First sequence-confirmed case of infection with the new influenza A(H1N1) strain in Germany

Here, we report on the first sequence-confirmed case of infection with the new influenza A(H1N1) virus in Germany. Two direct contacts of the patient were laboratory-confirmed as cases and demonstrate a chain of direct human-to-human transmission

Seismic-scale petrophysical interpretation and gas-volume estimation from simultaneous impedance inversion

© 2017 by The Society of Exploration Geophysicists. Simultaneous impedance inversion was performed to obtain the seismic-scale P-and S-wave impedances as well as the bulk density volumes from seismic angle stacks at a siliciclastic turbidite offshore gas reservoir. To translate these variables into seismic-scale total porosity (φ), clay content, and water saturation (S w ), we used a deterministic rock-physics model established at the well. A crucial input into this model is the bulk modulus (K f ) of the brine/gas system. We need to link it to S w at the seismic scale. This link can be one of simple mixing laws, such as harmonic and arithmetic. Alternately, it can be derived at the well by using upscaled variables and ensuring that they obey the well-data-driven rock-physics model. These different K f -S w relations produce different interpretations for φ and S w thus allowing one to assess the variability in the estimates of the gas volume in place that is proportional to the product of φ and (1 - S w )

Ki-1 Large Cell Lymphoma with Regressing Lesions in a Child

An 8-year-old boy was seen with a cutaneous Ki-1 anaplastic, large cell lymphoma with multiple lesions. Some of the lesions showed spontaneous regression. During more than seven years of disease no systemic Involvement was observed, but recurrent, self-healing lesions did appear. Histopathologic examination of five lesions revealed a variety of findings, from an inflammatory infiltrate to a highly anaplastic pattern. The neoplastic cells expressed Ki-1 and leukocyte common antigens. Ultrastructurally, those cells showed ruffled indentations. The differential diagnosis includes microvillous malignant lymphoma. The patient has had a four-year follow-up without relapses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72895/1/j.1525-1470.1992.tb01226.x.pd

Optical Coherence Tomography in Parkinsonian Syndromes

BACKGROUND/OBJECTIVE: Parkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases. METHODS: This cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls. RESULTS: The mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%. CONCLUSION: Different parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial

Background: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment dur

Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) in the early stages of Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most common causes of dementia in the world. Patients with AD frequently complain of vision disturbances that do not manifest as changes in routine ophthalmological examination findings. The main causes of these disturbances are neuropathological changes in the visual cortex, although abnormalities in the retina and optic nerve cannot be excluded. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) tests are commonly used in ophthalmology to estimate bioelectrical function of the retina and optic nerve. The aim of this study was to determine whether retinal and optic nerve function, measured by PERG and PVEP tests, is changed in individuals in the early stages of AD with normal routine ophthalmological examination results. Standard PERG and PVEP tests were performed in 30 eyes of 30 patients with the early stages of AD. The results were compared to 30 eyes of 30 normal healthy controls. PERG and PVEP tests were recorded in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. Additionally, neural conduction was measured using retinocortical time (RCT)—the difference between P100-wave latency in PVEP and P50-wave implicit time in PERG. In PERG test, PVEP test, and RCT, statistically significant changes were detected. In PERG examination, increased implicit time of P50-wave (P < 0.03) and amplitudes reductions in P50- and N95-waves (P < 0.0001) were observed. In PVEP examination, increased latency of P100-wave (P < 0.0001) was found. A significant increase in RCT (P < 0.0001) was observed. The most prevalent features were amplitude reduction in N95-wave and increased latency of P100-wave which were seen in 56.7% (17/30) of the AD eyes. In patients with the early stages of AD and normal routine ophthalmological examination results, dysfunction of the retinal ganglion cells as well as of the optic nerve is present, as detected by PERG and PVEP tests. These dysfunctions, at least partially, explain the cause of visual disturbances observed in patients with the early stages of AD

The Metalloprotease Meprinβ Processes E-Cadherin and Weakens Intercellular Adhesion

BACKGROUND: Meprin (EC 3.4.24.18), an astacin-like metalloprotease, is expressed in the epithelium of the intestine and kidney tubules and has been related to cancer, but the mechanistic links are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used MDCK and Caco-2 cells stably transfected with meprin alpha and or meprin beta to establish models of renal and intestinal epithelial cells expressing this protease at physiological levels. In both models E-cadherin was cleaved, producing a cell-associated 97-kDa E-cadherin fragment, which was enhanced upon activation of the meprin zymogen and reduced in the presence of a meprin inhibitor. The cleavage site was localized in the extracellular domain adjacent to the plasma membrane. In vitro assays with purified components showed that the 97-kDa fragment was specifically generated by meprin beta, but not by ADAM-10 or MMP-7. Concomitantly with E-cadherin cleavage and degradation of the E-cadherin cytoplasmic tail, the plaque proteins beta-catenin and plakoglobin were processed by an intracellular protease, whereas alpha-catenin, which does not bind directly to E-cadherin, remained intact. Using confocal microscopy, we observed a partial colocalization of meprin beta and E-cadherin at lateral membranes of incompletely polarized cells at preconfluent or early confluent stages. Meprin beta-expressing cells displayed a reduced strength of cell-cell contacts and a significantly lower tendency to form multicellular aggregates. CONCLUSIONS/SIGNIFICANCE: By identifying E-cadherin as a substrate for meprin beta in a cellular context, this study reveals a novel biological role of this protease in epithelial cells. Our results suggest a crucial role for meprin beta in the control of adhesiveness via cleavage of E-cadherin with potential implications in a wide range of biological processes including epithelial barrier function and cancer progression

Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface

Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche

Altered Perceptual Sensitivity to Kinematic Invariants in Parkinson's Disease

Ample evidence exists for coupling between action and perception in neurologically healthy individuals, yet the precise nature of the internal representations shared between these domains remains unclear. One experimentally derived view is that the invariant properties and constraints characterizing movement generation are also manifested during motion perception. One prominent motor invariant is the “two-third power law,” describing the strong relation between the kinematics of motion and the geometrical features of the path followed by the hand during planar drawing movements. The two-thirds power law not only characterizes various movement generation tasks but also seems to constrain visual perception of motion. The present study aimed to assess whether motor invariants, such as the two thirds power law also constrain motion perception in patients with Parkinson's disease (PD). Patients with PD and age-matched controls were asked to observe the movement of a light spot rotating on an elliptical path and to modify its velocity until it appeared to move most uniformly. As in previous reports controls tended to choose those movements close to obeying the two-thirds power law as most uniform. Patients with PD displayed a more variable behavior, choosing on average, movements closer but not equal to a constant velocity. Our results thus demonstrate impairments in how the two-thirds power law constrains motion perception in patients with PD, where this relationship between velocity and curvature appears to be preserved but scaled down. Recent hypotheses on the role of the basal ganglia in motor timing may explain these irregularities. Alternatively, these impairments in perception of movement may reflect similar deficits in motor production

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis