Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group.

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

First Report of Natural Infection of Pea (Pisum sativum) by Tomato spotted wilt virus in Hungary.

In June of 2009, stem vascular necrosis, interveinal necrosis of upper leaves, wilting of flowers, and necrotic spots on the pods were observed on garden pea (Pisum sativum L. 'Rajnai törpe') in northeast Hungary. A mechanical transmissible plant virus designated Ps091 was isolated from leaves of severely affected plants. Pathological investigations demonstrated that Ps091 had a host range very similar to that of Tomato spotted wilt virus (TSWV). It caused necrotic local lesions on Chenopodium spp. and induced systemic yellowing and necrosis on the upper leaves of Nicotiana benthamiana, N. clevelandii, and N. glutinosa by mechanical inoculation. Typical symptoms of TSWV infection appeared on the top leaves of pepper (Capsicum annuum L. 'Albaregia') and tomato (Solanum lycopersicum 'Kecskeméti 3') inoculated with Ps091. For molecular identification, total nucleic acids were extracted from Ps091-infected tobacco with a standard phenol-chloroform extraction method (2), and reverse transcription-PCR was conducted with TSWV N-gene specific, own designed primers (TSWV-S for: 5'-CCCAGCATTATGGCAAGCC-3', TSWV-S rev: 5'-TGATCTGGTCGAGGTTTTCCGCTAGCCC-3'). A tobacco plant infected with a reference pepper isolate, TSWV-Ca1 (1), and a healthy tobacco plant served as positive and negative controls, respectively. An approximately 300-bp DNA fragment was amplified from tobacco infected with Ps091 and TSWV-Ca1. The Ps091 amplicon was cloned, sequenced in both directions, and the sequence was deposited in GenBank (Accession No. HQ615692). Blast search analysis showed that TSWV-Ps091 had the highest identity (99%) with TSWV-P170RB strain (GenBank Accession No. DQ431238) in the cognate region. Since the latter isolate is a resistance breaking (RB) strain on pepper, pathogenicity of Ps091 on TSWV resistant pepper and tomato lines was studied. Mechanically inoculated pepper (C. annuum × C. chinense TSR F4 line) and tomato (S. lycopersicum 'Stevens') genotypes carrying the Tsw and Sw5 resistance genes, respectively, reacted with necrotic local lesions, but no systemic infections were detected by applying bioassays to N. clevelandii. These results demonstrate that Ps091 does not belong to the RB strains of TSWV. Back inoculations to pea ('Rajnai törpe') resulted in necrotic local spots as well as systemic stem and top necrosis, proving the causal relationship between TSWV-Ps091 and the pea disease observed in the field. Although TSWV has been known to cause epidemy in solanaceous crops and tobacco, to our knowledge, this is the first report of its natural occurrence on a legume plant, particularly on pea in Hungary. Because of the extreme severity of the disease caused on pea and high infection pressure, TSWV is a new threat to pea production in this country, where pea is a very important crop. References: (1) P. Salamon et al. Page 23 in: Plant Protection Days. Budapest, February, 2010. (2) J. L. White and J. M. Kaper. J. Virol. Methods 23:83, 1989.

[Classification of epileptic diseases according to potential of fitting with dental prosthesis]. / Az epilepsziás betegségek osztályozása protetikai elláthatóságuk alapján.

Epileptic patients seem to have generally poorer dental condition in comparison with the healthy population for many reasons. It is important to endeavor to provide the same dental care to epileptic patients than to others, however certain factors in connection with their disease must be taken into consideration. Among these, the most important is to concern about the type of seizure with special emphasis on the involvement of the masticatory apparatus and the chances of oral soft tissue injuries and aspiration. In addition seizure frequency and patients' mental compliance might also play a decisive role. According to these factors epileptic patients were grouped into four categories with special regard to their dental manageability from the prosthodontic point of view. The planning of their dental prosthesis was carried out according to the Fábián-Fejérdy classification like in case of any other healthy patients.

Colorectal adenomas and diet: a case-control study. Colorectal Adenoma Study Group.

It has been postulated that high intakes of animal fat and protein and low intakes of fiber, calcium, and antioxidants increase the risk of colorectal cancer. Whether specific types of protein such as that from red meat are important, and whether vegetables might be key protective factors will also be considered in this study. Dietary intake over the past year was studied according to the diet history method by means of a case-control study in 184 cases and matched controls. After adjustment for energy, relative weight, and social class, no associations were found for fat or protein in comparison with either control group. Unexpectedly, carbohydrate intake was inversely related with adenoma risk, the RR being 0.29 (0.10-0.81) for quintile 5 versus 1 in comparison with hospital controls. None of the antioxidants showed a significant protective effect except beta-carotene intake in comparison with hospital controls, the RR being 0.24 (0.11-0.50) for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile. There was, however, a statistically significant positive association between adenomas and meat consumption with the RR for the highest versus the lowest quintile of intake being 3.6 (1.7-7.5) in comparison with hospital controls and 4.4 (1.6-12.1) in comparison with population controls. Our data support the protective role for carbohydrate intake and of beta-carotene intake in the etiology of colorectal adenomas and show a strong increased risk for developing adenomas in those with high meat intake.

Relation of serum antioxidant vitamins to the risk of colorectal adenoma.

The relation between risk of colorectal adenoma and serum concentrations of vitamins A, C, E and carotene was examined in a population-based case-control study of 105 cases of colorectal adenoma and a similar number of hospital controls showing no polyps at colonoscopy and a second control group of population controls. There were no significant associations with serum concentrations of vitamins C and E and carotene. Serum concentrations of vitamin A were significantly inversely related to the risk of colorectal adenoma when cases were compared with both control groups. After adjustment for energy intake, smoking, alcohol, estrogen therapy, body-mass-index and social class the inverse association between vitamin A and colorectal adenoma was even more marked. For the highest versus the lowest quartile of serum levels the adjusted RR was 0.23 (0.07-0.73) in relation to hospital controls and 0.08 (0.02-0.25) in relation to population controls. These findings suggest that the risk of developing colorectal adenomas is reduced in those with high vitamin A levels.

[Dental rehabilitation of two epileptic patients suffering from grand mal seizures]. / Az epilepsziás betegségek protetikai elláthatóságának III. Osztályába tartozó (grand mal) rohamban szenvedó páciensek protetikai rehabilitációja.

Inspite of the antiepileptic therapy, both of our patients were suffering from grand mal seizures. They belong to class III according to our previously described clinical guideline from prosthetic treatment at epileptic patients. Since during these seizures, loading is great on the remaining teeth and on the denture, we tried to reduce it with all disposable appliances in prosthetic dentistry. In class III we suggest metal baseplate for the treatment of full edentulousness. In some of the cases of Fábián-Fejérdy class 2B, we approve great allowance in the interest of planning solely fixed denture. Otherwise we suggest combined, fixed and removable part with precisional attachment, rigidly, securely fixed together. In our two cases, we followed the mentioned guiding principles.

Determination of deramciclane and N-desmethylderamciclane in human plasma by liquid chromatography-tandem mass spectrometry using off-line robotic sample pretreatment.

A rapid and highly sensitive LC-MS-MS method using deuterium-labelled internal standards was developed and evaluated for the simultaneous determination of deramciclane and its pharmacologically active metabolite (N-desmethylderamciclane). The sample preparation based on liquid-liquid extraction was carried out with an off-line robotic system. Evaluation of this analytical method shows that samples can be assayed with acceptable accuracy and precision in the 0.1 to 50 ng/ml concentration range for both compounds. The method was applied for the quantitative determination of deramciclane and its metabolite in human plasma samples during a food interaction pharmacokinetic study.

Alcohol and cigarette smoking and the risk of colorectal adenomas.

Whether alcohol and tobacco can be considered as risk factors for the occurrence of adenomas remains inconclusive. A case-control study was carried out to examine these factors while taking into account possible confounding factors. One hundred eighty-two patients with colorectal adenomas and similar numbers of hospital and population controls were compared as to intake of alcohol and various nutrients including smoking and drug intake. There was a positive association between cigarette smoking and adenoma risk compared with hospital controls, the RR being 2.3 (1.1-4.6). Overall alcohol intake was no risk factor in hospital controls, but drinking liquor was associated with an increased risk, the RR being 4.1 (1.3-13.4) and was especially marked in males [RR 10.2 (2.3-46.2)]. Compared with population controls, there was no increased RR associated with smoking or alcohol intake. None of the risk factors was positively associated with disease risk in those with small or large adenomas. These findings suggest that alcohol and tobacco play no major role in the formation or growth of adenomas.

Long-term use of nonsteroidal antiinflammatory drugs and the risk of colorectal adenomas. The Colorectal Adenoma Study Group.

AIMS: Previous studies have suggested that the regular use of NSAIDs reduces the risk of colorectal adenomas. The aim of this study was to examine this association while taking possible confounding factors into account. METHODS: The intake of drugs including NSAID intake during the last 20 years was assessed by means of a case-control study in 184 cases and matched hospital and community controls. RESULTS: Overall, there were few individuals with a relevant drug intake for more than 5 years. NSAID intake for more than five years was associated with decreased risk in comparison with both control groups. The RR was 0.20 (0.04-1.04) compared with hospital and 0.21 (0.04-0.99) compared with population controls, the latter association being statistically significant. Subgroup analysis by type of drug revealed a significant protective effect only for long-term aspirin intake in relation to hospital controls, the RR being 0.09 (0.01-0.82). CONCLUSION: Our data support the hypothesis that there is a protective effect of NSAID intake of more than 5 years against the development of colorectal polyps.

Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat.

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.

Helicobacter pylori and the risk of colonic adenomas. Colorectal Adenoma Study Group.

AIMS: Previous studies have found a positive association between Helicobacter pylori infection and colorectal adenomas. The aim of the present study was to examine this association while taking possible confounding factors into account. METHODS: 98 serum samples were available from 182 patients with colorectal adenomas who entered a case-control study of colorectal adenomas and diet. The H. pylori status in patients was compared with a hospital control group and a population control group. RESULTS: H. pylori IgG antibodies were more common in colorectal polyp patients compared with either control group, the prevalence being 79% in cases compared with 62% in both control groups. The corresponding RR was 1.4 (0.76-2.6) compared with hospital controls and 2.1 (1.1-3.9) compared with population controls. After adjusting for possible confounding variables the association between H. pylori status and adenoma risk was even more marked. There was an RR of 1.6 (0.80-3.4) compared with hospital controls and an RR of 2.6 (1.3-5.4) compared with population controls, the latter association being statistically significant. CONCLUSION: These findings suggest a statistically significant association between H. pylori infection and colorectal polyps. A possible mechanism might be increased gastrin levels in H. pylori-infected subjects which exhibit a trophic effect on colonic mucosa.

Application of overpressured layer chromatography combined with digital autoradiography and mass spectrometry in the study of deramciclane metabolism.

Overpressured layer chromatography was combined with the highly sensitive and rapid digital autoradiography (DAR) and mass spectrometry to separate, detect, and identify 3H- and 14C-labeled deramciclane metabolites in different biological matrixes. Several minor and major metabolites were separated from plasma and urine samples. The radioactive metabolites localized by DAR were scraped from the thin-layer chromatographic plate and transferred to a mass spectrometer for structure identification. Several metabolites were isolated and characterized, including hydroxy-N-desmethyl deramciclane, which is described in detail. The combination of techniques is efficient and has good sensitivity: about 2 micrograms metabolite from a biological matrix was isolated and identified this way.

Food interaction pharmacokinetic study of cordaflex 20 mg retard filmtablet in healthy volunteers.

The aim of the present study was to investigate the effect of food consumption on the pharmacokinetics of Cordaflex 20 mg retard filmtablet in healthy volunteers through measuring nifedipine plasma levels by an HPLC-ED method both after fasting and food ingestion. The food interaction pharmacokinetic study of Cordaflex 20 mg retard filmtablet was carried out in 12 healthy male volunteers treated with a single dose of the preparation both after fasting and after food ingestion, in a crossover design allowing 1 week of wash-out period between the 2 treatments. Nifedipine concentration of plasma samples were determined by an isocratic HPLC-ED method [Horvai et al. 1994] with robotic sample processing [Horváth et al. 1995, 1996]. The pharmacokinetic parameters (AUC0-infinity, AUC0-t, Cmax, MRT) were analyzed by calculating 90% confidence interval for logarithmic transformed test/reference ratio values, and Schuirmann's statistical tests, the tmax and HVD values were analyzed by Wilcoxon's nonparametric statistical test. The above statistical tests of the present food interaction study indicated significant differences for each one of the respective pharmacokinetic parameter pairs calculated for treatments after fasting and after food ingestion. On the basis of the above findings and also by comparing the mean pharmacokinetic curves, it was evident, that, in agreement with the data of literature [Kleinbloesem et al. 1993, Schall et al. 1994], food ingestion increased the relative bioavailability and maximum plasma concentration (Cmax). Considering the average of the parameter values and also the respective statistical tests, it was also apparent that the time to maximum plasma concentration (tmax), the mean residence time (MRT), and the half-value duration (HVD) all decreased significantly upon the effect of food ingestion.

Automated determination of levodopa and carbidopa in plasma by high-performance liquid chromatography-electrochemical detection using an on-line flow injection analysis sample pretreatment unit.

An automated analytical procedure is described for the parallel determination of L-3,4-dihydroxyphenylalanine (levodopa, L-dopa, LD) and the analogous hydrazine compound carbidopa (CD) in dog plasma by ion-pair high-performance liquid chromatography with electrochemical detection (HPLC-ED). After deproteinization of the plasma samples with perchloric acid the catecholamines were extracted from the supernatant by adsorption on a small column filled with alumina. The extraction and redissolution were automatically performed in a flow injection analysis unit (FIA) coupled to the HPLC system. The performance of the whole system was tested on dog plasma samples including specimens taken after oral administration of the anti-Parkinsonism drug Duellin, which is a combination tablet of levodopa and carbidopa.

Human bioequivalence study of a new nifedipine containing retard filmtablet after single and repeated administration.

A clinical pharmacokinetic bioequivalence study with two retard filmtablet preparations, both containing 20 mg of nifedipine (CAS 219829-25-4) was carried out. The investigated test preparation was Cordaflex 20 mg retard filmtablet. The pharmacokinetic parameters were determined after single and repeated administration in 15 and 16 healthy male volunteers, respectively, in open, randomised studies of cross-over design. Plasma levels of nifedipine were determined by HPLC with electrochemical detection using a robotic sample preparation technique. Statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss, tau tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from plasma concentration-time curves by ANOVAlog, confidence interval, Schuirman's, Westlake's, Anderson's and Wilcoxon's tests, furthermore the comparison of the clinical results did not show any significant difference between the two preparations. It is concluded that the two preparations are bioequivalent after repeated administration.

Food interaction study of a new theophylline (Egifilin) 200 and 400 mg retard tablet in healthy volunteers.

The aim of the present food interaction study was to determine the blood plasma levels of theophylline upon the administration of new Egifilin 200 and 400 mg retard tablets, either on an empty stomach or after meal, and to make comparative pharmacokinetic evaluation in 26 healthy volunteers. For determination of the plasma levels of theophylline an improved isocratic HPLC-UV method was used in the concentration range of 0.1-18 micrograms/ml. The mean pharmacokinetic curves obtained with 200 and 400 mg tablets before and after meal were in good agreement also on the basis of statistical evaluation, although, as usual with theophylline, the evaluation of the individual pharmacokinetic curves indicated great variations. The pharmacokinetic parameters (AUCzero-t, AUCzero-infinity, HVD, MRT, Cmax, tmax) calculated for Egifilin 200 and 400 mg retard tablets were analyzed by ANOVA, ANOVAlog, Wilcoxon, and Schuirmann statistical tests as well as by the confidence interval calculation. As it was found, under the circumstances of the present food interaction study, food consumption did not have a biologically significant effect on the pharmacokinetic parameters of either the 200 or the 400 mg Egifilin retard preparations.

Sensitive high-performance liquid chromatographic determination of nifedipine in dog plasma using an automated sample preparation system with laboratory robot.

Nifedipine, a calcium-channel blocking drug was analysed in dog plasma after oral dosing with two different formulations. Sample preparation was automated with a laboratory robot. Quantitative determination of the drug was performed on a reversed-phase HPLC system with electrochemical detection (ED) using an internal standard. Validation of the analytical method showed that the system is well suited for pharmacokinetic studies on dogs. The assay was linear in the range 1-50 ng/ml. Inter-day and intra-day variability were between 6.43-18.15% C.V. and 1.57-5.53% C.V., respectively.

Influence of direct and cross-relaxation pumping processes on the output energy and thermal load of an Er:YAG laser.

The dependence of the output-energy efficiency and thermal load of an Er:YAG laser on the spectrum of exciting flash-lamp light has been measured. In particular, the influence of the direct and crossrelaxation pumping process has been studied. For pump pulses of 400 µs cross-relaxation pumping processes provide four times the efficiency and 1.5 times less thermal load normalized to fixed output energy.

Effect of aeration on cortisol and androgen output by pig adrenal homogenate.

Of the steroids produced by pig adrenal homogenate, the output of cortisol+11-deoxycortisol, corticosterone, 11 beta-hydroxyandrostenedione, and the steroid intermediates: pregnenolone, 17 alpha-hydroxypregnenolone, progesterone, 17 alpha-hydroxyprogesterone were analysed. The incubations were carried out with and without aeration. Without aeration the oxygen tension in assay medium decreased during incubation in spite of constant shaking. However, it remained constant (140 Hgmm) with aeration throughout the incubation (60 min). The results of steroid analysis demonstrated that the output of 11 beta-hydroxyandrostenedione decreased strongly, and that of cortisol slightly without aeration, however, the output of corticosterone did not change. The addition of 17 alpha-hydroxypregnenolone or 17 alpha-hydroxyprogesterone to the incubation medium eliminated the decrease in the output of cortisol, but not that of 11 beta-hydroxyandrostenedione. The observations suggest that the activation of oxygen in the enzyme reaction catalyzed by 17, 20-lyase, and perhaps by 17 alpha-hydroxylase is weaker than the activation mediated by 21-hydroxylase and 11 beta-hydroxylase.