Melatonin daily oral supplementation attenuates inflammation and oxidative stress in testes of men with altered spermatogenesis of unknown aetiology.

We have previously shown an inverse correlation between testicular melatonin concentration and inflammation/oxidative stress-related markers levels in infertile men showing unexplained azoospermia. Here, we evaluated the impact of melatonin oral supplementation (daily 3 mg dose used to treat sleep disorders) in the incidence of local inflammation, oxidative stress, and tubular wall fibrosis development in young and middle-aged infertile adult men. Compared with testes without histological alterations, gonads with morphological abnormalities showed lower melatonin concentration along with increased macrophage numbers, TBARS generation, and expression levels of inflammation-related markers and antioxidant enzymes, as well as tubular wall collagen fibers disorganization and thickening. Melatonin oral supplementation not only increased its own testicular levels but also decreased inflammation- and oxidative stress-related markers levels, and improved the tubular wall aspect. Overall, our work provides insights into the potential benefits of melatonin on the inflammatory and oxidative status in testes of patients suffering from unexplained infertility.

New insights into melatonin/CRH signaling in hamster Leydig cells.

We have previously described that melatonin inhibits androgen production in hamster testes via melatonin subtype 1a (mel1a) receptors and the local corticotrophin-releasing hormone (CRH) system. This study attempted to determine the initial events of the melatonin/CRH signaling pathway. In Leydig cells from reproductively active Syrian hamsters, Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and a colorimetric assay demonstrated that melatonin and CRH activate tyrosine phosphatases and subsequently reduce the phosphorylation levels of extracellular signal-regulated kinase (erk) and c-jun N-terminal kinase (jnk), down-regulate the expression of c-jun, c-fos and steroidogenic acute regulatory (StAR), and inhibit the production of testosterone. These effects were prevented by a highly selective CRH antagonist, thus indicating that melatonin does not exert a direct role. Specific mitogen-activated protein kinase kinase (MEK) and jnk blockers inhibited expression of c-jun, c-fos, StAR and the production of testosterone, confirming that these are events triggered downstream of erk and jnk. In Leydig cells from photoperiodically regressed adult hamsters, CRH inhibited the production of androstane-3α,17ß-diol (3α-diol), the main androgen produced, through the same signaling pathway. Testicular melatonin concentration was 3-4-fold higher in reproductively inactive hamsters than that detected in active animals. Since melatonin, CRH, and their receptors are present not only in hamster testes but also in testicular biopsies of infertile men, we can conjecture about the relevance of this previously uncharacterized pathway in human fertility disorders. In summary, our study identifies crucial intracellular events triggered by melatonin/CRH in the testis that lead to a down-regulation of the steroidogenic process.

Expression of the TGF-beta1 system in human testicular pathologies.

BACKGROUND: In non-obstructive azoospermia, histological patterns of Sertoli cell-only Syndrome (SCO) and hypospermatogenesis (H) are commonly found. In these pathologies, Leydig cell hyperplasia (LCH) is detected in some patients. Since TGF-ß1 is involved in cellular proliferation/development, the aim of this work was to analyze the expression of TGF-ß1, its receptors TGFBRII, TGFBRI (ALK-1 and ALK-5), and the co-receptor endoglin in human biopsies from patients with idiopathic infertility. METHODS: Specific immunostaining of TGF-ß1, its receptors TGFBRII, TGFBRI (ALK-1 and ALK-5), co-receptor endoglin and Smads proteins, were carried out in testicular biopsies from normal and infertile men with SCO or H. Gene expression of TGF-ß1 system were made in biopsies from infertile patients with semi-quantitative and quantitative PCR. RESULTS: Immunohistochemical studies revealed that TGF-ß1 and its specific receptors are present in Leydig cells in biopsies from normal tissue or patients with SCO or H with or without LCH. Smad proteins, which are involved in TGF-ß1 signaling, are also detected in both their phosphorylated (activated) and dephosphorylated form in all samples TGF-ß1, ALK-1 and endoglin gene expression are stronger in human biopsies with LCH than in those with SCO or H. Neither TGFBRII nor ALK-5 gene expression showed significant differences between pathologies. A significant correlation between ALK-1 and endoglin expression was observed. CONCLUSIONS: In conclusion, the high levels of mRNA and protein expression of the TGF-ß1 system in patients with LCH, particularly ALK1 and its correlation with endoglin, suggest that these proteins acting in concert might be, at least in part, committed actors in the Leydig cell hyperplasia.

Cyclooxygenase-2 in testes of infertile men: evidence for the induction of prostaglandin synthesis by interleukin-1ß.

As we previously reported, testes of men suffering from hypospermatogenesis and germ cell arrest or Sertoli cell-only syndrome show a major increase in the number of macrophages expressing interleukin-1ß (IL-1ß) and abundant expression of cyclooxygenase-2 (COX-2), the inducible isoform of the key enzyme in the biosynthesis of prostaglandins (PGs), in Leydig cells. In the present study we report [1] a positive correlation between IL-1ß levels and COX-2 expression in testes of infertile patients, [2] the induction of COX-2 by IL-1ß in mouse Leydig cells (TM3) and human macrophages (THP-1), and therefore [3] evidence for an IL-1ß-dependent induction of testicular inflammatory states.

Reproducción asistida en hombres infectados con el virus de VIH / Assisted reproduction in HIV positive men

Objetivo: Describir un programa de procreación responsable en parejas donde el varón está infectado con el VIH organizado en un centro ambulatorio infectológico de la ciudad de Bs. As. y llevado a cabo por un equipo interdisciplinario conformado por Infectólogos, Bioquímicos, Ginecólogos y Biólogos. Comentar algunas revisiones de la literatura que avalan la evidencia cientifica para realizar estos procedimientos. Métodos: las parejas serodiscordantes son candidatas para este programa si el varón tiene seguimiento infectológico, los estudios de esperma demuestran carga viral (CV) indetectable y DNA proviral de VIH negativo, y, la mujer tiene ADN proviral de VIH negativo en sangre, en el ciclo en el cual se realizará el procedimiento de fertilización asistida. Se realiza en la mujer pesquisa de infecciones connatales. Las muestras de esperma son procesadas con técnicas de lavado, swim up y swim down, y congeladas. Después de cada procedimiento de fertilización asistida la mujer es controlada controlada con estudios serológicos para anticuerpos (VIH ELISA) periódicos. Los recién nacidos son evaluados a través de ADN proviral de VIH en el 1er mes de vida, o, durante los primeros 6 meses de vida a través de anticuerpos (VIH ELISA). Resultadaos: desde 12/2000 y hasta mayo 2009 se incluyeron 165 parejas serodiscordantes. 147 pacientes VIH (+) realizaron estudios de muestras de esperma, 26, tuvieron muestras con estudios microbiológicos positivos (23, CV detectable, y 3, ADN proviral de VIH positivo). En 123 parejas se realizaron: 329 inseminaciones, 55 ICSI y 28 FIV. Se concretron 44 embarazos y nacieron 51 bebés. Todos los estudios realizados a las mujeres y recién nacidos mostraron resultados negativos. Conclusiones: este programa logró resultados satisfactorios en la prevención de infecciones por VIH y connatales.

Objective: to describe the data obtained during the development of an assisted reproduction program for couples where the man is HIV - Infected organized by an ambulatory infectologist center in BsAs city. a multidisciplinary team with infectious disease MD, biochemists, ginecologists and bilogist collaborate in the follow-up of the patients. Methods: couples seeking reproductive counseling were eligible for this programme if: the HIV positive male partner adhered to an infectious disease follow-up, he has undetectable viral load in the fresh sperm sample and is negative for HIV proviral DNA in the swim-up material after sperm washing, the female partner is negative for HIV proviral DNA immediately beforme each assisted reproduction attempt. Procedures comprised intrauterine insemination, intracytoplasmic sperm injection and in vitro fertilization accordin to gynecologist indication. After each procedure, women were tested for indication. After each procedure, women were tested for HIV antibodies periodically. Newborns were tested for HIV proviral DNA at one month of age or HE during the first six months. Results: One hundred and sixty five couples were assessed, semen analyses results were obtained from 147 HIV positive men, 23 had detectable viral load, 3 had positive HIV proviral DNA in swim up. One hundred and twenty three couples undervent AR procedures: 329 intrauterine inseminations, 55 intracytoplasmic sperm injections, and 28 in-vitro fertilizations. Forty four pregnancies resulted in fifty one live Births. All HE and HDP tests performed in women and new-borns were negative. Conclusions: This programme achieved satisfactory results in prevention of HIV and congenital infections.

Reproducción asistida en hombres infectados con el virus de VIH / Assisted reproduction in HIV positive men

Objetivo: Describir un programa de procreación responsable en parejas donde el varón está infectado con el VIH organizado en un centro ambulatorio infectológico de la ciudad de Bs. As. y llevado a cabo por un equipo interdisciplinario conformado por Infectólogos, Bioquímicos, Ginecólogos y Biólogos. Comentar algunas revisiones de la literatura que avalan la evidencia cientifica para realizar estos procedimientos. Métodos: las parejas serodiscordantes son candidatas para este programa si el varón tiene seguimiento infectológico, los estudios de esperma demuestran carga viral (CV) indetectable y DNA proviral de VIH negativo, y, la mujer tiene ADN proviral de VIH negativo en sangre, en el ciclo en el cual se realizará el procedimiento de fertilización asistida. Se realiza en la mujer pesquisa de infecciones connatales. Las muestras de esperma son procesadas con técnicas de lavado, swim up y swim down, y congeladas. Después de cada procedimiento de fertilización asistida la mujer es controlada controlada con estudios serológicos para anticuerpos (VIH ELISA) periódicos. Los recién nacidos son evaluados a través de ADN proviral de VIH en el 1er mes de vida, o, durante los primeros 6 meses de vida a través de anticuerpos (VIH ELISA). Resultadaos: desde 12/2000 y hasta mayo 2009 se incluyeron 165 parejas serodiscordantes. 147 pacientes VIH (+) realizaron estudios de muestras de esperma, 26, tuvieron muestras con estudios microbiológicos positivos (23, CV detectable, y 3, ADN proviral de VIH positivo). En 123 parejas se realizaron: 329 inseminaciones, 55 ICSI y 28 FIV. Se concretron 44 embarazos y nacieron 51 bebés. Todos los estudios realizados a las mujeres y recién nacidos mostraron resultados negativos. Conclusiones: este programa logró resultados satisfactorios en la prevención de infecciones por VIH y connatales.(AU)

Objective: to describe the data obtained during the development of an assisted reproduction program for couples where the man is HIV - Infected organized by an ambulatory infectologist center in BsAs city. a multidisciplinary team with infectious disease MD, biochemists, ginecologists and bilogist collaborate in the follow-up of the patients. Methods: couples seeking reproductive counseling were eligible for this programme if: the HIV positive male partner adhered to an infectious disease follow-up, he has undetectable viral load in the fresh sperm sample and is negative for HIV proviral DNA in the swim-up material after sperm washing, the female partner is negative for HIV proviral DNA immediately beforme each assisted reproduction attempt. Procedures comprised intrauterine insemination, intracytoplasmic sperm injection and in vitro fertilization accordin to gynecologist indication. After each procedure, women were tested for indication. After each procedure, women were tested for HIV antibodies periodically. Newborns were tested for HIV proviral DNA at one month of age or HE during the first six months. Results: One hundred and sixty five couples were assessed, semen analyses results were obtained from 147 HIV positive men, 23 had detectable viral load, 3 had positive HIV proviral DNA in swim up. One hundred and twenty three couples undervent AR procedures: 329 intrauterine inseminations, 55 intracytoplasmic sperm injections, and 28 in-vitro fertilizations. Forty four pregnancies resulted in fifty one live Births. All HE and HDP tests performed in women and new-borns were negative. Conclusions: This programme achieved satisfactory results in prevention of HIV and congenital infections.(AU)

Book citations: influence of epidemiologic thought in the academic community.

Whilst their 'death' has often been certified, books remain highly important to most professions and academic disciplines. Analyses of citations received by epidemiologic texts may complement other views on epidemiology. The objective was to assess the number of citations received by some books of epidemiology and public health, as a first step towards studying the influence of epidemiological thought and thinking in academia. For this purpose, Institute for Scientific Information/ Thomson Scientific - Web of Science/ Web of Knowledgedatabase was consulted, in May 2006. The book by Rothman & Greenland appeared to have received the highest number of citations overall (over 8,000) and per year. The books by Kleinbaum et al, and by Breslow & Day received around 5,000 citations. In terms of citations per year the book by Sackett et al ranks 3rd, and the one by Rose, 4th of those included in this preliminary study. Other books which were influential in the classrooms collected comparatively less citations. Results offer a rich picture of the academic influences and trends of epidemiologic methods and reasoning on public health, clinical medicine and the other health, life and social sciences. They may contribute to assess epidemiologists' efforts to demarcate epidemiology and to assert epistemic authority, and to analyze some historical influences of economic, social and political forces on epidemiological research.

Book citations: influence of epidemiologic thought in the academic community

Ainda que sua 'morte' tenha sido freqüentemente certificada, os livros continuam sendo relevantes para muitas profissões e disciplinas acadêmicas. Análises de citações recebidas por textos epidemiológicos podem complementar outras visões em epidemiologia. O objetivo do estudo foi avaliar o número de citações recebidas por alguns livros de epidemiologia e saúde pública, como um primeiro passo para estudar a influência do pensamento epidemiológico e o pensar da academia. Para este propósito, a base de dados do Institute for Scientific Information/ Thomson Scientific - Web of Science/ Web of Knowledge foi consultada em maio de 2006. O livro de Rothman & Greenland recebeu o maior número de citações no total (mais de 8.000) e por ano. Os livros de Kleinbaum et al, e de Breslow & Day tiveram em torno de 5.000 citações. Em termos de citações por ano, o livro de Sackett et al ocupou o terceiro lugar, e o de Rose, o quarto entre os incluídos no estudo. Outros livros que tiveram influência em salas de aula, comparativamente, tiveram menos citações. Os achados oferecem um rico retrato das influências acadêmicas e tendências de métodos epidemiológicos e interpretação em saúde pública, medicina clínica e outras ciências da saúde, da vida, e sociais. Eles podem contribuir para avaliar os esforços dos epidemiologistas para demarcar a epidemiologia e afirmar sua autoridade epistemológica, e para analisar algumas influências históricas de forças econômicas, sociais e políticas sobre as pesquisas epidemiológicas.