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.

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.

[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.

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).

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.

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.

Neurologic disorder of vitamin E deficiency in acquired intestinal malabsorption.

Fifteen years after onset of a malabsorption syndrome, a 49-year-old man had sensory and oculomotor disorder with marked vitamin E deficiency. After 6 months of treatment with high parenteral doses of vitamin E, the neurologic signs slowly receded, but the patient died of gastrointestinal hemorrhage. Autopsy and sural nerve biopsy showed the changes in both central and peripheral nerves; these changes are considered characteristic of vitamin E deficiency.

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.

Deficient cerebral activation pattern in stroke recovery.

Specific cerebral activations induced by unilateral tactile discrimination of macrogeometric objects were identified in positron emission tomography images of regional cerebral blood flow in patients recovered from hemiplegic stroke and in healthy volunteers. Primary sensorimotor cortex, supplementary motor area, superior parietal lobule contralateral to moving hand, and premotor cortex on both sides were regularly activated in normals contrary to patients showing consistent activations only in the primary sensorimotor cortex. Furthermore, areas of activations in parietal association, premotor and midfrontal cortical areas were far less consistently activated in patients than in healthy subjects. These results demonstrated in correspondence to the clinical observations that the patients had regained their ability to move the fingers of the affected hand but remained impaired in tactile discrimination.

Locked-in state in Borrelia burgdorferi meningitis.

The case is reported of a 28-year-old woman with persistent tetraplegia following acute meningitis due to Borrelia burgdorferi infection. The patient developed erythema chronicum migrans before radicular pain occurred in the upper extremities. The poor clinical outcome was suggestive of pontine infarction due to vasculitis of branches of the basilar artery.

Chronic progressive neurological involvement in Borrelia burgdorferi infection.

Five patients with chronic meningitis were hospitalized several times for progressive neurological symptoms. The clinical manifestations included cranial neuritis, radiculoneuritis, myelitis and encephalitis. In two cases cerebral infarction occurred. The course was commonly characterized by a tendency to deteriorate. From the clinical point of view, it was repeatedly difficult to exclude multiple sclerosis or tuberculous meningitis. Finally, specific antibodies against Borrelia burgdorferi were detected by indirect immunofluorescence assay. The diagnosis of a borreliosis was not considered initially because there was no history of tick-bite or erythema chronicum migrans, and the neurological involvement of the central nervous system seemed unusual. The latency between the first symptoms and diagnosis varied from 3 months to 5 years. After a parenteral, high-dose therapy with penicillin, there was a significant improvement in all patients. In two cases, there was evidence of intrathecally produced antibodies to myelin basic protein.

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.

In vitro and in vivo testing of the dopamine D1 ligand [123I]SCH 23982 with respect to its potential application in SPET investigations.

[123I]SCH 23982, a dopamine D1 ligand, was labelled in a large scale process and then tested in vitro for binding to rat brain sections and membranes. Because of the promising values of KD = 1.5 x 10(-10) M and Bmax = 0.7 x 10(-11) mol/g, in vivo evaluation was performed on rats and normal volunteers to test its possible usefulness for SPET imaging. In competition experiments, a higher binding in the presence of sulpiride was found while ketanserin displaced [123I]SCH 23982 only at a 10,000-fold excess. Differences between rats and men were seen with respect to their metabolism. SPET investigations failed because the washout of [123I]SCH 23982 was too rapid.

Neuroimaging findings in a patient recovering from global alexia to spelling dyslexia.

The authors report findings in a 67-year-old right-handed man who had an ischemic infarct in the territory of the left posterior cerebral artery. The clinical manifestation consisted mainly of total alexia without agraphia. The patient gradually recovered, subsequently showing the syndrome of spelling dyslexia. Cerebral MR-images revealed a circumscript infarction of medial and basal parts of left temporal lobe. In the acute stage [99mTc]HM-PAO SPECT was characterized by a diminished uptake in the definitely infarcted area and hyperfixation in the region of the left forceps major. Because high retention of HM-PAO indicates potentially salvageable tissue after an ischemic event, the depicted area might be correlated with the recovery of function. Thus, the authors' neuroimaging data give further support to the assumption that the left forceps major is a critical area for global alexia, whereas spelling dyslexia is due to involvement of the left medio-basal temporal lobe.

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.

[Semiquantitative display of regional cerebral blood flow and neuronal function using N-isopropyl-(123I)-p-iodoamphetamine (IMP) and emission tomography]. / Ein Beitrag zur semiquantitativen Darstellung der regionalen Hirndurchblutung und neuronalen Funktion mittels N-isopropyl-(123J)-p-Jodoamphetamin (IMP) und Emissionstomographie.

Between June 1983 and March 1985 197 patients were examined with 123I-IMP brain scintigraphy and ECT. They had various neurological diseases, the majority suffered from cerebrovascular affections. The reference for pathological findings was a group of 14 healthy volunteers. A visual interpretation of the ECT-slices alone is not reliable enough. A semiquantitative assessment of perfusion abnormalities seems to be very important, especially in diffuse or bilateral alterations. The proposed semiquantitative evaluation makes use of the total cerebral accumulation in the control group (35.6 +/- 4.3 cts/pixel/mCi/min) and right-left ratios of 14 paired and fixed regions of interest (ROI) in three ECT slices. The ROIs are related to the anatomical flow supply areas in the brain. The right-left ratios are around 1.0 with a physiological asymmetry of +/- less than 2% (standard deviation). The asymmetry is an important parameter in assessing presence and severity of disease. If pathological findings are diffuse or symmetric, the visual interpretation of scintigrams or the calculation of right-left ratios are often unsuccessful. Thus, the same ROI-data were separated for the right and left hemisphere and drawn as cts/ROI/pixel/mCi in diagrams as profile. The diagram demonstrates perfusion abnormalities semiquantitatively without using calculation of asymmetry, since asymmetry alone cannot differentiate between hypoperfusion of one and hyperperfusion of the contralateral side.

Single photon emission computed tomography with 99mTc hexamethyl propylene amine oxime (HMPAO) and focal motor seizures.

The proper localization of regions of interest (ROIs) in Single Photon Emission Computed Tomography (SPECT) is an essential task. The limited spatial resolution makes it difficult to define regions by their structure. The particular problems are: 1) the difficulty to find the appropriate slice and its orientation in space; 2) the individual variation of the brain in dimension and shape. Referring to the basic work of Talairach and Szikla (1967), research is conducted to overcome these methodical problems in interpreting cranial computed tomography by using a proportional localization system. We analyzed four cases with focal motor seizures of different aetiology (tumour, hemorrhagic infarction, intracerebral hematoma, multifocal leukencephalopathy) by 99mTc HMPAO SPECT. The accumulation of the radiopharmacon was measured in ROIs which were delineated with the aid of the above mentioned system. The regions were selected in accordance to the autoradiographic study of penicillin induced epileptic seizures in animal experiments. Dependent on the severity of the clinical manifestation we were able to document the involvement of the supposed primary focus and of several related zones. We suggest that this approach should prove some usefulness in the examination of the interdependency of different brain areas.