Risk factors in ischemic stroke (preliminary study)

The aim of the study was the epidemiological analysis of patients with ischemic stroke hospitalised in the Department of Neurology Medical Academy in Gdańsk in 2000 year. We especially investigated the risk factors for ischemic stroke in order to improve our ability to prevent stroke. We studied 222 patients with ischemic stroke. There were 79 (35.5%) women and 143 (64.4%) men. The mean age of the patients was 68.05 ± 13.4 years and it was statistically significantly higher in women (72.05 ± 12.4) than in men (65.9 ± 13.4) (p = 0.001). Stroke was more severe in women (mostly TACS), than in men (mostly PACS) and it was statistically significant. The statistical analysis were made using computer program StatView version 5.5. The most often observed risk factors were hypertension (68%), morbus coronarius (50.8%), hypercholesterolemia (27.9%). Diabetes mellitus and alcoholism were recognised in lower percent of the cases. In 60 (26.1%) patients the presence of a few risk factors in one patients were observed. The patients arrival to the hospital was: within 3 h from onset of stroke - 24.6%, within 6 h - 43.7% of patients. Early presentation of patients with acute stroke to the hospital is important for immediate treating within limited therapeutic time window. The CT examination was made in 94.9% of patients and in 53.7% within 24 h of symptom onset. During hospitalisation 38.7% patients significantly improved and 13.8% patients died within 30 days of stroke beginning. Comparison of the examination of the patients using Rankin scale showed improvement of our patients after treatment.Celem pracy jest analiza epidemiologiczna chorych z udarem niedokrwiennym mózgu hospitalizowanych w Klinice Neurologii Dorosłych AMG. Szczególną uwagę zwrócono na analizę czynników ryzyka udaru mózgu pod kątem pierwotnej i wtórnej profilaktyki udaru. Badania przeprowadzono w ramach Narodowego Programu Udaru Mózgu. Analizy statystyczne przeprowadzono na podstawie komputerowego programu Statistica. Badano 222 chorych z udarem niedokrwiennym, w tym 79 (35,5%) kobiet i 143 (64,4%) mężczyzn hospitalizowanych w Klinice Neurologii Dorosłych AMG w 2000 roku. Wiek chorych wynosił średnio 68,05 ± 13,4 lata i był statystycznie znamiennie wyższy wśród kobiet (72,05 ± 12,4) niż wśród mężczyzn (65,9 ± 13,4) (p = 0,001). Udar mózgu jest cięższy w przebiegu u kobiet niż u mężczyzn (p = 0,001). Do najczęstszych czynników ryzyka udaru mózgu należały: nadciśnienie tętnicze (68%), choroba wieńcowa (50,8%), hipercholesterolemia (27,9%), stosunkowo rzadko występowała cukrzyca (19,5%). Znamienne było współwystępowanie kilku czynników ryzyka u 1 chorego. Chorzy docierali do Kliniki stosunkowo szybko: do 3 h od wystąpienia udaru - 24,6% chorych, do 6 h - 43,7% chorych. Tomografię komputerową (CT) głowy wykonano u 94,9% chorych, w tym u 53,7% w 1. dobie hospitalizacji. Zgon stwierdzono u 13,8% pacjentów, a wyraźną poprawę - u 38,7% chorych. Porównując stan neurologiczny chorych w momencie przyjęcia i wypisu w skali Rankina, stwierdzono znamienną poprawę stanu chorych po leczeniu

Hyperhomocysteinemia - important risk factor for ischemic stroke

Udary mózgu są trzecią co do częstości przyczyną śmierci oraz najczęstszą przyczyną inwalidztwa w populacji osób dorosłych. Etiologia udarów często pozostaje nieustalona. Wśród licznych czynników etiopatogenetycznych udaru mózgu należy uwzględnić hiperhomocysteinemię, która odgrywa istotną rolę w patogenezie udaru mózgu jako czynnik wywołujący proces miażdżycowy i wpływający na zaburzenia krzepnięcia. Metabolizm homocysteiny zależy od wielu czynników, takich jak: stężenia kwasu foliowego, witamin B6 i B12 lub mutacji genów kodujących metabolizm homocysteiny: reduktazy N5, N10-metylenotetrahydrofolianowej (MTHFR, methylenetetrahydrofolate reductase), β-syntazy cystationinowej (CBS, cystationine β syntase) i syntazy metioninowej (MS, metionine syntase). Ocena stężenia homocysteiny u pacjentów z chorobami naczyniowymi, w tym u chorych z udarem mózgu, nie tylko poszerza wiedzę o etiologii i mechanizmach udarów mózgu, ale w sposób praktyczny wpływa na ich leczenie i zapobieganie im.Hyperhomocysteinemia is emerging as possible risk factor for cardiovascular disease, including cerebral stroke. Stroke is one of the leading causes of mortality and disability in Poland. The etiology of stroke is often unknown; it has been estimated that etiology and pathophysiology in more that 40% of strokes remains unexplained. Hyperhomocysteinemia is considered a modifiable risk factor for stroke, possibly because of atherogenic and prothrombotic mechanism. Both, genetics and environmental (e.g. dietary intake of folic acid and B vitamins) factors affects homocysteine level. One of the most common genetics defects of homocysteine metabolism is a mutation in the enzyme methylenetetrahydrofolate reductase (MTHFR), metionine syntase (MS) and cystationine beta syntase (CBS). Identification of the role of hyperhomocysteinemia as the modifiable risk factor for stroke may lead to more effective prevention of stroke through dietary and pharmacological modification of homocysteine level

The model homologue of the partially defective human 5,10-methylenetetrahydrofolate reductase, considered as a risk factor for stroke due to increased homocysteine level, can be protected and reactivated by heat shock proteins

The A222V substitution in the human MTHFR gene product (5,10-methylenetetrahydrofolate reductase) is responsible for a decreased activity of this enzyme. This may cause an increased homocysteine level, considered as a risk factor for arteriosclerosis and stroke. The bacterial homologue of the human enzyme, MetF, has been found to be a useful model in genetic and biochemical studies. The similarity of Escherichia coli MetF and human MTHFR proteins is so high that particular mutations in the corresponding human gene can be reflected by the bacterial mutants. For example, the A222V substitution in MTHFR (caused by the C667T substitution in the MTHFR gene) can be ascribed to the A117V substitution in MetF. Here, it is reported that a temperature-sensitive MetF117 (A117V) protein can be partially protected from a thermal inactivation by the heat shock proteins from the Hsp70/100 systems. Moreover, activity of the thermally denatured enzyme can be partially restored by the same heat shock proteins. High temperature protein G (HtpG) had no effect on MetF117 activity in both experimental systems. The presented results indicate that functions of heat shock proteins may be required for maintenance of the MetF117 function. This may have implications for the mechanisms of arteriosclerosis and stroke, especially in the light of previous findings that the A222V MTHFR polymorphism may be a risk factor for stroke, as well as recently published results which demonstrated the increased levels of antibodies against heat shock proteins in stroke patients

Glycosaminoglycans and mucopolysaccharidosis type III

Mucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is a lysosomal storage disease in which heparan sulfate is accumulated in lysosomes, as well as outside of cells, as the primary storage material. This disease is a complex of four conditions caused by dysfunctions of one of genes coding for lysosomal enzymes involved in degradation of heparan sulfate: SGSH (coding for heparan N-sulfatase) – causing MPS IIIA, NAGLU (coding for -N-acetylglucosaminidase) - causing MPS IIIB, HGSNAT (coding for acetyl CoA -glucosaminide acetyltransferase) - causing MPS IIIC), and GNS (coding for N-acetylglucosamine-6-sulfatase) – causing MPS IIID. The primary storage is responsible for some disease symptoms, but other arise as a result of secondary storage, including glycosphingolipids, and subsequent processes, like oxidative stress and neuroinflammation. Central nervous system is predominantly affected in all subtypes of MPS III. Heparan sulfate and its derivatives are the most commonly used biomarkers for diagnosis and prediction procedures. Currently, there is no therapy for Sanfilippo syndrome, however, clinical trials are ongoing for enzyme replacement therapy, gene therapy and substrate reduction therapy (particularly gene expression-targeted isoflavone therapy)

The role of lipoprotein(a) in ischemic stroke

Badano grupę 159 pacjentów, w wieku 40-89 lat (średnia wieku 66,43 lata), u których 3 miesiące wcześniej wystąpił udar niedokrwienny mózgu. Grupę kontrolną stanowiło 137 osób zdrowych w podobnym wieku. Stężenie Lp(a) oznaczano metodą immunoturbidymetryczną. Podwyższone stężenie Lp(a) powyżej 30 mg/dl stwierdzono w grupie badanej u 71 osób (44,65%), a w grupie kontrolnej - u 36 osób (26,2%). Średnie stężenie Lp(a) w grupie badanej było wyższe niż w grupie kontrolnej (odpowiednio 46,21 i 27,65 mg/dl). Analizowano występowanie niektórych czynników ryzyka udaru w grupie chorych z Lp(a)+ i w grupie chorych Lp(a)–. Nadciśnienie tętnicze, choroba wieńcowa, migotanie przedsionków, cukrzyca, a także zaburzenia lipidowe występowały z podobną częstością w obu grupach. Jedynie zmiany w tętnicach szyjnych występowały częściej w grupie chorych Lp(a)+, jednak różnica ta nie była statystycznie znamienna. Stwierdzono także, że w grupie Lp(a)+ więcej było chorych młodszych w wieku 40–50 lat (odpowiednio 12 (16,9%) i 6 (6,82%)), ale różnica ta nie była istotna p = 0,058. Wnioski. 1. Podwyższone stężenie Lp(a) w grupie chorych po udarze mózgu, obciążonych innymi czynnikami ryzyka występowało znacznie częściej niż w grupie kontrolnej; 2. Nie stwierdzono statystycznie znamiennych zależności między podwyższonym stężeniem Lp(a), wiekiem pacjentów i uznanymi czynnikami ryzyka udaru; 3. W związku ze złożoną etiologią udaru uzasadnione są dalsze badania oceniające wzajemne zależności parametrów gospodarki tłuszczowej u pacjentów z chorobą niedokrwienną mózgu.Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) - like substance whose protein component is apolipoprotein(a) linked to apolipoprotein B-100. Lp(a) play an important role in thrombogenesis and atherosclerosis and is considered to be an independent, genetically determined, risk factor for atherosclerosis. The correlation of the serum level of lipoprotein(a) with an ischaemic brain infarction has not been fully established. The aim of this study was to determine the occurence of increased levels of Lp(a) in patients with ischaemic stroke and to establish the correlation between serum Lp(a) concentration and various conventional risk factors of ischaemic stroke. Materials and methods. We evaluated a group of 159 patients 3 months after ischaemic stroke (104 males and 55 females), aged 40–89 years (mean age 66.4) and 137 control subjects with no history of stroke. Results. A high Lp(a) level above 30 mg/dl was found in 71 (44.65%) patients with ischaemic stroke and in 36 (26.2%) controls. The mean level of Lp(a) was higher in patients with history of ischaemic stroke than in control group (46.21 mg/dL and 27.65 mg/dL respectively). Some risk factors of stroke were analyzed in patients with high Lp(a) (Lp(a)+) and with normal level of Lp(a) (Lp(a)–). Hypertension, coronary heart disease, atrial fibrillation, diabetes mellitus, hyperlipidemia appeared with similar frequency in both groups. Changes in carotid arteries occured more frequently in Lp(a)+ group, but it was not statistically significant. There were more patients aged 40–50 years in Lp(a)+ than in Lp(a)– group (12 (16.9%) and 6 (6.82%) respectively), but this difference was also not statistically significant. Conclusions. 1. We observed higher Lp(a) level in patients with other risk factors and with history of ischaemic stroke in comparison with the control group; 2. There were no statistically significant correlations between high serum level of lipoprotein(a) and age of patients or other conventional risk factors; 3. Because of complex etiology of stroke more clinical investigation is needed to establish the association between different lipoprotein subtypes in atherothrombotic patients, (especially those with ischaemic cerebral infarction)

Evidence for interactions between homocysteine and genistein: insights into stroke risk and potential treatment

Elevated plasma homocysteine (2-amino-4- sulfanylbutanoic acid) level is a risk factor for stroke. Moreover, it has been suggested that high levels of homocysteine in the acute phase of an ischemic stroke can predict mortality, especially in stroke patients with the large-vessel atherosclerosis subtype. In clinical studies, supplementation with genistein(5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) decreased plasma homocysteine levels considerably. Therefore, genistein could be considered as a potential drug for prevention and/or treatment of stroke. However, the mechanism of the effect of genistein on homocysteine level remains to be elucidated. In this report, direct functional interactions between homocysteine and genistein are demonstrated in in vitro experimental systems for determination of methylenetetrahydrofolate reductase (MetF) and glutathione peroxidase(GPx) activities, reconstructed with purified compounds, and in a simple in vivo system, based on measurement of growth rate of Vibrio harveyi and Bacillus subtilis cultures. Results of molecular modelling indicated that homocysteine can directly interact with genistein. Therefore, genisteinmediated decrease in plasma levels of homocysteine, and alleviation of biochemical and physiological effects of one of these compounds by another, might be ascribed to formation of homocysteine-genistein complexes in which biological activities of these molecules are abolished or alleviated

Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses

Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT). Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is an isoflavone that has been used in SRT for MPS III. In this report, we tested effects of other flavonoids (apigenin, daidzein, kaempferol and naringenin) on GAG synthesis. Their cytotoxicity and anti-proliferation features were also tested. We found that daidzein and kaempferol inhibited GAG synthesis significantly. Moreover, these compounds were able to reduce lysosomal storage in MPS IIIA fibroblasts. Interestingly, although genistein is believed to inhibit GAG synthesis by blocking the tyrosine kinase activity of the epidermal growth factor receptor, we found that effects of other flavonoids were not due to this mechanism. In fact, combinations of various flavonoids resulted in significantly more effective inhibition of GAG synthesis than the use of any of these compounds alone. These results, together with results published recently by others, suggest that combination of flavonoids can be considered as a method for improvement of efficiency of SRT for MPS III

Comparison of siRNA-mediated silencing of glycosaminoglycan synthesis genes and enzyme replacement therapy for mucopolysaccharidosis in cell culture studies

Cytotoxicity of laronidase (Aldurazyme®), employed in enzyme replacement therapy (ERT) for mucopolysaccharidosis type I (MPS I) and various siRNAs, tested previously in studies on substrate reduction therapy (SRT) for mucopolysaccharidoses, was tested. The enzyme did not cause any cytotoxic effects, and the siRNAs did not inhibit growth of most investigated cell lines. However, some cytotoxic effects of some tested siRNAs were observed in one MPS IIIA cell line. The efficacy of a combination of enzyme replacement therapy and siRNA-based substrate deprivation therapy was tested on three MPS I cell lines. Surprisingly, different results were obtained for different cell lines. The decrease of glycosaminoglycan storage in cells treated simultaneously with both methods was: (i) less pronounced than obtained with either of those methods used alone in one cell line, (ii) similar to that observed for enzyme replacement therapy in another cell line, and (iii) stronger than that obtained with either of the methods used alone in the third cell line. Therefore, it appears that the effects of various therapeutic methods may strongly depend on the features of the MPS cell line