Contrast enhanced CT-scans are not comparable to non-enhanced scans in emphysema quantification.

Systemic, interventional and surgical treatments have gone new ways in treatment of emphysema. For longitudinal therapy monitoring and as end-points for clinical trials, quantification of the disease is necessary. Sensitive, easy to measure, as well as stable and reproducible parameters have to be characterized. One parameter that might affect emphysema quantification is IV contrast enhancement, which might also be indicated. Whether or not the contrast enhanced scan is also suited for emphysema quantification or an additional scan is necessary, a retrospective analysis of 12 adult patients undergoing clinically indicated both, a non-enhanced and enhanced thin section MSCT within a week (median 0 days, range 0-4 days) was done. The in-house YACTA software was used for automatic quantification of lung and emphysema volume, emphysema index, mean lung density, and 5th, 10th, 15th percentile. After IV contrast administration, the median CT derived lung volume decreased mild by 1.1%, while median emphysema volume decreased by relevant 11%. This results in a decrease of median emphysema index by 9%. The median lung density (15th percentile) increased after contrast application by 18 HU (9 HU). CT quantification delivers emphysema values that are clearly affected by IV contrast application. The detected changes after contrast application show the results of higher density in the lung parenchyma. Therefore the amount of quantified emphysema is reduced and the lung density increased after contrast enhancement. In longitudinal analyses, non-enhanced scans should be the reference, while enhanced scans cannot be used.

Fully automatic quantitative assessment of emphysema in computed tomography: comparison with pulmonary function testing and normal values.

Characterisation and quantification of emphysema are necessary for planning of local treatment and monitoring. Sensitive, easy to measure, and stable parameters have to be established and their relation to the well-known pulmonary function testing (PFT) has to be investigated. A retrospective analysis of 221 nonenhanced thin-section MDCT with a corresponding PFT was carried out, with a subgroup analysis in 102 COPD stage III+IV, 44 COPD stage 0, and 33 investigations into interstitial lung disease (ILD). The in-house YACTA software was used for automatic quantification of lung and emphysema volume [l], emphysema index, mean lung density (MLD [HU]) and 15(th) percentile [HU]. CT-derived lung volume is significantly smaller in ILD (3.8) and larger in COPD (7.2) than in controls (5.9, p < 0.0001). Emphysema volume and index are significantly higher in COPD than in controls (3.2 vs. 0.5, p < 0.0001, 45% vs. 8%, p < 0.0001). MLD and 15(th) percentile are significantly smaller in COPD (-877/-985, p < 0.0001) and significantly higher in ILD (-777, p < 0.0006/-914, p < 0.0001) than in controls (-829/-935). A relevant amount of COPD patients apparently do not suffer from emphysema, while controls who do not fulfil PFT criteria for COPD also demonstrate CT features of emphysema. Automatic quantification of thin-section CT delivers convincing parameters and ranges that are able to differentiate among emphysema, control and ILD. An emphysema index of lower 20%, MLD higher than -850, and 15(th) percentile lower than -950 might be regarded as normal (thin-section, nonenhanced, B40, YACTA). These ranges might be helpful in the judgement of individual measures.

Assessment of 3D-TOF-MRA at 3.0 Tesla in the characterization of the angioarchitecture of cerebral arteriovenous malformations: a preliminary study.

BACKGROUND: The characterization of brain arteriovenous malformation (AVM) angioarchitecture remains rewarding in planning and predicting therapy. The increased signal-to-noise ratio at higher field strength has been found advantageous in vascular brain pathologies. PURPOSE: To evaluate whether 3.0T time-of-flight (TOF) magnetic resonance angiography (MRA) is superior to 1.5T TOF-MRA for the characterization of cerebral AVMs. MATERIAL AND METHODS: Fifteen patients with AVM underwent TOF-MRA at 3.0T and 1.5T and catheter angiography (DSA), which was used as the gold standard. Blinded readers scored image quality on a four-point scale, nidus size, and number of feeding arteries and draining veins. RESULTS: Image quality of TOF-MRA at 3.0T was superior to 1.5T but still inferior to DSA. Evaluation of nidus size was equally good at 3.0T and 1.5T for all AVMs. In small AVMs, however, there was a tendency of size overestimation at 3.0T. MRA at 3.0T had increased detection rates for feeding arteries (+21%) and superficial (+13%) and deep draining veins (+33%) over 1.5T MRA. CONCLUSION: 3.0T TOF-MRA offers superior characterization of AVM angioarchitecture compared with 1.5T TOF-MRA. The image quality of MRA at both 3.0 and 1.5T is still far from equal to DSA, which remains the gold standard for characterization of AVM.

Bleeding complications after endovascular therapy of cerebral arteriovenous malformations.

BACKGROUND AND PURPOSE: Intracerebral hemorrhages after embolization of arteriovenous malformations (AVMs) are the most dreaded complications of this well-established therapy. Apart from the known risk factors, our center noticed a high incidence of complications during postinterventional monitoring in medical intensive care units (ICUs) and stroke units. MATERIALS AND METHODS: We report 125 consecutive interventions performed on 66 patients by using flow-dependent microcatheters and n-butyl cyanoacrylate as the embolic agent. Postinterventional intensive care monitoring was performed in an interdisciplinary operative ICU, a stroke unit, or a medical ICU. Patients were compared with regard to bleeding complications, AVM morphology, embolization result, postinterventional monitoring, and demographic factors. RESULTS: Intracerebral hemorrhages occurred in 7 patients. Significant differences in outcome were found between 66 patients monitored in the interdisciplinary operative ICU from medical ICU or stroke unit. This was also true when adjusted for age and extent of AVM reduction by using exact logistic regression. A partial AVM reduction of >60% was a considerable risk factor for hemorrhage (odds ratio [OR] = 18.8; 95% confidence interval [CI] [1.341, not available]. Age was also an essential risk factor. An age difference of 10 years leads to an OR of 2.545 (95% CI [1.56, 7.35]). DISCUSSION: A considerable AVM reduction in one session appears to increase the risk of hemorrhage technically. This suggests a distribution of the interventions in many partial steps.

Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice.

Environmental and genetic factors that contribute to the pathogenesis of Parkinson's disease are discussed. Mutations in the alpha-synuclein (alphaSYN ) gene are associated with rare cases of autosomal-dominant Parkinson's disease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]alphaSYN under the control of a neurone-specific Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed somal and neuritic accumulation of transgenic [A30P]alphaSYN in TH-positive neurones in the substantia nigra. However, there was no difference in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum between these transgenic mice and non-transgenic littermates. To investigate whether forced expression of [A30P]alphaSYN increased the sensitivity to putative environmental factors we subjected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. The MPTP-induced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]alphaSYN transgenic mouse lines compared with wild-type controls. These results suggest that mutations and forced expression of alphaSYN are not likely to increase the susceptibility to environmental toxins in vivo.

Tumor necrosis factor alpha induces a metalloprotease-disintegrin, ADAM8 (CD 156): implications for neuron-glia interactions during neurodegeneration.

ADAM proteases, defined by extracellular disintegrin and metalloprotease domains, are involved in protein processing and cell-cell interactions. Using wobbler (WR) mutant mice, we investigated the role of ADAMs in neurodegeneration and reactive glia activation in the CNS. We found that ADAM8 (CD 156), a suspected leukocyte adhesion molecule, is expressed in the CNS and highly induced in affected CNS areas of WR mice, in brainstem and spinal cord. ADAM8 mRNA and protein are found at low levels throughout the normal mouse CNS, in neurons and oligodendrocytes. In the WR CNS regions in which neurodegeneration occurs, ADAM8 is induced in neurons, reactive astrocytes, and activated microglia. Similarly, the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is upregulated and shows the same cellular distribution. In primary astrocytes from wild-type and WR mice, in primary cerebellar neurons, and in mouse motoneuron-like NSC19 cells, ADAM8 expression was induced up to 15-fold by mouse TNF-alpha, in a dose-dependent manner. In both cell types, ADAM8 was also induced by human TNF-alpha, indicating that TNF receptor type I (p55) is involved. Induction of ADAM8 mRNA was suppressed by treatment with an interferon-regulating factor 1 (IRF-1) antisense oligonucleotide. We conclude that IRF-1-mediated induction of ADAM8 by TNF-alpha is a signaling pathway relevant for neurodegenerative disorders with glia activation, proposing a role for ADAM8 in cell adhesion during neurodegeneration.

Elevated expression of membrane type 1 metalloproteinase (MT1-MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system.

Reactive astrocytes occurring in response to neurodegeneration are thought to play an important role in neuronal regeneration by upregulating the expression of extracellular matrix (ECM) components as well as the ECM degrading metalloproteinases (MMPs). We examined the mRNA levels and cellular distribution of membrane type matrix metalloproteinase 1 (MT1-MMP) and tissue inhibitors 1-4 of MMPs (TIMPs) in brain stem and spinal cord of wobbler (WR) mutant mice affected by progressive neurodegeneration and astrogliosis. MT1-MMP, TIMP-1 and TIMP-3 mRNA levels were elevated, whereas TIMP-2 and TIMP-4 expression was not affected. MT1-MMP was expressed in reactive astrocytes of WR. In primary astrocyte cultures, MT1-MMP mRNA was upregulated by exogeneous tumor necrosis factor alpha. Increased plasma membrane and secreted MMP activities were found in primary WR astrocytes.

Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD). Here we show that a peptide caspase inhibitor, N-benzyloxy-carbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.

Spatiotemporal progression of neurodegeneration and glia activation in the wobbler neuropathy of the mouse.

The wobbler mouse (phenotype WR; genotype wr/wr) has been investigated as a model for neurodegenerative diseases like SMA and ALS. A new diagnostic marker based on a polymorphism in the closely linked chaperonine gene Cct4 enabled us to diagnose the allelic status at the wr locus within the original background strain C57BL/6. Using this marker, we investigated the spatiotemporal progression of neuropathology in WR mice from postnatal day (d.p.n.) 10 to 60. Neurodegeneration starts at 13 d.p.n. in the thalamus (N. ventralis), in deep cerebellar nuclei, brain stem (N. vestibularis) and spinal cord interneurons. The motor nuclei of spinal nerves and motoneurons degenerate from 15 d.p.n. onward. Reactive astrocytes are observed around 17 d.p.n. in the white and grey matter of the spinal cord. Microgliosis occurs only from 23 d.p.n. onward. Our data demonstrate that in the WR disease, neurodegeneration in thalamus, cerebellum, and brain stem precedes motoneuron degeneration, astrogliosis and microgliosis.

A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the loss of alpha-motoneurons in the spinal cord followed by atrophy of skeletal muscles. SMA-determining candidate genes, SMN1 and SMN2, have been identified on human chromosome 5q. The corresponding SMN protein is expressed ubiquitously. It is coded by seven exons and contains conspicuous proline-rich motifs in its COOH-terminal third (exons 4, 5, and 6). Such motifs are known to bind to profilins (PFNs), small proteins engaged in the control of actin dynamics. We tested whether profilins interact with SMN via its polyproline stretches. Using the yeast two-hybrid system we show that profilins bind to SMN and that this binding depends on its proline-rich motifs. These results were confirmed by coimmunoprecipitation and by in vitro binding studies. Two PFN isoforms, I and II, are known, of which II is characteristic for central nervous system tissue. We show by in situ hybridization that both PFNs are highly expressed in mouse spinal cord and that PFN II is expressed predominantly in neurons. In motoneurons, the primary target of neurodegeneration in SMA, profilins are highly concentrated and colocalize with SMN in the cytoplasm of the cell body and in nuclear gems. Likewise, SMN and PFN I colocalize in gems of HeLa cells. Although SMN interacts with both profilin isoforms, binding of PFN II was stronger than of PFN I in all assays employed. Because the SMN genes are expressed ubiquitously, our findings suggest that the interaction of PFN II with SMN may be involved in neuron-specific effects of SMN mutations.

[The prone position in ARDS. A successful therapeutic strategy]. / Bauchlagerung im ARDS. Ein erfolgversprechender therapeutischer Ansatz.

As early as 1974, Brian advocated the prone position for ventilated patients. He suggested that this position might enhance ventilation of the dorsal parts of the lungs, thereby improving oxygenation. These considerations have been confirmed by several experimental and clinical studies. Better secretion removal, decreased intrapulmonary shunting, and an increased FRC are thought to be responsible for the observed improvement of oxygenation. However, the prone position never became very popular in the clinical treatment of the adult respiratory distress syndrome (ARDS). Routine performance of thoracic CT scans in ARDS patients demonstrated preferential distribution of pathological densities in the dependent lung areas. The prone position therefore could possibly benefit these patients, as shown by two recent studies. The aim of our study was to evaluate the influence of repeatedly turning the patient to the prone position on gas exchange and thoracic CT findings in multiple-trauma patients. METHODS. Seven ventilated intensive care patients with severe ARDS (Murray Score > 2.5, Quotient > 0.7, mean airway pressure > 18 cm H2O, thoracic CT scan showing dorsal atelectases) were included in the study. Patients were turned from the supine to the prone position at 12-h intervals using an air-cushion bed (Mediscus, Austria). Redistribution of dystelectatic or atelectatic dependent lung areas was verified by means of repeated thoracic CT scans (Figs. 1, 8). RESULTS. The patients were intermittently turned for 6.5 +/- 1.1 days. The course of gas exchange is shown in Figs. 2 and 3. Initially, improvement of the respiratory quotient could only be achieved during prone positioning, from the 2nd day in the supine position as well. Intrapulmonary shunting showed a similar trend (Figs. 4 and 5). No significant changes in cardiovascular parameters could be observed. Control thoracic CT scans showed uniform reduction of atelectases in dependent lung areas (Figs. 1 and 8). The inspiratory fraction of oxygen could be reduced significantly as of the 2nd day (Fig. 7). Constant levels of positive end-expiratory pressure and tidal volume were associated with decreasing mean and plateau airway pressures (Fig. 6). DISCUSSION. Repeatedly turning the patient to the prone position produced long-lasting improvement of arterial oxygenation, which persists up to the end of the weaning process. This is in good accordance with other studies, however, this is the first study to report an observation period of more than 6 days of repeatedly turning the patient. These positive effects on gas exchange can be attributed to sudden improvement of the ventilation-perfusion ratio within the lung areas that become dependent after turning to the prone position. Due to reduced hydrostatic pressure and relative hyperventilation, previously collapsed alveoli are recruited in the lung areas that become non-dependent after turning to the prone position.