related genes in cumulus cells (CCs) from smoking and non-smoking women undergoing IVF techniques. Real time PCR technology was used to analyze the gene expression profile of 88 oxidative stress genes enclosed in a 96-well plate array. Statistical significance was assessed by one-way ANOVA. The biological functions and networks/pathways of modulated genes were evidenced by ingenuity pathway analysis software. Promoter methylation analysis was performed by pyrosequencing. Our results showed a down-regulation of 24 genes and an up-regulation of 2 genes (IL6 and SOD2, respectively) involved in defense against oxidative damage, cell cycle regulation, as well as inflammation in CCs from smoking women. IL-6 lower promoter methylation was found in CCs of the smokers group. In conclusion, the disclosed overall downregulation suggests an oxidant-antioxidant imbalance in CCs triggered by cigarette smoking exposure. This evidence adds a piece to the puzzle of the molecular basis of female reproduction and could help underlay the importance of antioxidant treatments for smoking women undergoing IVF protocols.

Cannabinoid receptor 1 gene (CNR1) variants have been related to affective information processing and, in particular, to stress release. Here, we aimed to examine whether the endocannabinoid system via CNR1 signaling modulates affective working memory, the memory system that transiently maintains and manipulates emotionally charged material. We focused on rs2180619 (A > G) polymorphism and examined genotype data collected from 231 healthy females. Analyses showed how a general positivity bias in working memory (i.e., better memory for positive words) emerged as task strings lengthened only in carriers of the major allele (AA/AG). Differently, GG carriers showed better memory for affective items in general (i.e., positive and negative words). These findings are some of the first to directly highlight the role of variant on promoter of the CNR1 gene in affective working memory and to evidence a differentiation among CNR1 genotypes in terms of larger difficulties in disengaging from negative stimuli in GG carriers.

Objective To investigate the association between male factor infertility and openness to discussing assisted reproductive technology (ART) treatment with levels of depression among men undergoing infertility treatment. Design Cross-sectional. Setting Not applicable. Patient(s) Three hundred forty participants (170 men and their partners) undergoing ART treatments. Intervention(s) Administration of a set of questionnaires. Main Outcome Measure(s) Depressive symptoms were detected by means of the Zung Depression Self-Rating Scale. Participants' willingness to share their infertility treatment experience with other people was assessed by means of self-report questionnaires. Result(s) In this study, 51.8% of males chose not to discuss their ART treatments with people other than their partner. In addition, the decision to discuss or not discuss the ART treatments with others was significantly associated with men's depressive symptoms. Male factor infertility was significantly associated with depression when considered together with the decision not to discuss ART treatments with others. A general disposition characterized by a lack of openness with others seemed to be a significant predictor of depression. Conclusion(s) There is a need for routine fertility care to pay greater attention to men's emotional needs. Before commencing reproductive treatment, male patients may benefit from undergoing routine screening for variables (i.e., male factor infertility and openness to others about ART) that may affect their risk of depression.

Evidence from family and twin studies points to a genetic contribution to the etiology of eating disorders (EDs), confirmed by the association of several single nucleotide polymorphisms (SNPs) with this group of disorders. Previous reports have suggested that the serotonin receptor (5-HT2AR) and brain-derived neurotrophic factor (BDNF) genes could be both involved in EDs susceptibility. In order to provide further evidence about such association, we focused our attention on two SNPs located in these genes carrying out a genetic association study on a large Italian cohort composed of 556 ED patients and 355 controls (CTRs). Obtained results confirm the presence of an association between 5-HT2AR and BDNF genes and the susceptibility to EDs.

Many studies have found that memory for affective material is better than memory for neutral information and memory for positive material compared to negative material is better in older adults. Behavioral, neurophysiological as well as single polymorphism differences have been advanced to account for these effects. Here, we aimed to examine whether the combination of two polymorphisms (ADRA2B and CB1) in older adults influences active maintenance and manipulation of emotional information in aging working memory. We examined genotype data from 207 older adults (56 double deletion carriers, 116 single deletion carriers and 35 no deletion carriers) who performed a verbal operation span-like task with positive, negative and neutral words. We found that subjects carrying both ADRA2B and CB1 variants generally remembered a higher number of words. In addition, double carriers showed positivity effects while single carriers showed more general emotional enhancement effects, especially as strings lengthened. These findings are amongst the first to suggest a haplotype account of positivity effects in older adults’ memory.

The primary aim of the present study was to conduct a systematic review of short-, intermediate- and long-term psychological effects, such as anxiety, depression and distress, on individuals undergoing genetic testing to determine BRCA1 and BRCA2 gene mutation. The different instruments used for the measurement of each construct were reported. In addition, risk and protective factors associated with psychological outcomes of genetic tests were explored. Bibliographic databases were searched for studies published over the period 1998–2018. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, 21 articles were selected for the current review. Overall, the collected data revealed rather diverse results, although most studies reported higher levels of distress, anxiety and depression in carriers, as compared to non-carriers. The two genders were not equally represented, with men constituting only 6% of the sample. Risk factors and protective factors that may influence psychological outcomes and adjustment to genetic tests are highlighted and discussed in this review. The increased risk of developing cancer associated with positive genetic testing results may be experienced as traumatic by many patients, although not all individuals with positive genetic testing results will experience increased distress. Hence, future studies should consider specific risk factors in order to select those who are more likely to be in need of psychological support. Finally, it is necessary to increase the number of male samples to better understand the male experience related to genetic testing outcomes.

A successful embryo implantation depends on the synchronization between a competent blastocyst and a receptive endometrium. Recently, potential modulators of endometrial receptivity (OVGP1, MRAP2, ZCCHC12, and HAP1) have been reported likely with a functional role during embryo implantation. The aim of this study was to evaluate the gene expression of these genes in the endometrium of infertile women. Eighteen endometrial biopsies, during secretory lutheal phase, were recruited from women with unexplained infertility and women who cannot conceive due to their partners' fertility problems. qRT-PCR was carried out to evaluate MRAP2, OVGP1, ZCCHC12 and HAP1 gene expression. MRAP2 expression was also detected by western blot and it was localized by immunohistochemistry. Morphological analysis was performed by light microscopy. MRAP2 was significantly up-regulated in study vs. control group. Western blot analysis confirmed the observed MRAP2 up-expression. MRAP2 resulted mainly localized in the epithelial cells of uterine glands. Morphological analysis displayed that the epithelium of the uterine glands undergo hypertrophy in women with unexplained infertility in respect to women with male infertility factor. MRAP2 could be considered a mediator of endometrial receptivity likely acting on endometrial stability by binding to MCRs and PKR1.

In recent years, increasing interest has been devoted to the susceptibility gene polymorphisms in type 1 diabetes (T1D) as well as in other autoimmune diseases. Among these, a nucleotide polymorphism of the gene encoding for the protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been associated with T1D in several studies. The aim of this study is to define the frequency of the C1858T polymorphism in the PTPN22 gene in a cohort of 113 Caucasian patients (58 males and 55 females) with T1D, and to assess a possible correlation with a group of clinically relevant variables: age at onset, gender, diabetes-related autoantibodies, residual β-cell function and daily insulin requirement (IR) 6 months after diagnosis. Using a PCR-RFLP approach, we evidenced a 17.7% frequency of the PTPN22 C1858T polymorphism in diabetic patients, higher than the frequency showed in the general population. A statistically significant correlation between this polymorphism and higher levels of C-peptide at diagnosis and lower IR at 6 months from diagnosis was observed (P=0.001 and P=0.04). Moreover, 1858T variant carriers were more frequently positive for glutamic acid decarboxylase (GAD) autoantibodies at diagnosis than wild-type subjects (P=0.19). On the other hand, no significant difference regarding age at onset, gender distribution, insulinoma-associated 2 molecule (IA2) and islet cell antibodies (ICA) positivity was found. These findings, if adequately confirmed in the future and extended to larger samples, may characterize a subset of T1D patients with a defined genetic pattern, who may be eligible for trials aimed to preserve residual β-cell function in the coming years.

BACKGROUND AND OBJECTIVE: The aim of the study was to determine optical coherence tomography angiography (OCTA) findings and to identify mutations in the RS1 gene in a three-generation family with X-linked juvenile retinoschisis (XLRS). PATIENTS AND METHODS: Clinical and genetic assessments were performed in 12 family members. OCTA was performed at baseline (12 members including cases and carriers) and after acetazolamide administration (three cases). Twenty healthy subjects (20 eyes, controls) were chosen for comparison. Molecular genetic analysis of the RS1 gene was performed in all family members. RESULTS: Deep capillary plexus density was reduced in cases compared with controls ( P < .01) and was negatively related with retinal thickness ( P < .05). After treatment, retinal thickness decreased ( P < .05) and deep capillary plexus density increased ( P < .05) in cases. In three cases and in four carriers, p.Arg197 His mutation was found. CONCLUSION: OCTA shows reduced macular deep vessel density in patients with XLRS probably related to vessel displacement and disruption due to schitic cysts. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:e20–e31.]

Gestational diabetes mellitus (GDM) can be considered a silent risk for out-of-pregnancy diabetes mellitus (DM) and cardiovascular disease (CVD) later in life. We aimed to assess the predictive role of 3rd trimester lipid profile during pregnancy for the susceptibility to markers of subclinical atherosclerosis (CVD susceptibility) at 3 years in a cohort of women with history of GDM. A secondary aim is to evaluate the usefulness of novel nutrigenetic markers, in addition to traditional parameters, for predicting early subclinical atherosclerosis in such women in order to plan adequate early prevention interventions. We assessed 28 consecutive GDM women in whom we collected socio-demographic characteristics and clinical and anthropometric parameters at the 3rd trimester of pregnancy. In a single blood sample, from each patient, we assessed 9 single nucleotide polymorphisms (SNPs) from 9 genes related to nutrients and metabolism, which were genotyped by High Resolution Melting analysis. All women then attended a 3-year-postpartum follow-up and on that occasion performed an oral glucose tolerance test (OGTT, with 75 g oral glucose), the measurement of carotid artery intima-media thickness (cIMT), and analyses of metabolic parameters. In addition, we evaluated the physical activity level and the adherence to Mediterranean diet (MedDiet) using the International Physical Activity Questionnaire (IPAQ-short version) and PREDIMED questionnaires. We found an association between 3rd trimester triglycerides and cIMT (p=0.014). We also found significant associations between the APOA5 CC genotype and cIMT after adjustments for age and body mass index (p=0.045) and between the interaction CC APOA5/CC LDLR and cIMT (p=0.010). At the follow-up, the cohort also featured a mean BMI in the overweight range and a high mean waist circumference. We found no difference in the MedDiet adherence, physical activity, and smoking but an inverse correlation between the PREDIMED and the IPAQ scores with the IMT. In conclusion, this preliminary study provides insight into the predictive role of lipid profile during pregnancy and of some genetic variants on cIMT taken as a parameter of subclinical CVD susceptibility in GDM.

The field of regenerative medicine is moving toward clinical practice in veterinary science. In this context, placenta-derived stem cells isolated from domestic animals have covered a dual role, acting both as therapies for patients and as a valuable cell source for translational models. The biological properties of placenta-derived cells, comparable among mammals, make them attractive candidates for therapeutic approaches. In particular, stemness features, low immunogenicity, immunomodulatory activity, multilineage plasticity, and their successful capacity for long-term engraftment in different host tissues after autotransplantation, allo-transplantation, or xenotransplantation have been demonstrated. Their beneficial regenerative effects in domestic animals have been proven using preclinical studies as well as clinical trials starting to define the mechanisms involved. This is, in particular, for amniotic-derived cells that have been thoroughly studied to date. The regenerative role arises from a mutual tissue-specific cell differentiation and from the paracrine secretion of bioactive molecules that ultimately drive crucial repair processes in host tissues (e.g., anti-inflammatory, antifibrotic, angiogenic, and neurogenic factors). The knowledge acquired so far on the mechanisms of placenta-derived stem cells in animal models represent the proof of concept of their successful use in some therapeutic treatments such as for musculoskeletal disorders. In the next future, legislation in veterinary regenerative medicine will be a key element in order to certify those placenta-derived cell-based protocols that have already demonstrated their safety and efficacy using rigorous approaches and to improve the degree of standardization of cell-based treatments among veterinary clinicians.

Multiple Sclerosis (MS) is an autoimmune disease, having not fully understood aetiology, and both genetic and environmental factors contribute to the pathogenesis of the disease. The cholinergic system has been indicated as a mediator of neuro-immune interactions, as well as an internal regulator of immune responses. The aim of the present research was to assess the associations between BChE and AChE genetic variations and serum cholinergic and inflammatory profiles in 102 Relapsing Remitting-MS patients and 117 healthy controls. An increased frequency of the BChE K-allele in MS patients as compared to controls was found. In addition, data showed that patients had higher BChE enzymatic activity, which is increased by the presence of the polymorphic allele and reduced amounts of circulating ACh. AChE polymorphism was significantly associated to reduced activity in both patients and controls. We propose that serum BChE and AChE activity may be used as a secondary markers to assess the role of non-neuronal cholinergic system in regulating peripheral inflammation via ACh regulation. This pilot study shed light on the role of the non-neuronal cholinergic system in immune cells to better understand MS pathogenesis. The cross-talk between the periphery and the CNS could have a new undescribed crucial role for MS, regarded as a systemic disease.

To investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA).74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at positions -163, -244, -238, -376, and -308.No SNPs at position -163 were observed, while we observed only SNPs at positions -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the -238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p0.01 vs GA and p0.01 vs AA) and 12 months from baseline (p0.01 vs GA and p0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308 AA respect to both GA (p = 0.012) and GG (p = 0.016).JIA patients carrying the TNF-α -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

The widely observed between-subject variability in cognitive responses to coffee may have a genetic basis. We evaluated cognitive responses to caffeine throughout three complex cognitive tasks assessing different subdomains of attention, namely Alerting and Orienting (Categorical Search Task) and Executive Control (Stroop Task and Eriksen Flanker Task). We explored whether they are influenced by gene variants affecting adenosine metabolism or catecholamine receptors. We recruited 106 healthy male subjects who were administered, in a double-blind design, 40mL of either a decaffeinated coffee preparation plus 3mg/kg caffeine (caf) or the corresponding vehicle (decaf). The protocol was repeated 24h later with the alternative preparation. Cognitive tasks were performed between 30min and 2h after caf or decaf administration. Each subject underwent ambulatory blood pressure monitoring for 2h. Blood samples were collected for genetic evaluations and for plasma caffeine and catecholamines measures. We found a significant reduction of reaction times in two of the cognitive tasks (Categorical Search Task and Stroop Task) after caf compared with decaf, indicating that caffeine, on average, improved the attention level in the domains under investigation. We also found, however, a great inter-individual variability in the cognitive performance responses to caffeine. In exploring genetic sources for such variability, we found a relation between polymorphisms of adenosine A2A and the caffeine effects on the attentional domains of Orienting and Executive control. In conclusion, variability in the attentional response to coffee may be partly explained by genetic polymorphisms of adenosine and adrenergic receptors.

Our coherent perception of external events is enabled by the integration of inputs from different senses occurring within a range of temporal offsets known as the temporal binding window (TBW), which varies from person to person. A relatively wide TBW may increase the likelihood that stimuli originating from different environmental events are erroneously integrated and abnormally large TBW has been found in psychiatric disorders characterized by unusual perceptual experiences. Despite strong evidence of inter-individual differences in TBW, both within clinical and nonclinical populations, the neurobiological underpinnings of this variability remain unclear. We adopted an integrated strategy linking TBW to temporal dynamics in functional magnetic resonance imaging (fMRI)-resting-state activity and cortical excitation/inhibition (E/I) balance. E/I balance was indexed by glutamate/Gamma-AminoButyric Acid (GABA) concentrations and common variation in glutamate and GABA genes in a healthy sample. Stronger resting-state long-range temporal correlations, indicated by larger power law exponent (PLE), in the auditory cortex, robustly predicted narrower audio-tactile TBW, which was in turn associated with lower cognitive-perceptual schizotypy. Furthermore, PLE was highest and TBW narrowest for individuals with intermediate levels of E/I balance, with shifts towards either extreme resulting in reduced multisensory temporal precision and increased schizotypy, effectively forming a neural "tuning curve" for multisensory experience and schizophrenia risk. Our findings shed light on the neurobiological underpinnings of multisensory integration and its potentially clinically relevant inter-individual variability.

False memories are common memory distortions in everyday life and seem to increase with affectively connoted complex information. In line with recent studies showing a significant interaction between the noradrenergic system and emotional memory, we investigated whether healthy volunteer carriers of the deletion variant of the ADRA2B gene that codes for the α2b-adrenergic receptor are more prone to false memories than non-carriers. In this study, we collected genotype data from 212 healthy female volunteers; 91 ADRA2B carriers and 121 non-carriers. To assess gene effects on false memories for affective information, factorial mixed model analysis of variances (ANOVAs) were conducted with genotype as the between-subjects factor and type of memory error as the within-subjects factor. We found that although carriers and non-carriers made comparable numbers of false memory errors, they showed differences in the direction of valence biases, especially for inferential causal errors. Specifically, carriers produced fewer causal false memory errors for scripts with a negative outcome, whereas non-carriers showed a more general emotional effect and made fewer causal errors with both positive and negative outcomes. These findings suggest that putatively higher levels of noradrenaline in deletion carriers may enhance short-term consolidation of negative information and lead to fewer memory distortions when facing negative events.

Study question Is the phosphoinositol 1,3-kinase/protein kinase B (PI3K/AKT) pathway expression profile in cumulus cells (CCs) a potential marker of oocyte competence and predictive of pregnancy outcome? Summary answer Eleven genes (AKT1, ARHGEF7, BCL2L1, CCND1, E2F1, HRAS, KCNH2, PIK3C2A, SHC1, SOS1 and SPP1) in the PI3K/AKT pathway were significantly down-regulated in CCs from oocytes that went on to produce a pregnancy compared to CCs associated with a negative outcome. What is known already The PI3K/AKT pathway plays a pivotal role in the interdependence and continuous feedback between the oocyte and CCs. Study design size, duration The expression analysis of 92 transcripts in the PI3K/AKT pathway in CCs from patients with negative or positive pregnancy outcome, after single embryo transfer, was performed. Mouse CCs target gene expression was conducted to associate the expression profile of PI3K/AKT pathway to oocyte developmental profile. Participants/materials, setting, methods Fifty-five good prognosis IVF patients who had been referred to IVF or intracytoplasmic sperm injection treatment for male-factor infertility or tubal disease were enroled. CCs from single cumulus-oocyte complexes (COCs) from 16 patients who underwent a single embryo transfer were analyzed. Twenty-five CD-1 mice were used to assess gene expression in CCs associated with oocytes with different competence in relation to hCG priming. A total 220 human COCs were collected. The RNA extracted from CCs of 16 selected patients was used to analyze PI3K/AKT pathway gene expression employing a 96-well custom TaqMan Array. Expression data of CCs associated to positive IVF outcome were compared to data from negative outcome samples. Mice were sacrificed after 9, 12, 15, 21 and 24 h post-hCG administration to obtain CCs from MII oocytes with different developmental competence. Akt1, Bcl2l2 and Shc1 expression were tested in the collected mouse CCs. In addition, the expression of upstream regulator ESR1, the gene encoding for the oestrogen receptor ERβ, and the downstream effectors of the pathway FOXO1, FOXO3 and FOXO4 was evaluated in human and mouse samples. Main results and the role of chance Transcripts involved in the PI3K Signaling Pathway were selectively modulated according to the IVF/ICSI outcome of the oocyte. Eleven transcripts in this pathway were significantly down-regulated in all samples of CCs from oocytes with positive when compared those with a negative outcome. These outcomes were confirmed in mouse CCs associated with oocytes at different maturation stages. Expression data revealed that the down-regulation of ESR1 could be related to oocyte competence and is likely to be the driver of expression changes highlighted in the PI3K/AKT pathway. Limitations reasons for caution Small sample size and retrospective design. Wider implications of the findings The CCs expression profile of PI3K/AKT signaling genes, disclosed a specific CCs gene signature related to oocyte competence. It could be speculated that CCs associated with competent oocytes have completed their role in sustaining oocyte development and are influencing their fate in response to metabolic and hormonal changes by de-activating anti-apoptotic signals. Study funding/competing interest(s) Supported by Merck Serono an affiliate of Merck KGaA, Darmstadt, Germany (research grant for the laboratory session; Merck KGaA reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors). The authors declare no conflict of interest.

Eating Disorders (EDs) show a multifactorial etiopathogenesis including environmental, psychological and biological factors. In the present study, we propose a model of interactions between genetic vulnerability—represented by Fat Mass and Obesity-Associated (FTO) gene—and stable psychopathological traits, such as bodily disorders and emotion dysregulation for EDs patients. The distribution of a polymorphism of the FTO (rs9939609 T>A) was evaluated in a series of 250 EDs patients and in a group of 119 healthy control subjects. Clinical data were collected through a face-to-face interview and several self-reported questionnaires were applied, including the Emotional Eating Scale and the IDentity and EAting disorders (IDEA) questionnaire for bodily disorders and self-identity. The A-allele was associated with an increased vulnerability to EDs (AA+AT genotypes frequency 72.8% in EDs vs. 52.9% in controls). The presence of the A-allele was associated with binge eating behavior, higher emotional eating and higher IDEA scores. Finally, the FTO rs9939609 SNP was found to influence the relationship between these variables, as an association between disorder of corporeality and emotional eating was found only in A-allele carriers. A-allele seems to represent a potential additive risk factor for EDs persons, with bodily disorders to develop emotional eating and binge eating behaviors.

Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy. Women with a GDM history are at increased risk of developing diabetes and cardiovascular diseases. Studies have demonstrated a significant correlation between several genes involved in the metabolic pathway of insulin and environmental factors. The aim of this study was to investigate the relationship between clinical parameters in GDM and variants in genes involved with nutrients and metabolism. Several variantsPPARG2rs1801282 (C>G);PPARGC1Ars8192678 (C>T);TCF7L2rs7903146 (C>T);LDLRrs2228671 (C>T);MTHFRrs1801133 (C>T);APOA5rs662799 (T>C);GCKRrs1260326 (C>T);FTOrs9939609 (T>A);MC4Rrs17782313 (T>C) were genotyped in 168 pregnant Caucasian women with or without GDM by High Resolution Melting (HRM) analysis. A significant correlation was observed between TT genotype ofTCF7L2gene and increased risk of GDM (OR 5.4 [95% CI 1.5–19.3]). Moreover, a significant correlation was observed between lipid parameters and genetic variations in additional genes, namely,PPARG2[p= 0,02],APOA5[p= 0,02],MC4R[p= 0,03],LDLR[p= 0,01], andFTO[p= 0,02]. Our findings support the association betweenTCF7L2rs7903146 variant and an increased GDM risk. Results about the investigated genetic variants provide important information about cardiometabolic risk in GDM and help to plan future prevention studies.

Background Mannose-binding lectins and human ficolins are pattern-recognition proteins involved in innate immunity. A role for MBL2 and FCN2 gene polymorphisms in the pathogenesis of recurrent severe streptococcal infections and rheumatic carditis has been suggested. Objectives The aim of this study is to evaluate the presence of MBL2 and FCN2 gene polymorphisms (SNPs) in children with a history of rheumatic fever (RF) and to investigate their possible role in RF clinical presentation and disease course. Methods A total of 50 Caucasian patients with RF were recruited with a control group of 52 healthy children. DNA was extracted for analysis of MBL2 gene (exon 1, codons: 52, 54, and 57) and FCN2 gene (promoter region at position −986, −602, and −4). Results The FCN2 AG genotype at the −986 position was more frequently observed in patients, as compared to healthy subjects ( p = 0.006); furthermore, the A allele was identified as a possible risk factor for the development of RF (OR = 7.14, CI: 2.439–20.89). Conversely, the GG genotype at the same position was observed more frequently in the control group and can be considered a protective factor for the development of the disease ( p = 0.001, OR=8.37, 95% CI: 2.763–25.33). In addition, the FCN2 GG and AG genotypes in the −4 position were also found to be protective factors for the development of RF and for carditis respectively (OR = 3.32, CI: 1.066–10.364; OR=0.15, 95% CI: 0.037–0.566). Finally, the AA genotype in the −602 position was associated with a late onset of RF ( p = 0.006). The analysis of the MBL2 gene only resulted in a higher frequency of the AA genotype on position 57 in controls as compared to patients ( p = 0.025). Conclusions This is the first study evaluating the FCN2 gene polymorphisms in patients with RF and rheumatic carditis finding a protective effect of −986 GG and −4 GG genotypes in the development of RF and the −4 AG genotype for the development of carditis. Our data do not support a possible role for MBL2 polymorphisms in the pathogenesis and in the clinical manifestations of RF.

The somatic component of follicular structure is a mixture of different cell types, represented by Granulosa cells (GCs) that are the paracrine regulators of the oocyte growth. GCs finely support this process by a continuous bidirectional talk with oocyte, which ensure oocyte quality and competence. Specific pathways are involved in the cross-talk and in both GCs and oocyte development. This review summarizes data from GCs gene expression analysis concerning both their physiological role and their interaction with oocyte. We also explore the CGs transcriptome modifications induced by controlled ovarian stimulation (COS) or pathological conditions and their impact in reproduction. The transcriptome analysis of GCs could be a powerful tool to improve our knowledge about the pathways involved in oocyte development. This approach, associated with new technologies as RNA-seq could allow the identifications of new noninvasive biological markers of oocyte quality to increase the efficiency of clinical IVF. Moreover, GCs expression analysis could be useful to shed light on new therapeutic targets by providing new options for the treatment of infertility.

Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD) and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescence cell percentages. Moreover, an increase in ataxia–telangiectasia-mutated staining 1 h after oxidative stress induction and a return to basal level at 48 h, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity. This article is protected by copyright. All rights reserved

During the past years, several empirical and statistical models have been developed to discriminate between carriers and non-carriers of germline BRCA1/BRCA2 (breast cancer 1, early onset/breast cancer 2, early onset) mutations in families with hereditary breast or ovarian cancer. Among these, the BRCAPRO or CaGene model is commonly used during genetic counseling, and plays a central role in the identification of potential carriers of BRCA1/2 mutations. We compared performance and clinical applicability of BRCAPRO version 5.1 vs version 6.0 in order to assess diagnostic accuracy of updated version. The study was carried out on 517 pedigrees of patients with familial history of breast or ovarian cancer, 150 of which were submitted to BRCA1/2 mutation screening, according to BRCAPRO evaluation or to criteria based on familial history. In our study, CaGene 5.1 was more sensitive than CaGene 6.0, although the latter showed a higher specificity. Both BRCAPRO versions better discriminate BRCA1 than BRCA2 mutations. This study evidenced similar performances in the two BRCAPRO versions even if the CaGene 6.0 has underestimated the genetic risk prediction in some BRCA mutation-positive families. Genetic counselors should recognize this limitation and during genetic counseling would be advisable to use a set of criteria in order to improve mutation carrier prediction.

Item does not contain fulltext PURPOSE: To describe the variable ocular phenotype associated with a heterozygous mutation in the BEST1 gene. METHODS: Clinical and genetic assessment was performed in five members of the same family. Molecular genetic analysis of the BEST1 gene was performed by direct sequencing. Extensive ophthalmic examination included color fundus imaging, spectral domain optical coherence tomography, fundus autofluorescence, electro-oculography (EOG), and full-field electroretinography (ERG). The main outcome measures were BEST1 mutations, imaging, and electroretinography findings. RESULTS: All affected family members carried a single heterozygous c.614T>C (p.I205T) mutation in exon 5 of the BEST1 gene. The 46-year-old proband showed nanophthalmos with chorioretinal atrophy in the macula, extensive coarse hyperpigmentation in the (mid) peripheral retina with tractional vitreous strands. Full-field ERG revealed nonrecordable cone and rod responses, and EOG showed an absent light rise. The daughter and son of the proband showed a phenotype resembling autosomal recessive bestrophinopathy, including short axial lengths, cystoid fluid collections, and shallow serous subretinal fluid accumulation on spectral domain optical coherence tomography throughout the macula in combination with mild retinal pigment epithelium changes. The son of the proband also showed subretinal yellowish deposits inferiorly in the macula as well as outside the temporal vascular arcade, that were hyperfluorescent on fundus autofluorescence, similar to those seen in autosomal recessive bestrophinopathy. Full-field ERG revealed a reduced rod and cone response and a markedly reduced or absent EOG light peak in both brother and sister of the proband. CONCLUSION: The clinical spectrum of bestrophinopathy may encompass severe ocular phenotypes that affect the development and function of the entire eye. A clinical picture similar to autosomal recessive bestrophinopathy can also be caused by a single heterozygous mutation in the BEST1 gene, such as the c.614T>C (p.I205T) variant in this family.

We report on a 10-year-old patient with childhood apraxia of speech (CAS) and mild dysmorphic features. Although multiple karyotypes were reported as normal, a bacterial artificial chromosome array comparative genomic hybridization revealed the presence of a de novo 14.8-Mb mosaic deletion of chromosome 7q31. The deleted region involved several genes, including FOXP2, which has been associated with CAS. Interestingly, the deletion reported here was observed in about 50% of cells, which is the first case of mosaicism in a 7q31 deletion. Despite the presence of the deletion in only 50% of cells, the phenotype of the patient was not milder than other published cases. To date, 6 cases with a deletion of 9.1-20 Mb involving the FOXP2 gene have been reported, suggesting a new contiguous gene deletion syndrome characterized mainly by CAS caused by haploinsufficiency of the genes encompassed in the 7q critical region. This report suggests that children found with a deletion involving the FOXP2 region should be evaluated for CAS and that analysis of the FOXP2 gene including array comparative genomic hybridization should be considered in selected patients with CAS. Mosaic deletions in this area may also be considered as causative of CAS.

α-thalassemia belongs to those inherited diseases in which large genomic deletions/duplications represent a significant proportion of causative mutations. Until recently, large α-globin gene cluster rearrangements have been mainly detected by gap-PCR and Southern blotting, methods that have significant drawbacks. We tested the recently developed multiplex ligation-dependent probe amplification (MLPA) assay for deletional screening of the α-globin gene cluster in a cohort of 25 individuals suspected of having α-globin alteration(s), in which no or doubtful mutations had been found using conventional methods. In 13 out of 18 α-thalassemia carriers and in all 5 patients with HbH we found the causative α-globin defects. In 2 thalassemia intermedia patients, carriers of heterozygous β-globin mutations, the co-inheritance of homozygous α-genes triplication was detected. MLPA results were subsequently confirmed by real-time PCR. This study shows that MLPA can effectively identify different and unknown types of α-globin gene rearrangements, to allow characterizing previously unsolved α-thalassemia genotypes.

Noonan, LEOPARD, and cardiofaciocutaneous Syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N = 270), LS (N = 6), and CFCS (N = 33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (5296), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 30, 695-702, 2009. (C) 2009 Wiley-Liss, Inc.

We analyzed the role of six common polymorphisms in folate metabolizing genes as possible risk factors for having a child with Down syndrome (DS) in 94 Italian mothers of a DS child (MDS) and 113 matched control mothers, both aged less than 35 years at conception. Investigated polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677CT and 1298AC, methionine synthase (MTR) 2756AG, methionine synthase reductase (MTRR) 66AG, and thymidylate synthase (TYMS) 28bp repeat and 1494del6. We also measured the amount of chromosome damage in peripheral blood lymphocytes of 42 MDS and 41 matched controls, by means of the micronucleus assay, and searched for association between this cytogenetic endpoint and any of the studied polymorphisms. Micronuclei in peripheral blood lymphocytes have been analyzed several years after conception: the mean age at sampling was 45.6+/-11.4 years for MDS and 47.95+/-6.9 years for controls. The combined MTHFR 677TT/MTR 2756AA genotype was associated with increased DS risk (P=0.034), and the combined MTHFR 1298AC/TYMS 2R/2R genotype with reduced risk (P=0.003). Moreover, we observed a significant increased frequency of micronucleated lymphocytes in MDS as compared to controls (P0.0001) and, in the total population, a significant correlation between micronucleated cells and both MTHFR 677CT (P=0.031) and 1298AC (P=0.047) polymorphisms.

SummaryCOX-1 polymorphism C50T, in complete linkage disequilibrium with the other polymorphism A-842G, has been depicted as a determinant of pharmacological response to aspirin treatment. Whether these polymorphisms exert an effect on response to aspirin both in vitro and ex vivo is still controversial. We geno-typed a population of 148 healthy individuals for the C50T/A-842G haplotype. Thirty of them underwent low-dose aspirin (100 mg daily) treatment for four weeks and were followed up for seven days after withdrawal. In this subgroup, we evaluated the thromboxane-dependence of biochemical and functional indexes used to monitor the antiplatelet effect of low-dose aspirin. Among the 148 subjects studied, 10 were heterozygous for the C50T/A-842G haplotype (6.7%) and only one was homozygous for the 50T/-842G haplotype (0.67%). In the group on low-dose aspirin, serum thromboxane (TX) B2 as well as urinary 11-dehydro-TXB2 and arachidonic acid (AA)-induced aggregation were similarly suppressed in carriers and non-carriers of the 50T/-842G haplotype, with an increase until basal levels of all the parameters within seven days after withdrawal. We found no relationship between the 50T/-842G haplotype and the so-called phenomenon of aspirin resistance. Platelet cyclooxygenase activity, as reflected by serum TXB2, was uniformly and persistently suppressed by low-dose aspirin in both carriers and non carriers of these polymorphisms.

Previous studies found that the ADRA2B gene modulates early perception and attention. Here, we aimed to examine whether ADRA2B polymorphisms also influence emotional working memory and the willingness to implement behaviors (switching affective intonation) in order to avoid negative information, both considered indexes of cognitive-affective flexibility. We examined genotype data collected from 212 healthy females, 91 ADRA2B carriers and 121 non-carriers, and found that carriers showed a positivity bias in working memory. That is, carriers remembered a higher number of positive words compared to negative and neutral words. In addition, although carriers were more unwilling to switch intonation in order to avoid negative information, they showed better recognition memory for words read with a positive intonation. These findings suggest that deletion variants of ADRA2B may show greater levels of cognitive-affective flexibility compared to non-carriers.

Many genes expressed in the central nervous system are candidates for increased susceptibility to suicidal behavior.... Language: en

The association between alexithymia and post-traumatic stress disorder (PTSD) symptoms has been demonstrated in several studies, but never in victims of a collective trauma such as a natural disaster, which has an impact on an entire community.The aim was to assess the relationship between alexithymia and post-traumatic symptoms in a group of people who lived in L'Aquila exposed to the earthquake that hit the town in 2009.Eighty-seven participants were included and assessed for alexithymia, PTSD symptoms, depression, anxiety, and psychiatric symptoms. Linear regression models were used to test the hypothesis.The main finding was an association between "Difficulty-Describing-Feelings" and the intensity of post-traumatic symptoms in the worst month after trauma. Depression, anxiety and psychiatric comorbidity also showed a significant association with PTSD symptoms.In the present study of a collectively shared trauma, the alexithymic factor "difficulty-describing-feelings" was significantly associated with the intensity of post-traumatic symptoms.