No description available.

Pro-inflammatory cytokines have been implicated in the pathophysiology and maintenance of depression. This study investigated the effects of a short mindfulness intervention on pro-inflammatory correlates of depression (IL-6 and TNF-α) and selfreported psychological health. Sixty-four college females were assigned to a four-week mindfulness training group or a contact-control group. Cytokines and psychological health were assessed at baseline, post-treatment, and 3-month follow-up (mindfulness group only). IL-6 and TNF-α significantly decreased from baseline to post-treatment in the mindfulness group only; these changes were sustained at 3-month follow-up. No between-group differences in psychological health emerged. Although reductions in proinflammatory cytokines in the mindfulness condition were not attributable to psychological changes, they may serve to protect against the development of future depressive episodes.

The concept of sickness behavior offers a framework to view both the neurovegetative and psychological symptoms that accompany illness as a common entity that results from increased inflammatory activation. Despite the prevalence of sickness behavior in medical populations, to our knowledge this study provides the first attempt to develop a standardized measure to assess sickness behavior using standard self-report questionnaires commonly used with cancer patients. The set of items included in the measure match theoretical conceptualizations of sickness behavior and target symptoms that comprise anhedonia, depressed mood, cognitive dysfunction, social disinterest, fatigue, low libido, poor appetite, somnolence, sensitivity to pain, and malaise. The measure showed high internal consistency, adequate test-retest reliability, and good convergent validity with both psychological and biological correlates. A confirmatory factor analysis also determined that a two-factor, rather than a single-factor measurement model, encompassing a physical and a psychological sickness symptom dimension, accounted for sickness behavior. Future psychometric work is still needed to further validate this new practical assessment tool. Descriptive analyses revealed relatively low levels of sickness behavior symptoms in the sample as a whole with both physical and psychological sickness behavior symptoms exhibiting a significant linear decrease over time. As expected, both physical and psychological sickness behavior symptoms showed associations with two pro-inflammatory cytokine markers, IL6 and TNF-alpha and a neuroendocrine marker, cortisol. Longitudinal associations suggest that higher levels of the pro-inflammatory cytokine TNF-alpha may impact the progressive decline of physical sickness symptoms over time with symptoms taking longer to disappear. Because cortisol was associated with more rather than less physical sickness symptoms, results raise the question of whether the anti-inflammatory neuroendocrine activity may be dysregulated in breast cancer survivors. The mechanistic basis for these associations requires further examination. In this study it was also evaluated whether a cognitive behavioral stress management intervention and relaxation training intervention could reduce sickness symptoms over time. Breast cancer survivors were assessed at baseline and then randomly assigned to a 10-week cognitive behavioral stress management intervention (N = 70) or a 1-day control condition (N = 55). Psychosocial measures, urine, and blood were obtained from participants at 3 months, 6 months, and 12 months post-intervention to assess relevant behavioral, endocrine and immune variables. Relative to the control group, the experimental group showed marginally more prevalence of physical sickness behavior symptoms in the short term (post-intervention, 3-months; p = .08) and a steadier decline of symptoms in the long-term (15-month follow-up period). The adaptive nature of sickness behavior as a motivational strategy that helps restore homeostatic balance in the long run may be one possible interpretation of these results. Whether these intervention effects on sickness behavior were mediated by changes in pro-inflammatory cytokines or cortisol was examined but not supported by these data and needs to be further examined in future studies.

The circadian system provides living organisms a means to adapt their internal physiology to constantly changing environmental conditions that exists on our rotating planet, Earth. Clocks in peripheral tissues are referred to as peripheral which may participate in tissue-specific functions. The first step to investigating the circadian regulation in the peripheral tissues of avians was to examine for the presence of avian orthologs of core components of the molecular clock using Quantitative real time (qRTPCR) assays. We investigated the avian spleen for daily and circadian control of core clock genes and regulation of the inflammatory response by the spleen clock. The core clock genes, bmal1, bmal2, per2, per3 and clock displayed both daily and circadian rhythms. Proinflammatory cytokines TNFα, IL-1β, IL-6 and IL-18 exhibited daily and circadian rhythmic oscillations. A differential expression of proinflammatory cytokine induction was observed in the spleen undergoing lipopolysaccharide (LPS)-induced acute inflammation. Exogenous melatonin administration during inflammation seems to enhance some and repress a few inflammatory cytokines, implying that melatonin is pleiotropic molecule. To compare and contrast the role of peripheral clocks in regulating energy balance and reproduction in layer vs. broiler chicken, the visceral adipose tissue (VAT), ovary and hypothalamus were examined for the presence of core clock genes were investigated in these two lines of poultry birds. Quantitative RT-PCR was employed to examine daily control of core clock genes in these three peripheral tissues over a 24hr period. The layer hens exhibit rhythmic oscillations in the mRNA abundance of the core clock genes in the VAT, ovary and the hypothalamus. The hypothalamus and VAT of the broiler hens exhibit rhythmic mRNA abundance of the core clock genes. However, the clock genes in the ovary of the broiler pullets exhibit marked reduction in their amplitude and rhythms over a 24hr period. The broiler hens are prone to poor energy balance, obesity and reproductive capacity. In summary, these data provide evidence for a functional link between the circadian clock and the ovary by determining clock gene regulation under conditions of disrupted or eliminated reproductive function vs. normal reproductive output.

No description available.

Type II diabetes mellitus is currently on the rise and reaching epidemic proportions in the United States. In addition to this increase, the number of cases of diabetic complication such as kidney disease has increased. Currently diabetic kidney disease is the leading cause for end stage renal disease in the United States accounting for nearly half of all cases. Type II diabetes is the result of metabolic, hemodynamic and inflammatory alterations within the body. Currently there is a standard of care to treat both metabolic and hemodynamic perturbations by enforcing tight glycemic control and utilizing anti-hypertensive drugs, most notably RAS inhibitors. These therapeutic interventions however, are not sufficient as many patients with type II diabetes will still develop diabetic kidney disease therefore another treatment option is imperative. Currently there are no treatments available to counteract the adverse inflammatory responses associated with type II diabetes which are strong contributors to the progression of the diabetic kidney disease. Among the inflammatory parameters studied as potential targets for therapeutic intervention the inflammatory cytokine tumor necrosis factor-α (TNF-α) stands out among the rest for its multifaceted role in disease progression. TNF-α has been shown to both directly and indirectly involved in development and progression of diabetic kidney disease. The inflammatory cytokine itself is toxic to renal cells initially increasing the permeability of the glomerular filtration barrier and contributing to proteinuria which eventually causes cellular apoptosis. TNF-α also activates second messengers and up-regulates transcription factors that further contribute to the progression of diabetic kidney disease. Two TNF-α inhibitors, pentoxifylline and chrysin have stood out among the other investigational drugs which have been studied as potential therapeutic options to delay the progression of diabetic kidney disease. Pentoxifylline is a methyl-xanthine derivative that is currently used to treat peripheral vascular disease. It has shown good effect in clinical trials decreasing both urinary TNF-α concentrations as well as urinary protein excretion. Chrysin is a natural plant derivative belonging to the flavonoid family and is known for its anti-inflammatory and anti-oxidant properties. Currently chrysin has only been studied in animal models of diabetic kidney disease but has shown to not only decrease concentrations of inflammatory cytokines to control levels and improve renal functions but also prevented the histopathological changes associated with diabetic kidney disease suggesting that chrysin has the ability to not only slow the progression of disease and preserve renal function, it has the ability to prevent the disease from ever taking root. Diabetic kidney disease is a devastating disease affecting millions of people worldwide. It is important for further investigation with these investigational drugs to be performed in large scale clinical trials to produce safety and efficacy data with the end goal of becoming approved as new treatments for diabetic kidney disease.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23079号 / 医博第4706号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 道行, 教授 稲垣 暢也, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Peritoneal adhesions occur in up to 93% of adults after peritoneal trauma during surgery. Most adhesions are asymptomatic but can cause female infertility, small bowel obstruction (SBO) and chronic abdominal pain. Adhesion prophylaxis is needed to reduce the significant morbidity and increased health care costs resulting from peritoneal adhesions. This thesis aims to establish a relevant and reproducible experimental adhesion model to simultaneously study the healing processs and adhesion formation and later to examine whether carbazate-activated polyvinyl alcohol (PVAC), an aldehyde-carbonyl scavenger, can reduce adhesion formation or not; and, in a long-term follow-up, to investigate the incidence of and identify risk factors for adhesive SBO requiring surgical treatment after laparotomy during infancy and to survey the prevalence of self-reported chronic abdominal pain and female infertility. Male Sprague-Dawley rats were subjected to laparotomy, cecal abrasion, and construction of a small bowel anastomosis and examined at various time points after surgery. Early elevation of IL-6, IL-1β and TNF-α concentrations in peritoneal fluid but not in plasma correlate to adhesion formation in this rodent adhesion model, indicating that anti-adhesion treatment should be early, local and not systemic. The animals were treated with either peritoneal instillation of PVAC, or the anastomosis was sutured with PVAC-impregnated resorbable polyglactin sutures. At day 7, bursting pressure of the anastomosis was measured and adhesions were blindly evaluated using Kennedy- and Nair scoring systems. PVAC-impregnated sutures reduced adhesion formation without reducing bursting pressure. Infants who underwent laparotomy between 1976 and 2011 were identified (n=1185) and 898 patients were included with a median follow-up time of 14.7 (range 0.0-36.0) years. The median age at first laparotomy was 6 (range 1.0-365.0) days. There were 113 patients (12.6%) with adhesive SBO, with the highest incidence found in patients with Hirschsprung’s disease (19 of 65, 29%), malrotation (13 of 45, 29%), intestinal atresia (11 of 40, 28%) and necrotizing enterocolitis (16 of 64, 25%). Lengthy duration of surgery (hazard ratio (HR) 1.25, 95% CI, 1.07 to 1.45), stoma formation (HR 1.72, 1.15 to 2.56) and postoperative complications (HR 1.81, 1.12 to 2.92) were independent risk factors. Chronic abdominal pain was reported in 180 (24.0%) of 750 patients, and 17 (13.8%) of 123 women reported infertility. The morbidity after laparotomy in neonates and infants is high. Awareness of the risk factors may promote changes in surgical practice.

A number of investigators have examined psychological stress-induced endothelial dysfunction, however, the underlying mechanisms for these responses have not been clearly elucidated. The purpose of this study was to compare the effects of mental challenge on forearm blood flow, total antioxidant capacity (a measure of oxidative stress), the release of norepinephrine (NE; stress induced neurotransmitter), and pro-inflammatory cytokine responses [both lipopolysaccharide (LPS)-stimulated TNF-α and IL-6 cytokine and mRNA] in lean and obese individuals. Twelve subjects who had a BMI above 30 kg/m2 and were above 30% body fat were categorized as obese and twelve subjects with a BMI below 25 kg/m2 and were below 25% body fat were categorized as lean subjects. Blood samples were drawn and forearm blood flow was assessed prior to and following subjects’ participation in a mental challenge protocol consisting of a computer-based Stroop Color-Word task and mental arithmetic task, for a total of 20 minutes. The mental challenge elicited an elevation in HR and NE in both the lean and obese groups. Furthermore, both lean and obese groups demonstrated an increase in FBF following the mental challenge, whereas no changes in total antioxidant capacity were observed. In addition, the lean group exhibited an increase in LPS-stimulated TNF-α cytokine production from baseline to following the mental challenge, whereas the obese group demonstrated a decrease in LPS-stimulated TNF-α cytokines. This corresponded with a decrease in LPS-stimulated TNF-α mRNA expression in the obese group, although the obese subjects maintained higher levels of both measurements (LPS-stimulated TNF-α cytokine and mRNA expression) compared with the lean group. Furthermore, in the LPS-stimulated IL-6 cytokine response, the obese group demonstrated a greater increase than the lean group following the mental challenge, even though both groups showed an increase in LPS-stimulated IL-6 mRNA expression. These findings suggest that the magnitude and direction of LPS-stimulated TNF-α cytokine response and mRNA expression and LPS-stimulated IL-6 cytokine response to acute stress may be dependent upon the effects of the additional percentage of body fat seen in obese individuals.