[Augmented psychotherapy with rTMS in functional neurological disorder]. / Psychothérapie augmentée par rTMS pour les troubles neurologiques fonctionnels.

BACKGROUND: We report the observation of a 47-year-old woman with functional neurological disorder (tetraparesis, mixed tremors and non-epileptic seizures) treated with a protocol of augmented psychotherapy in combination with repeated transcranial magnetic stimulation (rTMS). INTERVENTION: We carried out a biofeedback psychotherapy protocol with rTMS (twenty sessions, two sessions per day for ten days; 1Hz, 150% of the motor threshold, twenty minute sessions, 300 pulses per session) in which the patient visualized the motor activity of her upper limbs during stimulation of the primary motor area (PMA). The evolution of neurological symptoms was assessed using the Medical Research Council Scale for Muscle Strength (MRC). RESULTS: Symptoms were improved between the 4th and 6th days of treatment (8th and 12th sessions) with first a relief of paresis, then a secondary cascade improvement of other functional symptoms. At two months the patient no longer presented any functional neurological symptoms. DISCUSSION & CONCLUSION: We propose several hypotheses concerning the effectiveness of this type of biofeedback protocol using rTMS. We also suggest that this type of protocol should be systematically associated with psychotherapeutic support on biographical elements for holistic management. This observation underlines the interest of potentiating cognitive-behavioral therapies using the principle of operant conditioning with the aid of brain stimulation in functional neurological disorders, and motivates the realization of future studies.

[Mental Health and sexual orientation in adolescents in a school environment]. / Santé mentale des adolescents selon leur attirance sexuelle : enquête en milieu scolaire.

INTRODUCTION: Although homosexuality is a subject often addressed by the media, little is said about homosexuality in adolescents who are particularly affected by the question of sexual orientation. This work aims to study the mental health of adolescents who report being exclusively attracted to members of the same sex. We explore the evidence for an association between homosexuality and depression, suicide attempts, and consulting a psychiatrist or a psychologist. METHODS: We used data from the cross-sectional study "Adolescent Portraits - A Multicenter Epidemiological Survey in Schools in 2013" (CHU Fondation Vallée, Inserm CESP U1018). Data were gathered through the use of an anonymous, self-administered questionnaire (348 questions) given to students between the "4e" and "terminaleschool" years (comparable to the 8th and 12th grade in the U.S. education system) in three contrasting French geographical areas. The risk of depression was measured using the Adolescent Depression Rating Scale (ADRS). RESULTS: The results reflect the survey responses provided by 15,235 young people. Of these, 1.5 % reported only being attracted to members of the same sex (homosexual group). This group contained twice as many girls as boys. Students who did not report sexual attraction, who reported bisexual attraction, or who did not answer the question were excluded from the results (830 students). In the homosexual group, 24 % presented with depression versus 11.5 % of those attracted exclusively to members of the opposite sex (heterosexual group). There is also a significant difference between sexes: 13.2 % of boys in the homosexual group were depressed compared to 29.3 % of girls in the same group; 6.7 % of boys in the heterosexual group reported being depressed versus 16.1 % of girls in the same group. In the heterosexual group, 10.7 % of respondents reported having already made at least one suicide attempt versus 20.7 % of those in the homosexual group. There was a difference according to sex, since 6.3 % of boys in the heterosexual group had a history of attempted suicide versus 14.9 % of girls in the same group. This gap disappeared completely within the homosexual group, as 21.4 % of boys and 20.4 % of girls had already made at least one suicide attempt at the time of the survey. Depressed adolescents in the homosexual group also reported a higher number of previous suicide attempts than those in the heterosexual group (46.9 % versus 31.6 %). In terms of sex, 25.3 % of depressed boys in the heterosexual group made at least one suicide attempt versus 34.1 % of girls. In the homosexual group, 44.4 % of depressed boys reported having made at least one suicide attempt versus 47.5 % of depressed girls. Adolescents in the homosexual group were significantly more likely to report having consulted a psychiatrist or psychologist than those in the heterosexual group (14.6 % versus 6.5 %), regardless of sex (16.7 % versus 4.7 % for boys; 13.5 % versus 8.2 % for girls). This difference was also found among depressed subjects (26.0 % in the homosexual group versus 15.4 % in the heterosexual group). Sexual activity (having already had sex) was higher in the homosexual group than in the heterosexual group (53.7 % versus 37.5 %), and this difference remained significant after adjusting for age. Fifty percent of the sexually active homosexual respondents reported having engaged in sexual activity of a homosexual nature versus 0.7 % of sexually active heterosexual respondents. In the homosexual group, mental suffering appeared to be more severe among sexually active subjects, in terms of dark thoughts (64 % versus 46 %) and a prior history of attempted suicide (29.3 % versus 10 %), but not in terms of depression (27.9 % versus 18.9 %; NS). CONCLUSION: Young people who reported being exclusively attracted to members of the same sex presented a higher level of mental distress compared to those who reported being attracted to members of the opposite sex. This was especially the case for boys. These findings led to the identification of risk and protective factors that can inform the development of appropriate preventive measures.

The cost of diabetic foot ulcers and amputations to the National Health Service in England.

AIM: To estimate the healthcare costs of diabetic foot disease in England. METHODS: Patient-level data sets at a national and local level, and evidence from clinical studies, were used to estimate the annual cost of health care for foot ulceration and amputation in people with diabetes in England in 2014-2015. RESULTS: The cost of health care for ulceration and amputation in diabetes in 2014-2015 is estimated at between £837 million and £962 million; 0.8% to 0.9% of the National Health Service (NHS) budget for England. More than 90% of expenditure was related to ulceration, and 60% was for care in community, outpatient and primary settings. For inpatients, multiple regression analysis suggested that ulceration was associated with a length of stay 8.04 days longer (95% confidence interval 7.65 to 8.42) than that for diabetes admissions without ulceration. CONCLUSIONS: Diabetic foot care accounts for a substantial proportion of healthcare expenditure in England, more than the combined cost of breast, prostate and lung cancers. Much of this expenditure arises through prolonged and severe ulceration. If the NHS were to reduce the prevalence of diabetic foot ulcers in England by one-third, the gross annual saving would be more than £250 million. Diabetic foot ulceration is a large and growing problem globally, and it is likely that there is potential to improve outcomes and reduce expenditure in many countries.

Progress of the Healthier You: NHS Diabetes Prevention Programme: referrals, uptake and participant characteristics.

AIMS: To describe early progress of the Healthier You: NHS Diabetes Prevention Programme, a behavioural intervention designed to prevent or delay onset of Type 2 diabetes in people in England already identified to be at high risk, to assess numbers of referrals received by Programme providers and the proportion that attended the initial assessment, and to identify the factors associated with attendance rates. METHODS: These analyses examine the data for referrals received between June 2016 and March 2017. RESULTS: There were 43 603 referrals received, 16% higher than expected. Of those referred, 49% attended the initial assessment, higher than the 40% modelled uptake. Of those referred, there was no significant difference in uptake by sex (P=0.061); however, attendance per 100 000 population varied significantly by sex, age group, ethnicity and deprivation; it was significantly lower for men (P<0.001), higher as age increased (P<0.001) and higher for individuals from Asian, Afro-Caribbean, mixed and other ethnic groups compared with individuals from white European groups (P<0.001). There was significant interaction between attendance rates by ethnicity and deprivation (P<0.001) such that attendance rates were significantly higher in the most deprived quintile vs the least deprived quintile for Asian, Afro-Caribbean, mixed and other ethnic groups but not significantly different for white European ethnic groups. CONCLUSION: The analyses show that referral numbers and percentage uptake are in excess of prior modelled values. Characteristics of attendees suggest that the programme is reaching those who are both at greater risk of developing Type 2 diabetes and who typically access healthcare less effectively.

Finding out what matters: validity of quality of life measurement in young people with ASD.

BACKGROUND: Compared with other conditions there has been a lack of focus on quality of life (QoL) as an outcome measure for children and young people with Autism Spectrum Disorder (ASD). This pilot study aimed to evaluate the validity of existing QoL questionnaires for use with children with ASD aged 8-12 years. METHODS: A literature review (1990-2011) identified the PedsQL (Pediatric Quality of Life Inventory) and Kidscreen as robust measures used with children with neurodevelopmental disorders. These measures were completed by 10 children and 11 parents. In addition semi-structured interviews were conducted with 10 parents and four children to explore their experience of completing the QoL questionnaires. RESULTS: Young people with ASD, and their parents, report lower child QoL compared with a normative sample. Framework analysis of the data highlighted six key themes which may affect the validity of generic QoL measures when administered within an ASD sample and which warrant further investigation. CONCLUSIONS: Our results indicate that a new condition-specific measure of QoL, grounded in ASD children's own perspectives of their lives, is needed and that such a measure should assess experiences of anxiety and access to special interests when measuring QoL of children with ASD. Active involvement of young people and their families is critical for the development of a theoretical framework for QoL within ASD, and any future development of an ASD-specific measure.

Three-dimensional ultrasound in the diagnosis of Müllerian duct anomalies and concordance with magnetic resonance imaging.

OBJECTIVES: To demonstrate the value of three-dimensional (3D) ultrasound in the diagnosis of uterine malformations and its concordance with magnetic resonance imaging (MRI). METHODS: This study included 286 women diagnosed with uterine malformation by 3D ultrasound, having been referred to our clinics on suspicion of uterine malformation following clinical and/or conventional two-dimensional ultrasound examination. With the exception of three with intact hymen, patients underwent both bimanual examination and speculoscopy before and/or after sonography. MRI was performed in 65 cases. We analyzed the diagnostic concordance between the techniques in the study of uterine malformations. RESULTS: Using 3D ultrasound we diagnosed: one case with uterine agenesis; 10 with unicornuate uterus, four of which also underwent MRI; six with didelphic uterus, one of which had MRI; 45 with bicornuate uterus, 12 of which had MRI; 125 with septate uterus (18 with two cervices), 42 of which had MRI (six with two cervices); 96 with arcuate uterus, three of which had MRI; and three with diethylstilbestrol (DES) iatrogenic uterine malformations, all of which had MRI. Among the 65 which underwent MRI, the diagnosis was: four cases with unicornuate uterus, 10 with bicornuate uterus (two with two cervices), 45 with septate uterus (five with two cervices), three with arcuate uterus and three with DES-related uterine malformations. The concordance between 3D ultrasound and MRI was very good (kappa index, 0.880 (95% CI, 0.769-0.993)). Discrepancies in diagnosis between the two techniques occurred in four cases. There was very good concordance in the diagnosis of associated findings (kappa index, 0.878 (95% CI, 0.775-0.980)), this analysis identifying differences in two cases. CONCLUSIONS: There is a high degree of concordance between 3D ultrasound and MRI in the diagnosis of uterine malformations, the relationship between cavity and fundus being visualized equally well with both techniques. 3D ultrasound should be complemented by careful gynecological exploration in order to identify any alterations in the cervix.

The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells.

In mammalian cells, endoplasmic reticulum (ER) stress has recently been shown to induce autophagy and the induction requires the unfolded protein response (UPR) signaling pathways. However, little is known whether autophagy regulates UPR pathways and how specific UPR targets might control autophagy. Here, we demonstrated that although ER stress-induced autophagy was suppressed by class III phosphatidylinositol-3'-kinase (PI3KC3) inhibitor 3-methyladenine (3-MA), wortmannin and knockdown of Beclin1 using small interfering RNA (siRNA), only 3-MA suppressed UPR activation. We discovered that the UPR regulator and ER chaperone GRP78/BiP is required for stress-induced autophagy. In cells in which GRP78 expression was knocked down by siRNA, despite spontaneous activation of UPR pathways and LC3 conversion, autophagosome formation induced by ER stress as well as by nutrition starvation was inhibited. GRP78 knockdown did not disrupt PI3KC3-Beclin1 association. However, electron microscopic analysis of the intracellular organelle structure reveals that the ER, a putative membrane source for generating autophagosomal double membrane, was massively expanded and disorganized in cells in which GRP78 was knocked down. ER expansion is known to be dependent on the UPR transcription factor XBP-1. Simultaneous knockdown of GRP78 and XBP-1 recovered normal levels of stress-induced autophagosome formation. Thus, these studies uncover 3-MA as an inhibitor of UPR activation and establish GRP78 as a novel obligatory component of autophagy in mammalian cells.

Model simulation of the cretaceous ocean circulation.

Three-dimensional numerical ocean circulation model experiments that were designed to evaluate the circulation characteristics for the mid-Cretaceous ( approximately 100 million years ago) show that the primary direction of flow through the Tethys Ocean was eastward; in contrast, a westward flowing circumglobal Tethys current has been a consistent feature of earlier reconstructions of Cretaceous ocean circulation. The model studies demonstrate that (i) ocean circulation is sufficiently sensitive to the role of continental positions, sea level, and climate to limit the application of modern analogs to past circulations, and (ii) reconstructions based on limited biogeographic data may not provide unique surface circulation patterns.

An ice-free cretaceous? Results from climate model simulations.

We have quantitatively investigated the mechanisms that could explain the warm, equable climate that is believed to have been typical of the mid-Cretaceous (100 million years ago). By performing simulations with a climate model based on zonal energy balance, we demonstrate that past changes in geography were important in bringing about climatic change. However, the meridional distribution of Cretaceous temperatures cannot be successfully simulated unless additional physical "feedback mechanisms" are included in the model. These mechanisms may involve cloud and meridional heat transport changes. We also conclude that paleoclimatologists should reexamine carefully both existing data and their interpretations with regard to reconstruction of Cretaceous tropical and polar surface temperatures.

Three-dimensional ultrasound diagnosis of cleft palate: 'reverse face', 'flipped face' or 'oblique face'--which method is best?

OBJECTIVES: To compare the performance of three sonographic techniques, the 'reverse-face', 'flipped-face' and 'oblique-face' methods, for visualizing the hard and soft palate in diagnosing cleft lip and palate (CLP). METHODS: A total of 60 fetuses (10 with CLP) with a gestational age ranging from 20 to 33 weeks were examined. We compared visualization of the secondary palate with the previously described reverse-face and flipped-face methods (the latter modified by us) and the oblique-face method developed by us using Oblique View imaging technology. RESULTS: Among the 10 fetuses with CLP the defect involved the lip, alveolus and secondary palate in seven, and the primary palate only in the remaining three. The upper lip and alveolar ridge were well visualized in all cases with all three methods. Involvement of the hard palate was diagnosed correctly in 71% (5/7) of the cases using the reverse-face view, in 86% (6/7) with the flipped-face view, and in 100% (7/7) with the oblique-face view; the hard palate was correctly found to be intact in 78%, 84% and 86%, respectively, of the 50 normal fetuses examined with each view. Involvement of the soft palate was diagnosed correctly in only one of the seven fetuses with defects of the secondary palate in flipped-face and oblique-face views, and was correctly considered intact in only 16% of normal fetuses in flipped-face view and in 26% in oblique-face images. CONCLUSIONS: Accurate visualization of the soft palate requires an excellent initially acquired volume, fluid between the fetal tongue and palate, and curving of the plane to follow the structure of the palate. The oblique-face or flipped-face views make it possible to visualize the soft palate well in selected cases.

The case for re-evaluating the upper limit value for selenium in drinking water in Europe.

Selenium is an essential trace element for life, which can be toxic for humans when intakes reach a certain amount. Therefore, since the margin between healthy intake and toxic intake is narrow, the selenium concentration of tap water is a parameter that must be monitored because of its potential for increased intake. The present work gives an overview of the different approaches used to calculate safe limits for selenium. As recommended by WHO, the guidelines for drinking water form the basis of national legislated standards for drinking water. Before setting a maximum acceptable level in drinking water, it is necessary to take into account the total intake of selenium in both food and beverage. The limit value of 10 microg l(-1) for drinking water laid down in the European regulations for all countries should be adapted depending on geographic area, as previously recommended by WHO.

Prolactin upstream factor I mediates cell-specific transcription.

DNA sequence-specific chromatography was used to purify prolactin upstream factor I (PUF-I) approximately 10,000- to 20,000-fold from rat GH3 cells. The purified transcription factor reconstituted enhanced pituitary-specific prolactin RNA synthesis in nonpituitary in vitro transcription assays. In vitro mutagenesis demonstrated that the capacity to stimulate prolactin gene transcription was directly correlated with PUF-I binding to an A+T-rich region located from -63 to -36 in the prolactin 5'-flanking DNA. We propose that PUF-I is a critical modulator of transcriptional activity in pituitary cells and has a central role in the stimulation of prolactin gene transcription in the mammalian pituitary lactotroph.

Reconstitution of cell-type-specific transcription of the rat prolactin gene in vitro.

We present evidence for the existence of prolactin upstream factor 1 (PUF-1) in rat pituitary-derived cells and demonstrate its interaction with a symmetrical DNA element located in the 5' flanking region of the gene. An in vitro expression system developed from pituitary-derived GH3 cells was used to determine that 420 base pairs (bp) of 5' flanking DNA was sufficient for cell-specific, accurate, and efficient RNA polymerase II transcription of the rat prolactin gene. Reconstitution of in vitro transcription with pituitary and nonpituitary nuclear extracts suggested that the presence of GH3 cell-specific factors mediated the activation of prolactin gene expression. We also demonstrated that a functionally stable transcription complex assembled on the prolactin promoter. Using DNase I protection procedures, we have identified the DNA-protein binding area in the prolactin 5' flanking region. GH3 nuclear extracts contain a cell-specific protein (PUF-I) that binds to a 28-bp region (-63 to -36)which contains an 18-bp imperfect palindrome (-63 to -46). The role that the interaction between PUF-I and the imperfect palindrome plays in in vitro pituitary-specific prolactin gene expression is discussed.

Dual functions of a cis-acting element within the rat prolactin gene promoter.

Within the promoter region of the rat prolactin gene lies a TA-rich imperfect palindrome. The possible functions of the 18-base-pair symmetrical sequence were investigated by using an in vitro transcription system. Prolactin templates with and without the palindrome were transcriptionally assayed in both pituitary and nonpituitary extracts. Our results indicated that the palindromic sequence has at least two functions in the regulation of prolactin transcription.

Palliation for suspected unresectable hilar cholangiocarcinoma.

AIM: The aim of this study was to evaluate the outcome of different techniques of palliation for patients with hilar cholangiocarcinoma. METHOD: All patients treated with palliative intent between 1988 and 2004 at the Royal Infirmary of Edinburgh were reviewed. Patients were analysed on an intention to treat basis. Demographics, procedure and outcome (including re-admissions) were recorded. RESULTS: Two hundred and thirty-three patients underwent palliative treatment for suspected hilar cholangiocarcinoma. The diagnosis was confirmed histologically in 109 patients. The procedure related morbidity and mortality was 54/225 and 18/207 respectively. Seventy-one patients required re-admission. Twenty patients underwent surgical biliary bypass for jaundice. Those undergoing surgical palliation had a longer median (95% CI) time to re-admission (16 (0-36) vs.7 (2-12) weeks, p=0.001). Endoscopic retrograde cholangio-pancreatography (ERCP) and stenting was only successful in 28 patients and was associated with a significantly higher re-admission rate compared to patients in whom ERCP was not performed (60/179 vs. 4/27, p=0.050). The overall median (95% CI) survival was 145 (124-185) days. CONCLUSION: Current options for palliation of hilar cholangiocarcinoma provide good short term success but are all associated with significant early and late morbidity. Due to its low success and association with an increased re-admission rate, ERCP for definitive palliation should not be used in the first line staging and management of these patients.

Localization of amyloid P component in human brain: vascular staining patterns and association with Alzheimer's disease lesions.

Amyloid P component is a normal serum protein that is highly conserved across phylogeny. Although it resembles the classic acute-phase reactant C-reactive protein, and is considered to be a normal extracellular matrix component, its physiologic role in humans is unknown. Amyloid P component is also colocalized with accumulations of all recognized forms of amyloid. The present study uses light and electron microscopy to compare the cerebral localization of amyloid P component in cases with (n = 19) and without (n = 15) Alzheimer's disease (AD). In non-AD cases, amyloid P component was predominantly localized to the cerebrovasculature. Perivascular staining was observed in most cases, more so in the white than in the gray matter. In AD cases, amyloid P component was localized to all three characteristics histopathologic lesions, namely, neurofibrillary tangles, senile plaques, and amyloid angiopathy. Furthermore, in cases with prominent staining of gray matter parenchymal lesions, intravascular staining was decreased. Given the fixation and processing methods used, amyloid P component was never seen to be localized to the cerebrovascular basement membrane. These data argue against amyloid P component's postulated role as the anchor for vascular beta-amyloid deposition. Because there is no evidence for intrinsic amyloid P component production in brain, its perivascular and parenchymal distributions suggest either compromise of the blood-brain barrier or transport across vascular endothelium.

Quantitative cytochemistry of glucose-6-phosphate dehydrogenase in benign and malignant breast tumours.

Glucose-6-phosphate dehydrogenase (G6PD) activity was quantified cytochemically in mammary epithelial cells within frozen tissue sections from 38 patients with breast cancer and 44 with benign breast disease. G6PD activities were measured under atmospheres of both N2 and O2. The mean (S.E.) G6PD value 2.5 (0.23) IE U/min measured in N2 in mammary epithelial cells from the group of malignancies was significantly greater than that of 1.6 (0.37) IE U/min in the benign group (P less than 0.001), but there was considerable overlap between individual values. G6PD measured in O2 was detectable in 84% of malignancies compared to only 14% of benign biopsies and the group mean of 1.3 (0.18) IE U/min in the former was significantly greater than that of 0.35 (0.20) IE U/min in the latter (P less than 0.001). Significant correlations between G6PD activities measured in N2 and O2 were observed in both groups. The techniques present a sensitive method of identifying increases in G6PD activity in mammary epithelial cells and provide an assay that in a majority of cases permits the separation of malignant from benign tissues.

Insulin antibodies in patients receiving penicillamine.

In a patient receiving penicillamine for treatment of rheumatoid arthritis, antibodies to insulin developed, which resulted in symptomatic hypoglycemia. When 30 additional patients receiving penicillamine were screened, another patient was discovered to have antibodies to insulin. The level of antibody fell sharply in both patients after penicillamine was discontinued. This particular immunologic reaction to penicillamine has not been reported previously.

Experimental evaluation of Tc-99m sulfur colloid as a potential imaging agent in thromboembolic disease: concise communication.

Based on literature reports suggesting the possible incorporation of Tc-99m sulfur colloid (Tc-SC) into fibrin deposits, this study was undertaken to evaluate the potential of this radiopharmaceutical as an imaging agent in thromboembolic disease. Animal models of deep-vein thrombosis and pulmonary embolism were used. The mean thrombus-to-blood (T/B) uptake ratios were comparable for fresh and older thrombi (up to 72 hr). Thrombus uptake was significantly lower in a group of five control dogs that received pertechnetate instead of Tc-SC. Intravenous heparin administration (5,000 IU) 2 hr before injection of Tc-SC caused a depression in T/B ratios but did not totally block Tc-SC uptake. Gamma imaging with Tc-SC allowed demonstration of deep-vein thrombi, but imaging of pulmonary emboli as areas of increased activity was not satisfactory. This study supports the concept of thrombus detection with radiolabeled particles but not the extension of this principle to the imaging of pulmonary emboli.