Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular disorder causing ischaemic attacks and strokes in middle-aged adults. Though the clinical spectrum includes some typical symptoms, recognition of the disease, especially at an earlier stage, is very difficult because of the highly variable manifestation and incomplete clinical picture. Characteristic brain MRI findings and the presence of pathogenic variants in the NOTCH3 gene are fundamental for CADASIL diagnosis. In this paper, we provide the first comprehensive report on CADASIL patients from Slovakia. Altogether, we identified 23 different pathogenic variants in 35 unrelated families. In our cohort of patients with clinical suspicion of CADASIL, we found a causal genetic defect and confirmed the diagnosis in 10.2% of cases. We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype-genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13). The most frequently described location for pathogenic variants was in exon 4, whereas the most common single variant was p.Arg1076Cys in exon 20. Based on the results of our study, we propose a re-evaluation of the criteria for the selection of patients suitable for NOTCH3 gene analysis. We hereby state that the currently used protocol of a high score requirement is not ideal for assessing molecular analysis, and it will be desirable to be less strict in criteria for genetic testing.

[Nijmegen breakage syndrome in Slovakia]. / Nijmegen breakage syndrom na slovensku.

BACKGROUND: The autosomal recessive Nijmegen breakage syndrome (NBS) is a DNA repair disorder due to a mutation in the NBS1 gene on 8q21. Hyperradiosensitivity and high risk for lymphoreticular malignancy are important reasons for early diagnosis and prevention by avoidance of ionisation. The frequency of NBS heterozygotes of the mutation 657de15, which is predominant in the Slavic population was estimated to be in the range of 1:90-1:314 in different parts of Poland, and 1:128-154 among Czech newborns, born 20 years ago. METHODS AND RESULTS: Lower prevalence of affected homozygotes born in Czechoslovakia in the period 1969- 1992 (24 among 5.2 million newborns corresponds to 1:271000) than expected on the basis of carrier frequency is explained to be due to underdiagnosing because the rate of prenatal lethality in the NBS families is not increased or it is even lower than in the general population. The underdiagnosing of NBS is emphasized also by the mean age at diagnosis (7.5 years) although severe microcephaly is present at birth. The possibility to offer effective prevention of primary and secondary malignancies becomes the motivation for interdisciplinary collaboration with paediatricians, neurologists, immunologists and clinical geneticists. A decrease of the mean age down to 6 months at diagnosis among the 11 newly recognized patients has been achieved in the previous 4 years. The occurrence of homozygotes was relatively higher in Slovakia with 5 million inhabitants (14 patients in 11 families) than in the Czech Republic with a population of 10 million (21 patients in 14 families), and therefore the frequency of NBS heterozygotes was studied among 2996 newborns born in 2002-2003 in 12 maternity hospitals of west, middle and east Slovakia. Surprisingly, only 3 heterozygotes were found. CONCLUSIONS: This discrepancy of heterozygote frequency and the number of homozygotes shows that due to traditional subisolates the population is not in the genetic equilibrium. It explains the high prevalence of alcaptonuria in Slovakia in the middle of last century, which is a rare disorder in other countries.

Lunar influence on atrial fibrillation?

The most popular periodicities in biology and medicine-the circadians and circannuals-stem undoubtedly from the Earth's rotation and its revolution around the sun. The problem is how to explain the existence of circaseptan, i.e. 5-9-day, and other infradian rhythms. They may correspond to the lunar cycles and their 2nd to 6th harmonics. To test such hypothesis, the calendar dates of 127 attacks of atrial fibrillation in one male subject (M.M.) between 1980 and 1994 were transformed into the days numbered 0-29 for the synodic, and 0-26 for tropic lunar cycle. The daily frequencies obtained in this way were smoothed by moving averages of three successive days each. Considerable fluctuations of frequencies of attacks during both cycles were visible by inspection of the corresponding graphs, called lunar plexograms. Thus, a conspicuous nadir is found under the full moon in the synodic cycle, and a marked peak shortly after the extreme southern position of the moon in the tropic cycle. Halberg's cosinor analysis testing the presence of the 1st to 6th harmonic of either lunar cycle rejected the null hypothesis at the alpha = 0.05 level for all harmonics. Accordingly, the occurrence of attacks was cycling with the period lengths of synodic and tropic lunar cycles, and with those of their 1/2-1/6 period lengths, i.e. with a cluster of approximately circa(di)-septan rhythms. This conclusion is supported by similar findings obtained earlier for various medical and biological events.

[The effect of beta-escin on metabolism in experimental liver steatosis in rats]. / Vplyv beta-escínu na metabolizmus pri experimentálnej steatóze pecene u potkana.

The aim of the study was to investigate the effect of beta-aescin on the selected indices of sugar and lipid metabolisms in blood and hepatic tissue. The study was performed under the conditions of toxic impairment of the liver caused by carbon tetrachloride or hydrazinsulphate which were used in order to evoke experimentally the steatosis of the liver. The study investigated whether beta-aescin can cause deterioration of hepatic steatosis. Carbon tetrachloride was administered to rats by stomach probe in dosis of 2.5 ml per kg of body weight, or hydrazinsulphate in dosis of 2 mmol per kg of body weight, i.m.. Twenty-four hours after administration of these two substances beta-aescin water solution was administered in dosis of 10 mg per kg of body weight by means of stomach probe. The analysis of blood and liver tissue samples discovered that beta-aescin did not affect the metabolic indices, steatosis of the liver did not become more profound. (Tab. 2, Fig. 11, Ref. 23.)

[Oxidative phosphorylation in liver mitochondria after injury with carbon tetrachloride and during regeneration]. / Oxidacná fosforylácia v mitochondriách pecene po poskodení chloridom uhlicitým a pocas regenerácie.

The study investigates the effect of a singular dose of CCl4 (2.5 ml/kg) on the concentration of triacylglycerols in the liver and oxidative phosphorylation in hepatic mitochondria after 24, 72 hours, 2 and 4 weeks since CCl4 application. It was discovered that 24 and 72 hours after CCl4 application the concentration of triacylglycerols increased significantly and steatosis of the liver supervened. After 2 and 4 weeks the triacylglycerol concentration values reached the level of those of control. The hepatic steatosis disappeared. The indices of oxidative phosphorylation index of respiration control, oxygen consumption during stimulated respiration (state 3), oxygen consumption during basal respiration (state 4), and phosphorylation velocity decreased significantly after 24 and 72 hours after CCl4 application in all observed substrates--glutamate, pyruvate and jantarane. After 2 to 4 weeks the observed indices reached the level of values characteristic for healthy controls. The results have indicated that after the CCl4 toxic impairment the energy metabolism in hepatic mitochondria has been significantly impaired. This impairment, in spite of its severeness, was irreversible and hepatocytes were able to compensate it (Tab. 4, Ref. 33).

Cronobiologic analysis of abortions in two related populations of teenager girls during two decades.

STUDY OBJECTIVE: To identify and compare the time dynamics of artificial abortions in two (Czech and Slovak) ethnically, historically and socially closely related populations. DESIGN: Data have been taken separately for 12-15 and 16-18 year age girls from official exhaustive statistical sources and processed by advanced procedures of time series analysis. SETTING: Czech and Slovak Republics. PARTICIPANTS: All girls of the given age. INTERVENTIONS: Legislative liberalization of abortions 1987. MAIN OUTCOME MEASURES: Estimated starting values of relative numbers of abortions by 1971, increasing linear trends, period lengths of fluctuation, coefficients of determination and those of cross-correlation. Level of significance alpha = 0.05. RESULTS: The Czech figures are significantly higher than the Slovak. Thus, estimated abortion percentage (from pregnancies) for 1971 was for younger Czech girls 53%, and for those from Slovakia 29%. All estimated trends were increasing significantly in all cases for the Czech population (by 1.5% per year in the younger group) and in one case for Slovakia. The estimated period lengths were usually 10-12 years. Czech and Slovak data display significant positive mutual cross-correlation, the delay being 1-3 years in Slovak girls. Surprisingly, all data significantly cross-correlate with the geomagnetic index value Ap, acting as lead-lag, with 3-6-year delay for abortions. CONCLUSIONS: Despite living in the same federal state--the former Czechoslovak Republic, both Czech and Slovak populations do differ in starting values and general trends of abortions in teenagers. This can be due to historical, racial and religious peculiarities as well as a more advanced process of industrialization in the western part--the Czech Republic. The latter hypothesis is corroborated by strong dynamism of changes and by the time delay in Slovakia. The periodicity exhibits a frequency resembling that known for solar motion round barycenter of solar system, for sunspots and geomagnetism.

Human postmortem thyroid 131I content and risk estimates in Bratislava, Czechoslovakia following the Chernobyl accident.

From 3 May to 4 August 1986, thyroids of 416 postmortem subjects in Bratislava (population: approximately 400,000) were measured for 131I. Subsequently, dose rates in this organ for the day of exitus were calculated. Mean dose commitments were estimated by integrating linear or quadratic-periodic regression lines drawn through scatterplots of logarithmically transformed daily dose rates. The mean dose-commitment estimates in thyroids of adults were 0.74 and 0.58 mGy for linear and quadratic-periodic regression, respectively. The same for thyroids obtained from donors of fetal to 18 y of age were 1.67 and 1.77 mGy for liner and quadratic-periodic regression, respectively. A comparison of the actual thyroid radiation burden with its theoretical values calculated in the first days of contamination of the environment showed that the models used were safe enough to protect the population. Estimates of absolute risk for thyroid cancer showed that excess incidence that could be expected as a result of the Chernobyl accident shall remain obscured by the "spontaneous" incidence of this disease at geographic localization.

Cosinor demonstration of circatrigintan (circavigintan) biorhythm in cell component volume of female urethral ejaculate.

In urethral expulsions of a multipara, aged 37 years, induced by digital stimulation over a time span of almost one and a half 26-day menstrual cycle, the volume of desquamated cellular component changed, according to two nearly identical versions of cosinor, with the period of 22-27 days, with the acrophase between 17th and 23rd day of menstrual cycle and with the amplitude between 0.5 and 1.2 ml/day. The issue testifies to periodic quantitative changes in squamous cells of vaginal type in female urethra, large paraurethral ducts and trigone of the bladder during menstrual cycle, with maximal desquamation during its secretory phase. A link on stop function of urethral epithelium and thus on female miction problems is suggested.