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Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.
The article “Integrity of dural closure after autologous platelet rich fibrin augmentation: an in vitro study”, written by Vasilikos, I., Beck, J., Ghanaati, S., Grauvogel, J., Nisyrios, T., Grapatsas, K., and Hubbe, U., was originally published Online First without Open Access. After publication in volume 162, issue 4, page 737–743 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0. Open access funding enabled and organized by Projekt DEAL.
Background and purpose: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. Methods: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. Results: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20–1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07–1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. Conclusion: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.
Purpose: The prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries. Methods: 50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. Results: The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. Conclusion: The strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results. Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
Aims: To compare the effects of Ayurvedic and conventional nutritional therapy in patients with irritable bowel syndrome (IBS). Methods: Sixty-nine patients with IBS were randomized to Ayurvedic (n = 35) or conventional nutritional therapy according to the recommendations of the German Nutrition Society including the low-FODMAP diet (n = 34). Study visits took place at baseline and after 1, 3, and 6 months. The primary outcome was IBS symptom severity (IBS-SSS) after 3 months; secondary outcomes included stress (CPSS), anxiety and depression (HADS), well-being (WHO-5) and IBS-specific quality of life (IBS-QOL). A repeated measures general linear model (GLM) for intent-to-treat-analyses was applied in this explorative study. Results: After 3 months, estimated marginal means for IBS-SSS reductions were 123.8 [95% confidence interval (95% CI) = 92.8–154.9; p < 0.001] in the Ayurvedic and 72.7 (95% CI = 38.8–106.7; p < 0.001) in the conventional group. The IBS-SSS reduction was significantly higher in the Ayurveda group compared to the conventional therapy group (estimated marginal mean = 51.1; 95% CI = 3.8–98.5; p = 0.035) and clinically meaningful. Sixty-eight percentage of the variance in IBS-SSS reduction after 3 months can be explained by treatment, 6.5% by patients' expectations for their therapies and 23.4% by IBS-SSS at pre-intervention. Both therapies are equivalent in their contribution to the outcome variance. The higher the IBS-SSS score at pre-intervention and the larger the patients' expectations, the greater the IBS-SSS reduction. There were no significant group differences in any secondary outcome measures. No serious adverse events occurred in either group. Conclusion: Patients with IBS seem to benefit significantly from Ayurvedic or conventional nutritional therapy. The results warrant further studies with longer-term follow-ups and larger sample sizes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03019861, identifier: NCT03019861.
Der Morbus Basedow zählt zu den häufigsten Ursachen einer Hyperthyreose. Zur Behandlung stehen neben der medikamentösen thyreostatischen Therapie auch ein operatives sowie ein nuklearmedizinisches Verfahren zur Verfügung.
Die beiden zuletzt genannten Behandlungsmöglichkeiten stellen aufgrund ihrer Wirkungsweise ein definitives Verfahren dar, bei dem Schilddrüsengewebe entfernt bzw. zerstört wird. Dadurch ist in der Regel eine dauerhafte Substitution der lebensnotwendigen Schilddrüsenhormone erforderlich. Im Gegensatz dazu bleibt bei der medikamentösen Therapie mit Thyreostatika die gesamte Schilddrüse erhalten und funktionsfähig. Der Nachteil besteht in der hohen Rezidivrate von über 50 % im Vergleich zur definitiven Therapie. Damit mehr Patienten von den Vorteilen der thyreostatischen Therapie profitieren, ist eine Optimierung dieser zur Reduktion der Rezidivrate notwendig.
Ziel dieser Arbeit war es, mittels einer retrospektiven Analyse zu ermitteln, welche anamnestischen, klinischen, sonographischen und laborchemischen Parameter mit einem Rezidiv des Morbus Basedow bei Patienten mit thyreostatischer Therapie in Zusammenhang stehen. Weiterhin erfolgte eine Analyse von sonographischen und laborchemischen Werten im Krankheitsverlauf, um daraus Indikatoren für eine optimale Dauer der thyreostatischen Therapie abzuleiten. Hierzu wurden die Daten von 260 Patienten bezüglich der folgenden Faktoren zwischen Remissions- und Rezidivgruppe verglichen: Erkrankungsalter, Geschlecht, Dauer der Thyreostatikagabe, Vitamin D-Spiegel, Nikotinkonsum, endokrine Orbitopathie, fam. Autoimmunerkrankung, fam. Schilddrüsenerkrankung und Veränderungen im Hormonhaushalt anderer Hormonachsen. Zudem erfolgte eine Zeitreihenanalyse Schilddrüsen-spezifischer Laborwerte (fT3, fT4, TSH, TRAK, anti-TPO-Ak, TgAk) und des sonographisch bestimmten Schilddrüsenvolumens jeweils zu den Zeitpunkten Diagnosestellung sowie sechs und zwölf Monate darauf. Die Rezidivrate im untersuchten Patientenkollektiv betrug 68,8 %.
Für das Erkrankungsalter, die Therapiedauer, das Schilddrüsenvolumen, die Schilddrüsenfunktionsparameter und die TSH-Rezeptor-Antikörper ließen sich signifikante Unterschiede zwischen Remissions- und Rezidivkohorte nachweisen. Patienten, die bei Diagnose das 35. Lebensjahr noch nicht vollendet hatten, erlitten signifikant häufiger ein Rezidiv als ältere Patienten. In der Remissionsgruppe war die Therapiedauer mit zwölf Monaten zudem signifikant länger als in der Rezidivgruppe. Patienten, deren Schilddrüse zum Zeitpunkt der Diagnose oder zwölf Monate darauf in der sonographischen Messung über die Norm vergrößert war, erlitten signifikant häufiger ein Rezidiv des Morbus Basedow, ebenso wie Patienten mit anhaltend pathologischen Schilddrüsenfunktionsparametern sechs und zwölf Monate nach Diagnose. Die Werte der TSH-Rezeptor-Antikörper fielen in der Rezidivgruppe zu allen Erhebungszeitpunkten signifikant höher aus als in der Remissionsgruppe. Diese Ergebnisse lassen für die medikamentöse Behandlung des Morbus Basedow den Schluss zu, dass die Dauer der thyreostatischen Therapie dem Krankheitsverlauf, der sich in den Schilddrüsenfunktionswerten und den Leveln der TSH-Rezeptor-Antikörper widerspiegelt, angepasst werden sollte, um deren Erfolgsrate zu steigern. Weiterhin lässt sich folgern, dass bei jüngeren Patienten und Patienten mit vergrößerter Schilddrüse ein erhöhtes Rezidivrisiko besteht und diese Patienten möglicherweise von einem verlängerten Therapieintervall profitieren.
Während in der aktuellen europäischen Leitlinie zur Behandlung der Immunhyperthyreose eine feste Spanne von zwölf bis achtzehn Monaten für die Gabe der Thyreostatika empfohlen wird, lautet die Empfehlung der amerikanischen Hyperthyreose-Leitlinie die thyreostatische Therapie bis zur Normalisierung der TSH-Rezeptor-Antikörper fortzuführen. Die Ergebnisse der vorliegenden Arbeit sprechen dafür, die europäische Leitlinie dahingehend der amerikanischen Leitlinie anzupassen.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
Periodontal furcation lesions: a survey of diagnosis and management by general dental practitioners
(2021)
Aim: The aim of this study was to explore general dental practitioners' (GDPs) attitude to periodontal furcation involvement (FI). Materials and methods: An online survey focused on diagnosis and management of periodontal FI was circulated to GDPs in seven different countries. Results: A total of 400 responses were collected. Nearly a fifth of participants reported rarely or never taking 6-point pocket charts; 65.8% of participants had access to a Nabers probe in their practice. When shown clinical pictures and radiographs of FI-involved molars, the majority of participants correctly diagnosed it. Although 47.1% of participants were very/extremely confident in detecting FI, only 8.9% felt very/extremely confident at treating it. Differences in responses were detected according to country and year of qualification, with a trend towards less interest in periodontal diagnosis and treatment in younger generations. Lack of knowledge of management/referral pathways (reported by 22.8%) and lack of correct equipment were considered the biggest barriers to FI management. Most participants (80.9%) were interested in learning more about FI, ideally face to face followed by online tutorials. Conclusions: Plans should be put in place to improve general dentists' knowledge and ability to manage FI, as this can have a significant impact on public health.
Cytochrome P450 (CYP) signalling pathway has been shown to play a vital role in the vasoreactivity of wild type mouse ophthalmic artery. In this study, we determined the expression, vascular responses and potential mechanisms of the CYP-derived arachidonic acid metabolites. The expression of murine CYP (Cyp2c44) and soluble epoxide hydrolase (sEH) in the wild type ophthalmic artery was determined with immunofluorescence, which showed predominant expression of Cyp2c44 in the vascular smooth muscle cells (VSMC), while sEH was found mainly in the endothelium of the wild type ophthalmic artery. Artery of Cyp2c44−/− and sEH−/− mice were used as negative controls. Targeted mass spectrometry-based lipidomics analysis of endogenous epoxide and diols of the wild type artery detected only 14, 15-EET. Vasorelaxant responses of isolated vessels in response to selective pharmacological blockers and agonist were analysed ex vivo. Direct antagonism of epoxyeicosatrienoic acids (EETs) with a selective inhibitor caused partial vasodilation, suggesting that EETs may behave as vasoconstrictors. Exogenous administration of synthetic EET regioisomers significantly constricted the vessels in a concentration-dependent manner, with the strongest responses elicited by 11, 12- and 14, 15-EETs. Our results provide the first experimental evidence that Cyp2c44-derived EETs in the VSMC mediate vasoconstriction of the ophthalmic artery.