Troubles du cycle à l'adolescence: une banalité [Menstrual disorders in adolescents: commonplace or worrisome?].

The first menstrual cycles following menarche are often caracterized by irregular and/or heavy bleeding. The adolescent patient may be worried by these episodes of bleeding. In 50-80% of cases these are anovulatory bleeding due to the immaturity of the gonadotrophic axis. Nevertheless pathologies such as von Willebrand disease, genital infection, polycystic ovary syndrom, eating disorders, a tumor or a pregnancy may be diagnosed by bleeding abnormalities. The challenge for the physician is to distinguish between bleeding abnormalities secondary to anovulation and pathologies where investigations and specific follow-up is mandatory. Adolescents who experience abnormal bleeding must be counceled according to their perceptions and expectations.

Rapid prototyping of compliant human aortic roots for assessment of valved stents.

Adequate in-vitro training in valved stents deployment as well as testing of the latter devices requires compliant real-size models of the human aortic root. The casting methods utilized up to now are multi-step, time consuming and complicated. We pursued a goal of building a flexible 3D model in a single-step procedure. We created a precise 3D CAD model of a human aortic root using previously published anatomical and geometrical data and printed it using a novel rapid prototyping system developed by the Fab@Home project. As a material for 3D fabrication we used common house-hold silicone and afterwards dip-coated several models with dispersion silicone one or two times. To assess the production precision we compared the size of the final product with the CAD model. Compliance of the models was measured and compared with native porcine aortic root. Total fabrication time was 3 h and 20 min. Dip-coating one or two times with dispersion silicone if applied took one or two extra days, respectively. The error in dimensions of non-coated aortic root model compared to the CAD design was <3.0% along X, Y-axes and 4.1% along Z-axis. Compliance of a non-coated model as judged by the changes of radius values in the radial direction by 16.39% is significantly different (P<0.001) from native aortic tissue--23.54% at the pressure of 80-100 mmHg. Rapid prototyping of compliant, life-size anatomical models with the Fab@Home 3D printer is feasible--it is very quick compared to previous casting methods.

Variability of a peripheral dose among various linac geometries for second cancer risk assessment.

Second cancer risk assessment for radiotherapy is controversial due to the large uncertainties of the dose-response relationship. This could be improved by a better assessment of the peripheral doses to healthy organs in future epidemiological studies. In this framework, we developed a simple Monte Carlo (MC) model of the Siemens Primus 6 MV linac for both open and wedged fields that we then validated with dose profiles measured in a water tank up to 30 cm from the central axis. The differences between the measured and calculated doses were comparable to other more complex MC models and never exceeded 50%. We then compared our simple MC model with the peripheral dose profiles of five different linacs with different collimation systems. We found that the peripheral dose between two linacs could differ up to a factor of 9 for small fields (5 × 5 cm(2)) and up to a factor of 10 for wedged fields. Considering that an uncertainty of 50% in dose estimation could be acceptable in the context of risk assessment, the MC model can be used as a generic model for large open fields (≥10 × 10 cm(2)) only. The uncertainties in peripheral doses should be considered in future epidemiological studies when designing the width of the dose bins to stratify the risk as a function of the dose.

Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.

BACKGROUND: Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications. MATERIALS AND METHODS: Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR). RESULTS: Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis. CONCLUSIONS: Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca2+ Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction.

Although the activation of the A(1)-subtype of the adenosine receptors (A(1)AR) is arrhythmogenic in the developing heart, little is known about the underlying downstream mechanisms. The aim of this study was to determine to what extent the transient receptor potential canonical (TRPC) channel 3, functioning as receptor-operated channel (ROC), contributes to the A(1)AR-induced conduction disturbances. Using embryonic atrial and ventricular myocytes obtained from 4-day-old chick embryos, we found that the specific activation of A(1)AR by CCPA induced sarcolemmal Ca(2+) entry. However, A(1)AR stimulation did not induce Ca(2+) release from the sarcoplasmic reticulum. Specific blockade of TRPC3 activity by Pyr3, by a dominant negative of TRPC3 construct, or inhibition of phospholipase Cs and PKCs strongly inhibited the A(1)AR-enhanced Ca(2+) entry. Ca(2+) entry through TRPC3 was activated by the 1,2-diacylglycerol (DAG) analog OAG via PKC-independent and -dependent mechanisms in atrial and ventricular myocytes, respectively. In parallel, inhibition of the atypical PKCζ by myristoylated PKCζ pseudosubstrate inhibitor significantly decreased the A(1)AR-enhanced Ca(2+) entry in both types of myocytes. Additionally, electrocardiography showed that inhibition of TRPC3 channel suppressed transient A(1)AR-induced conduction disturbances in the embryonic heart. Our data showing that A(1)AR activation subtly mediates a proarrhythmic Ca(2+) entry through TRPC3-encoded ROC by stimulating the phospholipase C/DAG/PKC cascade provide evidence for a novel pathway whereby Ca(2+) entry and cardiac function are altered. Thus, the A(1)AR-TRPC3 axis may represent a potential therapeutic target.

Development of the Crohn's disease digestive damage score, the Lémann score.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011).

Factors associated with comorbidity patterns in full and partial PTSD: Findings from the PsyCoLaus study.

Subtypes of comorbid conditions and their associated trauma and clinical characteristics in full and partial PTSD were examined. Data from 289 subjects from the general population that met criteria for full or partial PTSD were analyzed. Latent class analyses (LCA) were performed to derive homogeneous patterns of DSM-IV Axis-I disorders and anti-social personality comorbid to PTSD. Logistic regression models were conducted to characterize these classes by trauma-related and clinical features. The LCA revealed three classes: (1) low comorbidity; (2) high comorbidity with primarily substance-related disorders and a higher proportion of males; and (3) more severe PTSD-symptomatology and higher comorbid anxiety disorders and depression, almost entirely represented by females. Exposure to sexual abuse was more likely in the substance-dependent class and contributed strongly to the distinction between classes. Affective disorders tended to precede the onset of PTSD in the substance-dependent class, whereas phobias were more likely to follow PTSD in the depressed-anxious class. Posttrauma onset of alcohol use disorders in the substance dependent class confirmed the self-medication hypothesis. The three classes of comorbidity and their sequence of onset with PTSD suggest different mechanisms involved in their development. Our findings suggest that PTSD-related comorbidity subtypes also apply to individuals with partial PTSD.

Zebrafish hmx1 promotes retinogenesis.

Ocular development is controlled by a complex network of transcription factors, cell cycle regulators, and diffusible signaling molecules. Together, these molecules regulate cell proliferation, apoptosis and specify retinal fate. In the zebrafish (Danio rerio), hmx1 is a homeobox transcription factor implicated in eye and brain development. Hmx1 transcripts were detected in the nasal retina and lens as well as otic vesicles and pharyngeal arches by 24-32 hpf. Before this stage, transcripts were more uniformly expressed in the optic vesicle. Knockdown of hmx1 led to microphthalmia. Delayed withdrawal of retinal progenitors from the cell cycle resulting in retarded retinal differentiation was observed in morphant. The retina and brain also showed an increased cell death at 24 hpf. The polarized expression of hmx1 to the nasal part in the zebrafish retina strongly suggested an involvement in the nasal-temporal patterning. However, the key patterning genes tested so far were not regulated by hmx1. Altogether, these results suggest an important role for hmx1 in retinogenesis.

Adiposity in children born small for gestational age.

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.

Efficacy of the barbecue manoeuvre in benign paroxysmal vertigo of the horizontal canal

Five to ten percent of benign paroxysmal positional vertigo are caused by the horizontal semi-circular variant (h-BPPV). In this study, we reviewed the efficacy of the Barbecue repositioning manoeuvre in h-BPPV, and we assessed the possible effect of different factors on the outcome. Barbecue manoeuvre consists in turning the supine patient around his longitudinal axis toward the unaffected side until 360 degrees are accomplished. After every 90 degrees step the patient is maintained in the new position for 30 s. We reviewed 46 patients with h-BPPV, treated by barbecue rotation from 2003 to 2005. After the first Barbecue manoeuvre, the patients were followed-up at intervals of approximately 1 week and the rotation was repeated if h-BPPV persisted (up to three rotations). Factors assessed were age, gender, duration of symptoms before treatment and type of h-BPPV (canalolithiasis vs. cupulolithiasis). Fisher's exact test was used for the analysis. Results: 85% of patients (39/46) were cured after a maximum of 3 rotations. 74% (34/46) were cured after the first manoeuvre and 80% (37/46) after the second one. None of the evaluated factors did significantly affect the efficacy (P > 0.05). The Barbecue manoeuvre is an efficient treatment of h-BPPV demonstrating 85% cure rate after a maximum of three sessions. 74% of the patients are healed after one manoeuvre. The efficacy is not affected by the evaluated factors.

Effects of perinatal stress and maternal traumatic stress on the cortisol regulation of preterm infants.

Preterm infants experience intense stress during the perinatal period because they endure painful and intense medical procedures. Repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis during this period may have long-term effects on subsequent cortisol regulation. A premature delivery may also be intensely stressful for the parents, and they may develop symptoms of posttraumatic stress disorder (PTSD). Usable saliva samples were collected (4 times per day over 2 days, in the morning at awakening, at midday, in the afternoon, and in the evening before going to bed) to assess the diurnal cortisol regulation from 46 preterm infants when the infants were 12 months of corrected age (∼ 14 months after birth). Mothers reported their level of PTSD symptoms. The results showed an interaction between perinatal stress and maternal traumatic stress on the diurnal cortisol slope of preterm infants (R(2) = .32). This suggests that the HPA axis of preterm infants exposed to high perinatal stress may be more sensitive to subsequent environmental stress.

Neurobiology of suicide: do biomarkers exist?

Clinical risk factors have a low predictive value on suicide. This may explain the increasing interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. This review aims to present the current neurobiological findings that have been shown to be implicated in suicide completers and to discuss how postmortem studies may be useful in characterizing these individuals. Data on the role of the main neurobiological systems in suicidality, such as the neurotransmitter families, hypothalamic-pituitary-adrenal axis, neurotrophic factors, and polyamines, are exposed at the different biochemical, genetic, and epigenetic levels. Some neuroanatomic and neuropathological aspects as well as their in vivo morphological and functional neuroimaging correlates are also described. Except for the serotoninergic system, particularly with respect to the polymorphism of the gene coding for the serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor, data did not converge to produce a univocal consensus. The possible limitations of currently published studies are discussed, as well as the scope for long-term prospective studies.

1H-[13C] NMR spectroscopy of the rat brain during infusion of [2-13C] acetate at 14.1 T.

Full signal intensity (1)H-[(13)C] NMR spectroscopy, combining a preceding (13)C-editing block based on an inversion BISEP (B(1)-insensitive spectral editing pulse) with a spin-echo coherence-based localization, was developed and implemented at 14.1 T. (13)C editing of the proposed scheme was achieved by turning on and off the (13)C adiabatic full passage in the (13)C-editing block to prepare inverted and noninverted (13)C-coupled (1)H coherences along the longitudinal axis prior to localization. The novel (1)H-[(13)C] NMR approach was applied in vivo under infusion of the glia-specific substrate [2-(13)C] acetate. Besides a approximately 50% improvement in sensitivity, spectral dispersion was enhanced at 14.1 T, especially for J-coupled metabolites such as glutamate and glutamine. A more distinct spectral structure at 1.9-2.2 ppm(parts per million) was observed, e.g., glutamate C3 showed a doublet pattern in both simulated (1)H spectrum and in vivo (13)C-edited (1)H NMR spectra. Besides (13)C time courses of glutamate C4 and glutamine C4, the time courses of glutamate C3 and glutamine C3 obtained by (1)H-[(13)C] NMR spectroscopy were reported for the first time. Such capability should greatly improve the ability to study neuron-glial metabolism using (1)H-observed (13)C-edited NMR spectroscopy.

Vascular continuity, cell axialization and auxin.

Phytohormones have been implicated in vascular development in various ways, but their precise function and the extent of their influence is still controversial. Recent results from experimental manipulation of developing organs and Arabidopsis developmental genetics support a role for polar auxin flow in cell axis formation within the vascular system and, interestingly, also in the embryonic establishment of the plant body axis. Vascular responses to auxin transport inhibition indicate patterns of auxin distribution during leaf development and new technologies may enable these predictions to be tested within the near future. Moreover, recently discovered Arabidopsis axialisation mutants seem to identify essential genes that relay auxin signals in vascular development. A first gene in this class, MONOPTEROS (MP) has been cloned and encodes a transcription factor capable of binding to auxin response elements in the control regions of auxin regulated genes. Molecular identification of further axialisation genes may provide access to a mechanistic understanding of plant cell axis formation.

The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations.

A widely dispersed network of hypothalamic GnRH neurons controls the reproductive axis in mammals. Genetic investigation of the human disease model of isolated GnRH deficiency has revealed several key genes crucial for GnRH neuronal ontogeny and GnRH secretion. Among these genes, prokineticin 2 (PROK2), and PROK2 receptor (PROKR2) have recently emerged as critical regulators of reproduction in both mice and humans. Both prok2- and prokr2-deficient mice recapitulate the human Kallmann syndrome phenotype. Additionally, PROK2 and PROKR2 mutations are seen in humans with Kallmann syndrome, thus implicating this pathway in GnRH neuronal migration. However, PROK2/PROKR2 mutations are also seen in normosmic GnRH deficiency, suggesting a role for the prokineticin signaling system in GnRH biology that is beyond neuronal migration. This observation is particularly surprising because mature GnRH neurons do not express PROKR2. Moreover, mutations in both PROK2 and PROKR2 are predominantly detected in the heterozygous state with incomplete penetrance or variable expressivity frequently seen within and across pedigrees. In some of these pedigrees, a "second hit" or oligogenicity has been documented. Besides reproduction, a pleiotropic physiological role for PROK2 is now recognized, including regulation of pain perception, circadian rhythms, hematopoiesis, and immune response. Therefore, further detailed clinical studies of patients with PROK2/PROKR2 mutations will help to map the broader biological role of the PROK2/PROKR2 pathway and identify other interacting genes/proteins that mediate its molecular effects in humans.