Characterization of cultural traits and fungicidal activity of strains belonging to the fungal genus Chaetomium.

AIMS: Compare and characterize Chaetomium strains with special regard to their potentialities as biocontrol agents. METHODS AND RESULTS: Twelve strains of the fungal genus Chaetomium from diverse ecological niches were identified as belonging to six different species. Large differences were observed between the strains with regard to temperature requirements for mycelial growth and pigmentation of culture filtrates. Culture filtrates and ethyl acetate extracts were assayed for fungicidal effects against important phytopathogens both on agar media and in multiwell plates. The samples from Chaetomium globosum were particularly active against Botrytis cinerea, Pyrenophora graminea and Bipolaris sorokiniana, while those from C. cochliodes and C. aureum were inhibitory towards Phytophthora infestans, and P. infestans and Fusarium culmorum respectively. To narrow down the active principle, the most promising extracts were separated by preparative HPLC and the resulting fractions tested in bioassays. Chaetoglobosins were identified as active compounds produced by C. globosum. CONCLUSIONS: The bioassays revealed C. aureum and C. cochliodes as promising candidates for use in biocontrol. Both showed remarkably good activity against the prominent plant pathogen P. infestans. SIGNIFICANCE AND IMPACT OF THE STUDY: We provide the first systematic study comparing six different Chaetomium species with regard to their use as biocontrol agents.

Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists. OBJECTIVES: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK. METHODS: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials). RESULTS: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner's solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14-0.90, two studies, I2  = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85-0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69-0.82, two studies, I2  = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD -20.48, 95% CI: -31.55 to -9.41, two studies, I2  = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD -1.71 95% CI: -3.02 to -0.41, two studies, I2  = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias. CONCLUSIONS: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.

Menthacarin induces calcium ion influx in sensory neurons, macrophages and colonic organoids of mice.

AIMS: Menthacarin is a herbal combination that is clinically used for the treatment of functional gastrointestinal disorders (FGIDs). In several clinical studies, Menthacarin reduced visceral hypersensitivity-related symptoms. Pathogenesis of visceral hypersensitivity is multifactorial. This involves several cell types and different transient receptor potential ion channels (TRPs); these ion channels are highly conductive for calcium ions. Since transient changes in cytosolic calcium levels are crucial for many functions of living cells, we investigated if Menthacarin can induce calcium influx in sensory, largely nociceptive, neurons from dorsal root ganglia (DRG), peritoneal macrophages (PMs) and colonic organoids. MAIN METHODS: We employed the calcium imaging technique on sensory neurons from DRG, PMs and colonic organoids isolated from mice. All cells were superfused by Menthacarin at several concentrations (600, 1200, 1800 µg/ml) during the experiments, followed by calcium ionophor ionomycin (Iono., 1 µM) as a positive control. KEY FINDINGS: Menthacarin induced concentration-dependent calcium ion influx in all investigated cell types. Furthermore, repeated applications of Menthacarin induced tachyphylaxis (desensitisation) of calcium responses in sensory neurons and colonic organoids. SIGNIFICANCE: Menthacarin-induced calcium influx into sensory neurons, macrophages and colonic organoids is probably related to its clinical desensitising effects in patients with FGIDs.

Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks.

CONTEXT: Pain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose. OBJECTIVES: We assessed the safety and tolerability of prolonged treatment with oral cebranopadol for up to 26 weeks in patients suffering from chronic moderate-to-severe cancer-related pain. METHODS: This was a non-randomized, multi-site, open-label, single-arm clinical trial with patients who had completed a double-blind trial comparing morphine prolonged release with cebranopadol. In this extension trial, patients were treated with oral cebranopadol for up to 26 weeks. RESULTS: Cebranopadol was safe and well tolerated in patients with chronic moderate-to-severe pain related to cancer in the dose range tested (200-1000 µg once daily). The median and mean pain levels remained in the range of mild pain during the treatment period. CONCLUSION: Our data suggest that cebranopadol was safe and well tolerated when administered for up to 26 weeks in patients with chronic cancer-related pain who were previously treated with cebranopadol or morphine prolonged release.

Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila.

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.

Reversal of visceral hypersensitivity in rat by Menthacarin® , a proprietary combination of essential oils from peppermint and caraway, coincides with mycobiome modulation.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder associated with altered gastrointestinal microflora and increased nociception to colonic distension. This visceral hypersensitivity can be reversed in our rat maternal separation model by fungicides. Menthacarin® is a proprietary combination of essential oils from Mentha x piperita L. and Carum carvi. Because these oils exhibit antifungal and antibacterial properties, we investigated whether Menthacarin® can reverse existing visceral hypersensitivity in maternally separated rats. METHODS: In non-handled and maternally separated rats, we used the visceromotor responses to colorectal distension as measure for visceral sensitivity. We evaluated this response before and 24 hours after water-avoidance stress and after 7 days treatment with Menthacarin® or control. The pre- and post-treatment mycobiome and microbiome were characterized by sequencing of fungal internal transcribed spacer 1 (ITS-1) and bacterial 16s rDNA regions. In vitro antifungal and antimicrobial properties of Menthacarin® were studied with radial diffusion assay. KEY RESULTS: Menthacarin® inhibited in vitro growth of yeast and bacteria. Water-avoidance caused visceral hypersensitivity in maternally separated rats, and this was reversed by treatment. Multivariate analyses of ITS-1 and 16S high throughput data showed that maternal separation, induced changes in the myco- and microbiome. Menthacarin® treatment of non-handled and maternally separated rats shifted the mycobiomes to more similar compositions. CONCLUSIONS & INFERENCES: The development of visceral hypersensitivity in maternally separated rats and the Menthacarin® -mediated reversal of hypersensitivity is associated with changes in the mycobiome. Therefore, Menthacarin® may be a safe and effective treatment option that should be tested for IBS.

Performance of International Medical Students In psychosocial medicine.

BACKGROUND: Particularly at the beginning of their studies, international medical students face a number of language-related, social and intercultural challenges. Thus, they perform poorer than their local counterparts in written and oral examinations as well as in Objective Structured Clinical Examinations (OSCEs) in the fields of internal medicine and surgery. It is still unknown how international students perform in an OSCE in the field of psychosocial medicine compared to their local fellow students. METHODS: All students (N = 1033) taking the OSCE in the field of psychosocial medicine and an accompanying written examination in their eighth or ninth semester between 2012 and 2015 were included in the analysis. The OSCE consisted of four different stations, in which students had to perform and manage a patient encounter with simulated patients suffering from 1) post-traumatic stress disorder, 2) schizophrenia, 3) borderline personality disorder and 4) either suicidal tendency or dementia. Students were evaluated by trained lecturers using global checklists assessing specific professional domains, namely building a relationship with the patient, conversational skills, anamnesis, as well as psychopathological findings and decision-making. RESULTS: International medical students scored significantly poorer than their local peers (p < .001; η2 = .042). Within the specific professional domains assessed, they showed poorer scores, with differences in conversational skills showing the highest effect (p < .001; η2 = .053). No differences emerged within the multiple-choice examination (p = .127). CONCLUSION: International students showed poorer results in clinical-practical exams in the field of psychosocial medicine, with conversational skills yielding the poorest scores. However, regarding factual and practical knowledge examined via a multiple-choice test, no differences emerged between international and local students. These findings have decisive implications for relationship building in the doctor-patient relationship.

[Preoperative, neuropathic component in patients with back pain]. / Präoperative, neuropathische Komponente bei Rückenschmerzen.

BACKGROUND: The objectification of pain is essential for evaluation, treatment plan and follow-up; therefore, it is necessary to find reliable clinical parameters. OBJECTIVE: The goal of the study was the preoperative screening of a neuropathic component in patients with vertebral compression fracture (WKF), herniated disc (NPP) or spinal cord compression (SKS). MATERIAL AND METHODS: Depending on the preoperative condition on admittance, patients were classified into three groups: group 1 WKF, group 2 NPP and group 3 SKS. To characterize the pain we used the painDETECT questionnaire, the Oswestry questionnaire and further questionnaires. All patients were surgically treated according to the diagnosis, e.g. radiofrequency kyphoplasty, nucleotomy or spondylodesis. RESULTS: We evaluated the data from 139 patients (45% WKF, 34% NPP and 21% SKS). There were no differences in preoperative pain intensity (median ordinal scale 0-10) with a mean preoperative score of 7 for all groups. The total score of the painDETECT questionnaire showed significantly higher results in group 2 (median 18) and in group 3 (median 14) than in group 1 (median 9). There was even a significant difference between groups 2 and 3 (p = 0.03). The highest pain intensity was detected in group 1 with a median visual analog scale (VAS) of 71 mm. The total scores in the painDETECT questionnaire and the scores in the Oswestry questionnaire correlated in groups 2 and 3. CONCLUSION: The painDETECT questionnaire was shown to be a very suitable instrument for evaluating the neuropathic pain component in patients with dorsalgia. This could be very useful in planning further therapy.

Diagnosis of Neuropathic Components in Patients with Back Pain Before and After Surgery.

Background: The perception of back pain subjective is hard for physicians to measure. For this reason, questionnaires are an important instrument to evaluate the pain 1. The main point of this study was to verify differentiation of pain symptoms in patients with different pain mechanisms. The most important parameter was the PainDetect questionnaire, which can differentiate between nociceptive and neuropathic pain. Additional parameters were measured before and after surgery to characterise pain symptoms in detail. Material and Methods: We selected patients with diagnosed vertebral compression fracture, herniated disc or with spinal cord compression. To characterise the preoperative condition on admittance, we collected the data from the physical examination, as well as clinical data, including X-ray, CT and MRI. To characterise the pain, we used the painDetect questionnaire, the Oswestry Index questionnaire (ODI) and the visual analogue scale (VAS). Depending on the diagnosis, patients were treated by surgery (radiofrequency kyphoplasty, nucleotomy, spondylodesis). At 2 to 3 days and 6 months after surgery, we repeated the questionnaire and compared the results with those before the operation. Data on patient satisfaction and adverse events were also collected. Results: This study included 62 patients with vertebral compression fracture (group 1: VBF, 89 % female, mean age 71 years) and 77 patients with herniated disc or spinal cord compression (group 2: non-VBF, 55 % female, mean age 53 years). There was no difference between both groups in preoperative pain intensity (acute, maximum, average): median ordinal scale 0 to 10; group 1: 6, 8, 7; group 2: 6, 9, 7. The total score in the painDetect questionnaire differed significantly between the two groups (median group 1 = 9, group 2 = 17; effect size r = 0.5; p = 0.000). The existence of neuropathic pain was presumed (> 90 %) in 3 % of the patients in group 1 and in 13 % of patients it was not excluded. In contrast, in group 2 it was presumed (> 90 %) in 43 % of patients and in 30 % of patients it could not be excluded. Patients with vertebral compression fracture had greater pain intensity (VAS 71) than patients from group 2 (VAS 53). There was no difference in the total score of the Oswestry questionnaire between the two groups (56 % vs. 58 %). Pain intensity was significantly reduced in both groups after the operations. Six months postoperatively, pain intensity (median ordinal scale 0 to 10; acute, maximum, average) was 2, 5, 3 in group 1 and 2, 4, 2 in group 2. Moreover, the final scores of the painDetect questionnaires were significantly lower in both groups after the operations (4 in both groups). The median score of the ODI was reduced in both groups, with an effect size of 0.6. 98 % of the patients in group 1 and 94 % in group 2 were satisfied with the outcome of the operation. Conclusion: The preoperative pain characteristics of patients with vertebral compression fracture is different from those of patients with herniated disc or with spinal cord compression. 43 % of patients in group 2 exhibited a neuropathic pain component and in 30 % this could not be excluded. In contrast, in group 1 only 3 % of the patients exhibited a neuropathic pain component. Postoperatively, pain symptoms were significant reduced in both groups, so that the risk of chronic pain was considerably less.

[Transition of Adolescents with Chronic Neurologic Disorders into Adult Health Care]. / Transition chronisch neurologisch kranker Jugendlicher in die Erwachsenenmedizin.

BACKGROUND: Transition of care from pediatric to adult services is a complex process. Factors influencing the success of health care transition of adolescents with chronic neurological disorders are poorly understood. METHODS: Young adults with chronic neurological disorders who had been cared for in an Interdisciplinary Pediatric Center participated in this study. Using the Patient Satisfaction Questionnaire Short-form (PSQ-18) we investigated whether satisfaction of these patients with their medical care in adult services was depending on the severity and complexity of their condition. They were assigned to a group of severely disabled patients (group 1; intellectual disability or learning disability plus motor handicap or degree of disability≥80, n=11) or a group 2 of patients with milder impairment (N=39). We used descriptive and t-statistics to compare both groups. RESULTS: Patients of group 1 reported slightly lower satisfaction with their present medical care in adult services (M=3.25; 95%-KI=[2.96-3.55]) compared to patients of group 2 (M=3.59; 95%.KI=[3.37-3.81]; p=0.084). Satisfaction with transition was significantly lower in group 1 (M=2.65; 95% KI=[2.29-3.01]) than in group 2 (M=3.11; 95% KI=[2.89-3.33], p=0.045). The difference of mean values of 0.46 reflects a moderate effect size (Hedges' g=0.68). CONCLUSION: Health care transition of adolescent patients with chronic neurological disorders is significantly more successful in patients with minor impairment compared to patients with severe complex neurological conditions.

[Clinical Trial to Test the iFuse Implant System® in Patients with Sacroiliac Joint Syndrome: One Year Results]. / Klinische Studie zur Prüfung des iFuse Implant Systems® bei Patienten mit Iliosakralgelenksyndrom: 1-Jahres-Ergebnisse.

Background: This study reports one year post-operative monitoring of the efficacy and safety of iFuse Implant System® in patients with sacroiliac joint syndrome. Material and Methods: After 6 months of inadequate conservative treatment, patients with properly proven ISG syndrome were selected for surgery. The iFuse implants had a triangular profile and coating of porous titanium plasma spray and were used in the minimally invasive procedures. The procedure was performed under general anaesthesia and fluoroscopic control. In each case, three implants were placed. Results: 24 patients (22 f; 92 %; 54.9 ± 14 years) participated in the study. The operations were performed in 11 patients (46 %) on the left and in 13 patients (54 %) on the right. The mean operative time was 42.4 minutes (95 % CI: 35.6-49.3). The reduction in pain intensity on the VAS scale was 58 ± 11 mm (68 ± 7 %). The Oswestry score showed a median decrease of 44 percentage points (57 %). After 12 months, 15 patients (63 %) reported that they were taking no more painkillers. Conclusion: The minimally invasive treatment of patients with sacroiliac joint syndrome using the iFuse Implant System leads to significant analgesic effects over the period of one year; it also contributes significantly to improving the functioning of the patient.