Band 2, Heft 3

The young human brain is highly plastic and thus early brain lesions can lead to aberrant development of connectivity and mapping of functions. This is why initially in cerebral palsy only subtle changes in spontaneous movements are seen after the time of lesion, followed by a progressive evolution of a movement disorder over many months and years. Thus we propose that interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One such treatment might be autologous stem cell transplantation either intracerebrally or intravenously. All babies come with an accessible supply of stem cells, the umbilical cord, which can supply cells that could theoretically replace missing neural cell types, or act indirectly by supplying trophic support or modulating inflammatory responses to hypoxia/ischaemia. However, for such radical treatment to be proposed, it is necessary to be able to detect and accurately predict the outcomes of brain injury from a very early age. This article reviews our current understanding of perinatal injuries that lead to cerebral palsy, how well modern imaging might predict outcomes, what stem cells are yielded from umbilical cord blood and experimental models of brain repair using stem cells.

Glioblastoma is the most frequent, the most malignant and the best vascularised primary brain tumor. Substantial evidence suggests that IGFBP-2 (insulin-like growth factor binding protein) may play a significant role in the development and progression of various types of cancer, including the anaplastic progression of astroglial tumors. The correlation of IGFBP-2 and VEGF over-expression in diffuse gliomas and strong IGFBP-2 immunostaining and co-expression with VEGF in the cells of pseudopalisading necrosis suggests the induction of IGFBP-2 expression by hypoxia and/or possible involvement of its protein product in angiogenesis. The aim of this study was to analyze the expression of IGFBP-2 and the relationship between the IGFBP-2 expression, extent of bizarre angiogenesis and the presence of pseudopalisades. The prognostic impact of these variables was estimated, as well. Our results revealed that most glioblastoma (75%) express IGFBP2 and that IGFBP2 expression was associated with the presence of pseudopalisading necrosis as well as extensive bizarre angiogenesis. IGFBP-2 immunoreactivity in more than 5% of tumor cells and the presence of pseudopalisading necrosis were prognostically significant in univariate analysis (p=0.034) while in multivariate analysis only a patient’s age and the presence of pseudopalisades remained statistically significant (p=0.004). The results of our study showed the association of IGFBP-2 expression in glioblastoma with pseudopalisades and bizarre angiogenesis thus confirming on morphological grounds presumed induction of this gene under hypoxic conditions and its possible role in angiogenesis.

We quantitatively analyzed the dendritic and dendritic spine development on basal and oblique dendrites of large layer IIIc pyramidal neurons of the prospective prefrontal area 9 in the brains of three infants with Down syndrome (DS) and five age-matched-controls over the period from 32 weeks postconception to the 7th postnatal month. By using Neurolucida 3.1 software on rapid Golgi impregnated slices, 9–10 neurons were three-dimensionally reconstructed. There were no significant differences in the pattern of the dendritic and spine development between the basal and apical oblique dendrites. The DS subjects did not depart significantly from the developmental curve of the control subjects. Our data showed that large and significant segment outgrowth, in parallel with dendritic elongation occurred during a limited period of time, between 36 weeks postconception and the first postnatal month. Dendritic spines appeared at the time of birth and their density continued to increase up to the age of 7 months. During the first postnatal month long thin spines and filopodia-like protrusions predominated, but the spines later changed their morphology to a more mature form. No differences in the spine morphology were qualitatively observed between the DS infants and the age matched controls. This data suggests that intensive formation of cortical circuitry occurs on large layer IIIc pyramidal neurons during perinatal period and is not disturbed in DS infants. Consequently, this could be a biological potential to mitigate psychomotor impairment in DS patient.

Research results indicate systemic odor identification deficits in patients with Alzheimer’s disease (AD). The aims of this study were: 1) to compare the ability to identify different odors and to compare cognitive status among patients with AD, patients with vascular dementia (VaD) and a comparison group of elderly persons; 2) to test the efficiency of olfactory and neuropsychological measures to classify patients and 3) to relate the odor identification ability with cognitive functioning for each group, respectively. The participants were 15 patients with AD, 11 patients with VaD and 30 non-demented elderly persons, age range 58 to 90. To assess olfactory function, we used the Scandinavian Odor-Identification Test. To assess cognitive functions, we used the Dementia Rating Scale-2, the Clock Drawing Test, the Boston Naming Test and the Category Fluency Test. The ANOVA showed that patients with AD correctly identifed significantly fewer odors presented to them compared to patients with VaD and control group. Patients with AD achieved significantly lower scores on all neuropsychological measures compared to the control group and differ in the DRS-2 total score, initiation/perseveration, constructive and naming abilities comparing to patients with VaD. Discriminant analysis showed that category fluency and olfactory identification were the best predictors of AD. Significant correlations were found between the olfactory and initiation/perseveration, memory and animal naming abilities for patients with AD. Differences among patients with AD, VaD and elderly persons exist in their abilities to identify odors. The findings suggest that olfactory functional testing in combination with memory testing are important.

Mutations in human dysferlin (DYSF) gene cause both limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), also named dysferlinopathy. They are autosomal recessive muscular dystrophies characterized by degeneration and weakness of proximal and/or distal limb girdle muscles caused by partial or complete absence of a sarcolemmal protein dysferlin. The size and large mutational spectrum of DYSF impose a multistep diagnosis strategy before gene analysis. Here we report the first three patients from two unrelated Croatian families in which diagnosis of dysferlinopathy was suggested on the basis of clinical picture, family history and linkage analysis. In order to confirm the presumed diagnosis, we performed a blood-based assay in which dysferlin expression is screened in blood monocytes. All three tested patients showed complete absence of dysferlin expression, giving strong evidence of dysferlinopathy that was recently confirmed by mutation analysis. In conclusion, we would suggest the presented diagnostic strategy as a reliable and non-invasive method to be used as an alternative to muscle tissue protein analysis in routine diagnostics of dysferlinopathies, prior to the more complex and demanding search for causative DYSF mutations. This non-aggressive approach seems especially useful in situation in which multiplex Western blot (WB) analysis of different muscular dystrophy proteins on muscle sample is not available.

Natriuretic peptides (NPs) regulate salt and water homeostasis by inducing natriuresis and diuresis in the kidney. These actions in addition to those via the heart and vascular system play important roles in the regulation of blood pressure. In the central nervous system NPs play a significant role in neuronal development, synaptic transmission and neuroprotection. Currently, six different human NPs have been described: atrial natriuretic peptide (ANP), urodilatin (URO, renal natriuretic peptide), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) as well as guanylin and uroguanylin. ANP, URO and BNP activate the natriuretic peptide receptor A (NPR-A or guanylate cyclase A (GC-A)) while CNP activates natriuretic peptide receptor B (NPR-B or guanylate cyclase B (GC-B)). Guanylin and uroguanylin are known to activate guanylate cyclase C (GC-C). The receptors GC-A, GC-B, and GC-C are widely expressed in the human body. Currently, GC-B and CNP seems to have the highest expression in central nervous system compared to other NPs and their receptors. All known NPs generate intracellular cyclic GMP (cGMP) by activating their specific guanylate cyclase receptors. Subsequently, cGMP is able to activate protein kinase I or II (PKG I or II) and/or directly regulate transmembrane proteins such as ion channels, transporters and pumps. NPs also bind to the natriuretic peptide receptor C (also called clearance receptor NPR-C) which is a major pathway for the degradation of NPs and has no guanylate cyclase activity. In this review we will focus on new insights regarding the physiological effects of NPs in the brain, especially specific areas of their signaling pathways in neurons and glial cells.

Acute disseminated encephalomyelitis (ADEM) is an acute, monophasic neurologic syndrome that occurs after vaccination against various viruses and after many viral infections and rarely occurs again in the same patient. Weston Hurst disease or acute hemorrhagic encephalomyelitis (AHE) is a hyperacute ADEM variant that shares many pathological similarities with ADEM. ADEM clinically and neuropathologically faithfully reflects the animal model of experimental allergic encephalomyelitis (EAE), and animal studies have provided us with new insights into pathogenesis of this disorder. Although there is much controversy whether ADEM is a separate disease or just one of possible manifestations of multiple sclerosis, there are clear histopathological characteristics that support ADEM as a separate disease This mini review will focus on pathological characteristics of ADEM emphasizing differences from other types of idiopathic demyelinating diseases.

Autism spectrum disorders (ASD) represent complex neurodevelopmental disorders characterized by impairments in reciprocal social interactions, abnormal development and use of language, and monotonously repetitive behaviors. With an estimated heritability of more than 90%, it is the most strongly genetically influenced psychiatric disorder of the young age. In spite of the complexity of this disorder, there has recently been much progress in the research on etiology, early diagnosing, and therapy of autism. Besides already advanced neuropathologic research, several new technological innovations, such as sleep functional MRI, diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy imaging (1H-MRS) divulged promising breakthroughs in exploring subtle morphological and neurochemical changes in the autistic brain. This review provides a comprehensive summary of morphological and neurochemical alterations in autism known to date, as well as a short introduction to the functional research that has begun to advance in the last decade. Finally, we mention the progress in establishing new standardized diagnostic measures and its importance in early recognition and treatment of ASD.

Skeletal-extraskeletal angiomatosis is defined as a benign vascular proliferation affecting the medullar cavity of the bone and at least one other type of tissue, including skin, subcutaneous tissue, viscera, muscle, or synovium, and which does not spread to avascular tissue such as cartilage. Primary hemangiomas/cavernous hemangiomas (cavernomas) are exceedingly rare in the skull, accounting for 0.2% of all osseous neoplasms and are usually located in frontal and parietal bones. The authors present the case of a 66-year-old man who was admitted with right-side hemiparesis. MRI revealed a destructive bone lesion of the left frontal bone. Digital subtraction angiography of the brain did not reveal pathological vascularization, but a minor submucous hemangioma was seen in the nasal airway. Urine test for Bence-Jones proteins was positive for IgG λ light chain. Bone marrow aspiration and CSF analysis revealed no evidence of systemic myelomatosis suggesting a monoclonal gammopathy of undetermined significance. A highly vascular tumor was surgically removed. The histopathology verified cavernous hemangioma of the skull and the nasal submucous hemangioma. We discuss the diagnostic procedure, possible pathophysiological mechanisms and treatment implementation. It is possible that immunoglobulins from monoclonal gammopathies have an etiologic role in the development of the bone and skin changes in older patients, as an acquired condition, by producing a vascular injury that could lead to the multiple hemangiomas in skeletal-extraskeletal angiomatosis. To prevent misdiagnosis with lesions of other origins, multiple lesions of the head must be resected and histopathologically verified. In conclusion, to the best of our knowledge, this is the first case of giant cavernous hemangioma of the skull associated with paraproteinemia and skeletalextraskeletal angiomatosis limited to the head.

Jan Evangelista Purkyně (or Purkinje, as he was spelled in his German publications prior to 1850) was one of giants in the XIXth century science. His contributions are numerous, and his research interests were wide-ranging. This study is divided into two parts. In the Part I, we provide a general overview of Purkyně’s life and work, focusing on his pioneering role in the rise of experimental physiology and microscopical anatomy. In the Part II, we will: (a) focus on his contributions to neuroanatomy, neurohistology and cell theory; (b) provide the first complete English translation of his relevant publications, and (c) provide a critical historical review of the importance of his contributions in comparison to his main contemporary competitors: Christian Gottfried Ehrenberg, Gabriel Gustav Valentin, Theodor Schwann, Robert Remak and Adolf Hannover.