Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy.

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.

Alveolar echinococcosis of the liver: Diffusion-weighted MRI findings and potential role in lesion characterisation

PURPOSE: To report the diffusion-weighted MRI findings in alveolar echinococcosis (AE) of the liver and evaluate the potential role of apparent diffusion coefficients (ADCs) in the characterisation of lesions. MATERIALS AND METHODS: We retrospectively included 22 patients with 63 AE liver lesions (≥1cm), examined with 3-T liver MRI, including a free-breathing diffusion-weighted single-shot echo-planar imaging sequence (b-values=50, 300 and 600s/mm(2)). Two radiologists jointly assessed the following lesion features: size, location, presence of cystic and/or solid components (according to Kodama's classification system), relative contrast enhancement, and calcifications (on CT). The ADCtotal, ADCmin and ADCmax were measured in each lesion and the surrounding liver parenchyma. RESULTS: Three type 1, 19 type 2, 17 type 3, three type 4 and 21 type 5 lesions were identified. The mean (±SD) ADCtotal, ADCmin and ADCmax for all lesions were 1.73±0.50, 0.76±0.38 and 2.63±0.76×10(-3)mm(2)/s, respectively. The mean ADCtotal for type 1, type 2, type 3, type 4 and type 5 lesions were 1.97±1.01, 1.76±0.53, 1.73±0.41, 1.15±0.42 and 1.76±0.44×10(-3)mm(2)/s, respectively. No significant differences were found between the five lesion types, except for type 4 (p=0.0363). There was a significant correlation between the presence of a solid component and low ADCmin (r=0.39, p=0.0016), whereas an inverse correlation was found between the relative contrast enhancement and ADCtotal (r=-0.34, p=0.0072). CONCLUSION: The ADCs of AE lesions are relatively low compared to other cystic liver lesions, which may help in the differential diagnosis. Although ADCs are of little use to distinguish between the five lesion types, their low value reflects the underlying solid component.

Bone mineral density (BMD), micro-architecture estimation (TBS) and vertebral fracture assessment (VFA) extracted from a single DXA device in combination with clinical risk factors improve significantly the identification of women at high risk of fracture

Introduction: Osteoporosis (OP) is a systemic skeletal disease characterized by a low bone mineral density (BMD) and a micro-architectural (MA) deterioration. Clinical risk factors (CRF) are often used as a MA approximation. MA is yet evaluable in daily practice by the Trabecular Bone Score (TBS) measure. TBS is a novel grey-level texture measurement reflecting bone micro-architecture based on the use of experimental variograms of 2D projection images. TBS is very simple to obtain, by reanalyzing a lumbar DXA-scan. TBS has proven to have diagnosis and prognosis value, partially independent of CRF and BMD. The aim of the OsteoLaus cohort is to combine in daily practice the CRF and the information given by DXA (BMD, TBS and vertebral fracture assessment (VFA)) to better identify women at high fracture risk. Method: The OsteoLaus cohort (1400 women 50 to 80 years living in Lausanne, Switzerland) started in 2010. This study is derived from the cohort COLAUS who started in Lausanne in 2003. The main goals of COLAUS is to obtain information on the epidemiology and genetic determinants of cardiovascular risk in 6700 men and women. CRF for OP, bone ultrasound of the heel, lumbar spine and hip BMD, VFA by DXA and MA evaluation by TBS are recorded in OsteoLaus. Preliminary results are reported. Results: We included 631 women: mean age 67.4±6.7 y, BMI 26.1±4.6, mean lumbar spine BMD 0.943±0.168 (T-score -1.4 SD), TBS 1.271±0.103. As expected, correlation between BMD and site matched TBS is low (r2=0.16). Prevalence of VFx grade 2/3, major OP Fx and all OP Fx is 8.4%, 17.0% and 26.0% respectively. Age- and BMI-adjusted ORs (per SD decrease) are 1.8 (1.2- 2.5), 1.6 (1.2-2.1), 1.3 (1.1-1.6) for BMD for the different categories of fractures and 2.0 (1.4-3.0), 1.9 (1.4-2.5), 1.4 (1.1-1.7) for TBS respectively. Only 32 to 37% of women with OP Fx have a BMD < -2.5 SD or a TBS < 1.200. If we combine a BMD < -2.5 SD or a TBS < 1.200, 54 to 60% of women with an osteoporotic Fx are identified. Conclusion: As in the already published studies, these preliminary results confirm the partial independence between BMD and TBS. More importantly, a combination of TBS subsequent to BMD increases significantly the identification of women with prevalent OP Fx which would have been miss-classified by BMD alone. For the first time we are able to have complementary information about fracture (VFA), density (BMD), micro- and macro architecture (TBS & HAS) from a simple, low ionizing radiation and cheap device: DXA. Such complementary information is very useful for the patient in the daily practice and moreover will likely have an impact on cost effectiveness analysis.

Preclinical evaluation of implantable cardioverter-defibrillator developed for magnetic resonance imaging use.

BACKGROUND: Many patients with an implantable cardioverter-defibrillator (ICD) have indications for magnetic resonance imaging (MRI). However, MRI is generally contraindicated in ICD patients because of potential risks from hazardous interactions between the MRI and ICD system. OBJECTIVE: The purpose of this study was to use preclinical computer modeling, animal studies, and bench and scanner testing to demonstrate the safety of an ICD system developed for 1.5-T whole-body MRI. METHODS: MRI hazards were assessed and mitigated using multiple approaches: design decisions to increase safety and reliability, modeling and simulation to quantify clinical MRI exposure levels, animal studies to quantify the physiologic effects of MRI exposure, and bench testing to evaluate safety margin. RESULTS: Modeling estimated the incidence of a chronic change in pacing capture threshold >0.5V and 1.0V to be less than 1 in 160,000 and less than 1 in 1,000,000 cases, respectively. Modeling also estimated the incidence of unintended cardiac stimulation to occur in less than 1 in 1,000,000 cases. Animal studies demonstrated no delay in ventricular fibrillation detection and no reduction in ventricular fibrillation amplitude at clinical MRI exposure levels, even with multiple exposures. Bench and scanner testing demonstrated performance and safety against all other MRI-induced hazards. CONCLUSION: A preclinical strategy that includes comprehensive computer modeling, animal studies, and bench and scanner testing predicts that an ICD system developed for the magnetic resonance environment is safe and poses very low risks when exposed to 1.5-T normal operating mode whole-body MRI.

Evaluation des facteurs de risque cliniques et des données de la DXA (DMO, VFA, TBS) pour la prédiction du risque fracturaire. L'étude de la cohorte OséoLaus.

Introduction. - L'ostéoporose est caractérisée par une diminution dela densité minérale osseuse (DMO) et une détérioration de lamicroarchitecture osseuse (MO). En routine clinique, l'appréciationde la MO se fait de façon approximative en utilisant les facteurs derisque clinique (FRC). Il est maintenant possible d'estimer de façonsimple la MO en mesurant le Trabecular Bone Score (TBS) par réanalysed'une image DXA lombaire. TBS a une valeur diagnostiqueet pronostique indépendante des FRC et de la DMO. Le but de lacohorte lausannoise OstéoLaus est de combiner des éléments facilesà obtenir en routine clinique, à savoir les FRC et les éléments issusde la DXA (DMO, TBS, VFA) pour évaluer le risque fracturaire defaçon transversale puis prospective.Patients et Méthodes. - Nous avons constitué une cohorte d'environ1400 femmes entre 50 et 80 ans de la région lausannoise enrôléedepuis 7 ans dans une vaste cohorte (CoLaus, 6 700 participants)évaluant les facteurs génétiques et phénotypiques de maladies fréquentescardiovasculaires et psychiatriques. Le taux de participationà Ostéolaus est > 85%. Ces femmes sont vues entre mars 2010et décembre 2012. Elles passent un questionnaire, un ultrasonosseux du talon, une DXA de la colonne et de la hanche et une évaluationpar VFA (selon la méthode semi-quantitative de Genant) etle TBS. Nous rapportons les résultats préliminaires sur 631 participantes.Les données concernant les fractures (fx) vertébrales ne distinguentpas les origines traumatiques ou non.Résultats. - L'âge est de 67,4 ± 6,7 ans, l'IMC de 26.1 ± 4,6. Les donnéesbrutes de la colonne lombaire montrent une DMO à 0,943 ±0,168 (T-score -1,4 DS) et un TBS à 1,271 ± 0,103. La corrélationentre DMO et TBS est faible avec r2 = 0,16. La prévalence des fx vertébralesgrade 2/3, des fx ostéoporotiques majeures, et de toutes lesfx ostéoporotiques est de 8,4 %, 17,0 % et 26.0 % respectivement. LesORs (par diminution d'une déviation standard) ajustés pour l'âge etl'IMC sont pour la DMO de 1,8 (1,2-2,5), 1,6 (1,2-2,1), 1,3 (1,1-1,6),et pour TBS de 2,0 (1,4-3,0), 1,9 (1,4-2,5), 1.4 (1,1-1,7), respectivement.Le taux de fx avec DMO <þ- 2,5 DS se situe entre 35 et 37 %et le taux de fx avec un TBS < 1.200 entre 37 et 44 %. Par contre cetaux augmente entre 54 et 60 % si l'on combine une DMO < - 2,5 DSou un TBS < 1,200.Conclusion. - Ces données préliminaires confirment la faible corrélationentre la DMO et le TBS. Ajouter le TBS à la DMO permetd'augmenter significativement le nombre de participantes avec unefx ostéoporotique prévalente. Une mesure simple et peu irradiantepar DXA offre ainsi 3 informations complémentaires et pertinentespour la routine clinique : la DMO, la recherche des fractures vertébraleset le TBS.

Transcutaneous carbon dioxide tension in newborn infants: reliability and safety of continuous 24-hour measurement at 42 degrees C.

In 58 newborn infants a new iridium oxide sensor was evaluated for transcutaneous carbon dioxide (tcPCO2) monitoring at 42 degrees C with a prolonged fixation time of 24 hours. The correlation of tcPCO2 (y; mm Hg) v PaCO2 (x; mm Hg) for 586 paired values was: y = 4.6 + 1.45x; r = .89; syx = 6.1 mm Hg. The correlation was not influenced by the duration of fixation. The transcutaneous sensor detected hypocapnia (PaCO2 less than 35 mm Hg) in 74% and hypercapnia (PCO2 greater than 45 mm Hg) in 74% of all cases. After 24 hours, calibration shifts were less than 4 mm Hg in 90% of the measuring periods. In 86% of the infants, no skin changes were observed; in 12% of infants, there were transitional skin erythemas and in 2% a blister which disappeared without scarring. In newborn infants with normal BPs, continuous tcPCO2 monitoring at 42 degrees C can be extended for as many as 24 hours without loss of reliability or increased risk for skin burns.

Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures.

The intravenous, short-acting general anesthetic propofol was applied to three-dimensional (aggregating) cell cultures of fetal rat telencephalon. Both the clinically used formulation (Disoprivan, ICI Pharmaceuticals, Cheshire, England) and the pure form (2,6-diisopropylphenol) were tested at two different periods of brain development: immature brain cell cultures prior to synaptogenesis and at the time of intense synapses and myelin formation. At both time periods and for clinically relevant concentrations and time of exposure (i.e., concentrations > or = 2.0 micrograms/ml for 8 hr), propofol caused a significant decrease of glutamic acid decarboxylase activity. This effect persisted after removal of the drug, suggesting irreversible structural changes in GABAergic neurons. The gamma-aminobutyric acid type A (GABAA) blocking agents bicuculline and picrotoxin partially attenuated the neurotoxic effect of propofol in cultures treated at the more mature phase of development. This protective effect was not observed in the immature brain cells. The present data suggest that propofol may cause irreversible lesions to GABAergic neurons when given at a critical phase of brain development. In contrast, glial cells and myelin appeared resistant even to high doses of propofol.

What kind of relationships between the evolution of pain, beliefs and bio-psycho-social complexity after a locomotor traumatism?

Introduction: Pain and beliefs have an influence on the patient's course in rehabilitation, pain causes fears and fears influence pain perception. The aim of this study is to understand pain and beliefs evolutions during rehabilitation taking into account of bio-psycho-social complexity.Patients and methods: 631 consecutive patients admitted in rehabilitation after a musculoskeletal traumatism were included and assessed at admission and at discharge. Pain was measured by VAS (Visual Analogical Scale), bio-psycho-social complexity by Intermed scale, and beliefs by judgement on Lickert scales. Four kinds of beliefs were evaluated: fear of a severe origin of pain, fear of movement, fear of pain and feeling of distress (loss of control). The association between the changes in pain and beliefs during the hospitalization was assessed by linear regressions.Results: After adjustment for gender, age, education and native language, patients with a decrease in pain during rehabilitation have higher probability of decreasing their fears. For the distress feeling, this relationship is weaker among bio-psycho-socially complex patients (odds-ratio 1.22 for each decreasing of 10mm/100 VAS) than among non-complex patients (OR 1.47). Patients with a pain decrease of 30% or more during hospitalization have higher probability of seeing their fears decrease, this relationship being stronger in complex patient for fear of a severe origin of pain.Discussion: The relationships between evolution of pain and beliefs move in the same direction. The higher a patient feels pain, the less they could be able to modify their dysfunctional beliefs. When the pain diminishes of 30% or more, the probability to challenge the beliefs is increased. The prognostic with regard to feeling of distress and fear of a severe origin of pain, is worse among bio-psycho-socially complex patients.

Reorganization of a deeply incised drainage: role of deformation, sedimentation and groundwater flow

Deeply incised drainage networks are thought to be robust and not easily modified, and are commonly used as passive markers of horizontal strain. Yet, reorganizations (rearrangements) appear in the geologic record. We provide field evidence of the reorganization of a Miocene drainage network in response to strike-slip and vertical displacements in Guatemala. The drainage was deeply incised into a 50-km-wide orogen located along the North America-Caribbean plate boundary. It rearranged twice, first during the Late Miocene in response to transpressional uplift along the Polochic fault, and again in the Quaternary in response to transtensional uplift along secondary faults. The pattern of reorganization resembles that produced by the tectonic defeat of rivers that cross growing tectonic structures. Compilation of remote sensing data, field mapping, sediment provenance study, grain-size analysis and Ar(40)/Ar(39) dating from paleovalleys and their fill reveals that the classic mechanisms of river diversion, such as river avulsion over bedrock, or capture driven by surface runoff, are not sufficient to produce the observed diversions. The sites of diversion coincide spatially with limestone belts and reactivated fault zones, suggesting that solution-triggered or deformation-triggered permeability have helped breaching of interfluves. The diversions are also related temporally and spatially to the accumulation of sediment fills in the valleys, upstream of the rising structures. We infer that the breaching of the interfluves was achieved by headward erosion along tributaries fed by groundwater flow tracking from the valleys soon to be captured. Fault zones and limestone belts provided the pathways, and the aquifers occupying the valley fills provided the head pressure that enhanced groundwater circulation. The defeat of rivers crossing the rising structures results essentially from the tectonically enhanced activation of groundwater flow between catchments.

Evaluation Of "Safe" Trabeculectomy Versus "Safe" Phacotrabeculectomy

Purpose: To evaluate the safety and efficacy of "safe" trabeculectomy (ST) versus "safe" phacotrabeculectomy (SPT).Methods: This study included 72 eyes with medically uncontrolled chronic glaucoma who underwent fornix based trabeculectomy with adjustable/releasable sutures and intraoperative mitomycin C ± phacoemulsification. 36 eyes underwent SPT and 36 eyes had ST. There was no difference between groups for age, intraocular pressure (IOP), diagnosis and gender. Subconjunctival antimetabolite injections and bleb needlings were administered according to bleb vascularity and IOP trends. Main outcome measures were: success rate (definition: IOP≤21mmHg and 20% IOP reduction); number of antimetabolite injections; bleb needlings; glaucoma medications and complications.Results: Mean age (SPT vs ST) was 72.7±12.1 years vs 72.3±12.9 years; p=0.44. Mean preoperative IOP was 24.5±8.8 mmHg vs 24.3±8.2 mmHg; p=0.46. Postoperative IOP was 13.1±4.5mmHg vs 12.4±3.2; p=0.24. Ninety percent of both groups required at least one suture removal. There was no statistically significant difference in success rate between groups, 80% vs 83%; number of eyes requiring antimetabolite injections was 22 eyes (mean 3.2 per eye) vs 23 eyes (mean 2.6 per eye, p=0.24); bleb needlings was performed in 16 eyes (mean 2.5 per eye) vs in 11 eyes (mean 2.0 per eye, p=0.15). The number of eyes restarting glaucoma medications was 5 vs 4. Minor complications were infrequent in both groups, 9 vs 10 eyes.Conclusions: The success and complications rates were similar between groups. The number of postoperative interventions required was slightly greater in the SPT group (not statistically significant). SPT is a safe procedure for patients with coexistent glaucoma and cataract and produces similar IOP-lowering to safe trabeculectomy.