Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity.

Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-ß-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.

Vitamin D deficiency in children with a chronic illness-seasonal and age-related variations in serum 25-hydroxy Vitamin D concentrations.

INTRODUCTION: Children and adolescents with a chronic illness have potential risk factors for vitamin D deficiency. An optimal vitamin D status might have multiple health effects. This study evaluated vitamin D status and its association with age, gender, and season in a large cohort of chronically ill Finnish patients at a tertiary pediatric outpatient clinic. A cross-sectional register-based study was carried out, involving altogether 1351 children (51% boys, age range 0.2-18 years), who visited the outpatient clinic during 2007-2010 and had their vitamin D status (S-25-OHD) determined. A post-doc analysis was conducted to identify predisposing and preventing factors for vitamin D deficiency. RESULTS: Almost half (47%) of the S-25-OHD values were consistent with subnormal vitamin D status (S-25-OHD <50 nmol/L) while only 12% were >80 nmol/L. Age and season were the most important determinants for S-25-OHD concentration. Mean S-25-OHD concentration differed between age groups (Kruskal-Wallis; p<0.001), adolescents being at highest risk for vitamin D insufficiency. Young age and vitamin D supplementation were preventive factors for deficiency, while non-Finnish ethnic background was a predisposing factor. S-25-OHD showed significant seasonal variation in children older than 6 years. In the whole cohort, S-25-OHD was on average 13 nmol/L higher in summer than in winter, and the prevalence of vitamin D deficiency ( =  S-25-OHD <37.5 nmol/l) varied from 11% in summer to 29% in winter. CONCLUSIONS: The finding that almost half of the studied Finnish children with a chronic illness had suboptimal vitamin D status is alarming. Inferior vitamin D status was noted in adolescents compared with younger children, suggesting that imbalance between intake and requirement evolves with age. Although less common during summer, subnormal vitamin D status was still observed in 28% of those evaluated in summer. Clinicians should identify individuals at risk and actively recommend vitamin D supplementation.

Position paper on tuberculosis screening in patients with immune mediated inflammatory diseases candidates for biological therapy.

UNLABELLED: Chronic immunosuppression is a known risk factor for tuberculosis. Our aim was to reach a consensus on screening and prevention of tuberculosis in patients with immune mediated inflammatory diseases candidates to biologic therapy. METHODS: Critical appraisal of the literature and expert opinion on immunosuppressive therapies and risk of tuberculosis. RESULTS AND CONCLUSION: The currently recommended method for screening is the tuberculin skin test and the interferon gamma assay, after exclusion of active tuberculosis. Positively screened patients should be treated for latent tuberculosis infection. Patients may start biological therapy after 1 to 2 months, as long as they are strictly adhering to and tolerating their preventive regimen.

Sairei-to therapy on alloimmune recurrent spontaneous abortions and alloimmune-, autoimmune complicated recurrent spontaneous abortions.

Alloimmune recurrent spontaneous abortion (RSA) cases that could not be treated with lymphocyte transfusion due to medical and social reasons were treated with Sairei-to therapy as an emergency measure and all four cases resulted in live births. This may show that Sairei-to treatment is effective in preventing alloimmune RSA. The efficacy of Sojyutsu-Sairei-to and Byakujyutsu-Sairei-to on autoimmune RSA has already been proven. When they were used in the treatment of alloimmune-, autoimmune complicated RSA, the abortion prevention rates were 65.4% and 82.3% respectively. These results indicate that Sairei-to is effective in the treatment of alloimmune RSA and alloimmune-, autoimmune complicated RSA.

Breaking patterns of environmentally influenced disease for health risk reduction: immune perspectives.

BACKGROUND: Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or "pattern" of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases. OBJECTIVE: We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli. FINDINGS: Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood. CONCLUSIONS: Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern-based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management.

Possible role of engraftment syndrome and autologous graft-versus-host disease in myelodysplastic syndrome after autologous stem cell transplantations: retrospective analysis and review of the literature.

BACKGROUND: We report a retrospective study of 452 patients with lymphoma from 1991 to 2006, with 274 men and 178 women, median age of 50 years (range, 16-76 years). PATIENTS AND METHODS: There were 85 patients with Hodgkin lymphoma (HL) and 367 with non-Hodgkin lymphoma (NHL). Eleven patients received a second autologous transplantation for progressive lymphoma, and another 4 received a second allogeneic transplantation for myelodysplastic syndrome (MDS). Twenty-seven patients had skin biopsies, and 2 patients had gastrointestinal biopsies consistent with graft-versus-host disease (GVHD), and 11 patients developed severe engraftment syndrome (ES), as defined by noninfectious fever and skin rash with or without pulmonary infiltrates requiring systemic steroids. RESULTS: The median follow-up of the patients was 6.2 years, and median overall survival was 5.3 years. Twenty-four patients (5.3%) developed MDS with median time of onset of 4.2 years (range, 8 months to 7.5 years). An additional 5 patients developed clonal karyotypic abnormalities in the bone marrow without clinical MDS. Actuarial probabilities of developing MDS at 5 and 8 years after transplantation were 5% and 15%, respectively. CONCLUSION: The incidences of MDS are similar in HL and NHL. Multivariate analysis revealed older age, occurrence of ES/GVHD, and longer intervals between the initial diagnoses to transplantation as independent factors. It is conceivable that perturbation to the host immunity caused by either previous chemotherapy or conditioning regimens in the elderly might play a role in the development of MDS after autologous transplantation.

Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats.

A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.

Correlation of psychological and physical symptoms with chronically elevated cytokine levels associated with a common immune dysregulation.

BACKGROUND: Chronically elevated levels of proinflammatory cytokines are associated with inflammatory diseases and psychological symptoms of depression and tiredness. OBJECTIVE: To test the prediction that, in a healthy population without medically diagnosed diseases, psychological symptoms (depression and tiredness) associated with proinflammatory cytokines correlate with physical symptoms associated with inflammatory disease. METHODS: A total of 1,143 women between 45 and 65 years old completed a health complaint checklist containing 11 target symptoms (5 related to allergy, 4 to gastrointestinal symptoms, and 2 to pain), 7 control symptoms or health complaints, and 2 psychological symptoms (depression and tiredness). They also completed a menopausal quality-of-life questionnaire; to compensate for response bias, we removed variance attributable to quality of life. RESULTS: The partial correlations show that tiredness (but not depression) correlated with 9 of the 11 target symptoms (P < .001) but with 0 of the 7 control symptoms or complaints. Symptoms of both the specific and the systemic components of inflammatory disease are correlated in a healthy population. CONCLUSION: Immune dysregulation may explain the existence and covariation of psychological and physical symptoms in the healthy population, including people with medically unexplained symptoms.

Understanding the interaction between psychosocial stress and immune-related diseases: a stepwise progression.

For many years, anecdotal evidence and clinical observations have suggested that exposure to psychosocial stress can affect disease outcomes in immune-related disorders such as viral infections, chronic autoimmune diseases and tumors. Experimental evidence in humans supporting these observations was, however, lacking. Studies published in the last 2 decades in Brain, Behavior and Immunity and other journals have demonstrated that acute and chronic psychological stress can induce pronounced changes in innate and adaptive immune responses and that these changes are predominantly mediated via neuroendocrine mediators from the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal axis. In addition, psychological stress has predicted disease outcomes using sophisticated models such as viral challenge, response to vaccination, tracking of herpesvirus latency, exploration of tumor metastasis and healing of experimental wounds, as well as epidemiological investigations of disease progression and mortality. These studies have contributed significantly to our understanding that the neuroendocrine-immune interaction is disturbed in many pathophysiological conditions, that stress can contribute to this disturbance, and that malfunction in these communication pathways can play a significant role in the progression of disease processes. There are, however, significant gaps in the extant literature. In the coming decade(s), it will be essential to further analyze neuroendocrine-immune communication during disease states and to define the specific pathways linking the central nervous system to the molecular events that control important disease-relevant processes. This knowledge will provide the basis for new therapeutic pharmacological and non-pharmacological behavioral approaches to the treatment of chronic diseases via specific modulation of nervous system-immune system communication.

Cytokines as mediators of depression: what can we learn from animal studies?

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.

Inflammatory bowel disease: new insights into pathogenesis and treatment.

Despite all the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we do not know the cause. Some of the most recently available data have been discussed here and yet it is now becoming increasingly accepted that immunogenetics play an important role in the predisposition, modulation, and perpetuation of IBD. The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. The role of intestinal milium, and enteric flora in particular, appears to be of greater significance than previously held. A review is made of the main areas of research exploring the mechanisms more intimately associated with the development of IBD, providing advances in the agents currently used, and identifying a host of new therapeutic agents potentially interacting with or interrupting specific targets in the genesis of IBD.

Oral submucous fibrosis. A review.

Oral submucous fibrosis (OSF) affects an estimated 2.5 million people, mostly in the Indian subcontinent. Limitation of oral opening resulting in difficulty in eating is the main presenting feature. Although nutritional deficiencies and immunological processes may play a part in the pathogenesis, the available epidemiological evidence indicates that chewing betel quid (containing areca nut, tobacco, slaked lime or other species) is an important risk factor for OSF. Genetically determined susceptibility could explain why only a small fraction of those using betel quid develop the disease. In OSF there is an incidence of oral cancer of 7.6 per cent for a median 10-year follow-up period. Risk markers for malignant transformation in OSF include epithelial dysplasia, silver binding nucleolar organizer region counts, and sister-chromatid exchange frequencies; p53 tumour suppressor gene mutations may be involved in these potentially malignant changes.

Chronic fatigue syndrome update. Findings now point to CNS involvement.

Neither Epstein-Barr virus nor human herpesvirus 6 appears to play a causative role in chronic fatigue syndrome. The possibility that a novel human retrovirus may be present in patients with the syndrome needs further study. A number of abnormalities found in patients with chronic fatigue syndrome point to central nervous system (CNS) involvement. These include immunologic abnormalities, indications of pituitary and hypothalamic involvement, abnormal basal plasma levels of certain neurotransmitter metabolites, and cerebral perfusion abnormalities. The symptom pattern of chronic fatigue syndrome may eventually be explainable in terms of CNS dysfunction.