Assessment of the effect of ethanol extracts from Cinnamomum camphora seed kernel on intestinal inflammation using simulated gastrointestinal digestion and a Caco-2/RAW264.7 co-culture system.

Cinnamomum camphora seeds have multiple bioactivities. There were few studies on the effect of C. camphora seeds on intestinal inflammation in vitro and in vivo. The study aimed to investigate the effects of ethanol extracts from C. camphora seed kernel on intestinal inflammation using simulated gastrointestinal digestion and a Caco-2/RAW264.7 co-culture system. Results showed that the digested ethanol extracts (dEE) were rich in polyphenols, and a total of 17 compounds were tentatively identified using UPLC-LTQ-Orbitrap-MS/MS. dEE increased cell viability, while decreasing the production of reactive oxygen species, and the secretion and gene expression of inflammatory markers (NO, PGE2, TNF-α, IL-1ß and IL-6). dEE also down-regulated NF-κB/MAPK pathway activities by suppressing the phosphorylation of relevant signaling molecules (p65, IκBα, ERK and p38), as well as the expression of TLR4 receptor protein. Furthermore, dEE may improve intestinal barrier function by increasing the TEER value, and the expression of tight junction proteins (ZO-1, claudin-1 and occludin). The results suggest the ethanol extracts from C. camphora seed kernel may have strong anti-inflammatory activities, and a potential application in the prevention or treatment of intestinal inflammation and enhancement of intestinal barrier function in organisms.

Impacts of Microbial based Therapy on Growth Performance, Intestinal Health, Carcass Traits and Economic Efficiency of Clostridium perfringens-Infected Cobb and Arbor Acres Broilers.

The poultry farms need a safe and effective alternative for antibiotics that can counteract the negative impacts of necrotic enteritis (NE), which causes severe mortalities and economic losses. The current study was aimed to examine the influence of antibiotic (Flagymox) and the microbial-based administration on carcass traits in Clostridium (C.) perfringens-infected Cobb and Arbor Acres broilers. A total number of 360 Cobb and Arbor Acres broiler chicks (180 numbers per breed) were allocated to four groups; negative control group (without any treatments); positive control group (administration of C. perfringens at the rate of 1 × 109 cfu/bird via crop gavage twice daily from day 16 to 18 post-hatch); C. perfringens challenge plus antibiotic (Flagymox® ) group, and Clostridium perfringens challenge plus microbial-based treatment (Big-lactoα® ) group. The results indicated that the Flagymox and Big-lactoα treated Cobb breed group achieved a significant increase in their body weight (BW) than the positive control group at the third week post-infection. Also, the Arbor Acres breed gained significantly higher weight compared to the Cobb breed at the third week. Total weight gain (TWG) from 0 to the fifth week in the Cobb and Arbor Acres breeds were higher in the groups treated with Flagymox and Big-lactoα compared to the birds challenged with C. perfringens without any treatment, thus, increasing the total return (TR) in the treated groups. Economic efficiency showed no significant differences (p < .05) between the treatment groups of both the breeds. Although the treatment cost of Flagymox is higher than the microbial-based treatment (0.86 versus 0.35 LE), there were no mortalities reported in the microbial-based groups in both the breeds resulting in significantly low losses compared to the Flagymox treated groups. The groups treated with the microbial-based products in both breeds were superior in dressing percentage (75.16 and 77.06% for Cobb and Arbor Acres, respectively) compared to that of the other groups. In conclusion, microbial-based therapy improved the growth rate, carcass traits, survival rate, and economic efficiency in necrotic enteritis induced in Cobb and Arbor Acres broilers.

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment.

The recently introduced microphysiological systems (MPS) cultivating human organoids are expected to perform better than animals in the preclinical tests phase of drug developing process because they are genetically human and recapitulate the interplay among tissues. In this study, the human intestinal barrier (emulated by a co-culture of Caco-2 and HT-29 cells) and the liver equivalent (emulated by spheroids made of differentiated HepaRG cells and human hepatic stellate cells) were integrated into a two-organ chip (2-OC) microfluidic device to assess some acetaminophen (APAP) pharmacokinetic (PK) and toxicological properties. The MPS had three assemblies: Intestine only 2-OC, Liver only 2-OC, and Intestine/Liver 2-OC with the same media perfusing both organoids. For PK assessments, we dosed the APAP in the media at preset timepoints after administering it either over the intestinal barrier (emulating the oral route) or in the media (emulating the intravenous route), at 12 µM and 2 µM respectively. The media samples were analyzed by reversed-phase high-pressure liquid chromatography (HPLC). Organoids were analyzed for gene expression, for TEER values, for protein expression and activity, and then collected, fixed, and submitted to a set of morphological evaluations. The MTT technique performed well in assessing the organoid viability, but the high content analyses (HCA) were able to detect very early toxic events in response to APAP treatment. We verified that the media flow does not significantly affect the APAP absorption whereas it significantly improves the liver equivalent functionality. The APAP human intestinal absorption and hepatic metabolism could be emulated in the MPS. The association between MPS data and in silico modeling has great potential to improve the predictability of the in vitro methods and provide better accuracy than animal models in pharmacokinetic and toxicological studies.

[Psychosomatic research in 2018: Lost illusions, renewed hopes]. / La recherche psychosomatique en 2018 : illusions perdues, espoirs renouvelés.

A critical analysis of the basic hypotheses of psychosomatic research and the sometimes hasty assertions drawn from the previous works makes it possible to better discern the data confirmed by the most recent works or the most rigorous meta-analyses and to highlight the emerging tracks. If the hypothesis of behavioral patterns specifically related to the risk of certain pathologies seems abandoned, the predictive value of depression in the cardiovascular field, more than in that of oncology, becomes clearer. Negative affect and impaired emotional awareness emerge as two complementary factors of somatic vulnerability. Several vulnerability factors seem all the more effective as they affect individuals of lower socio-economic status. Social exclusion feeling and its links with the inflammatory response appear to be a possible common denominator, both for depression and for many somatic conditions. A series of studies on the cerebral regulation of emotions and stress, as well as on bidirectional brain-bowel relations and on the mediating role of the gut microbiota, complements the available epidemiological data. The same is true for certain advances in behavioral neuro-economics, which inform the decision-making processes of patients facing preventive health choices. Lastly, it appears that a significant part of the excess mortality associated with the existence of severe mental disorders is not due to factors inherent to the patients themselves, but to disparities in the quality of the care provided to them.

Biomarkers for monitoring intestinal health in poultry: present status and future perspectives.

Intestinal health is determined by host (immunity, mucosal barrier), nutritional, microbial and environmental factors. Deficiencies in intestinal health are associated with shifts in the composition of the intestinal microbiome (dysbiosis), leakage of the mucosal barrier and/or inflammation. Since the ban on growth promoting antimicrobials in animal feed, these dysbiosis-related problems have become a major issue, especially in intensive animal farming. The economical and animal welfare consequences are considerable. Consequently, there is a need for continuous monitoring of the intestinal health status, particularly in intensively reared animals, where the intestinal function is often pushed to the limit. In the current review, the recent advances in the field of intestinal health biomarkers, both in human and veterinary medicine are discussed, trying to identify present and future markers of intestinal health in poultry. The most promising new biomarkers will be stable molecules ending up in the feces and litter that can be quantified, preferably using rapid and simple pen-side tests. It is unlikely, however, that a single biomarker will be sufficient to follow up all aspects of intestinal health. Combinations of multiple biomarkers and/or metabarcoding, metagenomic, metatranscriptomic, metaproteomic and metabolomic approaches will be the way to go in the future. Candidate biomarkers currently are being investigated by many research groups, but the validation will be a major challenge, due to the complexity of intestinal health in the field.

Assessment of Passive Intestinal Permeability Using an Artificial Membrane Insert System.

Despite reasonable predictive power of current cell-based and cell-free absorption models for the assessment of intestinal drug permeability, high costs and lengthy preparation steps hamper their use. The use of a simple artificial membrane (without any lipids present) as intestinal barrier substitute would overcome these hurdles. In the present study, a set of 14 poorly water-soluble drugs, dissolved in 2 different media (fasted state simulated/human intestinal fluids [FaSSIF/FaHIF]), were applied to the donor compartment of an artificial membrane insert system (AMI-system) containing a regenerated cellulose membrane. Furthermore, to investigate the predictive capacity of the AMI-system as substitute for the well-established Caco-2 system to assess intestinal permeability, the same set of 14 drugs dissolved in FaHIF were applied to the donor compartment of a Caco-2 system. For 14 drugs, covering a broad range of physicochemical parameters, a reasonable correlation between both absorption systems was observed, characterized by a Pearson correlation coefficient r of 0.95 (FaHIF). Using the AMI-system, an excellent predictive capacity of FaSSIF as surrogate medium for FaHIF was demonstrated (r = 0.96). Based on the acquired data, the AMI-system appears to be a time- and cost-effective tool for the early-stage estimation of passive intestinal permeability for poorly water-soluble drugs.

Safety of mannitol use in bowel preparation: a prospective assessment of intestinal methane (CH4) levels during colonoscopy after mannitol and sodium phosphate (NaP) bowel cleansing / Segurança do uso do manitol no preparo para colonoscopia: avaliação prospectiva do nível de metano (CH4) intestinal durante colonoscopia após preparo com manitol e fosfato de sódio (NaP)

ABSTRACT Background - Adequate bowel preparation is critical for the quality of colonoscopy. Despite reported occurrence of colonic explosion due to methane and hydrogen production by bacterial fermentation during colonoscopy, gas exchange during the procedure is believed to be effective in lowering existing methane concentration, allowing for safe utilization of mannitol for bowel preparation. Thus, mannitol is widely used for bowel cleansing prior to colonoscopy, considering its low cost and effectiveness for bowel preparation. Objective - The aim of this study was to assess the safety of mannitol for bowel preparation, when compared to sodium phosphate (NaP). Methods - We conducted a prospective observational study in which 250 patients undergoing colonoscopy at Universidade Federal de São Paulo and Hospital Albert Einstein (São Paulo, Brazil) were approached for inclusion in the study. Patients received either mannitol (n=50) or NaP (n=200) for bowel preparation, based on physician indication. Study was conducted from August 2009 to December 2009. The main outcome of interest was presence of detectable levels of methane (CH4) during colonoscopy and reduction in such levels after gas exchange during the procedure. Methane concentrations were measured in three intestinal segments during scope introduction and withdrawal. Safety was assessed as the absence of high levels of methane, defined as 5%. Measurements were made using a multi-gas monitor (X-am 7000, Dräger Safety AG & Co. KGaA, Lübeck, Germany) connected to a plastic catheter introduced into the working channel of the colonoscope. Additional outcomes of interest included levels of O2. Methane and O2 levels are reported as ppm. Mean, difference and standard deviation of levels of gas measured in both moments were calculated and compared in both groups. Proportions of patients with detectable or high levels of methane in both groups were compared. Continuous variables were analyzed using t test and categorical variables using qui-square tests. The Ethics Committee in both study sites approved the study protocol. Results - Patients in both groups were similar regarding demographics, colonoscopy indication, ASA status and quality of bowel preparation. Seven (3.5%) patients in the NaP group had methane detected during introduction of the endoscope. Methane levels became undetectable during withdrawal of the scope. None of the patients in the mannitol group had detectable levels of methane. O2 levels did not differ in the groups. Conclusion - This is the largest study to assess the safety of mannitol for bowel preparation, considering methane measurements. Our results indicate that mannitol use is as safe as NaP, and gas exchange was efficient in reducing methane concentrations.

RESUMO Contexto - Preparo adequado é fundamental para garantia de boa qualidade em colonoscopia. Apesar de relatos de explosão do cólon durante colonoscopia, secundários à produção de metano e hidrogênio pela fermentação bacteriana, acredita-se que a troca gasosa durante o procedimento diminua a concentração existente de metano, permitindo a utilização com segurança, de manitol para o preparo de cólon. Assim, manitol é largamente utilizado para limpeza dos cólons antes da colonoscopia, especialmente devido ao seu baixo custo e eficácia. Objetivo - O objetivo do estudo foi avaliar a segurança do uso de manitol no preparo dos cólons, quando comparado ao uso de fosfo-soda (NaP). Métodos - Este foi um estudo observacional retrospectivo no qual foram incluídos 250 pacientes submetidos a colonoscopia na Universidade Federal de São Paulo e Hospital Albert Einstein (São Paulo - Brasil). Os pacientes receberam preparo de cólon com manitol (n=50) ou NaP (n=200), de acordo com preferências dos médicos que encaminharam os pacientes. O estudo foi realizado entre agosto e dezembro de 2009. O principal resultado pesquisado foi a presença de níveis detectáveis de metano (CH4) durante a colonoscopia, e a redução nestes níveis após troca gasosa durante o procedimento. As concentrações de metano foram dosadas com detector multi-gas (X-am 7000, Dräger Safety AG & Co., KGaA, Lübeck, Alemanha) conectado a um cateter plástico que foi introduzido no canal de instrumentação do colonoscópio. Outro achado de interesse foram níveis de O2. Níveis de metano e O2 foram relatados em ppm. Média, diferença entre as médias e desvio padrão nos níveis dos gases em ambos momentos foram comparados nos dois grupos. A proporção de pacientes com níveis detectáveis ou altos de metano em ambos os grupos foram comparados. Variáveis contínuas foram analisadas com teste t e variáveis categóricas com o teste do qui-quadrado. Os Comitês de Ética de ambas instituições aprovaram o protocolo do estudo. Resultados - Pacientes nos dois grupos foram comparáveis quanto aos dados demográficos, indicação para colonoscopia, classificação ASA e qualidade do preparo do cólon. Sete (3,5%) pacientes no grupo NaP tinham níveis detectáveis de metano durante a introdução do colonoscópio. Os níveis de metano se tornaram indetectáveis durante a retirada do aparelho. Nenhum dos pacientes no grupo manitol tinha níveis detectáveis de metano. Níveis de O2 foram semelhantes nos dois grupos. Conclusão - Este é o estudo com maior casuística que avaliou a segurança do uso de manitol para preparo de cólon, no que diz respeito a dosagem de metano. Nossos resultados indicam que o emprego do manitol é tão seguro quanto o NaP, e que a troca gasosa é eficaz na redução da concentração de metano.

SAFETY OF MANNITOL USE IN BOWEL PREPARATION: a prospective assessment of intestinal methane (CH4) levels during colonoscopy after mannitol and sodium phosphate (NaP) bowel cleansing.

BACKGROUND: - Adequate bowel preparation is critical for the quality of colonoscopy. Despite reported occurrence of colonic explosion due to methane and hydrogen production by bacterial fermentation during colonoscopy, gas exchange during the procedure is believed to be effective in lowering existing methane concentration, allowing for safe utilization of mannitol for bowel preparation. Thus, mannitol is widely used for bowel cleansing prior to colonoscopy, considering its low cost and effectiveness for bowel preparation. OBJECTIVE: - The aim of this study was to assess the safety of mannitol for bowel preparation, when compared to sodium phosphate (NaP). METHODS: - We conducted a prospective observational study in which 250 patients undergoing colonoscopy at Universidade Federal de São Paulo and Hospital Albert Einstein (São Paulo, Brazil) were approached for inclusion in the study. Patients received either mannitol (n=50) or NaP (n=200) for bowel preparation, based on physician indication. Study was conducted from August 2009 to December 2009. The main outcome of interest was presence of detectable levels of methane (CH4) during colonoscopy and reduction in such levels after gas exchange during the procedure. Methane concentrations were measured in three intestinal segments during scope introduction and withdrawal. Safety was assessed as the absence of high levels of methane, defined as 5%. Measurements were made using a multi-gas monitor (X-am 7000, Dräger Safety AG & Co. KGaA, Lübeck, Germany) connected to a plastic catheter introduced into the working channel of the colonoscope. Additional outcomes of interest included levels of O2. Methane and O2 levels are reported as ppm. Mean, difference and standard deviation of levels of gas measured in both moments were calculated and compared in both groups. Proportions of patients with detectable or high levels of methane in both groups were compared. Continuous variables were analyzed using t test and categorical variables using qui-square tests. The Ethics Committee in both study sites approved the study protocol. RESULTS: - Patients in both groups were similar regarding demographics, colonoscopy indication, ASA status and quality of bowel preparation. Seven (3.5%) patients in the NaP group had methane detected during introduction of the endoscope. Methane levels became undetectable during withdrawal of the scope. None of the patients in the mannitol group had detectable levels of methane. O2 levels did not differ in the groups. CONCLUSION: - This is the largest study to assess the safety of mannitol for bowel preparation, considering methane measurements. Our results indicate that mannitol use is as safe as NaP, and gas exchange was efficient in reducing methane concentrations.

Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs.

BACKGROUND: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG. METHODS: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naïve (N = 37), or had previous LCIG treatment for <2 (N = 22), or ≥2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored. RESULTS: Mean monthly costs per patient (€8226 ± 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naïve patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations. CONCLUSIONS: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naïve patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The long-term safety was consistent with the established LCIG profile.

Assessment of the Effect of Intestinal Permeability Probes (Lactulose And Mannitol) and Other Liquids on Digesta Residence Times in Various Segments of the Gut Determined by Wireless Motility Capsule: A Randomised Controlled Trial.

BACKGROUND: Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time. METHODS: Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms. RESULTS: The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity. CONCLUSIONS: Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra-abdominal pressure. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000596505.

In vivo radiobiological assessment of the new clinical carbon ion beams at CNAO.

In this article, the in vivo study performed to evaluate the uniformity of biological doses within an hypothetical target volume and calculate the values of relative biological effectiveness (RBE) at different depths in the spread-out Bragg peak (SOBP) of the new CNAO (National Centre for Oncological Hadrontherapy) carbon beams is presented, in the framework of a typical radiobiological beam calibration procedure. The RBE values (relative to (60)Co γ rays) of the CNAO active scanning carbon ion beams were determined using jejunal crypt regeneration in mice as biological system at the entrance, centre and distal end of a 6-cm SOBP. The RBE values calculated from the iso-effective doses to reduce crypt survival per circumference to 10, ranged from 1.52 at the middle of the SOBP to 1.75 at the distal position and are in agreement with those previously reported from other carbon ion facilities. In conclusion, this first set of in vivo experiments shows that the CNAO carbon beam is radiobiologically comparable with the NIRS (National Institute of Radiological Sciences, Chiba, Japan) and GSI (Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany) ones.

Experimental assessment of antidiarrheal and antisecretory activity of 80% methanolic leaf extract of Zehneria scabra in mice.

BACKGROUND: The leaf of Zehneria scabra is traditionally used for the management of diarrhea in Ethiopia. Its use, however, has not been scientifically validated for safety and efficacy. The aim of this study was to investigate antidiarrheal and antisecretory effects of hydroalcolic leaf extract of Z. scabra in mice models. METHODS: For each of antidiarrheal, gastrointestinal motility and antisecretory activity study Swiss albino mice were divided in to five groups. Group I was treated as control group and received 10 ml/kg of 2% Tween-80 orally; Group II served as a positive control and took standard drug in each of the experiments orally; Group III, IV and V were test groups which received the methanolic extract orally at 100, 200 and 400 mg/kg, respectively. Depending on the model total weight of fecal output, total weight of wet feces, total number of fecal output, number of wet faeces, length of intestinal transit and intestinal weight were collected. Finally, data were analyzed using one-way ANOVA followed by Tukey's post test. RESULT: In castor oil induced diarrhea model, the extract dose produced a significant reduction in mean stool score (1.94 ± 0.102) at 200 mg/kg. Moreover, the 100, 200, and 400 mg/kg doses inhibited stool frequency by 40, 45 and 55%, respectively. All test doses of extract and loperamide (3mg/kg) reduced fecal fluid content significantly (p<0.01). The 100 mg/kg dose of extract produced 25.74% reduction of fluid content (p<0.001) while both 200 and 400 mg/kg showed 29.70 % (p<0.001) compared to negative control group. CONCLUSION: The extract of Zehineria scabra showed antidiarrheal and antisecretory activity in mice model. Moreover, the extract found to be safe at dose of 2000mg/kg in mice model. The findings suggest the validity of the acclaimed effect of Zehineria scabra as antidiarrheal agent in Ethiopian traditional herbal medicine.

Limits to sustained energy intake. XXII. Reproductive performance of two selected mouse lines with different thermal conductance.

Maximal sustained energy intake (SusEI) appears limited, but the factors imposing the limit are disputed. We studied reproductive performance in two lines of mice selected for high and low food intake (MH and ML, respectively), and known to have large differences in thermal conductance (29% higher in the MH line at 21°C). When these mice raised their natural litters, their metabolisable energy intake significantly increased over the first 13 days of lactation and then reached a plateau. At peak lactation, MH mice assimilated on average 45.3% more energy than ML mice (222.9±7.1 and 153.4±12.5 kJ day(-1), N=49 and 24, respectively). Moreover, MH mice exported on average 62.3 kJ day(-1) more energy as milk than ML mice (118.9±5.3 and 56.6±5.4 kJ day(-1), N=subset of 32 and 21, respectively). The elevated milk production of MH mice enabled them to wean litters (65.2±2.1 g) that were on average 50.2% heavier than litters produced by ML mothers (43.4±3.0 g), and pups that were on average 27.2% heavier (9.9±0.2 and 7.8±0.2 g, respectively). Lactating mice in both lines had significantly longer and heavier guts compared with non-reproductive mice. However, inconsistent with the 'central limit hypothesis', the ML mice had significantly longer and heavier intestines than MH mice. An experiment where the mice raised litters of the opposing line demonstrated that lactation performance was not limited by the growth capacity of offspring. Our findings are consistent with the idea that the SusEI at peak lactation is constrained by the capacity of the mothers to dissipate body heat.

[Circulating citrulline levels: a biomarker for intestinal functionality assessment]. / La citrullinémie: un biomarqueur de la fonctionnalité intestinale.

Circulating citrulline is emerging as an innovating biomarker candidate for assessment of intestinal function. Amino acid synthesized by enterocytes of intestinal mucosal, citrulline is not included in proteins or nutrition products and is a precursor for production of arginine by the kidney. Plasma citrulline is, in clinical situation, an established biomarker of enterocyte functional metabolic mass (trophicity) in children and in adult patients due to its high relation to active functional small bowel remnant length in intestinal diseases (short bowel, extensive enteropathies, intestinal toxicity of chemotherapy and radiotherapy. Plasma citrulline concentration (30-50  µmol/L), independent of nutritional status, if less than 10  µmol/L can give an objective threshold for nutrition parenteral use in case of intestinal failure due to enterocyte abnormalities or lack. Its regular dosage allows the monitoring of intestinal function except in case of significant renal failure.

Bonding interactions and stability assessment of biopolymer material prepared using type III collagen of avian intestine and anionic polysaccharides.

The present study demonstrate bonding interactions between anionic polysaccharides, alginic acid (AA) and type III collagen extracted from avian intestine used for the preparation of thermally stable and biodegradable biopolymer material. Further the study describes, optimum conditions (pH, temperature and NaCl concentration) required for the formation of fibrils in type III collagen, assessment on degree of cross-linking, nature of bonding patterns, biocompatibility and biodegradability of the cross-linked biomaterial. Results revealed, the resultant biopolymer material exhibit high thermal stability with 5-6 fold increase in tensile strength compared to the plain AA and collagen materials. The degree of cross-linking was calculated as 75%. No cytotoxicity was observed for the cross-linked biopolymer material when tested with skin fibroblast cells and the material was biodegradable when treated with enzyme collagenase. With reference to bonding pattern analysis we found, AA cross-linked with type III collagen via (i) formation of covalent amide linkage between -COOH group of AA and ε-NH2 group of type-III collagen as well as (ii) intermolecular multiple hydrogen bonding between alginic acid -OH group with various amino acid functional group of type-III collagen. Comparisons were made with other cross-linking agents also. For better understanding of bonding pattern, bioinformatics analysis was carried out and discussed in detail. The results of the study emphasize, AA acts as a suitable natural cross-linker for the preparation of wound dressing biopolymer material using collagen. The tensile strength and the thermal stability further added value to the resultant biopolymer.

Assessment of CFTR function in homozygous R117H-7T subjects.

BACKGROUND: R117H is a frequent missense mutation included in most CFTR mutation panels. However knowledge about the residual function of R117H-CFTR channels in cystic fibrosis-affected organs, e.g. airways, intestines and sweat glands is presently lacking. METHODS: We evaluated clinical CF symptoms and assessed CFTR function by sweat tests, nasal potential difference and intestinal current measurements in 2 homozygous R117H individuals (7T variant). RESULTS: The CFTR activity in airways and intestine was within the normal range. However both individuals presented with a borderline sweat test and the male patient was infertile. CONCLUSIONS: The lack of impact of the R117H mutation on chloride secretion in intestine and nose contrasts with the ~80% loss of CFTR activity reported in patch clamp studies. Apparently CFTR activity is not rate-limiting for chloride secretion in both tissues at levels >20% of normal, or compensatory factors may operate that are absent in heterologous host cells in vitro.

Observational, nonintervention, multicenter study for validation of the Bowel Function Index for constipation in European countries.

OBJECTIVE: Constipation is a common adverse event of treatment with opioids for chronic non-malignant pain and may result in a considerable reduction in health-related quality of life. The aim of this study was to assess the psychometric properties of the Bowel Function Index (BFI) in european patients suffering from constipation secondary to opioid analgesic treatment for chronic, non-malignant pain. METHODS: This was a multinational study conducted at 15 clinical sites in the Czech Republic, Germany, Italy, and the United Kingdom. Patients suffering from constipation secondary to opioid analgesic treatment for chronic, non-malignant pain were recruited to complete a series of questionnaires including a socio-demographic form, the BFI, the Patient Assessment of Constipation - Symptoms (PAC-SYM), a global frequency item, and a clinical form. RESULTS: A total of 131 patients were included in this study. Inter-item correlations of the BFI were statistically significant in the moderate to large range and the analysis indicated a strong degree of internal consistency (Cronbach's alpha = 0.86). All correlations between the BFI and the global item were statistically significant in the moderate to high range (r = 0.59 to 0.69; p < 0.0001). Correlations between the BFI and the PAC-SYM were moderate and statistically significant (p < 0.01 to 0.0001). CONCLUSIONS: Although this study was limited by the relatively small sample size, it is a part of an extensive validation program. This study suggests that the BFI is a reliable and valid measure of constipation-related symptomatology in chronic pain patients. This measure may be a valuable indicator of patients' experience of symptoms of opioid treatment of chronic pain in future trials.

Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects.

The health benefits of breast-feeding have been recognised for a long time. In particular, breast-feeding is associated with lower incidence of necrotising enterocolitis and diarrhoea during the early period of life and with lower incidence of inflammatory bowel diseases, type 2 diabetes and obesity later in life. The higher nutritional and protective degree of human milk is related to its nutritional composition that changes over the lactation period and to the biological activities of specific components while lower growth rate of breast-fed infants may be attributed to their self-regulation of milk intake at a lower level than formula-fed infants. Many results now suggest that the developmental changes in intestinal and pancreatic function that occur postnatally are modulated by the diet. Indeed, formula-feeding induces intestinal hypertrophy and accelerates maturation of hydrolysis capacities; it increases intestinal permeability and bacterial translocation, but does not induce evident differences in microbiota composition. Whether these changes would be beneficial for enhancing absorptive capacities and for educating the gut-associated immune system remains to be further studied. Moreover, it is evident that formula-feeding increases basal blood glucose and decreases plasma ketone body concentrations, while discrepancies on postprandial glycaemia, insulin and incretin responses in both human studies and experimental studies are inconclusive. Manipulating the composition of formula, by reducing protein content, adding prebiotics, growth factors or secretory IgA can modulate intestinal and pancreatic function development, and thereby may reduce the differential responses between breast-fed and formula-fed neonates. However, the developmental responses of the digestive tract to different feeding strategies must be elucidated in terms of sensitivity to developing diseases, taking into account the major role of the intestinal microbiota.

Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substrates.

The first objective of the present study was to predict the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human. The second objective was to predict pharmacokinetics of the selected drugs in presence of inhibitors of the intestinal and/or hepatic CYP3A activity. We developed a whole-body physiologically based pharmacokinetics (WB-PBPK) model accounting for presystemic elimination of midazolam (MDZ), alprazolam (APZ), triazolam (TRZ), and simvastatin (SMV). The model also accounted for concomitant administration of the above-mentioned drugs with CYP3A inhibitors, namely ketoconazole (KTZ), itraconazole (ITZ), diltiazem (DTZ), saquinavir (SQV), and a furanocoumarin contained in grape-fruit juice (GFJ), namely 6',7'-dihydroxybergamottin (DHB). Model predictions were compared to published clinical data. An uncertainty analysis was performed to account for the variability and uncertainty of model parameters when predicting the model outcomes. We also briefly report on the results of our efforts to develop a global sensitivity analysis and its application to the current WB-PBPK model. Considering the current criterion for a successful prediction, judged satisfied once the clinical data are captured within the 5th and 95th percentiles of the predicted concentration-time profiles, a successful prediction has been obtained for a single oral administration of MDZ and SMV. For APZ and TRZ, however, a slight deviation toward the 95th percentile was observed especially for C(max) but, overall, the in vivo profiles were well captured by the PBPK model. Moreover, the impact of DHB-mediated inhibition on the extent of intestinal pre-systemic elimination of MDZ and SMV has been accurately predicted by the proposed PBPK model. For concomitant administrations of MDZ and ITZ, APZ and KTZ, as well as SMV and DTZ, the in vivo concentration-time profiles were accurately captured by the model. A slight deviation was observed for SMV when coadministered with ITZ, whereas more important deviations have been obtained between the model predictions and in vivo concentration-time profiles of MDZ coadministered with SQV. The same observation was made for TRZ when administered with KTZ. Most of the pharmacokinetic parameters predicted by the PBPK model were successfully predicted within a two-fold error range either in the absence or presence of metabolism-based inhibition. Overall, the present study demonstrated the ability of the PBPK model to predict DDI of CYP3A substrates with promising accuracy.