Orientation-invariance of individual differences in three face processing tasks.

Numerous studies have reported impairments in perception and recognition, and, particularly, in part-integration of faces following picture-plane inversion. Whether these findings support the notion that inversion changes face processing qualitatively remains a topic of debate. To examine whether associations and dissociations of the human face processing ability depend on stimulus orientation, we measured face recognition with the Cambridge Face Memory Test (CFMT), along with experimental tests of face perception and selective attention to faces and non-face objects in a sample of 314 participants. Results showed strong inversion effects for all face-related tasks, and modest ones for non-face objects. Individual differences analysis revealed that the CFMT shared common variance with face perception and face-selective attention, however, independent of orientation. Regardless of whether predictor and criterion had same or different orientation, face recognition was best predicted by the same test battery. Principal component decomposition revealed a common factor for face recognition and face perception, a second common factor for face recognition and face-selective attention, and two unique factors. The patterns of factor loadings were nearly identical for upright and inverted presentation. These results indicate orientation-invariance of common variance in three domains of face processing. Since inversion impaired performance, but did not affect domain-related associations and dissociations, the findings suggest process-specific but orientation-general mechanisms. Specific limitations by constraints of individual differences analysis and test selection are discussed.

ERBB2 gene amplification increases during the transition of proximal EGFR(+) to distal HLA-G(+) first trimester cell column trophoblasts.

INTRODUCTION: Although, DNA copy-number alterations (CNAs) have been well documented in a number of adverse phenotypic conditions, accumulating data suggest that CNAs also occur during physiological processes. Interestingly, extravillous trophoblasts induce the expression of the transforming, proto-oncogene ERBB2, which is frequently amplified in human cancer. However, no data are available to address whether trophoblast-related ERBB2 expression might also be linked to genomic amplification. METHODS: Dual color silver as well as fluorescence in situ hybridization analyses were carried out to evaluate frequency and degree of ERBB2 gene and chromosome 17 copy numbers in first trimester placental cell columns and isolated trophoblasts. Proliferative EGFR(+) and differentiated HLA-G(+) trophoblasts were identified or separated by means of in situ immunofluorescence co-stainings and magnetic beads cell isolation, respectively. RESULTS: ERBB2 gene amplification is detected in approximately 40% of isolated HLA-G(+) trophoblasts. Although already detectable in EGFR(+) cells, the percentage and extent of ERBB2 amplification was markedly increased in HLA-G(+) trophoblasts in situ and after isolation. Accordingly, HLA-G(+) trophoblasts highly express ERBB2 on protein level. Finally, ERBB2 copy number variations occur independently of aneuploidy as the majority of ERBB2 amplifying cells were cytogenetically diploid for chromosome 17. DISCUSSION: ERBB2 gene amplification is a frequent event during EVT differentiation. This finding challenges the long standing paradigm, which associates gene amplification with pathological conditions and further supports recent evidences suggesting that CNAs are a normal feature of developmental processes.

The preview benefit for familiar and unfamiliar faces.

Previewing distracters improves visual search - the preview benefit (Watson & Humphreys, 1997). Recent fMRI evidence suggests that the preview benefit rests on active inhibition in brain regions concerned with spatial memory, as well as in content selective areas (Allen, Humphreys, & Matthews, 2008). Using familiar and unfamiliar faces in a preview search task we show that search performance is much better with familiar than with unfamiliar faces. With both types of stimuli we obtained preview benefits of at least 10%, measured in terms of the advantage in reaction time relative to the no preview condition. The preview benefit increased up to 30% when distracter faces and their locations were previewed, compared to a benefit in the range of 10-25% for previewing just distracter locations. Analysis in terms of search time per item showed that familiar faces were processed with more than double the efficiency of the unfamiliar faces. Further, efficiency was enhanced relative to the no preview condition only when distracter locations and content were previewed, but not when participants previewed just distracter locations. These findings corroborate that the preview benefit involves both spatial and content-specific mechanisms, and indicate contribution of existing long-term memory representations independent of spatial memory.

Intratumoral expression profiling of genes involved in angiogenesis in colorectal cancer patients treated with chemotherapy plus the VEGFR inhibitor PTK787/ZK 222584 (vatalanib).

The phase III CONFIRM clinical trials demonstrated that metastatic colorectal cancer patients with elevated serum lactate dehydrogenase (LDH) had improved outcome when the vascular endothelial growth factor receptor (VEGFR) inhibitor PTK/ZK (Vatalanib) was added to FOLFOX4 chemotherapy. We investigated the hypothesis that high intratumoral expression of genes regulated by hypoxia-inducible factor-1 alpha (HIF1α), namely LDHA, glucose transporter-1 (GLUT-1), VEGFA, VEGFR1, and VEGFR2, were predictive of outcome in CONFIRM-1. Tumor tissue was isolated by laser-capture microdissection from 85 CONFIRM-1 tumor specimens; FOLFOX4/placebo n=42, FOLFOX4/PTK/ZK n=43. Gene expression was analyzed using quantitative RT-PCR. In univariate analyses, elevated mRNA expression of LDHA, GLUT-1, and VEGFR1 were associated with response to FOLFOX4/PTK/ZK. In univariate and multivariate analyses, elevated LDHA and VEGFR1 mRNA levels were associated with improved progression-free survival in FOLFOX4/PTK/ZK patients. Furthermore, increased HIF1α and VEGFR2 mRNA levels were associated with decreased survival in FOLFOX/placebo patients but not in patients who received FOLFOX4/PTK/ZK. These are the first data suggesting intratumoral mRNA expression of genes involved in angiogenesis/HIF pathway may predict outcome to VEGFR-inhibitors. Biomarkers that assist in directing VEGFR-inhibitors toward patients with an increased likelihood of benefit will improve the cost-effectiveness of these promising agents.

Vascular density analysis in colorectal cancer patients treated with vatalanib (PTK787/ZK222584) in the randomised CONFIRM trials.

BACKGROUND: Pharmacological inhibitors of vascular endothelial growth factor (VEGF) receptors, like vatalanib, have been tested in randomised trials (CONFIRM (Colorectal Oral Novel therapy For the Inhibition of Angiogenesis and Retarding of Metastases) 1 and 2) in colorectal cancer showing activity in a subgroup of patients with high serum LDH expression. In the current study, we assessed the predictive role of vascular density (VD) in patients treated in the above trials. METHODS: Paraffin-embedded materials from 141 patients were analysed with immunohistochemistry for the expression of the CD31 (pan-endothelial cell marker) and of phosphorylated pVEGFR2/KDR on endothelial cells. The VD was correlated with response to therapy and with progression-free (PFS) and overall survival (OS). RESULTS: A significant association of pVEGFR2/KDR+ VD with poor response in the placebo group was noted (response rates (RRs) 15% (3/20) when high VD vs 52% (26/50) when low VD; P=0.006). The RR increased from 15 (3/20) to 50% (11/22) in tumours with high VD when vatalanib was added to chemotherapy (P=0.02). A significantly improved PFS was noted in patients with high pVEGFR2/KDR+ VD when treated with vatalanib (P=0.002). A similar effect was also noted in patients with high CD31+ VD (P=0.07). Overall survival was marginally improved (P=0.07). CONCLUSION: Assessment of the activated vessel density may allow the stratification of patients recruited in randomised trials with VEGFR-targeting anti-angiogenic agents, unmasking their therapeutic potential and enabling their introduction in the clinical practice for the benefit of specific patient subgroups, at the same time reducing the cost of therapy.

Expression, regulation and functional characterization of matrix metalloproteinase-3 of human trophoblast.

MMP-3 has been detected in human placenta and reduced expression of the enzyme was observed in invasive trophoblasts of patients with severe preeclampsia. However, detailed expression pattern, regulation and biological properties of the placental protease have not been elucidated so far. RT-PCR analyses, Western blotting and enzyme activity assays revealed that pro- and active form of MMP-3 were predominantly expressed in purified first trimester villous trophoblasts, in invasive cytotrophoblasts of differentiating explant cultures and in trophoblastic SGHPL-4 cells. Accordingly, immunofluorescene of first trimester placental tissues detected MMP-3 mainly in villous and extravillous cytotrophoblasts. IL-1beta, an inducer of MMP-3 in decidual cells, increased secretion and activity of the protease in trophoblast supernatants in a dose- and time-dependent manner. IL-1beta-stimulated production of the enzyme was suppressed in the presence of inhibitors of MAPK and AKT signalling. Similar to recombinant MMP-3, MMP-3 in supernatants of IL-1beta-stimulated decidual stromal or SGHPL-4 cells degraded IGFBP-1 in vitro resulting in the appearance of cleavage products at approximately 25, 22, 17, 14 and 11kD. However, cleavage assays using recombinant MMP-2 suggested that the gelatinase may contribute to IGFBP-1 degradation in trophoblast supernatants. Despite its effects on MMP-3 expression IL-1beta failed to significantly alter invasion of SGHPL-4 cells through Matrigel-coated transwells. In conclusion, the data suggest that invasive trophoblast cell models secrete bioactive MMP-3. Inducible expression of the protease involves MAPK and AKT signalling. In addition to the decidua, MMP-3 of trophoblasts may contribute to the regulation of the IGF system by degrading IGFBP-1.

Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis.

OBJECTIVE: To evaluate the incidence of coronary vasospasm as a possible pathophysiological mechanism causing chest pain symptoms in patients with clinically suspected myocarditis. DESIGN AND SETTING: Prospective study in a teaching hospital. PATIENTS: 85 patients who presented at hospital with atypical chest pain and demonstrated clinical signs suggestive of myocarditis. MAIN OUTCOME MEASURES: Incidence of coronary vasospasm demonstrated by intracoronary acetylcholine (ACh) testing. METHODS: The combined procedure of intracoronary ACh testing and endomyocardial biopsy (EMB) was performed after ruling out significant coronary artery disease (CAD). EMBs were analysed for myocardial inflammation by immunohistological methods and for virus genome persistence. RESULTS: Pathological biopsy results, including myocardial inflammation or detection of viral genomes, or both, were found in 55 (64.7%) patients while 30 (35.3%) patients showed neither cardiac inflammation nor viral genomes and were defined as the control group. Coronary vasospasm was demonstrated in 39/55 (70.9%) patients with pathological results compared with only 12/30 (40.0%) with normal biopsy results (p = 0.01). Patients with isolated PVB19 infection (n = 22) demonstrated a significantly higher incidence of coronary vasospasm than both those with isolated HHV6 infection (86.4% vs 46.7%; p = 0.025) and those with normal biopsy results (86.4% vs 40.0%; p<0.001). Univariate and multivariate logistic regression analysis showed that only PVB19 infection was independently correlated with coronary vasospasm (OR = 4.9, 95% CI 1.56 to 15.28, p = 0.006). CONCLUSIONS: Coronary vasospasm is one of the main reasons for atypical chest pain in patients with clinical signs of myocarditis and biopsy-proven PVB19 myocarditis in the absence of significant CAD.

Biomarker analysis in polycythemia vera under interferon-alpha treatment: clonality, EEC, PRV-1, and JAK2 V617F.

Three consecutive polycythemia vera (PV) patients were analyzed before and during pegylated-interferon (rIFNalpha) treatment for the following markers: (1) granulocyte and CD34(+) cell clonality, (2) Jak2V617F expression, (3) PRV-1 mRNA overexpression, and (4) Epo-independent colony (EEC) growth. Before rIFNalpha therapy, all patients displayed clonal hematopoiesis, 100% Jak2V617F expression as well as PRV-1 overexpression, and EEC growth. After rIFNalpha treatment, all three patients demonstrated polyclonal hematopoiesis. Nonetheless, Jak2V617F expression, PRV-1 overexpression, and EEC-growth remained detectable, albeit at lower levels. We conclude that reemergence of polyclonal hematopoiesis after rIFNalpha treatment may be achieved in a substantial proportion of patients. However, this does not constitute elimination of the PV clone. These data demonstrate the usefulness of novel markers in monitoring minimal residual disease and caution against discontinuation of rIFNalpha treatment after hematologic remission. Long-term follow-up of large patient cohorts is required to determine whether rIFNalpha treatment can cause complete molecular remissions in PV.

Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.

BACKGROUND/AIMS: Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. METHODS: A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. RESULTS: ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. CONCLUSION: This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

Vascular ectasia of the whole intestine as a cause of recurrent gastrointestinal bleeding after high-dose chemotherapy.

We present the first case in the literature of vascular ectasia of the whole intestine as a cause of recurrent and profuse gastrointestinal bleeding in a patient with relapsing Hodgkin's disease. The 17-year-old patient experienced early relapse of his Hodgkin's disease after first-line chemotherapy. Salvage chemotherapy was followed by high-dose chemotherapy and autologous stem cell transplantation. Complete remission was achieved after another relapse by means of a second transplant. The patient presented with profuse gastrointestinal bleeding 5 months later, however. Gastric antral vascular ectasia following hematopoietic stem cell transplantation was diagnosed by endoscopy, with histological confirmation. Similar lesions were found in the duodenum, the ileum, and throughout the entire colon. In conclusion, vascular ectasia of the whole intestine should be considered as cause of acute gastrointestinal bleeding after stem cell transplantation. Physicians should be aware of this complication because its onset is typically delayed. Importantly, this disease is not limited to patients who have undergone allogeneic transplantation, but can also occur after autologous transplantation.

Transient left ventricular dysfunction with apical ballooning (tako-tsubo cardiomyopathy) in Germany.

AIMS: A peculiar type of an acute coronary syndrome is characterised by acute onset of chest pain, STsegment changes, elevated troponin I levels and a transient balloon-like apical left ventricular dysfunction, but without significant coronary artery disease. We sought to assess this syndrome in German patients. METHODS AND RESULTS: A total of 22 females and 1 male with acute transient left ventricular dysfunction were identified during an interval of 2 years and were investigated clinically and angiographically. All patients presented without obstructive coronary artery disease. In 16 patients (70%) ST-segment elevations were observed mimicking acute myocardial infarction, whereas the remaining patients (30%) revealed only negative T waves. Deep negative Twaves were characteristically seen during the course of recovery in all patients. Elevated troponin I levels>2.0 microg/l (upper level of normal) were measured in all patients (mean 18+/-26.5 microg/l, range from 2.2-135.7 microg/l). Creatine kinase rose up to a mean of 282+/-236 IU/l (upper level of normal 180 U/l). Emotional or physical stress situations associated with the onset of the symptoms were observed in 16 patients (70%). Other suspected trigger factors were gastrointestinal infection and in one case a surgical intervention. In four patients a trigger factor could not be identified. Left ventriculography showed an ejection fraction of 53+/-15%. After an interval of 7+/-2 days after the first angiogram, ejection fraction had increased from 48+/-11% to 64+/-11% in eight controlled patients by repeated ventriculography. Coronary spasm with a lumen reduction>75% could be provoked using acetylcholine in 10 of 17 tested patients (59%) with reproduction of the symptoms. Within 14 days the LV dysfunction returned to normal in all patients. The ECG abnormalities disappeared completely as early as 3 months (74%) and were not seen in any patient after 6 months. CONCLUSION: Tako-tsubo cardiomyopathy is not exclusively a Japanese or Northern American phenomenon. Despite increased patient reports the exact underlying cause and pathophysiology of this syndrome remain unclear. However, despite the initial dramatic presentation of this disease the prognosis is good.

Cell-cell contact mediated signalling - no fear of contact.

Cancer research with sole focus on the cancer cell and possibly growth factors cannot faithfully reproduce the environmental interaction, such as adhesion of tumor cells to e.g. stromal cells, which may determine the response of these tumors to therapy. Methodologically cell adhesion studies are often difficult since complete but careful detachment is the prerequisite for most signal transduction assays. We describe for the first time an alternative method for the co-incubation of multiple myeloma cells on long term primary bone marrow stromal cultures using the bone marrow stromal cell line HS-5. The methods are precisely described, advantages and disadvantages are discussed, and troubleshooting advises are given.

[Enlarged lymph nodes--rapid diagnosis of infectious and neoplastic causes]. / Entscheidungshilfe bei vergrösserten Lymphknoten. Aggressiv abklären oder ruhig abwarten?

Although lymphadenopathy is usually an expression of a harmless, self-limiting immune reaction, it may nevertheless also signify the presence of a malignant tumor or relevant infectious disease--in particular when the swelling is sizeable, rapidly progressive, and associated symptoms are present. If, however, unfavorable criteria are definitely absent (Table 1), a wait-and-see policy with re-evaluation in three to four weeks may initially be adopted.

Tissue-specific and ubiquitous basic helix-loop-helix transcription factors in human placental trophoblasts.

Tissue-specific class B basic helix-loop-helix (bHLH) transcription factors, dimerising with ubiquitously produced class A bHLH proteins, play a major role in murine trophoblast development. Here, we investigated expression patterns of class A and B bHLH factors in the human placenta and different trophoblast culture systems. Semi-quantitative RT-PCR and RNase protection assay revealed expression of the tissue-restricted factors Hash-2, I-mfa and Stra13 in placentae of early and late pregnancy, in purified villous trophoblasts as well as in invasive trophoblasts isolated from first trimester villous explant cultures. Accordingly, RNA in situ hybridisation localised Hash-2, I-mfa and Stra13 to the trophoblast epithelium, cell columns and extravillous trophoblasts invading maternal decidua. Villous stromal cells in situ and cultivated placental fibroblasts also produced I-mfa and Stra13 but failed to express Hash-2. The widely expressed class A proteins, E12/E47 were absent from all placental cell types while ITF-2 was restricted to placental stromal cells of early and late gestation. In contrast, HEB was identified in all trophoblast cell types using RT-PCR, Western blotting and immunohistochemistry. The negative HLH-regulators Id-1 and Id-2 lacking the DNA-binding domain, were detected in villous stromal cells and different cytotrophoblast subtypes but were absent from the syncytium. The data suggest that a complex interplay of activators (Hash-2, HEB) and repressors (Stra13, I-mfa) could be involved in extravillous trophoblast differentiation whereas downregulation of Id proteins could play a role in syncytialisation.

Evaluation of aortic stenosis by cardiovascular magnetic resonance imaging: comparison with established routine clinical techniques.

OBJECTIVE: To evaluate whether direct planimetry of aortic valve area (AVA) by cardiac magnetic resonance (CMR) imaging is a reliable tool for determining the severity of aortic stenosis compared with transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE), and cardiac catheterisation. METHODS: 44 symptomatic patients with severe aortic stenosis were studied. By cardiac catheterisation AVA was calculated by the Gorlin equation. AVA was measured with CMR from steady state free precession (true fast imaging with steady state precession) by planimetry. AVA was also determined from TOE images by planimetry and from TTE images by the continuity equation. RESULTS: Bland-Altman analysis evaluating intraobserver and interobserver variability showed a very small bias for both (-0.016 and 0.019, respectively; n = 20). Bias and limits of agreement between CMR and TTE were 0.05 (-0.35, 0.44) cm2 (n = 37), between CMR and TOE 0.02 (-0.39, 0.42) cm2 (n = 32), and between CMR and cardiac catheterisation 0.09 (-0.30, 0.47) cm2 (n = 36). The sensitivity and specificity of CMR to detect AVA < or = 0.80 cm2 measured by cardiac catheterisation was 78% and 89%, of TOE 70% and 70%, and of TTE 74% and 67%, respectively. CONCLUSION: CMR planimetry is highly reliable and reproducible. Further, CMR planimetry had the best sensitivity and specificity of all non-invasive methods for detecting severe aortic stenosis in comparison with cardiac catheterisation. Therefore, CMR planimetry of AVA with steady state free precession is a new powerful diagnostic tool, particularly for patients with uncertain or discrepant findings by other modalities.

Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.

Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.

Learning to discriminate simple sinusoidal gratings is task specific.

Learning transfer effects of a modified spatial frequency discrimination task with simple sinusoidal gratings on various untrained test tasks, testing performance in relative position, local width and global size discrimination, have been investigated. Six subjects were exposed to grating stimuli of varying spatial frequency and size but constant relative position while they had to respond only to spatial frequency. In the course of 7 consecutive days all subjects showed significant reduction of spatial frequency discrimination thresholds. Comparison of discrimination thresholds for the untrained test tasks, taken before and after the learning epoch, reveals complete learning transfer to spatial frequency discrimination with gratings of constant size and variable relative position, but complete lack of transfer when grating spatial frequency is shifted about one octave lower. Further, there is improvement of relative position discrimination and width discrimination of single luminance bars, which is not very specific for the learnt spatial frequency. Although size variation was part of the learning procedure, discrimination of global stimulus size did not improve. Generally, the observed scheme of learning transfer reveals that there is learning only for stimulus attributes that are behaviorally relevant in the learning task. The differential scheme of improvement and code usage in the test tasks strongly indicates involvement of higher stages capable of independent access to different coding domains, as well as attentionally guided attribute selection and suppression. Supported by other recent findings, it is suggested that discrimination learning can be understood as a higher level process of gradual refinement of code selection out of a rich code base provided by lower level stages.

Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis.

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.

Learning a grating discrimination task broadens human spatial frequency tuning.

The effect of spatial frequency discrimination learning on spatial frequency detection tuning curves, obtained by a summation to threshold paradigm, has been investigated. Three human observers were exposed to a grating discrimination task for longer than two weeks, and their detection thresholds for compound Gabor gratings were measured before and after this time interval. Discrimination thresholds decreased continuously and substantially during the course of learning, while the spatial frequency detection tuning curves show significant broadening in the posttest. Calculating the discrimination resolution of an ensemble of sensory coding units shows that larger bandwidths lead to better spatial frequency discrimination performance if pattern discrimination rests on multidimensional comparison or one-dimensional scaling of the spatial frequency parameter. Further, it is shown that a multiple-mechanism nonlinear pooling model is capable of explaining the results if plasticity of coding unit bandwidth or adaptive weights of the coding unit responses at the stage of response integration is assumed. The alternative sources of plasticity and the consequences of the findings for psychophysical modeling are discussed.

STAT3 is constitutively active in some patients with Polycythemia rubra vera.

OBJECTIVE: Polycythemia vera is a clonal stem cell disorder characterized by hyperproliferation of the erythroid, myeloid, and megakaryocytic lineages. While it has been shown that progenitor cells of P. vera patients are hypersensitive to several growth factors including erythropoietin, insulin-like growth factor-1, thrombopoietin, interleukin-3, and granulocyte/monocyte colony-stimulating factor, the molecular pathogenesis of this disease remains unknown. Growth factor hypersensitivity could be mediated by changes in signal transduction pathways. We therefore investigated a common downstream effector of cytokines, the signal transducers and activators of transcription (STATs). A constitutive activation of STAT factors could explain the increased proliferation of P. vera cells even in the absence of growth factor stimulation. METHODS: Peripheral granulocytes from patients with P. vera and from healthy volunteers were assayed for STAT1, 3, and 5 DNA binding by electrophoretic mobility shift assay. RESULTS: Four of 14 P. vera patients analyzed showed constitutive STAT3 DNA binding in unstimulated peripheral granulocytes, while none of the 17 healthy volunteers tested did. None of the subjects showed constitutive STAT1 or STAT5 activity. Western blotting demonstrated that, in the three patients, STAT3 is constitutively phosphorylated on Tyr 705, whereas it is unphosphorylated in the other patients and in controls. Interestingly, constitutive STAT3 activity did not correlate with the duration of disease or the treatment regimen. It was observed in a recently diagnosed patient and in two patients treated only with phlebotomy. CONCLUSION: Our data suggest that constitutive phosphorylation and activation of STAT3 is not a secondary event induced by mutagenizing agents or by prolonged hyperproliferation of hematopoietic cells, but rather represents a primary molecular aberration. Constitutively active STAT3 may contribute to the growth factor hypersensitivity of P. vera cells.