Inter-Rater Agreement of the Classification of Intraoperative Adverse Events (ClassIntra) in Abdominal Surgery.

OBJECTIVE AND SUMMARY OF BACKGROUND DATA: Adverse events in surgical patients can occur preoperatively, intraoperatively, and postoperatively. Universally accepted classification systems are not yet available for intraoperative adverse events (iAEs). ClassIntra has recently been developed and validated as a tool for grading iAEs that occur between skin incision and skin closure irrespective of the origin, that is, surgery, anesthesia, or organizational. The aim of this study is to assess the inter-rater agreement of ClassIntra and assess its predictive value for postoperative complications in elective abdominal surgery. METHODS: This study is a secondary use of data from the LAParotomy or LAParoscopy and ADhesiolysis (LAPAD) study, with detailed data on incidence and management of intra-operative and post-operative complications. Data were collected in a cohort of elective abdominal surgeries. Two teams graded all recorded events in the LAPAD study according to ClassIntra. Cohen Kappa coefficient was calculated to determine inter-rater agreement. Uni- and multivariable linear regression was used to assess the predictive value of the ClassIntra grades for postoperative complications. RESULTS: IAEs were rated in 333 of 755 (44%) surgeries by team 1, and in 324 of 755 (43%) surgeries by team 2. Cohen kappa coefficient for ClassIntra grades was 0.87 [95% confidence interval (CI) 0.84-0.90]. Discrepancies in grading were most frequent for intraoperative bleeding and adhesions' associated injuries. At least 1 postoperative complication was observed in 278 (37%) patients. The risk of a postoperative complications increased with every increase in severity grade of ClassIntra. Intraoperative hypotension [mean difference (MD) 23.41, 95% CI 12.93-33.90] and other organ injuries (MD 18.90, 95% CI -4.22 - 42.02) were the strongest predictors for postoperative complications. CONCLUSIONS: ClassIntra has an almost perfect inter-rater agreement for the classification of iAEs. An increasing grade of ClassIntra was associated with a higher incidence of postoperative complications. Discrepancies in grading related to common complications in abdominal procedures mostly consisted of intraoperative bleeding and adhesion-related injuries. Grading of interoperative events in abdominal surgery might further improve by consensus regarding the definitions of a number of frequent events.

Controlled Continuous Evolution of Enzymatic Activity Screened at Ultrahigh Throughput Using Drop-Based Microfluidics.

Enzymes are highly specific catalysts delivering improved drugs and greener industrial processes. Naturally occurring enzymes must typically be optimized which is often accomplished through directed evolution; however, this is still a labor- and capital-intensive process, due in part to multiple molecular biology steps including DNA extraction, in vitro library generation, transformation, and limited screening throughput. We present an effective and broadly applicable continuous evolution platform that enables controlled exploration of fitness landscape to evolve enzymes at ultrahigh throughput based on direct measurement of enzymatic activity. This drop-based microfluidics platform cycles cells between growth and mutagenesis followed by screening with minimal human intervention, relying on the nCas9 chimera with mutagenesis polymerase to produce in vivo gene diversification using sgRNAs tiled along the gene. We evolve alditol oxidase to change its substrate specificity towards glycerol, turning a waste product into a valuable feedstock. We identify a variant with a 10.5-fold catalytic efficiency.

Prevalence, diagnosis, and surgical management of complex ileocolic-duodenal fistulas in Crohn's disease.

BACKGROUND: The aim of the present study was to review the prevalence and surgical management of patients with Crohn's disease (CD) complicated by ileocolic-duodenal fistulas (ICDF). METHODS: We performed a retrospective chart review of CD patients who underwent surgical takedown and repair of ICDF during January 2011-December 2021 at two inflammatory bowel disease referral centers. RESULTS: We identified 17 patients with ICDF (1.3%) out of 1283 CD patients who underwent abdominal surgery. Median age was 42 (20-71) years, 13 patients were male (76%) and median body mass index was 22.7 (18.4-30.3) kg/m2. Four patients (24%) were diagnosed preoperatively and only 2 (12%) were operated on for ICDF-related symptoms. The most common procedure was ileocolic resection (13 patients, 76%) including 4 repeat ileocolic resections (24%). The duodenal defect was primarily repaired in all patients with no re-fistulization or duodenal stenosis, regardless of the repair technique. A laparoscopic approach was attempted in the majority of patients (14 patients, 82%); however, only 5 (30%) were laparoscopically completed. The overall postoperative complication rate was 65% including major complications in 3 patients (18%) and 2 patients (12%) who required surgical re-intervention for abdominal wall dehiscence and postoperative bleeding. Preoperative nutritional optimization was performed in 9 patients (53%) due to malnutrition. These patients had significantly less intra-operative blood loss (485 vs 183 ml, p = 0.05), and a significantly reduced length of stay (18 vs 8 days, p = 0.05). CONCLUSION: ICDF is a rare manifestation of CD which may go unrecognized despite the implementation of a comprehensive preoperative evaluation. Although laparoscopic management of ICDF may be technically feasible, it is associated with a high conversion rate. Preoperative nutritional optimization may be beneficial in improving surgical outcomes in this select group of patients.

Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution.

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma.

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.

Systematic review and simulation study of ignoring clustered data in surgical trials.

BACKGROUND: Multiple surgical procedures in a single patient are relatively common and lead to dependent (clustered) data. This dependency needs to be accounted for in study design and data analysis. A systematic review was performed to assess how clustered data were handled in inguinal hernia trials. The impact of ignoring clustered data was estimated using simulations. METHODS: PubMed, Embase and the Cochrane Library were reviewed systematically for RCTs published between 2004 and 2013, including patients undergoing unilateral or bilateral inguinal hernia repair. Study characteristics determining the appropriateness of handling clustered data were extracted. Using simulations, various statistical methods accounting for clustered data were compared with an analysis ignoring clustering by assuming 100 hernias, with a varying percentage of patients having bilateral hernias. RESULTS: Of the 50 eligible trials including patients with bilateral hernias, 20 (40 per cent) did not provide information on how they dealt with clustered data and 18 (36 per cent) avoided clustering by assessing the outcome by patient and not by hernia. None of the remaining 12 trials (24 per cent) considered clustering in the design or analysis. In the simulations, ignoring clustering led to an increased type I error rate of up to 12 per cent and to a loss in power of up to 15 per cent, depending on whether the patient or the hernia was the randomization unit. CONCLUSION: Clustering was rarely considered in inguinal hernia trials. The simulations underline the importance of considering clustering as part of the statistical analysis to avoid false-positive and false-negative results, and hence inappropriate study conclusions.

Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.

BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of ß-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of ß-catenin. Analysis of all patients with activating Wnt/ß-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/ß-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.

Reversal after Hartmann's procedure in patients with complicated sigmoid diverticulitis.

AIM: Hartmann's procedure (HP) is commonly used for the emergency treatment of complicated sigmoid diverticulitis (CSD). It is intended to restore intestinal continuity; however, in practice, reversal is not carried out in all patients. It is important to know the frequency of reversal and the impact of patient-related factors on the decision for reversal. METHOD: A retrospective study was conducted on all patients who underwent HP for CSD at a tertiary referral hospital between 1 May 2005 and 31 December 2010. We assessed the frequency of reversal over time and the prognostic factors affecting the decision for reversal. RESULTS: Of 67 patients [median age 76 (interquartile range: 68-81) years] who had HP for CSD, 28 (42%) underwent reversal. The cumulative incidence of reversal after 48 weeks was 48% (95% CI: 36-62%). Reversal was less likely in elderly patients [hazard ratio (HR) per decade increase = 0.43; 95% CI: 0.26-0.71], with cardiac insufficiency or coronary heart disease (HR = 0.60; 95% CI: 0.26-1.40) and with preoperative immunosuppression or chemotherapy (HR = 0.31; 95% CI: 0.07-1.33). There was no apparent effect of these factors on mortality. CONCLUSION: Approximately half of the patients having HP for CSD undergo reversal within 48 weeks of the initial operation. The finding that age, cardiac or coronary heart disease and preoperative immunosuppression or chemotherapy have an impact on the decision for reversal is relevant to healthcare professionals and patients.

Surgical treatment of uncomplicated diverticulitis in Switzerland: comparison of population-based data over two time periods.

AIM: The standard of care for acute uncomplicated diverticulitis used to be an elective colon resection after the second or third episode. This practice was replaced by a more conservative and individualized approach. This study investigates current surgical practice in the treatment of acute uncomplicated diverticulitis in Switzerland. METHOD: Retrospective cross-sectional analysis of all hospital admissions due to uncomplicated diverticulitis in Switzerland using prospectively collected data from the Swiss Federal Statistical Office in two periods: 2004/2005 and 2010/2011. Treatment options were compared between the two periods with adjustment for baseline characteristics of patients and treating institutions. RESULTS: A total of 24 497 patients (11 835 in 2004/2005; 12 662 in 2010/2011) were admitted to Swiss hospitals for uncomplicated diverticulitis. Between periods, the incidence increased from 81 to 85 admissions per 105 inhabitants per year. Elective admissions decreased from 46% (n = 5490) to 34% (n = 4294). The unadjusted resection rate decreased from 40% (n = 4730) to 34% (n = 4308). In the adjusted analysis, inpatients were more likely to have a resection in 2010/2011 than in 2004/2005 [odds ratio of 1.38 (95% confidence interval 1.25-1.54)]. In addition, private insurance, elective mode of admission and younger age increased the odds for resection while there was no evidence of an association between resection and either gender or comorbidities. CONCLUSION: The probability of colon resection for patients hospitalized with acute uncomplicated diverticulitis increased between periods while the overall number of colon resections declined. A change of practice expected given the paradigm shift towards conservative treatment could not be confirmed in this analysis.

Outcomes after laparoscopic conversion of failed adjustable gastric banding to sleeve gastrectomy or Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has a high incidence of long-term complications and failures. The best procedure to handle these failures and the optimal number of stages in such cases is still controversial. The aim of this retrospective study was to compare the results of conversions of LAGB to either laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass (LRYGB) in failed LAGB using a single-stage approach. METHODS: All patients who underwent conversion from LAGB to either LRYGB or LSG between January 2005 and March 2012 were included in the study. Early and late complications were reviewed. The percentage excess weight loss (%EWL) between the two groups was compared at 3, 6, 12 and 24 months of follow-up. RESULTS: Fifty-nine patients, 11 men and 48 women, were included in the study. The most frequent indication was insufficient weight loss or weight regain (non-responders group), in 44 patients (75 per cent); 15 patients had a revision for complicated LAGB. The early complication rate in the non-responders group was 7 per cent (3 of 44 patients), compared with 13 per cent (2 of 15) in the complicated LAGB group. Mean(s.d.) %EWL in the non-responders group was 55(22) per cent in patients converted to LRYGB and 28(25) in those converted to LSG (P = 0·001). CONCLUSION: LRYGB and LSG are both safe and feasible options for failed or complicated LAGB. In the non-responders group, %EWL was superior for conversion to LRYGB. The surgical morbidity rate was highest in patients having revision for band complications.

Lessons learnt from the construction and implementation of a prospective ventral hernia database.

PURPOSE: The New England VA Hernia Registry was created in 2011 to prospectively collect relevant details of ventral hernia repairs, with the intention to assess and improve long term outcomes. The goal of this study is to assess registry compliance. METHODS: All ventral hernia operations performed in five VA hospitals between 2011-2022 were obtained. We assessed compliance at the hospital and surgeon level. RESULTS: 3,516 cases were performed. Overall compliance with registry entry was 37.5%, ranging from 10.8% to 67.2% across hospitals. At the hospital level, there was a negative correlation between average yearly hernia volume per surgeon and registry compliance (r2 = 0.53). Surgeon compliance varied within hospitals and over time. CONCLUSION: Registry compliance was low and highly variable. Lack of interest, incentives, oversight, and surgeon turnover are possible factors for noncompliance. Building a registry with these factors in mind, providing timely feedback, and conducting frequent audits may improve compliance.

Consensus conference statement on fluorescence-guided surgery (FGS) ESSO course on fluorescence-guided surgery.

BACKGROUND: Fluorescence-guided surgery (FGS) has emerged as an innovative technique with promising applications in various surgical specialties. However, clinical implementation is hampered by limited availability of evidence-based reference work supporting the translation towards standard-of-care use in surgical practice. Therefore, we developed a consensus statement on current applications of FGS. METHODS: During an international FGS course, participants anonymously voted on 36 statements. Consensus was defined as agreement ≥70% with participation grade of ≥80%. All participants of the questionnaire were stratified for user and handling experience within five domains of applicability (lymphatics & lymph node imaging; tissue perfusion; biliary anatomy and urinary tracts; tumor imaging in colorectal, HPB, and endocrine surgery, and quantification and (tumor-) targeted imaging). Results were pooled to determine consensus for each statement within the respective sections based on the degree of agreement. RESULTS: In total 43/52 (81%) course participants were eligible as voting members for consensus, comprising the expert panel (n = 12) and trained users (n = 31). Consensus was achieved in 17 out of 36 (45%) statements with highest level of agreement for application of FGS in tissue perfusion and biliary/urinary tract visualization (71% and 67%, respectively) and lowest within the tumor imaging section (0%). CONCLUSIONS: FGS is currently established for tissue perfusion and vital structure imaging. Lymphatics & lymph node imaging in breast cancer and melanoma are evolving, and tumor tissue imaging holds promise in early-phase trials. Quantification and (tumor-)targeted imaging are advancing toward clinical validation. Additional research is needed for tumor imaging due to a lack of consensus.

Equine stomachs harbor an abundant and diverse mucosal microbiota.

Little is known about the gastric mucosal microbiota in healthy horses, and its role in gastric disease has not been critically examined. The present study used a combination of 16S rRNA bacterial tag-encoded pyrosequencing (bTEFAP) and fluorescence in situ hybridization (FISH) to characterize the composition and spatial distribution of selected gastric mucosal microbiota of healthy horses. Biopsy specimens of the squamous, glandular, antral, and any ulcerated mucosa were obtained from 6 healthy horses by gastroscopy and from 3 horses immediately postmortem. Pyrosequencing was performed on biopsy specimens from 6 of the horses and yielded 53,920 reads in total, with 631 to 4,345 reads in each region per horse. The microbiome segregated into two distinct clusters comprised of horses that were stabled, fed hay, and sampled at postmortem (cluster 1) and horses that were pastured on grass, fed hay, and biopsied gastroscopically after a 12-h fast (cluster 2). The types of bacteria obtained from different anatomic regions clustered by horse rather than region. The dominant bacteria in cluster 1 were Firmicutes (>83% reads/sample), mainly Streptococcus spp., Lactobacillus spp. and, Sarcina spp. Cluster 2 was more diverse, with predominantly Proteobacteria, Bacteroidetes, and Firmicutes, consisting of Actinobacillus spp. Moraxella spp., Prevotella spp., and Porphyromonas spp. Helicobacter sp. sequences were not identified in any of 53,920 reads. FISH (n = 9) revealed bacteria throughout the stomach in close apposition to the mucosa, with significantly more Streptococcus spp. present in the glandular region of the stomach. The equine stomach harbors an abundant and diverse mucosal microbiota that varies by individual.

Microbial ureteral stent colonization in renal transplant recipients: frequency and influence on the short-time functional outcome.

Ureteral stent insertion at the time of renal transplantation significantly decreases complications of urine leakage and obstruction, but bears an intrinsic risk of microbial colonization. Associated urinary tract infection (UTI) may pose a significant risk for graft infection and subsequent graft failure, in particular, during high-level immunosuppression in the early phase after transplantation. The aims of this prospective study were (i) to assess the frequency of microbial ureteral stent colonization (MUSC) in renal transplant recipients by sonication, (ii) to compare the diagnostic value of sonication with that of conventional urine culture (CUC), (iii) to determine biofilm forming organisms, and (iv) to investigate the influence of MUSC on the short-time functional outcome. A total of 80 ureteral stents from 78 renal transplant recipients (deceased donors n = 50, living donors n = 28) were prospectively included in the study. CUC was obtained prior to renal transplantation and at ureteral stent removal. In addition, a new stent sonication technique was performed to dislodge adherent microorganisms. CUCs were positive in 4% of patients. Sonicate-fluid culture significantly increased the yield of microbial growth to 27% (P < 0.001). Most commonly isolated microorganisms by sonication were Enterococcus species (31%), coagulase-negative staphylococci (19%), and Lactobacillus species (19%), microorganisms not commonly observed in UTIs after renal transplantation. The median glomerular filtraton rate (GFR) of the study population increases from 39 mL/min immediately after transplantation (time point A) to 50 mL/min 6 month post transplantation (time point B). In patients without MUSC, the GFR improves from 39 mL/min (A) to 48 mL/min (B) and in patients with MUSC from 39 mL/min (A) to 50 mL/min (B), respectively. In summary, MUSC in renal transplant recipients is common and remains frequently undetected by routine CUC, but colonization had no measurable effect on renal function.

The cost of surgical training: analysis of operative time for laparoscopic cholecystectomy.

BACKGROUND: Duration of surgery is a main cost factor of surgical training. The purpose of this analysis of operative times for laparoscopic cholecystectomies (LC) was to quantify the extra time and related costs in regards to the surgeons' experience in the operating room (OR). METHODS: All LC performed between January 01, 2005 and December 31, 2008 in 46 hospitals reporting to the database of the Swiss Association for Quality Management in Surgery (AQC) were analyzed (n = 10,010). Four levels of seniority were specified: resident (R), junior consultant (JC), senior consultant (SC), and attending surgeon (AS). The differences in operative time according to seniority were investigated in a multivariable log-linear and median regression analysis controlling for possible confounders. The OR costs were calculated by using a full cost rate in a teaching hospital. RESULTS: A total of 9,208 LC were available for analysis; 802 had to be excluded due to missing data (n = 212) or secondary major operations (n = 590). Twenty-eight percent of the LC were performed by R as teaching operations (n = 2,591). Compared with R, the multivariable analysis of operative time showed a median difference of -2.5 min (-9.0; 4.8) for JC and -18 min (-25; -11) for SC and -28 min (-35; -10) for AS, respectively. The OR minute costs were 17.57, resulting in incremental costs of 492 (159; 615) per operation in case of tutorial assistance. CONCLUSIONS: The proportion of LC performed as tutorial assistance for R remains low. Surgical training in the OR causes relevant case-related extra time and therefore costs.

Oncogenic Ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells.

Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti-FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.

The FGF receptor-1 tyrosine kinase domain regulates myogenesis but is not sufficient to stimulate proliferation.

Ligand-stimulated activation of FGF receptors (FGFRs) in skeletal muscle cells represses terminal myogenic differentiation. Skeletal muscle cell lines and subsets of primary cells are dependent on FGFs to repress myogenesis and maintain growth. To understand the intracellular events that transduce these signals, MM14 skeletal muscle cells were transfected with expression vectors encoding chimeric receptors. The chimeras are comprised of the PDGF beta receptor (PDGFbetaR) extracellular domain, the FGFR-1 intracellular domain, and either the PDGFbetaR or FGFR-1 transmembrane domain. The chimeric receptors were autophosphorylated upon PDGF-BB stimulation and are capable of stimulating mitogen-activated protein kinase activity. Activation of the tyrosine kinase domain of either chimera repressed myogenesis, suggesting intracellular responses regulating skeletal muscle differentiation are transduced by activation of the FGFR-1 tyrosine kinase. Unexpectedly, we found that activation of either chimeric receptor failed to stimulate cellular proliferation. Thus, it appears that regulation of skeletal muscle differentiation by FGFs requires only activation of the FGFR tyrosine kinase. In contrast, stimulation of proliferation may require additional, as yet unidentified, signals involving the receptor ectodomain, the FGF ligand, and heparan sulfate either alone, or in combination.

Malnutrition in morbidly obese patients: fact or fiction?

Reports of nutritional deficiencies after Bariatric surgery have lead investigators to inquire about the preoperative nutritional status of morbidly obese patients. Interestingly, numerous reports demonstrated a pattern of low levels of various micronutrients among overweight and obese patients, even in comparison with normal weight population. In this article we reviewed the literature for micronutrient deficiencies in obese patients prior to weight reduction surgery.