A comprehensive correlation of the KI-67 proliferation index to patient´s, imaging and tumor features and its value in predicting long-term course of patients with newly diagnosed intracranial meningiomas.

To analyze the correlation of KI-67-Proliferation Index (KI-67-PI) with preoperative patients and MRI characteristics, WHO grading, histological subtype and long-term-course of patients with newly diagnosed intracranial meningiomas (IM). In this single-center retrospective study, all consecutive patients with IM were analyzed from January 2007 to August 2019. Patient´s demographics (age, sex), imaging parameters (location, volume, edema, necrosis), and tumor features (WHO grade, histology) were assessed and correlated with KI-67-PI. Long-term data were retrieved from patient's last follow-up visits. This study included 463 IM in 457 surgically treated patients. Males exhibited a higher KI-67-PI than females (7.31 ± 0.22 vs. 5.37 ± 0.53; p < 0.01, Mann-Whitney U Test). Age positively correlated with KI-67-PI in both sexes (p < 0.01, Spearman), with older patients having a higher KI-67-PI. KI-67-PI was significantly higher in convexity IM compared to frontobasal IM (7.15 ± 5.56 vs. 4.66 ± 2.94; p < 0.05, ANOVA, Tukey´s HSD), while no difference in KI-67-PI expression was found when other locations were compared to each other (Tukey´s HSD). Higher KI-67-PI was significantly correlated with larger tumor volume (p < 0.01, Spearman), larger tumor necrosis and larger peritumoral edema (p < 0.01, Kruskal-Wallis). Patients with recurrent IM had a significantly higher KI-67-PI than patients without recurrence (8.24 ± 5.88 vs. 5.14 ± 3.53; p < 0.01, ANOVA, Tukey´s HSD) during a mean follow-up period of 80.92 ± 38.1 months. Atypical and anaplastic IM exhibited significantly higher KI-67-PI compared to all other WHO grade 1 histological subtypes (12.09 ± 0.73 vs. 4.51 ± 0.13; p < 0.01, Kruskal-Wallis test) and KI-67-PI was significantly higher in anaplastic IM compared to atypical meningioma (19.67 ± 1.41 vs. 11.01 ± 0.38; p < 0.01, ANOVA). Higher KI-67-PI is not only associated with atypical and anaplastic subtypes of IM, but is also significantly higher in males, positively correlates with patients age, larger tumor volume, lager peritumoral edema and necrosis on preoperative MRI and predicts tumor recurrence. Therefore, KI-67-PI may serve as a decision indicator for adjuvant treatment in patients with IM.

Impact of ambient temperature on inflammation-induced encephalopathy in endotoxemic mice-role of phosphoinositide 3-kinase gamma.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner. METHODS: Experiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30 ± 0.5 °C) or moderately lowered (26 ± 0.5 °C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection)-evoked systemic inflammatory response (SIR) and monitored 24 h for thermoregulatory response and blood-brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm-Sidak test or t tests with Bonferroni's correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn's multiple comparisons test. RESULTS: We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood-brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity. CONCLUSIONS: Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood-brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.

[Double vision and a wrong track]. / Doppelbilder und eine falsche Fährte.

A 72-year-old woman presented to our emergency centre with acute horizontal diplopia. Neurological examination revealed an isolated abducens nerve paresis on the left. Hilar enlargement seen on the chest x-ray and an elevated serum ACE level led us to suspect sarcoidosis, but the patient declined further evaluation. In the following days, her visual acuity decreased steadily, and she developed cervicothoracic pain, left sided ptosis, weakness of the right arm, and general asthenia. When she was readmitted as an emergency case, neurological examination revealed decreased visual acuity, external ophthalmoplegia and ptosis on the left and a C8 radicular lesion on the right. Imaging studies showed multilocular lesions, e. g. in the left orbital space, spinal epidural manifestations and lymphoma nodular involvement, including retroperitoneally. Laboratory chemistry showed elevated serum levels of ACE, sIL2 receptor and an elevated CD4 / CD8 ratio while bronchoalveolar lavage indicated lymphocytic alveolitis. The biopsy performed under the left M. masseter with a presumptive diagnosis of sarcoidosis, showed a diffuse large-cell B-cell lymphoma. We initiated immuno-chemotherapy following the R-CHOP schema with a curative approach. The case shows the lack of specificity of clinical, imaging and laboratory findings and thus underlines the need for histology in the differential diagnosis of sarcoidosis.

Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice.

Sepsis-induced myocardial depression (SIMD) is an early and frequent consequence of the infection-induced systemic inflammatory response syndrome. In homiotherms, variations in ambient temperature (Ta) outside the thermoneutral zone induce thermoregulatory responses mainly driven by a gradually increased sympathetic activity, which may affect disease severity. We hypothesized that thermoregulatory responses upon reduced Ta exposition aggravate SIMD in mice. Mice were kept at neutral Ta (30 ± 0.5 °C), moderately lowered Ta (26 ± 0.5 °C) or markedly lowered Ta (22 ± 0.5 °C), exposed to lipopolysaccharide- (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) evoked shock and monitored for survival, cardiac autonomic nervous system function and left ventricular performance. Primary adult cardiomyocytes and heart tissue derived from treated mice were analyzed for inflammatory responses and signaling pathways of myocardial contractility. We show that a moderate reduction of Ta to 26 °C led to a 40% increased mortality of LPS-treated mice when compared to control mice and that a marked reduction of Ta to 22 °C resulted in an early mortality of all mice. Mice kept at 26 °C exhibited increased heart rate and altered indices of heart rate variability (HRV), indicating sympathovagal imbalance along with aggravated LPS-induced SIMD. This SIMD was associated with reduced myocardial ß-adrenergic receptor expression and suppressed adrenergic signaling, as well as with increased myocardial iNOS expression, nitrotyrosine formation and leukocyte invasion as well as enhanced apoptosis and appearance of contraction band necrosis in heart tissue. While ineffective separately, combined treatment with the ß2-adrenergic receptor (AR) antagonist ICI 118551 (10 ng/gbw) and the inducible nitric oxide synthase (iNOS) inhibitor 1400 W (5 µg/gbw) reversed the increase in LPS-induced mortality and aggravation of SIMD at reduced Ta. Thus, consequences of thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range increase the mortality from LPS-evoked shock and markedly prolong impaired myocardial function. These changes are mitigated by combined ß2-AR and iNOS inhibition.

WHO grade of intracranial meningiomas differs with respect to patient's age, location, tumor size and peritumoral edema.

PURPOSE: To analyse whether the WHO grade of intracranial meningiomas differs itself depending on patients and meningioma characteristics at diagnosis. METHODS: Single center retrospective study of a series of consecutive patients with primary intracranial meningiomas who underwent surgery between January 2007 and March 2014. Patients (age, sex, outcome) and meningioma characteristics (histological diagnosis, tumor location, WHO grading, size, extend of peritumoral edema and tumor recurrence rate) were analysed. RESULTS: Of 240 included patients, 184 (76.7%) were female and 56 (23.3%) were male. 17 patients (7.1%) were in age group 20-40 years, 112 (46.7%) in group 41-60 years and 111 (46.3%) were in age group > 60 years. 189 patients (78.8%) were diagnosed with WHO grade I, 49 (20.4%) WHO grade II and 2 (0.8%) had a WHO grade III meningioma. WHO grade II meningiomas were significantly more frequent in the age group 20-40 years compared to age group 41-60 years (chi-square p < 0.05). Convexity meningiomas were significantly more frequent classified as WHO grade II meningiomas compared to all other locations (chi-square, p < 0.01). Mean calculated tumor volume and the tumor volume determined by volumetric measurement was significantly larger in grade II meningioma patients compared to grade I (46.3 ± 40.5 cc grade II versus 21.8 ± 27.8 cc grade I and 45.3 ± 38.2 cc versus 23.1 ± 30.0 cc respectively; t test < 0.01). Extend of the peritumoral edema was significantly larger in patients with grade II meningiomas (Wilcoxon test, p < 0.05). Short term outcome did not differ between different age groups nor was it associated with tumor size. During a mean follow up of 49 months (min 3, max 144 months) recurrence rate was significantly higher in WHO grade II (4 out of 49 [8.2]%) compared to WHO grade I patients (3 out if 186, [1.6%]; Chi-square, p < 0.05). CONCLUSION: In this series atypical meningioma was associated with younger age, location on the convexity, larger tumor size and more peritumoral edema.

Laparoscopic treatment of celiac artery compression syndrome in children and adolescents.

BACKGROUND: The celiac artery compression syndrome (CACS) is a rarely diagnosed disorder, which is characterized by chronic abdominal pain and vegetative symptoms. The role of surgical treatment in celiac artery decompression has been discussed controversially by numerous authors. After first casuistic descriptions of a laparoscopic treatment in adults we established this novel minimally invasive procedure for treatment in children and adolescents. PATIENTS AND METHODS: Between 2005 and 2014 we operated 58 patients (47 female, 11 male) from 7 to 25 years who had been diagnosed with celiac artery compression. The patients presented with severe chronic abdominal pain, vegetative symptoms and a reduced quality of life. Doppler sonography showed an increased blood flow velocity of the celiac artery with maximum of 190 - 450 cm/s (mean 259 cm/s).MR angiography demonstrated a characteristic hook-shaped appearance of the celiac artery with severe localized compression. RESULTS: All patients underwent laparoscopic decompression of the celiac artery. We observed complications in 3 patients (5,2 %). Postoperatively all patients (100 %) were immediately free of abdominal pain. Doppler sonography showed a marked reduction in celiac blood flow velocity to 70 - 190 cm/s postoperatively (mean 178 cm/s). A return of vessel diameters to normal dimensions was documented by postoperative MR angiography. During a median follow up of 62 months we observed a recurrence of the celiac artery compression in 4 patients (6,9 %). CONCLUSIONS: Laparoscopic treatment of celiac artery compression syndrome offers a novel, safe, reliable and, compared to open surgery, less invasive approach. The surgical treatment is indicated in patients with characteristic symptoms and typical findings at Doppler sonography and MRA after exclusion of other abdominal pathologies. The work-up of chronic abdominal pain in children and adolescents should include a color Doppler sonography to look for celiac artery compression.

Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3.

OBJECTIVE: Inherited ataxias are heterogeneous disorders affecting both children and adults. The primary cause can be identified in about half of the patients and only very few can receive causative therapy. METHODS: The authors performed sequencing of known Coenzyme Q10 (CoQ10) deficiency genes in 22 patients with unexplained recessive or sporadic ataxia. RESULTS: CABC1/ADCK3 mutations were detected in four patients and two siblings presenting with cerebellar ataxia, epilepsy and muscle symptoms. Spasticity, dystonia, tremor and migraine were variably present; cognitive impairment was severe in early childhood cases, but was absent in adults. In contrast to previous reports, two of the patients had a later-onset, very mild phenotype and remained ambulatory in their late forties. Muscle biopsy revealed lipid accumulation, mitochondrial proliferation and cytochrome c oxidase-deficient fibres, but no typical ragged red fibres. Respiratory-chain enzyme activities and CoQ10 were decreased in severely affected patients but remained normal in a mildly affected patient at 46 years of age. CONCLUSIONS: These observations highlight the importance of screening for a potentially treatable cause, CABC1/ADCK3 mutations, not only in severe childhood-onset ataxia, but also in patients with mild cerebellar ataxia in adult life.

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Abeta protofibrils.

The formation of amyloid fibrils is a common biochemical characteristic that occurs in Alzheimer's disease and several other amyloidoses. The unifying structural feature of amyloid fibrils is their specific type of beta-sheet conformation that differentiates these fibrils from the products of normal protein folding reactions. Here we describe the generation of an antibody domain, termed B10, that recognizes an amyloid-specific and conformationally defined epitope. This antibody domain was selected by phage-display from a recombinant library of camelid antibody domains. Surface plasmon resonance, immunoblots, and immunohistochemistry show that this antibody domain distinguishes Abeta amyloid fibrils from disaggregated Abeta peptide as well as from specific Abeta oligomers. The antibody domain possesses functional activity in preventing the formation of mature amyloid fibrils by stabilizing Abeta protofibrils. These data suggest possible applications of B10 in the detection of amyloid fibrils or in the modulation of their formation.

Neurofibromatosis type 2 and multiple sclerosis.

Comorbidity of neurofibromatosis type 2 (NF2) and multiple sclerosis (MS) has rarely been reported. Since immunological mechanisms have been implicated in Nf2, coexistence of the two entities may offer insights into schwannoma pathogenesis with respect to the impact of the immune system. We present the case of a woman with a de novo mutation in the NF2 gene who later developed MS. In addition, we found a significantly higher count of T cells in a laryngeal schwannoma of this patient as compared to a schwannoma removed from a NF2 patient without MS. This finding correlated with a higher growth rate in the case of NF+MS.

Metastatic glioblastoma cells use common pathways via blood and lymphatic vessels.

Generally, gliomas do not metastasize. Therefore, larger series are not available to investigate the pathways of tumour spread. Here, we present the case of a young man with a glioblastoma multiforme WHO grade IV and distant metastases in several tissues. The glioblastoma multiforme WHO grade IV of a young male patient recurred within a very short time along the surgical resection pathway within the temporalis muscle. After removal of the tumour bulk, the patient developed a distant intracranial tumour lesion around the contralateral ventricular system and a pulmonary tumour. Later on, the patient underwent an operation on a facial lesion representing a local extracranial glioblastoma recurrence and containing metastases within lymph nodes and lymphatic vessels. Our case report indicated a lymphatic pathway of metastasis, which could be demonstrated by our histopathological analysis. We suggest that altered gene expression stimulated by glioblastoma-environment interaction altered the properties of glioblastoma cells, whether caused by a spontaneous genetic shift or induced by factors provided by the extracranial tissue.

Dysregulation of GABAergic neurotransmission in mood disorders: a postmortem study.

Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Gamma-aminobutyric acid (GABA) acts via binding to A and B receptors, whereas the B receptor is G protein-coupled. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis. Immunohistochemical staining of GAD 65/67-immunoreactive neurons was performed in dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, superior temporal cortex, hippocampus formation, and mediodorsal thalamus with consecutive determination of neuronal density in 20 brains of patients with mood disorders (P) and 19 controls (C). In the patients' group were 11 patients with bipolar disorder (BD) and 9 patients with major depressive disorder (MDD). The data were tested statistically using analysis of variance (ANOVA) and post hoc Tukey tests. ANOVA revealed significant differences among the groups (C, BD, MDD) in dorsolateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and hippocampus. Post hoc tests demonstrated higher neuronal densities in unipolar patients compared with bipolar patients and controls in dorsolateral prefrontal cortex, superior temporal cortex, and hippocampus. In the orbitofrontal cortex, a higher neuronal density was found in bipolar and unipolar patients compared with controls. In mood disorder patients, dose equivalents of antidepressants given prior to death correlated positively with the neuronal density in superior temporal cortex and hippocampus. The current data on GAD 65/67 point to a dysregulation of the GABAergic system in mood disorders. Possibly, existing deficits of GABAergic neurotransmission will be compensated or overcompensated by antidepressants. Additionally, albeit speculative, an imbalance between GABA production and transport might be of relevance.

Betamethasone-related acute alterations of microtubule-associated proteins in the fetal sheep brain are reversible and independent of age during the last one-third of gestation.

OBJECTIVE: The purpose of this study was to examine whether glucocorticoid effects on neuronal cytoskeleton, which we have shown previously at 0.87 gestation when the hypothalamo-pituitary-adrenal axis matures, are age-dependent and reversible. STUDY DESIGN: Fetal sheep received 3.3 microg kg(-1) h(-1) betamethasone (n = 10) or saline solution (n = 9) intravenously over 48 hours at 0.75 gestation (ie, before the hypothalamo-pituitary-adrenal axis matures and when betamethasone is administered clinically). RESULTS: Betamethasone diminished microtubule-associated protein (MAP) 1B and 2 immunoreactivity in the frontal neocortex and caudate putamen (P < .05) and MAP2 in the hippocampus (P < .05), which is similar to the effects that are seen at 0.87 gestation. In agreement, the number of glucocorticoid receptors did not differ at both ages. Loss of MAP1B and MAP2 immunoreactivity was not accompanied by neuronal death and was reversible within 24 hours. CONCLUSION: Alteration of neuronal cytoskeletal proteins caused by antenatal betamethasone exposure is transient and independent of age during late gestation.

Outcome-based profiling of astrocytic tumours identifies prognostic gene expression signatures which link molecular and morphology-based pathology.

Astrocytomas are intracranial malignancies for which invasive growth and high motility of tumour cells preclude total resection; the tumours usually recur in a more aggressive and, eventually, lethal form. Clinical outcome is highly variable and the accuracy of morphology-based prognostic statements is limited. In order to identify novel molecular markers for prognosis we obtained expression profiles of: i) tumours associated with particularly long recurrence-free intervals, ii) tumours which led to rapid patient death, and iii) tumour-free control brain. Unsupervised data analysis completely separated the three sample entities indicating a strong impact of the selection criteria on general gene expression. Consequently, significant numbers of specifically expressed genes could be identified for each entity. An extended set of tumours was then investigated by RT-PCR targeting 12 selected genes. Data from these experiments were summarised into a sample-specific index which assigns tumours to high- and low-risk groups as successfully as does morphology-based grading. Moreover, this index directly correlates with definite survival suggesting that integrated gene expression data allow individualised prognostic statements. We also analysed localisation of selected marker transcripts by in situ hybridization. Our finding of cell-specificity for some of these outcome-determining genes relates global expression data to the presence of morphological correlates of tumour behaviour and, thus, provides a link between morphology-based and molecular pathology. Our identification of expression signatures that are associated individually with clinical outcome confirms the prognostic relevance of gene expression data and, thus, represents a step towards eventually implementing molecular diagnosis into clinical practice in neuro-oncology.

Stereotactic approach and electrophysiological characterization of thalamic reticular and dorsolateral nuclei of the juvenile pig.

Few reports exist on complex functions of pig's central nervous system. A direct access to thalamic structures enables a deeper understanding of neuronal networks. Here we present an easy to implement stereotactic approach to reach both reticular and dorsolateral thalamic nuclei (RTN and LD). In thirteen pigs (7 weeks old) the correct electrode position was confirmed for 22 out of 26 thalamic electrodes (RTN: A+2, L9, V24 and LD: A-2, L5, V20, with bregma A 0, L 0). Quantitative effects of isoflurane/nitrous oxide (State 1) and fentanyl sedation (State 2) were determined by brain hemodynamics and metabolism. Neurophysiologic features were performed by spectral power, coherence and SEP analysis. Brain blood flow (by 21 +/- 13%) and oxidative brain metabolism (CMRO, by 26 +/- 12%, CMRGlucose by 26 +/- 22%) were markedly reduced during State 1 (P<0.05). Regional thalamic blood flow exhibited similar alterations, but side-differences did not occur. State 1 induced quite similar brain activity in cortical as well as thalamic regions investigated. During State 2 electrocortical activity of low frequency ranges was markedly reduced, whereas spectral band power of high frequency ranges was additionally decreased in RTN (P<0.05). Thus, we used a convenient approach for targeted deep electrode implementation and characterized electrophysiological features in RTN and LD.

Phosphoinositide 3-Kinase γ Restrains Neurotoxic Effects of Microglia After Focal Brain Ischemia.

Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and phagocytosis. This study was conducted to elucidate conjectural differences of lipid kinase-dependent and kinase-independent functions of PI3Kγ in the evolvement of brain damage induced by focal cerebral ischemia/reperfusion. Therefore, PI3Kγ wild-type, knockout, and kinase-dead mice were subjected to middle cerebral artery occlusion followed by reperfusion. Tissue damage and cellular composition were assessed by immunohistochemical stainings. In addition, microglial cells derived from respective mouse genotypes were used for analysis of PI3Kγ effects on phagocytic activity, matrix metalloproteinase-9 release, and cAMP content under conditions of oxygen/glucose deprivation and recovery. Brain infarction was more pronounced in PI3Kγ-knockout mice compared to wild-type and kinase-dead mice 48 h after reperfusion. Immunohistochemical analyses revealed a reduced amount of galectin-3/MAC-2-positive microglial cells indicating that activated phagocytosis was reduced in ischemic brains of knockout mice. Cell culture studies disclosed enhanced metalloproteinase-9 secretion in supernatants derived from microglia of PI3Kγ-deficient mice after 2-h oxygen/glucose deprivation and 48-h recovery. Furthermore, PI3Kγ-deficient microglial cells showed a failed phagocytic activation throughout the observed recovery period. Lastly, PI3Kγ-deficient microglia exhibited strongly increased cAMP levels in comparison with wild-type microglia or cells expressing kinase-dead PI3Kγ after oxygen/glucose deprivation and recovery. Our data suggest PI3Kγ kinase activity-independent control of cAMP phosphodiesterase as a crucial mediator of microglial cAMP regulation, MMP-9 expression, and phagocytic activity following focal brain ischemia/recirculation. The suppressive effect of PI3Kγ on cAMP levels appears critical for the restriction of ischemia-induced immune cell functions and in turn tissue damage.

A pig model with secondary increase of intracranial pressure after severe traumatic brain injury and temporary blood loss.

There is a lack of animal models of traumatic brain injury (TBI) that adequately simulate the longterm changes in intracranial pressure (ICP) increase following clinical TBI. We therefore reproduced the clinical scenario in an animal model of TBI and studied long-term postinjury changes in ICP and indices of brain injury. After induction of anesthesia, juvenile piglets were randomly traumatized using fluid-percussion injury (FPI) to induce either moderate (mTBI = 6 pigs: 3.2 +/- 0.6 atm) or severe (sTBI = 7 pigs: 4.1 +/- 1.0 atm) TBI. Injury was followed by a 30% withdrawal of blood volume. ICP and systemic hemodynamic were monitored continuously. Repeated measurements of global cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were performed at baseline, at the end of blood withdrawal, after volume replacement, and at 8 and 24 h postinjury. Histological and immunocytochemical studies have also performed. ICP peaked immediately following FPI (mTBI: 33 +/- 16 mm Hg; sTBI: 47 +/- 14 mm Hg, p < 0.05) in both groups. In the sTBI group, we noted a second peak at 5 +/- 1.5 h postinjury. This second ICP peak was accompanied by a 50% reduction in CBF (44 +/- 31 mL . min . 100 g(-1)) and CMRO(2) (2.5 +/- 2.0 mL . min . 100 g(1)). Moderate TBI typically resulted in focal pathological change whereas sTBI caused more diffuse change, particularly in terms of the ensuing axonal damage. We thus describe an animal model of severe TBI with a reproducible secondary ICP increase accompanied by patterns of diffuse brain damage. This model may be helpful in the study of pathogenetic relevance of concomitant affections and verify new therapeutic approaches in severe TBI.

Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP and iNOS signalling.

AIMS: Sepsis-induced myocardial depression (SIMD), an early and frequent event of infection-induced systemic inflammatory response syndrome (SIRS), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase γ (PI3Kγ) is known to prevent ß-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kγ in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kγ in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS: PI3Kγ knockout mice (PI3Kγ(-/-)), mice expressing catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type mice (P3Kγ(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic inflammation and assessed for survival, cardiac autonomic nervous system function, and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyse PI3Kγ effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kγ(-/-) mice, followed by reduced contractility. In contrast, P3Kγ(+/+) mice and PI3Kγ(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kγ(+/+) and PI3Kγ(KD/KD) mice, cardiomyocytes from PI3Kγ(-/-) mice showed an enhanced and prolonged cAMP-mediated signalling upon norepinephrine and an intensified LPS-induced proinflammatory response characterized by nuclear factor of activated T-cells-mediated inducible nitric oxide synthase up-regulation. CONCLUSIONS: This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses.

Serial positron emission tomographic findings in an atypical presentation of fatal familial insomnia.

BACKGROUND: Genetic analyses of fatal familial insomnia, a prion disease, disclose a broader range of symptoms than previously described. Although insomnia and dysautonomia have been described as hallmarks of the disease, there is substantial variability in clinical presentation. OBJECTIVE: To evaluate serial fluorodeoxyglucose positron emission tomographic and electroencephalographic findings in atypical fatal familial insomnia without clinical insomnia. PATIENT: A 63-year-old man who had a history of gait ataxia developed rapidly progressive dementia with mild dysautonomic features. Genetic investigation confirmed diagnosis of fatal familial insomnia (D178N mutation of the prion protein gene and Val/Met polymorphism on position 129 of the mutated allele) with typical neuropathologic findings. RESULTS: Clinical signs were not specific. An electroencephalogram showed scanty triphasiclike elements and general slowing. We found thalamic hypometabolism in positron emission tomographic scans to be present in a very early stage with progressive deterioration, and patchy cortical alterations showing progression over 6 months. CONCLUSIONS: In the absence of clear clinical signs, an electroencephalogram was of major diagnostic value, although its specificity in fatal familial insomnia is under debate. Selective thalamic hypometabolism seems to be an early marker in fatal familial insomnia, while cortical changes vary with clinical presentation and stage.

Overexpression of protease-activated receptor type 1 (PAR-1) in glioblastoma multiforme WHO IV cells and blood vessels revealed by NCAM-assisted glioblastoma border labeling.

Glioblastomas are neuroepithelial tumors with lost cellular differentiation and tenfold increased growth rates compared to low-grade gliomas. Despite of very aggressive treatment options based on surgery, irradiation, and chemotherapy, the prognosis of affected patients has remained poor and showed only slight improvements during the last 30 years. Research on glioblastoma border zone was hindered by the tumor's intense invasion into the brain parenchyma and the lack of suitable tumor cell markers. Nevertheless, the compact tumor mass and tumor invasion zone are composed of distinct cell types that need to be distinguished from each other to be addressed selectively. As the isoform 140 of the neural cell adhesion molecule (NCAM-140) was recently demonstrated to be lost in human gliomas with rising WHO grade, human multiform glioblastomas were characterized as a NCAM-140 negative entity displaying three main distinct invasion patterns. Evaluation of putative therapy targets within the tumor tissue and tumor invasion zone has been made possible through NCAM-140 negativity. In the present study, brain tissue controls and human glioblastoma samples with compact tumor mass and invasion areas were analyzed for their vascularization at the tumor border and the expression of thrombin receptor protease-activated receptor type 1 (PAR-1) within tumor tissue and vascular vessel walls. Use of NCAM-140 enabled the identification of the tumor invasion zone and its experimental investigation. Tissue vascularization was found to be significantly increased in the compact tumor mass of glioblastomas compared to their invasion zone and tumor-free controls with a significantly high and specific overexpression of PAR-1 within tumor cells and within tumor blood vessels depending upon the tumor area. This suggests thereby a functional role of the thrombin receptor PAR-1 in glioma cell malignancy and glioblastoma neoangiogenesis.

Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.

Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). We therefore determined CBR densities and expression of the translocator protein 18 kDA (TSPO) in newborn piglets after experimental TBI. Newborn female piglets were subjected to sham operation (n=6) or fluid-percussion (FP) injury (n=7) under controlled physiological conditions. After six hours, brains were frozen, sagittally cut and incubated with radioligands for CBR ([3HCP-55,940, [3H]SR141716A) and TSPO ([3H]PK11195), an indicator of gliosis/brain injury. Early after injury, FP-TBI elicited a significant ICP increase at a temporary reduced cerebral perfusion pressure; however, CBF and CMRO2 remained within physiological range. At 6 hours post injury, we found a statistically significant increase in binding of the non-selective agonist [3H]CP-55,940 in 15 of the 24 investigated brain regions of injured animals. By contrast, no significant changes in binding of the CB1R-selective antagonist [3H]SR141716A were observed. A non-significant trend towards increased binding of [3H]PK11195 was observed, suggesting an incipient microglial activation. We therefore conclude that in this model and time span after injury, the increase in [3H]CP-55,940 binding reflects changes in CB2R density, while CB1R density is not affected. The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.