The effect of ocular nutritional supplements on macular pigment optical density

This thesis describes the investigation of the effects of ocular supplements with different levels of nutrients on the macular pigment optical density (MPOD) in participants with healthy eyes. Abstract A review of the literature highlighted that ocular supplements are produced in various combinations of nutrients and concentrations. The ideal concentrations of nutrients such as lutein (L) have not been established. It was unclear whether different stages of eye disease require different concentrations of key nutrients, leading to the design of this study. The primary aim was to determine the effects of ocular supplements with different concentrations of nutrients on the MPOD of healthy participants. The secondary aim was to determine L and zeaxanthin (Z) intake at the start and end of the study through completion of food diaries. The primary study was split into two experiments. Experiment 1 was an exploratory study to determine sample size and experiment 2 the main study. Statistical power was calculated and a sample size of 38 was specified. Block stratification for age, gender and smoking habit was applied and from 101 volunteers 42 completed the study, 31 with both sets of food diaries. Four confounders were accounted for in the design of the study; gender, smoking habit, age and diet. Further factors that could affect comparability of results between studies were identified during the study and were not monitored; ethnicity, gastro-intestinal health, alcohol intake, body mass index and genetics. Comparisons were made between the sample population and the Sheffield general population according to recent demographic results in the public domain. Food diaries were analysed and shown to have no statistical difference when comparing baseline to final results. The average L and Z intake for the 31 participants who returned both sets of food diaries was initially 1.96mg and 1.51mg for the final food diaries. The effect of the two ocular supplements with different levels of xanthophyll (6mg lutein/zeaxanthin and 10mg lutein only) on MPOD was not significantly different over a four-month period.

System packaging & integration for a swallowable capsule using a direct access sensor

Technological developments in biomedical microsystems are opening up new opportunities to improve healthcare procedures. Swallowable diagnostic capsules are an example of this. In this paper, a diagnostic capsule technology is described based on direct-access sensing of the Gastro Intestinal (GI) fluids throughout the GI tract. The objective of this paper is two-fold: i) develop a packaging method for a direct access sensor, ii) develop an encapsulation method to protect the system electronics. The integrity of the interconnection after sensor packaging and encapsulation is correlated to its reliability and thus of importance. The zero level packaging of the sensor was achieved by using a so called Flip Chip Over Hole (FCOH) method. This allowed the fluidic sensing media to interface with the sensor, while the rest of the chip including the electrical connections can be insulated effectively. Initial tests using Anisotropic Conductive Adhesive (ACA) interconnect for the FCOH demonstrated good electrical connections and functionality of the sensor chip. Also a preliminary encapsulation trial of the flip chipped sensor on a flexible test substrate has been carried out and showed that silicone encapsulation of the system is a viable option.

Primary neuroendocrine lung tumor presenting with acute ileal obstruction. Case report

The authors describe a clinical case of a patient with neuroendocrine carcinoma of the lung diagnosed after the onset of an intestinal obstruction from an ileal metastasis. A review of literature reveals that the incidence of symptomatic gastro-intestinal metastases from lung cancer has been estimated to be about 2-3% and is exceedingly rare that the intestinal symptoms may be the initial presentation of cancer of the lung. The authors emphasize the difficulty of preoperative diagnosis of gastro-intestinal metastases which is made, almost always, too late because of the lack of specific symptoms. In our case, on account of the computed tomography, we leaned towards the diagnosis of lymphoma because of the double mediastinal and abdominal localization. Furthermore, this diagnosis was supported by the fact that the pulmonary lesion did not have clear radiological features of a lung cancer. The prognosis is poor because once intestinal metastases occur, other metastatic sites, which would make surgery only a palliative measure, are already present. The review of the literature shows that the average survival rate of these patients is 136 days. In our case the patient survived 277 days.

A Case Against Fancy Decorated Drinks: Multi-Organ Failure After Drinking a Mojito Cocktail

We present the first case of gastro-intestinal perforation caused by a mint twig decorating a cocktail drink. A 76-year-old man was enjoying his Mojito cocktail on a cruise ship near Mexico when he accidently swallowed a mint twig, resulting in ileum perforation. This led to a cascade of events, eventually resulting in life-threatening multi-organ failure. Given this rare but potentially severe complication and the increasing popularity of decorated drinks, a less ‘fancy’ presentation for cocktails and similar drinks may be warranted.

Déterminer le rôle de C1orf106, un gène associé aux maladies inflammatoires de l’intestin

Les maladies inflammatoires de l’intestin (MIIs, [MIM 266600]) sont caractérisées par une inflammation chronique au niveau du tube gastro-intestinal. Les deux principales formes sont la maladie de Crohn (MC) et la colite ulcéreuse (CU). Les MIIs résulteraient d’un défaut du système immunitaire et de l’épithélium intestinal. Ce dernier forme une barrière physique et biochimique qui sépare notre système immunitaire des microorganismes commensaux et pathogènes de la microflore intestinale. Un défaut dans la barrière épithéliale intestinale pourrait donc mener à une réponse immunitaire soutenue contre notre microflore intestinale. Les études d’association pangénomiques (GWAS) ont permis d’identifier 201 régions de susceptibilité aux MIIs. Parmi celles-ci, la région 1q32 associée à la MC (p<2x10-11) et à la CU (p<6x10-7) contient 4 gènes, dont C1orf106, un gène codant pour une protéine de fonction inconnue. Le re-séquençage de la région 1q32 a permis d’identifier une variante génétique rare de C1orf106 (MAF˂1%) associée aux MIIs (p=0,009), Y333F. Nous avons démontré que la substitution de la tyr333 par une phénylalanine semble avoir un effet sur la stabilité protéique de C1orf106 tel que démontré lors de l’inhibition de la synthèse protéique induite par le cycloheximide. Nous avons déterminé que C1orf106 est exprimé dans le côlon et l’intestin grêle. De plus, son expression est augmentée lors de la différenciation des cellules épithéliales Caco-2 en épithélium intestinal polarisé. Son profil d’expression correspond aux types cellulaires et tissulaires affectés dans les MIIs. De plus, C1orf106 est partiellement co-localisée avec le marqueur des jonctions serrées, ZO-1. Toutefois, son marquage reproduit parfaitement celui du marqueur des jonctions adhérentes, E-cadhérine. Les jonctions serrées et adhérentes sont localisées du côté apical de la jonction intercellulaire et sont toutes deux impliquées dans l’établissement de la barrière épithéliale. Nous avons donc testé l’impact de C1orf106 sur la perméabilité de l’épithélium intestinal. Nous avons observé une augmentation de la perméabilité épithéliale chez un épithélium intestinal formé par des cellules Caco-2 sous-exprimant C1orf106. Nos résultats suggèrent que C1orf106 pourrait être le gène causal de la région 1q32.

Déterminer le rôle de C1orf106, un gène associé aux maladies inflammatoires de l’intestin

Les maladies inflammatoires de l’intestin (MIIs, [MIM 266600]) sont caractérisées par une inflammation chronique au niveau du tube gastro-intestinal. Les deux principales formes sont la maladie de Crohn (MC) et la colite ulcéreuse (CU). Les MIIs résulteraient d’un défaut du système immunitaire et de l’épithélium intestinal. Ce dernier forme une barrière physique et biochimique qui sépare notre système immunitaire des microorganismes commensaux et pathogènes de la microflore intestinale. Un défaut dans la barrière épithéliale intestinale pourrait donc mener à une réponse immunitaire soutenue contre notre microflore intestinale. Les études d’association pangénomiques (GWAS) ont permis d’identifier 201 régions de susceptibilité aux MIIs. Parmi celles-ci, la région 1q32 associée à la MC (p<2x10-11) et à la CU (p<6x10-7) contient 4 gènes, dont C1orf106, un gène codant pour une protéine de fonction inconnue. Le re-séquençage de la région 1q32 a permis d’identifier une variante génétique rare de C1orf106 (MAF˂1%) associée aux MIIs (p=0,009), Y333F. Nous avons démontré que la substitution de la tyr333 par une phénylalanine semble avoir un effet sur la stabilité protéique de C1orf106 tel que démontré lors de l’inhibition de la synthèse protéique induite par le cycloheximide. Nous avons déterminé que C1orf106 est exprimé dans le côlon et l’intestin grêle. De plus, son expression est augmentée lors de la différenciation des cellules épithéliales Caco-2 en épithélium intestinal polarisé. Son profil d’expression correspond aux types cellulaires et tissulaires affectés dans les MIIs. De plus, C1orf106 est partiellement co-localisée avec le marqueur des jonctions serrées, ZO-1. Toutefois, son marquage reproduit parfaitement celui du marqueur des jonctions adhérentes, E-cadhérine. Les jonctions serrées et adhérentes sont localisées du côté apical de la jonction intercellulaire et sont toutes deux impliquées dans l’établissement de la barrière épithéliale. Nous avons donc testé l’impact de C1orf106 sur la perméabilité de l’épithélium intestinal. Nous avons observé une augmentation de la perméabilité épithéliale chez un épithélium intestinal formé par des cellules Caco-2 sous-exprimant C1orf106. Nos résultats suggèrent que C1orf106 pourrait être le gène causal de la région 1q32.

Pathophysiology of bile acid aspiration in lung transplant recipients

Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD) and aspiration of bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. While links between reflux aspiration to lung disease have been identified, the relevance of bile acid as molecular ligands and outcome predictors is poorly defined. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes and to investigate their molecular effects on airway function and contractility.

Ultra-hypofractionated stereotactic radiotherapy for prostate cancer in 5 fractions: current evidences and our clinical experience

AIMS: The present is a retrospective evaluation of acute genito-urinary (GU) and gastro-intestinal (GI) toxicity, in addition to biochemical recurrence rate in 57 prostate cancer patients treated at our Institution with ultra-hypofractionated RT (UHRT) schedule. METHODS: From January 2021 to December 2022 we have treated 57 patients with prostate cancer, using an UHRT scheme of 5-fractions every other day for a total dose delivered of 36.25 Gy, according to the PACE-B trial treatment schedule. Good urinary function, assessed by International Prostate Symptom Score (IPSS), were required. The simulation CT scans were acquired in supine position and fused with MRI for CTVs definition for every patient. Each treatment was performed by Accuray's TomoTherapy with daily IGRT. The evaluation of the set-up was very restrictive before daily treatment delivery. RESULTS: According to RTOG toxicity scale, the acute GU toxicity at 3 months from RT, GU toxicity was G0 for 30 patients (52.6%), G1 for 26 (45.6%) and G2 for one only (1.75%); rectal toxicity was G0 for 56 patients (98.25%) and G1 for one only (1.75%). The median follow-up (FU) was 9 months (2-24 months). In the following FU months, we observed progressively lower urinary and rectal toxicity, except for one patient who showed G2 GU toxicity at 12 months. All but one patient had a progressive PSA value decrease. CONCLUSIONS: In our experience, UHRT appears to be safe and well tolerated even without the use of rectal spacer devices. A longer FU is necessary to evaluate late toxicity and disease control rate.

Troubles gastro-intestinaux et activités sportives [Lower intestinal distress during sports activities].

This article reviews the literature regarding gastrointestinal disturbances in particular in runners. The lower intestinal problems of motility and blood loss are discussed. These problems are directly related to running. These symptoms, especially diarrhea are common and can impact adversely both performance and the health of the athlete. Most cases are relatively benign. The sport medicine clinician should be familiar with the management of these problems in order to optimize the treatment and facilitate return to sport.

Lymphotoxin beta receptor signaling induces the chemokine CCL20 in intestinal epithelium.

BACKGROUND & AIMS: The follicle-associated epithelium (FAE) that overlies Peyer's patches (PPs) exhibits distinct features compared with the adjacent villus epithelium. Besides the presence of antigen-sampling membranous M cells and the down-regulation of digestive functions, it constitutively expresses the chemokine CCL20. The mechanisms that induce FAE differentiation and CCL20 expression are poorly understood. The aim of this work was to test whether lymphotoxin beta receptor signaling (LTbetaR), which plays a central role in PPs' organogenesis, mediates CCL20 gene expression in intestinal epithelial cells. METHODS: CCL20, lymphotoxin beta (LTbeta) and LTbetaR expression were monitored during embryonic development by in situ hybridization of mouse intestine. The human intestinal epithelial cell line T84 was used to study CCL20 expression following LTalpha(1)/beta(2) stimulation. In vivo CCL20 expression following agonistic anti-LTbetaR antibody treatment was studied by laser microdissection and quantitative RT-PCR. RESULTS: CCL20 was expressed in the FAE before birth at the time when the first hematopoietic CD4(+)CD3(-) appeared in the PP anlage. LTbetaR was expressed in the epithelium during PP organogenesis, making it a putative target for LTalpha(1)beta(2)signals. In vitro, CCL20 was induced in T84 cells upon LTbetaR signaling, either using an agonistic ligand or anti-LTbeta receptor agonistic antibody. LTalpha(1)beta(2)-induced CCL20 expression was found to be NF-kappaB dependent. LTbetaR signaling up-regulated CCL20 expression in the small intestinal epithelium in vivo. CONCLUSIONS: Our results show that LTbetaR signaling induces CCL20 expression in intestinal epithelial cells, suggesting that this pathway triggers constitutive production of CCL20 in the FAE.

Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice.

Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

CCL17 Promotes Intestinal Inflammation in Mice and Counteracts Regulatory T Cell-Mediated Protection From Colitis.

BACKGROUND & AIMS: Priming of T cells by dendritic cells (DCs) in the intestinal mucosa and associated lymphoid tissues helps maintain mucosal tolerance but also contributes to the development of chronic intestinal inflammation. Chemokines regulate the intestinal immune response and can contribute to pathogenesis of inflammatory bowel diseases. We investigated the role of the chemokine CCL17, which is expressed by conventional DCs in the intestine and is up-regulated during colitis. METHODS: Colitis was induced by administration of dextran sodium sulfate (DSS) to mice or transfer of T cells to lymphopenic mice. Colitis activity was monitored by body weight assessment, histologic scoring, and cytokine profile analysis. The direct effects of CCL17 on DCs and the indirect effects on differentiation of T helper (Th) cells were determined in vitro and ex vivo. RESULTS: Mice that lacked CCL17 (Ccl17(E/E) mice) were protected from induction of severe colitis by DSS or T-cell transfer. Colonic mucosa and mesenteric lymph nodes from Ccl17-deficient mice produced lower levels of proinflammatory cytokines. The population of Foxp3(+) regulatory T cells (Tregs) was expanded in Ccl17(E/E) mice and required for long-term protection from colitis. CCR4 expression by transferred T cells was not required for induction of colitis, but CCR4 expression by the recipients was required. CCL17 promoted Toll-like receptor-induced secretion of interleukin-12 and interleukin-23 by DCs in an autocrine manner, promoted differentiation of Th1 and Th17 cells, and reduced induction of Foxp3(+) Treg cells. CONCLUSIONS: The chemokine CCL17 is required for induction of intestinal inflammation in mice. CCL17 has an autocrine effect on DCs that promotes production of inflammatory cytokines and activation of Th1 and Th17 cells and reduces expansion of Treg cells.

Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome.

BACKGROUND & AIMS: Clostridium difficile-associated disease (CDAD) is the leading cause of nosocomial diarrhea in the United States. C difficile toxins TcdA and TcdB breach the intestinal barrier and trigger mucosal inflammation and intestinal damage. The inflammasome is an intracellular danger sensor of the innate immune system. In the present study, we hypothesize that TcdA and TcdB trigger inflammasome-dependent interleukin (IL)-1beta production, which contributes to the pathogenesis of CDAD. METHODS: Macrophages exposed to TcdA and TcdB were assessed for IL-1beta production, an indication of inflammasome activation. Macrophages deficient in components of the inflammasome were also assessed. Truncated/mutated forms of TcdB were assessed for their ability to activate the inflammasome. The role of inflammasome signaling in vivo was assessed in ASC-deficient and IL-1 receptor antagonist-treated mice. RESULTS: TcdA and TcdB triggered inflammasome activation and IL-1beta secretion in macrophages and human mucosal biopsy specimens. Deletion of Nlrp3 decreased, whereas deletion of ASC completely abolished, toxin-induced IL-1beta release. TcdB-induced IL-1beta release required recognition of the full-length toxin but not its enzymatic function. In vivo, deletion of ASC significantly reduced toxin-induced inflammation and damage, an effect that was mimicked by pretreatment with the IL-1 receptor antagonist anakinra. CONCLUSIONS: TcdA and TcdB trigger IL-1beta release by activating an ASC-containing inflammasome, a response that contributes to toxin-induced inflammation and damage in vivo. Pretreating mice with the IL-1 receptor antagonist anakinra afforded the same level of protection that was observed in ASC-/- mice. These data suggest that targeting inflammasome or IL-1beta signaling may represent new therapeutic targets in the treatment of CDAD.

Evaluating and optimizing oral formulations of live bacterial vaccines using a gastro-small intestine model

Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bacterial vaccines (LBV) can safely and effectively promote mucosal immunity but new formulations are required that provide controlled release of optimal numbers of viable bacterial cells, which must survive gastrointestinal transit overcoming various antimicrobial barriers. Here, we use a gastro-small intestine gut model of human GI conditions to study the survival and release kinetics of two oral LBV formulations: the licensed typhoid fever vaccine Vivotif comprising enteric coated capsules; and an experimental formulation of the model vaccine Salmonella Typhimurium SL3261 dried directly onto cast enteric polymer films and laminated to form a polymer film laminate (PFL). Neither formulation released significant numbers of viable cells when tested in the complete gastro-small intestine model. The poor performance in delivering viable cells could be attributed to a combination of acid and bile toxicity plus incomplete release of cells for Vivotif capsules, and to bile toxicity alone for PFL. To achieve effective protection from intestinal bile in addition to effective acid resistance, bile adsorbent resins were incorporated into the PFL to produce a new formulation, termed BR-PFL. Efficient and complete release of 4.4x107 live cells per dose was achieved from BR-PFL at distal intestinal pH, with release kinetics controlled by the composition of the enteric polymer film, and no loss in viability observed in any stage of the GI model. Use of this in vitro GI model thereby allowed rational design of an oral LBV formulation to maximize viable cell release.

Preparação e avaliação de cápsulas gastro-resistentes de diclofenaco de sódio

Cápsulas resistentes ao trato gastrintestinal são freqüentemente usadas com diversos propósitos. Estas cápsulas promovem eficácia farmacológica e farmacocinética de substâncias que são instáveis, ou irritantes para a mucosa gástrica. O diclofenaco de sódio é um antiinflamatório não-esteróide, que, por ser muito utilizado, despertou o interesse do setor magistral para sua manipulação. Porém, o fármaco é irritante para a mucosa gástrica, havendo necessidade de se empregar substâncias capazes de proteger o meio gástrico da ação do medicamento e uma alternativa para o setor magistral é a manipulação de cápsulas gastro-resistentes. Estas cápsulas devem resistir, sem alteração, à ação do suco gástrico, mas desagregar-se rapidamente no suco intestinal. O objetivo deste trabalho foi preparar cápsulas na concentração de 50 mg/cápsula de diclofenaco de sódio formiladas ou revestidas com acetoftalato de celulose ou com Eudragit L100 na máquina de revestimento entérico “Enteric Coating Machine” PCCA ou manualmente. Foram analisados os resultados considerando o perfil de dissolução das formulações. Observou-se que as cápsulas revestidas na máquina com Eudragit L100 e com acetoftalato em acetona revestidas na máquina e manualmente mostraram bons resultados quanto à dissolução, porém, não apresentaram boa aparência no caso das cápsulas de cor vermelha. Quanto às cápsulas revestidas com formol, estas apresentam boa aparência, mas não deram bons resultados no teste de dissolução.