Peterus Thajeb

Neuregulin-1 reduces ischemia-induced brain damage in rats

Neuregulin-1 (NRG-1) is expressed throughout the immature and adult central nervous system and it has been demonstrated to influence the migration of a variety of cell types in developing brain. Elevated levels of NRG-1 transcript are found in the adult brain after injury, leading to the suggestion that NRG-1 is involved in the physiological response to neuronal injury. Here, we report our findings that rats pre-treated with NRG-1 protein, undergoing cerebral ischemia 30 min later, had increased motor performance and less cerebral infarction than untreated rats. In the cortex of NRG-1 treated rats, ischemia induced a decrease in caspase-3 immunoreactivity and a reduction in the density of cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end-labeling. Improvement in behavioral assays was also found in animals treated with NRG-1. Pre-treatment with NRG-1 did not alter cerebral blood flow or other physiological parameters. NRG-1 reduced ischemia/reperfusion injury, indicating that it may act as an endogenous neuroprotective factor against stroke. Therefore, NRG-1 may represent a target for the development of new treatments for stroke.

Valproic Acid Aggravates Epilepsy due to MELAS in a Patient with an A3243G Mutation of Mitochondrial DNA

Epilepsy is one of the most common presentations of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is typically caused by an A-to-G substitution at nucleotide position 3243 of mitochondrial DNA. Valproic acid, a common anticonvulsant, can actually increase the frequency of seizures in individuals with MELAS. Here, we report a single case-study of a 38-year-old man who presented with focal seizures and had MELAS Syndrome due to the A3243G mitochondrial DNA mutation. Manifestation of epilepsia partialis continua was aggravated by use of valproic acid. Convulsions abated after discontinuation of valproic acid. Our experience suggests that valproic acid should be avoided for the treatment of epilepsy in individuals with mitochondrial disease.

Fatal Strokes in Patients with Rhino-orbito-cerebral Mucormycosis and Associated Vasculopathy

Within a 10-y period, fatal strokes occurred during parenteral administration of amphotericin B and surgical debridement of paranasal sinuses in 6 pathologically verified cases of rhino-orbito-cerebral mucormycosis (ROCM). All patients had unnoticed type-2 diabetes mellitus without ketoacidosis. They presented with unilateral orbital cellulitis and cavernous sinus syndrome. Fatal malignant cerebral infarctions occurred in the carotid system in 5 patients, and in the basilar artery or its major branches in 2 patients. Accelerated thrombotic occlusion of the cavernous portion of the carotid artery or the basilar artery was likely to be due to mucormycosis associated-vasculopathy and diabetic vasculopathy. One patient died of massive subarachnoid hemorrhage following rupture of the mycotic aneurysm. Despite parenteral administration of amphotericin B, fatal outcome of ROCM in patients with unnoticed diabetes mellitus occurs due to mucormycosis-associated malignant strokes. To improve outcome, a combination of early radical debridement, ocular exenteration, parenteral and local administration of amphotericin B, and decompression craniotomy should be considered.

Hyperbaric oxygen enhances the expression of prion protein and heat shock protein 70 in a mouse neuroblastoma cell line

Abstract1. Cellular prion protein, PrPC, is a ubiquitous glycoprotein strongly expressed in neurons with an as yet unknown biological function. In previous studies, we demonstrated that PrPC could be regulated by heat shock stress, implying that it might be a stress-responsive protein. Hyperbaric oxygen (HBO) administration is a well-defined model for the study of oxidative stress.2. This study investigated the effect of HBO on PrPC and Hsp 70 expression in mouse neuroblastoma cell lines (N18), assessing the expression of PrPC and Hsp 70 using RT-PCR and Western blotting. HBO administration resulted in a time- and dose-dependent increase in PrPC and Hsp70 expression in N18 cells at both mRNA and protein levels, with a concomitant upregulation of c-Jun N-terminal kinase (JNK).3. Under HBO treatment, luciferase reporter constructs of the rat PrPC promoter, containing the heat shock element (HSE) also present in Hsp70, expressed higher luciferase activity (3- to 10-fold) than those constructs without HSE.4. In summary, these data suggest that PrPC and Hsp 70 may be regulated by HBO, through the activation of JNK. Thus, the activated heat shock transcriptional factor 1, phosphorylated by JNK interacted with HSE in the promoter of PrPC resulted in increased gene expression. These findings are vital for future therapeutic approaches in transmissible spongiform encephalopathies and the understanding of the function of the PrPC.

Cerebral and oculorhinal manifestations of a limited form of Wegener's granulomatosis with c-ANCA-associated vasculitis.

The authors report on cerebral and oculorhinal manifestations in a patient with a cytoplasmic pattern of antineutrophil cytoplasmic autoantibody (c‐ANCA)—associated vasculitis. Recurrent Tolosa‐Hunt syndrome, cavernous sinus syndrome, Raeders paratrigeminal neuralgia, and seizures were the major clinical manifestations. Brain MRI showed localized enhancing lesions initially in the cavernous sinus and later in the convexity pachymeninges. The lesions disappeared following 9 months of oral prednisolone (15 mg/day) and cyclophosphamide (100 mg/day) therapy. The presence of c‐ANCA, demonstration of vasculitis, and depositions of immunoglobulin G (IgG) and fibrinogen in the vessel walls of pachymeninges of the patient confirmed an immune‐mediated cause of the vasculitis. Cranial pathology without renal and pulmonary involvement suggests a variant of Wegeners granulomatosis, which is called the “limited” form of Wegeners granulomatosis.

Crossed cerebellar diaschisis in herpes simplex encephalitis

Diaschisis is extremely rare in patients with viral encephalitis. We report the phenomenon of crossed cerebellar diaschisis (CCD) in a 73-year-old man with acute herpes simplex type-1 (HSV-1) encephalitis. The diagnosis of HSV-1 encephalitis was confirmed by detecting HSV-1 deoxyribonucleic acid in the cerebrospinal fluid (CSF). Magnetic resonance images (MRI) showed enhancing lesions at bilateral temporal lobes, insular cortices, and right frontoparietal lobes. Increase signal intensity on T2-weighted images was seen in the mesecephalon. Technetium-99m ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) of the brain showed a large area of hypoperfusion in the right frontotemporoparietal lobes. The side-to-side cerebellar count revealed 19% reduction of the radioisotope tracer uptake in the left cerebellum. The phenomenon of CCD was proposed to be due to both anterograde disconnection of the corticopontocerebellar tracts and retrograde deafferentation of dentatothalamocortical projections.

Brain Single Photon Emission Computed Tomography in Patients with A3243G Mutation in Mitochondrial DNA tRNA

Abstract: Brain single photon emission computed tomography (SPECT) studies were conducted in three patients with A3243G mutation of the mitochondrial (mt) DNA tRNA. All were born to mothers suffering from chronic progressive external ophthalmoplegia (CPEO) with the same A3243G point mutation of the mtDNA tRNA. The first case manifested clinically with MELAS, the second case manifested with CPEO, and third case was characterized by recurrent migraine‐like headache, tremor, and epilepsy. Brain SPECT of all patients, regardless of whether they had or had not suffered from stroke‐like episodes, showed multiple areas of asymmetrical decreased perfusion, particularly in the posterior and lateral head regions, especially the temporal lobes. Crossed‐cerebellar diaschisis may occur. Conventional brain magnetic resonance images failed to show some of the lesions. Decreased regional cerebral blood flow, rather than previously proposed hyperemia, is likely to be the cause. We conclude that mitochondrial vasculopathy with regional cerebral hypoperfusion may be seen on brain SPECT in patients with mitochondrial disorders and A3243G mutations, regardless of whether they have or have not suffered from stroke‐like episodes.

Multiparametric analysis of cerebral substrates and nitric oxide delivery in cerebrospinal fluid in patients with intracerebral haemorrhage: correlation with hemodynamics and outcome

SummaryBackground. There is no information regarding the possible role of cerebral substrates in the pathogenesis of neuronal injury in intracerebral haemorrhages (ICHs). Purposes of this prospective study were to clarify whether changes in substrates are the consequence of the initial brain damage in ICH and to elucidate the relationship among the biochemical mechanisms and clinical course of patients with ICH. Method. During a period of two years, patients (GCS ≤8) who had ICH secondary to an aneurysm (SAH), stroke (sICH), or trauma (tICH) and underwent ventriculostomy with ICP monitoring and/or underwent cranial surgery were randomly enrolled in this study. Extracellular concentrations of glutamate, aspartate, glycine, GABA, lactate, lactate/pyruvate ratio, and glucose in the CSF were measured by use of high-performance liquid chromatography (HPLC). The nitric oxide (NO) concentration in the CSF was analyzed by chemiluminescence. Findings. There were 75 patients (38 women and 37 men) with ICH included in this study. Twenty-one patients had SAH, 28 sICH, and 26 tICH. In tICH patients, there was a 30-fold increase in glutamate and a 10-fold in aspartate over reference values. The levels of glutamate, aspirate, GABA, lactate, glucose, and NO differed significantly among the three groups (p<0.001). There were no significant differences in glycine and L/P ratio among the groups. The initial GCS, the mean CPP and outcome six months after the insult were all significantly correlated with the concentration of substrates (p<0.01), both within groups and among the total sample. The CSF levels of glutamate lactate, NO and glucose correlated significantly with outcome (p<0.005). Conclusions. This study confirms the correlation between the level of EAAs and the outcome of ICHs, suggesting that neurochemical monitoring of these substances may have a role in caring for patients.

Genotype-Phenotype Correlation of Maternally Inherited Disorders due to Mutations in Mitochondrial DNA

Mitochondrial disorders are heterogeneous systemic ailments that are most often caused by maternal inheritance of a variety of mutations of the mitochondrial (mt) DNA. Paternal inheritance and somatic mutation are rare. The disorders are well recognized not only for the genotypic heterogeneity, but also the phenotypic variation among the affected members of a single family. The genotype-phenotype correlation of the diversity of the syndromic and non-syndromic features of mitochondrial disorders are discussed. Some aspects of the molecular mechanisms of this heterogeneity, and the histopathologic findings are highlighted.

Cross-cultural studies using a modified mini mental test for healthy subjects and patients with various forms of vascular dementia

Existing neuropsychological tests are often complex and time-consuming. We designed a modified Mini Mental Test (MMT) battery for clinical assessment of the global and regional higher cortical functions of the brain. We tested its applicability in healthy subjects with different ethnic, cultural and educational backgrounds. The usefulness of our MMT as a tool for the clinical evaluation of patients with various forms of vascular dementia was determined. The MMT comprises five subtests, including clinical evaluations of: (A) orientation (6 points); (B) attention, right-left discrimination, speech, and calculation (20); (C) immediate recall, and recent and remote memory retrieval (10); (D) praxis (10); and (E) visuospatial orientation, agnosia, hemianopsia, and visual hemineglect (14). The MMT was administered to 100 healthy subjects from two different ethnic backgrounds (Indonesian and Chinese/Taiwanese) and diverse cultural and educational backgrounds, and to 61 patients with various forms of vascular dementia. MMT scores were significantly lower in healthy subjects with a low level of education regardless of their ethnic background (p<0.001). Patients with vascular dementia had much lower MMT scores than did the comparable age-adjusted normal controls (p<0.001). Of the patients with vascular dementia, those with Binswangers disease had the lowest MMT scores (25.5+/-28.9), followed by those with large cerebral infarcts (48.0+/-7.1), cerebral haemorrhage (49.0+/-8.5), and multiple lacunar infarctions (55.0+/-0.5) (P<0.001). With a cut-off point of 33/55 (partial score/total score), the sensitivity and positive predictive value of the MMT were 0.98 and 0.94, respectively. The MMT is a simple and useful tool for clinical assessment of the cognitive functions of healthy subjects and patients with or without vascular dementia. It can be used for individuals with different ethnic, cultural and educational backgrounds.