Neural correlates of script-driven imagery in adolescents with interpersonal traumatic experiences: A pilot study.

In adults, trauma imagery has proven to be a useful tool to assess the neural mechanisms of psychological trauma processing. In adolescents, heterogeneous results could be found for other tasks, however, a trauma imagery paradigm has not been evaluated. For this purpose, we investigated a trauma imagery paradigm with control scripts to assess neural correlates of traumatic experiences in youth. 15 adolescents, who had experienced a traumatic interpersonal event in the past and have developed clinically relevant symptoms, underwent an fMRI scan while listening to their individual trauma- versus two control scripts (positive/negative). We analysed a parametric contrast of the imagery phases (trauma > negative > positive) which revealed activity in the thalamus, dorsal anterior cingulate cortex, cuneus, dorsomedial prefrontal cortex and amygdala. Additionally, amygdala-activity correlated positively with depression-symptom-severity. Our data provide evidence for the feasibility of fMRI during a trauma imagery task in adolescents to investigate networks previously related to hyperarousal in adults with PTSD. Further, we demonstrate the specificity of the activated networks for trauma imagery as compared to imagery of other emotional situations. The task might be particularly useful to evaluate neural correlates of treatment in adolescents when hyperarousal is a target symptom.

[Urinary tract infections in children]. / Harnwegsinfekte bei Kindern.

Urinary tract infections (UTI) are the most common bacterial infections in children. The symptoms are not very specific and range from abdominal pain, poor feeding to nocturnal urinary incontinence. The technique of collecting urine plays an important role for securing the diagnosis. The best way to obtain urine in non-toilet-trained children is catheterization or suprapubic bladder aspiration. In toilet-trained children midstream urine is an acceptable alternative after cleaning the foreskin or labia. In the case of an infection a prompt empirical antibiotic therapy is necessary to reduce the risk of parenchymal scarring of the kidneys. There are different approaches to diagnose vesicoureteral reflux in different countries. The commonly used standard approach in Germany is voiding cystourethrography. In the case of reflux dimercaptosuccinic acid (DMSA) scintigraphy should be performed additionally to exclude renal scarring (bottom-up approach).

Successful group psychotherapy of depression in adolescents alters fronto-limbic resting-state connectivity.

BACKGROUND: Current resting state imaging findings support suggestions that the neural signature of depression and therefore also its therapy should be conceptualized as a network disorder rather than a dysfunction of specific brain regions. In this study, we compared neural connectivity of adolescent patients with depression (PAT) and matched healthy controls (HC) and analysed pre-to-post changes of seed-based network connectivities in PAT after participation in a cognitive behavioral group psychotherapy (CBT). METHODS: 38 adolescents (30 female; 19 patients; 13-18 years) underwent an eyes-closed resting-state scan. PAT were scanned before (pre) and after (post) five sessions of CBT. Resting-state functional connectivity was analysed in a seed-based approach for right-sided amygdala and subgenual anterior cingulate cortex (sgACC). Symptom severity was assessed using the Beck Depression Inventory Revision (BDI-II). RESULTS: Prior to group CBT, between groups amygdala and sgACC connectivity with regions of the default mode network was stronger in the patients group relative to controls. Within the PAT group, a similar pattern significantly decreased after successful CBT. Conversely, seed-based connectivity with affective regions and regions processing cognition and salient stimuli was stronger in HC relative to PAT before CBT. Within the PAT group, a similar pattern changed with CBT. Changes in connectivity correlated with the significant pre-to-post symptom improvement, and pre-treatment amygdala connectivity predicted treatment response in depressed adolescents. LIMITATIONS: Sample size and missing long-term follow-up limit the interpretability. CONCLUSIONS: Successful group psychotherapy of depression in adolescents involved connectivity changes in resting state networks to that of healthy controls.

[Pediatric outpatient surgery]. / Ambulantes Operieren im Kindesalter.

BACKGROUND: The number of outpatient surgeries for routine surgical interventions continues to increase, especially in adults. For many patients, there is no doubt that interventions like arthroscopy will be performed on an outpatient basis. Regarding urologic surgeries in adults (e.g., vasectomy, hydrecelectomy), outpatient treatment is well established. For adults such a procedure represents a well-calculable situation in most cases, as the patient can quite accurately imagine the events that will follow. In terms of pediatric outpatient surgery, the scenario is sometimes quite different. Parents are more anxious and uncertain because they must decide for the well-being of their children and they often do not exactly know what will happen during the procedure. In addition, they do not have to decide for themselves but for their children. DISCUSSION: Unfortunately, parents often lack information prior to surgery. Therefore, all persons involved in the treatment of children (e.g., urologists, anesthesiologists, nurses) must be trained and educated in giving adequate and appropriate information especially for parents. CONCLUSION: The purpose of this article is to provide different starting points for an optimized preparation and care of children and parents concerning outpatient surgery in pediatric urology.

[Vesico-ureteral reflux: Diagnosis and treatment recommendations]. / Vesikoureteraler Reflux : Diagnose und Therapieempfehlungen.

BACKGROUND: Vesico-ureteral reflux (VUR) is one of the most common urologic diseases in childhood. About every third child that presents with a urinary tract infection (UTI) has urinary reflux to the ureter or kidney. Demonstration of a backflow of urine into the ureters or kidneys proves vesicoureteral reflux. In unclear cases, a positioned instillation of contrast agent (PIC) cystogram might be performed and is able to prove vesico-ureteral reflux. OBJECTIVES: Since low-grade VUR has a high probability of maturation and self-limitation, infants with VUR should be given prophylactic antibiotics during their first year of life, reevaluating the status of VUR after 12 months. The aim of any treatment is to prevent renal damage. THERAPY: The individual risk of renal scarring is decisive for the choice of adequate therapy. This risk is mainly dependent on reflux grade, age, and gender of the child as well as parental therapy adherence. In principle, therapeutic options include conservative as well as endoscopic or open surgical antireflux therapies. CONCLUSION: Decisions on treatment should be made individually with parents taking into account all the findings available.

[Imaging in pediatric urology]. / Bildgebung in der Kinderurologie.

BACKGROUND: For many years, sonography and the intravenous pyelogram (IVP) were the most important examination methods for the evaluation of the urinary tract in children. Both methods have their pros and cons: sonography provides ideal visualization of normal kidneys and the evaluation of the pelvicalyceal system. For detection or exclusion of renal scarring, however, this method is not well suited. It provides no information regarding kidney function. METHODS: With an IVP, it is possible to evaluate urinary excretion and, thus, indirectly assess kidney function. As this examination method involves radiation exposure and the necessity of a contrast agent, it should be avoided in the examination of children. The CT is an excellent examination method that can diagnose nearly all urological diseases in children or answer urological questions; however, a CT scan applies the highest radiation dose of all discussed methods. For this reason, examination via MRI is of increasing importance in uroradiology. Initially only the T2 sequences for the visualization of the urinary tract in children were applied. CONCLUSION: The current technical developments as well as the use of the contrast agent gadolinium and the antidiuretic agent furosemide allow an all-in-one evaluation of the kidneys and urinary tract.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO).

BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.

Neural correlates of successful psychotherapy of depression in adolescents.

BACKGROUND: While major effort has been put in investigating neural correlates of depression and its treatment in adults, less is known about the effects of psychotherapy in adolescents. Given the concordance of the ventral striatum, amygdala, hippocampus and the subgenual anterior cingulate cortex (sgACC) as correlates of depression and their involvement in reward processing, we used functional magnetic resonance imaging (fMRI) during performance of a monetary reward task in an intervention versus waitlist-control design to investigate the clinical and neural effects of cognitive behavioral group therapy (CBT-G). METHODS: 22 medication naïve adolescents with major depressive disorder were scanned before and after five sessions of CBT-G (PAT-I), or before and after five weeks of waiting (PAT-W). Changes in symptom scales were analyzed along with neural activation changes within the amygdala, hippocampus, sgACC and ventral striatum regions of interest (ROI). RESULTS: Psychometric assessments and ROI activation remained unchanged in PAT-W. In PAT-I, significant reduction in clinical symptoms accompanied significant changes in brain activation within the left amygdala, left hippocampus and bilateral sgACC. In line with previous findings in adults, pre-to-post-activation changes in the bilateral sgACC correlated with pre-to-post and pre-to-follow-up symptom improvement, and individual expressions of sgACC activation before treatment were related to pre-to-follow-up therapeutic success. LIMITATIONS: Future studies should include larger sample sizes. CONCLUSIONS: Successful group psychotherapy of depression in adolescents was related to signal changes in brain regions previously demonstrated to be reliably linked with successful, particularly pharmacological treatment in adults.

Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial.

BACKGROUND: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). METHODS: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. RESULTS: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvß6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C. CONCLUSION: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475.

Exploiting monitoring data in environmental exposure modelling and risk assessment of pharmaceuticals.

In order to establish the environmental impact of an active pharmaceutical ingredient (API), good information on the level of exposure in surface waters is needed. Exposure concentrations are typically estimated using information on the usage of an API as well as removal rates in the patient, the wastewater system and in surface waters. These input data are often highly variable and difficult to obtain, so model estimates often do not agree with measurements made in the field. In this paper we present an approach which uses inverse modelling to estimate overall removal rates of pharmaceuticals at the catchment scale using a hydrological model as well as prescription and monitoring data for a few representative sites for a country or region. These overall removal rates are then used to model exposure across the broader landscape. Evaluation of this approach for APIs in surface waters across England and Wales showed good agreement between modelled exposure distributions and available monitoring data. The use of the approach, alongside estimates of predicted no-effect concentrations for the 12 study compounds, to assess risk of the APIs across the UK landscape, indicated that, for most of the compounds, risks to aquatic life were low. However, ibuprofen was predicted to pose an unacceptable risk in 49.5% of the river reaches studied. For diclofenac, predicted exposure concentrations were also compared to the Environmental Quality Standard previously proposed by the European Commission and 4.5% of river reaches were predicted to exceed this concentration. While the current study focused on pharmaceuticals, the approach could also be valuable in assessing the risks of other 'down the drain' chemicals and could help inform our understanding of the important dissipation processes for pharmaceuticals in the pathway from the patient to ecological receptors.

Low molecular weight heparins for thromboprophylaxis during induction chemotherapy in patients with multiple myeloma.

BACKGROUNDS: Patients with multiple myeloma have a high risk of venous thromboembolism (VTE), especially during the induction chemotherapy. The aim of our observational study was to determine the impact of prophylaxis with low molecular weight heparin (LMWH) on the incidence of thromboembolic complications. PATIENTS AND METHODS: We analyzed the incidence of thromboembolic events in 258 patients treated with induction chemotherapy containing vincristin, doxorubicin or idarubicin, and dexamethasone, followed by stimulation chemotherapy with cyclophosphamide and G-CSF, and high-dose chemotherapy with melphalan. Two groups of these patients were compared based on the practice of thromboprophylaxis. Patients in the first group (Control, n = 140) were either not treated or treated with a short duration of anticoagulation therapy while the patients in the second group (Prophylactic, n = 118) underwent standard prophylaxis with LMWH throughout the entire period of induction chemotherapy. A total of 102 patients were selected for a close monitoring of the prophylactic effect of different LMWH doses and to be compared to patients without treatment. RESULTS: Standard prophylaxis with LMWH significantly (p < 0.007) lowered a risk of VTE when compared to patients without such prophylaxis (3.4% versus 12.9%, respectively). Furthermore, analysis of the subgroup of 102 patients revealed that higher LMWH doses (> 70 IU/kg per day) achieved full prophylaxis in 28 patients while lower doses were less effective leading to DVT in 3 (7.7%) out of 39 patients. In contrast, VTE was diagnosed in 5 (14.3%) out of 35 patients without any LMWH prophylaxis. CONCLUSION: Prophylaxis with LMWH leads to a significant reduction of the risk of thromboembolic complications during the induction chemotherapy in patients suffering from MM. The prophylactic effect of LMWH is dose-dependent.

Retrospective analysis of the results of high-dose chemotherapy with the support of autologous blood stem cells in patients with multiple myeloma. The experience of a single centre.

Despite new medical products introduced in multiple myeloma therapy, autologous stem cell transplant (ASCT) remains a standard procedure in younger patients with symptomatic disease. We analyzed a group of 190 patients who underwent ASCT at our clinic for multiple myeloma as primary therapy in years 1995-2008. The total number of transplants performed in this group was 291. 110 patients underwent one ASCT, 59 patients had double transplant, out of which 51 patients underwent tandem transplant, 21 patients underwent triple ASCT, out of which 15 patients were transplanted front-line throughout a clinical trial and 6 patients underwent follow-up transplants due to disease progression. The assessment of the best therapeutic effect of ASCT showed the total rates of patients with complete remission--22%, very good partial remission (VGPR)--8%, partial remission--63%, stabilized disease--6% and progression--1%. The transplant related mortality (TRM) was 4.1%. With the median follow-up of surviving patients 2.6 years, the median progression-free survival (PFS) and overall survival (OS) were 21 and 54 months, respectively; the likelihood of a 7-year overall survival was 28%. Comparing tandem versus single transplants, there was a significant increase in the median PFS (25.8 versus 20.8 months, respectively); however, there was no difference in overall survivals. The IVE mobilization regimen was found to be more efficacious for PBPC collection than high-dosed cyclophosphamide.

Factors governing fibrillogenesis of polypeptide chains revealed by lattice models.

Using lattice models we explore the factors that determine the tendencies of polypeptide chains to aggregate by exhaustively sampling the sequence and conformational space. The morphologies of the fibril-like structures and the time scales (τ(fib)) for their formation depend on a balance between hydrophobic and Coulomb interactions. The extent of population of an ensemble of N* structures, which are fibril-prone structures in the spectrum of conformations of an isolated protein, is the major determinant of τ(fib). This observation is used to determine the aggregating sequences by exhaustively exploring the sequence space, thus providing a basis for genome wide search of fragments that are aggregation prone.

Probing the mechanisms of fibril formation using lattice models.

Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature (T) and the number of chains (M). While these models are, at best, caricatures of peptides, we show that a number of generic features thought to govern fibril assembly are captured by the toy model. The monomer, which contains eight beads made from three letters (hydrophobic, polar, and charged), adopts a compact conformation in the native state. In both the single-layered protofilament (seen for M10) structures, the monomers are arranged in an antiparallel fashion with the "strandlike" conformation that is perpendicular to the fibril axis. Partial unfolding of the folded monomer that populates an aggregation prone conformation (N(*)) is required for ordered assembly. The contacts in the N(*) conformation, which is one of the four structures in the first "excited" state of the monomer, are also present in the native conformation. The time scale for fibril formation is a minimum in the T-range when the conformation N(*) is substantially populated. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first "burst" stage, highly mobile oligomers of varying sizes form. The conversion to the N(*) conformation occurs within the oligomers during the second stage in which a vast number of interchain contacts are established. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation of N(*) particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the Lifshitz-Slyazov growth kinetics for crystallization from supersaturated solutions. The detailed analysis shows that elements of the three popular models, namely, nucleation and growth, templated assembly, and nucleated conformational conversion are present at various stages of fibril assembly.

Dissecting contact potentials for proteins: relative contributions of individual amino acids.

Knowledge-based contact potentials are routinely used in fold recognition, binding of peptides to proteins, structure prediction, and coarse-grained models to probe protein folding kinetics. The dominant physical forces embodied in the contact potentials are revealed by eigenvalue analysis of the matrices, whose elements describe the strengths of interaction between amino acid side chains. We propose a general method to rank quantitatively the importance of various inter-residue interactions represented in the currently popular pair contact potentials. Eigenvalue analysis and correlation diagrams are used to rank the inter-residue pair interactions with respect to the magnitude of their relative contributions to the contact potentials. The amino acid ranking is shown to be consistent with a mean field approximation that is used to reconstruct the original contact potentials from the most relevant amino acids for several contact potentials. By providing a general, relative ranking score for amino acids, this method permits a detailed, quantitative comparison of various contact interaction schemes. For most contact potentials, between 7 and 9 amino acids of varying chemical character are needed to accurately reconstruct the full matrix. By correlating the identified important amino acid residues in contact potentials and analysis of about 7800 structural domains in the CATH database we predict that it is important to model accurately interactions between small hydrophobic residues. In addition, only potentials that take interactions involving the protein backbone into account can predict dense packing in protein structures.

[Lenalidomid (Revlimid) in the treatment of multiple myeloma--first experience in the Czech Republic]. / Lenalidomid (Revlimid) v lécbe mnohocetného myelomu-- první zkusenosti v Ceské republice.

The prognosis of multiple myeloma (MM) has substantially improved during last decades due to new, so-called targeted drugs--proteasome inhibitor bortezomib and immunomodulatory drugs (ImiDs), thalidomide and lenalidomide. They could be used in various combinations and/or sequentially thanks to different mechanism of action and toxicity. Both bortezomib and thalidomide are widely used in Czech republic, however, lenalidomide was approved for the treatment of MM (and MDS) at the very latest and its usage is limited due to high costs, as well. According to the results of clinical trials lenalidomide is effective in myeloma refractory to various therapy including other new drugs. First time in the Czech republic the combination of lenalidomide and dexamethasone was given in our center to 2 patients with relapsed myeloma as 7th and 10th line of therapy. Acceptable results of treatment with improved clinical status in the first patient enabled to suspend his therapeutic plasmaferesis. Disease stabilization lasting three months was observed also in the second patient.

[Detection of free light chains--a new method of diagnostics of haematological diseases]. / Detekce volných lehkých retezcu ("free light chains")--nová metoda diagnostiky hematologickych onemocneí.

BACKGROUND: To diagnose monoclonal gamopathy, one of the most frequent haematological diseases, we use immunochemical assays, which are based on the detection of paraprotein in serum and/or urine. METHODS AND RESULTS: The most common laboratory assays we use are SPE (serum protein electrophoresis) and IFE (immunofixation electrophoresis). New method represents the detection of free light chain (FLC) in serum. In our study we compared those three methods (SPE, IFE and FLC) from the point of sensitivity of paraprotein detection. For FLC detection was used Freelite system analyzer (Immunotech Beckman Coulter). We examined 51 patients with diagnosis of multiple myeloma, nonHodgkin's lymphoma, primary amyloidosis and monoclonal gammopathy of undetermined significance. CONCLUSIONS: Detection of FLC is a valuable method which sometimes could specify diagnosis of MG and make the treatment more accurate.