Soil and Vegetation Drive Sesquiterpene Lactone Content and Profile in Arnica montana L. Flower Heads From Apuseni-Mountains, Romania

Arnica montana L. (AM, Asteraceae) is a perennial, herbaceous vascular plant species of commercial importance. The flower heads’ pharmacological properties are attributed mainly to sesquiterpene lactones (SLs), with phenolic acids and flavonoids also considered of relevance. The botanical drug is still partly collected in different European mountain regions. The SL content can be influenced by genetic factors and environmental conditions (altitude, temperature and rainfall). Surprisingly, the influence of the soil on SL-content have rarely been investigated. However, the soil determines the occurrence, distribution and overall fitness of AM. Equally, environmental factors are crucial determinants for the biosynthesis and fluctuations in plant secondary metabolites. Therefore, different abiotic (pH, C/N ratio, base saturation, cation exchange capacity) and biotic (species richness, vegetation cover) parameters need to be assessed as potential drivers of the variable content of AM’s secondary metabolites. Consequently, we developed an in situ experimental design aiming to cover a wide range of soil pH conditions. We detected and investigated different AM populations growing in grassland on acidic soils, on siliceous as well as calcareous geologies within the same geographical region and altitudinal belt. The total SL content and most single SL contents of the AM flower heads differed significantly between the two geologies. AM flower heads of plants growing on loam on limestone showed a significant higher total SL content than the flower heads of plants growing in siliceous grasslands. Furthermore, the SL contents were significantly correlated with geobotanical species richness and vegetation cover pointing toward an effect of species interactions on the production of SLs. Moreover, the ratios of the main SLs helenalin to dihydrohelenalin esters were significantly correlated to environmental parameters indicating that SL composition might be a function of habitat conditions. The findings of this study shed light upon the often ignored, complex interactions between environmental conditions and plant secondary metabolites. We highlight the importance of both abiotic and biotic habitat parameters for SLs in AM

Self-potential signals caused by eruptions of the galeras volcano – colombia

The National Institute of Geology and Mining, INGEOMINAS - Colombia, and the Federal Institute for Geosciences and Natural Resources, BGR - Germany, perform since 1997 as a joint venturemulti-parameter measurements at the Galeras volcano, in the southwest of Colombia. Since the end of 1998 the Multi-parameter Station at Galeras (Estación Multiparámetro del Galeras - EMG) includes the continuous monitoring of electromagnetic variations. The electromagnetic (EM) station is located at the north-eastern foot walls of the central cone inside the caldera.During almost six years of electromagnetic monitoring, the data did not show significant variations of the electromagnetic field, which could be related to the volcanic activity. In July 2004 a new active period of Galeras began with two strong ash emissions. During both emissions strong self potential- (SP) signals were recorded lasting for several hours. The present paper will present the data which could give some indications on the movements of liquids during ash emissions

High-throughput detection of mutations responsible for childhood hearing loss using resequencing microarrays

Background: Despite current knowledge of mutations in 45 genes that can cause nonsyndromic sensorineural hearing loss (SNHL), no unified clinical test has been developed that can comprehensively detect mutations in multiple genes. We therefore designed Affymetrix resequencing microarrays capable of resequencing 13 genes mutated in SNHL (GJB2, GJB6, CDH23, KCNE1, KCNQ1, MYO7A, OTOF, PDS, MYO6, SLC26A5, TMIE, TMPRSS3, USH1C). We present results from hearing loss arrays developed in two different research facilities and highlight some of the approaches we adopted to enhance the applicability of resequencing arrays in a clinical setting. Results: We leveraged sequence and intensity pattern features responsible for diminished coverage and accuracy and developed a novel algorithm, sPROFILER, which resolved >80% of no-calls from GSEQ and allowed 99.6% (range: 99.2-99.8%) of sequence to be called, while maintaining overall accuracy at >99.8% based upon dideoxy sequencing comparison. Conclusions: Together, these findings provide insight into critical issues for disease-centered resequencing protocols suitable for clinical application and support the use of array-based resequencing technology as a valuable molecular diagnostic tool for pediatric SNHL and other genetic diseases with substantial genetic heterogeneity

Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial

A list of investigators of the International Salofalk OD Study Group is given in the appendix. Investigators from Latvia are: Jelena Derova, Aleksejs Derovs, Juris Pokrotnieks, Aldis Pukitis, Mairita Ergle.Objectives: To determine the therapeutic equivalence and safety of once daily (OD) versus three times daily (TID) dosing of a total daily dose of 3 g Salofalk (mesalazine) granules in patients with active ulcerative colitis. Design: A randomised, double-blind, double-dummy, parallel group, multicentre, international, phase III noninferiority study. Setting: 54 centres in 13 countries. Patients: 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis (clinical activity index (CAI)>4 and endoscopic index ≥ 4 at baseline) were randomised and treated. Interventions: 8-week treatment with either 3 g OD or 1 g TID mesalazine granules. Main outcome measures: Clinical remission (CAI ≤ 4) at study end. Results: 380 patients were evaluable for efficacy and safety by intention-to-treat (ITT); 345 for per protocol (PP) analysis. In the ITT population, 79.1% in the OD group (n = 191) and 75.7% in the TID group (n = 189) achieved clinical remission (p<0.0001 for non-inferiority). Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group (86%; n = 97) versus the TID group (73%; n = 100; p = 0.0298). About 70% of patients in both treatment groups achieved endoscopic remission, and 35% in the OD group and 41% in the TID group achieved histological remission. About 80% of all patients preferred OD dosing. Similar numbers of adverse events occurred in 55 patients (28.8%) in the OD group and in 61 patients (32.3%) in the TID group, indicating that the two dosing regimens were equally safe and well tolerated. Conclusions: OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule. With respect to the best possible adherence of patients to the treatment, OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis. ClinicalTrials.gov Identifier: NCT00449722.publishersversionPeer reviewe

Once versus three times daily dosing of oral budesonide for active Crohn's disease : A double-blind, double-dummy, randomised trial

Note: J.Pokrotnieks is in the list of the main authors of the article, as well as in the list of International Budenofalk Study Group collaboration list. His surname is made visible as the main author in this bibliographic record. Funding Information: The study was funded by Dr Falk Pharma GmbH, Freiburg, Germany . The study sponsor contributed to the design of the study in collaboration with the authors, funded the analysis of the data by an independent biostatistics company, worked in conjunction with the authors to interpret the data, and reviewed the draft manuscript. The sponsor was not involved in data collection. The final decision to publish was made by the first author (AD).Background: Oral budesonide 9. mg/day represents first-line treatment of mild-to-moderately active ileocolonic Crohn's disease. However, there is no precise recommendation for budesonide dosing due to lack of comparative data. A once-daily (OD) 9. mg dose may improve adherence and thereby efficacy. Methods: An eight-week, double-blind, double-dummy randomised trial compared budesonide 9. mg OD versus 3. mg three-times daily (TID) in patients with mild-to-moderately active ileocolonic Crohn's disease. Primary endpoint was clinical remission defined as CDAI < 150 at week 8 (last observation carried forward). Results: The final intent-to-treat population comprised 471 patients (238 [9 mg OD], 233 [3 mg TID]). The confirmatory population for the primary endpoint analysis was the interim per protocol population (n = 377; 188 [9 mg OD], 189 [3 mg TID]), in which the primary endpoint was statistically non-inferior with budesonide 9. mg OD versus 3. mg TID. Clinical remission was achieved in 71.3% versus 75.1%, a difference of - 3.9% (95% CI [- 14.6%; 6.4%]; p = 0.020 for non-inferiority). The mean (SD) time to remission was 21.9 (13.8) days versus 21.4 (14.6) days with budesonide 9 mg OD versus 3. mg TID, respectively. In a subpopulation of 122 patients with baseline SES-CD ulcer score ≥ 1, complete mucosal healing occurred in 32.8% (21/64) on 9 mg OD and 41.4% (24/58) on 3 mg TID; deep remission (mucosal healing and clinical remission) was observed in 26.6% (17/64) and 32.8% (19/58) of patients, respectively. Treatment-emergent suspected adverse drug reactions were reported in 4.6% of 9 mg OD and 4.7% of 3 mg TID patients. Conclusions: Budesonide at the recommended dose of 9 mg/day can be administered OD without impaired efficacy and safety compared to 3 mg TID dosing in mild-to-moderately active Crohn's disease.publishersversionPeer reviewe

Novel Budesonide Suppository and Standard Budesonide Rectal Foam Induce High Rates of Clinical Remission and Mucosal Healing in Active Ulcerative Proctitis : a Randomised, Controlled, Non-inferiority Trial

Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.BACKGROUND AND AIMS: Proctitis is the least extensive type of ulcerative colitis, for which rectal therapy is rarely studied and is underused. This study evaluated the efficacy, safety, and patient's preference of a novel formulation of budesonide suppository 4 mg, compared with a commercially available budesonide rectal foam 2 mg, for the treatment of mild to moderate ulcerative proctitis. METHODS: This was a randomised, double-blind, double-dummy, active-controlled trial. Patients were randomly assigned in a 1:1 ratio to receive either budesonide 4 mg suppository or budesonide 2 mg foam once daily for 8 weeks. The co-primary endpoints were changes from baseline to Week 8 in clinical symptoms, for which clinical remission was defined as having a modified Ulcerative Colitis-Disease Activity Index [UC-DAI] subscore for stool frequency of 0 or 1 and a subscore for rectal bleeding of 0, and mucosal healing, defined as having a modified UC-DAI subscore for mucosal appearance of 0 or 1. Using a more stringent criterion, we additionally analysed deepened mucosal healing, which was defined as a mucosal appearance subscore of 0. Patient's preference, physician's global assessment, and quality of life were also assessed and analysed. RESULTS: Overall, 286 and 291 patients were included in the 4 mg suppository and 2 mg foam groups, respectively. Budesonide 4 mg suppository met the prespecified criterion for non-inferiority to the 2 mg foam in both co-primary endpoints of clinical remission and mucosal healing. Secondary endpoints consistently supported the non-inferiority of the suppository. Trends in favour of the suppository were observed in the subgroup of mesalazine non-responders. More patients reported a preference for the suppository over rectal foam. CONCLUSIONS: In patients with ulcerative proctitis, budesonide 4 mg suppository was non-inferior to budesonide 2 mg foam in efficacy, and both were safe and well tolerated.publishersversionPeer reviewe

Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. METHODS: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. RESULTS: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. CONCLUSIONS: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance

No more rattling: biomechanical evaluation of a hexapod ring fixator free of play.

Hexapod-ring-fixators have a characteristic rattling sound during load changes due to play in the hexapod struts. This play is perceived as unpleasant by patients and can lead to frame instability. Using slotted-ball-instead of universal-joints for the ring-strut connection could potentially resolve this problem. The purpose of the study was to clarify if the use of slotted-ball-joints reduces play and also fracture gap movement. A hexapod-fixator with slotted-ball-joints and aluminum struts (Ball-Al) was compared to universal-joint-fixators with either aluminum (Uni Al) or steel struts (Uni Steel). Six fixator frames each were loaded in tension, compression, torsion, bending and shear and mechanical performance was analyzed in terms of movement, stiffness and play. The slotted-ball-joint fixator was the only system without measurable axial play (<0.01 mm) compared to Uni-Al (1.2 ± 0.1) mm and Uni-Steel (0.6 ± 0.2) mm (p≤0.001). In both shear directions the Uni-Al had the largest play (p≤0.014). The resulting axial fracture gap movements were similar for the two aluminum frames and up to 25% smaller for the steel frame, mainly due to the highest stiffness found for the Uni-Steel in all loading scenarios (p≤0.036). However, the Uni-Steel construct was also up to 29% (450 g) heavier and had fewer usable mounting holes. In conclusion, the slotted-ball-joints of the Ball-Al fixator reduced play and minimized shear movement in the fracture while maintaining low weight of the construct. The heavier and stiffer Uni-Steel fixator compensates for existing play with a higher overall stiffness

Curva de resistividad aparente en una región del volcán Galeras

Utilizando registros de la estación electromagnética Cráter perteneciente a la red de monitoreo del volcán Galeras (INGEOMINAS), se ha implementado el método magnetotelúrico. Se presenta la curva de resistividad aparente obtenida con base en este método