Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome.

We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood-testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17-2.93), ORaddrs2233678 = 1.62 (1.11-2.36), ORaddrs62105751 = 1.43 (1.06-1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia.

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33-02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRß1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.

Influence of body mass index in anti-Müllerian hormone levels in 951 non-polycystic ovarian syndrome women followed at a reproductive medicine unit.

PURPOSE: Anti-Müllerian hormone (AMH) is a useful marker of ovarian reserve. Obesity/overweight are increasing and may affect the reproductive health. Previous studies regarding the effect of body mass index (BMI) on AMH levels are discordant. Our main goal was to evaluate the influence of BMI on AMH levels in women without polycystic ovarian syndrome. METHODS: Revision of medical records of 951 women who performed AMH determinations as part of their fertility workup, between 2011 and 2016. RESULTS: Median AMH concentration was 1.75 [interquartile range (IQR) 2] ng/mL (12.9 pmol/mL) and median age at AMH determination was 35 (IQR 6) years. These women evidenced a median BMI of 23 (IQR 5) kg/m2. Caucasian women were more represented [889(89.3%)]. Smoking habits (present/past) were present in 359(36.1%), and 147(14.8%) harboured a history of ovarian surgery. On univariable analysis AMH was not correlated with BMI (r = 0.048/p = 0.135); the only factors influencing AMH were age (p < 0.001), ethnicity (p = 0.004), and previous ovarian surgery (p < 0.001). On multivariable analysis, age was the only variable significantly associated with AMH, evidencing a reduction of 6.2% for each additional year (p < 0.0001). Furthermore, we verified a trend suggesting an AMH reduction of 22% (p = 0.08) in black patients comparing with the caucasian ones, when controlling for the other variables. CONCLUSION: We report one of the largest series evaluating the influence of BMI on AMH levels and, consequently, on ovarian reserve. BMI does not seem to affect AMH levels. The reported concerns on infertility in overweight and obese women may be related to follicular development/oocyte maturation or endometrial disorders, rather than decreased ovarian reserve.

Characterizing partial AZFc deletions of the Y chromosome with amplicon-specific sequence markers.

BACKGROUND: The AZFc region of the human Y chromosome is a highly recombinogenic locus containing multi-copy male fertility genes located in repeated DNA blocks (amplicons). These AZFc gene families exhibit slight sequence variations between copies which are considered to have functional relevance. Yet, partial AZFc deletions yield phenotypes ranging from normospermia to azoospermia, thwarting definite conclusions on their real impact on fertility. RESULTS: The amplicon content of partial AZFc deletion products was characterized with novel amplicon-specific sequence markers. Data indicate that partial AZFc deletions are a male infertility risk [odds ratio: 5.6 (95% CI: 1.6-30.1)] and although high diversity of partial deletion products and sequence conversion profiles were recorded, the AZFc marker profiles detected in fertile men were also observed in infertile men. Additionally, the assessment of rearrangement recurrence by Y-lineage analysis indicated that while partial AZFc deletions occurred in highly diverse samples, haplotype diversity was minimal in fertile men sharing identical marker profiles. CONCLUSION: Although partial AZFc deletion products are highly heterogeneous in terms of amplicon content, this plasticity is not sufficient to account for the observed phenotypical variance. The lack of causative association between the deletion of specific gene copies and infertility suggests that AZFc gene content might be part of a multifactorial network, with Y-lineage evolution emerging as a possible phenotype modulator.

Short and Long-Term Efficacy of Laparoscopic Ovarian Diathermy in Women with Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome is the most frequent cause of anovulatory infertility and management involves a multistep approach. Laparoscopic ovarian diathermy is accepted as a second-line treatment of patients who failed to respond to clomiphene citrate. The aims of this study were to determine the efficacy of this technique at short and long-term and to perform an analysis of predictive factors of spontaneous pregnancy. MATERIAL AND METHODS: This retrospective study involved 76 women who underwent laparoscopic ovarian diathermy between 2004 and 2013 in a university hospital. Main outcomes were cycle regularity and pregnancy. Short-term outcomes recorded during followup in our centre were reviewed and long-term outcomes were evaluated by a telephone interview to all women whose surgery was undertaken more than three years ago. Clinical and biochemical data were analysed as predictive factors of spontaneous conceptionin patients without other infertility factors. RESULTS: Menstrual cycle regularity was initially achieved in 53 (70%) women and in the long-term follow-up subgroup, 52% (12/23) had regular periods. In general, 53 (70%) women conceived and 77 pregnancies were achieved, 60% of which were spontaneous. The only prognostic factor found to be significantly associated with spontaneous conception was a shorter duration of infertility (< 3 years) (p < 0.05). DISCUSSION: Laparoscopic ovarian diathermy showed pregnancy rates comparable to other ovulation induction treatments with the advantage of having a long lasting beneficial effect in menstrual regularity and fertility. CONCLUSION: Laparoscopic ovarian diathermy is a safe and effective treatment option for anovulatory infertility in women with polycystic ovary syndrome.

Introdução: A síndrome dos ovários poliquísticos é a causa mais frequente de anovulação e o tratamento envolve uma abordagem faseada. A electrocoagulação laparoscópica dos ovários é aceite como segunda linha no tratamento das doentes que não respondem ao citrato de clomifeno. Os objectivos deste estudo foram determinar a eficácia desta técnica a curto e longo prazo e definir os factores preditivos de gravidez espontânea. Material e Métodos: Este estudo retrospectivo envolveu 76 mulheres submetidas a electrocoagulação dos ovários entre 2004 e 2013, num hospital universitário. Os desfechos principais foram a regularidade menstrual e gravidez. Os resultados a curto prazo registados durante a vigilância na unidade foram revistos e os desfechos a longo prazo foram avaliados através de entrevista telefónica realizada a todas as mulheres operadas há mais de três anos. Dados clínicos e bioquímicos foram analisados como factores preditivos de gravidez espontânea em doentes sem outros factores de infertilidade. Resultados: A regularidade do ciclo menstrual foi alcançada inicialmente em 53 (70%) mulheres e a longo prazo, 52% (12/53) tinham ciclos regulares. Em geral, 53 (70%) mulheres engravidaram e foram obtidas 77 gravidezes, 60% das quais foram espontâneas. O único factor de prognóstico associado a gravidez espontânea foi a duração da infertilidade inferior a três anos (p < 0,05). Discussão: A electrocoagulação dos ovários demonstrou taxas de gravidez comparáveis a outros tratamentos de indução da ovulação com a vantagem de ter efeitos benéficos duradouros na regularidade menstrual e fertilidade. Conclusão: A electrocoagulação dos ovários é uma opção de tratamento segura e eficaz na infertilidade anovulatória em mulheres com síndrome dos ovários poliquísticos.

Aquisiçäo de medicamentos no setor público: o binômio qualidade - custo / Pharmaceutical procurement by the public sector: the quality/cost relationship

Aborda, dentro do âmbito da administraçäo de materiais, a aquisiçäo e o aprovisionamento de medicamentos no setor público de saúde, discutindo as duas principais vertentes da questäo: qualidade e custo. Säo relatados os fatores que devem ser considerados pelo comprador quando se avalia o quesito qualidade de medicamentos, em especial a questäo dos genéricos, a bioequivalência e a estabilidade das formulaçöes. Por outro lado, o item custo é examinado, assim como as implicaçöes que uma demanda diferenciada e voltada para as inovaçöes tecnológicas tem sobre ele. Por fim, discutem-se alternativas, já empregadas em algumas instituiçöes, apresentando-se sugestöes cuja finalidade implica na possibilidade de compra de produtos de qualidade aliada à contençäo de custos.

Eficiência da lavagem de carcaças de frango com contaminação fecal aparente, comparada ao corte das áreas afetadas, para redução de contagem bacteriana / Efficiency of washing of carcasses with fecal contamination of chicken apparent, compared to the cutting of the affected areas, to reduce bacterial

A fonte de contaminação com fezes em carcaças de frango ocorre quando o trato intestinal se rompe, é cortado ou quando as fezes são expulsas da carcaça do frango. Amostras de carcaças de frango com contaminação fecal visível foram analisadas, após a retirada com faca da área comprometida. Foram analisadas 1080 carcaças de frango durante 18 dias diferentes de abate, sendo coletadas 10 carcaças por dia em cada ponto de coleta testado, antes e após o chiller. (...) Para as amostras de carcaças de frango coletadas após o chiller, a contagem de Coliformes totais, para o tratamento controle (FDCN), não difere significativamente do tratamento teste FDCL (p>0,05), mas difere do tratamento FDCC (P>0,05) e, o tratamento FDCL, não difere significamente do tratamento FDCC (p>0,05). Para a contagem de Enterobacteriaceae, não há diferença significativa entre o tratamento controle FDCN e FDCL (p>0,05) e ambos, FDCN e FDCL diferem significativamente de FDCC. Para os três tratamentos não houve diferença significativa na pesquisa de E.coli (p=0,30). O procedimento de corte de partes das carcaças contaminadas com fezes, antes do resfriamento, não diminuiu a contaminação microbiológica, comparado com o procedimento de lavagem das carcaças.