The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis.

Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

Severity of local inflammation does not impact development of fibrosis in mouse models of intestinal fibrosis.

Intestinal fibrosis is thought to be a consequence of excessive tissue repair, and constitutes a common problem in patients with Crohn's disease (CD). While fibrosis seems to require inflammation as a prerequisite it is unclear whether the severity or persistence of inflammation influences the degree of fibrosis. Our aim was to investigate the role of sustained inflammation in fibrogenesis. For the initiation of fibrosis in vivo the models of Il10-/- spontaneous colitis, dextran sodium sulfate (DSS)-induced chronic colitis and heterotopic transplantation were used. In Il10-/- mice, we determined a positive correlation between expression of pro-inflammatory factors (Il1ß, Tnf, Ifnγ, Mcp1 and Il6). We also found a positive correlation between the expression of pro-fibrotic factors (Col3a1 Col1a1, Tgfß and αSma). In contrast, no significant correlation was determined between the expression of pro-inflammatory Tnf and pro-fibrotic αSma, Col1a1, Col3a1, collagen layer thickness and the hydroxyproline (HYP) content. Results from the DSS-induced chronic colitis model confirmed this finding. In the transplantation model for intestinal fibrosis a pronounced increase in Mcp1, inos and Il6 in Il10-/- as compared to WT grafts was observed, indicating more severe inflammation in Il10-/- grafts. However, the increase of collagen over time was virtually identical in both Il10-/- and WT grafts. Severity of inflammation during onset of fibrogenesis did not correlate with collagen deposition. Although inflammation might be a pre-requisite for the initiation of fibrosis our data suggest that it has a minor impact on the progression of fibrosis. Our results suggest that development of fibrosis and inflammation may be disconnected. This may be important for explaining the inefficacy of anti-inflammatory treatments agents in most cases of fibrotic inflammatory bowel diseases (IBD).

BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice.

In inflammatory bowel disease (IBD), inflammation is sustained by an exaggerated response of lymphocytes. This results from enhanced expression of anti-apoptotic B cell lymphoma (BCL-2) and BCL-XL associated with a diminished turnover. Azathioprine (AZA) directly targets BCL-2 family-mediated apoptosis. We investigated whether the BCL-2 family expression pattern could be used to predict treatment response to AZA and determined whether BCL-2 inhibitor A-1211212 effectively diminishes lymphocytes and ameliorates inflammation in a model of colitis. BCL-2 family expression pattern was determined by next-generation sequencing (NGS). BCL-2 inhibitor was administered orally to Il10-/- mice. Haematological analyses were performed with an ADVIA 2120 and changes in immune cells were investigated using quantitative polymerase chain reaction (qPCR) and fluorescence activated cell sorter (FACS). We determined similar expression levels of BCL-2 family members in patients with remission and patients refractory to treatment, showing that BCL-2 family expression can not predict AZA treatment response. Expression was not correlated with the modified Truelove and Witts activity index (MTWAI). BCL-2 inhibitor initiated cell death in T cells from patients refractory to AZA and reduced lymphocyte count in Il10-/- mice. FACS revealed diminished CD8+ T cells upon BCL-2 inhibitor in Il10-/- mice without influencing platelets. Tnf, Il1ß, IfnƔ and Mcp-1 were decreased upon BCL-2 inhibitor. A-1211212 positively altered the colonic mucosa and ameliorated inflammation in mice. Pro-apoptotic BCL-2 inhibitor A-1211212 diminishes lymphocytes and ameliorates colitis in Il10-/- mice without inducing thrombocytopenia. BCL-2 inhibition could be a new therapy option for patients refractory to AZA.

Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for intestinal fibrosis development.

Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger intestinal fibrosis. MyD88 is a key component of microbiota signalling but its influence on intestinal fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88-/-) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-ß1) expression was equal in MyD88+/+ and MyD88-/-, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88-/- recipients compared to MyD88+/+ recipients (0.2 ± 0.1 vs. 153.0 ± 23.1, respectively, p < 0.05), similarly recruitment of neutrophils was significantly reduced (16.3 ± 4.5 vs. 25.4 ± 3.1, respectively, p < 0.05). Development of intestinal fibrosis appears to be independent of MyD88 signalling indicating a minor role of bacterial wall compounds in the process which is in contrast to published concepts and theories. Development of fibrosis appears to be uncoupled from acute inflammation.

Neuroanatomical correlates of tube dependency and impaired oral intake after hemispheric stroke.

BACKGROUND AND PURPOSE: Acute stroke patients with severely impaired oral intake are at risk of malnutrition and dehydration. Rapid identification of these patients is necessary to establish early enteral tube feeding. Whether specific lesion location predicts early tube dependency was analysed, and the neural correlates of impaired oral intake after hemispheric ischaemic stroke were assessed. METHODS: Tube dependency and functional oral intake were evaluated with a standardized comprehensive swallowing assessment within the first 48 h after magnetic resonance imaging proven first-time acute supratentorial ischaemic stroke. Voxel-based lesion symptom mapping (VLSM) was performed to compare lesion location between tube-dependent patients versus patients without tube feeding and impaired versus unimpaired oral intake. RESULTS: Out of 119 included patients 43 (36%) had impaired oral intake and 12 (10%) were tube dependent. Both tube dependency and impaired oral intake were significantly associated with a higher National Institutes of Health Stroke Scale score and larger infarct volume and these patients had worse clinical outcome at discharge. Clinical characteristics did not differ between left and right hemispheric strokes. In the VLSM analysis, mildly impaired oral intake correlated with lesions of the Rolandic operculum, the insular cortex, the superior corona radiata and to a lesser extent of the putamen, the external capsule and the superior longitudinal fascicle. Tube dependency was significantly associated with affection of the anterior insular cortex. CONCLUSIONS: Mild impairment of oral intake correlates with damage to a widespread operculo-insular swallowing network. However, specific lesions of the anterior insula lead to severe impairment and tube dependency and clinicians might consider early enteral tube feeding in these patients.

Grey matter volumetric changes related to recovery from hand paresis after cortical sensorimotor stroke.

Preclinical studies using animal models have shown that grey matter plasticity in both perilesional and distant neural networks contributes to behavioural recovery of sensorimotor functions after ischaemic cortical stroke. Whether such morphological changes can be detected after human cortical stroke is not yet known, but this would be essential to better understand post-stroke brain architecture and its impact on recovery. Using serial behavioural and high-resolution magnetic resonance imaging (MRI) measurements, we tracked recovery of dexterous hand function in 28 patients with ischaemic stroke involving the primary sensorimotor cortices. We were able to classify three recovery subgroups (fast, slow, and poor) using response feature analysis of individual recovery curves. To detect areas with significant longitudinal grey matter volume (GMV) change, we performed tensor-based morphometry of MRI data acquired in the subacute phase, i.e. after the stage compromised by acute oedema and inflammation. We found significant GMV expansion in the perilesional premotor cortex, ipsilesional mediodorsal thalamus, and caudate nucleus, and GMV contraction in the contralesional cerebellum. According to an interaction model, patients with fast recovery had more perilesional than subcortical expansion, whereas the contrary was true for patients with impaired recovery. Also, there were significant voxel-wise correlations between motor performance and ipsilesional GMV contraction in the posterior parietal lobes and expansion in dorsolateral prefrontal cortex. In sum, perilesional GMV expansion is associated with successful recovery after cortical stroke, possibly reflecting the restructuring of local cortical networks. Distant changes within the prefrontal-striato-thalamic network are related to impaired recovery, probably indicating higher demands on cognitive control of motor behaviour.

[The new S2k AWMF guideline for the treatment of Bell's palsy in commented short form]. / Die neue S2k AWMF Leitlinie zur idiopathischen Fazialisparese in kommentierter Kurzform.

A new S2k AWMF guideline for the treatment of idiopathic facial palsy has been published. An accurate differential diagnosis is indispensable as 25-40% of all facial palsy cases are of non-idiopathic origin. It is explicitly recommended to treat patients with idiopathic facial palsy with steroids. Steroids favour a complete recovery, decrease the risk of synkinesis, autonomic sequelae and contractures. Adjuvant antiviral therapy cannot be recommended. On current data there is not sufficient evidence that the combination of steroids with antiviral drugs has a benefit for the patients. Even when not supported by randomized trials, adjuvant symptomatic therapy to protect the cornea and to avoid complications is recommended. There is no scientific evidence that physical therapy has any benefit but it should be taken into account because of psychological reasons. A benefit of acupuncture has not been proven. If eye closure remains incomplete as result of defective healing, one therapeutic option is lid loading of the upper eye lid. Moreover, in case of severe persistent palsy, several well-established microsurgical nerve and muscle plasty procedures are available.

Outcome of intravenous thrombolysis in stroke patients weighing over 100 kg.

BACKGROUND: Intravenous thrombolysis with alteplase for ischemic stroke is fixed at a maximal dose of 90 mg for safety reasons. Little is known about the clinical outcomes of stroke patients weighing >100 kg, who may benefit less from thrombolysis due to this dose limitation. METHODS: Prospective data on 1,479 consecutive stroke patients treated with intravenous alteplase in six Swiss stroke units were analyzed. Presenting characteristics and the frequency of favorable outcomes, defined as a modified Rankin scale (mRS) score of 0 or 1, a good outcome (mRS score 0-2), mortality and symptomatic intracranial hemorrhage (SICH) were compared between patients weighing >100 kg and those weighing ≤100 kg. RESULTS: Compared to their counterparts (n = 1,384, mean body weight 73 kg), patients weighing >100 kg (n = 95, mean body weight 108 kg) were younger (61 vs. 67 years, p < 0.001), were more frequently males (83 vs. 60%, p < 0.001) and more frequently suffered from diabetes mellitus (30 vs. 13%, p < 0.001). As compared with patients weighing ≤100 kg, patients weighing >100 kg had similar rates of favorable outcomes (45 vs. 48%, p = 0.656), good outcomes (58 vs. 64%, p = 0.270) and mortality (17 vs. 12%, p = 0.196), and SICH risk (1 vs. 5%, p = 0.182). After multivariable adjustment, body weight >100 kg was strongly associated with mortality (p = 0.007) and poor outcome (p = 0.007). CONCLUSION: Our data do not suggest a reduced likehood of favorable outcomes in patients weighing >100 kg treated with the current dose regimen. The association of body weight >100 kg with mortality and poor outcome, however, demands further large-scale studies to replicate our findings and to explore the underlying mechanisms.

Intravenous thrombolysis in patients with stroke attributable to small artery occlusion.

BACKGROUND: Intravenous thrombolysis (IVT) for stroke seems to be beneficial independent of the underlying etiology. Recent observations raised concern that IVT might cause harm in patients with strokes attributable to small artery occlusion (SAO). OBJECTIVE: The safety of IVT in SAO-patients is addressed in this study. METHODS: We used the Swiss IVT databank to compare outcome and complications of IVT-treated SAO-patients with IVT-treated patients with other etiologies (non-SAO-patients). Main outcome and complication measures were independence (modified Rankin scale 0.8). Fatal ICH occurred in 3.3% of the non-SAO-patients but none amongst SAO-patients. Ischaemic stroke within 3 months after IVT reoccurred in 1.5% of SAO-patients and in 2.3% of non-SAO-patients (P = 0.68). CONCLUSION: IVT-treated SAO-patients died less often and reached independence more often than IVT-treated non-SAO-patients. However, the variable 'SAO' was a dependent rather than an independent outcome predictor. The absence of an excess in ICH indicates that IVT seems not to be harmful in SAO-patients.

Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis.

This databank-based, multicenter study compared all stroke patients with IV tissue plasminogen activator aged > or = 80 years (n = 38) and those < 80 years old (n = 287). Three-month mortality was higher in older patients. Favorable outcome (modified Rankin scale < or = 1) and intracranial hemorrhage (asymptomatic/symptomatic/fatal) were similarly frequent in both groups. Logistic regression showed that stroke severity, time to thrombolysis, glucose level, and history of coronary heart disease independently predicted outcome, whereas age did not.

Left and right superior parietal lobule in tactile object discrimination.

Tactile object discrimination is one of the major manual skills of humans. While the exploring finger movements are not perceived explicitly, attention to the movement-evoked kinaesthetic information gates the tactile perception of object form. Using event-related functional magnetic resonance imaging in seven healthy subjects we found one area in the right superior parietal cortex, which was specifically activated by kinaesthetic attention during tactile object discrimination. Another area with similar location in the left hemisphere was related to the maintenance of tactile information for subsequent object discrimination. We conclude that kinaesthetic information is processed in the anterior portion of the superior parietal cortex (aSPL) with a right hemispheric predominance for discrimination and a left hemispheric predominance for information maintenance.

Hierarchical versus parallel processing in tactile object recognition: a behavioural-neuroanatomical study of aperceptive tactile agnosia.

The organization of the normal perceptual processing subserving tactile object recognition is poorly understood. While perceptual deficits associated with cases of tactile agnosia may pinpoint sites of critical interference with normal tactile information processing, the precise character of such deficits remains unclear. The aim of the present study was to explore the behavioural and neuroanatomical correlates of perceptual disturbances in two cases of unilateral aperceptive tactile agnosia. Perception of microgeometrical and macrogeometrical features was tested using an alternative forced choice paradigm. While both patients were impaired in the assessment of microgeometrical properties of objects (i.e. detecting subtle differences in grating profiles), one patient showed an additional deficit in the perception of macrogeometrical properties of objects (i.e. detecting differences in length of cuboids). The pattern of perceptual deficits for both patients suggested a severely compromised (if not totally lost) ability to recognize everyday objects. Perceptual performance improved when the patients had complementary tactile information (i.e. for intramodal comparison), despite a persistent inability to explicitly name the objects. That is, the patients were able to recognize objects, but only implicitly. Improved perceptual performance was also observed when complementary visual information was available (i.e. transmodal information transfer). In this case, the perceptual improvement was accompanied by a corresponding improvement in explicit object recognition. High resolution MRIs identified lesions in the postcentral gyrus in both patients, and additionally in the secondary somatosensory area (SII) and the posterior parietal cortex in the more severely affected patient. The results demonstrate that the underlying failure in tactile agnosia is mainly impaired perception of microgeometrical properties of objects due to a lesion of primary sensory cortex. The related neuroanatomical findings suggest a degradation of serial information processing within postcentral gyrus. In one case tactile agnosia was almost complete due to additionally impaired perception of macrogeometrical properties of objects, which correlated with the extension of lesion to the posterior parietal cortex. Importantly, the findings indicate traces of two distributed networks for tactile information processing and the associated parallel processing of complementary micro- and macrogeometrical information within postcentral gyrus and posterior parietal lobe.

Diffusion and perfusion MRI for the localisation of epileptogenic foci in drug-resistant epilepsy.

Drug-resistant epilepsy is an important clinical challenge, both diagnostically and therapeutically. More and more surgical options are being considered, but precise presurgical assessment is necessary. We prospectively studied eight patients with drug-resistant epilepsy, who underwent clinical examination, single photon emission computed tomography (SPECT) and interictal MRI, including diffusion- and perfusion-weighted echoplanar sequences. Lesions suspected on SPECT of being epileptogenic showed mild hypoperfusion, while the diffusion-weighted MRI (DWI) revealed increased apparent diffusion coefficients relative to the other side. However, these abnormalities were not visible on the corresponding maps. We showed that DWI and perfusion-weighted MRI could be used confirm the characteristics and site of an epileptogenic area in patients with drug-resistant epilepsy.

Hyperperfusion of anterior cingulate gyrus in a case of paroxysmal nocturnal dystonia.

The authors report the clinical, EEG, and SPECT findings of a patient with nocturnal paroxysmal dystonia. Ictal and interictal scalp EEG showed epileptiform activity over both frontal lobes. Subtraction ictal SPECT co-registered to MRI indicated a bilateral significant hyperperfusion in the anterior part of the cingulate gyrus. These results support earlier electrophysiologic investigations by others suggesting that anterior cingulate epilepsy may manifest as nocturnal paroxysmal dystonia, and illustrate the usefulness of computer-assisted SPECT analysis.

Cerebral networks in sensorimotor disturbances.

Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior, including the performance of laboratory tasks. Brain diseases are expected to affect these networks directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease-related changes in the human brain. Here, we review our analytic approach based on principal component analysis (PCA) to address such questions. We will discuss its methodological foundations and applications in patients with sensorimotor disorders. We will show that PCA in combination with, both, hypothesis-driven testing and correlation statistics provides a powerful tool for elucidating disease-related abnormalities and postlesional reorganization of neural networks in the human brain.

Disturbed functional brain interactions underlying deficient tactile object discrimination in Parkinson's disease.

Somatosensory discrimination of cuboid objects was studied in a group of healthy volunteers and patients with Parkinson's disease using regional cerebral blood flow (rCBF) measurements obtained with positron emission tomography (PET) and 15O labeled water [H2 15O]. A 6-[18F]-fluoro-L-dopa (FDOPA) PET scan demonstrated that the patients may be grouped into those with normal and those with abnormally lowA FDOPA uptake in the caudate nucleus. The categorical group comparisons revealed that task-induced rCBF increases were deficient in bilateral motor and sensory cortical areas in the Parkinson patients. Moreover, deficient rCBF increases were evident in the mesial and right dorsolateral prefrontal cortex for patients in a more advanced disease state, who showed low FDOPA uptake in the caudate nucleus. A principal component analysis (PCA), performed on the rCBF data, identified three patterns (principal components, PCs) that differentiated patients from normals. The first PC represented a right-hemisphere dominant, bilateral group of brain areas known to be involved in tactile exploration. A second PC reflected a cortical-subcortical pattern of functional interactions, comprising cortical areas important for working memory processes. The third group-differentiating PC revealed a pattern of functional interactions involving bilateral temporo-parieto-occipital association cortices, which was consistent with a hypothesized supramodal network necessary for object discrimination. In an additional subgroup analysis, greater expression of the third PC pattern predicted greater caudate FDOPA uptake in patients. Our neuroimaging data revealed a disturbance of distinct patterns of brain functional interactions related to the sensorimotor deficit in Parkinson's disease and to deficits of cognitive information processing deficits in the more advanced stage of Parkinson's disease.

SPECT during sleepwalking.

Sleepwalking is a dissociation between body sleep and mind sleep. We report single photon emission computed tomography (SPECT) in a man with a history of sleepwalking. Our findings suggest that this dissociation arises from activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems.

Extracranial vertebral artery dissection causing cervical root lesion.

The authors report an unusual manifestation of extracranial vertebral artery dissection (VAD), presenting with a predominantly motor radicular manifestation. Cervical magnetic resonance imaging (MRI) revealed the intramural hematoma in the dissected vessel wall, compressing mainly the segmental motor root and, to a lesser degree, the sensory ganglion. In the digital subtraction angiography (DSA), a circumscribed narrowing of the incriminated vessel was demonstrated. Color-coded Duplex imaging (CDDI) revealed complete recanalization after a few days of anticoagulation treatment. Complete neurologic recovery was seen after 3 months. Considering the MRI data, the likely pathogenetic mechanism was compression of the nerve root by the intramural hematoma. The synopsis with similar cases in the literature points to the characteristic features, i.e., the association of neck pain with radicular motor deficit and the absence of degenerative disk disease. The respective syndrome should raise the suspicion of vertebral artery dissection, especially in young individuals.

Prediction of angiographic carotid artery stenosis indexes by colour Doppler-assisted duplex imaging. A critical appraisal of the parameters used.

The aim of our study was to establish colour Doppler-assisted duplex imaging (CDDI)-criteria to predict an angiographic internal carotid artery (ICA) stenosis of at least 70%, according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trialists (ECST) methods of measurement. In the following, we describe the findings in 79 patients who were screened for carotid endarterectomy by CDDI and further evaluated by digital subtraction angiography (DSA). In 158 carotid arteries, 107 stenoses of > 30% and nine occlusions were found. Receiver operator characteristic graphs were constructed in order to calculate sensitivities and specificities of the assessment by CDDI in the prediction of high-grade stenoses determined by angiography. Optimal cut-off points were defined by highest accuracy which reflects the combination of high sensitivity and specificity. The critical index of a high-grade ICA stenosis according to the ECST method could be predicted with an accuracy greater than 90% by a systolic peak velocitiy of 1.25 m/s or an area reduction by CDDI of 70%. Corresponding values, 1.6 m/s and 80% area reduction, predicted the stenosis indexes according to the NASCET method less reliably, with accuracies of between 80% and 90%. Flow velocity criterion was slightly less accurate than the area reduction criterion by CDDI. Finally, double-blind evaluation performed by two readers per examination modality showed that the measurement of area reduction in CDDI is at least as reliable as stenosis indexes according to ECST and NASCET methods.