The genetic basis of major depression.

Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.

Unraveling the genetic architecture of major depressive disorder: merits and pitfalls of the approaches used in genome-wide association studies.

To identify genetic risk loci for major depressive disorder (MDD), two broad study design approaches have been applied: (1) to maximize sample size by combining data from different phenotype assessment modalities (e.g. clinical interview, self-report questionnaires) and (2) to reduce phenotypic heterogeneity through selecting more homogenous MDD subtypes. The value of these strategies has been debated. In this review, we summarize the most recent findings of large genomic studies that applied these approaches, and we highlight the merits and pitfalls of both approaches with particular attention to methodological and psychometric issues. We also discuss the results of analyses that investigated the heterogeneity of MDD. We conclude that both study designs are essential for further research. So far, increasing sample size has led to the identification of a relatively high number of genomic loci linked to depression. However, part of the identified variants may be related to a phenotype common to internalizing disorders and related traits. As such, samples containing detailed clinical information are needed to dissect depression heterogeneity and enable the potential identification of variants specific to a more restricted MDD phenotype. A balanced portfolio reconciling both study design approaches is the optimal approach to progress further in unraveling the genetic architecture of depression.

New measurements of high-momentum nucleons and short-range structures in nuclei.

We present new measurements of electron scattering from high-momentum nucleons in nuclei. These data allow an improved determination of the strength of two-nucleon correlations for several nuclei, including light nuclei where clustering effects can, for the first time, be examined. The data also include the kinematic region where three-nucleon correlations are expected to dominate.

Thickness and volume dependence of dielectric strength in advanced nanodielectric materials allowing for further size reduction of ultrahigh voltage capacitor prototypes.

We have developed a high dielectric, nanocomposite material, MU100, for use in pulsed power applications that include dielectric loaded antennas and ultra-high voltage capacitors. This paper presents the electrical properties of the first full-scale capacitor prototype along with sub-element modules. Additionally, refinements in the development process have sparked interest in a third-generation capacitor that would use similar dimensions as the initial small-scale samples that recorded breakdown fields of 225 kV/cm on average with peak breakdown fields of 328 kV/cm. The dielectric constant of these large-scale capacitors was 160. These capacitor prototypes have demonstrated voltage hold off of 500 kV. Similarly, thin samples that operated at 35-40 kV had lifetimes without failure in excess of 800 000 discharges at 80% of their maximum rated field strength.

Precise extraction of the induced polarization in the 4He(e,e'p)3H reaction.

We measured with unprecedented precision the induced polarization P(y) in (4)He(e,e'p)(3)H at Q(2)=0.8 and 1.3 (GeV/c)(2). The induced polarization is indicative of reaction-mechanism effects beyond the impulse approximation. Our results are in agreement with a relativistic distorted-wave impulse approximation calculation but are overestimated by a calculation with strong charge-exchange effects. Our data are used to constrain the strength of the spin-independent charge-exchange term in the latter calculation.

Angiotensin-converting enzyme inhibition and blood pressure response during total intravenous anaesthesia for minor surgery.

BACKGROUND: This study investigates whether long-term treatment with an angiotensin-converting enzyme inhibitor (ACEI) impairs the haemodynamic regulation during total intravenous anaesthesia (TIVA) for minor surgery. METHODS: In a prospective, two-armed observational study, 36 patients undergoing TIVA for minor surgery were studied. Seventeen were taking ACEIs regularly but no other antihypertensive medication (ACEI group); 19 patients without any cardiovascular medication served as controls (non-ACEI group). Haemodynamic variables were measured every minute during induction and every 5 min during surgery. The plasma levels of renin, angiotensin II, vasopressin and catecholamines were measured before and 18 min after the induction of anaesthesia. RESULTS: The mean arterial pressure decreased to the same extent in both the groups during the induction of TIVA. There were also no differences between the groups regarding the heart rate, systolic and diastolic arterial pressure, as well as the use of vasoconstrictors, and fluids during induction and throughout surgery. In the ACEI group, the plasma renin concentration was higher at baseline and after the induction of anaesthesia presumably due to the interruption of the negative renin-angiotensin feedback loop (P<0.05). Angiotensin II increased only in the non-ACEI group (6.2 ± 2.2 before vs. 9.6 ± 3.5 pg/ml after induction; P<0.05). In both groups, the plasma norepinephrine concentration decreased after the induction of TIVA (P<0.05). Plasma vasopressin and plasma epinephrine concentrations did not change in either group. CONCLUSION: Long-term ACEI treatment does not further aggravate the blood pressure decrease under TIVA during minor surgery, provided the induction procedure is slow, the patient is kept well hydrated and vasoconstrictors are promptly applied.

[Restless legs syndrome and cardiovascular risk]. / Restless-legs-Syndrom und kardiovaskuläres Risiko.

Large epidemiological studies have repeatedly suggested a possible association between restless legs syndrome (RLS) and common cardiovascular diseases and cardiovascular risk factors. Patients complaining of symptoms of RLS were also more likely to suffer from coronary artery disease, stroke, or, in some instances, hypertension. The underlying pathogenesis of the disease association depicted above has not been elucidated conclusively. Increased activation of the sympathetic nervous system - due to the RLS itself and the frequently accompanying periodic limb movements - has been linked to increased cardiovascular stress in patients with RLS.

Electrochemical adsorption of hydrogen on mixed Pd2Pt nanostructures.

In the present contribution we have focused on the electrochemical adsorption of a proton from the solution-the Volmer reaction-on a variety of systems based on bimetallic nanostructures-clusters and wires-of Pd and Pt deposited on a surface of Au(111). We have calculated the free energy surface for the electron transfer step by a combination of DFT calculations, MD simulations and the theory of electrocatalysis. We analyze in detail the interaction of the metal d band with the valence orbital of the hydrogen and its effect on the catalytic activity as well as several aspects that influence the electrode reactivity such as spatial arrangements of the nanostructures, the solvation shell and chemical factors. We found that the mixed Pd2Pt wire interacts strongly with hydrogen, and retains an almost complete solvation shell, which is reflected in a substantially reduced activation energy for the Volmer step. Thus, Pd2Pt wires on Au(111) are predicted to be efficient electrocatalysts for the reaction.

Polarization transfer in the 4He(e,e'p)3H reaction at Q2=0.8 and 1.3 (GeV/c)2.

Proton recoil polarization was measured in the quasielastic 4He(e,e'p)3H reaction at Q{2}=0.8 and 1.3 (GeV/c){2} with unprecedented precision. The polarization-transfer coefficients are found to differ from those of the 1H(e,e'p) reaction, contradicting a relativistic distorted-wave approximation and favoring either the inclusion of medium-modified proton form factors predicted by the quark-meson coupling model or a spin-dependent charge-exchange final-state interaction. For the first time, the polarization-transfer ratio is studied as a function of the virtuality of the proton.

Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery.

BACKGROUND: Intraoperative stress may suppress the adaptive immune system. Abolished proinflammatory lymphocyte function is associated with higher risk of infection and postoperative complications. We hypothesized that thoracic epidural anaesthesia (TEA) reduces intraoperative stress and thus attenuates lymphocyte decrease and impairment of proinflammatory lymphocyte function. METHODS: Fifty-four patients undergoing major abdominal surgery who had a thoracic epidural catheter inserted were studied. In the TEA-I group, this catheter was used for intraoperative analgesia, whereas the TEA-P group received systemic opioids during surgery. In both groups, patient-controlled epidural analgesia was used for postoperative pain management. Blood samples for immune analyses were obtained before induction of anaesthesia, 2 h after skin incision, and at days 1 and 4 after surgery. Lymphocyte subpopulations, expression of human leucocyte antigen (HLA)-DR on monocytes, plasma concentrations of interleukin (IL)-10, interferon-gamma (IFN-gamma), and IL-12, and concanavalin-A-stimulated concentrations of IFN-gamma and IL-10 were measured. Intraoperative data including bispectral index and plasma concentrations of epinephrine/cortisol were analysed; APACHE-II, SAPS II, and additional postoperative data were documented. RESULTS: Plasma concentrations of epinephrine and cortisol were significantly lower in the TEA-I patients during surgery. IFN-gamma/IL-10 ratio was significantly higher in the TEA-I group from 2 h after skin incision until day 1. Lymphocyte numbers and T-helper cells were significantly higher in the TEA-I group at day 1, whereas no significant differences were detected among IL-12, HLA-DR, and postoperative clinical course. CONCLUSIONS: Intraoperative use of thoracic epidural catheter reduced stress response and prevented stress-induced perioperative impairment of proinflammatory lymphocyte function.

[Bullectomy as emergency intervention in a mechanically ventilated patient with refractory type II respiratory failure due to chronic obstructive lung disease (COPD)]. / Erfolgreiche Notfall-Bullektomie bei einer invasiv beatmeten Patientin mit refraktärer ventilatorischer Insuffizienz im Rahmen einer akuten Exazerbation einer chronisch-obstruktiven Lungenerkrankung (COPD).

A 44-year-old female patient presented with an extensive exacerbation of severe chronic obstructive lung disease (COPD) and bullous emphysema. Because of a severe type II respiratory failure, the patient was intubated and mechanically ventilated. Respiratory failure was refractory despite appropriate ventilation regimes and pCO2 values ranged from 110 mm Hg to 180 mm Hg. Chest radiography revealed hyperinflation of two giant bullae with mediastinal shifting to the left lung. We describe a successful rescue bullectomy.

Estimation of the muscle fibre semi-length under varying joint positions on the basis of non-invasively extracted motor unit action potentials.

Changes in muscle fibre length and surface electrode position with respect to the muscle fibres affect the amplitude and frequency characteristics of surface electromyography (SEMG) in different ways. Knowledge of changes in muscle fibre length would help towards a better interpretation of the signals. The possibility of estimating the length through SEMG during voluntary contractions was checked in this study. The fibres' semi-length was estimated from the product of the conduction velocity and conduction time during which the wave of excitation propagated from the end-plate region to the ends of the fibres. Short (10 s), moderate (30% of maximum voluntary contraction) isometric contractions were performed by 10 subjects at different elbow joint angles (80-140 degrees in steps of 20 degrees ). Monopolar signals were detected non-invasively, using a two-dimensional electrode array. High spatial resolution EMG and a decomposition technique were utilised to extract single motor unit activities for triggered averaging and to estimate conduction velocity. A significant increase with joint angle was found in conduction time and estimated fibre semi-length. Changes in conduction velocity with joint angle were found to be not significant. The methodology described allows the relative changes in fibres' semi-length to be estimated from SEMG data.

Quality of life in relation to symptoms in patients with gastro-oesophageal reflux disease-- an analysis based on the ProGERD initiative.

AIMS: To determine the impact of gastro-oesophageal reflux disease (GERD) on the quality of life, to assess changes in the quality of life during treatment with esomeprazole and to define factors that can predict these changes. METHODS: Patients with GERD (n=6215) were included in a prospective cohort study (ProGERD). All patients underwent endoscopy and received esomeprazole. At baseline and after 2 weeks of treatment, symptoms and quality of life were assessed. Factors that influenced changes in the quality of life were determined by multiple regression analyses. RESULTS: At baseline, the quality of life in GERD patients was lower than that in the general population, and was similar to that in patients after acute coronary events. No differences in symptoms or quality of life were observed between the subgroups of patients with non-erosive GERD, erosive GERD and Barrett's oesophagus. After treatment with esomeprazole, the symptoms and quality of life were improved in all subscales within 2 weeks (P<0.001). The mean score of the disease-specific quality of life instrument (Quality of Life in Reflux and Dyspepsia Patients) increased from 4.6 to 6.2 points, representing a highly relevant clinical improvement. The generic quality of life (SF-36) reached levels similar to those in the general population, but, again, no difference was found between the three different subgroups of GERD patients. The main factors associated with an improvement in the quality of life after treatment were symptom relief, severe erosive reflux disease, absence of extra-oesophageal disorders, avoidance of non-steroidal anti-inflammatory drug intake and positive Helicobacter pylori status. CONCLUSIONS: GERD causes a significant impairment in the quality of life that can be attenuated or normalized within a time period as short as 2 weeks by treatment with esomeprazole. These findings were similar across the whole GERD patient spectrum.

Hospitalizations for respiratory syncytial virus infection in Alaska Native children.

To characterize the epidemiology of Alaska Native children hospitalized for respiratory syncytial virus infections, we reviewed records of hospitalizations during the winter seasons of 1991 to 1992 and 1992 to 1993 at a hospital in Anchorage and a rural hospital in the Yukon Kuskokwim Delta (YKD) region of southwestern Alaska. The median age of hospitalization for respiratory syncytial virus infection was 2 months of age for YKD residents and 4.5 months for Anchorage residents. Sixteen percent of the hospitalized YKD children were less than 1 month of age, whereas the same was true for only 3% of the Anchorage children. Eight percent of the YKD patients required mechanical ventilation, whereas none of the Anchorage patients required ventilation. The median hospital stay was 4.8 days for YKD patients and 3.2 days for Anchorage patients. Hospitalization rates for infants less than 1 year of age were 33/1000 for Alaska Natives in Anchorage and 100/1000 for those in the YKD region. The extremely high hospitalization rate, especially among very young infants in the rural YKD region, points to a need for early preventive efforts.

The use of texture analysis to study the time course of chromatolysis.

Image analysis of the textural feature entropy of the Nissl substance was used to monitor the time course of chromatolysis in regenerating hypoglossal motoneurons and degenerating facial motoneurons 4-112 days after hypoglossal-facial anastomosis in rats. Changes in the Nissl substance were detected that were not obvious on the basis of subjective judgement of the light-microscopical appearance of the neurons. Chromatolysis started 4 days post operation (dpo) and was not reversed at 112 dpo in both nuclei. The increase of chromatolysis was 14-28 dpo faster in the regenerating hypoglossal neurons than in degenerating facial neurons. Maximal chromatolysis was measured at 56-70 dpo in both nuclei. Afterwards chromatolysis persisted at a significantly higher level in the degenerating facial motoneuron pool. In conclusion, chromatolysis is a very long persisting reaction. In the beginning chromatolysis is faster and greater in regenerating rather than in degenerating neurons. In contrast, passing the maximal reaction, chromatolysis is maintained at a higher level in degenerating motoneurons. Image analysis of textural features is a suitable and reliable tool to monitor the time course of neuronal cell body changes. The presented quantitative method could be applied in any neurobiological study influencing the regeneration or degeneration of motoneurons.

Experimental muscle pain increases trapezius muscle activity during sustained isometric contractions of arm muscles.

OBJECTIVE: In the present study, the influence of experimental muscle pain on muscle co-ordination and fatigue development during sustained isometric elbow flexion was investigated. METHODS: Conventional surface electromyography (EMG) was recorded from the biceps brachii, brachioradialis, deltoideus and trapezius muscle during isometric elbow flexion at 40% maximum force. Single motor unit (MU) conduction velocity in the biceps brachii was assessed using a high spatial resolution surface EMG technique. Measurements were performed on 15 healthy subjects before, during and after (1) injection of hypertonic (pain condition) and (2) isotonic saline (control) into the biceps brachii. The pain intensity was assessed on a 10 cm visual analogue scale. RESULTS: The experimental results showed in both experimental sessions a fatigue-related increase of the root mean square value of EMG (222+/-164% of the baseline), and a decrease of the median frequency (118+/-16% of the baseline) in all investigated muscles. A maximum pain level of in average 3.2 cm on the visual analogue scale was reached after injection of hypertonic saline during contraction. Differences between painful and control condition were seen in an increased trapezius activity (230+/-141%) during pain. The global EMG activity of the brachioradialis and biceps brachii was unaffected by experimental muscle pain in line with unaffected single MU conduction velocity in the biceps brachii. Differences in endurance time (mean 89.3 and 102.3 s, pain and control, respectively) were not significant. CONCLUSIONS/SIGNIFICANCE: The findings suggest that upper extremity pain could be a possible source for overloading the trapezius muscle and as such is an important factor in occupational settings.

Repeatability of patellar cartilage thickness patterns in the living, using a fat-suppressed magnetic resonance imaging sequence with short acquisition time and three-dimensional data processing.

A fast, reproducible, and noninvasive method is required for quantifying cartilage thickness clinically and for studying the deformation of articular cartilage during and after mechanical loading in vivo. The objective of the current investigation was to test the repeatability of regional distribution patterns of patellar cartilage thickness in the living on the basis of a fat-suppressed magnetic resonance imaging sequence with a short acquisition time and three-dimensional digital data processing. The knees of eight healthy volunteers were transversally imaged with a fat-suppressed FLASH-3D (fast low angle shot) sequence (acquisition time: 4 minutes and 10 seconds). In each case, the joint was newly positioned before each of the six replicate measurements was taken. The patellar cartilage was reconstructed three-dimensionally, and the distribution of cartilage thickness was determined with a three-dimensional minimal-distance algorithm. Whereas the cartilage volume ranged from 3,198 to 7,149 mm3, the mean coefficient of variation for the 6-fold volume measurement was 1.35%. On average, 75.1% (+/- 4.1%) of all test pixels could be attributed to the same cartilage thickness interval (0.5 mm) by image analysis; 14.8% (+/- 2.4%) deviated by one interval; 6.6% (+/- 1.5%), by two intervals; and 3.5% (+/- 1.8%), by more than two intervals. We conclude that, on the basis of a magnetic resonance imaging sequence with an acquisition time of less than 5 minutes, the quantitative distribution of cartilage thickness can be determined with high precision in vivo.

The motivation of alcohol dependents to undergo treatment.

The purpose of this study was to investigate the determinants and factors influencing the motivation of alcohol dependents to undergo treatment. As well as exploring the influence of socio-demographic and illness-related variables, the study concentrated in particular on the influence of the clients' attitudes towards their current life situation, their alcohol problem and the treatment, also the influence of specific interventions aimed at increasing their motivation for treatment. On the basis of the results obtained in the study from 239 alcohol-dependent clients, it is shown to what extent these variables are of value as a means of predicting and modifying the motivation for treatment. In the motivation programme a variety of procedures was applied using a 2 x 2 design: motivation on an individual basis and motivation on a group basis were combined with two different approaches, one client-centred and one in accordance with the principles of cognitive-behavioural therapy. A group placed on a waiting list for 3 weeks was used as a control group. The clients were allocated to the various groups on a random basis. Specific attitudes on the part of the clients and aspects of the motivation programme provided significant indicators of the clients' likelihood to undergo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive determination of cartilage thickness throughout joint surfaces using magnetic resonance imaging.

Data on articular cartilage thickness in the living are important for the design for computer models, aimed at preoperatively assessing the effect of surgical procedures on joint contact and load transmission, and for the calculation of cartilage material properties from its deformational behavior as determined during arthroscopy. A non-invasive method for measuring cartilage thickness in living subjects is, however, not available. A technique based on magnetic resonance imaging has therefore been tested for assessing articular cartilage thickness throughout joint surfaces. The accuracy is determined by comparing cartilage thickness maps obtained from three patellar specimens with a fat-suppressed three-dimensional gradient-echo sequence (resolution 2 x 0.31 x 0.31 mm) to those obtained with CT arthrography, A-mode ultrasound and anatomical sections. The distribution patterns are quantitatively compared using image analysis. The highest agreement was obtained for MRI and the sections (50% identical pixels), but all techniques yielded very similar results. On average, MR slightly underestimated the cartilage thickness compared with CT and the sections, and overestimated it compared with ultrasound. No evidence of differences in the degree of similarity could be detected in areas of thin and thick cartilage. We conclude that, if the resolution and accuracy of the method presented are considered acceptable, MRI is available for repeatable determination of topographical maps of articular cartilage thickness in living subjects. These data can be used to determine joint contact and stress in computer models and to calculate cartilage material properties in vivo.