Modulation of central endocannabinoid system results in gastric mucosal protection in the rat.

Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors. METHODS: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene-related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). RESULTS: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. or i.p. 2. URB 937, the peripherally restricted FAAH inhibitor failed to exert significant action injected i.p. 3. Ethanol-induced decreased levels of mucosal CGRP and somatostatin were reversed by URB 597, JZL 184 and AM 404, the decreased SOD activity was elevated significantly by URB 597 and JZL 184. 4. Neither compounds given i.c.v. influenced gastric motility, elicited catalepsy, or hypothermia. CONCLUSION: Elevation of central endocannabinoid levels by blocking their degradation or uptake via stimulation of mucosal defensive mechanisms resulted in gastroprotective action against ethanol-induced mucosal injury. These findings might suggest that central endocannabinoid system may play a role in gastric mucosal defense and maintenance of mucosal integrity.

Gastric mucosal protection: from the periphery to the central nervous system.

Gastric mucosal integrity can be influenced both by peripheral and central mechanisms. In the periphery several protective factors play a role in gastric mucosal defense. Moreover, receptors located in the gastric mucosa (e.g. toll-like receptors, proteinase-activated receptors, α2-adrenoceptors, opioid receptors) may also be involved in the regulation of gastric mucosal integrity. Activation of peripheral δ-opioid receptors by opioid peptides was shown to induce gastric mucosal defense. In contrast, the gastroprotective action mediated by α2-adrenoceptors (α2B/C-subtypes) is likely to be initiated centrally. Namely, central nervous system (CNS) is also involved in the regulation of gastrointestinal functions; hypothalamus and dorsal vagal complex (DVC) have prominent role in this process. In DVC several receptors have been identified, among others, µ and δ-opioid-, α2-adrenergic-, cannabinoid CB1- and CB2-, angiotensin II AT1-, nociceptin NOP-, neurokinin NK1- and TRH-receptors. Activation of these receptors results in gastric mucosal protection, mainly in a vagal dependent manner. In addition, glutamate (together with GABA and norepinephrine) is involved in synaptic connections between nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV) neurons. AP-7, a selective NMDA receptor antagonist blocked the gastroprotective effect of opioid peptides, indicating that N-Methyl-D-aspartic acid (NMDA) might play a role in centrally induced gastroprotective effect. Moreover, interactions between neuropeptides may have also importance in centrally initiated gastric mucosal protection. Clarification of the role of neuropeptides in gastric mucosal defense may serve as a basis for the development of new strategies to enhance gastric mucosal resistance against injury.

The direct effect of specific training and walking on bone metabolic markers in young adults with peak bone mass.

As a prevention, a physically active lifestyle including the performance of weight-bearing exercises is important to enhance and maintain bone mineral content. Fifty young women were selected for the study. Twenty-five women carried out a specific training directed by a physiotherapist in the training group (TG), while 25 women were walking for 60 minutes in the control group (CG). Total and bone-specific alkaline phosphatase (ALP and BALP) and C-terminal cross-linked telopeptide (CTX) levels were measured at the beginning and at the end of exercise. The most remarkable change was seen in CTX levels (TG -28.89%, p < 0.001; CG -52.54%, p < 0.001), and there was also a significant difference in the values of CTX between TG and CG (p = 0.012). Therefore, walking more significantly reduced the level of CTX than special exercise. The decrease of BALP in TG was considerable but not significant (TG -4.63%, p = 0.091), while BALP levels dropped significantly in CG (-7.65%, p = 0.011), and there was a non-significant difference between the two groups (p = 0.22). Regarding the ALP level, a significant reduction was detected in TG and CG (-6.84%, p < 0.001 vs. -4.57%, p < 0.001). This study reveals that the 60-minute, middle-intensity training and the brisk walking have an immediate effect on bone metabolic markers.

Multi-site voxel-based morphometry--not quite there yet.

Voxel-based morphometry (VBM) is a widely applied method in computational neurosciences but it is currently recommended to compare only data collected at a single MRI scanner. Multi-site VBM would be a desirable approach to increase group size and, thus, statistical power. We aimed to assess if multi-site VBM is feasible on similar hardware and compare the magnitude of inter- and intra-scanner differences. 18 healthy subjects were scanned in two identical 3T MRI scanners using different head coil designs, twice in scanner A and once in scanner B. 3D T1-weighted images were processed with SPM8 and FSL4.1 and compared as paired t-test (scan versus re-scan) on a voxel basis by means of a general linear model (GLM). Additionally, coefficient-of-difference (coeffD) maps were calculated for respective pairs of gray matter segmentations. We found considerable inter-scanner differences clearly exceeding a commonly used GLM significance threshold of p<0.05 (FWE corrected). The spatial pattern of detected differences was dependent on whether SPM8 or FSL4.1 was used. The inclusion of global correcting factors either aggravated (SPM8) or reduced the GLM detected differences (FSL4.1). The coeffD analysis revealed markedly higher variability within the FSL4.1 stream both for the inter- and the intra-scanner comparison. A lowered bias cutoff (30 mm FWHM) in SPM8 improved the comparability for cortical areas. Intra-scanner scan/re-scan differences were generally weaker and did not exceed a p<0.05 (FWE corrected) threshold in the GLM analysis. At 3T profound inter-scanner differences are to be expected that could severely confound an unbalanced VBM analysis. These are like related to the receive bias of the radio-frequency hardware.

Periictal heart rate variability analysis suggests long-term postictal autonomic disturbance in epilepsy.

BACKGROUND: One of the possible pathomechanisms of sudden death in epilepsy (SUDEP) is a postictal dysregulation of autonomic nervous system. We performed a heart rate variability (HRV) analysis of the periictal state to analyze whether a cardiac autonomic disturbance exists after an epileptic seizure. METHODS: We included 31 periictal video-EEG-ECG recordings of 31 patients with epilepsy who had consecutively undergone pre-surgical evaluation. Nine generalized tonic-clonic (GTCS), 15 complex partial, and seven simple motor seizures were included. HRV was evaluated by analyzing 5-min-long ECG epochs, sampling from baseline, direct preictal, early-postictal (<15 min after the seizure), and late-postictal (5-6 h after the seizure) periods. RESULTS: The heart rate was elevated immediately after the seizures, but 5-6 h postictally returned to the baseline level. Time-domain components of HRV decreased after the seizure and this decrease lasted for 5-6 h. Low-frequency power decreased in the early-postictal phase and high-frequency power of HRV dropped in the late-postictal phase. GTCS had an impact on short-term but not on long-term postictal HRV decrease. CONCLUSIONS: We found decreased HRV immediately after the seizures, which lasted at least 5-6 h postictally, indicating a long-term postictal disturbance of the autonomous nervous system. GTCS were accompanied by a more decreased HRV than other seizures. Our results may have relevance in explaining pathomechanism of SUDEP.

Peri-ictal vegetative symptoms in temporal lobe epilepsy.

We investigated peri-ictal vegetative symptoms (PIVS) in 141 patients with adult temporal lobe epilepsy (TLE) and assessed frequency, gender effect, and lateralizing value of peri-ictal autonomic signs. We recorded abdominal auras in 62%, goosebumps in 3%, hypersalivation in 12%, spitting in 1%, cold shivering in 3%, urinary urge in 3%, water drinking in 7%, postictal nose wiping (PNW) in 44%, and postictal coughing in 16%. At least one vegetative sign appeared in 86% of the patients. The presence of PIVS did not have a significant lateralizing value. PNW occurred in 52% of women and in 33% of men, whereas any PIVS was present in 93% of women and 77% of men. In summary, contradictory to previous studies, the presence of PIVS has no lateralizing value, which may be linked to a low frequency of occurrence of PIVS. PIVS, especially PNW, occurred more frequently in women, supporting the gender differences in epilepsy.

Patients' ability to react before complex partial seizures.

OBJECTIVE: The purpose of the study described here was to investigate the pathophysiology of patients' ability to react during the conscious (aura) phase of complex partial seizures (CPS) originating from the temporal lobe. METHODS: We reviewed video recordings of CPS experienced by 130 adult patients who had undergone epilepsy surgery for intractable medial temporal lobe epilepsy. All patients were instructed to push the alarm button when they felt an aura. We defined the preictal reactivity as the ability to push the alarm button before the complex partial (unconscious) phase of seizures. RESULTS: Seventy-seven patients (59%) pushed the alarm button before seizures. Patients with preictal reactivity were significantly younger, more often had lateralized EEG seizure patterns, and had a better postoperative outcome. Patients who did not push the alarm button had secondarily generalized seizures more often. CONCLUSIONS: Ability to react before CPS is associated with a circumscribed region involved at seizure onset and spread, and with a seizure-free postoperative outcome.

Investigations on the germination depth of Johnson grass (Sorghum halepense [L.] pers).

The aim of our experiment was to gain data about the germination depth of Johnson grass, and to investigate the dynamics of germination at different sowing depths. These investigations have great importance in respect of effective weed control. The experiments were carried out in the summer of 2005, using pots, in glasshouses. 50 Sorghum halepense chaffy seeds per pot were sown at 1, 5, 10, 15, 20, 25 cm depth. Treatments were used in 4 repeats. Peat:sand mixture in 3:1 ratio was used in the experiments. From the first germination, weeds were counted in every second day for 3 weeks. Finally, we measured the length of sprouts, the fresh root and sprout weight of the weeds, and--after drying--the dry-matter weight as well. The results of the first experiment (carried out in July 2005) showed that 25% of the seeds came up from 15 cm. Most of the weeds (64%) came up from 1 cm depth. Answering to our expectations, the ratio of germination from 5 cm depth was also high: it was 56%. The ratio of germination from 10 cm depth was also good (58%). Another experiment was carried out in August 2005, where the germination of Sorghum halepense was investigated from 20 and 25 cm depth. The results show that in spite of the small size of its seeds (5-7 mm), Johnson grass is able to germinate from 20, 25 cm depth. 30% of the sown seeds germinated from 20 cm depth, and because of the slowing-down of the growth only 6% of them germinated from 25 cm depth.

[Combination, transition and degrees of severity of various syndromes]. / A szindrómák kombinálódása, átmenetek, súlyossági fokozatok?

Nowadays it is difficult to recognise and separate the various syndromes. The geneticists and the morphologists often change the classification of syndromes. The problem may be caused by a new case of a known syndrome, when new symptoms are described among the known ones. Then it is not sure, if a new syndrome discovered or it is a more complicated variation of an already known syndrome. To emphasise and exemplify the difficulties of syndrome identification 5 patients are presented and analysed: on with anadysplasia, two with cleidocranial dysplasia and a sibling pair with Larsen syndrome. It is concluded that no new syndrome could be described, and in a similar context, the definition of several new syndromes is not justified. The classification of syndromes based on bone disorders must be modified in order to fit the Genetic Classification easier and more clearly.

Proteus virulence: involvement of the pore forming alpha-hemolysin (a short review).

The genus Proteus belongs to the tribe of Proteae in the family of Enterobacteriaceae, and consists of five species: P. mirabilis, P. vulgaris, P. morganii, P. penneri and P. myxofaciens. They are distinguished from the rest of Enterobacteriaceae by their ability to deaminate phenylalanine and tryptophane. They hydrolyze urea and gelatin and fail to ferment lactose, mannose, dulcitol and malonate; and do not form lysine and arginine decarboxylase or beta-galactosidase [1]. Colonies produce distinct "burned chocolate" odor and frequently show the characteristics of swarming motility on solid media. P. mirabilis, P. vulgaris and P. morganii are widely recognized human pathogens. They have been isolated from urinary tract infections, wounds, ear, and nosocomial bacteremic infections, often in immuncompromised patients [2-6]. P. myxofaciens has no clinical interest to this time. P. penneri as species nova was nominated by the recommendation of Hickman and co-workers [7]. Formerly it was recognized as P. vulgaris biogroup 1 or indole negative P. vulgaris [8, 9]. Although it has been less commonly isolated from clinical samples than the other three human pathogenic Proteus species, it has nevertheless been connected with infections of the urinary tract, wounds and has been isolated from the feces of both healthy and diarrheic individuals [10-12]. Potential virulence factors responsible for virulence of Proteae are: IgA protease, urease, type3 fimbriae associated with MR/K haemagglutinins of at least two antigenic types, endotoxin, swarming motility and HlyA and/or HpmA type hemolysins [for review see ref. 13]. In the followings we give a survey of accumulated concepts about the position and characteristics of HlyA type alpha-hemolysins both in general and with emphasis on virulence functions in the tribe of Proteae.

Capillary electrophoretic analysis of wild type and mutant Proteus penneri outer membrane proteins.

In this study the virulence factors, outer membrane proteins (OMP), lipopolysaccharides (LPS), hemolysin, and the in vivo and in vitro virulence of wild-type Proteus penneri 357 and its two isogenic mutant variants--a transposon and a spontaneous mutant--were examined. The OMPs of these variants were analyzed by a new and fast technique, "dynamic sieving" capillary electrophoresis (CE). The OMP profiles were dominated by two peaks (39 and 43 kDa). In the P. penneri clone examined, both the transposon and the spontaneous mutations induced significant changes in the OMP patterns (in the relative percentage of the dominant proteins). CE was suitable for the comparative analysis of bacterial protein patterns in the genetic variants of this strain, and provided valuable results in connection with the bacteriological virulence. The LPS composition of the genetic variants also showed alterations. The wild type of P. penneri 357 showed a typical ladder pattern, an "S" form, and the mutants possessed "R" LPS patterns (only few bands) in the gels. In the bacteriological virulence tests the wild type of P. penneri 357 was virulent in the in vivo, and toxic in the in vitro assays, while both mutants showed neither toxicity nor pathogenicity.

AX.25 amateur packet radio as a possible emergency network.

In modern society more and more medical applications need a reliable data transfer. In emergency situations, such transfer may not be available because parts of the communications infrastructure may be affected. An alternative way could be the use of the amateur radio packet network, which offers almost global coverage. We analyzed its use as an emergency data transfer support, including transport of real-time medical data.

5-ethyl-2'-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil.

The aim of the present studies was to elucidate the effects and optimal modulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively enhanced the antitumour action of 5-FU, without significantly increasing its toxic side-effects, thus resulting in an approximately three times higher therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg EtdUrd administration - i.e. at the time of 5-FU treatment - the plasma concentration of EtdUrd was 269 microM, and that of 5-ethyluracil, as the major metabolite of EtdUrd, was 421 microM. It is of interest that EtdUrd pretreatment did not change the maximal plasma concentration of 5-FU; however, the half-life of the terminal elimination increased from 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose significantly (P < 0.05). After the combined treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma decreased from 61.06 microM to 29.70 microM (P < 0.01). The intratumoral concentrations of 5-FU were 34%-158% higher 6-96 h after the combined treatment than after the single 5-FU treatment. EtdUrd also caused a moderate increase in the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concentration in the plasma from 18 microM to a maximum of 249 microM, and the level remained high for longer than 6 h. The present studies indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at the same time, offering protection to normal organs by increasing the endogenous uridine level.

Warthin-like tumor of the thyroid a case report.

A case of Warthin-like tumor of the thyroid (WaLTT) with cervical lymph node metastasis is presented. The problems of the FNA diagnosis of this type of tumor is discussed as well as the histogenesis, nature and behaviour of this peculiar tumor.

Diversity among clinical isolates of Proteus penneri detected by random amplified polymorphic DNA analysis.

DNA of thirteen haemolytic Proteus penneri strains of clinical origin, all producing calcium dependent haemolysin and having been derived from four European countries was examined for plasmid profile, and outer membrane protein profile, by random amplified polymorphic DNA-PCR (RAPD-PCR) method, and digestions with restriction endonucleases were performed. All strains contained two large plasmids of approximately 60 and 70 kilobase pairs (kb). In addition, four strains contained a small plasmid of about 6 kb. These four strains produced cell-bound haemolysin only. Outer membrane protein analysis revealed subtle differences between strains. RAPD-PCR with primer I (CCGCAGCCAA) revealed 13 types, whereas primer II (AACGCGCAAC) yielded only two main types of different patterns. Results with primer I suggests a DNA sequence diversity within this species. The RAPD-PCR method provides a fast, economical and reproducible means for the typing of P. penneri. Digestion with restriction endonucleases indicated a high level of DNA methylation in this species.

The value of colposcopy in screening cervical carcinoma.

The value of colposcopy and cytology in screening CIN was analyzed in a retrospective study of 1,504 patients treated at the Department of Gynecologic Oncology, National Institute of Oncology, Budapest from 1980 to 1991. The majority (1,451) of the patients were admitted for histological confirmation of atypical colposcopic and/or cytologic findings, and 53 women were treated for cervical repair. All women underwent either cervical excision or conization. Cytologic and colposcopic findings were compared with the histological results. Sensitivity and specificity rates of cytology were 47% and 77%, respectively. The corresponding figures for colposcopy were 87% and 15% and for cytology and colposcopy together, 96% and 14%. The low sensitivity of cytology suggests that as many as 50% of CIN lesions may be overlooked if cytology alone is used for screening, i.e. in 50% of CIN associated with abnormal colposcopy the cytology was negative. We found 194 asymptomatic patients with carcinoma in situ, 40 with microinvasive and 8 with frank invasive carcinoma. This finding emphasizes the importance of cervical cancer screening. Our data suggest that, with colposcopy as a screening tool, the rate of false-negative cytology can be significantly reduced. Clinical implications of the "cytology-negative abnormal colposcopy and cytology-negative CIN" have yet to be determined. The major drawback of primary colposcopy is its low specificity with the consequence of high false-positive rate and over-treatment in a substantial number of cases. To overcome the problem of low specificity, further studies are required to identify those atypical colposcopic changes that most likely represent CIN--and high-grade CIN in particular.

Pharmacokinetics of panomifene in healthy volunteers at phase I/a study.

Panomifene (PAN) /E/-1,2,-diphenyl-1-[4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl]-3, 3,3-trifluoropropene is a new original Hungarian compound and is a tamoxifen (TMX) analog. In the phase I/a study presented here the human tolerance, pharmacokinetics and endocrine effects of a single oral dose of panomifene were evaluated in healthy, post-menopausal, female volunteers. As to the dose escalation, pharmacokinetic studies were carried out at doses of 24, 48 and 96 mg in two volunteers, and 120 mg in one volunteer. To find a suitable dose or dose range, for further evaluation of the drug detailed pharmacokinetics were performed at a selected dose level (24 mg) in 10 volunteers. The pharmacokinetic study showed considerable interindividual variability of the parameters, and only a medium correlation between dose and AUC (r=0.876). At the selected dose level (24 mg p.o.) the peak concentration of the plasma was 67.7 +/- 17.4 ng/ml (Cmax(meas)), the time to peak was 3.6 +/- 1.8 h (t[max(meas)]). The mean of the terminal half-life was 70.0 +/- 23.1 h (t(1/2beta)). The area under the plasma concentration time curve (AUC) calculated by the kinetic equation (AUCcalc) was 4814 +/- 1172 and by the trapezoidal rule (AUCtrap) was 4612 +/- 1357 (ng/ml) h.

Distribution of calcitonin-containing parafollicular cells of the thyroid in patients with chronic lymphocytic thyroiditis: a clinical, pathological and immunohistochemical study.

The C-cell hyperplasia of the thyroid gland is recognized as precursor to medullary carcinoma, particularly in multiple endocrine neoplasias, however it can be associated with hypercalcemic states and follicular tumours as well. The authors analysed 46 of their cases with Hashimoto's and/or lymphocytic thyroiditis from the immunohistological point of view with the aim of determining to what extent is C-cell hyperplasia associated with these pathological pictures. C-cell hyperplasia was demonstrated on sections of intraoperative preparations with the immunoperoxidase method with anticalcitonin MoAb. Moderate, focal C-cell hyperplasia was found in 17.4% (8 patients), extensive focal hyperplasia similarly in 17.4% (8 patients). Diffuse C-cell hyperplasia occurred in 1 case (2.2%). These results suggest the possibility that in the case of diffuse or more pronounced focal hyperplasia the serum calcitonin concentration of these patients is also elevated. Further clinical and pathological studies are needed to find out whether there is some pathogenetic relationship between chronic lymphocytic thyroiditis and C-cell hyperplasia or whether the finding is coincidental, and to establish what degree of C-cell hyperplasia is associated with elevated serum calcitonin levels. This relationship has been unknown until the present time, whereas it can be of great clinical significance, in part because of the changes in serum calcitonin levels, in part for screening out the MEN IIa type and working out the operating strategy.

Surgical chemotherapy in the management of melanoblastoma of the lower extremities.

The therapy of advanced melanoblastomas of the lower extremities is limited. Surgery alone is insufficient due to the extent of the tumor, the radicality of mutilating surgery is questionable because of the existing or suspected subclinical metastasis. To avoid amputation, regional chemoperfusion and simultaneous hemofiltration may be the choice of treatment. Between 1993 and 1995 the authors performed surgical chemotherapy on 21 occasions in 14 patients with advanced melanoblastoma of the lower limb. Partial remission of 4 to 11 months developed in 10 patients, 3 patients achieved subjective improvement for 3 to 6 months, 1 patient had disease progression. Simultaneous application of surgical regional chemotherapy and hemofiltration offers an alternative approach in the management of patients suffering from advanced melanoblastoma.