Randomized Controlled-Feeding Study of Dietary Emulsifier Carboxymethylcellulose Reveals Detrimental Impacts on the Gut Microbiota and Metabolome.

BACKGROUND & AIMS: Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized. METHODS: To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days. RESULTS: Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition. CONCLUSIONS: These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).

Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.

The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

Efficacy of Sodium Carboxymethylcellulose Compared to Sodium Hyaluronate as Submucosal Injectant for Gastric Endoscopic Submucosal Dissection: A Randomized Controlled Trial.

INTRODUCTION: Sodium hyaluronate (SH) is a useful submucosal injectant for gastric endoscopic submucosal dissection (ESD). On the other hand, sodium carboxymethylcellulose (SCMC), which has high viscosity, has also been applied clinically. We evaluated the efficacy of SCMC compared to that of SH in gastric ESD. METHODS: A prospective randomized controlled trial was conducted to assess the efficacy of 1.0% SCMC as the injectant (SCMC group) compared to 0.4% SH (SH group) for ESD of gastric neoplasms. The primary end point was the procedure time of ESD. Secondary end points were treatment outcomes such as en bloc and R0 resection rates, number of hemostases, amount of injectant, ease of treatment (visual analog scale, 1-10 points), adverse events, and rate of ulcer healing 8 weeks after ESD. RESULTS: A total of 60 patients were enrolled between October 2014 and October 2018, and 30 patients were allocated in each group. The procedure time (mean ± SD, minutes) was not significantly different between the SCMC (74.7 ± 54.5) and SH groups (67.1 ± 41.4) (p = 0.547). Furthermore, there were no differences between the 2 groups in terms of en bloc and R0 resection rates, number of hemostases, amount of injectant, ease of treatment, and rate of ulcer healing. No serious adverse events were observed in either group. CONCLUSION: SCMC was comparable to SH in terms of procedure time, treatment outcome, and ease and safety of treatment in gastric ESD. Further studies are needed to demonstrate the differences between the 2 injectants.

Adverse events following injection laryngoplasty: An analysis of the MAUDE database.

OBJECTIVE: Injection laryngoplasty (IL) is considered safe in both the operating room and clinical setting. However, safety data is limited to single-institution studies with reduced sample sizes. The objective of this study is to examine a national database for adverse events related to IL in an effort to further confirm the safety of this procedure and better characterize potential complications. MATERIALS AND METHODS: Retrospective analysis of the Manufacturer and User Facility Device Experience (MAUDE) database for reported adverse events of IL procedures utilizing calcium hydroxyapatite (CAHA), hyaluronic acid (HA) and carboxymethylcellulose (CMC) implants from 2009 to 2020. RESULTS AND ANALYSIS: We identified 47 reported adverse events. The average patient age was 54 years old. 59.3% of patients were female. Adverse events more frequently involved the use of CAHA compared to HA or CMC (n = 27, 57.4%, n = 13, 27.7% and n = 7, 14.9%, respectively). The most common adverse events were laryngeal edema (n = 18, 39.1%), improper placement of injected material (n = 12, 26.1%), persistent dysphonia (n = 13, 28.3%), and post-injection dysphagia or odynophagia (n = 11, 23.9%). Major events, defined as requiring emergency room treatment, hospitalization, or surgical intervention accounted for 29 (60.4%) of cases. Four cases of edema required intubation, and one patient necessitated a surgical airway. CONCLUSION: Complications arising from IL range from minor events to airway obstruction and may happen with a variety of injectable materials including CAHA, HA and CMC. Few cases of airway obstruction requiring immediate intervention were identified, confirming the safety of IL in both the operative and office setting.

Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model.

A neuropsychiatric drug overdose impairs physiological function via central nervous system (CNS) depression. In drug-related deaths, only the drug concentration can currently provide information regarding CNS depression in victims. In this study, using a drug overdose model, we investigated the ability of neurotransmitters in the cerebrospinal fluid (CSF) to serve as biomarkers for CNS depression. Four groups of rats were orally administered diazepam (200 mg/kg) and/or phenobarbital (100 mg/kg) or vehicle. In a hot plate test performed to assess physiological impairment, drug-administered animals showed prolongation of the response latency. Serum drug concentrations were also sufficient to observe the effect of drug overdose. The levels of benzoyl-derivatized neurotransmitters were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Noradrenaline, adrenaline, serotonin, melatonin, phosphoethanolamine, and histamine levels in the CSF decreased as the response latencies in the hot plate test increased. These reduced CSF neurotransmitter levels may represent physiological dysfunction through CNS depression.

Outcomes of oral lichen planus and oral lichenoid lesions treated with topical corticosteroid.

OBJECTIVE: To determine corticosteroid treatment effectiveness in patients with oral lichen planus/oral lichenoid lesions (OLP/OLL). MATERIAL AND METHODS: Twenty-one patients with OLP and eighty-one patients with OLL received 0.05% clobetasol propionate (CP) or 0.05% triamcinolone acetonide (TA) in aqueous solution (AS) or orabase (OB), evaluating responses to treatment and follow-up compliance. RESULTS: Lesions were atrophic (72 of 102; 70.6%), extensive (58 of 100; 58%), producing eating difficulties (62 of 102; 60.8%), and spontaneous pain (30 of 102; 29.4%); 50 patients (49%) received CP-AS. The mean ± SD percentage of follow-ups attended was 43 ± 32%. Symptom remission was achieved in 46% of patients receiving CP-AS, 36.36% of those receiving TA-AS, 20% of those receiving CP-OB, and 25% of those receiving TA-OB. Follow-up compliance was poor in 66.7% of patients. Among 51 patients with continuous symptoms, 64.7% evidenced total remission at treatment completion; among 33 with intermittent symptoms, 73.1% had outbreaks 2-3 times/year and 51.5% controlled outbreaks with <6 corticosteroid applications. Adverse effects were observed in seven patients (6.8%) (moon face, hirsutism, capillary fragility) in induction stage, subsiding with dose; among 15 patients under maintenance treatment for >6 months, one showed hypothalamic-pituitary-adrenal (HPA) axis inhibition but not adrenal insufficiency. CONCLUSIONS: Our treatment proved highly effective and safe. Recall programs are desirable to enhance follow-up compliance.

Effectiveness and short-term safety of modified sodium hyaluronic acid-carboxymethylcellulose at cesarean delivery: a randomized trial.

BACKGROUND: The rising cesarean birth rate has drawn attention to risks associated with repeat cesarean birth. Prevention of adhesions with adhesion barriers has been promoted as a way to decrease operative difficulty. However, robust data demonstrating effectiveness of such interventions are lacking. OBJECTIVE: We report data from a multicenter trial designed to evaluate the short-term safety and effectiveness of a modified sodium hyaluronic acid (HA)-carboxymethylcellulose (CMC) absorbable adhesion barrier for reduction of adhesions following cesarean delivery. STUDY DESIGN: Patients who underwent primary or repeat cesarean delivery were included in this multicenter, single-blinded (patient), randomized controlled trial. Patients were randomized into either HA-CMC (N = 380) or no treatment (N = 373). No other modifications to their treatment were part of the protocol. Short-term safety data were collected following randomization. The location and density of adhesions (primary outcome) were assessed at their subsequent delivery using a validated tool, which can also be used to derive an adhesion score that ranges from 0-12. RESULTS: No differences in baseline characteristics, postoperative course, or incidence of complications between the groups following randomization were noted. Eighty patients from the HA-CMC group and 92 controls returned for subsequent deliveries. Adhesions in any location were reported in 75.6% of the HA-CMC group and 75.9% of the controls (P = .99). There was no significant difference in the median adhesion score; 2 (range 0-10) for the HA-CMC group vs 2 (range 0-8) for the control group (P = .65). One third of the HA-CMC patients met the definition for severe adhesions (adhesion score >4) compared to 15.5% in the control group (P = .052). There were no significant differences in the time from incision to delivery (P = .56). Uterine dehiscence in the next pregnancy was reported in 2 patients in HA-CMC group vs 1 in the control group (P = .60). CONCLUSION: Although we did not identify any short-term safety concerns, HA-CMC adhesion barrier applied at cesarean delivery did not reduce adhesion formation at the subsequent cesarean delivery.

Efficacy and Safety of Cross-Linked Carboxymethylcellulose Filler for Rejuvenation of the Lower Face: A 6-Month Prospective Open-Label Study.

BACKGROUND: Cross-linked carboxymethylcellulose (CMC) filler is a biosynthetic filler with very low antigenic risk. OBJECTIVE: To assess the efficacy and safety of CMC filler in the rejuvenation of the lower face. MATERIALS AND METHODS: Two hundred eighty-seven procedures were performed in 174 patients: 115 nasolabial folds, 86 marionette lines, 29 bar codes, 14 cheek rhytides, and 43 lip rejuvenations. Results were evaluated at 3 (T1) and 6 months (T2) with photographic evaluation, Global Aesthetic Improvement Scale (GAIS), Modified Fitzpatrick Wrinkle Scale (MFWS) for nasolabial folds, Marionette Lines Grading Scale (MLGS), and Medicis Lip Fullness Scale (LFS). RESULTS: GAIS was ≥2 in >91.05% of patients both in T1 and T2. MFWS score significantly improved at T1 (86.9% class ≤1, p < .001) and T2 (82.6% class ≤1, p < .001); in all patients in T1 and T2, median amelioration of MLGS was 2 ± 1 and there was a significant amelioration of at least 1 grade in LSF in both upper and lower lips. CONCLUSION: The use of CMC filler resulted in a significant and satisfactory amelioration of lower face aging signs with very low incidence of adverse events. Therefore, it should be considered a valid alternative to cross-linked hyaluronic acid fillers.

Pediatric phase II trials of poly-ICLC in the management of newly diagnosed and recurrent brain tumors.

Brain tumors are the most common solid tumor diagnosed in childhood that account for significant morbidity and mortality. New therapies are urgently needed; hence, we conducted the first ever prospective open-label phase II trials of the biological response modifier, poly-ICLC, in children with brain tumors. Poly-ICLC is a synthetic double-stranded RNA that has direct antiviral, antineoplastic, and immune adjuvant effects. A total of 47 children representing a variety of brain tumor histopathologic subtypes were treated with poly-ICLC. On the basis of the results of the initial phase II trial, an expanded prospective phase II trial in low-grade glioma (LGG) has been initiated. MRI was used to acquire volume-based measures of tumor response. No dose-limiting toxicities have been observed. In the initial study 3 of 12 subjects with progressive high-grade gliomas (HGGs) responded, and 2 of 4 children with progressive LGG experienced stable disease for 18 to 24 months. In the follow-up LGG phase II study, 2 of 5 LGG patients were stable over 18 months, with 1 stable for 6 months. Overall 5 of 10 LGG patients have responded. On the basis of low toxicity and the promising LGG response, poly-ICLC may be effective for childhood LGG, and the results justify biomarker studies for personalization of poly-ICLC as a single agent or adjuvant.

Dentifrice fluoride and abrasivity interplay on artificial caries lesions.

Incipient caries lesions on smooth surfaces may be subjected to toothbrushing, potentially leading to remineralization and/or abrasive wear. The interplay of dentifrice abrasivity and fluoride on this process is largely unknown and was investigated on three artificially created lesions with different mineral content/distribution. 120 bovine enamel specimens were randomly allocated to 12 groups (n = 10), resulting from the association of (1) lesion type [methylcellulose acid gel (MeC); carboxymethylcellulose solution (CMC); hydroxyethylcellulose gel (HEC)], (2) slurry abrasive level [low (REA 4/ RDA 69); high (REA 7/RDA 208)], and (3) fluoride concentration [0/275 ppm (14.5 mM) F as NaF]. After lesion creation, specimens were brushed in an automated brushing machine with the test slurries (50 strokes 2×/day). Specimens were kept in artificial saliva in between brushings and overnight. Enamel surface loss (SL) was determined by optical profilometry after lesion creation, 1, 3 and 5 days. Two enamel sections (from baseline and post-brushing areas) were obtained and analyzed microradiographically. Data were analyzed by analysis of variance and Tukey's tests (α = 5%). Brushing with high-abrasive slurry caused more SL than brushing with low-abrasive slurry. For MeC and CMC lesions, fluoride had a protective effect on SL from day 3 on. Furthermore, for MeC and CMC, there was a significant mineral gain in the remaining lesions except when brushed with high-abrasive slurries and 0 ppm F. For HEC, a significant mineral gain took place when low-abrasive slurry was used with fluoride. The tested lesions responded differently to the toothbrushing procedures. Both slurry fluoride content and abrasivity directly impacted SL and mineral gain of enamel caries lesions.

[Influence of immobilized forms of sodium hypochlorite on the immediate and long-term results of treatment of the patients with diffuse peritonitis].

An analysis of complex examination and results of treatment was made in 290 patients with diffuse peritonitis. The patients were divided into two groups according to way of sanation of the abdominal cavity. The sanation with 0.03% aqueous solution of sodium hypochlorite was used for the first group of 155 patients. The immobilized forms of sodium hypochlorite in carboxymethyl cellulose gel were applied in the second group. The rate of postoperative complications was decreased on 15.4%, the lethality--on 8.2% in the case of application of the immobilized forms of sodium hypochlorite. The developed technology allowed increasing of physical component of life quality of the patients in 1.3 times, though it didn't influence on psychical component.

Utilization and safety of sodium hyaluronate-carboxymethylcellulose adhesion barrier.

BACKGROUND: Little is known about the use and toxicity of antiadhesion substances such as sodium hyaluronate-carboxymethylcellulose. OBJECTIVE: We analyzed the patterns of use and safety of sodium hyaluronate-carboxymethylcellulose in patients undergoing colectomy and gynecologic surgery. DESIGN: This is a retrospective cohort study. SETTING: This study covered hospitals nationwide. PATIENTS: All patients in the Premier Perspective database who underwent colectomy or hysterectomy from 2000 to 2010 were included in the analyses. MAIN OUTCOME MEASURE: Hyaluronate-carboxymethylcellulose use was determined by billing codes. For the primary outcome, we used hierarchical mixed-effects logistic regression models to determine the factors associated with the use of hyaluronate-carboxymethylcellulose, whereas a propensity score-matched analysis was used to secondarily assess the association between hyaluronate-carboxymethylcellulose use and toxicity (abscess, bowel and wound complications, peritonitis). RESULTS: We identified 382,355 patients who underwent hysterectomy and 267,368 who underwent colectomy. For hysterectomy, hyaluronate-carboxymethylcellulose use was 5.0% overall, increasing from 1.1% in 2000 to 9.8% in 2010. Hyaluronate-carboxymethylcellulose was used in 8.1% of those who underwent colectomy and increased from 6.2% in 2000 to 12.4% in 2010. The year of diagnosis and procedure volume of the attending surgeon were the strongest predictors of hyaluronate-carboxymethylcellulose use. After matching and risk adjustment, hyaluronate-carboxymethylcellulose use was not associated with abscess formation (1.5% vs 1.5%) (relative risk = 0.97; 95% CI, 0.84-1.12) in those who underwent hysterectomy. A patient receiving hyaluronate-carboxymethylcellulose had a 13% increased risk of abscess (17.4% vs 15.0%) (relative risk = 1.13; 95% CI, 1.08-1.17) after colectomy. LIMITATIONS: This was an observational study. CONCLUSION: Hyaluronate-carboxymethylcellulose use has increased over the past decade for colectomy and hysterectomy. Although there is no association between hyaluronate-carboxymethylcellulose use and abscess following hysterectomy, hyaluronate-carboxymethylcellulose use was associated with a small increased risk of abscess after colectomy.

Foreign body reaction to Radiesse: 2 cases.

We report 2 cases of a foreign body reaction to Radiesse, a semipermanent soft-tissue filler consisting of 30% calcium hydroxylapatite microspheres and 70% carboxymethyl cellulose gel carrier. In one case, injection of this filler provoked a nodule on the columella, which was discovered during rhinoplasty. In the second case, the reaction was revealed during histopathologic examination of the deep section of a surgically removed basal-cell carcinoma. Histopathology showed a foreign body reaction with numerous giant cells and histiocytes, some plasma cells, and lymphocytes. Within this inflammatory reaction, a nonpolarizing exogenous material was identified consisting of numerous, round, uniformly sized, yellowish, extracellular deposits with a crackled appearance. Although many authors claim that Radiesse does not induce any foreign body reactions, we found a number of similar histopathologic pictures in studies describing animal or human auricular area test sites or even in reports of lip nodules, which are a well-known adverse effect after injection of this filler into this site. The histopathologic appearance of Radiesse is particularly distinctive and easily recognizable by dermatologists and dermatopathologists.

L-selectin and P-selectin are novel biomarkers of cervicovaginal inflammation for preclinical mucosal safety assessment of anti-HIV-1 microbicide.

A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.

A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion.

STUDY OBJECTIVE: To estimate the efficacy of alginate carboxymethylcellulose hyaluronic acid (ACH) gel to prevent intrauterine adhesions after hysteroscopic surgery in comparison with carboxymethylcellulose hyaluronic acid (CH) gel, which is known as an effective adhesion inhibitor. DESIGN: Randomized, multicenter, single-blind, clinical trial (Canadian Task Force classification I). SETTING: Tertiary university hospital. PATIENTS: One hundred eighty-seven patients with a surgically treatable intrauterine lesion (myomas, polyps, septa, intrauterine adhesion, dysfunctional uterine bleeding). INTERVENTIONS: Patients were randomized to 2 groups: hysteroscopic surgery plus intrauterine application of ACH or CH. MEASUREMENTS AND RESULTS: The rate of adhesion formation and the adhesion severity score with type and extent were calculated 4 weeks after surgery. The ACH group had results that were comparable to the CH group in terms of the development of intrauterine adhesions at 4 weeks follow-up. The adhesion severities were not different between the 2 groups. In a subgroup without baseline intrauterine adhesion, the ACH group showed a lower intrauterine adhesion rate than the CH group (p = .016). CONCLUSIONS: ACH had a comparable efficacy to CH in terms of the adhesion rate and severity. In the case of no baseline intrauterine adhesion, intrauterine application of ACH after hysteroscopic surgery had a lower rate of intrauterine adhesion than application of CH.

Rapamycin and a hyaluronic acid-carboxymethylcellulose membrane did not lead to reduced adhesion formations in a rat abdominal adhesion model.

PURPOSE: Rapamycin, an immunosuppressive in transplant surgery, has an additional antiproliferative effect. The aim of this study was to investigate the potential protective effects of rapamycin on postoperative adhesion development. METHODS: Ten rats per group underwent midline incision laparotomy and adhesion induction including bowel sutures. Therapy groups received daily intraperitoneal rapamycin injections (1.5 mg/kg body weight) for 3 weeks postoperatively. Controls were rats without any postoperative treatment, rats receiving the rapamycin solvent or a hyaluronic acid-carboxymethylcellulose membrane (Seprafilm(™)). RESULTS: Postoperative rapamycin application led to enhanced adhesion development and there was a higher rate of wound infections. In addition, Seprafilm(™) did not reduce adhesions, in subgroups there were even more. CONCLUSIONS: Rapamycin is not recommendable for perioperative immunosuppression, it enhances adhesion development and leads to a higher rate of wound infections. Surprisingly, the established Seprafilm(™) membrane led to more adhesions in our experimental setting.