Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis.

BACKGROUND: Probiotics may correct intestinal dysbiosis and proinflammatory conditions in patients with liver cirrhosis. AIM: To test the effects of a multispecies probiotic on innate immune function, bacterial translocation and gut permeability. METHODS: In a randomised, double blind, placebo-controlled study, stable cirrhotic out-patients either received a daily dose of a probiotic powder containing eight different bacterial strains (Ecologic Barrier, Winclove, Amsterdam, The Netherlands) (n = 44) or a placebo (n = 36) for 6 months and were followed up for another 6 months. RESULTS: We found a significant but subclinical increase in neutrophil resting burst (2.6-3.2%, P = 0.0134) and neopterin levels (7.7-8.4 nmol/L, P = 0.001) with probiotics but not with placebo. Probiotic supplementation did not have a significant influence on neutrophil phagocytosis, endotoxin load, gut permeability or inflammatory markers. Ten severe infections occurred in total; one during intervention in the placebo group, and five and four after the intervention has ended in the probiotic and placebo group, respectively. Liver function showed some improvement with probiotics but not with placebo. CONCLUSIONS: Probiotic supplementation significantly increased serum neopterin levels and the production of reactive oxygen species by neutrophils. These findings might explain the beneficial effects of probiotics on immune function. Furthermore, probiotic supplementation may be a well-tolerated method to maintain or even improve liver function in stable cirrhosis. However, its influence on gut barrier function and bacterial translocation in cirrhotic patients is minimal.

Investigation of potential stress parameters in rainbow trout (Oncorhynchus mykiss).

The transportation of rainbow trout in the presence of the anesthetic clove oil was investigated. Before the transportation tests, an acute experiment was conducted to verify that removal of the fish from the water for one minute does not significantly increase the glucose or cortisol concentration of the blood plasma. In the main experiment two different transportation conditions were compared: transport in water only and in water with anesthetic. During transportation without addition of clove oil, blood plasma glucose and cortisol concentrations changed significantly. The concentration of glucose increased from 4.92 mmol/L prior to transportation to 6.16 mmol/L and values similar to the initial ones (4.95 mmol/L) were observed 5 hours after transportation. Concentration of the stress hormone cortisol increased from the initial 37.2 ng/mL to 89.2 ng/mL and returned to a value of 36.1 ng/mL 3 hours post transportation. Respective values of glucose concentration have not changed significantly during transportation in the presence of clove oil (4.3; 4.4; 4.4 mmol/L), whereas those of cortisol showed a slight decrease with the passing of time (28.1; 26.7; 20.18 ng/mL). Results show that transportation stress can significantly be reduced by the use of anesthetics.

4-thio-deoxyuridylate-modified thrombin aptamer and its inhibitory effect on fibrin clot formation, platelet aggregation and thrombus growth on subendothelial matrix.

BACKGROUND: The consensus thrombin aptamer C15-mer is a single-stranded DNA of 15 nucleotides [d(GGTTGGTGTGGTTGG)] that was identified by the selection of thrombin-binding molecules from a large combinatorial library of oligonucleotides. It is capable of inhibiting thrombin at nanomolar concentrations through binding to a specific region within thrombin exosite 1. As has been shown in our earlier studies, the 4-thio-deoxyuridylate (s4dU)-containing oligonucleotides have high affinity for a number of proteins, due to the reduced hydrophilic character of the modified oligonucleotide. METHODS: Three different analogs of the original thrombin-inhibiting sequence, in which some of the thymidylate residues were replaced by 4-thio-deoxyuridylates, were synthesized. The inhibitory effect of modified aptamers was tested on thrombin-catalyzed fibrin clot formation and fibrinopeptide A release from fibrinogen, thrombin-induced platelet aggregation/secretion, and the formation of thrombus on coverslips coated with human collagen type III, thrombin-treated fibrinogen or subendothelial matrix of human microvascular endothelial cells. RESULTS: As compared with the C15-mer, the analog with the sequence GG(s4dU)TGG(s4dU)G(s4dU)GGT(s4dU)GG (UC15-mer) showed a 2-fold increased inhibition of thrombin-catalyzed fibrin clot formation, fibrinopeptide A release, platelet aggregation and secretion in human plasma and thrombus formation on thrombin-treated fibrinogen surfaces under flow conditions. Concerning the inhibition of thrombin-induced fibrin formation from purified fibrinogen and activation of washed platelets, UC15-mer was 3-fold and twelve-fold more effective than C15-mer, respectively. CONCLUSION: The replacement of four thymidylate residues in C15-mer by 4-thio-deoxyuridylate resulted in a new thrombin aptamer with increased anticoagulant and antithrombotic properties.

Meta-analysis: enteral nutrition in active Crohn's disease in children.

BACKGROUND: Controversy exists surrounding the optimal treatment for inducing remission in active Crohn's disease. AIM: To review and update evidence on the effectiveness of enteral nutrition (EN) in treating active Crohn's disease in children. METHODS: MEDLINE, EMBASE and The Cochrane Library (up to February 2007) were searched for randomized controlled trials (RCTs) relevant to Crohn's disease and EN in children. RESULTS: We included 11 RCTs (n = 394). Seven RCTs (n = 204) compared EN with corticosteroid therapy. On the basis of pooled results of four RCTs (n = 144), we found no significant difference in the remission rates between groups (relative risk, RR 0.97, 95% CI 0.7-1.4, random effect model). Four RCTs (n = 190) compared two EN regimens. One of the four RCTs (n = 50) revealed a significant increase in the percentage of patients achieving remission in the total EN group compared with the partial EN group (RR 2.7, 95% CI 1-7.4). Because of lack of data, formal pooling of results was not possible for many outcomes (e.g., time until remission, duration of remission, growth data). CONCLUSIONS: Limited data suggest similar efficacy for EN and corticosteroids. As the number of patients needed to provide a definite answer is too large, future studies should focus on detailed outcome measurements including growth and quality of life.

Synchronous balneophototherapy is effective for the different clinical types of psoriasis.

BACKGROUND: The efficacy of synchronous balneophototherapy in clearing psoriasis is based on the multiple-targeted effects of UVB light and Dead Sea salt. Their synchronous application produces a synergic effect. OBJECTIVE: The purpose of this retrospective study is: 1) to evaluate the efficacy of synchronous balneophototherapy for treating different clinical types of psoriasis; 2) to determine whether there is any difference between response to treatment, and 3) to gain more data in order to predict the effect of treatment in different clinical types, and thus to support the selection of patients for treatment. METHODS: Patients received a basic course of synchronous balneophototherapy according to the Regensburg scheme, consisting of 35 treatment sessions, followed by a maintenance course of a further 25 treatments. The patients' skin status was monitored by weekly assessment using the PASI score throughout the course. The efficacy of the treatment was evaluated through the results of 373 patients treated according to protocol during the basic course, and the results of 78 of these patients during the maintenance course. One hundred and eighty-six patients were enrolled into the study comparing the efficacy of the basic course for the different clinical types of psoriasis: data of patients with large plaques, small plaques, guttate and confluating type of skin signs were summarized and compared. RESULTS: During the basic course of treatment 70.7% improvement of the average PASI index was observed; the average PASI index decreased from 16.14 to 4.73. A further improvement from 4.58 to 4.27 of the average PASI was found during the maintenance therapy. Small plaque-type skin signs showed the best response with a PASI decrease of 76.1%; Guttate type had a PASI decrease of 73.7%, large plaque type, 67.1% and confluating type, 62%. Comparing data with the average PASI decrease, a statistically significant lower decrease was found in confluating type cases. CONCLUSIONS: These results confirm that synchronous balneophototherapy is an effective treatment modality for different clinical types of psoriasis. Patients with small plaques have the greatest chance of the most marked clinical clearing; guttate and large plaque types of psoriasis also respond well to the treatment.

Results of a randomised, multicentre study comparing a new water-based gel of clindamycin 1% versus clindamycin 1% topical solution in the treatment of acne vulgaris.

Several topical formulations of clindamycin phosphate are currently marketed for the treatment of acne vulgaris. This 12 week, multi-centre, investigator-blind, randomised, active and placebo-controlled, parallel group study assessed the clinical efficacy and safety of clindamycin 1% gel once-a-day vs clindamycin 1% solution twice-a-day, and to demonstrate its superiority vs its vehicle alone. A total of 592 subjects were included. After 12 weeks, a 65% reduction in inflammatory lesion count was observed with both active treatments. The gel was superior to its vehicle for total and inflammatory lesion reduction, Global Assessment of Improvement, and Global Severity Grade at final visit (all p < 0.01). No difference was found between the 2 active treatments for any of the evaluated criteria. Local tolerance in each active treatment group was slightly better with clindamycin gel (1.9% of subjects) relative to 3.1% in the topical solution group. In conclusion, the new water-based gel once-a-day formulation of clindamycin 1% is an effective, safe, and convenient alternative to the twice-a-day topical solution formulation in the treatment of acne vulgaris.

No significant change of plasma beta-endorphin levels of psoriasis patients after synchronous balneophototherapy.

BACKGROUND/PURPOSE: Previous studies suggested that beta-endorphin has a pathogenic role in psoriasis: its increased plasma concentration may play a role in the neuroimmunological processes in the pathomechanism of the disease, and plasma beta-endorphin levels should reflect the changes in the patients' skin status. The purpose of this study was to investigate the changes of peripheral blood beta-endorphin levels in psoriatic patients in conjunction with changes in their skin symptoms after synchronous balneophototherapy. METHODS: With synchronous balneophototherapy, 12 patients with extended skin symptoms of psoriasis were treated. The therapy followed the Regensburg protocol, consisting of a basic course of 35 sessions. Patients' skin status was characterized by evaluating the Psoriasis Area and Severity Index score before and after the therapy course. Blood samples were taken before treatment, and 1 day after the last session, with symptom-free skin. Plasma beta-endorphin levels were measured by a specific radioimmunoassay developed by the authors. RESULTS: There was no significant change in plasma levels of beta-endorphin after clinical clearance of psoriatic skin symptoms. CONCLUSION: In this non-randomized, uncontrolled study no significant difference could be detected between plasma beta-endorphin levels before and after a basic course of synchronous balneophototherapy in patients with psoriasis. Although beta-endorphin has many neuroimmunological effects, the changes of its plasma level do not consistently reflect the skin status. Inflammation in psoriatic skin lesions is probably not mediated directly by circulating beta-endorphin.

Anti-inflammatory effect of synthetic somatostatin analogues in the rat.

1. Somatostatin (6.11 nmol kg(-1) i.p.) inhibited neurogenic plasma extravasation evoked by 1% mustard oil and non-neurogenic oedema induced by 5% dextran in the rat skin. 2. Cyclic synthetic octapeptide (TT-248 and TT-250) and heptapeptide (TT-232) somatostatin analogues proved to be more effective in reducing neurogenic and non-neurogenic inflammatory reactions but octreotide had no influence on either neurogenic or non-neurogenic inflammation. 3. TT-232 administered i.p. or i.v. (1.06 - 42.40 nmol kg(-1)) inhibited in a dose-dependent manner the plasma extravasation evoked by mustard oil in the rat's paw. Neither diclofenac (15.78 - 315.60 micromol kg(-1)) nor the selective COX-2 inhibitor meloxicam (2.95 - 569.38 micromol kg(-1)) attenuated the mustard oil-induced neurogenic plasma extravasation. 4. TT-232, diclofenac and meloxicam dose-dependently diminished non-neurogenic dextran-oedema of the paw the ED(35) values were 1.73 nmol kg(-1) for TT-232 and 34.37 micromol kg(-1) for diclofenac. 5. TT-232 inhibited in the dose range of 1.06 - 21.21 nmol kg(-1) the bradykinin-induced plasma extravasation in the skin of the chronically denervated paw. 6. Mustard oil-induced cutaneous plasma extravasation was dose-dependently diminished by s.c. TT-232 1, 2, 4, 6 or 16 h after the treatment. TT-232 (2 x 106, 2 x 212 and 2 x 530 nmol kg(-1) per day s.c. for 18 days) caused dose-dependent inhibition of chronic Freund adjuvant-induced arthritis during the experimental period. 7. TT-232 (200 and 500 nM) inhibited the release of SP, CGRP and somatostatin from the rat isolated trachea induced by electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) or by capsaicin (10(-7) M), but did not influence the basal, non-stimulated peptide release. 8. It is concluded that somatostatin analogues without endocrine functions as TT-232 are promising compounds with a novel site of action for inhibition of non-neurogenic and neurogenic inflammatory processes.

[Interferon-alpha and PUVA therapy for mycosis fungoides]. / Mycosis fungoides interferon-alfa- és PUVA-kezelése.

14 patients suffering from early stage mycosis fungoides were treated with interferon alpha 2-a and PUVA/1 patient in stage I a, 3 patients in stage I b, 4 patients in stage II a and 6 patients in stage II b/during 3-21 months time course. Interferon alpha 2-a was administered 3 times a week, in escalating dose from 3 MU to 9 MU, determining the individual maximal tolerated dose. All of the patients responded well to the treatment. Partial remission was observed after 4-13 weeks of treatment. Total remission developed in 8 cases, after 8 weeks- 9 months of the treatment. Side effects occurred frequently: weight loss, pain, fever, fatigue, leucopenia, thrombopenia, liver enzyme elevation. Because of the side effects the dose of the interferon was reduced individually, the dose reduction did not cause relapse.

Expression of inositol 1,4,5-trisphosphate receptors in rat adrenocortical zones.

Previously we demonstrated the presence of InsP3R-I, -II and -III subtypes in the zona glomerulosa. Now we have examined the expression of different subtypes of inositol 1,4,5-trisphosphate receptor (InsP3R) in the inner zones of rat adrenal cortex. RNA extracted from decapsulated adrenal tissue (zonae fasciculata-reticularis and the medulla) or from fasciculata-reticularis cells was reverse transcribed. Subsequent polymerase chain reaction revealed the presence of InsP3R-I, -II and -III subtypes in decapsulated tissue but failed to demonstrate the expression of any known subtypes of InsP3R in fasciculata-reticularis cells. Accordingly, InsP3 receptors expressed in the decapsulated tissue are of medullary origin.

In the central role of GnRH in the regulation of reproductive functions: mechanism of action and practical results.

The regulation of reproductive functions is influenced by several hormones. The hypothalamic hormone GnRH has a central role in reproduction. Several superactive and inhibitory analogs of GnRH synthesized in our laboratory showed use in animal breeding. GnRH was suggested to be degraded by the hypothalamus itself and also by the pituitary. We have used cultured fetal hypothalamic cells, and cultured pituitary cells to study the storage, the release and the action of this neuropeptide. It was found that neither the cultured hypothalamic nor the pituitary cells degrade GnRH, and pretreatment of these cultured cells with steroids do not induce GnRH degradation. The basal GnRH secretion from the cultured hypothalamic cells was increased by steroid pretreatment while the neurotransmitter induced GnRH release did not change. At the pituitary level it was found that GnRH regulates its own effect by priming or desensitizing gonadotropin release depending on the pretreatment time or the concentration of GnRH. The self-regulatory action of GnRH follows a similar pattern for both LH and FSH release.

Nitrogen bridgehead compounds. 44. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 4.

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbox yli c acid (1) in the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of an (arylamino)methylene moiety into position 9 of the pyridopyrimidine ring. Compound 34, (+)-6(S)-methyl-9-[(m-methylphenyl)-hydrazono]-4-oxo-4H-pyrido[1,2 -a] pyrimidine-3-carboxylic acid, displayed about 10 000 times the activity of the starting compound 1. A structure-activity relationship study of 9-[(arylamino)methylene]tetrahydropyridopyrimidine-3-carb ox ylic acids resulted in conclusions similar to those found for the 9-(arylhydrazono)tetrahydro-and 9-(arylamino)dihydropyridopyrimidine series. Replacement of the 3-carboxy group of 9-(phenylhydrazono)-tetrahydropyridopyrimidin-4-ones with an acrylic acid moiety caused slight increases in potency. In the 6-methyl-substituted series, a high stereospecificity was observed between the enantiomers with 6S and 6R absolute configurations, the former being responsible for the antiallergic activity. The effects of some 9-[(arylamino)-methylene]tetrahydropyridopyrimidine-3-car box ylic acids on the rat passive peritoneal anaphylaxis test were also investigated.

Nitrogen bridgehead compounds. 38. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 3.

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (4) on the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of appropriate functional groups into position 9 of the pyridopyrimidine ring. The most active 9-substituted pyridopyrimidinecarboxylic acids contained an oxime, a phenylamino, or a (phenylamino)thioxomethyl group in position 9. The 9-phenylcarboxamido and 9-phenylhydrazono moieties may be regarded as bioisosteric groups in the pyridopyrimidinone series. In the series of 9-(arylamino)dihydropyridopyrimidines, the structure-activity relationship study revealed similar relationships as found for the 9-(arylhydrazono)tetrahydropyridopyrimidines. The biological activity was due to the 6S enantiomers. A monosubstituted arylamino moiety in position 9 was necessary for the intravenous activity. The most active compound, 9-[(3-acetylphenyl)amino]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidine-3-carboxylic acid (40) was three times as active as the reference sodium chromoglycate (DSCG) in the passive cutaneous anaphylaxis (PCA) test.

Cardiobacterium hominis endocarditis: description of two patients and characterization of the organism.

Two cases of endocarditis caused by Cardiobacterium hominis are reported. In both instances infection was subacute and characterized by (i) implantation on abnormal valves, (ii) chronic course lasting weeks to months before recognition, and (iii) rapid clinical and bacteriological response to penicillin, as well as other antibiotics commonly used to treat infections caused by gram-negative bacilli. Our isolates of C. hominis are compared with strains in the National Institutes of Health culture collection. Optimal growth requires yeast extract and incubation at 37 degrees C with increased humidity and supplemental CO2. The production of indole, a positive oxidase reaction, and characteristic sugar fermentation distinguish C. hominis from other slow-growing, gram-negative bacilli.