Computational Synaptic Modeling of Pitch and Duration Mismatch Negativity in First-Episode Psychosis Reveals Selective Dysfunction of the N-Methyl-D-Aspartate Receptor.

Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis.

Inefficient Magnetic-Field Amplification in Supersonic Laser-Plasma Turbulence.

We report a laser-plasma experiment that was carried out at the LMJ-PETAL facility and realized the first magnetized, turbulent, supersonic (Ma_{turb}≈2.5) plasma with a large magnetic Reynolds number (Rm≈45) in the laboratory. Initial seed magnetic fields were amplified, but only moderately so, and did not become dynamically significant. A notable absence of magnetic energy at scales smaller than the outer scale of the turbulent cascade was also observed. Our results support the notion that moderately supersonic, low-magnetic-Prandtl-number plasma turbulence is inefficient at amplifying magnetic fields compared to its subsonic, incompressible counterpart.

Imaging epilepsy in larval zebrafish.

Our understanding of the genetic aetiology of paediatric epilepsies has grown substantially over the last decade. However, in order to translate improved diagnostics to personalised treatments, there is an urgent need to link molecular pathophysiology in epilepsy to whole-brain dynamics in seizures. Zebrafish have emerged as a promising new animal model for epileptic seizure disorders, with particular relevance for genetic and developmental epilepsies. As a novel model organism for epilepsy research they combine key advantages: the small size of larval zebrafish allows high throughput in vivo experiments; the availability of advanced genetic tools allows targeted modification to model specific human genetic disorders (including genetic epilepsies) in a vertebrate system; and optical access to the entire central nervous system has provided the basis for advanced microscopy technologies to image structure and function in the intact larval zebrafish brain. There is a growing body of literature describing and characterising features of epileptic seizures and epilepsy in larval zebrafish. Recently genetically encoded calcium indicators have been used to investigate the neurobiological basis of these seizures with light microscopy. This approach offers a unique window into the multiscale dynamics of epileptic seizures, capturing both whole-brain dynamics and single-cell behaviour concurrently. At the same time, linking observations made using calcium imaging in the larval zebrafish brain back to an understanding of epileptic seizures largely derived from cortical electrophysiological recordings in human patients and mammalian animal models is non-trivial. In this review we briefly illustrate the state of the art of epilepsy research in zebrafish with particular focus on calcium imaging of epileptic seizures in the larval zebrafish. We illustrate the utility of a dynamic systems perspective on the epileptic brain for providing a principled approach to linking observations across species and identifying those features of brain dynamics that are most relevant to epilepsy. In the following section we survey the literature for imaging features associated with epilepsy and epileptic seizures and link these to observations made from humans and other more traditional animal models. We conclude by identifying the key challenges still facing epilepsy research in the larval zebrafish and indicate strategies for future research to address these and integrate more directly with the themes and questions that emerge from investigating epilepsy in other model systems and human patients.

Cerebellar Asymmetry and Cortical Connectivity in Monozygotic Twins with Discordant Handedness.

Handedness differentiates patterns of neural asymmetry and interhemispheric connectivity in cortical systems that underpin manual and language functions. Contemporary models of cerebellar function incorporate complex motor behaviour and higher-order cognition, expanding upon earlier, traditional associations between the cerebellum and motor control. Structural MRI defined cerebellar volume asymmetries and correlations with corpus callosum (CC) size were compared in 19 pairs of adult female monozygotic twins strongly discordant for handedness (MZHd). Volume and asymmetry of cerebellar lobules were obtained using automated parcellation.CC area and regional widths were obtained from midsagittal planimetric measurements. Within the cerebellum and CC, neurofunctional distinctions were drawn between motor and higher-order cognitive systems. Relationships amongst regional cerebellar asymmetry and cortical connectivity (as indicated by CC widths) were investigated. Interactions between hemisphere and handedness in the anterior cerebellum were due to a larger right-greater-than-left hemispheric asymmetry in right-handed (RH) compared to left-handed (LH) twins. In LH twins only, anterior cerebellar lobule volumes (IV, V) for motor control were associated with CC size, particularly in callosal regions associated with motor cortex connectivity. Superior posterior cerebellar lobule volumes (VI, Crus I, Crus II, VIIb) showed no correlation with CC size in either handedness group. These novel results reflected distinct patterns of cerebellar-cortical relationships delineated by specific CC regions and an anterior-posterior cerebellar topographical mapping. Hence, anterior cerebellar asymmetry may contribute to the greater degree of bilateral cortical organisation of frontal motor function in LH individuals.

Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures.

Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C). The variant channels produced a temperature-dependent destabilization of activation and fast inactivation. Implementing these empirical abnormalities in a computational model predicts a higher threshold for depolarization block in the variant, particularly at 40 °C, suggesting a failure to autoregulate at high-input states. These results reveal direct effects of abnormalities in NaV1.1 biophysical properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different observational scales (gene/channel to patient).

First set of gated x-ray imaging diagnostics for the Laser Megajoule facility.

The Laser Megajoule (LMJ) facility located at CEA/CESTA started to operate in the early 2014 with two quadruplets (20 kJ at 351 nm) focused on target for the first experimental campaign. We present here the first set of gated x-ray imaging (GXI) diagnostics implemented on LMJ since mid-2014. This set consists of two imaging diagnostics with spatial, temporal, and broadband spectral resolution. These diagnostics will give basic measurements, during the entire life of the facility, such as position, structure, and balance of beams, but they will also be used to characterize gas filled target implosion symmetry and timing, to study x-ray radiography and hydrodynamic instabilities. The design requires a vulnerability approach, because components will operate in a harsh environment induced by neutron fluxes, gamma rays, debris, and shrapnel. Grazing incidence x-ray microscopes are fielded as far as possible away from the target to minimize potential damage and signal noise due to these sources. These imaging diagnostics incorporate microscopes with large source-to-optic distance and large size gated microchannel plate detectors. Microscopes include optics with grazing incidence mirrors, pinholes, and refractive lenses. Spatial, temporal, and spectral performances have been measured on x-ray tubes and UV lasers at CEA-DIF and at Physikalisch-Technische Bundesanstalt BESSY II synchrotron prior to be set on LMJ. GXI-1 and GXI-2 designs, metrology, and first experiments on LMJ are presented here.

Colonic wall changes in patients with diverticular disease - is there a predisposition for a complicated course?

BACKGROUND: The aim of this study was to evaluate colonic wall changes and enteric neuropathy in patients with either uncomplicated (UDD) or complicated diverticular disease (CDD). Furthermore, we evaluated the presence of an anatomic sphincter at the rectosigmoid junction (RSJ). METHODS: Samples of colonic tissue from fifteen patients with UDD, fifteen patients with CDD and fifteen patients as control were collected. Collagen quotient I/III was measured with the Sirius-red test, expression of MMP-1, MMP-13, innervation (S100), proliferation (Ki67) and apoptosis (TUNEL) in the colonic wall were investigated by immunohistochemical studies. Furthermore, measurements of the different layers were performed to investigate the RSJ. RESULTS: Patients with either UDD or CDD had lower collagen I/III quotients compared to the control group, significant for CDD (p = 0.007). For MMP-1 and MMP-13 only a slight increase for patients with CDD was found. The percentage of proliferating (Ki67) and apoptotic (TUNEL) cells was significantly higher for patients with CDD than in the control group (p = 0.016; p = 0.037). Upon investigating the S100-expression a significant reduce in glial cells density was found in the myenteric and mucosal plexus for both groups (UDD and CDD) compared to the control group. Measurements of the different colon layers oral, aboral and at the RSJ revealed equal values. CONCLUSIONS: This study has shown that colonic wall changes and enteric neuropathy seem to play a role in the pathogenesis of colonic diverticulosis. None of our results suggest a predisposition for a complicated diverticular disease. Furthermore, the presence of an anatomic sphincter at the rectosigmoid junction could not be detected.

Primary anastomosis with a defunctioning stoma versus Hartmann's procedure for perforated diverticulitis--a comparison of stoma reversal rates.

PURPOSE: The ideal treatment of patients with perforated diverticulitis is still controversial. Hartmann's procedure has been the treatment of choice for decades, but primary anastomosis with a defunctioning stoma has become an accepted alternative. The aim of this study was to evaluate the stoma reversal rates after these two surgical strategies. METHODS: A retrospective review of the data from patients with perforated sigmoid diverticulitis between 2002 and 2011 undergoing a Hartmann's procedure (HP) versus a primary anastomosis with a defunctioning stoma (PA) was performed. Additionally, patients were contacted by mail or telephone in March 2012 using a standardized questionnaire. RESULTS: A total of 98 patients were identified: 72 undergoing HP and 26 patients receiving PA. The median follow-up time was 63 months (range 4-118). Whilst 85 % of patients with PA have had their stoma reversed, only 58 % of patients with an HP had a stoma reversal (p = 0.046). The median period until stoma reversal was significantly longer for HP (19 weeks) than for PA (12 weeks; p = 0.03). The 30-day mortality for PA was 12 % as opposed to 25 % for HP (p = 0.167). According to the Clavien-Dindo classification, surgical complications occurred significantly less frequently in patients with PA (p = 0.014). CONCLUSION: The stoma reversal rates for PA are significantly higher than for HP. Thus, depending on the overall clinical situation, primary resection and anastomosis with a proximal defunctioning stoma might be the optimal procedure for selected patients with perforated diverticular disease.

Suture-free and mesh reinforced small intestinal anstomoses: a feasibility study in rabbits.

INTRODUCTION: Anastomotic leakage still remains a major complication in general surgery. Beside general risk factors, the ideal method of anastomotic technique has not been found until now. The aim of the present study was to analyze wound healing in suture-free small intestine anastomoses using fibrin glue with and without mesh-reinforcement. METHODS: Laparotomy and four different types of small bowel anastomoses were performed in 32 chinchilla rabbits. Standard hand-sewn anastomoses (CG), suture-free glued anastomoses (FG) with and without mesh reinforcement using two different types of meshes [Vicryl-mesh (VM) and Surgisis (SM)]. Animals were sacrificed after 5 and 21 days. Bursting pressure, collagen type I/III ratio, and matrix-metalloproteinase 2, 9, and 13 were analyzed. RESULTS: None of the animals died due to an anastomotic leakage. All animals in the long term group with Surgisis mesh died due to a mechanical bowel obstruction based on a distinctive stenosis of the anastomosis. The bursting pressures did significantly differed in animals with fibrin glue alone compared to animals with Vicryl-mesh reinforcement (p < 0.05). Histological examination revealed statistically significant differences (p < 0.05) in the values for MMP-2 (VM < SM), MMP-9 (VM < CG), and MMP-13 (CG < SM, VM < FG, and VM < SM). However, collagen type I/III ratios were not significantly different between groups. CONCLUSIONS: Our results suggest that a mesh reinforced glued anastomosis is technically feasible. Furthermore, mesh-reinforcement using VM increased the integrity and simplified the technique of suture-free anastomoses.

Impact of pressure and gas type on adhesion formation and biomaterial integration in laparoscopy.

BACKGROUND: Laparoscopic mesh repair of inguinal and incisional hernias has been widely adopted. Nevertheless, knowledge about the impact of pneumoperitoneum on mesh integration is rare. The present study investigates pressure and gas-dependent effects of pneumoperitoneum on adhesion formation and biomaterial integration in a standardized animal model. METHODS: Laparoscopic intraperitoneal onlay mesh implantation (IPOM) was performed in 32 female chinchilla rabbits using CO(2) or helium for pneumoperitoneum. Intra-abdominal pressures were 3 or 6 mmHg. Animals were killed after 21 days, and the abdominal wall was explanted for subsequent histopathological examinations. Adhesions were assessed qualitatively with a scoring system, and the adhesion surface was analyzed semiquantitatively by planimetry. Infiltration of macrophages (CD68), expression of matrix metalloproteinase 13 (MMP-13), and cell proliferation (Ki67) were analyzed at the mesh to host interface by immunohistochemistry. The collagen type I/III ratio was analyzed by cross-polarization microscopy to determine the quality of mesh integration. RESULTS: After 21 days, perifilamental infiltration with macrophages (CD68) and percentage of proliferating cells (Ki67) were highest after 6 mmHg of CO(2) pneumoperitoneum. The extent of adhesions, as well as the expression of MMP-13 and the collagen type I/III ratio, were similar between groups. CONCLUSIONS: Our experiments showed no pressure or gas-dependent alterations of adhesion formation and only minor effects on biomaterial integration. Altogether, there is no evidence for a clinically negative effect of CO(2) pneumoperitoneum.

[Hepatobiliary anastomosis techniques]. / Hepatobiliäre Anastomosentechniken.

The success of hepatobiliary anastomoses is influenced by the diameter of the bile duct, the location within the biliary tract, the situation of primary or revision surgery and accompanying infections. The exact preoperative diagnostics of the anatomy of the biliary tract are indispensable for low complication rates. Within reconstructive surgery, hepaticojejunostomy has been established as the standard technique and a biliodigestive anastomosis is performed proximal to the cystic duct and 2-3 cm below the fork in the hepatic duct. In general, end-to-end anastomoses of the common bile duct are not recommended due to the high risk for stenosis. Within the liver hilus an exact preparation of all tubular structures is mandatory. With regard to possible perioperative complications operations on the hepatic duct or segmental bile ducts should be performed in specialized centers. Methods of drainage in hepatobiliary surgery are percutaneous transhepatic cholangiodrainage (PTCD), internal-external drainage, internal drainage with endoscopic or surgically placed stents, external-internal-external drainage and the T-drain.

[Conventional reparation of parastomal hernia]. / Konventionelle Reparation der parastomalen Hernie.

The reparation of parastomal hernias and their recurrence remain problematic although the implementation of mesh techniques has lowered recurrences rates. Conventional surgical techniques include suture repair, relocation of the stoma as well as diverse hernia repair procedures with mesh implantation. Suture repair has been abandoned due to its high recurrence rate. Simple relocation is not recommended because of high rates of recurrent parastomal hernias. Conventional hernia repair using mesh implants is classified according to the mesh position into epifascial (onlay), retromuscular (sublay) and intraperitoneal (IPOM) techniques. Furthermore, a combination of relocation with additional mesh enforcement is also possible. The value of the different mesh techniques and of new biological mesh prostheses must be evaluated in randomized controlled studies.

Large-pore PDS mesh compared to small-pore PG mesh.

BACKGROUND: Currently, absorbable meshes are used as temporary closure in case of laparostoma. Unfortunately the multifilament polyglycolic acid (PG) meshes with small pores reveal little elasticity acting rather as a fluid barrier than permitting drainage of intra-abdominal fluids. Therefore, a new mesh was constructed of absorbable polydioxanon monofilaments (PDS) with increased porosity and longer degradation time. MATERIAL AND METHODS: For evaluation of the tissue response the new PDS mesh was implanted as abdominal wall replacement in each five rats for 7, 21, or 90 days, respectively, and compared to a PG mesh. Histological analysis included HE staining with measurement of the size of the granuloma and immunoshistochemistry for TUNEL, Ki67, TNF-R2, MMP-2, YB1, FVIII, gas6, AXL. Parameters for neovascularization and nerve ingrowth were analyzed. RESULTS: The inflammatory and fibrotic tissue reaction is attenuated with PDS in comparison to PG, e.g., the size of the granuloma was smaller with less cell turnover, and less remodeling as represented by, e.g., reduction of apoptosis, expression of MMP-2, or TNF-R2. The number of ingrowing nerves and vessels explored via AXL, gas6, and factor VIII was increased in the PDS mesh. CONCLUSION: The results from the present investigation showed that a mesh can be constructed of monofilament PDS that induce significant less inflammatory and fibrotic reaction, however permits fluid drainage and preserves elasticity.

Diagnostics hardening for harsh environment in Laser Megajoule (invited).

The diagnostic designs for the Laser Megajoule (LMJ) will require components to operate in environments far more severe than those encountered in present facilities. This harsh environment will be induced by fluxes of neutrons, gamma rays, energetic ions, electromagnetic radiations, and, in some cases, debris and shrapnel, at levels several orders of magnitude higher than those experienced today on existing facilities. The lessons learned about the vulnerabilities of present diagnostic parts fielded mainly on OMEGA for many years, have been very useful guide for the design of future LMJ diagnostics. The present and future LMJ diagnostic designs including this vulnerability approach and their main mitigation techniques will be presented together with the main characteristics of the LMJ facility that provide for diagnostic protection.

[Surgical treatment and prophylaxis of parastomal hernias]. / Operative Versorgung und Strategien zur Prophylaxe parastomaler Hernien.

Despite the progress concerning operative techniques, parastomal hernias remain a surgical challenge. The high risk for recurrence demands precise indications for operative repair. Mesh implants reduce the recurrence rate. Among such procedures, the retromuscular mesh augmentation represents an established method, whereas the value of other techniques still has to be defined. Also, the prophylactic use of meshes is able to reduce the incidence of parastomal hernias. With regard to short- and long-term complications, their general recommendation must be proven in further studies.

Influence of mesh materials on the integrity of the vas deferens following Lichtenstein hernioplasty: an experimental model.

BACKGROUND: The utilization of mesh reinforcement of the inguinal area with polypropylene mesh has increased drastically over the last decade. Infertility due to obstructive azoospermia is a rare but serious complication following inguinal hernia repair, especially in young patients. The aim of this study was to evaluate the effect of different mesh structures on integrity of the vas deferens. MATERIALS AND METHODS: Twenty male Chinchilla rabbits were used. The spermatic cord was dissected free and a Lichtenstein repair was performed with a low-weight polypropylene mesh (UltraPro) and a heavy-weight polypropylene mesh (Prolene) on the contralateral side. A vasography was performed after six months in order to investigate obstructions of the vas deferens. Light microscopy of the mesh host tissue interface was also performed and the foreign body reaction analyzed. Spermatogenesis was evaluated using the Johnsen score. RESULTS: Vasography revealed relevant obstructions (>75% of lumen diameter) located at the mesh margins (50% of Prolene and 22.2% of UltraPro mesh samples). Microscopic investigation of the mesh-host tissue interface showed typical formation of foreign body granulomas. The diameters of the foreign body granulomas were significantly reduced in the UltraPro mesh group (41.7 +/- 5.5 microm) compared to the Prolene mesh group (48.7 +/- 7.7 microm). Upon investigating the percentages of apoptotic (TUNEL) and proliferating (Ki67) cells, no significant differences were found. Following Prolene mesh implantation, a mean Johnsen score of 9.1 +/- 1.2 was estimated, which was not significantly different from the UltraPro mesh samples (8.9 +/- 1.4, P > 0.05). CONCLUSIONS: If a mesh material is needed for inguinal hernia repair in young patients, the use of modern low-weight large porous and elastic samples appears to have a beneficial effect on integrity of the vas deferens.

[Medicine between humanitarianism and competition: the patients' point of view]. / Medizin zwischen Humanität und Wettbewerb: Ein aktuelles Patientenmeinungsbild.

BACKGROUND: An open medical market is supposed to be a promising tool for preserving the meagre resources of the German public health care system. The competition between humane and economic practice induces conflicts which burden physicians as well as patients. To analyse this problem by scientific means, inpatients were interviewed with the help of a standardised protocol. PATIENTS AND METHODS: During 10 weeks 524 inpatients were interviewed. The structured questionnaire consisted of nine closed-ended questions with multiple-choice answers. Question 3 included a free amendment. The gender ratio was balanced, and the age pattern represented the typical patient collective of our clinic. RESULTS AND CONCLUSION: The majority of patients expect negative changes in their medical service and the social attitude towards patients and physicians due to promoted medical competition. Besides an increasing financial load, losses in trust, self-determination, and therapeutic freedom are expected. Instead a responsible transparency will not be achieved. Patients still judge the economically dominated reforms on the German health care market with scepticism or even hostility. In their point of view future discussions must aim at a more modern attitude towards health economics in order to bridge the schism they perceive between medical competition and humanitarianism. The understanding of strong financial management as a prime condition for stable social security is the basis of synergies to deal with upcoming reforms.

Gas-related impact of pneumoperitoneum on systemic wound healing.

INTRODUCTION: The aim of the present study was to investigate the gas-dependent effects of pneumoperitoneum on wound healing distant from the abdomen. MATERIALS AND METHODS: Dorsal skin incisions were performed in 54 male Sprague-Dawley rats. A CO(2) or a helium pneumoperitoneum of 3 mmHg was maintained before, with an overall duration of 30 min (each n = 18). Rats in the control group received laparotomy only (n = 18). Animals were killed after 5 and 10 days. The infiltration of macrophages (CD 68), expression of matrix metalloproteinase 13 (MMP-13) and collagen I/III ratios were analysed in the dorsal skin wounds. RESULTS: Both after 5 and 10 days, infiltration of macrophages and expression of MMP-13 were greatest after helium pneumoperitoneum. After 5 days, collagen I/III ratio was significantly increased in the helium group. After 10 days, collagen I/III ratio was lowest in the CO(2) group. CONCLUSION: Our results suggest beneficial effects on systemic wound healing for helium pneumoperitoneum as compared to CO(2).

Analysis of c-myc, PAI-1 and uPAR in patients with incisional hernias.

BACKGROUND: Disturbed wound healing leading to alterations in collagen composition has been thought to play a key role in the pathogenesis of incisional hernia formation. The aim of the present study was to further characterise the scarring process in such patients. METHODS: Mature skin scars from patients with either primary or recurrent incisional hernias were compared to mature abdominal skin scars from patients without hernias. The distribution of collagen types I and III was analysed using crosspolarisation microscopy. Expression of c-myc--a parameter for cell differentiation and proliferation--and of PAI-1 and uPAR--parameters of the proteolytic cascade in wound healing--were determined by immunohistochemistry. RESULTS: In agreement with previous studies, decreased collagen I/III ratios were found in patients with incisional hernias. In these patients, c-myc levels were significantly elevated whereas plasminogen activator inhibitor-1 (PAI-1) and urokinase-plasminogen activator receptor (uPAR) levels were only slightly increased. In contrast to controls, a significant correlation between c-myc, PAI-1 and uPAR expression and collagen I/III ratios was found in patients with incisional hernias. CONCLUSION: The differential correlation of collagen types and expression of c-myc, PAI-1 and uPAR within the scar tissue might represent a causal factor in incisional hernia formation.