The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study.

BACKGROUND: European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. METHODS: The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. RESULTS: Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. CONCLUSIONS: Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

Detection of the movement of the humerus during daily activity.

A new ambulatory technique for qualitative and quantitative movement analysis of the humerus is presented. 3D gyroscopes attached on the humerus were used to recognize the movement of the arm and to classify it as flexion, abduction and internal/external rotations. The method was first validated in a laboratory setting and then tested on 31 healthy volunteer subjects while carrying the ambulatory system during 8 h of their daily life. For each recording, the periods of sitting, standing and walking during daily activity were detected using an inertial sensor attached on the chest. During each period of daily activity the type of arm movement (flexion, abduction, internal/external rotation) its velocity and frequency (number of movement/hour) were estimated. The results showed that during the whole daily activity and for each activity (i.e. walking, sitting and walking) the frequency of internal/external rotation was significantly higher while the frequency of abduction was the lowest (P < 0.009). In spite of higher number of flexion, abduction and internal/external rotation in the dominant arm, we have not observed in our population a significant difference with the non-dominant arm, implying that in healthy subjects the arm dominance does not lie considerably on the number of movements. As expected, the frequency of the movement increased from sitting to standing and from standing to walking, while we provide a quantitative value of this change during daily activity. This study provides preliminary evidence that this system is a useful tool for objectively assessing upper-limb activity during daily activity. The results obtained with the healthy population could be used as control data to evaluate arm movement of patients with shoulder diseases during daily activity.

Improved accuracy of co-morbidity coding over time after the introduction of ICD-10 administrative data.

BACKGROUND: Co-morbidity information derived from administrative data needs to be validated to allow its regular use. We assessed evolution in the accuracy of coding for Charlson and Elixhauser co-morbidities at three time points over a 5-year period, following the introduction of the International Classification of Diseases, 10th Revision (ICD-10), coding of hospital discharges.METHODS: Cross-sectional time trend evaluation study of coding accuracy using hospital chart data of 3'499 randomly selected patients who were discharged in 1999, 2001 and 2003, from two teaching and one non-teaching hospital in Switzerland. We measured sensitivity, positive predictive and Kappa values for agreement between administrative data coded with ICD-10 and chart data as the 'reference standard' for recording 36 co-morbidities.RESULTS: For the 17 the Charlson co-morbidities, the sensitivity - median (min-max) - was 36.5% (17.4-64.1) in 1999, 42.5% (22.2-64.6) in 2001 and 42.8% (8.4-75.6) in 2003. For the 29 Elixhauser co-morbidities, the sensitivity was 34.2% (1.9-64.1) in 1999, 38.6% (10.5-66.5) in 2001 and 41.6% (5.1-76.5) in 2003. Between 1999 and 2003, sensitivity estimates increased for 30 co-morbidities and decreased for 6 co-morbidities. The increase in sensitivities was statistically significant for six conditions and the decrease significant for one. Kappa values were increased for 29 co-morbidities and decreased for seven.CONCLUSIONS: Accuracy of administrative data in recording clinical conditions improved slightly between 1999 and 2003. These findings are of relevance to all jurisdictions introducing new coding systems, because they demonstrate a phenomenon of improved administrative data accuracy that may relate to a coding 'learning curve' with the new coding system.

Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring.

Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug-resistant epilepsy, including electric source and nuclear imaging. Left operculo-insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years.

Intérêt de l'angiographie numérisée au vert d'indocyanine dans le diagnostic différentiel des tumeurs non pigmentées de la choroïde [Value of indocyanine green videoangiography in differential diagnosis of nonpigmented tumors of the choroid]

BACKGROUND: Indocyanine green video-angiography (ICG) is a recent examination technique, its possibilities and limitations as far as intraocular tumours are concerned, haven't been fully explored yet. MATERIAL AND METHODS: We have studied 50 cases of non-pigmented choroidal tumours, including 14 cases of choroidal hemangioma's, 11 cases of posterior uveal metastases and 25 cases of non-pigmented melanoma's. RESULTS: Characteristic images were obtained when examining choroidal hemangioma's and, until a certain point, posterior choroidal metastases. Non pigmented melanoma's on the contrary, presented a great variety of different indocyanine green angiographic pictures. CONCLUSION: Indocyanine green video-angiography (ICG) has a definite value in the differential diagnosis of non-pigmented posterior choroidal tumours.

Immunocytochemical and pharmacological characterization of metabotropic glutamate receptors of the vestibular end organs in the frog.

Using immunocytochemistry and multiunit recording of afferent activity of the whole vestibular nerve, we investigated the role of metabotropic glutamate receptors (mGluR) in the afferent neurotransmission in the frog semicircular canals (SCC). Group I (mGluR1alpha) and group II (mGluR2/3) mGluR immunoreactivities were distributed to the vestibular ganglion neurons, and this can be attributed to a postsynaptic locus of metabotropic regulation of rapid excitatory transmission. The effects of group I/II mGluR agonist (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) and antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) on resting and chemically induced afferent activity were studied. ACPD (10-100 microM) enhanced the resting discharge frequency. MCPG (5-100 microM) led to a concentration-dependent decrease of both resting activity and ACPD-induced responses. If the discharge frequency had previously been restored by L-glutamate (L-Glu) in high-Mg2+ solution, ACPD elicited a transient increase in the firing rate in the afferent nerve suggesting that ACPD acts on postsynaptic receptors. The L-Glu agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA), were tested during application of ACPD. AMPA- and NMDA-induced responses were higher in the presence than absence of ACPD, implicating mGluR in the modulation of ionotropic glutamate receptors. These results indicate that activation of mGluR potentiates AMPA and NMDA responses through a postsynaptic interaction. We conclude that ACPD may exert modulating postsynaptic effects on vestibular afferents and that this process is activity-dependent.

Can neurally adjusted ventilatory assist (NAVA) improve patient-ventilator interaction? A preliminary study

INTRODUCTION. NAVA is a new spontaneous-assisted ventilatory mode based on thedetection of diaphragmatic electrical activity (Eadi) and its feedback to adjust ventilatorsettings. NAVA uses the Eadi, an expression of the respiratory center's activity, to initiatepressurization, set the level of pressure support and cycle the ventilator into exhalation.Therefore, NAVA should theoretically allow near-perfect synchronization between the patientand the ventilator. However there are few data documenting these effects in intensive carepatients.OBJECTIVES. To determine whether NAVA can improve patient-ventilator synchronycompared to standard pressure support (PS) in intubated intensive care patients.METHODS. Comparative study of patient-ventilator interaction during PS with cliniciandetermined ventilator settings and NAVA with NAVA gain (proportionality factor betweenEadi and the amount of delivered inspiratory pressure) set as to obtain the same peak airwaypressure as the total pressure obtained in PS. A 20 min continuous recording with eachventilatory mode was performed allowing determination of trigger delay (Td), patient neuralinspiratory time (Tin), duration of pressurization by the ventilator (Tiv), excess durationof pressurization (Ti excess = Tiv - Tin/Tin 9 100) and number of asynchrony events byminute: non-triggering breaths, auto-triggering, double triggering, premature and delayedcycling.Results are given in mean ± SD. p is considered significant if\0.05.RESULTS. Preliminary results (mean ± SD): five patients (age 75 ± 12 years, 1 M/4F,BMI 25.7 ± 4.1 kg m-2), two pts with COPD, 1 with restrictive disease, initial settings: PS14.6 ± 1.7 cm H2O, PEEP 6.4 ± 1.5 cm H2O, NAVA gain 2.8 ± 1.3PS NAVA % reduction NAVAversus PSTd (ms) 210.4 ± 63.0 51.8 ± 12.1* 74.5 ± 5.0Ti excess (%) 12.9 ± 19.6 2.2 ± 0.6 70.8 ± 37.8n asynchrony/minute 7.6 ± 6.4 4.1 ± 3.7* 47.5 ± 17.0Respiratory rate (min-1) 16.8 ± 2.6 20.4 ± 4.7 NA* p\0.05CONCLUSION. Compared to standard PS, NAVA improves patient ventilator interaction byreducing Td and the overall incidence of asynchrony events. There is also a strong trend inreducing delayed cycling. This ongoing trial should provide evidence that NAVA can indeedimprove patient-ventilator synchrony in intubated patients undergoing PS.REFERENCE(S). 1. Sinderby C, Navalesi P et al (1995) Neural control of mechanicalventilation in respiratory failure. Nat Med 5(12):1433-1436.2. Colombo D, Cammarota G et al (2008) Physiologic response to varying levels of pressuresupport and neurally adjusted ventilator assist in patients with acute respiratory failure.Intensive Care Med 34(11):2010-2018.

Prevention of Caval Collapse During Venous Drainage for CPB.

A new plastic self-expanding Smartcanula (Smartcanula LLC, Lausanne, Switzerland) is designed for central insertion and prevention of caval collapse. The objective of our work is to assess the influence of the new design on atrial chatter. Caval collapse over the entire caval axis, right atrial, hepatic, renal vein, and iliac vein is realized in drainage tubes with holes at 5 cm distance intervals. Smartcanulas with various lengths (26 cm [= right atrial], 34 cm [= hepatic], 43 cm [= renal], and 53 cm [= iliac]) versus two-stage cannulas are compared. Pressure drop (ΔP) is measured using Millar pressure-transducers. Flow rate (Q) is measured using an ultrasonic flow meter. Cannula resistance is defined as the ΔP/Q ratio. Data display and recording are controlled using LabView virtual instruments. At an 88 cm height differential, Q values are 8.69 and 6.8 l/min, and ΔP/Q ratios are 0.63 and 1.28 for the 26-cm Smartcanula and the reference cannula, respectively. The 34-cm Smartcanula showed 8.89 l/min and 0.6 ΔP/Q ratio vs. 7.59 l/min and 0.9 for the control cannula (P < 0.05). The 43-cm and 53-cm Smartcanulas showed Q values of 9.04 and 8.81 l/min, respectively, and ΔP/Q2 ratio of 0.6. The Smartcanula outperforms the two-stage cannula, and direct cannula insertion without guide wire is effective.

Dépistage du syndrome des apnées du sommeil [Screening for sleep apnea syndrome]

Sleep apnea syndrome (SAS) consists of nocturnal snoring interrupted by obstructive apnea and of diurnal symptoms like hypersomnolence as a consequence of sleep fragmentation. Cardiovascular morbidity and mortality associated with this syndrome justify early detection and appropriate treatment. Polysomnography is still a frequently used method for early detection; however, several disadvantages like duration, discomfort and expense led to a search for alternatives. Since the beginning of the eighties, oximetry allows recording of nocturnal oxygen saturation of hemoglobin even at home. Nocturnal oximetry reveals O2-desaturation associated with apnea and thus permits often to diagnose or exclude SAS. Diagnosis of SAS is made when at least 20 desaturations per hour with an amplitude of at least 4% are recorded. On the other hand, normal nocturnal oximetry nearly excludes SAS. In those cases where nocturnal oximetry is not diagnostic, polysomnography remains the method of choice. Departing from published work, a model for SAS detection, based mainly on nocturnal oximetry, is proposed.

Intermittent atrial tachycardia promotes repolarization alternans and conduction slowing during rapid rates, and increases susceptibility to atrial fibrillation in a free-behaving sheep model.

INTRODUCTION: Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood. METHODS AND RESULTS: Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF. CONCLUSION: This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

FIB-SEM tomography in biology.

Three-dimensional information is much easier to understand than a set of two-dimensional images. Therefore a layman is thrilled by the pseudo-3D image taken in a scanning electron microscope (SEM) while, when seeing a transmission electron micrograph, his imagination is challenged. First approaches to gain insight in the third dimension were to make serial microtome sections of a region of interest (ROI) and then building a model of the object. Serial microtome sectioning is a tedious and skill-demanding work and therefore seldom done. In the last two decades with the increase of computer power, sophisticated display options, and the development of new instruments, an SEM with a built-in microtome as well as a focused ion beam scanning electron microscope (FIB-SEM), serial sectioning, and 3D analysis has become far easier and faster.Due to the relief like topology of the microtome trimmed block face of resin-embedded tissue, the ROI can be searched in the secondary electron mode, and at the selected spot, the ROI is prepared with the ion beam for 3D analysis. For FIB-SEM tomography, a thin slice is removed with the ion beam and the newly exposed face is imaged with the electron beam, usually by recording the backscattered electrons. The process, also called "slice and view," is repeated until the desired volume is imaged.As FIB-SEM allows 3D imaging of biological fine structure at high resolution of only small volumes, it is crucial to perform slice and view at carefully selected spots. Finding the region of interest is therefore a prerequisite for meaningful imaging. Thin layer plastification of biofilms offers direct access to the original sample surface and allows the selection of an ROI for site-specific FIB-SEM tomography just by its pronounced topographic features.

Intracellular nanomanipulation by a photonic-force microscope with real-time acquisition of a 3D stiffness matrix.

A traditional photonic-force microscope (PFM) results in huge sets of data, which requires tedious numerical analysis. In this paper, we propose instead an analog signal processor to attain real-time capabilities while retaining the richness of the traditional PFM data. Our system is devoted to intracellular measurements and is fully interactive through the use of a haptic joystick. Using our specialized analog hardware along with a dedicated algorithm, we can extract the full 3D stiffness matrix of the optical trap in real time, including the off-diagonal cross-terms. Our system is also capable of simultaneously recording data for subsequent offline analysis. This allows us to check that a good correlation exists between the classical analysis of stiffness and our real-time measurements. We monitor the PFM beads using an optical microscope. The force-feedback mechanism of the haptic joystick helps us in interactively guiding the bead inside living cells and collecting information from its (possibly anisotropic) environment. The instantaneous stiffness measurements are also displayed in real time on a graphical user interface. The whole system has been built and is operational; here we present early results that confirm the consistency of the real-time measurements with offline computations.

Advantages of a modified gastroscope for video-assisted internal mammary artery harvesting.

Instead of standard rigid thoracoscopes, we used a modified gastroscope for video assistance during 12 minimally invasive left internal mammary harvesting. Flexibility and remote control of its last centimeters give to the gastroscope a total freedom of movements, and perfect positioning in every direction. The scope is equipped with cold light, a suction canal and an irrigation canal, which allow for in situ washing without needing to remove it from the thoracic cavity. Thanks to these advantages, vision and lighting are always perfect.

The future key role of LC-high-resolution-MS analyses in clinical laboratories: a focus on quantification.

For the last decade, high-resolution (HR)-MS has been associated with qualitative analyses while triple quadrupole MS has been associated with routine quantitative analyses. However, a shift of this paradigm is taking place: quantitative and qualitative analyses will be increasingly performed by HR-MS, and it will become the common 'language' for most mass spectrometrists. Most analyses will be performed by full-scan acquisitions recording 'all' ions entering the HR-MS with subsequent construction of narrow-width extracted-ion chromatograms. Ions will be available for absolute quantification, profiling and data mining. In parallel to quantification, metabotyping will be the next step in clinical LC-MS analyses because it should help in personalized medicine. This article is aimed to help analytical chemists who perform targeted quantitative acquisitions with triple quadrupole MS make the transition to quantitative and qualitative analyses using HR-MS. Guidelines for the acceptance criteria of mass accuracy and for the determination of mass extraction windows in quantitative analyses are proposed.

Diagnosis and treatment of resistant hypertension.

Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice. It is most often defined as a blood pressure remaining ≥ 140/90 mmHg despite the regular intake of at least three drugs lowering blood pressure by different mechanisms, one of them being a diuretic. It now appears justified to include, unless contraindicated or not tolerated, a blocker of the renin-angiotensin system and a calcium channel blocker in this drug regimen, not only to gain antihypertensive efficacy, but also to prevent or regress target organ damage and delay the development of cardiorenal complications. A non-negligible fraction of treatment-resistant hypertension have normal "out of office" blood pressures. Ambulatory blood pressure monitoring and/or home blood pressure recording should therefore be routinely performed to identify patients with true resistant hypertension, i.e. patients who are more likely to benefit from treatment intensification.