Increased circulating endothelial progenitor cells in patients with haemorrhagic and ischaemic stroke: the role of endothelin-1.

Ischaemic stroke induces endothelial progenitor cell (EPC) mobilisation from bone marrow into peripheral blood. Circulating EPCs play an important role in post-injury regeneration of vasculature, whereas endothelial cells (ECs) have been shown to reflect endothelial damage and may be responsible for increased Endothelin-1 (ET-1) expression. We investigated herein the association between numbers of circulating ECs and EPCs, the levels of soluble factors regulating their migration and function, and the clinical outcome in patients with haemorrhagic (HS) or ischaemic stroke (IS). Sixteen patients with HS and eighteen with IS were assessed during the first 24h, day 3, and day 7 after stroke and compared them with twenty-three control subjects. We found elevated EPC and EC concentrations using flow cytometry and increase in VEGF, SDF-1, HGF, and ET-1 plasma levels by ELISA in the HS patients, while ET-1 mRNA expression in peripheral blood cells was elevated in the IS patients. Significant correlations were observed between EPCs or ECs and Big ET-1 protein or mRNA levels in HS but not in the IS patients. We suggest that ET-1 may play a role in pathophysiology of stroke and subsequent EPC mobilisation; however, further studies aimed at the precise elucidation of this issue are required.

Stem cells for neural regeneration--a potential application of very small embryonic-like stem cells.

The goal of regenerative medicine is to ameliorate irreversible destruction of brain tissue by harnessing the power of stem cells in the process of neurogenesis. Several types of stem cells, including mesenchymal stem cells, hematopoietic stem cells, as well as neural cells differentiated from embryonic stem cell lines, have been proposed as potential therapeutic vehicles. In this review paper we will discuss a perspective of stem cell therapies for neurological disorders with special emphasis on potential application of cells isolated from adult tissues. In support of this our group found that murine bone marrow contains a mobile population of Oct-4+CXCR4+SSEA-1+Sca-1+lin⁻CD45⁻ very small embryonic-like stem cells (VSELs) that are mobilized into peripheral blood in a murine stroke model. The number of these cells in circulation increases also after pharmacological mobilization by administration of granulocyte colony stimulating factor (G-CSF). Recently we found that VSELs are present in various non-hematopoietic adult organs and, interestingly, our data indicate that the brain contains a high number of cells that display the VSEL phenotype. Based on our published data both in human and mice we postulate that VSELs are a mobile population of epiblast/germ line-derived stem cells and play an important role as an organ-residing reserve population of pluripotent stem cells that give rise to stem cells committed to particular organs and tissues--including neural tissue. In conclusion human VSELs could be potentially harnessed in regenerative medicine as a source of stem cells for neurogenesis.

Endolymphatic sac tumours and von Hippel-Lindau disease - case report, molecular analysis and histopathological characterization.

Endolymphatic sac tumours (ELST) are aggressive papillary tumours of the temporal bone. The name was finally determined after the endolymphatic sac was determined as the site of their origin. They should be considered in patients with tumours eroding the petrous part of the temporal bone, extending to the cerebellopontine angle or other adjacent structures. These very rare tumours in the general population have much higher prevalence in von Hippel-Lindau disease. Hence molecular analysis of the VHL gene should be performed in patients with ELST and their relatives. The purpose of this study is to present a case report, histopathological characterization of endolymphatic sac tumours, their association with von Hippel-Lindau disease and use of molecular analysis.

Can we talk about CD4+CD28- lymphocytes as a risk factor for ischemic stroke?

BACKGROUND: CD4+CD28- lymphocytes are implicated in the destabilization of atheromatous plaque, leading to acute coronary episodes. One may ask whether these cells play a similar role in ischemic stroke pathogenesis with an atherosclerotic background. METHODS: Flow cytometry was applied to determine the percentage of CD4+CD28- lymphocytes in the peripheral blood of patients during the acute phase of their first ischemic stroke (group I) and in patients without a history of stroke but with two of the most important risk factors (hypertension, diabetes) for atherosclerosis-related ischemic stroke (group II). The results were compared with healthy controls. RESULTS: The median percentages of CD4+CD28- lymphocytes in groups I and II did not differ significantly, but for each of these groups the percentage was higher than in the control group. The time of blood sampling from onset of stroke, presence of the ischemic focus in the CT brain scan and severity of neurological deficits did not correlate with the percentage of CD4+CD28- lymphocytes. CONCLUSIONS: We conclude that CD4+CD28- lymphocytes are implicated in mechanisms enhancing the risk of acute ischemic stroke and not a consequence of stroke.

Different presentations of late-detected phenylketonuria in two brothers with the same R408W/R111X genotype in the PAH gene.

Although the clinical heterogeneity of phenylketonuria (PKU) is well established, some questions about this condition remain. Subjects from the same family who share the same mutations in the phenylalanine hydroxylase (PAH) gene are expected to display similar disease courses, and therefore, when blood phenylalanine (Phe) levels, genotype and dietary treatment are all similar, differences in patient outcomes require additional explanations. The present authors describe two entirely different courses of late-detected PKU in two brothers with the same R408W/R111X genotype in the PAH gene. The older sibling was diagnosed with PKU at the age of 4 years and given treatment. His IQ was 97 at 26 years of age and moderate involvement of periventricular white matter was detected. The younger brother was diagnosed with PKU at the age of 11 months and given treatment. His IQ was < 25 at 22 years of age and severe dysmyelination changes were found by magnetic resonance imaging. The differences in the courses of the disease between these two brothers appear to be related to variations in their blood-brain barriers.

Peritumoral angiogenesis around primary and metastatic brain neoplasms. Morphometric analysis.

In an interface between brain tumour and surrounding tissue there occur simultaneously two very important phenomena. On the one hand there is a proliferation of peritumoral vessels penetrating into the neoplasm in which they make alike tumoral vessels. On the other hand, neoplastic cells penetrate from the tumour into the vicinity along peritumoral vessels. To determine the influence of the histological type of different brain tumours, their malignancy degree as well as location in the central nervous system on peritumoral vessels morphological appearance, the detailed morphometric analysis was carried out. The morphological examination and computerised morphometric analysis were conducted on 166 primary and metastatic CNS neoplasms taken during routine neurosurgical procedure. It turned out that the peritumoral angiogenesis depends predominantly on the malignancy of brain tumours. This angiogenesis may be modified by local environmental factors--it is more evident within the white matter than in the cerebral cortex. One of the important factors may be reactive peritumoral astrogliosis. There is no specific CNS region predisposed to the development of peritumoral angiogenesis.

Guillain-Barre syndrome in patient with Burkitt's lymphoma and type 2 diabetes mellitus.

Although peripheral neuropathies are commonly observed in patients with non-Hodgkin's malignant lymphomas (NHML), Guillain-Barre syndrome (GBS) belongs to the occasional complications of lymphoproliferative disorders. It appears in less than 0.3 per cent of NHML. It is worthy of note that in the reported case there occurred three independent risk factors of peripheral neuropathy: Burkitt's lymphoma, chemotherapy and type 2 diabetes mellitus. Based on clinical course, EMG finding and neuropathological examination, in spite of normal cerebrospinal fluid protein content, GBS as a paraneoplastic disorder was diagnosed. It was assumed that chemotherapy and diabetes mellitus conduced to severe neuropathy.

Morphometric analysis of axons in the minute multiple sclerosis lesions and shadow plaques in patients with multiple sclerosis.

The objective of the present study was to quantitatively detect axons in the minute multiple sclerosis (MS) lesions and in shadow plaques, taking into consideration the relapsing-remitting(R-R) and secondary progressive(SP) stages of MS. The brain tissue of 12 patients deceased due to MS was investigated. An image-computerized analysis was made for measurements of axons. Based on the findings we concluded that damage to axons appears in both the minute MS lesions and in shadow plaques. Demyelination and ineffective (too late or too slow) remyelination seemed to be very important factors in axonal damage. Irreversible damage to axons may appear in both the secondary progressive and relapsing-remitting stages of MS, causing permanent neurological deficits, irrespective of the duration of the disease.

Cardiovascular load of competitive golf in cardiac patients and healthy controls.

PURPOSE: Sports in cardiovascular patients (CVP) should serve for risk factor management, increase of exercise capacity, and reintegration into daily life. Competition of cardiac patients with healthy sportsmen is often discouraged and thus reintegration hampered. Golf, with its endurance component and exceptional rules (e.g., the handicap) should be an alternative. METHODS: In 20 male golfers (65.2 +/- 6.1 yr, 1.4 +/- 0.3 W x kg(-1) body weight (approximately 4.8 METs)) with cardiovascular diseases and eight controls (C) (62 +/- 5 yr, 2 +/- 0.4 W x kg(-1) body weight (approximately 6.9 METs)), the performance assessed in the laboratory (ergospirometry, serum lactate) allowed for comparison of the cardiovascular load on the golf course (lactate, Holter monitoring, blood pressure, urine catecholamines). RESULTS: In comparison with in the hospital, resting heart rates were significantly (P < 0.001) elevated in both groups immediately before the tournament (CVP: 76.1 +/- 10.8 vs 90.1 +/- 8.6 bpm; C: 74.8 +/- 6.3 vs 92.3 +/- 9.7 bpm). On the course, the mean heart rates of the patients were closer (P < 0.01) to the anaerobic threshold (105.4 +/- 11.0 vs 115.3 +/- 10.8 bpm) in comparison with controls (100.5 +/- 7.3 vs 125.6 +/- 16.6 bpm) corresponding to 0.9 +/- 0.3 W x kg(-1) (approximately 3.1 METs) or 76.0 +/- 13.1%VO2max (CVP) and to 0.9 +/- 0.2 W x kg(-1) (approximately 3.1 METs) or 55.3 +/- 9.1%VO2max (C). Serum lactate levels were 1.36 +/- 0.7 mmol x L(-1) (approximately 12.4 +/- 6.4 mg x dL(-1)) (CVP) and 1.1 +/- 0.4 mmol x L(-1) (approximately 9.1 +/- 3.6 mg x dL(-1)) (C). In patients, arrhythmias were lower in quantity and quality (LOWN) in comparison with other activities as registered by means of the 24-Holter-ECG. CONCLUSION: In cardiovascular patients, competitive golf reaches an intensity that may positively influence cardiovascular risk factors, depending on the type of the course and may provide patients the desired integration with healthy sportsmen.

[Coexistence of intrathecal immunoglobulin synthesis with amyloidosis in patient with polyneuropathy in the course of multiple myeloma]. / Wspólwystepowanie intratekalnej syntezy immunoglobuliny i amyloidozy u chorego z neuropatia obwodowa w przebiegu szpiczaka plazmatycznokomórkowego.

A coexistence of high level of intrathecal monoclonal immunoglobulin (intrathecal synthesis?) and amyloidosis as a possible cause of peripheral neuropathy in multiple myeloma patient was presented. In the reported case neurological symptoms and intrathecal monoclonal protein existence had been manifested several months before the appearance of plasmocytoma.

Changes in blood coagulation and fibrinolysis associated with maximal exercise and physical conditioning in women taking low dose oral contraceptives.

Blood coagulation parameters (thromboplastin time. PT; activated partial thromboplastin time, aPTT; fibrinogen; antithrombin III, ATIII; von Willebrand factor-concentration, vWF; factor VIII-activity, FVIII) and fibrinolytic parameters (plasminogen; (alpha-antiplasmin; euglobulin-lysis-time, Elt; tissue plasminogenactivator-antigen, tPA-antigen; plasminogenactivator-1-antigen, PAI-1-antigen) were evaluated in 34 women on low-dose oral contraceptives (OC) twice at intervals of 12 weeks each time before and after maximal exercise. During the 12 weeks, 24 women took part in an aerobic conditioning program and 10 women were requested to avoid any kind of sports activity for this period. Blood samples were taken before training and before and after maximal treadmill exercise. This procedure was repeated after the training program. After maximal exercise we found a significant reduction of aPTT and PT (increase in %), a decrease in ATIII, vWF, fibrinogen, plasminogen and alpha2-antiplasmin but an increase in fibrinolytic activity (all p<0.05). Maximal exercise is associated with an increase in blood coagulation and fibrinolysis also in women taking OC. After the physical conditioning program an increase in fibrinolytic activity at rest was noted in the training group. Opposed to that the fibrinolytic activity at rest decreased in the control group after abstinence of sports activity over this period (p<0.05, MANOVA).

Amyotrophic form of Creutzfeldt-Jakob disease with rapid course in 82-year-old man.

The authors present a case of Creutzfeldt-Jakob disease in 82-year-old man. Besides the onset of the disease in the elderly and short survival time (8 weeks), other uncommon clinical and morphological features also characterized our case. An evident amyotrophic syndrome, confirmed in morphological findings, developed soon after the CJD onset. The spongiform change also observed within the white matter of cerebral hemispheres allowed us to diagnose the 'panencephalopathic' form of CJD.

Guidelines and recommendations for content, structure, and deployment of mutation databases: II. Journey in progress.

The HUGO Mutation Database Initiative has produced guidelines and recommendations addressing uniform nomenclature of (human) genes and alleles, and computing standards to permit a moderate level of built-in redundancy, searchable interfaces, and compatibility between the comprehensive (genomic) and locus-specific types of databases. The participating community (developers and users) have been moving the project along rapidly, as described here.

PAHdb: a locus-specific knowledgebase.

PAHdb is an online relational locus-specific "mutation database" (http://www.mcgill.ca/pahdb) for the human phenylalanine hydroxylase gene (symbol PAH) and its associated phenotypes (protein, metabolic, clinical). When combined with associated information (population distribution of allele, haplotype association, etc.) PAHdb functions as a knowledgebase. From the outset, and in the absence of raw data (e.g., sequence gels), PAHdb has instead been an annotated repository of information about mutations maintained by a team of curators. It is also disease-oriented, being focused on a variant phenotype (hyperphenylalaninemia (HPA) and its most important form of disease, phenylketonuria (PKU)) resulting from primary dysfunction of the PAH enzyme (EC 1.14.16.1); it is "patient friendly" in that it contains information for those personally involved with HPA/PKU (MIM# 261600). PAHdb also serves its community through direct interaction.

[Fibrinogen and lipids: associated risk factors for ischemic cerebral stroke]. / Fibrynogen i lipidowe czynniki ryzyka w niedokrwiennym udarze mózgu.

The study included 55 patients (18 females, 37 males); aged 32-75 yr. who divided into three groups according to the severity of clinical picture: 12 people with reversible ischaemic stroke (RIS), 20 with progressive ischaemic stroke (PIS), 23 with complete stroke (CS). Levels of total cholesterol, high density lipoproteins (HDL), apolipoproteins A1 and B (ApoA1 and ApoB), fibrinogen (Fb) and Lp (a) were measured. Lipid factor of atherosclerosis (ATHi) was quantified. Qualitative evaluation of lipids contents in cerebrospinal fluid (CSR) was performed. Distribution of cholesterol--containing lipids among the fractions, despite low values, had clearly atherogenic profile. 12% patients with irreversible ischaemic stroke, 16% with progressive ischaemic stroke and 85% with complete stroke had Fb level above 4 g/l. Lp (a) levels in all cases were significantly higher in the cells isolated from CSF. The severity of the stroke correlated with increasing levels of lipids in the cells isolated from SF. There was correlation between LDL cholesterol and content of lipids in the cells from CSF.

Computerized morphometric analysis of human leukemic and lymphomatous cells in various histological environments of central nervous system.

The leukemic and lymphomatous cells appear within the central nervous system (CNS) in 5 different environments: in CNS vessels, perivascular spaces, meninges, nervous tissue and in CNS hemorrhages. A computerized analysis of geometric and densitometric parameters of neoplastic cells in these compartments were done for better recognition of penetration and spreading of leukemia and lymphoma within the CNS. A post-mortem neuropathological investigations were carried out on 16 patients deceased due to acute myeloblastic leukemias (M1, M2), blastic phase of chronic myelogenous leukemia, lymphoblastic lymphoma and acute lymphoblastic leukemia. Following nuclear parameters of neoplastic cells were analyzed: area, "form factor", mean, minimal and maximal density. An evident differentiation of nuclear parameters within the CNS environments was found. The nuclei within the perivascular spaces and especially in CNS hemorrhages were significantly shrunken and dense (p < 0.01), but not evidently deformed. The intracerebral infiltrates appeared to be most differentiated group (p < 0.01). Morphometric values of leukemic and lymphomatous cells show regressive changes of neoplastic cells within the CNS perivascular spaces, nervous tissue and in CNS hemorrhages. These changes depend on unfavorable factors in the mentioned CNS environments, and also on time of cell persistence in these regions. Meninges were found to be the only CNS structure facilitating the survival and proliferation of leukemic and lymphomatous cells.

Genomics, mutations and the Internet: the naming and use of parts.

Mutations are the source of genetic variation and diversity; by their effect, some are neutral, others are pathogenic. In contemporary genetics, mutations appear at the interface between genomics (structural and functional) and genetics (heredity), where they serve gene discovery and mapping (genomics) and generate challenges to modify their phenotypic effects (medical genetics). Assuming the human genome harbours 80,000 transcribed genes each possessing at least 100 different (germline) alleles in a typical population, how then to record and recover data on at least 8 million human alleles? Bioinformatics is the essential resource to create the corresponding accessible digital libraries (genomic and locus-specific mutation databases) for this purpose, a goal to which The HUGO Mutation Database Initiative (Science 279: 10-11, 1998) aspires. Guidelines now exist for naming alleles (Hum Mutat 11: 1-3, 1998). The principles behind the practice are illustrated by PAHdb (http:/(/)www.mcgill.ca/ pahdb), a prototype locus-specific mutation database (NAR 26: 220-225, 1998), and by prototype genomic mutation databases (HGMD (NAR 26: 285-287, 1998), http:/(/)www.uwcm.ac.uk/uwcm/mg/hgmd0.h tml; the EBI mutation database, http:/(/)www2.ebi.ac.uk/mutations/; and OMIM, http:/(/)www.ncbi.nlm. nih.gov/Omim.html).

Guidelines and recommendations for content, structure, and deployment of mutation databases.

These Guidelines recognize the need for annotated online mutation databases documenting allelic variation (both pathogenic and phenotype modifying, and also neutral polymorphic); the databases will be both generalized (genomic) and specialized (locus specific), and a seamless integration of the two types is intended. Each requires a Document (its "biography"). Different mutation databases will have different content and structure, but a minimum core of content in a shared syntax is a necessity; the core includes: (1) a unique identifier of the allele; (2) the source/report of the data; (3) context of the allele; and (4) the allele itself (the description). The allele description should be validated. There is no single correct way to design a mutation database. The uses to which databases are put dictate the design. Software and deployment together recognize the different needs of specialized and generalized databases, while making them mutually compatible through shared content and the appropriate search facilities. A set of eight Recommendations completes these Guidelines for Content, Design, and Deployment of Mutation Databases.

Computerized morphometric analysis of the cerebellum in patients with lymphoblastic lymphomas of various survival time.

Post-mortem neuropathological investigations of the cerebellum were carried out in 15 patients deceased due to lymphoblastic lymphoma (LBL). In patients with survival time of LBL longer than 20 months, neuronal structures of the cerebellum appeared to be significantly rarefied. It was especially observed within granular layer, less frequently in Purkinje and dentate nuclei cells. In cases with longer survival time shrinkage and deformation of neurons, especially Purkinje and dentate nuclei cells were observed. The morphometric analysis suggests that the cerebellar neuronal changes might be a consequence of remote effects of LBL on nervous tissue. The longer survival time contribute to the nervous system exposure on remote effects of neoplasm. The dentate nuclei cells are damaged due to remote effect of lymphoma, irrespective of Purkinje cells destruction.