Ythdf2 regulates cardiac remodeling through its mRNA target transcripts.

m6A mRNA methylation controls cardiomyocyte function and increased overall m6A levels are a stereotyping finding in heart failure independent of the underlying etiology. However, it is largely unknown how the information is read by m6A reader proteins in heart failure. Here we show that the m6A reader protein Ythdf2 controls cardiac function and identified a novel mechanism how reader proteins control gene expression and cardiac function. Deletion of Ythdf2 in cardiomyocytes in vivo leads to mild cardiac hypertrophy, reduced heart function, and increased fibrosis during pressure overload as well as during aging. Similarly, in vitro the knockdown of Ythdf2 results in cardiomyocyte growth and remodeling. Mechanistically, we identified the eucaryotic elongation factor 2 as post-transcriptionally regulated by Ythdf2 using cell type specific Ribo-seq data. Our study expands our understanding on the regulatory functions of m6A methylation in cardiomyocytes and how cardiac function is controlled by the m6A reader protein Ythdf2.

Closed-loop gastric electrical stimulation versus laparoscopic adjustable gastric band for the treatment of obesity: a randomized 12-month multicenter study.

OBJECTIVE: To compare the weight loss, change in quality of life (QOL) and safety of closed-loop gastric electrical stimulation (CLGES) versus adjustable gastric band (LAGB) in the treatment of obesity. METHODS: This multicenter, randomized, non-inferiority trial randomly assigned the patients in a 2:1 ratio to laparoscopic CLGES versus LAGB and followed them for 1 year. We enrolled 210 patients, of whom 50 were withdrawn preoperatively. Among 160 remaining patients (mean age=39±11 years; 75% women; mean body mass index=43±6 kg m-2) 106 received CLGES and 54 received LAGB. The first primary end point was non-inferiority of CLGES versus LAGB, ascertained by the proportion of patients who, at 1 year, fulfilled: (a) a ⩾20% excess weight loss (EWL); (b) no major device- or procedure-related adverse event (AE); and (c) no major, adverse change in QOL. Furthermore, ⩾50% of patients had to reach ⩾25% EWL. The incidence and seriousness of all AE were analyzed and compared using Mann-Whitney's U-test. RESULTS: At 1 year, the proportions of patients who reached all components of the primary study end point were 66.7 and 73.0% for the LAGB and CLGES group, respectively, with a difference of -6.3% and an upper 95% CI of 7.2%, less than the predetermined 10% margin for confirming the non-inferiority of CLGES. The second primary end point was also met, as 61.3% of patients in the CLGES group reached ⩾25% EWL (lower 95% CI=52.0%; P<0.01). QOL improved significantly and similarly in both groups. AE were significantly fewer and less severe in the CLGES than in the LAGB group (P<0.001). CONCLUSIONS AND RELEVANCE: This randomized study confirmed the non-inferiority of CLGES compared with LAGB based on the predetermined composite end point. CLGES was associated with significantly fewer major AE.

[Current Situation of Antibiotic Prophylaxis in Obesity and Metabolic Surgery - Data Analysis from the Study for Quality Assurance in Operative Treatment of Obesity in Germany]. / Aktueller Stand der Antibiotikaprophylaxe in der Adipositas- und metabolischen Chirurgie - Datenanalyse aus der Studie zur Qualitätskontrolle der operativen Therapie der Adipositas in Deutschland.

BACKGROUND: Since January 2005, the situation of metabolic and obesity surgery in Germany has been constantly evaluated by the German Bariatric Surgery Registry (GBSR). Data registration is performed using an internet online database with prospective data collection. All registered data were analysed in cooperation with the Institute of Quality Assurance at the Otto-von-Guericke University Magdeburg. METHODS: Data collection includes primary and revision/redo-procedures. A main focus of the current study is the analysis of data regarding the perioperative management, in particular, administration of antibiotics. RESULTS: Since 2005 a significant increase of primary bariatric procedures has been reported. For evaluation of the antibiotic regimen 12 296 primary operations including 684 balloons (BIB), 2950 gastric bandings (GB), 5115 Roux-en-Y-gastric bypasses (RYGBP), 120 Scopinaro's biliopancreatic diversions (BPD), 164 duodenal switches (DS), 3125 sleeve gastrectomies (SG) and 138 other procedures were analysed. In total 77.3 % of the patients with primary procedures received perioperative antibiotics. Patients without concomitant comorbidities received antibiotics significantly less often compared to those with comorbidities. Wound infection rates were comparable for patients who underwent either gastric banding or sleeve gastrectomy. CONCLUSION: Surgery has been accepted step by step as a treatment for morbid obesity and its comorbidities in Germany during the last few years. There is only little experience in the literature regarding antibiotic therapy as well as prophylaxis in bariatric surgery. Based on the results of the current study we recommend rather the selective than the routine use of antibiotics depending on different parameters, e.g., operative time, preoperative BMI and concomitant comorbidities.

[Nutrient Deficiencies after Bariatric Surgery - Systematic Literature Review and Suggestions for Diagnostics and Treatment]. / Nutritive Defizite nach bariatrischer Chirurgie - systematische Literaturanalyse und Empfehlungen für Diagnostik und Substitution.

The increasing prevalence of morbid obesity in Germany is associated with an increasing number of metabolic surgical interventions. Short-term surgical and long-term metabolic complications such as nutrient deficiencies can be considered the main risks of metabolic surgery and its restrictive and malabsorbant surgical procedures. The aim of this compact short overview based on a selective literature search and our own clinical experience is to characterise the long-term metabolic complications, which are specific for the various bariatric procedures, and to refine the published guidelines for supplementation. Restrictive bariatric procedures can be associated with well-known surgical problems such as pouch dilatation or band migration, e.g., after gastric banding. After sleeve gastrectomy, emerging reflux disease can become a substantial problem. The most frequent deficiencies after restrictive procedures are related to B-vitamins whereas iron, folate, vitamin B1 and B12 and vitamin D deficiencies are associated with the malabsorptive procedure such as biliopancreatic diversion, duodenal switch and Roux-en-Y gastric bypass. Due to possible metabolic and surgical complications after bariatric surgery, patients need to undergo life-long medical follow-up investigations. The currently available guidelines of German Society of Treatment of Obesity (CAADIP) of DGAV for supplementation should be known and followed, in particular, by the physicians who i) are exceptionally involved in medical care of obese people and ii) do it in full awareness of the obligatory postoperative clinical observation.

[Comment on Gender-Specific Aspects in Obesity and Metabolic Surgery--Analysis of Data from the German Bariatric Surgery Registry]. / Kommentar zu genderspezifischen Aspekten in der Adipositas- und metabolischen Chirurgie--Daten der Qualitätssicherungsstudie für operative Therapie der Adipositas.

BACKGROUND: The current situation in obesity and metabolic surgery since January 2005 has been investigated with the help of the quality assurance study on surgical therapy for obesity = German Bariatric Surgery Registry (GBSR). The data were acquired and analysed in cooperation with the Institute for Quality Assurance in Surgical Medicine at the Otto-von-Guericke University. METHODS: Data acquisition was done with the help of an online database. On a voluntary basis, all obesity and metabolic surgical interventions since 2005 have been recorded. In addition to the surgical data, the findings of the yearly follow-up investigations were recorded. RESULTS: Since 2005 there have been 1,263 gastric balloon procedures, 11,840 sleeve gastrectomies, 13,722 Roux-en-Y gastric bypasses and 3999 gastric banding operations. The average age of the male patients in all interventions was significantly higher. The average BMI of female patients who received a gastric banding or a gastric balloon procedure was significantly lower than that of the male patients. Men exhibited a higher incidence of comorbidities than women. CONCLUSION: The number of obesity and metabolic surgical interventions in Germany is continuously increasing. The results of the study on surgical therapy for obesity (GBSR) reveal significant differences in the gender-specific incidence of preoperative comorbidities. postoperative complications and mortality. Further studies on gender-specific aspects are necessary in order to optimise patient selection and reduce the incidence of postoperative complications.

Bariatric surgery in adolescents and young adults--safety and effectiveness in a cohort of 345 patients.

OBJECTIVE: To examine the safety and effectiveness of adolescent bariatric surgery and to improve treatment recommendations for this age group. DESIGN: Prospective longitudinal registry. Since January 2005, patients undergoing bariatric surgery in Germany are enlisted in an online registry called 'study for quality assurance in obesity surgeries'. SUBJECTS: Adolescents and young adults up to the age of 21 years, operated from January 2005 to December 2010. MEASUREMENTS: Weight, BMI, comorbidities, complication rates. RESULTS: N=345 primary procedures were recorded by 58 hospitals. N=51 patients were under the age of 18 years. Follow-up information was available for 48% (n=167) of patients, with an average observation period of 544±412 days (median: 388 days). The most common surgical techniques were gastric banding (n=118, 34.2%), gastric bypass (n=116, 33.6%) and sleeve gastrectomy (n=78, 22.6%). Short-term complications (intra-operative; general postoperative; specific postoperative) were slightly lower for gastric banding (0.8%; 2.5%; 0.8%) than for gastric bypass (2.6%; 5.2%; 1.7%) or sleeve gastrectomy (0%; 9.0%; 7.7%). In accordance with published findings, weight and BMI reduction were lower for gastric banding (-28 kg; -9.5 kg m(-2)) compared to gastric bypass (-50 kg; -16.4 kg m(-2)) P< 0.001 or sleeve gastrectomy (-46 kg; -15.4 kg m(-2)) P< 0.001. Outcomes did not differ between the <18 and ≥18-year-old patients. CONCLUSION: Like in adults, bariatric surgery has low short-term complication rates and results in sustained weight loss in adolescents. However, the missing long-term observations prohibit a final conclusion about lasting effectiveness and safety. Clinical trials with structured follow-up programs and mechanisms to ascertain patient adherences are needed.

[Increased requirements for the challenging abdominosurgical management of morbid obesity - what does the abdominal surgeon need to know?]. / Gewachsene Erfordernisse im anspruchsvollen viszeralchirurgischen Management bei morbider Adipositas - Was muss der Viszeralchirurg wissen?

In the international comparison and in Europe, the Federal Republic of Germany belongs to the countries with a very high prevalence of obesity (men, 67.1 %; women, 53 %). Among the European countries, the incidence of diabetes mellitus type 2 is also high ("Study of the health of adults in Germany" [DEGS]) - Robert Koch Institute). Not only for surgeons, this can be considered as a great challenge even in usual abdominosurgical interventions. 1. Surgical equipment needs to be adapted to the requirements for obese patients. 2. Minimally invasive surgery reduces not only complication rates with regard to postsurgical wound infection and hernia in such patients, it allows a competent assessment of the peritoneal cavity. 3. A great number of surgical tools and instruments can be used in normal weight as well as morbidly obese patients with no limitations - for conventional (open) surgical interventions, retractor systems should be available. 4. With regard to emergency surgery in patients who had formerly undergone bariatric surgery, a competent basic knowledge on the usual bariatric surgical interventions and the subsequent anatomic consequences as well as the more frequent mid- and long-term complications is necessary, which need to be partially approached with the surgical intervention. 5. For numerous oncosurgical interventions, no differences in postoperative outcome were found between normal weight and morbidly obese patients.

[New data on quality assurance in bariatric surgery in Germany]. / Aktuelle Daten der Qualitätssicherungsstudie für operative Therapie der Adipositas in Deutschland.

BACKGROUND: Since January 1st 2005, the situation of bariatric surgery has been examined in Germany. All data are registered prospectively in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University of Magdeburg. METHODS: The voluntary data registration occurs in an internet online data bank. All primary bariatric procedures as well as re- and redo-procedures are documented. Follow-up data were collected once a year. Participation in the quality assurance study is obligatory for certificated centres. RESULTS: Since 2005 13,879 bariatric procedures have been performed at 83 hospitals. The number of primary procedures has increased from 596 in 2005 to 11,835 in 2010. Revisional surgery has been performed in 1,438 patients since 2005. Sleeve gastrectomy (SG) is the major procedure with 1,564 operations in 2010. The mean BMI was 48.8 kg/m². The incidence of comorbidities was 84.8%. CONCLUSION: Bariatric surgery has become more accepted in Germany. Beside the Roux-en-Y gastric bypass, sleeve gastrectomy is the most frequently performed operation. BMI and incidence of comorbidities are still high in comparison with literature values. Due to the lack of evidence, more randomised studies are necessary to standardise operative techniques and evaluate patient selection criteria. Quality assurance studies support a detailed analysis of these parameters.

One-stage versus two-stage Roux-Y gastric bypass as redo surgery of failed adjustable gastric banding.

INTRODUCTION: The study focussed on whether a one-stage Roux-Y gastric bypass (OS-RYGB) or a two-stage RYGB (TS-RYGB) has a significant advantage in terms of perioperative risk in patients after failed adjustable gastric banding (AGB). METHODS: Data collection included patients who underwent OS-RYGB or TS-RYGB after AGB between 2005 and 2019 and whose outcomes were compared with those after primary RYGB (P-RYGB). Outcome criteria were perioperative complications, comorbidities, 30-day mortality and operating time. RESULTS: The study analysed data from patients who underwent OS-RYGB (N = 525), TS-RYGB (N = 382) and P-RYGB (N = 26,445). Intraoperative and postoperative complication rates were significantly lower for P-RYGB (p < 0.001). Total intraoperative and specific postoperative complication rates were significantly lower in TS-RYGB than in OS-RYGB (p = 0.048 and p < 0.001, respectively). In contrast, the total general postoperative complication rate was lower in OS-RYGB than in TS-RYGB (p < 0.001). The mean operating time differed significantly among the three groups (P-RYGB 96.5min, OS-RYGB 141.2min and TS-RYGB 190.9min; p < 0.001). The mortality rate was not significantly different between the three groups. CONCLUSIONS: Based on the significant difference between the two groups in revision surgery and the slight difference with the results of primary RYGB, this study concludes that removal of a failed AGB is safe and feasible with either the OS- or TS-RYGB procedure. However, we cannot directly recommend either procedure in our study. Proper patient selection and surgeon experience are critical to avoid potential adverse effects.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study.

BACKGROUND: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. PATIENTS AND METHODS: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. RESULTS: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. CONCLUSION: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

[Bariatric surgery in children and adolescents]. / Adipositaschirurgie bei Kindern und Jugendlichen.

Obesity in childhood and adolescents has gained epidemic proportions; in Germany 15-20 % of boys and girls are overweight, more than 6 % are known to be obese. By now, 25 % of relevant people show a pathological glucose intolerance, 4-5 % are developing type 2 diabetes mellitus (T2DM). In addition, metabolic disorders leading to hypertension and cardiac, renal or ophthalmological complications could be named as serious comorbidities. Medical and behavioural intervention as treatment for obesity in childhood remains largely ineffective: 5-10 % weight loss within 2 years rarely results in significant durable success. In adults, bariatric surgery is being used increasingly as an effective approach to achieve weight loss and to improve serious medical comorbidities, in particular T2DM. Enhancement of quality of life and explicit extension of survival are concomitant phenomenons. To date, a range of different types of bariatric procedures has been performed in adolescents, but studies evaluating and analysing preoperative data, postoperative course and follow-up in a representative number of patients younger than 18 years are still lacking. Nevertheless, current experience suggests significant weight loss and improving obesity-related medical comorbidities after bariatric surgery in adolescents too. Moreover, bariatric surgery in adolescents seems to induce less complications and a shorter hospital stay than in adults. Al-though surgical therapy for obesity in this group of patients remains an individual decision, even though explicit guidelines have been published specifying inclusion and exclusion criterias. Analysis of our own patient group and results of the study of the quality assurance "surgical treatment of morbid obesity" are appropriate tools to evaluate surgical techniques and to provide long-term follow-up.

Perceived Barriers in the Decision for Bariatric and Metabolic Surgery: Results from a Representative Study in Germany.

BACKGROUND: Attitudes of the general public may be an influencing factor for low surgery rates: When skepticism is high, support for individuals wanting or needing to undergo surgery may diminish. This study assesses the relevance of barriers to metabolic surgery. METHODS: The study was conducted using a representative sample of the German population (n = 1007). Participants were asked to imagine that they would have to decide for or against metabolic surgery and rate how this decision would be influenced by a number of reasons given to them (Likert scale). Results are presented by weight status. RESULTS: The barrier found most irrelevant is that surgery could be considered cheating across all weight groups. About a fourth of the sample state that not knowing enough about surgery (28.5%), being afraid of surgery (28.3%), and potential negative consequences after surgery (24.5%) are reasons against metabolic surgery that were rated extremely relevant. Having obesity was a significant predictor of endorsement in two variables: feeling like cheating (lower probability for relevance, OR = 0.58, p = 0.025) and a lack of knowledge (lower probability for relevance, OR = 0.59, p = 0.031). CONCLUSIONS: In summary, the public's view of weight loss surgery lacks information about post-surgical consequences. It is important to address these points in the public and in social networks of patients as they may be pre- or antecedent of surgery stigma.

Gastric cancer after laparoscopic adjustable gastric banding.

A 63-year-old woman with BMI 46 underwent laparoscopic gastric banding. In the standardized follow-up after 14 and 24 months, the GI series and gastroscopy showed no pathological signs. The patient had hematemesis 32 months after gastric banding, followed by symptoms of obstruction, for which a laparotomy was performed. At operation, peritoneal carcinomatosis due to gastric cancer was found. Symptoms after bariatric procedures can be similar to symptoms of gastric or esophageal cancer. We believe that yearly postoperative gastroscopy is indicated to exclude pathological changes.

[Referral behavior of general physicians for patients with obesity]. / Zuweisungsverhalten der Hausärzte bei Patienten mit Adipositas.

The prevalence of obesity and overweight is constantly rising. Thus, obesity is increasingly considered as one of the most important healthcare problems in Germany. Surgical interventions have been proven to be the only treatment option to achieve sustained weight loss along with a reduction of obesity-related comorbidities in the vast majority of morbidly obese patients. With respect to the small numbers of weight loss surgeries conducted in Germany, several reasons are currently discussed. General practitioners play a very important role in gatekeeping when it comes to decisions about treatment. Research has shown that knowledge and stigma play a role when treatment pathways for patients with obesity are defined. Interventions are required to make treatment decisions by physicians or patients independent of social pressure due to stigma or gaps in expertise.

Unique and overlapping substrate specificities of caspase-8 and caspase-10.

Although caspase-8 has an established role as an initiator of death receptor-mediated apoptosis, the function of its closest homolog, caspase-10, is almost completely unknown. To gain a closer insight into the physiological function of caspase-10, we compared the cleavage of known caspase-8 substrates by both initiator caspases. We demonstrate that caspase-10 and -8 have overlapping cleavage preferences for several substrates such as the kinases RIP and PAK2. Interestingly, in other substrates, such as the Bcl-2 protein Bid, we found additional and distinct cleavage sites for both caspases, which might have important consequences for mitochondrial targeting and propagation of the death signal. Caspase-8 and -10 also caused different interchain cleavage patterns of their enzyme precursors. Together, these results suggest that caspase-8 and -10, despite having overlapping functions, also have selective substrate cleavage specificities and might thereby exert nonredundant roles in apoptosis signaling.

The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression.

Tyrosine kinases of the Src family have been implicated in key biological processes. Here, we provide evidence that p56(Lck), a lymphoid-specific Src kinase, is involved in the activation of the mitochondrial apoptosis pathway. Lck-deficient T cells were completely resistant to anticancer drugs. In contrast, apoptosis sensitivity to death receptors was not altered, indicating a specific interference of Lck with the mitochondrial pathway. Re-expression of Lck restored sensitivity to drug-induced apoptosis and triggered mitochondrial cytochrome c release and caspase activation. Further analysis identified that the sensitization by Lck was independent of classical mediators of T-cell signaling, but essentially involved the Bcl-2 protein Bak. Expression of Bak was completely absent in Lck-deficient cells, while re-expression of Lck transcriptionally triggered Bak expression and conferred sensitivity to apoptosis, associated with a proapoptotic conformational change of Bak. Furthermore, in vitro the truncated fragment of Bid specifically activated Bak and cytochrome c release only from mitochondria of Lck-expressing cells. These results do not only demonstrate a sentinel role of Lck in drug resistance but also delineate a hitherto unknown pathway of Src kinases in regulation of Bcl-2 proteins.