The relationship between oral contraceptives and pelvic inflammatory disease: Policy implications and recommendations

One of the most widely accepted noncontraceptive benefits of oral contraceptive use is the reduction in the development of pelvic inflammatory disease (PID) and its sequelae in users. While much of the research over the past forty years has found an association between oral contraceptive use and reduced rates of PID [Senanayake, 1980], more recent studies have qualified and even challenged this widely held belief. [Henry-Suchet, 1997; Ness 1997; Ness, 2001] PID, an infection in the upper genital tract causing infertility and ectopic pregnancy, affects over one million women in the United States each year, exacting an enormous toll on women's reproductive and emotional health, as well as our economy. [CDC Factsheet, 2007] This thesis examines the public health implications of pelvic inflammatory disease and the use of oral contraceptives. Sixteen original studies are reviewed and analyzed, thirteen of which found a protective benefit with oral contraceptive use against PID and three more recent studies which found no protective benefit or association between oral contraceptive use and PID. Analysis of the research findings suggests a need for additional research, provider and patient education, and an increased government role in addressing the ongoing and significant public health concerns raised by current rates of Chlamydia- and gonorrheal-PID. ^

Risk factors and inflammatory markers in pouchitis

Individuals who do not respond to medical therapy for ulcerative colitis (UC) often undergo proctocolectomy followed by ileal-pouch anal anastomosis (IPAA) in hopes of resolving symptoms associated with UC. Inflammation of the ileal pouch, better known as pouchitis, is the most common complication of the IPAA procedure. The causes and development of pouchitis is not well understood. To better understand pathogenesis of pouchitis, pouch aspirates of patients having undergone IPAA were quantitatively analyzed for fecal IL-8, IL-17, and IL-23 levels. According to published literature IL-8 has been linked to pouchitis whereas IL-17 and IL-23 are associated with intestinal inflammation. The study had 80 participants, 33 patients diagnosed with Crohn's Disease (CD) of the pouch, 19 patients diagnosed with pouchitis, and 28 diagnosed with having normal pouches. Patient characteristics and histopathological findings for all patients were noted and statistically compared in addition to fecal cytokine levels. This study supported previous literature that IL-8 production was associated with pouch inflammation. However, IL-17 and IL-23 levels in both CD of the pouch and pouchitis were not significantly different to the levels noted in normal pouch.^

T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6

An important signaling pathway for the differentiation of T helper type 2 (TH2) cells from uncommitted CD4 T cell precursors is activation of the STAT6 transcription factor by interleukin 4 (IL-4). The protooncogene BCL-6 is also involved in TH2 differentiation, as BCL-6 −/− mice develop an inflammation of the heart and lungs associated with an overproduction of TH2 cells. Surprisingly, IL-4 −/− BCL-6 −/− and STAT6 −/− BCL-6 −/− double-mutant mice developed the same TH2-type inflammation of the heart and lungs as is characteristic of BCL-6 −/− mice. Furthermore, a TH2 cytokine response developed in STAT6 −/− BCL-6 −/− and IL-4 −/− BCL-6 −/− mice after immunization with a conventional antigen in adjuvant. In contrast to these in vivo findings, STAT6 was required for the in vitro differentiation of BCL-6 −/− T cells into TH2 cells. BCL-6, a transcriptional repressor that can bind to the same DNA binding motifs as STAT transcription factors, seems to regulate TH2 responses in vivo by a pathway independent of IL-4 and STAT6.

On the etiology of Crohn disease.

Crohn disease (CD) is a chronic, panenteric intestinal inflammatory disease. Its etiology is unknown. Analogous to the tuberculoid and lepromatous forms of leprosy, CD may have two clinical manifestations. One is aggressive and fistulizing (perforating), and the other is contained, indolent, and obstructive (nonperforating) [Gi]-berts, E. C. A. M., Greenstein, A. J., Katsel, P., Harpaz, N. & Greenstein, R. J. (1994) Proc. Natl. Acad. Sci. USA 91, 12721-127241. The etiology, if infections, may be due to Mycobacterium paratuberculosis. We employed reverse transcription PCR using M. paratuberculosis subspecies-specific primers (IS 900) on total RNA from 12 ileal mucosal specimens (CD, n = 8; controls, n = 4, 2 with ulcerative colitis and 2 with colonic cancer). As a negative control, we used Myobacterium avium DNA, originally cultured from the drinking water of a major city in the United States. cDNA sequence analysis shows that all eight cases of Crohn's disease and both samples from the patients with ulcerative colitis contained M. paratuberculosis RNA. Additionally, the M. avium control has the DNA sequence of M. paratuberculosis. We demonstrate the DNA sequence of M. paratuberculosis from mucosal specimens from humans with CD. The potable water supply may be a reservoir of infection. Although M. paratuberculosis signal in CD has been previously reported, a cause and effect relationship has not been established. In part, this is due to conflicting data from studies with empirical antimycobacterial therapy. We conclude that clinical trials with anti-M. paratuberculosis therapy are indicated in patients with CD who have been stratified into the aggressive (perforating) and contained (nonperforating) forms.

A tract upon dyspepsy, or indigestion, and the hypochondriac disease : and upon the inflammatory or regular gout, and the atonic, irregular, or flying gout ... /

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Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease ( COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition ( Health ABC) study is a prospective observational cohort of well functioning individuals aged 70 - 79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease ( OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p< 0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p< 0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p< 0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 ( adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to -1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.

Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA

Celiac disease is characterized by the presence of specific autoantibodies targeted against transglutaminase 2 (TG2) in untreated patients' serum and at their production site in the small-bowel mucosa below the basement membrane and around the blood vessels. As these autoantibodies have biological activity in vitro, such as inhibition of angiogenesis, we studied if they might also modulate the endothelial barrier function. Our results show that celiac disease patient autoantibodies increase endothelial permeability for macromolecules, and enhance the binding of lymphocytes to the endothelium and their transendothelial migration when compared to control antibodies in an endothelial cell-based in vitro model. We also demonstrate that these effects are mediated by increased activities of TG2 and RhoA. Since the small bowel mucosal endothelium serves as a "gatekeeper" in inflammatory processes, the disease-specific autoantibodies targeted against TG2 could thus contribute to the pathogenic cascade of celiac disease by increasing blood vessel permeability.

LDL-Lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells:mitigation by statin intervention

Elevated LDL concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidative modification (oxLDL) and nitration is observed during dementia and hypercholesterolemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVEC) were maintained on transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naïve, normo- and hyperlipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40mg simvastatin intervention/day for three months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after three months. LDL isolated from statin-naïve hyperlipidaemic, AD and AD-plus subjects was more oxidised (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared to control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 Vs 3.95±0.2nmol/mg; P<0.001) and 8-isoprostane F2α (30.4±4.0 pg/ml Vs 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7nmol/mg protein) compared to untreated cells (23.8±1.2 vs nmol/mg protein). Basolateral IL-6 secretion was increased by LDL-lipids from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared to healthy subject lipids (18.6±3.6 pg/ml). LDL-Lipids isolated after statin intervention did not affect endothelial function. In summary, LDL-lipids from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVEC. In vivo intervention with statins reduces the damaging effects of LDL-lipids on HMVEC.

Mapping nitro-tyrosine modifications in fibrinogen by mass spectrometry as a biomarker for inflammatory disease

There is a growing awareness that inflammatory diseases have an oxidative pathology, which can result in specific oxidation of amino acids within proteins. It is known that patients with inflammatory disease have higher levels of plasma protein nitro-tyrosine than healthy controls. Fibrinogen is an abundant plasma protein, highly susceptible to such oxidative modifications, and is therefore a potential marker for oxidative protein damage. The aim of this study was to map tyrosine nitration in fibrinogen under oxidative conditions and identify susceptible residues. Fibrinogen was oxidised with 0.25mM and 1mM SIN-1, a peroxynitrite generator, and methionine was used to quench excess oxidant in the samples. The carbonyl assay was used to confirm oxidation in the samples. The carbonyl levels were 2.3, 8.72 and 11.5nmol/mg protein in 0, 0.25mM and 1mM SIN-1 samples respectively. The samples were run on a SDS-PAGE gel and tryptically digested before analysis by HPLC MS-MS. All 3 chains of fibrinogen were observed for all treatment conditions. The overall sequence coverage for fibrinogen determined by Mascot was between 60-75%. The oxidised samples showed increases in oxidative modifications in both alpha and beta chains, commonly methionine sulfoxide and tyrosine nitration, correlating with increasing SIN-1 treatment. Tyrosines that were most susceptible were Tyr135 (tryptic peptide YLQEIYNSNNQK) and Tyr277 (tryptic peptide GGSTSYGTGSETESPR), but several other nitrated tyrosines were also identified with high confidence. Identification of these susceptible peptides will allow design of sequences-specific biomarkers of oxidative and nitrative damage to plasma protein in inflammatory conditions.

Cardiopulmonary bypass down-regulates NOD signaling and inflammatory response in children with congenital heart disease

In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatorycytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients.

Dietary Inflammatory Index and Incidence of Cardiovascular Disease in the PREDIMED Study

[EN]Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevención con Dieta Mediterránea) study including 7216 high-risk participants.

Plasma inflammatory biomarkers response to aerobic versus resisted exercise training for chronic obstructive pulmonary disease patients.

Background: Chronic obstructive pulmonary disease (COPD) is a main risk for morbidity, associated with alterations in systemic inflammation. Recent studies proved that morbidity and mortality of COPD is related to systemic inflammation as it contributes to the pathogenesis of atherosclerosis and cardiovascular disease. However, increase of inflammatory cytokines adversely affects quality of life, alteration in ventilatory and skeletal muscles functions. Moreover, exercise training has many beneficial effects in correction of the adverse effects of COPD. Objective: This study aimed to compare the response of inflammatory cytokines of COPD to aerobic versus resisted exercises. Materials and methods: One hundred COPD diseased patients participated in this study and were randomly included in two groups; the first group received aerobic exercise, whereas the second group received resisted exercise training for 12 weeks. Results: The mean values of TNF-α, Il-2, IL-4, IL-6 and CRP were significantly decreased in both groups. Also; there was a significant difference between both groups at the end of the study with more reduction in patients who received aerobic exercise training. Conclusion: Aerobic exercise is more appropriate than resisted exercise training in modulating inflammatory cytokines level in patients with chronic obstructive pulmonary disease.