Andres Kulla

Comparative expression analysis of the genes encoding polypyrimidine tract binding protein (PTB) and its neural homologue (brPTB) in prenatal and postnatal mouse brain

The polypyrimidine tract binding protein (PTB) and its recently discovered homologue brain-enriched PTB (brPTB) are RNA binding proteins involved in the control of alternative splicing. We have characterized expression patterns of the PTB and brPTB in course of mouse brain development, using mRNA in situ hybridization. PTB is expressed in choroid plexi and ependyma at all the stages of development and temporarily in the mantle layer of migrating neuroblasts of fore-, mid- and hindbrain and in the external granular layer of cerebellum. In the neurons of adult mouse cerebrum and cerebellum expression of PTB is undetectable. In contrast to this, brPTB is expressed ubiquitously in neuroblasts of various parts of embryonic brain and in the differentiated neurons of postnatal cerebrum and cerebellum. brPTB mRNA is not observed in choroid plexi and ependymal layer. Thus, in the embryonic brain expression patterns of PTB and brPTB overlap, but in the course of brain development the patterns become complementary to each other.

Epidemiology of Primary Central Nervous System Tumors in Estonia

During the period from 1986 to 1996, 1,665 cases of primary central nervous system (CNS) tumors were identified in the resident population of Estonia. Histological verification was available in 81% of the cases. Gliomas were more common in men, while meningiomas and neurinomas were more common in women. No significant difference was observed between the sexes for all primary CNS tumors. The age-specific incidence increased from the age of 30, reached a maximum in the age range of 50–69 years and declined in the elderly which may reflect under-diagnosis. The age-adjusted incidence rate for CNS tumors was 8.5/100,000 population. A comparison of our results with those of a previous study carried out in Estonia revealed a significant histology-specific increase in incidence in all age groups.

Neonatal spinal muscular atrophy type 1 with bone fractures and heart defect.

The authors present the case of an infant girl with severe generalized weakness, multiple bone fractures, and heart defect. She needed mechanical ventilation from birth. Radiographs showed mid-diaphyseal fractures of both humeri and of the right femur as well as generalized osteopenia. Electroneuromyography showed spontaneous fibrillations at rest with no active movements. Motor response to a stimulus could not be registered. A systolic heart murmur was detected, and echocardiography showed a large atrial septal defect and an additional membrane in the left atrium. DNA analysis confirmed the diagnosis of spinal muscular atrophy on the third day of life. Histology of the muscle showed both hypertrophic and atrophic fibers. Degenerating swollen neurons were found in the ventral horns of the spinal cord and also in the mesencephalic red nucleus, which has not been described before. Humeral bone showed only partly formed cortical bone. The spectrum of spinal muscular atrophy is very diverse, and atypical clinical findings do not always rule out 5q spinal muscular atrophy. The SMN1 gene should still be investigated.

Tenascin expression patterns and cells of monocyte lineage: relationship in human gliomas.

Stromal extracellular matrix (ECM) components are thought to play an important role in regulating invasion of human gliomas. Macrophages and microglial cells may heavily influence the integrity of the extracellular compartment of gliomas, and the affected ECM may play a key role in regulating migratory activity of both tumor cells and macrophages/microglia. The aim of this investigation was to study immunohistochemically the expression patterns of four ECM components: fibronectin, laminin, collagen IV, and tenascin (TN) in human gliomas, with special attention to TN. Our main goal was to study the possible correlation between TN expression and macrophagic/microglial infiltration in gliomas. Altogether, 90 gliomas were studied. Tumors included 46 glioblastomas, 19 anaplastic gliomas, 22 low grade gliomas, and 3 pilocytic astrocytomas. Vascular TN prevailed in perinecrotic areas of glioblastomas, whereas interstitial TN was more often expressed distant from necrosis and in the ECM of anaplastic and low grade gliomas. Double staining with CD68 and anti-TN antibodies showed that macrophagic/microglial density was significantly higher in TN-positive areas of most of the glioblastomas and anaplastic gliomas, whereas microglial percentage from total number of CD68-positive cells was in most of the cases significantly higher in TN-negative areas. In addition, we saw a morphologically spatial correlation between higher densities of macrophagic/microglial infiltration and TN expression in perinecrotic areas in glioblastomas. Attachment of macrophages to TN-positive basement membrane zones of newly formed stromal blood vessels was evident. On the basis of our results, we conclude that TN may play a crucial role in regulating trafficking of cells of monocyte lineage in human gliomas.

Survival of patients with primary CNS tumours in Estonia.

We studied a population-based survey that included 1417 patients with a primary central nervous system (CNS) tumour diagnosed in Estonia between 1986 and 1996. Survival rates at 1 and 5 years and median survival by histology and patients age at diagnosis were estimated. Median survival time for all tumours was 33.2 months and 1- and 5-year survival rates were 59.3 and 46.0%, respectively. In multivariate analysis, younger age, better clinical condition (i.e. a Karnofsky Performance Status (KPS) score of 60 and more) and tumour histology were all dependent prognostic factors for better survival. Risk of death was more than 8 times greater for glioblastoma (Risk Ratio (RR) 8.31) and approximately seven times greater for anaplastic astrocytoma (RR 7.22) and other gliomas (RR 5.74) compared with meningiomas. Comparing the first (1986-1989) and the third (1994-1996) time periods, statistically significant improvements in survival occurred for all tumours and astrocytomas. Declines in survival during the second period (1990-1993) were statistically significant for all the tumour groups, but the most striking decrease took place in patients with glioblastoma. Age-specific rates showed that the increase in survival was more evident for patients aged between 45 and 64 years.

Plasminogen Activators in CNS Physiology and Disease

Extracellular proteolysis represents a potent and irreversible mechanism of modulating cell-cell and cell-matrix interactions and remodeling structural components of tissues. Understanding of the role of extracellular proteolysis has evolved during the last decade from a somewhat simplistic concept of proteases being important for breaking down/ remodeling mechanical tissue barriers of the extracellular matrix (ECM) into a more complex view of proteases affecting indirectly many aspects of cell physiology, from cell division and differentiation to programmed cell death (Basbaum and Werb, 1996; Werb, 1997). Not surprisingly, proteases and their regulatory molecules are involved in a wide range of physiological processes of tissue growth and remodeling, as well as in pathological conditions such as tumorigenesis and tissue-destructive diseases (Werb et al., 1999; Andreasen et al., 2000).