La biologie moléculaire est-elle utile au praticien [Is molecular biology useful to the practitioner?]

The relative importance of molecular biology in clinical practice is often underestimated. However, numerous procedures in clinical diagnosis and new therapeutic drugs have resulted from basic molecular research. Furthermore, understanding of the physiological and physiopathological mechanisms underlying several human diseases has been improved by the results of basic molecular research. For example, cloning of the gene encoding leptin has provided spectacular insights into the understanding of the mechanisms involved in the control of food intake and body weight maintenance in man. In cystic fibrosis, the cloning and identification of several mutations in the gene encoding the chloride channel transmembrane regulator (CFTR) have resolved several important issues in clinical practice: cystic fibrosis constitutes a molecular defect of a single gene. There is a strong correlation between the clinical manifestations or the severity of the disease (phenotype) with the type of mutations present in the CFTR gene (genotype). More recently, identification of mutations in the gene encoding a subunit of the renal sodium channel in the Liddle syndrome has provided important insight into the physiopathological understanding of mechanisms involved in this form of hereditary hypertension. Salt retention and secondary high blood pressure are the result of constitutive activation of the renal sodium channel by mutations in the gene encoding the renal sodium channel. It is speculated that less severe mutations in this channel could result in a less severe form of hypertension which may correspond to patients suffering from high blood pressure with low plasma renin activity. Several tools, most notably PCR, are derived from molecular research and are used in everyday practice, i.e. in prenatal diagnosis and in the diagnosis of several infectious diseases including tuberculosis and hepatitis. Finally, the production of recombinant proteins at lower cost and with fewer side effects is used in everyday clinical practice. Gene therapy remains an extraordinary challenge in correcting severe hereditary or acquired diseases. The use of genetically modified animal cell lines producing growth factors, insulin or erythropoetin, which are subsequently encapsulated and transferred to man, represents an attractive approach for gene therapy.

Congenital tracheal anomalies.

Congenital tracheal lesions are rare, but important, causes of morbidity in infants and children. Consequently, experience in their management is limited and dispersed. Given its small diameter, the juvenile trachea is obstructed easily by various natural causes, or following a surgical intervention. The diagnosis of a congenital, tracheal, obstructive anomaly is based on a high degree of suspicion in infants and children with respiratory distress accompanied by retraction. In this article, the authors discuss the various causes of these conditions, their diagnostic features, and the treatment possibilities.

Modificaciones en el consumo de tabaco durante la gestación y el posparto

Objetivo: Averiguar el consumo de tabaco y las modificaciones del hábito durante la gestación, y observar las recaídas después del parto. Personas y método: Estudio descriptivo transversal, realizado en el PASSIR «Casagemas», Badalona, desde febrero de 2006 a septiembre de 2007. Se incluyó a 115 gestantes que acudieron a la consulta de control prenatal en el tercer trimestre de gestación, y se excluyeron las que no fumaban al inicio de la gestación. Se recogieron variables sociodemográficas y las relacionadas con el hábito tabáquico a través de un cuestionario en la gestación y otro en el posparto. Resultados: Dejaron de fumar el 26% (30) de las gestantes, y las que continuaron fumando redujeron el consumo de una media de 19,2 (DE= 6,7) a 7,2 (DE= 6) cigarrillos/día. Se observaron diferencias en el abandono del tabaco en aquellas que fumaban un menor número de cigarrillos (p <0,001), en las que iniciaron el tabaquismo más tarde y en las de mayor edad (p= 0,013). Al año del parto, seguían fumando el 73% (70) de las mujeres, y habían recaído en el hábito el 39,2% (11) de las que lo habían abandonado en la gestación. Las mujeres que no fumaban lactaron a sus hijos un 76,9% (20), mientras que las que fumaban lo hicieron un 57,1% (40). La duración media de la lactancia fue inferior en las mujeres que fumaron en el posparto (2,81 meses [DE= 3,4]) en relación con las que no lo hicieron (4,96 meses [DE= 4,1]; p= 0,01). Conclusiones: La tasa de abandono del tabaco durante el embarazo es aún muy baja, y el índice de recaída del hábito tabáquico en el posparto, elevada.

Modificaciones en el consumo de tabaco durante la gestación y el posparto

Objetivo: Averiguar el consumo de tabaco y las modificaciones del hábito durante la gestación, y observar las recaídas después del parto. Personas y método: Estudio descriptivo transversal, realizado en el PASSIR «Casagemas», Badalona, desde febrero de 2006 a septiembre de 2007. Se incluyó a 115 gestantes que acudieron a la consulta de control prenatal en el tercer trimestre de gestación, y se excluyeron las que no fumaban al inicio de la gestación. Se recogieron variables sociodemográficas y las relacionadas con el hábito tabáquico a través de un cuestionario en la gestación y otro en el posparto. Resultados: Dejaron de fumar el 26% (30) de las gestantes, y las que continuaron fumando redujeron el consumo de una media de 19,2 (DE= 6,7) a 7,2 (DE= 6) cigarrillos/día. Se observaron diferencias en el abandono del tabaco en aquellas que fumaban un menor número de cigarrillos (p <0,001), en las que iniciaron el tabaquismo más tarde y en las de mayor edad (p= 0,013). Al año del parto, seguían fumando el 73% (70) de las mujeres, y habían recaído en el hábito el 39,2% (11) de las que lo habían abandonado en la gestación. Las mujeres que no fumaban lactaron a sus hijos un 76,9% (20), mientras que las que fumaban lo hicieron un 57,1% (40). La duración media de la lactancia fue inferior en las mujeres que fumaron en el posparto (2,81 meses [DE= 3,4]) en relación con las que no lo hicieron (4,96 meses [DE= 4,1]; p= 0,01). Conclusiones: La tasa de abandono del tabaco durante el embarazo es aún muy baja, y el índice de recaída del hábito tabáquico en el posparto, elevada.

Fetal laser therapy: applications in the management of fetal pathologies.

Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy.

Anxiety, depression, and attachment before and after the first-trimester screening for Down syndrome: comparing couples who undergo ART with those who conceive spontaneously.

OBJECTIVES: This study's aim was to describe the emotional status of parents to be before and after the first-trimester combined prenatal screening test. METHODS: One hundred three couples participated, of which 52 had undergone an in vitro fertilization/intracytoplasmic sperm injection treatment [assisted reproductive technology (ART)] and 51 had conceived spontaneously. Participants completed the state scale of the State-trait Anxiety Inventory, the Edinburgh Depression Scale, and the Maternal and Paternal Antenatal Attachment Questionnaire before the first-trimester combined prenatal screening test at around 12 weeks of gestational age (T1) and just after receiving the results at approximately 14 weeks of gestational age (T2). RESULTS: We observed a significant decrease in anxiety and depression symptoms and a significant increase in attachment from T1 to T2. Results showed no differences between groups at either time point, which suggests that ART parents are more similar to than different from parents conceiving spontaneously. Furthermore, given the importance of anxiety during pregnancy, a subsample of women with clinical anxiety was identified. They had significantly higher rates of clinical depression and lower attachment. CONCLUSIONS: These results indicate that, regardless of whether conception was through ART or spontaneous, clinical anxiety in women over the prenatal testing period is associated with more vulnerability during pregnancy (i.e. clinical depression and less attachment to fetus). © 2015 John Wiley & Sons, Ltd.

Imaging findings in fetal diaphragmatic abnormalities.

Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome.

Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study.

BACKGROUND: Pregnant women with asthma need to take medication during pregnancy. OBJECTIVE: We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. METHODS: We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. RESULTS: Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). CONCLUSIONS: The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.

Nouveautés dans l'ostéogenèse imparfaite: de la recherche à la prise en charge multidisciplinaire [News in osteogenesis imperfecta: from research to clinical management]

Osteogenesis imperfecta (OI) is a rare genetic disease. Today we are able to propose an adapted and efficient management to the patients with this rare disorder (and their families) thanks to a strong collaboration of clinicians and researchers. Recent knowledge regarding the genetics of OI permits an accurate diagnosis of the specific type of OI and its own molecular mechanism, a genetic counseling for family planning and prenatal diagnosis, and in addition more targeted therapeutic options. A specific support with re-education for patients with OI is necessary and efficient. To optimize patient care, a multidisciplinary consultation is proposed at the CHUV, moreover a web site is available for patients, families and therapists: www.infomaladiesrares.ch

Birth Weight, Working Memory and Epigenetic Signatures in IGF2 and Related Genes: A MZ Twin Study.

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

Prediction of preeclampsia by means of Doppler flowmetry of uterine artery and flow-mediated dilation of brachial artery

Objective To evaluate the association of Doppler of uterine artery and flow-mediated dilation of brachial artery (FMD) in the assessment of placental perfusion and endothelial function to predict preeclampsia. Materials and Methods A total of 91 patients considered as at risk for developing preeclampsia were recruited at the prenatal unit of the authors' institution. All the patients underwent FMD and Doppler of uterine arteries between their 24th and 28th gestational weeks. Calculations of sensitivity and specificity for both isolated and associated methods were performed. Results Nineteen out of the 91 patients developed preeclampsia, while the rest remained normotensive. Doppler flowmetry of uterine arteries with presence of bilateral protodiastolic notch had sensitivity of 63.1% and specificity of 87.5% for the prediction of preeclampsia. Considering a cutoff value of 6.5%, FMD showed sensitivity of 84.2% and specificity of 73.6%. In a parallel analysis, as the two methods were associated, sensitivity was 94.2% and specificity, 64.4%. Conclusion The association of Doppler study of uterine arteries and FMD has proved to be an interesting clinical strategy for the prediction of preeclampsia, which may represent a positive impact on prenatal care of patients considered as at high-risk for developing such a condition.

Imaging findings of bronchial atresia in fetuses, neonates and infants.

Congenital lung malformations are increasingly detected before birth. However, bronchial atresia is rarely identified in utero and not always recognized in neonates. There are two types of atresia: 1) proximal, located at the level of the mainstem or the proximal lobar bronchi, which is extremely rare and usually lethal during pregnancy, causing a tremendous volume increase of the distal involved lung with secondary hypoplasia of the normal lung, and 2) peripheral, located at the segmental/subsegmental bronchial level, which may present as an isolated lesion or as part of a complex congenital malformation. Prenatal findings are mostly nonspecific. Postnatal exams show overinflated lung areas and focal bronchial dilations. The typical fluid-filled bronchoceles are not always observed in neonates but develop progressively in the first months of life. This pictorial essay describes the spectrum of imaging findings of bronchial atresia in fetuses, neonates and infants.

The Effects of Endocrine Disrupters on Fetal Male Rat Testicular and Adrenal Development

Many of the reproductive disorders that emerge in adulthood have their origin during fetal development. Numerous studies have demonstrated that exposure to endocrine disrupting chemicals can permanently affect the reproductive health of experimental animals. In mammals, male sexual differentiation and development are androgen-dependent processes. In rat, the critical programming window for masculinization occurs between embryonic days (EDs) 15.5 and 19.5. Disorders in sex steroid balance during fetal life can disturb the development of the male reproductive tract. In addition to the fetal testis, the adrenal cortex starts to produce steroid hormones before birth. Glucocorticoids produced by the adrenal cortex are essential for preparing the fetus for birth. In the present study, the effects of exposure to endocrine disrupters on fetal male rat testicular and adrenal development were investigated. To differentiate the systemic and direct testicular effects of endocrine disrupters, both in vivo and in vitro experiments were performed. The present study also clarified the role of desert hedgehog signalling (Dhh) in the development of the testis. The results indicate that endocrine disrupters, diethylstilbestrol (DES) and flutamide, are able to induce rapid steroidogenic changes in fetal rat testis under in vitro conditions. Although in utero exposure to these chemicals did not show overt effects in fetal testis, they can induce permanent changes in the developing testis and accessory sex organs later in life. We also reported that exposure to antiandrogens can interfere with testicular Dhh signalling and result in impaired differentiation of the fetal Leydig cells and subsequently lead to abnormal testicular development and sexual differentiation. In utero exposure to tetrachlorodibenzo-p-dioxin (TCDD) caused direct testicular and pituitary effects on the fetal male rat but with different dose responses. In a study in which the effects of developmental exposure to environmental antiandrogens, di-isononylphthalate and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p^’-DDE), on fetal male rat steroidogenesis were investigated, chemicals did not down-regulate testicular or adrenal steroid hormone synthesis or production in 19.5-day-old fetal rats. However, p,p^’-DDE-treatment caused clear histological and ultrastructural changes in the prenatal testis and adrenal gland. These structural alterations can disturb the development and function of fetal testis and adrenal gland that may become evident later in life. Exposure to endocrine disrupters during fetal life can cause morphological abnormalities and alter steroid hormone production by fetal rat Leydig cells and adrenocortical cells. These changes may contribute to the maldevelopment of the testis and the adrenal gland. The present study highlights the importance of the fetal period as a sensitive window for endocrine disruption.

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Prevención de la infección neonatal precoz por estreptococo del grupo B

El estreptococo del grupo B (EGB) constituye la principal causa de morbimortalidad neonatal y de morbilidad materna durante el embarazo y el posparto. Coloniza el aparato digestivo y el genitourinario en un 10-30% de las gestantes, con una tasa de transmisión vertical del 50%. De entre los recién nacidos colonizados, un 1-2% desarrollará una sepsis grave precoz. Se ha realizado una revisión bibliográfica con el objetivo de conocer las estrategias de prevención de la infección neonatal por EGB. Los resultados ponen de manifiesto que las recomendaciones para su prevención consisten en el cribado universal prenatal de colonización por EGB mediante cultivo vaginorrectal a las 35-37 semanas, y la administración de profilaxis antibiótica intraparto a todas las embarazadas portadoras.