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1.  Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonary hypertension 
Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.
PMCID: PMC3749888  PMID: 23200808
Endothelin; Pulmonary hypertension; NADPH oxidase; Uncoupled eNOS; Free radicals
2.  A Neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects 
Brain and Behavior  2014;4(2):215-226.
Background: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. Methods: We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Results: Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Conclusion: Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
PMCID: PMC3967537  PMID: 24683514
Anatomic connectivity; brain; DTI; gene; hippocampus; MRI; Neuregulin-1
3.  Manual Khalifa Therapy Improves Functional and Morphological Outcome of Patients with Anterior Cruciate Ligament Rupture in the Knee: A Randomized Controlled Trial 
Rupture of the anterior cruciate ligament (ACL) is a high incidence injury usually treated surgically. According to common knowledge, it does not heal spontaneously, although some claim the opposite. Regeneration therapy by Khalifa was developed for injuries of the musculoskeletal system by using specific pressure to the skin. This randomized, controlled, observer-blinded, multicentre study was performed to validate this assumption. Thirty patients with complete ACL rupture, magnetic resonance imaging (MRI) verified, were included. Study examinations (e.g., international knee documentation committee (IKDC) score) were performed at inclusion (t0). Patients were randomized to receive either standardised physiotherapy (ST) or additionally 1 hour of Khalifa therapy at the first session (STK). Twenty-four hours later, study examinations were performed again (t1). Three months later control MRI and follow-up examinations were performed (t2). Initial status was comparable between both groups. There was a highly significant difference of mean IKDC score results at t1 and t2. After 3 months, 47% of the STK patients, but no ST patient, demonstrated an end-to-end homogeneous ACL in MRI. Clinical and physical examinations were significantly different in t1 and t2. ACL healing can be improved with manual therapy. Physical activity can be performed without pain and nearly normal range of motion after one treatment of specific pressure.
PMCID: PMC3926243  PMID: 24600477
4.  Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases 
Stereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED).
Patients and methods
50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed.
The median BED2 was 83 Gy. 12 lesions were treated with a BED2 of <80 Gy, and 38 lesions with a BED2 of >80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%.
Intensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control.
PMCID: PMC3909294  PMID: 24401323
Hypofractionated intensity modulated breath-hold image-guided (ig)SABR; Lung tumors; Lung metastases; Local control; Survival; Toxicity
5.  Imaging the where and when of tic generation and resting state networks in adult Tourette patients 
Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with the core phenomenon of tics, whose origin and temporal pattern are unclear. We investigated the When and Where of tic generation and resting state networks (RSNs) via functional magnetic resonance imaging (fMRI).
Methods: Tic-related activity and the underlying RSNs in adult TS were studied within one fMRI session. Participants were instructed to lie in the scanner and to let tics occur freely. Tic onset times, as determined by video-observance were used as regressors and added to preceding time-bins of 1 s duration each to detect prior activation. RSN were identified by independent component analysis (ICA) and correlated to disease severity by the means of dual regression.
Results: Two seconds before a tic, the supplementary motor area (SMA), ventral primary motor cortex, primary sensorimotor cortex and parietal operculum exhibited activation; 1 s before a tic, the anterior cingulate, putamen, insula, amygdala, cerebellum and the extrastriatal-visual cortex exhibited activation; with tic-onset, the thalamus, central operculum, primary motor and somatosensory cortices exhibited activation. Analysis of resting state data resulted in 21 components including the so-called default-mode network. Network strength in those regions in SMA of two premotor ICA maps that were also active prior to tic occurrence, correlated significantly with disease severity according to the Yale Global Tic Severity Scale (YGTTS) scores.
Discussion: We demonstrate that the temporal pattern of tic generation follows the cortico-striato-thalamo-cortical circuit, and that cortical structures precede subcortical activation. The analysis of spontaneous fluctuations highlights the role of cortical premotor structures. Our study corroborates the notion of TS as a network disorder in which abnormal RSN activity might contribute to the generation of tics in SMA.
PMCID: PMC4035756  PMID: 24904391
resting state networks; Tourette; tics; basal ganglia; cortico-striato-thalamo-cortical circuit
6.  The Electrophysiological Signature of Motivational Salience in Mice and Implications for Schizophrenia 
Neuropsychopharmacology  2012;37(13):2846-2854.
According to the aberrant-salience hypothesis, attribution of motivational salience is severely disrupted in patients with schizophrenia. To provide a translational approach for investigating underlying mechanisms, neural correlates of salience attribution were examined in normal mice and in a MK-801 model of schizophrenia. Electrophysiological responses to standard and deviant tones were assessed in the medial prefrontal cortex (mPFC) using an auditory oddball paradigm. Motivational salience was induced by aversive conditioning to the deviant tone. Analysis of the auditory evoked potential (AEP) showed selective modulation of the late frontal negativity (LFN) by motivational salience, which persisted throughout a 4-week delay. MK-801, an N-methyl-𝒟-aspartic acid receptor antagonist, abolished this differential response to motivational salience in conditioned mice. In contrast, a pronounced LFN response was observed towards the deviant, ie, perceptually salient tone, in nonconditioned mice. The finding of a selective modulation of a late frontal slow wave suggests increased top–down processing and emotional evaluation of motivationally salient stimuli. In particular, the LFN is discussed as the mouse analog to the human stimulus preceding negativity, which reflects preparatory processes in anticipation of reward or punishment. MK-801 led to a disruption of the normal response in conditioned and nonconditioned mice, including an aberrantly increased LFN in nonconditioned mice. This pattern of ‘false-negative' and ‘false-positive' responses suggests a degradation of salience attribution, which points to mPFC responses to be relevant for translational research on cognitive alterations in schizophrenia.
PMCID: PMC3499726  PMID: 22910459
salience; electrophysiology; anticipation; mPFC; schizophrenia; mouse; animal models; schizophrenia/antipsychotics; cognition; neurophysiology; salience; electrophysiology; anticipation; mPFC; mouse
7.  Anger under Control: Neural Correlates of Frustration as a Function of Trait Aggression 
PLoS ONE  2013;8(10):e78503.
Antisocial behavior and aggression are prominent symptoms in several psychiatric disorders including antisocial personality disorder. An established precursor to aggression is a frustrating event, which can elicit anger or exasperation, thereby prompting aggressive responses. While some studies have investigated the neural correlates of frustration and aggression, examination of their relation to trait aggression in healthy populations are rare. Based on a screening of 550 males, we formed two extreme groups, one including individuals reporting high (n=21) and one reporting low (n=18) trait aggression. Using functional magnetic resonance imaging (fMRI) at 3T, all participants were put through a frustration task comprising unsolvable anagrams of German nouns. Despite similar behavioral performance, males with high trait aggression reported higher ratings of negative affect and anger after the frustration task. Moreover, they showed relatively decreased activation in the frontal brain regions and the dorsal anterior cingulate cortex (dACC) as well as relatively less amygdala activation in response to frustration. Our findings indicate distinct frontal and limbic processing mechanisms following frustration modulated by trait aggression. In response to a frustrating event, HA individuals show some of the personality characteristics and neural processing patterns observed in abnormally aggressive populations. Highlighting the impact of aggressive traits on the behavioral and neural responses to frustration in non-psychiatric extreme groups can facilitate further characterization of neural dysfunctions underlying psychiatric disorders that involve abnormal frustration processing and aggression.
PMCID: PMC3799631  PMID: 24205247
8.  Neural correlates of depressive realism – An fMRI study on causal attribution in depression 
Journal of affective disorders  2012;138(3):268-276.
Biased causal attribution is a critical factor in the cognitive model of depression. Whereas depressed patients interpret events negatively, healthy people show a self-serving bias (internal attribution of positive events and external attribution of negative events).
Using fMRI, depressed patients (n=15) and healthy controls (n=15) were confronted with positive and negative social events and made causal attributions (internal vs. external). Functional data were analyzed using a mixed effects model.
Behaviourally, controls showed a self-serving bias, whereas patients demonstrated a balanced attributional pattern. Analysis of functional data revealed a significant group difference in a fronto-temporal network. Higher activation of this network was associated with non self-serving attributions in controls but self-serving attributions in patients. Applying a psycho-physiological interaction analysis, we observed reduced coupling between a dorsomedial PFC seed region and limbic areas during self-serving attributions in patients compared to controls.
Results of the PPI analysis are preliminary given the liberal statistical threshold.
The association of the behaviourally less frequent attributional pattern with activation in a fronto-temporal network suggests that non self-serving responses may produce a self-related response conflict in controls, while self-serving responses produce this conflict in patients. Moreover, attribution-modulated coupling between the dorsomedial PFC and limbic regions was weaker in patients than controls. This preliminary finding suggests that depression may be associated with disturbances in fronto-limbic coupling during attributional decisions. Our results implicate that treatment of major depression may benefit from approaches that facilitate reinterpretation of emotional events in a more positive, more self-serving way.
PMCID: PMC3565123  PMID: 22377511
locus of control; emotions; emotional disturbances; affective disorders; reappraisal; cognitive control
9.  Modulating the processing of emotional stimuli by cognitive demand 
Emotional processing is influenced by cognitive processes and vice versa, indicating a profound interaction of these domains. The investigation of the neural mechanisms underlying this interaction is not only highly relevant for understanding the organization of human brain function. Rather, it may also help in understanding dysregulated emotions in affective disorders and in elucidating the neurobiology of cognitive behavioural therapy (e.g. in borderline personality disorder), which aims at modulating dysfunctional emotion processes by cognitive techniques, such as restructuring. In the majority of earlier studies investigating the interaction of emotions and cognition, the main focus has been on the investigation of the effects of emotional stimuli or, more general, emotional processing, e.g. instituted by emotional material that needed to be processed, on cognitive performance and neural activation patterns. Here we pursued the opposite approach and investigated the modulation of implicit processing of emotional stimuli by cognitive demands using an event-related functional magnetic resonance imaging––study on a motor short-term memory paradigm with emotional interferences. Subjects were visually presented a finger-sequence consisting either of four (easy condition) or six (difficult condition) items, which they had to memorize. After a short pause positive, negative or neutral International affective picture system pictures or a green dot (as control condition) were presented. Subjects were instructed to reproduce the memorized sequence manually as soon as the picture disappeared. Analysis showed that with increasing cognitive demand (long relative to short sequences), neural responses to emotional pictures were significantly reduced in amygdala and orbitofrontal cortex. In contrast, the more difficult task evoked stronger activation in a widespread frontoparietal network. As stimuli were task-relevant go-cues and hence had to be processed perceptually, we would interpret this as a specific attenuation of affective responses by concurrent cognitive processing––potentially reflecting a relocation of resources mediated by the frontoparietal network.
PMCID: PMC3304476  PMID: 21258093
neuroimaging; distraction; cognition; attention; valence
10.  How specific are emotional deficits? A comparison of empathic abilities in schizophrenia, bipolar and depressed patients 
Schizophrenia Research  2012;142(1-3):58-64.
Empathy is a rather elaborated human ability and several recent studies highlight significant impairments in patients suffering from psychiatric disorders, such as schizophrenia, bipolar disorder or major depression.
Therefore, the present study aimed at comparing behavioral empathy performance in schizophrenia, bipolar and depressed patients with healthy controls. All subjects performed three tasks tapping the core components of empathy: emotion recognition, emotional perspective taking and affective responsiveness. Groups were matched for age, gender, and verbal intelligence.
Data analysis revealed three main findings: First, schizophrenia patients showed the strongest impairment in empathic performance followed by bipolar patients while depressed patients performed similar to controls in most tasks, except for affective responsiveness. Second, a significant association between clinical characteristics and empathy performance was only apparent in depression, indicating worse affective responsiveness with stronger symptom severity and longer duration of illness. Third, self-report data indicate that particularly bipolar patients describe themselves as less empathic, reporting less empathic concern and less perspective taking.
Taken together, this study constitutes the first approach to directly compare specificity of empathic deficits in severe psychiatric disorders. Our results suggest disorder-specific impairments in emotional competencies that enable better characterization of the patient groups investigated and indicate different psychotherapeutic interventions.
PMCID: PMC3514634  PMID: 23116884
Empathy; Emotional competencies; Schizophrenia; Bipolar disorder; Depression
11.  Fine motor skills in adult Tourette patients are task-dependent 
BMC Neurology  2012;12:120.
Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics. Deficient motor inhibition underlying tics is one of the main hypotheses in its pathophysiology. Therefore the question arises whether this supposed deficient motor inhibition affects also voluntary movements. Despite severe motor tics, different personalities who suffer from Tourette perform successfully as neurosurgeon, pilot or professional basketball player.
For the investigation of fine motor skills we conducted a motor performance test battery in an adult Tourette sample and an age matched group of healthy controls.
The Tourette patients showed a significant lower performance in the categories steadiness of both hands and aiming of the right hand in comparison to the healthy controls. A comparison of patients’ subgroup without comorbidities or medication and healthy controls revealed a significant difference in the category steadiness of the right hand.
Our results show that steadiness and visuomotor integration of fine motor skills are altered in our adult sample but not precision and speed of movements. This alteration pattern might be the clinical vignette of complex adaptations in the excitability of the motor system on the basis of altered cortical and subcortical components. The structurally and functionally altered neuronal components could encompass orbitofrontal, ventrolateral prefrontal and parietal cortices, the anterior cingulate, amygdala, primary motor and sensorimotor areas including altered corticospinal projections, the corpus callosum and the basal ganglia.
PMCID: PMC3527195  PMID: 23057645
12.  Neural correlates of social approach and withdrawal in patients with major depression 
Social neuroscience  2011;6(5-6):482-501.
Successful human interaction is based on correct recognition, interpretation and appropriate reaction to facial affect. In depression, social skill deficits are among the most restraining symptoms leading to social withdrawal, thereby aggravating social isolation and depressive affect. Dysfunctional approach and withdrawal tendencies towards emotional stimuli have been documented but the investigation of their neural underpinnings has received limited attention. We performed an fMRI study including 15 depressive patients and 15 matched healthy controls. All subjects performed two tasks, an implicit joystick task as well as an explicit rating task both using happy, neutral, and angry facial expressions.
Behavioral data analysis indicated a significant group effect, with depressed patients showing more withdrawal than controls. Analysis of the functional data revealed significant group effects for both tasks. Amongst other regions, we observed significant group differences in amygdala activation with patients showing less response particularly during approach of happy faces. Additionally, significant correlations of amygdala activation with psychopathology emerged, suggesting that more pronounced symptoms are accompanied by stronger decreases of amygdala activation.
Hence, our results demonstrate that depressed patients show dysfunctional social approach and withdrawal behavior, which in turn may aggravate the disorder by negative social interactions contributing to isolation and reinforcing cognitive biases.
PMCID: PMC3203307  PMID: 21777105
depression; approach; withdrawal; emotion; amygdala; fMRI
13.  Patella re-alignment in children with a modified Grammont technique 
Acta Orthopaedica  2012;83(5):504-510.
Background and purpose
In skeletally immature patients, surgical options due to recurrent patella dislocation are limited, because bony procedures bear the risk of growth disturbances. In this retrospective study, we report the long-term functional and radiographic outcome in skeletally immature patients using the modified Grammont surgical technique.
Between 1999 and 2004, 65 skeletally immature knees (49 children) were treated with a modified Grammont procedure: an open lateral release and a shift of the patella tendon insertion below the growth plate on the tuberositas tibia, allowing the tendon to medialize. At mean 8 (5.6–11) years after surgery, 58 knees in 43 patients were evaluated by clinical examination, from functional scores (Lysholm, Tegner), and from radiographs of the knees.
Mean Lysholm score was 82 postoperatively. Tegner score decreased from 6.2 to 5. Eight knees had a single dislocation within 3 months of surgery. 3 knees had repeated late dislocations, all with a high grade of trochlea dysplasia. 6 knees showed mild signs of osteoarthritis. No growth disturbances were observed.
The modified Grammont technique in skeletally immature patients allows restoration of the distal patella tendon alignment by dynamic positioning. Long-term results showed that there were no growth disturbances and that there was good functional outcome. However, patients with a high grade of trochlea dysplasia tended to re-dislocate.
PMCID: PMC3488178  PMID: 23039166
14.  Rationale and Baseline Characteristics of PREVENT: A Second-Generation Intervention Trial in Subjects At-Risk (Prodromal) of Developing First-Episode Psychosis Evaluating Cognitive Behavior Therapy, Aripiprazole, and Placebo for the Prevention of Psychosis 
Schizophrenia Bulletin  2011;37(Suppl 2):S111-S121.
Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.
PMCID: PMC3160113  PMID: 21860040
schizophrenia; aripiprazole; cognitive behavior therapy; prodrome; early intervention; prevention; psychosis
15.  Hypofractionated image-guided breath-hold SABR (Stereotactic Ablative Body Radiotherapy) of liver metastases – clinical results 
Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive therapy option for inoperable liver oligometastases. Outcome and toxicity were retrospectively evaluated in a single-institution patient cohort who had undergone ultrasound-guided breath-hold SABR.
Patients and methods
19 patients with liver metastases of various primary tumors consecutively treated with SABR (image-guidance with stereotactic ultrasound in combination with computer-controlled breath-hold) were analysed regarding overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity.
PTV (planning target volume)-size was 108 ± 109cm3 (median 67.4 cm3). BED2 (Biologically effective dose in 2 Gy fraction) was 83.3 ± 26.2 Gy (median 78 Gy). Median follow-up and median OS were 12 months. Actuarial 2-year-OS-rate was 31%. Median PFS was 4 months, actuarial 1-year-PFS-rate was 20%. Site of first progression was predominantly distant. Regression of irradiated lesions was observed in 84% (median time to detection of regression was 2 months). Actuarial 6-month-LC-rate was 92%, 1- and 2-years-LC-rate 57%, respectively. BED2 influenced LC. When a cut-off of BED2 = 78 Gy was used, the higher BED2 values resulted in improved local control with a statistical trend to significance (p = 0.0999). Larger PTV-sizes, inversely correlated with applied dose, resulted in lower local control, also with a trend to significance (p-value = 0.08) when a volume cut-off of 67 cm3 was used.
No local relapse was observed at PTV-sizes < 67 cm3 and BED2 > 78 Gy. No acute clinical toxicity > °2 was observed. Late toxicity was also ≤ °2 with the exception of one gastrointestinal bleeding-episode 1 year post-SABR. A statistically significant elevation in the acute phase was observed for alkaline-phosphatase; in the chronic phase for alkaline-phosphatase, bilirubine, cholinesterase and C-reactive protein.
A trend to statistically significant correlation of local progression was observed for BED2 and PTV-size. Dose-levels BED2 > 78 Gy cannot be reached in large lesions constituting a significant fraction of this series. Image-guided SABR (igSABR) is therefore an effective non-invasive treatment modality with low toxicity in patients with small inoperable liver metastases.
PMCID: PMC3464721  PMID: 22710033
Hypofractionated image-guided breath-hold SABR; Liver metastases; Local control; Survival; Toxicity
16.  Outcome of repaired unstable meniscal tears in children and adolescents 
Acta Orthopaedica  2012;83(3):261-266.
Unstable meniscal tears are rare injuries in skeletally immature patients. Loss of a meniscus increases the risk of subsequent development of degenerative changes in the knee. This study deals with the outcome of intraarticular meniscal repair and factors that affect healing. Parameters of interest were type and location of the tear and also the influence of simultaneous reconstruction of a ruptured ACL.
We investigated the outcome of 25 patients (29 menisci) aged 15 (4–17) years who underwent surgery for full thickness meniscal tears, either as isolated lesions or in combination with ACL ruptures. Intraoperative documentation followed the IKDC 2000 standard. Outcome measurements were the Tegner score (pre- and postoperatively) and the Lysholm score (postoperatively) after an average follow-up period of 2.3 years, with postoperative arthroscopy and MRT in some cases.
24 of the 29 meniscal lesions healed (defined as giving an asymptomatic patient) regardless of location or type. 4 patients re-ruptured their menisci (all in the pars intermedia) at an average of 15 months after surgery following a new injury. Mean Lysholm score at follow-up was 95, the Tegner score deteriorated, mean preoperative score: 7.8 (4–10); mean postoperative score: 7.2 (4–10). Patients with simultaneous ACL reconstruction had a better outcome.
All meniscal tears in the skeletally immature patient are amenable to repair. All recurrent meniscal tears in our patients were located in the pars intermedia; the poorer blood supply in this region may give a higher risk of re-rupture. Simultaneous ACL reconstruction appears to benefit the results of meniscal repair.
PMCID: PMC3369152  PMID: 22616744
17.  Brain Circuitries Involved in Semantic Interference by Demands of Emotional and Non-Emotional Distractors 
PLoS ONE  2012;7(5):e38155.
Previous studies have indicated that the processes leading to the resolution of emotional and non-emotional interference conflicts are unrelated, involving separate networks. It is also known that conflict resolution itself suggests a considerable overlap of the networks. Our study is an attempt to examine how these findings may be related.
Methodology/Principal Findings
We used functional magnetic resonance imaging (fMRI) to study neural responses of 24 healthy subjects to emotional and non-emotional conflict paradigms involving the presentation of congruent and incongruent word-face pairs based on semantic incompatibility between targets and distractors. In the emotional task, the behavioral interference conflict was greater (compared to the non-emotional task) and was paralleled by involvement of the extrastriate visual and posterodorsal medial frontal cortices. In both tasks, we also observed a common network including the dorsal anterior cingulate, the supplemental motor area, the anterior insula and the inferior prefrontal cortex, indicating that these brain structures are markers of experienced conflict. However, the emotional task involved conflict-triggered networks to a considerably higher degree.
Our findings indicate that responses to emotional and non-emotional distractors involve the same systems, which are capable of flexible adjustments based on conflict demands. The function of systems related to conflict resolution is likely to be adjusted on the basis of an evaluation process that primarily involves the extrastriate visual cortex, with target playing a significant role.
PMCID: PMC3362560  PMID: 22666470
18.  Assessing Implicit Odor Localization in Humans Using a Cross-Modal Spatial Cueing Paradigm 
PLoS ONE  2011;6(12):e29614.
Navigation based on chemosensory information is one of the most important skills in the animal kingdom. Studies on odor localization suggest that humans have lost this ability. However, the experimental approaches used so far were limited to explicit judgements, which might ignore a residual ability for directional smelling on an implicit level without conscious appraisal.
A novel cueing paradigm was developed in order to determine whether an implicit ability for directional smelling exists. Participants performed a visual two-alternative forced choice task in which the target was preceded either by a side-congruent or a side-incongruent olfactory spatial cue. An explicit odor localization task was implemented in a second experiment.
No effect of cue congruency on mean reaction times could be found. However, a time by condition interaction emerged, with significantly slower responses to congruently compared to incongruently cued targets at the beginning of the experiment. This cueing effect gradually disappeared throughout the course of the experiment. In addition, participants performed at chance level in the explicit odor localization task, thus confirming the results of previous research.
The implicit cueing task suggests the existence of spatial information processing in the olfactory system. Response slowing after a side-congruent olfactory cue is interpreted as a cross-modal attentional interference effect. In addition, habituation might have led to a gradual disappearance of the cueing effect. It is concluded that under immobile conditions with passive monorhinal stimulation, humans are unable to explicitly determine the location of a pure odorant. Implicitly, however, odor localization seems to exert an influence on human behaviour. To our knowledge, these data are the first to show implicit effects of odor localization on overt human behaviour and thus support the hypothesis of residual directional smelling in humans.
PMCID: PMC3246472  PMID: 22216331
19.  Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays? 
Radiation induced secondary cancers are a rare but severe late effect after breast conserving therapy. Intraoperative radiotherapy (IORT) is increasingly used during breast conserving surgery. The purpose of this analysis was to estimate secondary cancer risks after IORT compared to other modalities of breast radiotherapy (APBI - accelerated partial breast irradiation, EBRT - external beam radiotherapy).
Computer-tomography scans of an anthropomorphic phantom were acquired with an INTRABEAM IORT applicator (diameter 4 cm) in the outer quadrant of the breast and transferred via DICOM to the treatment planning system. Ipsilateral breast, contralateral breast, ipsilateral lung, contralateral lung, spine and heart were contoured. An INTRABEAM source (50 kV) was defined with the tip of the drift tube at the center of the spherical applicator. A dose of 20 Gy at 0 mm depth from the applicator surface was prescribed for IORT and 34 Gy (5 days × 2 × 3.4 Gy) at 10 mm depth for APBI. For EBRT a total dose of 50 Gy in 2 Gy fractions was planned using two tangential fields with wedges. The mean and maximal doses, DVHs and volumes receiving more than 0.1 Gy and 4 Gy of organs at risk (OAR) were calculated and compared. The life time risk for secondary cancers was estimated according to NCRP report 116.
IORT delivered the lowest maximal doses to contralateral breast (< 0.3 Gy), ipsilateral (1.8 Gy) and contralateral lung (< 0.3 Gy), heart (1 Gy) and spine (< 0.3 Gy). In comparison, maximal doses for APBI were 2-5 times higher. EBRT delivered a maximal dose of 10.4 Gy to the contralateral breast and 53 Gy to the ipsilateral lung. OAR volumes receiving more than 4 Gy were 0% for IORT, < 2% for APBI and up to 10% for EBRT (ipsilateral lung). The estimated risk for secondary cancer in the respective OAR is considerably lower after IORT and/or APBI as compared to EBRT.
The calculations for maximal doses and volumes of OAR suggest that the risk of secondary cancer induction after IORT is lower than compared to APBI and EBRT.
PMCID: PMC3260102  PMID: 22176703
Secondary cancer induction; radiotherapy; breast cancer; intraoperative radiotherapy; accelerated partial breast irradiation
20.  Assessment of NMDA Receptor NR1 Subunit Hypofunction in Mice as a Model for Schizophrenia 
Genes, brain, and behavior  2009;8(7):661-675.
N-methyl-D-aspartate receptors (NMDAR) play a pivotal role in excitatory neurotransmission, synaptic plasticity, and brain development. Clinical and experimental evidence suggests a dysregulation of NMDAR function and glutamatergic pathways in the pathophysiology of schizophrenia. We evaluated electrophysiological and behavioral properties of NMDAR deficiency utilizing mice that express of only 5-10% of the normal level of NMDAR NR1-subunit. Auditory and visual event related potentials yielded significantly increased amplitudes for the P20 and N40 components in NMDAR deficient (NR1neo-/-) mice suggesting decreased inhibitory tone. Compared to wildtypes, NR1neo-/- mice spent less time in social interactions and demonstrated reduced nest building. NR1neo-/- mice displayed a preference for open arms of a zero-maze and central zone of an open field, possibly reflecting decreased anxiety-related behavioral inhibition. However, locomotor activity did not differ between groups in either home cage environment or during behavioural testing. NR1neo-/- mice displayed hyperactivity only when placed in a large unfamiliar environment, suggesting that neither increased anxiety nor nonspecific motor activation accounts for differential behavioral patterns. Data suggest that NMDAR NR1 deficiency causes disinhibition in sensory processing, as well as reduced behavioral inhibition and impaired social interactions. The behavioral signature in NR1neo-/-mice supports the impact of impaired NMDAR-function in a mouse model with possible relevance to negative symptoms in schizophrenia.
PMCID: PMC2757454  PMID: 19563516
Models, Animal; Behavior; Deficiency; Evoked Potentials; Receptors, N-Methyl-D-Aspartate; Schizophrenia
21.  Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases 
Instable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.
60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12th thoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.
In conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.
PMCID: PMC2829586  PMID: 20149237
22.  Internal capsule size associated with outcome in first-episode schizophrenia 
Subtle structural brain abnormalities are an established finding in first-episode psychosis. Nevertheless their relationship to the clinical course of schizophrenia is controversially discussed. In a multicentre study 45 first-episode schizophrenia patients (FE-SZ) underwent standardized MRI scanning and were followed up to 1 year. In 32 FE-SZ volumetric measurement of three regions of interests (ROIs) potentially associated with disease course, hippocampus, lateral ventricle and the anterior limb of the internal capsule (ALIC) could be performed. The subgroups of FE-SZ with good (12 patients) and poor outcome (11 patients), defined by a clinically relevant change of the PANSS score, were compared with regard to these volumetric measures. Multivariate analysis of covariance revealed a significant reduced maximal cross sectional area of the left ALIC in FE-SZ with clinically relevant deterioration compared to those with stable psychopathology. There were no differences in the other selected ROIs between the two subgroups. In conclusion, reduced maximal area of ALIC, which can be interpreted as a disturbance of fronto-thalamic connectivity, is associated with poor outcome during the 1 year course of first-episode schizophrenia.
PMCID: PMC3085770  PMID: 19224108
first-episode schizophrenia; magnetic resonance imaging; disease course; outcome
23.  The Viral Oncoprotein LMP1 Exploits TRADD for Signaling by Masking Its Apoptotic Activity 
PLoS Biology  2008;6(1):e8.
The tumor necrosis factor (TNF)-receptor 1–associated death domain protein (TRADD) mediates induction of apoptosis as well as activation of NF-κB by cellular TNF-receptor 1 (TNFR1). TRADD is also recruited by the latent membrane protein 1 (LMP1) oncoprotein of Epstein-Barr virus, but its role in LMP1 signaling has remained enigmatic. In human B lymphocytes, we have generated, to our knowledge, the first genetic knockout of TRADD to investigate TRADD's role in LMP1 signal transduction. Our data from TRADD-deficient cells demonstrate that TRADD is a critical signaling mediator of LMP1 that is required for LMP1 to recruit and activate I-κB kinase β (IKKβ). However, in contrast to TNFR1, LMP1-induced TRADD signaling does not induce apoptosis. Searching for the molecular basis for this observation, we characterized the 16 C-terminal amino acids of LMP1 as an autonomous and unique virus-derived TRADD-binding domain. Replacing the death domain of TNFR1 by LMP1′s TRADD-binding domain converts TNFR1 into a nonapoptotic receptor that activates NF-κB through a TRAF6-dependent pathway, like LMP1 but unlike wild-type TNFR1. Thus, the unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD's pro-apoptotic function.
Author Summary
For viral infection to succeed, viral proteins must interact with the cellular signaling machinery of its target cell. An oncoprotein encoded by the Epstein-Barr virus (EBV) called latent membrane protein 1 (LMP1) is a primary contributor to the transformation of human B cells by the virus and the development of EBV-associated B cell malignancies by recruiting signaling molecules provided by the host. One such molecule, the cellular adapter protein TRADD, is among the few direct interaction partners of LMP1. But because TRADD promotes cell death (apoptosis) in the cellular tumor necrosis factor-receptor 1 (TNFR1) signaling pathway, it seems counterintuitive that TRADD could play a role in LMP1 biology, since LMP1 promotes cell survival and proliferation. We provide genetic evidence that TRADD is critical for LMP1 to assemble its transforming signaling network. LMP1 requires TRADD to recruit and activate I-κB kinase β and, thus, to induce canonical NF-κB signaling. Simultaneously, LMP1 masks TRADD's pro-apoptotic activity. We show that LMP1 carries a unique and autonomous viral TRADD-binding domain, which dictates an unusual structure of the LMP1-TRADD complex and the nonapoptotic phenotype of TRADD signaling, irrespective of the receptor context in which this domain is located. Thus, DNA tumor viruses alter the functional properties of cellular signaling molecules to exploit them for their own purpose of cell transformation.
A unique Epstein Barr virus-derived protein interaction domain uses the cellular death domain protein TRADD to assemble its transforming signaling complex and dictates a transferable nonapoptitic phenotype of TRADD signaling.
PMCID: PMC2174972  PMID: 18198944
24.  Prevention of epidural scarring after microdiscectomy: a randomized clinical trial comparing gel and expanded polytetrafluoroethylene membrane 
European Spine Journal  2006;15(9):1360-1366.
A randomized clinical trial compared two materials used to prevent epidural scarring after microdiscectomy. To determine whether ADCON®-L Gel (ALG) or Preclude Spinal Membrane® (PSM) was more effective in preventing scarring, reducing pain, and improving quality of life postoperatively. Postdiscectomy syndrome may result from epidural scarring. Various materials have been used in attempts to prevent this problem, but none have provided optimal results. Previous laboratory and clinical studies have found ALG and PSM to be effective, but none compared the two materials. Thirty-one patients undergoing primary microdiscectomy were randomly assigned to receive either ALG or PSM. Postoperatively, patients were evaluated by magnetic resonance imaging (MRI), with contrast, for volume and rostral–caudal extent of scar tissue and nerve root involvement. Back and leg pain and quality of life were assessed by neurologic examinations and standardized patient surveys. Findings at any reoperations were recorded. Results in the PSM (n = 18) and ALG (n = 13) groups were compared statistically. No operative or postoperative complications occurred. Two patients in each group required reoperation. MRI at 6 months showed no, mild or mild-moderate scarring in most patients, with no significant differences between the ALG and PSM groups in scar volume and extent or nerve root involvement. Neurologic examinations and patient surveys showed substantial reductions in pain over time in both groups but no significant differences between groups. PSM was easy to see and remove at reoperation. PSM and ALG are equally effective in preventing epidural scarring associated with postdiscectomy syndrome.
PMCID: PMC2438565  PMID: 16763848
Postdiscectomy syndrome; Microdiscectomy; Epidural scarring; ADCON®-L Gel; Preclude spinal membrane®
25.  Optimization of extracranial stereotactic radiation therapy of small lung lesions using accurate dose calculation algorithms 
The aim of this study was to compare and to validate different dose calculation algorithms for the use in radiation therapy of small lung lesions and to optimize the treatment planning using accurate dose calculation algorithms.
A 9-field conformal treatment plan was generated on an inhomogeneous phantom with lung mimics and a soft tissue equivalent insert, mimicking a lung tumor. The dose distribution was calculated with the Pencil Beam and Collapsed Cone algorithms implemented in Masterplan (Nucletron) and the Monte Carlo system XVMC and validated using Gafchromic EBT films. Differences in dose distribution were evaluated. The plans were then optimized by adding segments to the outer shell of the target in order to increase the dose near the interface to the lung.
The Pencil Beam algorithm overestimated the dose by up to 15% compared to the measurements. Collapsed Cone and Monte Carlo predicted the dose more accurately with a maximum difference of -8% and -3% respectively compared to the film. Plan optimization by adding small segments to the peripheral parts of the target, creating a 2-step fluence modulation, allowed to increase target coverage and homogeneity as compared to the uncorrected 9 field plan.
The use of forward 2-step fluence modulation in radiotherapy of small lung lesions allows the improvement of tumor coverage and dose homogeneity as compared to non-modulated treatment plans and may thus help to increase the local tumor control probability. While the Collapsed Cone algorithm is closer to measurements than the Pencil Beam algorithm, both algorithms are limited at tissue/lung interfaces, leaving Monte-Carlo the most accurate algorithm for dose prediction.
PMCID: PMC1769387  PMID: 17132177

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