Prevalence of DNA-Repair Gene mutations in Mexican men with prostate cancer.

INTRODUCTION AND OBJECTIVE: Mexico reported 26,742 new cases of prostate cancer in 2020. Different risk factors have been identified in the pathogenesis of prostate cancer. Among them, genetic factors and alterations or mutations in specific genes have been described in different ethnic groups worldwide. The aim of our study is to report the prevalence of germline DNA-repair gene mutations in Mexican patients with prostate cancer. MATERIAL AND METHOD: We performed germline genetic testing in 50 patients with localized prostate cancer and 50 patients with metastatic prostate cancer. Demographic, clinical, and histopathological data were collected. RESULTS: Thirty-seven germline mutations were identified in 32 patients. The most commonly affected genes were ATM in 6%, followed by FANCA (5%), and ATR (4%). BRCA2 mutations were identified in 3%. The frequency of mutations was higher in the metastatic group. DISCUSSION AND CONCLUSION: The results of our study show different mutations from those reported in different populations or regions. The use of PARP inhibitors is indicated in patients with germline mutations, specifically BRCA2, showing improvement in overall survival and progression free survival. To our knowledge, this is the first study reporting the prevalence of mutations in DNA-repair genes in Mexican patients with prostate cancer.

Hormone replacement therapy and cervical cancer: a systematic review of the literature.

Gynecological tumor treatment, including cervical cancer (CC) treatment, often leads to iatrogenic premature menopause. This highlights the critical importance of investigating indications for hormone replacement therapy (HRT), as most patients, thanks to the improvement in diagnosis and treatment, have to deal with the sequelae of their cancer treatments for many years. This systematic review aims to provide an overview of the current knowledge regarding the risks of HRT and CC. In particular, we aim to investigate whether the use of HRT can increase CC incidence, and evaluate its risk in CC survivors. A systematic review, in agreement with PRISMA guidelines, of the English literature present in PubMed and SCOPUS has been performed. A total of 2805 articles have been screened, of which 10 were considered eligible. Several studies reported a significantly reduced risk of developing cervical squamous cell carcinoma in postmenopausal women treated with HRT, while a weak increase in the incidence of adenocarcinoma has been shown. No evidence reports a harmful effect of HRT on CC oncological outcome, while several benefits, in terms of reduced metabolic risk and increased quality of life, have been described, thus concluding that HRT should be offered to young CC survivors for the management of early menopause.

The interplay between immune system and microbiota in gynecological diseases: a narrative review.

OBJECTIVE: The vaginal microbiome is a dynamic environment, depending on the results of a complex interplay between microbiota and the host. In physiological conditions, Lactobacillus species are the most represented, regulating glycogen metabolism in order to maintain normal pH. Vaginal flora has been divided into five subtypes. Pattern recognition receptors are present on both squamous epithelial cells lining the vagina and columnar cells lining the upper female genital tract. They respond directly to bacterial product expressed by vaginal microbiome. The vagina contains different immune related cells and receptors which can recognize and react with the microbial environment. Altered microbiota and altered interplay between microbiota and immune system underlie several gynecologic diseases. MATERIALS AND METHODS: In this review, literature data related to vaginal microbiota, vaginal inflammation, immune system and menopause, preterm labor and miscarriage, were summarized. Relevant publications were retrieved from: PubMed, Medline, Scopus and Web of Science. RESULTS: The vaginal microbiome and the relationship with immune system has been analyzed in different gynecologic conditions. Menopause is associated to estrogen loss which causes vaginal atrophy, reduced abundance of Lactobacilli and increased amount of other bacterial species. Estrogens influence vaginal immunity through known and unknown mechanisms. In bacterial vaginosis (BV), due to many bacterial species, there has been found an inhibition of the chemotaxis and cytokine secretion. A decreased concentration of Lactobacilli seems to be playing a role in preterm labor as well as the increased levels of pro-inflammatory cytokines. Finally, the disequilibrium in the Th1/Th2 immune adaptive response, with a shift from Th2 to Th1, appears to be playing a role in miscarriage. CONCLUSIONS: The interplay between microbiota and the host closely involves the immune system. In particular, the vaginal microbiota is classically characterized by Lactobacilli even if vaginal microbiome of asymptomatic woman of reproductive age includes multiple aerobic and facultative or obligate anaerobic species. The role of microbiota and immune system in determining gynecological and obstetric events has been studied throughout recent years reaching new advancements. Therefore, additional studies are needed to better comprehend the complexity of the issue.

Fertility preservation in chemo-radiotherapy for rectal cancer: A combined approach.

INTRODUCTION: Colorectal cancer is a very common form of cancer worldwide, affecting an increasing number of young women. Standard treatment for locally advanced rectal cancer (LARC) can pose a threat to fertility in these patients. CASE PRESENTATION: We present the case of a young woman affected by LARC who expressed a desire for child-bearing. The treatment she was proposed, according to guidelines, was neoadjuvant chemo-radiotherapy (CRT) followed by delayed surgery, carrying with it a high risk for amenorrhea. Counselling was performed before the initiation of treatment, with the aim of preserving fertility by the proposal of GnRH agonist administration, ovarian transposition and ovarian tissue cryopreservation, which the patient accepted. Treatment was then successfully completed. The patient presented regular menstrual period from before the surgery. DISCUSSION: Ovarian tissue is very sensitive to radiations. Transposition of the organ can prevent ovarian insufficiency by placing it outside the radiation field, while ovarian tissue cryopreservation and orthotopic transplantation offers the possibility to restore fertility in the case of organ failure. We performed both of the techniques. GnRH analogs administration allowed to diminish the risk of ovarian cytotoxicity. Radiation treatment plan was optimized in order to minimize the dose to organs at risk (ovary and vagina in particular); position of the uterus, which is quite radiosensitive too, was monitored with daily cone-beam CT (CBCT). CONCLUSION: The strategy proposed seemed safe and effective, resulting in radical treatment and persistence of regular menstrual period. Further studies are needed.

Approach to sexual dysfunction in women with cancer.

Sexual dysfunction in female cancer patients remains under-diagnosed and under-treated. As sexual dysfunction is becoming an increasingly common side effect of cancer treatments, it is imperative for healthcare providers and especially gynecologic oncologists to include a comprehensive evaluation of sexual health as a routine part of the workup of such patients. Although most oncologists are not experienced in treating sexual dysfunctions, simple tools can be incorporated into clinical practice to improve the management of these conditions. In this review, we propose a practical approach to selecting proper treatment for sexual dysfunctions in female cancer patients. This includes three main steps: knowledge, diagnosis, and sexual counseling. Knowledge can be acquired through a specific updating about sexual issues in female cancers, and with a medical training in female sexual dysfunctions. Diagnosis requires a comprehensive history and physical examination. Sexual counseling is one of the most important interventions to consider and, in some cases, it may be the only intervention needed to help cancer patients tolerate their symptoms. Sexual counseling should be addressed by oncologists; however, select patients should be referred for qualified psychological or sexological interventions where appropriate. Finally, a multidisciplinary team approach may be the best way to address this challenging issue.

Comparison of clinical and cognitive characteristics of a Mexican adult clinical population with and without ADHD / Comparación de las características clínicas y cognitivas de una población clínica adulta mexicana con y sin TDAH

Abstract Introduction Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting approximately 5% of the world population, with symptoms that may persist into adulthood. Despite the findings on the clinical course of this disorder, information regarding comorbidity patterns, psychosocial and executive functioning in adult life in those with and without ADHD in Latin American samples is scarce. Objective The aim of this study is to compare the comorbidity pattern, psychosocial, and executive functioning of adults with and without ADHD from a clinical sample. Method One hundred and fifty-one patients between 20 and 45 years, with screened positively on ASRS-V1.1, were invited to continue an evaluation process as part of clinical research program (PROMETEO): 1) K-SADS-PL Mx interview, 2) MINI-Plus interview, ASRS-V1-1 18 item version, BRIEF self-reported questionnaire, SCQA-ADHD, and 3) Individual case review by clinical expert in ADHD. Results Individuals in the ADHD group had a higher average of comorbid disorders (2.5 SD 1.1 vs. 1.3 SD 1.0 respectively, F = .439; t = -6.621; df = 149; p < .001), more likelihood of procrastinating (OR = 6.5; 95% CI[2.6, 16.2]; z = 4.0) and were more likely to present difficulties in both the behavior regulation index (OR = 104.9; 95% CI[31.8, 345.7]; z = 7.65) and the metacognitive index (OR = 94.79; 95% CI[29.10, 308.76]; z = 7.56) compared to the non-ADHD group, regardless of gender. Discussion and conclusions Our results indicate that the ADHD adult group presented with more comorbidity, and worse psychosocial and executive functioning than non-ADHD adults.

Resumen Introducción El trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno del neurodesarrollo que afecta aproximadamente al 5% de la población mundial, persistiendo hasta la adultez. A pesar de los hallazgos acerca del curso clínico de este trastorno, la información es escasa con respecto a los patrones de comorbilidad, funcionamiento psicosocial y ejecutivo en la vida adulta entre aquellos con y sin TDAH en muestras latinoamericanas. Objetivo Comparar el patrón de comorbilidad, el funcionamiento psicosocial y ejecutivo de adultos con y sin TDAH de una muestra clínica. Método Ciento cincuenta y un pacientes entre 20 y 45 años, quienes inicialmente presentaron un tamizaje positivo del ASRS-V1.1, fueron evaluados dentro de un programa de investigación clínica (PROMETEO) con los siguientes instrumentos: 1) la entrevista K-SADS-PL-Mx, 2) la entrevista MINI-Plus, la version de 18 items del ASRS-V1-1, y los cuestionarios autoaplicados BRIEF y SCQA-ADHD y 3) Revisión de cada caso por un clínico experto en el diagnóstico de TDAH. Resultados El grupo de TDAH comparado con aquel sin TDAH presentó un mayor promedio de trastornos comórbidos (2.5 DE 1.1 vs 1.3 DE 1.0 respectivamente, F = .439; t = -6.621; gl = 149; p < .001), mayor probabilidad de procrastinar (OR = 6.5; 95% IC[2.6, 16.2]; z = 4.0), y mayor probabilidad de presentar dificultades tanto en el índice de regulación de la conducta (OR = 104.9; 95% IC[31.8, 345.7]; z = 7.65) como en el índice metacognitivo (OR = 94.79; 95% IC[29.10, 308.76]; z = 7.56) independientemente del sexo. Discusión y conclusión Nuestros resultados señalan que los adultos con TDAH presentan mayor comorbilidad y peor funcionamiento psicosocial y ejecutivo que los adultos sin TDAH.

Menopausia y terapia hormonal de la menopausia. Las recomendaciones 2018 de la Unidad de Endocrinología Ginecológica de Clínica Alemana de Santiago -Sociedad Italiana de la Menopausia y la Sociedad Chilena de Endocrinología Ginecológica / Menopause and menopausal hormone therapy. The 2018 recommendations of the Gynecological Endocrinology Unit of Clínica Alemana de Santiago -Italian Society of Menopause and the Chilean Society of Gynecological Endocrinology

ABSTRACT In the last decade, the risk benefits ratio of MHT has been evaluated mainly in terms of cardiovascular risk. Present Consensus Statement is largely inspired by the Global Consensus on Menopausal Hormone Therapy in 2013 and 2016 by leading global menopause societies (The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society). The aim of these Recommendations is to provide a simple and updated reference on postmenopausal MHT. The term MHT typically includes estrogen replacement therapy (ERT) and estrogen-progestogen therapy (EPT). EPT can be sequential (Seq) when progestogen is added to ERT for 10-14 days a month, or continuous combined (CC) when progestogen is administered continuously every day along with a fixed amount of estrogen. MHT also includes Tibolone and the Tissue Selective Estrogen Complex (TSEC).

A non-invasive prevention program model for the assessment of osteoporosis in the early postmenopausal period: a pilot study on FRAX(®) and QUS tools advantages.

OBJECTIVE: The study analyses the performances of FRAX algorithm and quantitative ultrasound (QUS) tool in relationship to the dual-energy X-ray absorptiometry (DXA) categorization to identify patients at risk of osteoporosis during menopause and to reach new thresholds for recommending the first DXA examination. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Two hundred eighty-two postmenopausal patients filled out a questionnaire which determined their FRAX index and performed a bone evaluation by QUS of the calcaneus to determine their stiffness index (SI). Thereafter, they underwent assessments by the gold-standard DXA bone examination. RESULTS: Statistically significant correlations were observed between FRAX (calculated without BMD) and both QUS and DXA diagnosis. FRAX mean indices of risk corresponding to the diagnosis of osteoporosis by QUS and DXA were similar. Receiver operating characteristic (ROC) curve analysis showed that both FRAX and QUS tests were sufficiently accurate in predicting the alteration of bone mineral composition. The ROC curves of QUS allowed us to identify, in our population, SI cutoff for normal patients (SI > 90.5) and for patients having osteoporosis (SI < 78.5). We selected a cutoff screening value from FRAX ROC curve for major clinical fracture (2.94). The following diagnostic algorithm demonstrated that the use of FRAX test alone has a sensitivity of 85.3 % and a specificity of 33.8 % while the use of QUS exam alone showed a sensitivity of 81.3 % and a specificity of 45.1 %. When considering the capacity of QUS exam in combination with FRAX test, the final algorithm showed a sensitivity of 69.4 % and a specificity of 57.7 %. CONCLUSIONS: The use of QUS test with adjusted cutoffs offers a similar performance to the FRAX test alone in terms of sensitivity. The combined use of the tests reduces the sensibility but increases the specificity and adds clinical information related to the bone status of the patient.

Non-hormonal treatment of vulvo-vaginal atrophy-related symptoms in post-menopausal women.

In post-menopausal period vulvo-vaginal atrophy (VVA)-related symptoms may seriously affect women's quality of life. Hormonal replacement therapy effectively relieves these symptoms but it is not always safe or accepted, and a non-hormonal treatment is often needed instead. Over a period of 12 weeks, we tested the effect of a twice-a-week vulvo-vaginal application of a hyaluronic acid, AC collagen, isoflavones and vitamins-based cream (Perilei Pausa) on 35 women in post-menopausal period, reporting VVA-related symptoms. After 12 weeks of treatment with Perilei Pausa a significant improvement in vaginal dryness, vulvo-vaginal itching, dyspareunia (P < 0.001), dysuria (P = 0.02), nocturia (P = 0.009) and pollakiuria (P = 0.005) was reported by the women. Colposcopical score assessing the intensity of atrophic colpitis, cervico-vaginal paleness and petechiae was also reduced (P = 0.037, P = 0.016 and P = 0.032, respectively). No significant difference in terms of maturation value of cervico-vaginal epithelium was observed. In conclusion, Perilei Pausa may represent an effective and safe alternative treatment of symptomatic VVA in post-menopausal women.

Infecciones osteoarticulares no vertebrales por Candida spp. en un hospital de alta complejidad en Medellín, Colombia / Non vertebral osteoarticular infections by Candida spp. in a hospital of high complexity in Medellín, Colombia / Infecções osteoarticulares não vertebrais por Cândida spp. num hospital de alta complexidade em Medellín, Colômbia

Objetivo: describir las características clínicas y demográficas de pacientes con osteomielitis por Candida spp. en el Hospital Pablo Tobón Uribe de Medellín. Metodología: observacional descriptiva. Resultados: se encontraron 30 pacientes con osteomielitis por Candida spp. El 70% está conformado por hombres, con una media de edad de 49.9 años. El 46% tenía como antecedente algún tipo de inmunosupresión. El 60% tenía osteomielitis por Candida spp. como único aislamiento y 40%, osteomielitis bacteriana concomitante. Un paciente tuvo candidemia. El 46% tenía previamente una intervención quirúrgica y el 26% algún tipo de material de osteosíntesis. 26 pacientes (86%) recibieron antibióticos previamente, y son los carbapenémicos, piperacilina, tazobactam y vancomicina los más utilizados. El hueso largo fue el segmento óseo más afectado: 33%. Candida no albicans estuvo en el 63% y Candida spp. en un 3.3%. De Candida no albicans la más frecuente fue Candida. parapsilosis en 57%. El 97% de los aislamientos fue sensible a fluconazol y voriconazol. El 46% completó tratamiento. De un 43% no se obtuvo el dato de seguimiento y el 6.6% no completó el tratamiento. Conclusiones: la osteomielitis por Candida es una entidad que está en aumento y crea la necesidad de realizar estudios analíticos para explorar los factores de riesgo relacionados. Además, se confirma el aumento de los aislamientos de Candida no albicans que se describe en la literatura y se encontró sólo un caso con sensibilidad intermedia a fluconazol.

Objective: To describe the clinical and demographical characteristics of patients with osteomyelitis due to Candida spp. in Hospital Pablo Tobón Uribe in Medellín. Methodology: Observational, descriptive study. Results: Thirty patients were found to have osteomyelitis due to Candida spp. Of these, 70% were male, with a mean age of 49.9 years. 46% had a history of some type of immunosuppression; 60% had osteomyelitis due to Candida spp. where it was the only microorganism isolated and 40% had concomitant bacterial osteomyelitis. One patient had candidemia. 46% had previously undergone surgery and 26% had had some type of osteosynthesis material. Twenty-six patients (86%) had previously received antibiotics, where carbapenems, piperacillin, tazobactam, and vancomycin were the most frequently used. The long bones were the most affected osseous segments (33%). Non-albicans Candida was 63% and Candida spp. 3.3%. The most frequent of non-albicans Candida was Candida parapsilosis in 57%. 97% of isolations were sensitive to fluconazole and voriconazole. 46% finished treatment. Follow-up data were not collected from 43%, while 6.6% did not finish treatment. Conclusions: As osteomyelitis due to Candida is increasing, analytic studies are warranted to explore associated risk factors. There was also an increase in non-albicans Candida compared to that which has been described in the literature, and only one case was found to have intermediate sensitivity to fluconazole.

Objetivo: descrever as características clínicas e demográficas de pacientes com osteomelite por Cândida spp. no Hospital Pablo Tobón Uribe de Medellín. Metodologia: observacional descritiva. Resultados: se encontraram 30 pacientes com osteomelite por Cândida spp. 70% está conformado por homens, com uma idade meia de 49.9 anos. 46% tinha como antecedente algum tipo de imunossupressão. 60% tinha osteomelite por Cândida spp. como único isolamento e 40%, osteomelite bacteriana concomitante. Um paciente teve candidemia. 46% tinha previamente uma intervenção cirúrgica e 26% algum tipo de material de osteosíntese. 26 pacientes (86%) receberam antibióticos previamente, e são os carbapenémicos, piperacilina, tazobactam e vancomicina os mais utilizados. O osso longo foi o segmento ósseo mais afetado: 33%. Cândida não albicans esteve em 63% e Cândida spp. em 3.3%. De Cândida não albicans a más frequente foi Cândida parapsilosis em 57%. 97% dos isolamentos foi sensível a fluconazol e voriconazol. 46% completou tratamento. De um 43% não se obteve dato de seguimento e 6.6% não completou o tratamento. Conclusões: a osteomielitis por Cândida é uma entidade que está em aumento e cria a necessidade de realizar estudos analíticos para explorar os fatores de risco relacionados. Ademais, se confirma o aumento dos isolamentos de Cândida não albicans que se descreve na literatura e se encontrou só um caso com sensibilidade intermedia a fluconazol.

Low- and standard-estrogen dosage in oral therapy: dose-dependent effects on insulin and lipid metabolism in healthy postmenopausal women.

OBJECTIVE: To evaluate the influences of different doses of daily oral unopposed 17beta-estradiol compared with placebo, both on glucose tolerance and lipid metabolism in healthy postmenopausal women. PATIENTS AND METHODS: Forty-eight normoinsulinemic postmenopausal women were enrolled in the study. Patients were assigned to receive randomly 1 mg (group A) or 2 mg (group B) of oral micronized estradiol therapy daily or to the placebo (group C), for 12 weeks. RESULTS: The low-dose estradiol treatment determined an improvement of the peripheral insulin sensitivity, made evident by a significant increase both in the metabolic index and oral glucose insulin sensitivity index (p < 0.01 and p < 0.05, respectively) as well as a decrease in the homeostasis model assessment-estimated insulin resistance (p < 0.01). Conversely, in the standard-dose group, the metabolic index significantly decreased (p < 0.05), showing a slight deterioration in insulin sensitivity. For lipid metabolism, the 1 mg dose showed a neutral effect, while 2 mg had a beneficial effect on low density lipoprotein cholesterol, but caused an increase in triglycerides (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: The oral low dose of unopposed estradiol therapy had a favorable effect on glycoinsulinemic metabolism in healthy postmenopausal women; however, the standard dose caused a slight but significant deterioration in insulin sensitivity.

Diagnostic usefulness of inflammatory markers in acute cellular rejection after heart transplantation.

BACKGROUND: Acute cellular rejection (ACR) affects early morbidity and mortality after heart transplantation. The diagnostic technique of choice is endomyocardial biopsy. Our aim was to evaluate the diagnostic usefulness of inflammatory markers as a noninvasive method to monitor cellular rejection. MATERIAL AND METHODS: We prospectively analyzed 73 cardiac transplant patients by determining the serum levels of protein fibrinogen (fgpro), functional fibrinogen (fgfun), C-reactive protein (CRP), and sialic acid (SA) coinciding with an endomyocardial biopsy (5.1 revisions/patient). The statistical methods were chi(2), Student's t-test, and ROC curves. RESULTS: Of the 373 controls, significant rejection was detected in 19%. Analysis of the relationship between ACR and the markers showed significantly elevated levels of fgpro (345 +/- 90 versus 307 +/- 74 mg/dL; P = .03), fgfun (361 +/- 101 versus 318 +/- 89 mg/dL; P = .04), and SA (74 +/- 22 versus 66 +/- 15 mg/dL; P = .02), but not CRP (19 +/- 29 versus 10 +/- 21 mg/dL; P = .07). SA displayed a better diagnostic utility (area under the curve 0.7; P < .01), 35% sensitivity, 85% specificity, and 82% negative predictive value for a cutoff point of 80 mg/dL. CONCLUSIONS: Among the inflammatory markers increased in ACR, SA was the most useful noninvasive tool for screening.

Which treatment options should be used in adolescents with polycystic ovary syndrome?

Several studies have hypothesized a peripubertal onset of polycystic ovary syndrome (PCOS). This syndrome affects different pathogenetic pathways and includes endocrine-metabolic abnormalities such as hyperandrogenism, hyperinsulinism and insulin resistance. The therapeutic approaches must be addressed to individualization of therapy, considering the major clinical manifestations of the syndrome during adolescence. While the treatment of hyperandrogenism makes use of different drugs already studied, the debate about the use of insulin sensitizing drugs is still open. It will be more and more necessary to define the phenotypic and genotypic milieu in which all treatments will be as safe and effective as possible.

Insulin and GH secretion in adolescent girls with irregular cycles: polycystic vs multifollicular ovaries.

In the present study insulin (I) and GH secretion was studied in a group of twenty-five young adolescent girls (mean age: 15 +/- 0.23 yr) with cycle irregularity associated to clinical signs of hyperandrogenism in comparison with that observed in eleven normal matched subjects with regular menses. All patients underwent basal hormone measurements and, on two consecutive days, an oral glucose tolerance test (OGTT) and a GHRH iv test. Therefore, all subjects had a transabdominal US scan for the measurement of ovarian volume and the characterization of ovarian morphology. On the basis of the US examination we found patients with polycystic ovaries (PCO-like group) and subjects with multifollicular ovaries (MFO group). PCO-like group exhibited T (p<0.01) and LH (p<0.05) plasma levels higher than control group and the highest free androgen index (FAI) values (13 +/- 0.87). All patients with irregular menses showed plasma concentrations of AUC for I (AUC-I) significantly higher in respect to control group (7359.4 +/- 709 vs 5447 +/- 431 microIU/ml x 180 min, p<0.01) as well as both PCO-like group and MFO group did (p<0.001 and p<0.01) respectively. MFO group showed higher values of the AUC for GH (AUC-GH) (2809 +/- 432 ng/ml x 120 min) in respect to controls (1708 +/- 208 ng/ml x 120 min, p<0.05) and PCO-like subjects (p<0.001), who on the contrary showed the lowest AUC-GH values (618 +/- 119 ng/ml x 120 min). In conclusion, PCO-like patients associated hyperinsulinemia with a blunted GH secretion while MFO patients had higher GH secretion associated with higher AUC-I values in a way suggesting an immature and still developing reproductive system.

Individual effect of E2 and dydrogesterone on insulin sensitivity in post-menopausal women.

The aim of this study was to evaluate the impact of a three-month continuous administration of oral E2, alone, or combined with 2 different dosages of dydrogesterone, on the glucose tolerance and insulin sensitivity in postmenopausal women. In a prospective placebo-controlled study, 43 normal weight and normoinsulinemic women were randomized to receive either 2 mg of oral 17beta E2 daily (group A), or 2 mg E2 daily plus 5 mg daily oral dydrogesterone, from day 14 to 28, in a sequentially combined regimen (group B), or 2 mg of E2 and 10 mg dydrogesterone in the same sequentially combined regimen (group C) or placebo for 12 weeks. An OGTT and a euglycemic hyperinsulinemic clamp were performed before and after treatment. Serum glucose and insulin concentrations were measured both in fasting conditions and after OGTT. C-peptide pancreatic secretion was tested only in fasting conditions. Total body glucose utilization (M), for insulin sensitivity evaluation, was determined in each subject. Postmenopausal women treated with unopposed 17beta E2 (group A) showed a slight but statistically significant decrease of insulin sensitivity (p<0.05). A more marked deterioration of the same parameter was observed in the 2 groups treated with E2 plus dydrogesterone (group B and group C: p<0.01). Post hoc testing for the percent change from baseline indicated that group A significantly differed from group C (p<0.05) and all treated groups significantly differed from the placebo group (p<0.01). Finally, after treatment in group C, a significant reduction of insulin and an increase of glucose responses to OGTT (p<0.01) were observed. These results indicate that, in a short-term period, the use of 17beta E2 and overall 17beta E2 plus dydrogesterone, even with the reduction of insulin plasma levels, might cause a decrease in insulin sensitivity in normal weight and normoinsulinemic post-menopausal women.

Factor V Leiden and prothrombin G20210A in relation to arterial and/or vein rethrombosis: two cases.

The factor V Leiden (FV Leiden) and prothrombin G20210A mutations, are the most common established genetic risk factors for deep vein thrombosis (DVT). However, the relationship between these mutations and arterial thrombotic syndromes (coronary heart disease, myocardial infarction, stroke) has not been established. Some studies have suggested a relationship between them, but other authors have considered it unlikely that these anomalies are a major risk factor for arterial thrombosis. From the clinical point of view, a question arises concerning the risk of repeated thrombosis in patients carrying one of these two mutations. The question is whether the recurrence is attributable to the mutations or to the presence of additional circumstantial risk factors. As the risk of repeated thrombosis varies considerably from one patient to another, decisions about long-term treatment require weighing the persistence of risk factors for vascular disease (venous and arterial), especially in selected cases such as young patients or patients with thrombosis of unusual localization.

Synergistic efficacy of 3n-butyrate and 5-fluorouracil in human colorectal cancer xenografts via modulation of DNA synthesis.

BACKGROUND & AIMS: Butyrate, produced in the colon lumen, maintains mucosal cell homeostasis. Poorly diffusible, its access is compromised in growing colon cancers and absent in distant metastases. Butyrate regulates DNA synthesis. We postulated that systemic administration of butyrate should reduce colon cancer growth and enhance 5-fluorouracil (5-FU) efficacy. METHODS: A stable derivative of butyrate (3n-But) was used. The antitumoral efficacy of 5-FU and 3n-But, alone or combined, was evaluated in human colorectal cancers (hCRCs) subcutaneously, orthotopically, or intrasplenically grafted into nude mice. Thymidylate synthase (TS) and thymidine kinase (TK) mRNA expression, proliferation, apoptosis, and cell cycle alterations were studied. RESULTS: In vivo, 5-FU alone inhibited growth of only 3 of the 12 hCRCs tested and 3n-But alone had no effect; the 5-FU/3n-But combination inhibited growth of all 16 hCRCs tested. The hCRCs differed in their p53 and microsatellite instability status. 5-FU/3n-But decreased TK and TS mRNA expression by 20- and 40-fold, respectively, and TS activity by 75%, stopped cell proliferation without affecting cell differentiation, and significantly enhanced apoptosis. 3n-But potentiated the efficacy of Tomudex and methotrexate, 2 TS inhibitors, but not that of oxaliplatin. In vitro, 5-FU/3n-But inhibited [3H]thymidine but not bromodeoxyuridine incorporation and induced apoptosis in hCRC cell lines. Cells treated with 5-FU/3n-But did not accumulate in G1 nor in S phase of the cell cycle, while 5-FU and 3n-But arrested the cycle in S and in G1 phase, respectively. 3n-But prevented the cell rescue from 5-FU-induced cytotoxicity by uridine or thymidine. CONCLUSIONS: 3n-But and TS inhibitors acted synergistically against colorectal cancers, independently of the genetic alterations of the hCRCs. The mechanism of action of 5-FU/3n-But could be enhanced reduction of TS and prevention of thymidine salvage in DNA synthesis.

Effect of feeding on growth hormone response to growth hormone-releasing hormone in polycystic ovarian syndrome: relation with body weight and hyperinsulinism.

The plasma growth hormone (GH) response to direct stimulation with growth hormone-releasing hormone (GHRH) before and after a standard meal was investigated in 14 polycystic ovarian syndrome (PCOS) subjects. Data were compared with those obtained from 14 healthy normovulatory matched patients. All women underwent an oral glucose tolerance test (OGTT) (75 g) and basal plasma hormone concentrations were evaluated. On a different day all subjects had a GHRH test (50 microg GHRH) both before and after lunch randomly. In obese PCOS subjects the GH response to GHRH was blunted after a meal, while in obese control patients there was an enhanced response of GH to GHRH after a meal. Normal control subjects showed an inhibition of the GH response after feeding and lean PCOS subjects showed a trend toward an augmented GHRH related secretion after a meal significantly higher than normal controls (P < 0.05) but not significantly higher than the pre-prandial response. In conclusion, the data indicate in PCOS a derangement of GH secretion related to food ingestion; in particular obese PCOS patients did not exhibit any change of GH response after a meal compared with the paradoxical response observed in obese controls. Several other factors beyond body mass index and hyperinsulinism could be involved in these pathophysiological events.

Decrease in brain cytochrome P450 enzyme activities during infection and inflammation of the central nervous system.

The effect of infection and inflammation of the central nervous system (CNS) on cytochrome-P450-dependent activities in brain, spinal cord and liver microsomes was determined. For this, two models were used: (1) the intracerebroventricularly injected lipopolysaccharide (LPS) model and (2) the experimental auto-immune encephalomyelitis (EAE) model. In the LPS model, aminopyrine N-demethylase (AMND) and ethoxycoumarin O-deethylase (ECOD) activities (both P450 dependent) were significantly decreased (35 and 20%, respectively) in brain microsomes. In the EAE model, only ECOD activity was significantly lower (18%). In the liver, a decrease in total P450, AMND and ECOD activities was only observed in the LPS model. In both models, tumour necrosis factor (TNF) was significantly elevated in brain and spinal cord tissues. In serum, TNF was only detectable in the LPS model. It is concluded that an infection or inflammation located in the CNS, which is accompanied by high TNF levels, results in a decrease in P450-dependent metabolism not only in the liver but in the brain as well.