Electrophysiological evidence of an attentional bias towards appetitive and aversive words in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: Emotional dysregulation has emerged as a core symptom domain in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the pathophysiological underpinnings remain poorly understood. This study investigated attentional biases to positive and negative emotional words as possible contributing mechanisms. METHODS: Event-related potentials (ERPSs) and behavioral attention bias indices were recorded from 39 adult patients with ADHD and 41 healthy controls during a verbal dot-probe task with positive-neutral, negative-neutral, and neutral-neutral word pairs. RESULTS: Cue-locked N2pc amplitudes indicated a significant attentional bias towards emotional words in patients with ADHD and healthy controls. In healthy controls, the bias was only significant in positive trials. In patients, the bias was associated with ADHD severity and self-reported poor emotion regulation skills. ADHD patients also exhibited reduced target-locked P1 amplitudes and inferior behavioral performance compared with healthy controls. CONCLUSIONS: Our findings provide evidence of an attention bias to positive and negative emotional stimuli in adult patients with ADHD and adverse effects of emotional stimuli on task performance. SIGNIFICANCE: An attentional bias to emotional stimuli might contribute to emotional reactivity and dysregulation in adult patients with ADHD.

Beam transport and space charge compensation strategies (invited).

The transport of intense ion beams is affected by the collective behavior of this kind of multi-particle and multi-species system. The space charge expressed by the generalized perveance dominates the dynamical process of thermalisation, which leads to emittance growth. To prevent changes of intrinsic beam properties and to reduce the intensity dependent focusing forces, space charge compensation seems to be an adequate solution. In the case of positively charged ion beams, electrons produced by residual gas ionization and secondary electrons provide the space charge compensation. The influence of the compensation particles on the beam transport and the local degree of space charge compensation is given by different beam properties as well as the ion beam optics. Especially for highly charged ion beams, space charge compensation in combination with poor vacuum conditions leads to recombination processes and therefore increased beam losses. Strategies for providing a compensation-electron reservoir at very low residual gas pressures will be discussed.

Microeconomic surplus in health care: applied economic theory in health care in four European countries.

INTRODUCTION: In economic theory economic surplus refers to two related quantities: Consumer and producer surplus. Applying this theory to health care "convenience" could be one way how consumer benefits might manifest itself. METHODS: Various areas of economic surplus were identified and subsequently screened and analyzed in Germany, Spain, The Netherlands, and the UK: Cesarean births, emergency room visits (nights or weekends), drug availability after test results, and response surplus. A targeted literature search was being conducted to identify the associated costs. Finally the economic surplus (convenience value) was calculated. RESULTS: The economic surplus for different health care areas was being calculated. The highest economic surplus was obtained for the example of response surplus IVF-treatments in The Netherlands. CONCLUSION: The analyzed examples in this article support the underlying hypothesis for this research: "Value of convenience defined as the consumer surplus in health care can be shown in different health care settings." Again, this hypothesis should be accepted as a starting point in this research area and hence further primary research is strongly recommended in order to fully proof this concept.

The times are changing: temporal shifts in patterns of fish invasions in central European fresh waters.

This study examines the invasion history of alien fish species based on exhaustive national data sets on fish invasions of two contiguous central European countries (Germany and Austria). Fifteen alien fish species are currently established in both countries, constituting 14 and 17% of the total freshwater fish fauna of Germany and Austria, respectively. In both countries, six alien species are present, but not established. The status of five alien species in Germany and three species in Austria remains unknown. Accumulation rates of alien fish species have increased in recent decades with >50% of them reported after 1971. North America and Asia were the primary sources of alien fish species in Germany and Austria up to the 1980s, whereas European species of Ponto-Caspian origin dominate now. Fisheries (including aquaculture) and the animal trade were responsible for most earlier introductions, whereas waterways were the main pathway for recent invaders. The extent of the spatial distribution of alien species was positively correlated with residence time, i.e. the time elapsed since the first national record. Different thermal preferences of early invaders (mostly coldwater species) and new invaders (typically warmwater adapted) may benefit the latter in the face of climate change. It is concluded that new challenges for alien fish management arise and that ecosystem-based approaches as endorsed by the E.U. Water Framework Directive (maintaining or restoring good ecological status of rivers and streams) should become the centrepiece of river management in Europe.

Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and ß1-triggered motility, migration and invasion of prostate cancer cells.

BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) might become a novel tool to treat advanced prostate cancer. However, chronic drug exposure may trigger resistance, limiting the utility of mTOR inhibitors. METHODS: Metastatic potential of PC3 prostate cancer cells, susceptible (PC3(par)) or resistant (PC3(res)) to the mTOR-inhibitor RAD001 was investigated. Adhesion to vascular endothelium or immobilised collagen, fibronectin and laminin was quantified. Motility, migration and invasion were explored by modified Boyden chamber assay. Integrin α and ß subtypes were analysed by flow cytometry, western blotting and real-time PCR. Integrin-related signalling, EGFr, Akt, p70S6kinase and ERK1/2 activation were determined. RESULTS: Adhesion was reduced, whereas motility, migration and invasion were enhanced in PC3(res). The α2 and ß1 integrin subtypes were dramatically elevated, integrins α1 and α6 were lowered, whereas α5 was nearly lost in PC3(res). Activation of the Akt signalling pathway was strongly upregulated in these cells. Treating PC3(par) cells with RAD001 reduced motility, migration and invasion and deactivated Akt signalling. Blocking studies revealed that α2 and ß1 integrins significantly trigger the motile behaviour of the tumour cells. CONCLUSION: Chronic RAD001 treatment caused resistance development characterised by distinct modification of the integrin-expression profile, driving prostate cancer cells towards high motility.

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro.

BACKGROUND: The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin ß subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose-dependently reduced tumor-cell growth but did not impair tumor-endothelium and tumor-matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated ß1-integrin in PC-3 and diminished ß4-integrin in PC-3 and DU-145 cells. CONCLUSIONS: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth.

Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor ß (ß-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of ß-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for ß-PDGFR in PCa and showed that PDGF-D is activated by serine protease-mediated proteolytic removal of the CUB domain in a two-step process, yielding first a hemidimer (HD) and then a growth factor domain dimer. Herein, we demonstrate that the expression of PDGF-D in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice. Histopathological analyses of bone tumors generated by PDGF-D-expressing LNCaP cells (LNCaP-PDGF-D) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases. Importantly, we discovered a novel function of PDGF-D in the regulation of osteoclast differentiation, independent of the RANKL/RANK signaling axis. Although both PDGF-B and -D were able to activate ß-PDGFR, only PDGF-D was able to induce osteoclastic differentiation in vitro, and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1, a master transcription factor for osteoclastogenesis. Taken together, these results reveal a new function of PDGF-D as a regulator of osteoclastic differentiation, an activity critical for the establishment of skeletal metastatic deposit in PCa patients.

[Metastatic renal cell carcinoma: therapeutic concepts for non-medicinal treatment]. / Metastasiertes Nierenzellkarzinom : Therapiekonzepte zur nichtmedikamentösen Behandlung.

Metastatic renal cell carcinoma has a poor prognosis with a median overall survival rate of approximately 2 years. The current standard medicinal therapy includes the use of tyrosine kinase inhibitors or antiangiogenic substances, such as VEGF receptor antagonists. Improvement in clinical response is to be expected when surgical tumor debulking by nephrectomy or metastasectomy is performed before medicinal therapy is started and should be considered especially in patients with a good performance status. Additionally, complete resection of solitary or at least a limited number of metastases can potentially be done with curative intent. Radiotherapy remains the standard procedure for palliative therapy of brain metastases to reduce clinical symptoms and to improve intracerebral tumor control.

CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells.

BACKGROUND: Metastasis is associated with poor prognosis for melanoma. The formation of metastases is a multi-step process, in which cancer cells can subsequently acquire the potential to intravasate into the blood or lymph vessels, disseminate through the circulation, extravasate through the endothelium and invade the connective tissue. There is increasing evidence that chemokines have a pivotal role in the dissemination and establishment of melanoma metastasis. METHODS: We isolated melanoma cells from melanoma metastasis and performed different migration assays and transendothelial resistance measurements of endothelial monolayers co-cultured with melanoma cells, in order to monitor barrier function and diapedesis and confirmed these results by confocal microscopy. RESULTS: We observed that tumour endothelial cells (ECs) secrete high levels of CXCL9 in all, and CXCL10 in most melanoma metastases. Migration studies revealed that low concentrations of these chemokines induce chemotaxis, whereas high concentrations induce spontaneous migration of melanoma cells (chemokinesis/chemorepulsion) and the disruption of the endothelial barrier, resulting in an accelerated transendothelial migration (TEM). Addition of anti-CXCL9 or anti-CXCR3 antibodies to the co-cultures delayed the TEM of melanoma cells. CONCLUSION: Our data represent novel mechanisms by which tumour cells in melanoma metastases might use the chemokine-expressing endothelium to leave the tumour and eventually to form additional metastases at distinct sites.

[Patients with metastatic hormone-refractory prostate cancer. Second-line chemotherapy with mitoxantrone plus prednisone]. / Docetaxel-refraktäre Patienten mit metastasiertem hormonrefraktären Prostatakarzinom. Mitoxantron plus Prednison als Zweitlinienchemotherapie.

BACKGROUND: To date there has been no accepted standard for second-line chemotherapy in docetaxel-refractory patients with metastatic hormone-refractory prostate cancer (mHRPC). Therefore, we evaluated our experience with mitoxantrone plus prednisone (MP) in this setting. MATERIAL AND METHODS: Ten patients with docetaxel-refractory mHRPC were treated with MP. The parameters under investigation were prostate-specific antigen (PSA) remission, biochemical progression-free survival, and pain reduction under chemotherapy. RESULTS: Partial PSA remission was seen in two patients, "stable disease" in three patients, and progression in five patients receiving MP. Progression-free survival was 8 months (mean) for patients with partial PSA remission and 2 months (median) for patients with "stable disease." Four of seven patients experienced pain reduction with MP. Grade 4 neutropenia was noted in only 10%. Patients with a decline of PSA under docetaxel and MP had a progression-free survival of 11.5 months (median). CONCLUSIONS: Presently, we see the indication for MP as being second-line chemotherapy in docetaxel-refractory patients with mHRPC who cannot be included in phase II/III studies. Even with only a moderate rate of partial PSA remission, every second patient had an improvement in tumor-related pain. Progression-free survival was prolonged, and the side effects of MP were comparatively low.

[Prevalence of lymph node metastases in non-muscle-invasive bladder cancer. Delay of radical cystectomy and upstaging in the cystectomy specimen as risk factors]. / Prävalenz von Lymphknotenmetastasen beim nicht muskelinvasiven Blasenkarzinom. Verzögerung der Zystektomie und Upstaging im Zystektomiepräparat als Risikofaktoren.

OBJECTIVE: To study clinical and histopathologic parameters after cystectomy and lymphadenectomy in non-muscle-invasive transitional cell carcinoma (TCC) of the bladder and their association with the prevalence of lymph node metastases (N+). PATIENTS AND METHODS: Of 866 patients treated with radical cystectomy and lymphadenectomy, 219 had non-muscle-invasive TCC of the bladder. The prevalence of N+ was related to parameters such as gender, age, number of transurethral resections of the bladder (TURBs), intervals between first TURB and cystectomy, adjuvant therapy, maximum histopathologic tumor stage and grade at TURB, and tumor upstaging in the cystectomy specimen by univariate and multivariate analysis. RESULTS: A total of 33 patients (15%) had N+. By multivariate analyses, tumor upstaging and the number of TURBs were independent predictors of N+ at cystectomy. The number of TURBs increased the prevalence of N+ from 8% (one TURB) to 24% (two to four TURBs). Tumor upstaging in the cystectomy specimen increased the prevalence of N+ from 4% to 36%. CONCLUSION: Inappropriate delay and staging errors of"high risk" non-muscle-invasive TCC of the bladder contribute to an increased prevalence of N+ and should be avoided. In our series, the number of TURBs and tumor upstaging in the cystectomy specimen were independent predictors for N+ by multivariate analysis.

Alpha-catulin, a Rho signalling component, can regulate NF-kappaB through binding to IKK-beta, and confers resistance to apoptosis.

Rho GTPases regulate diverse cellular functions including adhesion, cytokinesis and motility, as well as the activity of the transcription factors NF-kappaB, serum response factor and C/EBP. alpha-Catulin, an alpha-catenin-related protein that shares structural similarities with cytoskeletal linker proteins, facilitates Rho signalling by serving as a scaffold for the Rho-specific guanine nucleotide exchange factor Lbc. We report here that alpha-catulin also interacts with a key component of the NF-kappaB signalling pathway, namely the IkappaB kinase (IKK)-beta. In co-immunoprecipitations, alpha-catulin can bind IKK-beta and Lbc. Ectopic expression of alpha-catulin augmented NF-kappaB activity, promoted cell migration and increased resistance to apoptosis, whereas knockdown experiments showed the opposite effects. Together, these features suggest that alpha-catulin has tumorigenic potential.

[Which are reasonable diagnostic procedures in the evaluation of urinary incontinence in the elderly?]. / Welche Untersuchungen sind beim alten Menschen mit Harninkontinenz sinnvoll?

The ageing of our society continuously increases the number of frail elderly patients in the incontinence cohort. Shortage of financial and personnel resources demands reasonable and purposeful use of the diagnostic armamentarium. All intended diagnostic procedures should follow an algorithm hierarchized for invasiveness and should be limited to the minimum extent necessary for initiation of a conservative first-line treatment. Reasonable diagnostics objectify patients' complaints, differentiate between subgroups, reveal underlying pathologies and comorbidities, classify incontinence severity, support the therapeutic strategy, identify possible treatment complications and serve as follow-up tools. Diagnostic results have to be documented in detail and the procedures must be as easy and minimally invasive as possible. Basic diagnostics in urinary incontinence comprise patient history, clinical examination, urinalysis, uroflowmetry and sonographic post-void residual measurement, voiding diary and evaluation of the mental status. With these procedures, the vast majority of elderly patients can be classified correctly and a conservative first-line treatment can be started. Only a minority of patients with incongruent diagnostic results or recurrent incontinence refractory to conservative therapy should undergo further special diagnostics (urethrocystoscopy, urodynamics, morphologic and functional radiologic imaging, perineal or introital ultrasound) if they lead to therapeutic consequences. If not, expensive special diagnostics should be omitted in elderly patients due to their inherent morbidity.

[Established treatment options for male stress urinary incontinence]. / Etablierte Methoden in der Behandlung der Belastungsinkontinenz des Mannes.

Nowadays, male stress urinary incontinence is rare and almost always of iatrogenic origin (radiotherapy, pelvic surgery). However, the prognosis of urinary incontinence following surgery is good and can be improved by pelvic floor muscle exercises in combination with biofeedback systems. For the remaining patient cohort with persistent urinary incontinence, several established surgical treatment options are available. Suburothelial injections of bulking agents can easily be performed in an ambulatory setting. However, regardless of the material used, long-term results are disappointing. Moreover, the residual urethral function deteriorates due to cicatrization of the suburothelial plexus with consequent loss of urethral elasticity. The fascial sling procedure in males has to be performed in preoperated areas and is as technically demanding for the surgeon as it is burdening for the patient. Alloplastic material is not used, thus minimizing risks for arrosion or infection. Since the sling tension can neither be standardized nor postoperatively readjusted, the risk of overcorrection is considerable and the success of the procedure is heavily dependent on the surgeon's experience. Despite wear and high revision rates, the technically mature artificial sphincter produces excellent continence results and has become the gold standard in the therapy of male stress urinary incontinence. The circumferential and continuous urethral compression by the cuff is highly effective, but at the price of an almost inevitable urethral atrophy. To overcome this problem, various surgical techniques have been developed (tandem cuff, cuff downsizing, transcorporal cuff placement). However, the expensive artificial sphincter is not a nostrum for every incontinent man, since it requires certain minimal cognitive and manual capabilities. Therefore, the search for less demanding treatment alternatives seems to be necessary, even if one has to accept lower continence rates.

[Noninvasive and invasive bladder cancer: diagnostics and treatment]. / Nichtinvasives und invasives Harnblasenkarzinom: Diagnostik und Therapie.

Therapy of superficial bladder tumors is transurethral resection (TUR), and in cases of pT1 or high-grade tumors a re-TUR is indicated. Patients with carcinoma in situ receive intravesical chemotherapy or BCG for at least 3 months. Persistent carcinoma in situ may be treated by radical cystectomy. With the provision of a functionally adequate urinary diversion, cystectomy represents an effective treatment for patients with muscle-invasive bladder cancer without metastatic spread. Regional lymph node metastases can be found in up to 15% of stage T1 disease and are present in 33% of stage T3/4 lesions. Thus, lymphadenectomy gains diagnostic and possibly also therapeutic importance. For selected patients, who cannot be treated by radical cystectomy, multimodal concepts aiming to preserve the bladder are discussed. After or prior to cystectomy systemic chemotherapy may become necessary for some patients to positively affect the course of the disease in cases of locally advanced or metastatic lesions.

Grasp effects of the Ebbinghaus illusion are ambiguous.

The assumption that the Ebbinghaus/Titchener illusion deceives perception but not grasping, which would confirm the two-visual-systems hypothesis (TVSH) as proposed by Milner and Goodale (The visual brain in action, 1995), has recently been challenged. Franz et al. (Exp Brain Res 149:470-477, 2003) found that the illusion affects both perception and grasping, and showed that the effect of the illusion on the peak grip aperture (PGA) cannot be accounted for by different sizes of the gap that separates the central target disk from the surrounding flankers. However, it is not yet clear if the presence of flankers per se influences grasping. We therefore compared kinematic parameters of prehension, using the Ebbinghaus illusion, and a neutral control condition where normal subjects grasped a disk without any flankers. In accordance with the well-known effects of the illusion on perceived size, the PGA was smaller when the target disk was surrounded by large flankers, and larger when it was encircled by small flankers. However, the largest PGA values were reached in the neutral control condition. Hence the presence of flankers leads to a general reduction of the PGA, possibly because the flankers are regarded as obstacles. This 'reduction effect' casts doubts on how appropriate it is to directly compare perceptual measures and PGA values when using the Ebbinghaus illusion. Even smaller effects of the illusion on the PGA compared to larger perceptual effects cannot be unequivocally interpreted.

Pudendal nerve branch injury during radical perineal prostatectomy.

We report the first case of direct surgical injury to a pudendal nerve branch during radical perineal prostatectomy. A 65-year-old patient presented with typical symptoms of a pudendal nerve lesion after radical perineal prostatectomy. As the patient did not respond to conservative treatment, surgical exploration and exeresis of the injured sensory branch of the pudendal nerve was necessary, resulting in pain improvement. Urologic surgeons should be aware of the typical symptoms after iatrogenic injury to the pudendal nerve or its branches. Early diagnosis and neurosurgical intervention are important to obtain a more favorable outcome.

Influence of environmental humidity and dietary protein on pyramidal growth of carapaces in African spurred tortoises (Geochelone sulcata).

The carapaces of captive-raised tortoises (terrestrial chelonians of the zoological family Testudinidae, often develop pyramidal-shaped osseous growth centrally within the horny plates. With very few exceptions (e.g. Geochelone elegans, Psammobates sp.), this conical growth pattern is considered to be pathologic. This very common defect is believed to be an important indicator of the quality of captive tortoise management. This study was designed to examine the effect of dietary protein level and environmental humidity on the degree of pyramidal growth in the carapaces. Fifty recently hatched African spurred tortoises (G. sulcata) were raised for 5 months under artificial conditions of varying environmental humidity and dietary protein content (14% vs. 19% vs. 30% crude protein in dry matter). Humps of the carapaces that developed and blood values of calcium, phosphorus and haematocrit were measured and compared among groups. Dry environmental conditions (24.3-57.8% and 30.6-74.8% relative humidity) produced taller humps than humid conditions (45-99% relative humidity). Hump formation differed significantly (p < or = 0.001) between these three groups kept under different humidity conditions. Variable dietary protein had a minor, positive impact on this pathological formation of humps (pyramidal growth syndrome, PGS). Analysis of blood (calcium, phosphorus and haematocrit) offered no further explanation as to the development of the humps.