Assessment of health status for the purposes of benefi ts and social security services for people with lung cancer and the economic impact of this disease on social security in the Czech Republic.

BACKGROUND: The paper deals with temporary incapacity for work and newly created first, second or third degree disability in people dia-gnosed with lung cancer (dg. C34). The aim of this study was to describe the economic impacts on the budget in the Czech Republic, spent through the Czech Social Security Administration on temporary incapacity for work and newly created disability pensions due to the disease. For greater completeness of the impact on the budget of the Czech Republic, we have also provided an overview of applications for care allowance and applications for the purpose of granting a disability card. MATERIAL AND METHODS: The starting point for the evaluation was the data provided by the Czech Social Security Administration. The basic research group consisted of people with dg. C34, who applied for an invalidity pension in 2016-2019, due to first, second and third degree invalidities. The disability and temporary incapacity for work is therefore related to a group of people at working age. With the help of quantitative research using content analysis of the text, we performed data evaluation. RESULTS: We found that even though the number of people applying for a disability pension for dg. C34 is declining slightly, the expenditure on these pensions is still high. In the years 2016, 2017, 2018 and 2019, the research groups consisted of 612, 631, 576 and 543 people, respectively. CONCLUSION: The disease associated with lung cancer is not only characterized by high mortality, but is also one of the very common causes of temporary incapacity for work and new disabilities. This fact therefore contributes significantly to the economic costs of the Czech Republic.

[Assessment of invalidity as a result of infectious diseases]. / Posuzování invalidity u infekcních onemocnení.

AIM: The article features the new medical assessment paradigm for invalidity as a result of infectious disease which is applied as of 1 January 2010. MATERIAL AND METHODS: The invalidity assessment criteria are regulated specifically by Regulation No. 359/2009. Chapter I of the Annexe to the invalidity assessment regulation addresses the area of infectious diseases with respect to functional impairment and its impact on the quality of life. Since 2010, the invalidity has also been newly categorized into three groups. The new assessment approach makes it possible to evaluate a persons functional capacity, type of disability, and eligibility for compensation for reduced capacity for work. RESULTS: In 2010, a total of 170 375 invalidity cases were assessed, and in 2014, 147 121 invalidity assessments were made. Invalidity as a result of infectious disease was assessed in 177 persons in 2010, and 128 invalidity assessments were made in 2014. The most common causes of invalidity as a result of infectious disease are chronic viral hepatitis, other spirochetal infections, tuberculosis of the respiratory tract, tick-borne viral encephalitis, and HIV/AIDS. CONCLUSION: The number of assessments of invalidity as a result of infectious disease showed a declining trend between 2010 and 2014, similarly to the total of invalidity assessments. In spite of this fact, the cases of invalidity as a result of infectious disease account for approximately half percent of all invalidity assessments made in the above-mentioned period of time.

In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test.

BACKGROUND: Patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are often exposed simultaneously to a few potentially culprit drugs. However, both the standard lymphocyte transformation tests (LTT) with proliferation as the assay end-point as well as skin tests, if done, are often negative. OBJECTIVE: As provocation tests are considered too dangerous, there is an urgent need to identify the relevant drug in SJS/TEN and to improve sensitivity of tests able to identify the causative drug. METHODS: Fifteen patients with SJS/TEN with the ALDEN score ≥ 6 and 18 drug-exposed controls were included. Peripheral blood mononuclear cells (PBMC) were isolated and cultured under defined conditions with drugs. LTT was compared to the following end-points: cytokine levels in cell culture supernatant, number of granzyme B secreting cells by ELISpot and intracellular staining for granulysin and IFNγ in CD3(+) CD4(+), CD3(+) CD8(+) and NKp46(+) cells. To further enhance sensitivity, the effect of IL-7/IL-15 pre-incubation of PBMC was evaluated. RESULTS: Lymphocyte transformation tests was positive in only 4/15 patients (sensitivity 27%, CI: 8-55%). Similarly, with granzyme B-ELISpot culprit drugs were positive in 5/15 patients (sensitivity 33%, CI: 12-62%). The expression of granulysin was significantly induced in NKp46(+) and CD3(+) CD4(+) cells (sensitivity 40%, CI: 16-68% and 53%, CI: 27-79% respectively). Cytokine production could be demonstrated in 38%, CI: 14-68% and 43%, CI: 18-71% of patients for IL-2 and IL-5, respectively, and in 55%, CI: 23-83% for IFNγ. Pre-incubation with IL-7/IL-15 enhanced drug-specific response only in a few patients. Specificities of tested assays were in the range of 95 (CI: 80-99%)-100% (CI: 90-100%). CONCLUSIONS AND CLINICAL RELEVANCE: Granulysin expression in CD3(+) CD4(+) , Granzyme B-ELISpot and IFNγ production considered together provided a sensitivity of 80% (CI: 52-96%) and specificity of 95% (80-99%). Thus, this study demonstrated that combining different assays may be a feasible approach to identify the causative drug of SJS/TEN reactions; however, confirmation on another group of patients is necessary.

Mitotic phosphorylation prevents the binding of HMGN proteins to chromatin.

Condensation of the chromatin fiber and transcriptional inhibition during mitosis is associated with the redistribution of many DNA- and chromatin-binding proteins, including members of the high-mobility-group N (HMGN) family. Here we study the mechanism governing the organization of HMGN proteins in mitosis. Using site-specific antibodies and quantitative gel analysis with proteins extracted from synchronized HeLa cells, we demonstrate that, during mitosis, the conserved serine residues in the nucleosomal binding domain (NBD) of this protein family are highly and specifically phosphorylated. Nucleosome mobility shift assays with both in vitro-phosphorylated proteins and with point mutants bearing negative charges in the NBD demonstrate that the negative charge abolishes the ability of the proteins to bind to nucleosomes. Fluorescence loss of photobleaching demonstrates that, in living cells, the negative charge in the NBD increases the intranuclear mobility of the protein and significantly decreases the relative time that it is bound to chromatin. Expression of wild-type and mutant proteins in HmgN1(-/-) cells indicates that the negatively charged protein is not bound to chromosomes. We conclude that during mitosis the NBD of HMGN proteins is highly phosphorylated and that this modification regulates the interaction of the proteins with chromatin.

Early predictors of 30-day mortality in supratentorial ischemic stroke patients--first episode.

INTRODUCTION: Prognostic factors following stroke remain to be established. The aim of this study was to determine early prognostic factors related with a 30-day mortality in first episode ischemic stroke patients. MATERIALS AND METHODS: The study group comprised 329 consecutive patients, aged between 33 and 99 years (mean age +/- SD 69 +/- 12.6) admitted within 24 hours following their first supratentorial ischemic stroke, confirmed either by computer tomography (CT) and/or autopsy. The following data were assessed within 24 hours of hospitalization: gender, age, history of diabetes mellitus, history of ischemic heart disease, obesity, the neurological deficit at entry and after one day, level of consciousness at entry and after one day, electrocardiographic dysrhythmia at entry, blood pressure at entry and body temperature on the first day following stroke. We also assessed particular serum biochemical and hematological markers including: hematocrit, fibrinogen concentration, platelet count, white blood cell (WBC) count, gamma globulin level, glucose level, cholesterol level, the erythrocyte sedimentation rate (ESR), and creatinine kinase (CK) level. The end-point for assessment was early death (within 30 days). Statistical analysis consisted of univariate analysis and multiple regression. RESULTS: Univariate analysis demonstrated that an older age, increased neurological deficit at entry and on the next day, decreased consciousness at entry and on the next day, electrocardiographic dysrhythmia, increased body temperature and glucose level, decreased cholesterol level and increased CK level were significantly associated with death after 30 days (p < or = 0.05). During multivariate analysis, only a severe neurological deficit (Scandinavian Stroke Scale < or = 15 points) both at entry and on the next day (OR = 8.3; 95% CI: 2.83-24.35), decreased consciousness within the first 24 hours of hospitalization (OR = 19.2; 95% CI: 2.84-127.77) and electrocardiographic dysrhythmia (OR = 5.2; 95% CI: 2.37-13.77) were associated with death after 30 days. CONCLUSION: A severe neurological deficit lasting 24 hours, decreased consciousness within 24 hours of hospitalization and electrocardiographic dysrhythmia are the most important indicators of 30-day mortality in patients with first-time ischemic stroke.

Acetylation of novel sites in the nucleosomal binding domain of chromosomal protein HMG-14 by p300 alters its interaction with nucleosomes.

The reversible acetylation of histones is associated with structural alterations in the chromatin fiber that affect various DNA-related activities. Here we show that the histone acetyltransferase p300 specifically acetylates HMG-14, a nonhistone structural protein that binds to nucleosomes and reduces the compactness of the chromatin fiber. We identify 7 major acetylation sites, 6 of which are novel and have not been known to be acetylated in either HMG-14 or the closely related HMG-17 protein. All the acetylation sites involve evolutionarily conserved residues: 3 within the HMG-14/-17 nucleosomal binding domain and 4 in or near the bipartite nuclear localization domains of the proteins. In tissue culture cells the acetylation pattern is indicative of a selective process in which a subfraction of HMG-14 is preferentially acetylated. We find that the nucleosomal binding domain is a major target for acetylation in vivo and that the specific acetylation of HMG-14 by p300 weakens its interaction with nucleosome cores. Our results suggest that p300 modulates the interaction of HMG-14 with nucleosomes. Thus, p300 may affect chromatin-related activities not only by modifying histones or transcription factors but also by targeting structural nonhistone proteins.

Linker histones play a role in male meiosis and the development of pollen grains in tobacco.

To examine the function of linker histone variants, we produced transgenic tobacco plants in which major somatic histone variants H1A and H1B were present at approximately 25% of their usual amounts in tobacco chromatin. The decrease in these major variants was accompanied by a compensatory increase in the four minor variants, namely, H1C to H1F. These minor variants are smaller and less highly charged than the major variants. This change offered a unique opportunity to examine the consequences to a plant of major remodeling of its chromatin set of linker histones. Plants with markedly altered proportions of H1 variants retained normal nucleosome spacing, but their chromosomes were less tightly packed than those of control plants. The transgenic plants grew normally but showed characteristic aberrations in flower development and were almost completely male sterile. These features correlated with changes in the temporal but not the spatial pattern of expression of developmental genes that could be linked to the abnormal flower phenotypes. Preceding these changes in flower morphology were strong aberrations in male gametogenesis. The earliest symptoms may have resulted from disturbances in correct pairing or segregation of homologous chromosomes during meiosis. No aberrations were observed during mitosis. We conclude that in plants, the physiological stoichiometry and distribution of linker histone variants are crucial for directing male meiosis and the subsequent development of functional pollen grains.

Histone H1 overexpressed to high level in tobacco affects certain developmental programs but has limited effect on basal cellular functions.

Histone H1, a major structural component of chromatin fiber, is believed to act as a general repressor of transcription. To investigate in vivo the role of this protein in transcription regulation during development of a multicellular organism, we made transgenic tobacco plants that overexpress the gene for Arabidopsis histone H1. In all plants that overexpressed H1 the total H1-to-DNA ratio in chromatin increased 2.3-2.8 times compared with the physiological level. This was accompanied by 50-100% decrease of native tobacco H1. The phenotypic changes in H1-overexpressing plants ranged from mild to severe perturbations in morphological appearance and flowering. No correlation was observed between the extent of phenotypic change and the variation in the amount of overexpressed H1 or the presence or absence of the native tobacco H1. However, the severe phenotypic changes were correlated with early occurrence during plant growth of cells with abnormally heterochromatinized nuclei. Such cells occurred considerably later in plants with milder changes. Surprisingly, the ability of cells with highly heterochromatinized nuclei to fulfill basic physiological functions, including differentiation, was not markedly hampered. The results support the suggestion that chromatin structural changes dependent on H1 stoichiometry and on the profile of major H1 variants have limited regulatory effect on the activity of genes that control basal cellular functions. However, the H1-mediated chromatin changes can be of much greater importance for the regulation of genes involved in control of specific developmental programs.

Drug interactions with cardiac glycosides: evaluation of a possible digoxin-ethmozine pharmacokinetic interaction.

Problems in studying pharmacokinetic interactions with digoxin were evaluated using as a test model the examination of a possible interaction between digoxin and ethmozine in a group of 11 patients with cardiac disease. A single-blind, placebo-controlled, nonrandomized protocol design was used. Considerable intrapatient variability in day-to-day serum digoxin levels was documented that could not be accounted for by laboratory variability in digoxin assay measurements (mean coefficient of variation 10.1%) or alterations in blood urea nitrogen (BUN), serum creatinine, or body weight during the course of the study. No consistent, statistically significant alteration of mean serum digoxin levels occurred when the baseline, placebo, and ethmozine phases were compared, although the study design would have permitted detection of a 0.29-ng/ml alteration in mean serum digoxin levels. A discussion of the sources of variability in digoxin levels is provided.

Transtelephonic electrocardiographic transmission for management of cardiac arrhythmias.

Brief periods of transtelephonic electrocardiographic transmission conducted at periodic intervals or during sporadic symptoms may provide an inexpensive and reliable alternative to extended ambulatory electrocardiographic tape recordings. Sixty-one patients were enrolled in a transtelephonic electrocardiographic transmissions program. In 51 patients with documented arrhythmias (group I), telephone electrocardiographic transmissions were used to monitor antiarrhythmic drug therapy. In 10 patients, telephone electrocardiographic transmission was used in an attempt to diagnose infrequent symptoms suggestive of arrhythmia (group II). Of the 650 telephone electrocardiographic transmissions received, 73 (11%) revealed a clinically significant event, whereas 577 (89%) did not show any significant disturbances of cardiac rhythm. Of the 61 patients entered into the program, 29 (48%) had a clinically significant event identified during 1 or more transmissions. In group I, transtelephonic electrocardiographic transmission prompted a change in therapy in 37% of the patients. Of the 10 patients in group II, clinically significant events were noted during telephone electrocardiographic transmissions in each patient. Assuming a yield of 1 clinically significant event detected per 10 telephone electrocardiographic transmissions and a similar yield on long-term ambulatory electrocardiographic recordings, use of telephone electrocardiographic transmissions offers a cost-effective means of following patients with significant cardiac arrhythmias who are receiving potent antiarrhythmic drugs. In addition, telephone electrocardiographic transmission is a suitable diagnostic technique for patients with infrequent symptoms suggestive of cardiac arrhythmias.