Aplastic crisis as primary manifestation of systemic lupus erythematosus

Aplastic crisis is an unusual feature of systemic lupus erythematosus (SLE). We report the case of a 54-year-old woman presenting with both (extravascular) Coombs-positive hemolytic anemia and laboratory findings of bone marrow hyporegeneration with concomitant severe neutropenia. A bone marrow biopsy confirmed aplastic crisis. Diagnostic work-up revealed soaring titers of autoantibodies (anti-nuclear, anti-double-stranded DNA, anti-cardiolipin-IgM, and anti-β2-glykoprotein-IgM antibodies), indicating a connective tissue disease as the most plausible reason for bone marrow insufficiency. As the criteria for SLE were fulfilled, we initiated an immunosuppressive therapy by steroids, which led to a rapid complete hematologic and clinical remission in our patient. In this case, we could report on one of the rare cases of SLE-induced aplastic crisis showing that this condition can be entirely reversed by immunosuppressive treatment and that SLE-induced aplastic crisis yields a good prognosis. In conclusion, in a case of aplastic crisis, physicians should be aware that SLE can be a rare cause that is accessible to specific treatment.     

Diffusion-weighted MR-imaging for the detection of pulmonary nodules at 1.5 Tesla: intraindividual comparison with multidetector computed tomography

Introduction: To investigate the feasibility of diffusion‐weighted imaging (DWI) MRI for detecting pulmonary nodules at 1.5 Tesla in comparison with standard multidetector computed tomography (MDCT). Methods: Twenty patients with disseminated cancer disease in which MDCT had assured the presence of at least one pulmonary nodule were examined using a respiratory‐gated DWI MR‐sequence. Grey scale inverted source images and coronal maximum intensity projection (MIP) images were consensually analysed by two experienced radiologists. Size and location of any nodule detected were assessed. Additionally, the readers evaluated each hemithorax for the presence of at least one nodule and applied a four‐point conspicuity scale (1‐hemithorax definitely affected; 4‐hemithorax definitely not affected). MDCT data served as reference. Results: At MDCT, a total of 71 pulmonary noduIes was found (size 3–5 mm, n = 16; 6–9 mm, n = 22; ≥10 mm, n = 33). For the DWI MR‐sequence, a sensitivity of 86.4% was calculated for nodules ranging 6–9 mm and 97% for nodules ≥10 mm. In contrast, only 43.8% of lesions ≤5 mm was detected. The separate analysis of each hemithorax for the presence of at least one pulmonary nodule revealed a specificity rate, PPV and NPV of DWI‐MR of 92.3%, 96% and 80%, respectively. Conclusions: The presented study is the first to confirm the diagnostic potential of DWI‐MR in the detection of solid lung nodules. This technique allows for the detection of nodules ≥6 mm with reasonably high sensitivity rates (>86%). The observation of false positive findings decreases the accuracy of this approach compared with MDCT.     

The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells <Emphasis Type="Italic">in vitro</Emphasis>

Background  

Chondrosarcoma is virtually resistant to chemotherapy and radiation therapy. Survivin, the smallest member of the inhibitor of apoptosis protein family, is a critical factor for tumor progression and resistance to conventional therapeutic approaches in a wide range of malignancies. However, the role of survivin in chondrosarcoma has not been well studied. We examined the importance of survivin gene expression in chondrosarcoma and analysed its influences on proliferation, apoptosis and resistance to chemotherapy in vitro.     

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane protein- tyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.     

Ferredoxin:NADPH oxidoreductase is recruited to thylakoids by binding to a polyproline type II helix in a pH-dependent manner

Ferredoxin:NADPH oxidoreductase (FNR) is a key enzyme of photosynthetic electron transport required for generation of reduction equivalents. Recently, two proteins were found to be involved in membrane-anchoring of FNR by specific interaction via a conserved Ser/Pro-rich motif: Tic62 and Trol. Our crystallographic study reveals that the FNR-binding motif, which forms a polyproline type II helix, induces self-assembly of two FNR monomers into a back-to-back dimer. Because binding occurs opposite to the FNR active sites, its activity is not affected by the interaction. Surface plasmon resonance analyses disclose a high affinity of FNR to the binding motif, which is strongly increased under acidic conditions. The pH of the chloroplast stroma changes dependent on the light conditions from neutral to slightly acidic in complete darkness or to alkaline at saturating light conditions. Recruiting of FNR to the thylakoids could therefore represent a regulatory mechanism to adapt FNR availability/activity to photosynthetic electron flow.     

Modulation of the Ca conductance of nicotinic acetylcholine receptors by Lypd6

The agonist binding sensitivity and desensitization kinetics of nicotinic acetylcholine receptors (nAChRs) can be modulated by snake venom neurotoxins and related endogenous small proteins of the uPAR-Ly6 family. Here we identify Lypd6, a distantly related member of the u-PAR/Ly-6 family expressed in neurons as a novel modulator of nAChRs. Lypd6 overexpressed in trigeminal ganglia neurons selectively enhanced the Ca²⁺-component of nicotine-evoked currents through nAChRs, as evidenced by comparative whole-cell patch clamp recordings and Ca²⁺-imaging in wildtype and transgenic mice overexpressing Lypd6. In contrast, a knockdown of Lypd6 expression using siRNAs selectively reduced nicotine-evoked Ca²⁺-currents. Pharmacological experiments revealed that the nAChRs involved in this process are heteromers. Transgenic mice displayed behaviors that were indicative of an enhanced cholinergic tone, such as a higher locomotor arousal, increased prepulse-inhibition and hypoalgesia. These mice overexpressing Lypd6 mice were also more sensitive to the analgesic effects of nicotine. Transgenic mice expressing siRNAs directed against Lypd6 were unable to procreate, thus indicating a vital role for this protein. Taken together, Lypd6 seems to constitute a novel modulator of nAChRs that affects receptor function by selectively increasing Ca²⁺-influx through this ion channels.     

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice

Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.     

Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population

BACKGROUND: The 7-item Generalized Anxiety Disorder Scale (GAD-7) is a practical self-report anxiety questionnaire that proved valid in primary care. However, the GAD-7 was not yet validated in the general population and thus far, normative data are not available. OBJECTIVES: To investigate reliability, construct validity, and factorial validity of the GAD-7 in the general population and to generate normative data. RESEARCH DESIGN: Nationally representative face-to-face household survey conducted in Germany between May 5 and June 8, 2006. SUBJECTS: Five thousand thirty subjects (53.6% female) with a mean age (SD) of 48.4 (18.0) years. MEASURES: The survey questionnaire included the GAD-7, the 2-item depression module from the Patient Health Questionnaire (PHQ-2), the Rosenberg Self-Esteem Scale, and demographic characteristics. RESULTS: Confirmatory factor analyses substantiated the 1-dimensional structure of the GAD-7 and its factorial invariance for gender and age. Internal consistency was identical across all subgroups (alpha = 0.89). Intercorrelations with the PHQ-2 and the Rosenberg Self-Esteem Scale were r = 0.64 (P < 0.001) and r = -0.43 (P < 0.001), respectively. As expected, women had significantly higher mean (SD) GAD-7 anxiety scores compared with men [3.2 (3.5) vs. 2.7 (3.2); P < 0.001]. Normative data for the GAD-7 were generated for both genders and different age levels. Approximately 5% of subjects had GAD-7 scores of 10 or greater, and 1% had GAD-7 scores of 15 or greater. CONCLUSIONS: Evidence supports reliability and validity of the GAD-7 as a measure of anxiety in the general population. The normative data provided in this study can be used to compare a subject's GAD-7 score with those determined from a general population reference group.     

Increased shear rate resistance and fastest kinetics of erythrocyte aggregation in diabetes measured with ultrasound

OBJECTIVE—To measure with ultrasound the increased erythrocyte aggregation (EA) kinetics and adhesion energy between erythrocytes in patients with type 2 diabetes and poor metabolic control.RESEARCH DESIGN AND METHODS—Blood samples were analyzed in a Couette rheometer at 32 MHz following shear rate reductions from 500 s⁻¹ to residual shears of 0 (stasis), 1, 2, 10, 50, 100, and 200 s⁻¹. The increase in EA was determined with the integrated backscatter coefficient as a function of time and shear rate.RESULTS—The time required to form aggregates was shorter in diabetic patients at shear rates below 200 s⁻¹ (P < 0.01). Erythrocytes formed larger aggregates in diabetic patients than in control subjects (P < 0.05 at 2 to 100 s⁻¹).CONCLUSIONS—Ultrasound can potentially noninvasively demonstrate, in vivo and in situ, the impact of local abnormal EA on arteriovenous flow disorders in diabetes.Flow disorders in diabetes often lead to severe outcomes in various organs and tissues; abnormal rheology of erythrocytes (RBC) likely impairs macro- and microcirculatory blood flow, tissue oxygenation, and vascular tone regulation in affected patients (1–3). Diabetic retinopathy is attributed to microvascular flow disorders and enhanced RBC aggregation (4). Erythrocyte aggregation (EA) and plasma viscosity are also predictive of diabetic foot syndrome deterioration (5). EA is a reversible phenomenon responsible for increased blood viscosity at low shear rates. RBC hyperaggregation can also promote flow stasis and thrombosis in macrocirculation. This study proposes an ultrasound method that has the potential to noninvasively detect early rheological disorders in situ in blood vessels. The method is based on backscattering of ultrasound by blood; it measures the extent of EA and its shear rate dependency.