Necrotizing Bacillus cereus infection of the meninges without inflammatory reaction in a patient with acute myelogenous leukemia: a case report

A 64-year-old man in a severely immunocompromised state due to acute myelogenous leukemia died, respirator-unaided, about 10 h after the abrupt onset of coma. An earlier blood culture had yielded Bacillus cereus. The autopsy, performed 2 h after death, demonstrated diffuse subarachnoid hemorrhage without berry aneurysms, and the formalin-fixed brain was tinged with gray-brownish discoloration. The sections of the brain presented a whitish tint of the surface layer of all portion of the cerebral cortices, even those in the sulci. Histological examination of the brain revealed leptomeningeal B. cereus dissemination, and widespread necrosis of the leptomeninges and arachnoid vessels without inflammatory cell reaction. The grossly recognizable whitish surface layer of the cerebral cortex showed overt hyperchromatism, and contained neurons more degenerative than those located in the deeper cortical layer. The total absence of inflammatory reaction may be explained by a combination of the immunocompromised state of the patient and the character of B. cereus infection, which in itself induces little inflammatory reaction. The prominent lesions were confined to the cerebral surface layer and leptomeningeal tissue including the arachnoid vessels, which were all bathed in the cerebrospinal fluid, suggesting that some necrotizing toxins had been secreted into the fluid by the B. cereus. The necrosis of arachnoid vessels is thought to have in turn caused diffuse subarachnoid hemorrhage and marked disturbance of the cerebral blood flow, resulting in the terminal coma. Received: 4 April 1996 / Revised, accepted: 8 September 1996     

Neurobiological origin of spurious brain morphological changes: A quantitative MRI study

The high gray‐white matter contrast and spatial resolution provided by T1‐weighted magnetic resonance imaging (MRI) has made it a widely used imaging protocol for computational anatomy studies of the brain. While the image intensity in T1‐weighted images is predominantly driven by T1, other MRI parameters affect the image contrast, and hence brain morphological measures derived from the data. Because MRI parameters are correlates of different histological properties of brain tissue, this mixed contribution hampers the neurobiological interpretation of morphometry findings, an issue which remains largely ignored in the community. We acquired quantitative maps of the MRI parameters that determine signal intensities in T1‐weighted images (R₁ (=1/T1), R₂*, and PD) in a large cohort of healthy subjects (n = 120, aged 18–87 years). Synthetic T1‐weighted images were calculated from these quantitative maps and used to extract morphometry features—gray matter volume and cortical thickness. We observed significant variations in morphometry measures obtained from synthetic images derived from different subsets of MRI parameters. We also detected a modulation of these variations by age. Our findings highlight the impact of microstructural properties of brain tissue—myelination, iron, and water content—on automated measures of brain morphology and show that microstructural tissue changes might lead to the detection of spurious morphological changes in computational anatomy studies. They motivate a review of previous morphological results obtained from standard anatomical MRI images and highlight the value of quantitative MRI data for the inference of microscopic tissue changes in the healthy and diseased brain. Hum Brain Mapp 37:1801–1815, 2016. © 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas

Intracarotid low dose bradykinin infusion can selectively increase permeability in brain tumor capillaries. However, the mechanism by which bradykinin selectively increases transport into brain tumors and not normal brain has not been clearly defined. This study therefore sought to determine whether the mechanism by which bradykinin increases tumor permeability specifically involves the bradykinin B2 receptor in brain tumor tissue. In permeability studies, 27 Wistar rats with RG2 gliomas were utilized and a unidirectional transport, K_i, of radiolabeled [¹⁴C] sucrose was determined using quantitative autoradiography. Bradykinin (10 μg kg⁻¹ min⁻¹) increased the transport of sucrose to tumors 2.1-fold compared to saline infusion alone (p<0.001). The uptake of sucrose in tumors was significantly inhibited by the bradykinin B2 receptor antagonist,

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-Arg, [Hyp³, Thi^5,8,

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-Phe⁷]-bradykinin (p<0.01), but not by the B1 receptor antagonist, des-Arg⁹, [Leu⁸]-bradykinin. The distribution of B2 receptors in normal brain and tumor tissue was examined by immunohistochemistry using the B2 receptor antiserum, AS 424. High levels of B2 receptors were detected in intracerebral RG2 glioma and brain surrounding tumor (BST), but not in normal brain tissue. These results indicate that the permeabilizing effects of bradykinin are mediated through bradykinin B2 receptors, and that differences in distribution of B2 receptors between tumor tissue and normal brain may be responsible for the selective effects on tumor tissue.     

MR correlates of cerebral atrophy in patients with multiple sclerosis

Objective To investigate the in-vivo correlates of brain atrophy in patients with multiple sclerosis (MS) by assessing the relationship between normalized measures of brain volume (NBV) and other magnetic resonance (MR) measures of tissue damage. Background Brain atrophy diffusely occurs and progressively increases in patients with MS. Nevertheless, the mechanisms leading to brain atrophy in this disease are not fully understood. Methods MR examinations were performed in 20 patients with relapsing-remitting MS. Conventional MRI was used to assess NBV and total brain T2-hyperintense and T1-hypointense lesion volumes. Proton MR spectroscopic imaging and diffusion tensor MR imaging were also performed for large portions of brain containing mainly normal-appearing tissue to provide indices of tissue damage, including N-acetylaspartate to creatine ratio (NAA/Cr) and mean diffusivity (). Results Values of NBV correlated significantly with those of average brain (r = -0.58, p = 0.007) and NAA/Cr (r = 0.67, p < 0.001). The relationship of these markers of tissue damage to NBV was also found when NAA/Cr and were computed together in a composite MR score (r = 0.70, p < 0.001). In contrast, NBV values did not correlate with measurements of average lesion , T₂ and T₁ weighted total brain MRI lesion volumes. Conclusions This study suggests that brain atrophy in MS is not simply due to axonal loss, but rather reflects a more generalized process that involves various brain tissue components. Damage to the normal-appearing tissue rather than the extent and intrinsic pathology of macroscopic lesions seems to be important in the destructive process leading to MS-related irreversible cerebral atrophy. Received: 13 September 2001 Received in revised form: 18 January 2002 Accepted: 4 March 2002     

Oxygen free radical generation during in-utero hypoxia in the fetal guinea pig brain: the effects of maturity and of magnesium sulfate administration

Previous studies have shown, employing direct measurements with electron spin resonance (ESR) spectroscopy, that hypoxia induces an increased production of oxygen free radicals (OFR) in the brain of the guinea pig fetus. The present study using the same approach, investigated the effects of maturity and Mg²⁺-pretreatment on hypoxia-induced OFR formation in the guinea pig fetal brain. The normoxic and the hypoxic groups were exposed for 60 min to 21% or 7% oxygen, respectively. The control group consisted of term fetuses exposed to normoxia (n=7) and hypoxia (n=7). The experimental groups consisted of the following: (a) for the investigation on maturity effect, preterm fetuses (40 days) exposed to normoxia (n=6) or hypoxia (n=6); and (b) for the Mg²⁺-pretreatment investigation, term fetuses (60 days) exposed to normoxia (n=6) or hypoxia (n=6) following maternal pretreatment with Mg²⁺ which consisted of an initial bolus of MgSO₄ (600 mg/kg, i.p.) 1 h prior to hypoxia followed by a second dose (300 mg/kg, i.p.). Oxygen free radicals were measured by ESR spectroscopy in the fetal cerebral cortical tissue utilizing phenyl-N-tert-butylnitrone (PBN) spin trapping. Fetal brain tissue hypoxia was documented biochemically by decreased tissue levels of ATP and phosphocreatine. In the control group of term fetuses, the cortical tissue from hypoxic fetuses showed a significant increase in spin adducts (71% increase, p<0.01). In the preterm group, the cortical tissue from hypoxic fetuses showed a 33% increase in spin adducts (p<0.001). The baseline free radical generation during normoxia was 22.5% higher at preterm than at term (41.4±3.5 units/g issue vs. 33.8±9.3 units/g tissue, p<0.05). In Mg²⁺-treated groups, spin adduct levels in cortical tissue from hypoxic fetuses did not significantly differ from those of the normoxic group (30.2±9.9 units/g tissue, normoxic-Mg²⁺ vs. 30.6±8.1 units/g tissue, hypoxic-Mg²⁺). The results indicate that the fetal brain at term may be more susceptible to hypoxia-induced free radical damage than at preterm and that Mg²⁺ administration significantly decreased the hypoxia-induced increase in oxygen free radical generation in the term fetal guinea pig brain in comparison with non-treated hypoxic group.     

Diagnostic,prognostic and predictive relevance of molecular markers in gliomas

The advances of genome‐wide ‘discovery platforms’ and the increasing affordability of the analysis of significant sample sizes have led to the identification of novel mutations in brain tumours that became diagnostically and prognostically relevant. The development of mutation‐specific antibodies has facilitated the introduction of these convenient biomarkers into most neuropathology laboratories and has changed our approach to brain tumour diagnostics. However, tissue diagnosis will remain an essential first step for the correct stratification for subsequent molecular tests, and the combined interpretation of the molecular and tissue diagnosis ideally remains with the neuropathologist. This overview will help our understanding of the pathobiology of common intrinsic brain tumours in adults and help guiding which molecular tests can supplement and refine the tissue diagnosis of the most common adult intrinsic brain tumours. This article will discuss the relevance of 1p/19q codeletions, IDH1/2 mutations, BRAF V600E and BRAF fusion mutations, more recently discovered mutations in ATRX, H3F3A, TERT, CIC and FUBP1, for diagnosis, prognostication and predictive testing. In a tumour‐specific topic, the role of mitogen‐activated protein kinase pathway mutations in the pathogenesis of pilocytic astrocytomas will be covered.     

Comparison of brain tissue and local cerebral venous gas tensions and pH

Abstract

Neurosurgical monitoring devices have recently become available which are capable of measuring cerebral tissue gas tensions and pH. Brain tissue sensors have not been conclusively demonstrated to correlate with other measurements of regional cerebral gas tensions or pH. The present study was undertaken to correlate sensor values for p 0_2/ p C0₂ and pH with blood samples taken concurrently from local cerebral veins. Adult mongrel dogs were anesthetized and a craniotomy was performed. A small gyral vein was isolated and cannulated. Adjacent to the venous catheter tip, a Neurotrend® brain tissue probe was inserted in an intracortical location. Each subject received a sequence of manipulations in inspired oxygen and end tidal carbon dioxide conditions. Under each experimental condition, samples of arterial and gyral venous blood were obtained and blood gas analysis performed. Concurrent brain probe measurements of tissue p0₂, pC0₂ and pH were recorded. Statistical analysis determined that local tissue and cerebral venous blood values for p0₂, pC0₂ and pH were highly correlated (R_s= 0.62-0.82; p 0.001). This indicates that there exists a confirmable monotonic relationship between tissue values and conditions in the post-capillary venous bed. Tissue sensors such as the Neurotrend® probe can offer reliable trend indications in brain tissue gas tensions and pH. [Neurol Res 2000; 22: 642-644     

Pathophysiological aspects of brain edema

Summary Two mayor types of brain edema, related to two different pathomechanisms, can be recognized: 1)cytotoxic type-where the main feature is the swelling of cellular elements of brain parenchyma and 2)vasogenic type-where an increased vascular permeability leading to accumulation of edema fluid inthe extracellular spaces plays the principal role. In this type of edema, there is a close interrelationship between extravasation of serum proteins and retention of water in the brain tissue. In theischemic brain edema both cytotoxic and vasogenic mechanisms are involved. A biphasic opening of the blood-brain barrier, associated with vasogenic edema, is observed following release of major cerebral artery occlusion. The first opening of the barrier is related to a reactive hyperemia which follows promptly recirculation. The second opening, recognizable after a delay, is associated with a severe ischemic brain tissue injury.Dedicated to Prof. F. Seitelberger on the occasion of his seventieth birthday     

Brain tissue oxygenation in brain death

Introduction: The value of brain tissue oxygenation (PbtO₂) measurements in determining brain death is unknown. Methods: Eleven of 72 patients who had brain tissue oxygen monitors placed experienced brain death. Admission diagnoses included six severe traumatic brain injuries, one multiple trauma with cardiac arrest, one brain tumor, one subarachnoid hemorrhage, one intracerebral hemorrhage, and one cerebral stroke. Eleven males and zero females were studied, with an average age of 26 years (range: 20–70 years). Nine patients had Glasgow Coma Scores (GCS) of 3 on admission, one patient had a GCS of 5, and one patient had a GCS of 15.     

The interaction of [3H]PY 108-068 and of [3H]PN 200-110 with calcium channel binding sites in rat brain

Summary The binding properties of the tritiated calcium channel antagonists PY 108-068 and PN 200-110 were investigated in membrane fractions from rat brainin vitro. Both ligands reversibly interact with one apparent population of stereoselective binding sites which have pharmacological properties described for calcium channel binding sites. In a calcium buffer enhancement of [³H]PY 108-068 binding is observed with an EC₅₀ at pCa 6.28 [³H]PN 200-110 binding is less sensitive to allosteric stimulation by diltiazem and to allosteric inhibition by verapamil and D 600 than [³H]PY 108-068 binding, suggesting that the former ligand may stabilize a high affinity configuration of the binding sites. Afteri.v. administration of [³H]PY 108-068in vivo binding to membranes is observed in brain and heart, which, in contrast to total tissue radioactivity is sensitive to inhibition by unlabelled (+) PN 200-110. These observations suggest that PY 108-068 can interact with its binding sites alsoin vivo. The results ofex vivo binding studies in brain and heart with [³H]PY 108-068 confirm and extend these observations. It could be shown that all investigated 1,4-dihydropyridines (PY 108-068, PN 200-110, nifedipine, Bay K 8644) after i.p. administration can readily enter brain and heart tissue.     

Gliotoxin‐induced swelling of astrocytes hinders diffusion in brain extracellular space via formation of dead‐space microdomains

One of the hallmarks of numerous life‐threatening and debilitating brain diseases is cellular swelling that negatively impacts extracellular space (ECS) structure. The ECS structure is determined by two macroscopic parameters, namely tortuosity (λ) and volume fraction (α). Tortuosity represents hindrance imposed on the diffusing molecules by the tissue in comparison with an obstacle‐free medium. Volume fraction is the proportion of tissue volume occupied by the ECS. From a clinical perspective, it is essential to recognize which factors determine the ECS parameters and how these factors change in brain diseases. Previous studies demonstrated that dead‐space (DS) microdomains increased λ during ischemia and hypotonic stress, as these pocket‐like structures transiently trapped diffusing molecules. We hypothesize that astrocytes play a key role in the formation of DS microdomains because their thin processes have concave shapes that may elongate as astrocytes swell in these pathologies. Here we selectively swelled astrocytes in the somatosensory neocortex of rat brain slices with a gliotoxin DL‐α‐Aminoadipic Acid (DL‐AA), and we quantified the ECS parameters using Integrative Optical Imaging (IOI) and Real‐Time Iontophoretic (RTI) diffusion methods. We found that α decreased and λ increased during DL‐AA application. During recovery, α was restored whereas λ remained elevated. Increase in λ during astrocytic swelling and recovery is consistent with the formation of DS microdomains. Our data attribute to the astrocytes an important role in determining the ECS parameters, and indicate that extracellular diffusion can be improved not only by reducing the swelling but also by disrupting the DS microdomains. GLIA 2014;62:1053–1065     

Diagnostic implications of histological analysis of neurosurgical aspirate in addition to routine resections

Many neurosurgical centers use surgical aspirators to remove brain tumor tissue. The resulting aspirate consists of fragmented viable tumor, normal or tumor‐infiltrated brain tissue as well as necrotic tissue, depending on the type of tumor. Typically, such fragmented aspirate material is collected but discarded and not included when making the histopathological diagnosis. Whereas the general suitability of surgical aspirate for histological diagnosis and immunohistochemical staining has been reported previously, we have systematically investigated whether the collection and histological examination of surgical aspirate has an impact on diagnosis, in particular on the tumor grading, by providing additional features. Surgical and aspirate specimens from 85 consecutive neurosurgical procedures were collected and routinely processed. Sixty‐five of the 85 specimens were intrinsic brain tumors and the remainder consisted of metastatic tumors, meningiomas, schwannomas and lymphomas. Important diagnostic features seen in surgical aspirate were microvascular proliferation (n = 3), more representative necrosis (n = 2), and gemistocytic component (n = 2). In one case, microvasular proliferations were seen in the aspirate only, leading to a change of diagnosis. Collection of surgical aspirate also generates additional archival material which can be microdissected and used for tissue microarrays or for molecular studies.     

A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition

Viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. Murine reovirus infection serves as a classic experimental model of viral encephalitis. Infection of neonatal mice with T3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and CNS tissue injury. We have developed an ex vivo brain slice culture (BSC) system that recapitulates the basic pathological features and kinetics of viral replication seen in vivo. We utilize the BSC model to identify an innate, brain-tissue specific inflammatory cytokine response to reoviral infection, which is characterized by the release of IL6, CXCL10, RANTES, and murine IL8 analog (KC). Additionally, we demonstrate the potential utility of this system as a pharmaceutical screening platform by inhibiting reovirus-induced apoptosis and CNS tissue injury with the pan-caspase inhibitor, Q-VD-OPh. Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo.     

Prospects for investigating brain oxygenation in acute stroke: Experience with a non‐contrast quantitative BOLD based approach

Metabolic markers of baseline brain oxygenation and tissue perfusion have an important role to play in the early identification of ischaemic tissue in acute stroke. Although well established MRI techniques exist for mapping brain perfusion, quantitative imaging of brain oxygenation is poorly served. Streamlined‐qBOLD (sqBOLD) is a recently developed technique for mapping oxygenation that is well suited to the challenge of investigating acute stroke. In this study a noninvasive serial imaging protocol was implemented, incorporating sqBOLD and arterial spin labelling to map blood oxygenation and perfusion, respectively. The utility of these parameters was investigated using imaging based definitions of tissue outcome (ischaemic core, infarct growth and contralateral tissue). Voxel wise analysis revealed significant differences between all tissue outcomes using pairwise comparisons for the transverse reversible relaxation rate (R ₂′), deoxygenated blood volume (DBV) and deoxyghaemoglobin concentration ([dHb]; p < 0.01 in all cases). At the patient level (n = 9), a significant difference was observed for [dHb] between ischaemic core and contralateral tissue. Furthermore, serial analysis at the patient level (n = 6) revealed significant changes in R ₂′ between the presentation and 1 week scans for both ischaemic core (p < 0.01) and infarct growth (p < 0.05). In conclusion, this study presents evidence supporting the potential of sqBOLD for imaging oxygenation in stroke.     

Sensitive quantitative detection of somatic mosaic mutation in “double cortex” syndrome

Aims. Somatic mutation of the lissencephaly‐1 gene is a cause of subcortical band heterotopia (“double cortex”). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low‐level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low‐level mutation. Methods. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1 c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. Results. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin‐fixed paraffin‐embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. Conclusion. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.     

Effect of propofol on oxidative stress in an in vitro model of anoxia-reoxygenation in the rat brain

Propofol, an intravenous anaesthetic, is similar in chemical structure to the active nucleus of antioxidant substances such as α-tocopherol (vitamin E). The present study was designed to test whether propofol had antioxidant effects in an in vitro model of anoxia-reoxygenation in slices of rat brain. We used seven experimental groups: (1) control oxygenated tissue; (2) tissue subjected to anoxia for 20 min and reoxygenation for 3 h; and tissues processed as described and incubated with (3) Intralipid (commercial solvent for propofol), or propofol at a concentration of (4) 10 μmol/l, (5) 50 μmol/l, (6) 150 μmol/l or (7) 300 μmol/l. The production of lipid peroxides was quantified as thiobarbituric acid reactive substances (TBARS); tissular glutathione production and the activities of glutathione peroxidase (GSHpx), glutathione reductase (GSSGrd) and glutathione transferase (GSHtf) were also measured. Reoxygenation led to tissular oxidative stress, which was curtailed by propofol. The anaesthetic led to a 47% reduction in TBARS, a 165% increase in the reperfusion-inhibiting glutathione content, a 47% decrease in GSHpx activity, and an 87% increase in GSHtf activity. Intralipid had no effect on any of the parameters studied here. We conclude that propofol has a clear antioxidant effect in rat brain tissue subjected to anoxia-reoxygenation.     

Deleterious brain cell membrane effects after NMDA receptor antagonist administration to newborn piglets

Previous studies have shown that administration of the N-methyl- -aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-phosphonic acid (CPP) reduces NMDA-mediated neurotoxicity in animal models of hypoxia/ischemia but also may induce brain tissue vacuolization and alter glucose metabolism. The present study tests the hypothesis that CPP administration alters brain cell membrane structure and function in the cerebral cortex of normoxic newborn piglets through the generation of oxygen free radicals and induction of lipid peroxidation. Twenty six anesthetized, ventilated newborn piglets—13 treated with 2 mg/kg i.v. CPP and 13 untreated controls—were studied. ATP and phosphocreatine (PCr) levels were measured as an index of cellular energy metabolism and tissue glucose levels determined. Na⁺,K⁺-ATPase activity was measured as an index of brain cell membrane function and the lipid peroxidation products conjugated dienes (CD) and fluorescent compounds (FC) measured. Free radical generation was detected on cortical biopsies homogenized with α-phenyl-N-tert-butyl-nitrone (PBN) through electron spin resonance spectroscopy. Signal height of spectrum was divided by dry tissue weight and expressed as mm/g tissue. In the two groups brain tissue ATP and PCr levels were not different. Tissue glucose levels were higher in the CPP group (24±5 mg/dl) than in controls (14±3 mg/dl), p<0.05, whereas Na⁺,K⁺-ATPase activity was lower in the CPP group than in controls (34±4 vs. 43±6 μmol Pi/mg protein/h), p<0.05. Lipid peroxidation products were higher in the CPP group (CD: 57±19 nmol/g brain, FC: 1.5±0.3 μg/g brain) than in controls (CD: 0±0 nmol/g brain, FC: 0.9±0.2 μg/g brain), p<0.05. Free radical intensity was higher in the CPP group (493±397 mm/g tissue) than in controls (51±83 mm/g tissue), p<0.05. In vitro administration of CPP to brain cell membranes did not change Na⁺,K⁺-ATPase activity or the generation of lipid peroxidation products. The data demonstrate that administration of CPP induces lipid peroxidation, results in free radical generation, decreases brain cell membrane Na⁺,K⁺-ATPase activity and alters glucose metabolism in the cerebral cortex of newborn piglets. Since CPP is a potent antagonist of the NMDA receptor, we speculate that CPP generates free radicals through a pathway independent of the NMDA receptor by altering cellular metabolism and possibly glucose utilization during normoxia in newborn piglets.     

Family-based association study of SELENBP1 in schizophrenia

The SELENBP1 gene previously was found to be up-regulated in microarray analysis of both peripheral blood cell and brain tissue samples from schizophrenia patients. Quantitative PCR analysis subsequently corroborated the altered expression of SELENBP1 in schizophrenia brain tissue samples from the Stanley Array Correction. The aim of this study was to extend those findings by employing family-based association methods to a sample of over 2400 individuals (including 1214 individuals affected by schizophrenia) of Han Chinese descent living in Taiwan. One of four haplotype-tagging SNPs and two different two-marker haplotypes showed nominally significant evidence for association with schizophrenia under an additive model, suggesting that genetic variation in SELENBP1 may influence risk for the disorder, while this significance did not remain when other inheritance models were considered. Further comprehensive analysis with other SNPs and haplotypes is needed and warranted.     

Region specific distribution of levomepromazine in the human brain

Summary. Objective: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time. Methods: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case. Results: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. Conclusions: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.