In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9/TIMP-1 ratio and increased collagen type IV degradation

Adverse outcome in bacterial meningitis is associated with the breakdown of the blood-brain barrier (BBB). Matrix-metalloproteinases (MMPs) facilitate this process by degradation of components of the BBB. This in turn results in acute complications of bacterial meningitis including edema formation, increased intracranial pressure and subsequent ischemia. We determined the parenchymal balance of MMP-9 and TIMP-1 (tissue inhibitor of MMP) and the structural integrity of the BBB in relation to cortical damage in an infant rat model of pneumococcal meningitis. The data demonstrate that the extent of cortical damage is significantly associated with parenchymal gelatinolytic activity and collagen type IV degradation. The increased gelatinolysis was found to be associated with a brain parenchymal imbalance of MMP-9/TIMP-1. These findings provide support to the concept that MMPs mediated disruption of the BBB contributes to the pathogenesis of bacterial meningitis and that protection of the vascular unit may have neuroprotective potential.

Initiation of high-frequency oscillatory ventilation and its effects upon cerebral circulation in pigs: an experimental study

BACKGROUND: Current practice at high-frequency oscillatory ventilation (HFOV) initiation is a stepwise increase of the constant applied airway pressure to achieve lung recruitment. We hypothesized that HFOV would lead to more adverse cerebral haemodynamics than does pressure controlled ventilation (PCV) in the presence of experimental intracranial hypertension (IH) and acute lung injury (ALI) in pigs with similar mean airway pressure settings. METHODS: In 12 anesthetized pigs (24-27 kg) with IH and ALI, mean airway pressure (P(mean)) was increased (to 20, 25, 30 cm H(2)O every 30 min), either with HFOV or with PCV. The order of the two ventilatory modes (cross-over) was randomized. Mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF) (fluorescent microspheres), cerebral metabolism, transpulmonary pressures (P(T)), and blood gases were determined at each P(mean) setting. Our end-points of interest related to the cerebral circulation were ICP, CPP and CBF. RESULTS: CBF and cerebral metabolism were unaffected but there were no differences between the values for HFOV and PCV. ICP increased slightly (HFOV median +1 mm Hg, P<0.05; PCV median +2 mm Hg, P<0.05). At P(mean) setting of 30 cm H(2)O, CPP decreased during HFOV (median -13 mm Hg, P<0.05) and PCV (median -17 mm Hg, P<0.05) paralleled by a decrease of MAP (HFOV median -11 mm Hg, P<0.05; PCV median -13 mm Hg, P<0.05). P(T) increased (HFOV median +8 cm H(2)O, P<0.05; PCV median +8 cm H(2)O, P<0.05). Oxygenation improved and normocapnia maintained by HFOV and PCV. There were no differences between both ventilatory modes. CONCLUSIONS: In animals with elevated ICP and ALI, both ventilatory modes had effects upon cerebral haemodynamics. The effects upon cerebral haemodynamics were dependent of the P(T) level without differences between both ventilatory modes at similar P(mean) settings. HFOV seems to be a possible alternative ventilatory strategy when MAP deterioration can be avoided.

Effect of a lung recruitment maneuver by high-frequency oscillatory ventilation in experimental acute lung injury on organ blood flow in pigs

INTRODUCTION: The objective was to study the effects of a lung recruitment procedure by stepwise increases of mean airway pressure upon organ blood flow and hemodynamics during high-frequency oscillatory ventilation (HFOV) versus pressure-controlled ventilation (PCV) in experimental lung injury. METHODS: Lung damage was induced by repeated lung lavages in seven anesthetized pigs (23-26 kg). In randomized order, HFOV and PCV were performed with a fixed sequence of mean airway pressure increases (20, 25, and 30 mbar every 30 minutes). The transpulmonary pressure, systemic hemodynamics, intracranial pressure, cerebral perfusion pressure, organ blood flow (fluorescent microspheres), arterial and mixed venous blood gases, and calculated pulmonary shunt were determined at each mean airway pressure setting. RESULTS: The transpulmonary pressure increased during lung recruitment (HFOV, from 15 +/- 3 mbar to 22 +/- 2 mbar, P < 0.05; PCV, from 15 +/- 3 mbar to 23 +/- 2 mbar, P < 0.05), and high airway pressures resulted in elevated left ventricular end-diastolic pressure (HFOV, from 3 +/- 1 mmHg to 6 +/- 3 mmHg, P < 0.05; PCV, from 2 +/- 1 mmHg to 7 +/- 3 mmHg, P < 0.05), pulmonary artery occlusion pressure (HFOV, from 12 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 13 +/- 2 mmHg to 15 +/- 2 mmHg, P < 0.05), and intracranial pressure (HFOV, from 14 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 15 +/- 3 mmHg to 17 +/- 2 mmHg, P < 0.05). Simultaneously, the mean arterial pressure (HFOV, from 89 +/- 7 mmHg to 79 +/- 9 mmHg, P < 0.05; PCV, from 91 +/- 8 mmHg to 81 +/- 8 mmHg, P < 0.05), cardiac output (HFOV, from 3.9 +/- 0.4 l/minute to 3.5 +/- 0.3 l/minute, P < 0.05; PCV, from 3.8 +/- 0.6 l/minute to 3.4 +/- 0.3 l/minute, P < 0.05), and stroke volume (HFOV, from 32 +/- 7 ml to 28 +/- 5 ml, P < 0.05; PCV, from 31 +/- 2 ml to 26 +/- 4 ml, P < 0.05) decreased. Blood flows to the heart, brain, kidneys and jejunum were maintained. Oxygenation improved and the pulmonary shunt fraction decreased below 10% (HFOV, P < 0.05; PCV, P < 0.05). We detected no differences between HFOV and PCV at comparable transpulmonary pressures. CONCLUSION: A typical recruitment procedure at the initiation of HFOV improved oxygenation but also decreased systemic hemodynamics at high transpulmonary pressures when no changes of vasoactive drugs and fluid management were performed. Blood flow to the organs was not affected during lung recruitment. These effects were independent of the ventilator mode applied.

Early recurrent ischemic stroke in stroke patients undergoing intravenous thrombolysis

BACKGROUND: We assessed the incidence of early recurrent ischemic stroke in stroke patients treated with intravenous tissue-type plasminogen activator (tPA) and the temporal pattern of its occurrence compared with symptomatic intracranial hemorrhage (ICH). METHODS AND RESULTS: Prospectively collected, population-based data for 341 consecutive acute stroke patients (62% men; mean age, 66 years) treated with tPA according to the National Institute of Neurological Disorders and Stroke study protocol at 8 medical centers in Switzerland (3 academic and 5 community) between January 2001 and November 2004 were retrospectively analyzed. The primary outcome measure was neurological deterioration > or = 4 points on the National Institutes of Health Stroke Scale occurring within 24 hours of tPA treatment and caused either by recurrent ischemic stroke (defined as the occurrence of new neurological symptoms suggesting involvement of initially unaffected vascular territories and evidence of corresponding ischemic lesions on cranial computed tomography scans, in the absence of ICH) or by ICH. Early recurrent ischemic stroke was diagnosed in 2 patients (0.59%; 95% confidence interval, 0.07% to 2.10%) and symptomatic ICH in 15 patients (4.40%; 95% confidence interval, 2.48% to 7.15%). Both recurrent ischemic strokes occurred during thrombolysis, whereas symptomatic ICHs occurred 2 to 22 hours after termination of tPA infusion. CONCLUSIONS: Recurrent ischemic stroke is a rare cause of early neurological deterioration in acute stroke patients undergoing intravenous thrombolysis, with a different temporal pattern compared with that of symptomatic ICH.

Post-mortem forensic neuroimaging: correlation of MSCT and MRI findings with autopsy results

Multislice-computed tomography (MSCT) and magnetic resonance imaging (MRI) are increasingly used for forensic purposes. Based on broad experience in clinical neuroimaging, post-mortem MSCT and MRI were performed in 57 forensic cases with the goal to evaluate the radiological methods concerning their usability for forensic head and brain examination. An experienced clinical radiologist evaluated the imaging data. The results were compared to the autopsy findings that served as the gold standard with regard to common forensic neurotrauma findings such as skull fractures, soft tissue lesions of the scalp, various forms of intracranial hemorrhage or signs of increased brain pressure. The sensitivity of the imaging methods ranged from 100% (e.g., heat-induced alterations, intracranial gas) to zero (e.g., mediobasal impression marks as a sign of increased brain pressure, plaques jaunes). The agreement between MRI and CT was 69%. The radiological methods prevalently failed in the detection of lesions smaller than 3mm of size, whereas they were generally satisfactory concerning the evaluation of intracranial hemorrhage. Due to its advanced 2D and 3D post-processing possibilities, CT in particular possessed certain advantages in comparison with autopsy with regard to forensic reconstruction. MRI showed forensically relevant findings not seen during autopsy in several cases. The partly limited sensitivity of imaging that was observed in this retrospective study was based on several factors: besides general technical limitations it became apparent that clinical radiologists require a sound basic forensic background in order to detect specific signs. Focused teaching sessions will be essential to improve the outcome in future examinations. On the other hand, the autopsy protocols should be further standardized to allow an exact comparison of imaging and autopsy data. In consideration of these facts, MRI and CT have the power to play an important role in future forensic neuropathological examination.

Coincidence of semilobar holoprosencephaly and Chiari II malformation: correlation of prenatal diagnostics and neuropathologic findings

As holoprosencephaly and Chiari II malformation differ considerably, both in pathogenesis and in phenotypic localization, the coincidence of both entities is extremely rare. The case presented is, to our knowledge, the first published report comprising a combination of a semilobar holoprosencephaly associated with a Chiari II malformation and a myelomeningocele diagnosed prenatally and confirmed by postmortem neuropathologic evaluation. These findings indicate that in the case of pre- and postnatal detection of a myelomeningocele and/or Chiari II malformation, possible additional intracranial malformation, such as a semilobar holoprosencephaly, should also be taken into account and vice versa.

Differential expression of CD45 on canine microglial cells

CD45, also called leucocyte common antigen is a transmembrane protein tyrosine phosphatase on the surface of nearly all white blood cells and has a functional role in signal transduction. In the brain, the expression of CD45 can be used to distinguish microglial cells with a characteristic phenotype of CD11b/c+ and CD45(low) from other central nervous system (CNS) macrophages which show an expression of CD11b/c+ and CD45(high). In the course of pathological changes in the CNS, microglia in rodents is known to readily upregulate expression of various surface molecules, such as CD45. Understanding the mechanisms that regulate expression of surface molecules is essential to study the pathogenesis of CNS diseases. In the present study, the expression of CD45 on microglia of 42 dogs was examined ex vivo by means of flow cytometry. The dogs were classified in two groups according to the histopathological diagnosis in the CNS. All dogs without changes in the CNS (group I; n = 22) only showed low percentages of CD45+ microglial cells. In group II consisting of 20 dogs with different intracranial diseases varying results were obtained. Thirteen dogs showed a low percentage of CD45+ microglial cells whereas seven dogs exhibited high percentages of microglial cells expressing CD45. Evaluation of expression intensity in these seven dogs revealed two subpopulations of CD45+ microglial cells: a large subpopulation with CD45(low) and a small subpopulation with CD45(high). The expression intensity of CD45(high) was comparable with that of canine monocytes. It was attempted to correlate these findings to age of the animals, underlying disease, duration of clinical signs, medical treatment, occurrence of seizure activity and the expression of other surface molecules. It appeared that dogs with high percentages of CD45+ suffered from long-lasting CNS disease with seizures. In future studies, the reason and consequences for upregulated CD45 in long-lasting CNS diseases has to be further evaluated.

Necrotising encephalitis in a French bulldog

A 20-month-old, female French bulldog was presented with a three-month history of generalised seizures and progressive ataxia with occasional falling over on either side. Neurological examination revealed signs, suggesting a multifocal intracranial lesion. Magnetic resonance imaging of the brain revealed two connected lesions on the left side of the caudal brainstem and a further lesion in the cerebrum. The dog was euthanased, and histopathological examination revealed lesions which closely resembled those of necrotising encephalitis in Yorkshire terriers. This is the first case describing this type of necrotising encephalitis in a French bulldog.

Bridging hyperacute liver failure by ABO-incompatible auxiliary partial orthotopic liver transplantation

Uncontrollable intracranial pressure elevation in hyperacute liver failure often proves fatal if no suitable liver for transplantation is found in due time. Both ABO-compatible and auxiliary partial orthotopic liver transplantation have been described to control such scenario. However, each method is associated with downsides in terms of immunobiology, organ availability and effects on the overall waiting list.

Neuro-imaging of cerebral ischemic stroke

Major progress has recently been made in the neuro-imaging of stroke as a result of improvements in imaging hardware and software. Imaging may be based on either magnetic resonance imaging (MRI) or computed tomography (CT) techniques. Imaging should provide information on the entire vascular cervical and intracranial network, from the aortic arch to the circle of Willis. Equally, it should also give information on the viability of brain tissue and brain hemodynamics. CT has the advantage in the detection of acute hemorrhage whereas MRI offers more accurate pathophysiological information in the follow-up of patients.

The amygdala in schizophrenia: a trimodal magnetic resonance imaging study

In schizophrenic psychoses, structural and functional alterations of the amygdala have been demonstrated by several neuroimaging studies. However, postmortem examinations on the brains of schizophrenics did not confirm the volume changes reported by volumetric magnetic resonance imaging (MRI) studies. In order to address these contradictory findings and to further elucidate the possibly underlying pathophysiological process of the amygdala, we employed a trimodal MRI design including high-resolution volumetry, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) in a sample of 14 schizophrenic patients and 14 matched controls. Three-dimensional MRI volumetry revealed a significant reduction of amygdala raw volumes in the patient group, while amygdala volumes normalized for intracranial volume did not differ between the two groups. The regional diffusional anisotropy of the amygdala, expressed as inter-voxel coherence (COH), showed a marked and significant reduction in schizophrenics. Assessment of qMTI parameters yielded significant group differences for the T2 time of the bound proton pool and the T1 time of the free proton pool, while the semi-quantitative magnetization transfer ratio (MTR) did not differ between the groups. The application of multimodal MRI protocols is diagnostically relevant for the differentiation between schizophrenic patients and controls and provides a new strategy for the detection and characterization of subtle structural alterations in defined regions of the living brain.

Cerebral networks linked to the event-related potential P300

P300 is an event-related potential that is elicited by an oddball paradigm. In several neuropsychiatric diseases, differences in latencies and amplitude compared to healthy subjects have been reported. Because of its clinical significance, several investigations have tried to elucidate the intracranial origins of the P300 component. In the present study we could demonstrate a network of P300 generators. Investigated were 15 healthy subjects with an acoustical oddball paradigm within a fMRI block design, which enabled us to exclude attention or acoustical processing effects. The inferior and middle frontal, superior temporal, lower parietal cortex, the insula and the anterior cingulum were significantly activated symmetrical in both hemispheres.

[Perspectives in the treatment of subarachnoid-hemorrhage-induced cerebral vasospasm]

Cerebral vasospasm is still the most important cause of death and disability after rupture of intracranial aneurysms. The therapeutic strategies in the treatment of subarachnoid hemorrhage induced vasospasm vasospasm include four groups: 1) prevention of vasospasm; 2) reversion of vasospasm; 3) improvement of cerebral perfusion; and 4) neuroprotection and rescue therapies. Recent experimental studies allowed the design of phase II clinical studies which demonstrated positive results with medications and compounds such as statins (simvastatin and pravastatin) and endothelin-1 receptor antagonists (clasozentan). Moreover, experimental and clinical evidences showed the advantages of early cerebrospinal fluid drainage, intrathecal administration of NO-donors, effects of Ca2+ protein kinase inhibitor (Fasudil) and catecholamines on the cerebral vessels. This review article summarizes the stage of investigation of these medications and therapeutic strategies which will be relevant in the treatment of cerebral vasospasm.

3D C-arm as an alternative modality to CT in postmortem imaging: technical feasibility

OBJECT: The aim of our study was to demonstrate the image quality of the new device using human cadavers, extending the horizon of available imaging modalities in forensic medicine. MATERIALS AND METHODS: Six human cadavers were examined, revealing C-arm data sets of the head, neck thorax, abdomen and pelvis. High-resolution mode was performed with 500 fluoroscopy shots during a 190 degrees orbital movement with a constant tube voltage of 100 kV and a current of 4.6 mA. Based on these data sets subsequent three-dimensional reconstructions were generated. RESULTS: Reconstructed data sets revealed high-resolution images of all skeletal structures in a near-CT quality. The same image quality was available in all reconstruction planes. Artefacts caused by restorative dental materials are less accentuated in CBCT data sets. The system configuration was not powerful enough to generate sufficient images of intracranial structures. CONCLUSION: After the here-demonstrated encouraging preliminary results, the forensic indications that would be suitable for imaging with a 3D C-arm have to be defined. Promising seems the visualization local limited region of interest as the cervical spine or the facial skeleton.

Phenotype-genotype correlation in eight Polish patients with inherited Factor XIII deficiency: identification of three novel mutations

Inherited factor XIII (FXIII) deficiency is known as one of the most rare blood coagulation disorder in humans. In the present study, phenotype and genotype of eight FXIII deficient Polish patients from five unrelated families were compared. The patients presented with a severe phenotype demonstrated by a high incidence of intracerebral haemorrhages (seven of eight patients), haemarthrosis (six patients) and bleeding due to trauma (five patients). Introduction of regular substitution with FXIII concentrate prevented spontaneous bleeding in seven patients. In all patients, mutations within the F13A gene have been identified revealing four missense mutations (Arg77Cys, Arg260Cys, Ala378Pro, Gly420Ser), one nonsense mutation (Arg661X), one splice site mutation (IVS5-1 G>A) and one small deletion (c.499-512del). One homozygous large deletion involving exon 15 was detected by failure of PCR product. The corresponding mutations resulted in severely reduced FXIII activity and FXIII A-subunit antigen concentration, while FXIII B-subunit antigen remained normal or mildly decreased. Structural analysis demonstrated that the novel Ala378Pro mutation may cause a disruption of the FXIII catalytic triad leading to a non-functional protein which presumably undergoes premature degradation. In conclusion, the severe phenotype with high incidence of intracranial bleeding and haemarthrosis was in accordance with laboratory findings on FXIII and with severe molecular defects of the F13A gene.