The role of Galactose in human health and disease

According to the universal biological findings, cellular bodies are covered with an intense coating of glycans. Diversity of glycan chains, linked to lipids and proteins is due to isomeric and conformational modifications of various sugar residues, giving rise to unique carbohydrate structures with a wide range of sequences and anomeric configurations. Proteins and lipids, carrying specific sugar residues (like Galactose) with particular stereochemical properties (sequence, anomery and linkages) are involved in broad spectrums of biological processes, including intercellular and intracellular interactions, microbial adhesion and cellular signaling. By studying the role of specific seterochemical features of galactose (Gal), we have improved our understanding about the normal physiology and diseases in human bodies.     

Intestinal flora and Crohn's disease

The pathogenesis of inflammatory bowel diseases (IBD) proceeds through stages of initiation, amplification and healing. Abundant clinical and experimental data incriminate luminal bacteria or bacterial products in both the initiation and perpetuation of chronic intestinal inflammation. Macrophage and T-cell activation with accompanying inflammatory cytokine production appears to be an early event. Studies of lymphocyte responsiveness to autologous and heterologous intestinal bacteria have suggested that this activation may result from a breakdown in tolerance to the enteric flora in IBD. This lack of tolerance might be due to an imbalance between protective and aggressive commensal luminal bacterial species (dysbiosis), a decreased barrier function and/or an impaired mucosal clearance allowing the access of bacteria to the mucosal immune system and lack of regulatory mediators or cells. There is still controversy over whether the virulence traits of bacteria are expressed broadly or just in a small subset of bacteria. Individual bacterial species within the indigenous flora vary in their capacity to drive intestinal inflammation. In experimental models, some bacteria such as Bacteroides vulgatus can cause colitis alone when monoassociated in the HLA-B27 transgenic rat model. Others, including Lactobacillus and Bifidobacterium species have no proinflammatory capacity and have been used as probiotics. In patients with IBD, systematic approach to this issue is hampered by the limited knowledge of intestinal flora. Adherent-invasive Escherichia coli are a possible candidate for the onset and/or persistence of intestinal inflammation in patients with Crohn's disease, since they possess all the virulence factors that allow the bacteria to cross the intestinal barrier, to move to deep tissues, and to continuously activate macrophages. The recent identification of NOD2/CARD15 as a susceptibility gene for Crohn's disease has provided another link between the immune response to enteric bacteria and the development of mucosal inflammation. NOD2/CARD15 is composed of two caspase recruitment domain (CARD), a nucleotide-binding domain (NBD) and a leucin-rich-repeat (LRR) region. The LRR domain of NOD2/CARD15 has binding activity for bacterial peptidoglycans and its deletion stimulates the NF-kappaB pathway. The most frequent variants of NOD2/CARD15 observed in Crohn's disease tend to cluster in the LRR and its adjacent regions. This suggests that the LRR domain of CD-associated variants is likely to be impaired in its recognition of microbial components. Continuing studies are investigating the pathophysiological mechanisms induced by NOD2/CARD15 variants in the intestinal mucosa.     

Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease

Abstract

To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.     

Baclofen: Intestinal absorption mechanism in mice

• 1.1. The duodenal transfer of baclofen from sacs of mouse intestine was determined.
• 2.2. A linear relationship between the steady-state transfer rate of total and the initial mucosal baclofen concentration was observed, suggesting that the clearance is the same at different concentrations.
• 3.3. There was no significant difference in the amount of total drug removed between control and everted tissues.
• 4.4. The data support the idea that the principal transfer mechanism for baclofen is simple diffusion in mouse intestine.

     

How to define responders in osteoarthritis

Abstract

Background:

Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures.     

Economic evaluations in rheumatoid arthritis: a critical review of measures used to define health States

We reviewed the clinical measures used in rheumatoid arthritis (RA) economic evaluations with respect to their relevance and sensitivity to changes in survival, health-related quality of life (HR-QOL) and costs. We compared the measures from the economic perspective and discussed the validity of methods used to extrapolate beyond the trial data. Cost-effectiveness evaluations of disease-modifying antirheumatic drugs in RA were identified by searching MEDLINE, EMBASE, Econlit and NHS EED databases. Studies were retained if they extrapolated beyond randomized controlled trial evidence using relationships between clinical measures, costs and utilities.In the 22 studies identified, clinical severity was measured using the Health Assessment Questionnaire (HAQ) Disability Index, the American College of Rheumatology (ACR) response criteria, the Disease Activity Score (DAS) or a combination of the HAQ and DAS. The HAQ is correlated with mortality, costs and HR-QOL instruments, and several studies used linear relationships to model these associations. However, a polynomial relationship or discrete states may be more appropriate for patients at the extremes of the disease spectrum, and numerous HAQ health states may be required to capture differences in mortality risk. While the ACR response criteria is a more comprehensive measure than the HAQ, it is a relative measure, which creates difficulties when estimating absolute changes in HR-QOL, costs and mortality risk. The evidence base linking DAS scores with HR-QOL instruments, costs and mortality is less robust, possibly due to the comparatively recent development of the measure and the limited number of possible scores (mild/moderate/severe). While there is some evidence of a relationship between DAS scores and costs, the DAS does not capture all aspects of HR-QOL, and no significant relationship has been established with mortality risk.Evidence suggests the HAQ to be the primary clinical measure for use in economic evaluations as it is measured in almost all clinical studies, and is closely correlated to health utilities, mortality and costs. While new developments suggest the sensitivity of health states may be improved by combining the HAQ with measures such as the DAS, further research is required in this area. Further research is also required to explore the advantages in using either continuous or discrete health states.     

Effects of subchronic exposures to concentrated ambient particles in mice. IX. Integral assessment and human health implications of subchronic exposures of mice to CAPs

In order to examine the biologic plausibility of adverse chronic cardiopulmonary effects in humans associated with ambient particulate matter (PM) exposure, we exposed groups of normal mice (C57) and knockout mice that develop atherosclerotic plaque (ApoE-/- and ApoE-/- LDLr-/-) for 6 h/day, 5 days/wk for 5 or 6 mo during the spring/summer of 2003 to either filtered air or 10-fold concentrated ambient particles (CAPs) in Tuxedo, NY (average PM2.5 concentration during exposure = 110 microg/m3). Some of the mice had implanted electrocardiographic monitors. We demonstrated that: (1) this complex interdisciplinary study was technically feasible in terms of daily exposure, collection of air quality monitoring data, the collection, analysis, and interpretation of continuous data on cardiac function, and the collection and analyses of tissues of the animals sacrificed at the end of the study; (2) the daily variations in CAPs were significantly associated, in ApoE-/- mice, with daily variations in cardiac functions; (3) there were significant differences between CAPs and sham-exposed ApoE-/- mice in terms of cardiac function after the end of exposure period, as well as small differences in atherosclerotic plaque density, coronary artery disease, and cell density in the substantia nigra in the brain in the ApoE-/- mice; (4) there are suggestive indications of gene expression changes for genes associated with the control of circadian rhythm in the ApoE-/- LDLr-/- double knockout (DK) mice. These various CAPs-related effects on cardiac function and the development of histological evidence of increased risk of clinically significant disease at the end of exposures in animal models of atherosclerosis provide biological plausibility for the premature mortality associated with PM2.5 exposure in human subjects and provide suggestive evidence for neurogenic disease as well.     

Intestinal decarboxylation of L-Dopa in relation to dose requirement in Parkinson's disease

Summary The magnitude of the decarboxylation of L-Dopa in the intestinal organs was determined by a method based on oral and intravenous administration of L-3,4-dihydroxyphenylalanine-1-¹⁴C (carboxyl labelled L-Dopa) and analysis of the radioactivity in urine.In 11 parkinsonian patients studied under standardized conditions 74% of L-Dopa given orally as a 0.5 g tablet was decarboxylated in the intestinal organs. Thus less than 26% of the ingested L-Dopa reached the general circulation.The possibility that individual variations in the magnitude of intestinal decarboxylation might be at least partly responsible for the individual variations in the dose requirement of parkinsonian patients was tested. There was neither any correlation between dose requirement of L-Dopa and the intestinal decarboxylation nor between that dose and the plasma disappearance rate of L-Dopa.It is concluded that other factors than those responsible for the peripheral metabolism of L-Dopa determine the individual dose requirement.     

Revisit gut microbiota and its impact on human health and disease

Trillions of microbes have evolved with and continue to live on human beings. With the rapid advances in tools and technology in recent years, new knowledge and insight in cross-talk between the microbes and their hosts have gained. It is the aim of this work to critically review and summarize recent literature reports on the role of microbiota and mechanisms involved in the progress and development of major human diseases, which include obesity, hypertension, cardiovascular disease, diabetes, cancer, Inflammatory Bowel Disease (IBD), gout, depression and arthritis, as well as infant health and longevity.     

An attempt to define a just detectable effect for airborne chemicals on the respiratory tract in mice

 We have attempted to define a just detectable effect (JDE) for three different types of reactions along the respiratory tract: (a) sensory irritation of the upper airways (S), (b) airflow limitation along the conducting airways (A), and (c) pulmonary irritation at the alveolar level (P1 or P). Each type of reaction, S, A, P1 or P, was recognized by analyzing the breathing pattern of unanesthetized mice held in body plethysmographs. A rule-based computer program analyzed each breath during a period of 3.75 h and classified each breath as normal (N) or falling in any of the above categories (i.e., S, A, P1 or P). Eight groups of four mice were used for sham exposures: exposed to water vapor. These data sets were used, as sham exposure data, to define the variation which can occur with time in order to define an expected range of normal variation. Once this range was established, we defined JDE values for each type of effect and used such values to evaluate the results obtained in exposed animals. Eight groups of four mice were exposed to a mixture of airborne chemicals, machining fluid G (MFG), at concentrations from 0.17 to 55 mg/m³. Data sets for individual animals and for each group of animals exposed to MFG were analyzed to determine if and when a particular effect occurred. It was possible to recognize the effects of low exposure concentrations on groups of exposed animals or individual animals within each group. This procedure will be valuable when investigating the effect of airborne chemicals and when it is impossible to generate high exposure concentrations to define concentration-response relationships. Received: 4 October 1995/Accepted: 20 December 1995     

Respiratory exposure to chemicals and human health

Many hazardous chemicals are absorbed into human body through respiration and have effects on human health. The 21st Century COE (center of excellence) "Environmental Monitoring and Prediction of Long- and Short-term Dynamics of Pan-Japan Sea Area--Construction of Monitoring Network and Assessment of Human Effects" (Leader: Kazuichi Hayakawa, Graduate School of Natural Science and Technology, Kanazawa University) concentrates on atmospheric pollution caused by human activities occurred in countries, Japan, China, Korea and Russia, surrounding Pan-Japan Sea as one of major projects. My talk focuses on atmospheric pollution caused by polycyclic aromatic hydrocarbon (PAH) and nitropolycyclic aromatic hydrocarbon (NPAH), which clearly exists in this area, and demonstrates the following aspects concerning this issue: 1) The 21st Century "Environmental Monitoring and Prediction of Long- and Short-term Dynamics of Pan-Japan Sea Area--Construction of Monitoring Network and Assessment of Human Effects," 2) Importance of PAH and NPAH as hazardous pollutants emitted from combustion of fossil fuels such as coal and oil, 3) Current status of atmospheric pollution of PAH and NPAH of Pan-Japan Sea Area, focusing on coal combustion systems such as heating in China and diesel-engine automobiles in Japan, and 4) Health effects of PAH and NPAH such as lung cancer and endocrine disruption.     

Intestinal perforation due to miliary tuberculosis in a patient with Behcet's disease

Gastrointestinal manifestations of both Beh?et's disease and intestinal tuberculosis include the signs and symptoms of abdominal pain, weight loss, fever, vomiting, diarrhea and palpable mass in the right lower quadrant. We report the case of a male patient with Beh?et's disease who had multiple ileal perforations due to miliary tuberculosis. It was suspected that the perforations were due to intestinal manifestation of Beh?et's disease, but the final pathology report and chest X-ray one week after surgery demonstrated the presence of miliary tuberculosis. To our knowledge, this is the first reported case of Beh?et's disease with intestinal perforation due to miliary tuberculosis.