Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr−/− Mice

Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia cepacia (genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs of Cftr (m1unc-/-) (Cftr(-/-)) and congenic Cftr(+/+) controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptible Cftr(-/-) mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from the Cftr(-/-) mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages from Cftr(-/-) mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF.     

Elevated Serum IL-21 Levels in Hantavirus-Infected Patients Correlate with the Severity of the Disease

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral infection caused by Hantavirus (HTV). Capillary leakage is one of the hallmarks of HTV infection. The mechanisms underlying the pathogenesis of HFRS are not completely understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. In this study, we investigated the potential role of interleukin-21 (IL-21) which is a newly discovered cytokine that stimulates T-cell and B-cell responses in the pathogenesis of HFRS. Serum samples were collected from 58 patients hospitalized with laboratory-verified HTV infection and 20 healthy controls. Serum IL-21 concentration was measured using an enzyme-linked immunosorbent assay. Serum IL-21 levels began to increase in the fever phase when renal damage appeared. The highest serum IL-21 level was detected in oliguric phase along with the peak degree of urinary renal impairment. When entering the polyuric phase, with gradual increase in urine and recovered renal function, the serum IL-21 level was observed to fall, returning to normal level after the renal function recovered in the convalescent phase. The serum IL-21 level was positively correlated with blood urea nitrogen (BUN) and creatinine (Cr), suggesting that the serum IL-21 level is associated with the disease severity of HFRS. This study indicated that IL-21 may act as an important inflammatory mediator in the immunopathogenesis of HFRS. The strategy to control IL-21 may hamper the immune response in patients with HFRS.     

Clinical Implications of Routine Monitoring of Pulmonary Function and Ventilation in Patients with Duchenne Muscular Dystrophy

PurposeTo investigate the effect of regular monitoring of pulmonary function and ventilatory status on the initiation of non-invasive ventilation (NIV) between patients who were routinely monitored before receiving NIV and those who were not.Materials and MethodsThis retrospective cohort study included subjects with Duchenne muscular dystrophy (DMD) who first received NIV between 2010 and 2019. The subjects were assigned to either the regular-follow-up (REG) group or the non-REG group, according to their follow-up status, before initiating NIV. We compared the number of emergent cases, the results of nocturnal ventilatory monitoring, and the pulmonary function of each group at initial ventilatory support.ResultsIn total, 73 subjects were enrolled in the REG group and 47 subjects in the non-REG group. There were significantly more emergency cases due to respiratory insufficiency in the non-REG group (12/47, 25.5%) than in the REG group (3/73, 4.1%). At the time of initial ventilatory support, hypoventilatory symptoms were more common and relatively severe in the non-REG group (37/47, 78.7%) than in the REG group (18/73, 24.7%). The average age at initial ventilatory support of the non-REG group was 2.15 years older than that of the subjects in the REG group. Moreover, subjects who were not regularly monitored exhibited greater deterioration in pulmonary function compared to those who were regularly followed up.ConclusionRegular evaluation of pulmonary function and ventilatory status before the onset of ventilatory insufficiency is crucial to reduce the risk of patients with DMD requiring emergency care due to ventilatory insufficiency.     

Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses

Purpose

The human antibody repertoire forms in response to infections, the microbiome, vaccinations, and environmental exposures. The specificity of such antibody responses was compared among a cohort of toddlers to identify differences between seropositive versus seronegative responses.

Methods

An assessment of the serum IgM and IgG antibody reactivities in 197 toddlers of 1- and 2-years of age was performed with a microfluidic array containing 110 distinct antigens. Longitudinal profiling was done from years 1 to 2. Seropositivity to RNA and DNA viruses; bacteria; live attenuated, inactive, and subunit vaccines; and autoantigens was compared. A stratification was developed based on quantitative variations in the IgG responses. Clinical presentations and previously known genetic risk alleles for various immune system conditions were investigated in relation to IgG responses.

Results

IgG reactivities stratified toddlers into low, moderate, and high responder groups. The high group (17%) had elevated IgG responses to multiple RNA and DNA viruses (e.g., respiratory syncytial virus, Epstein-Barr virus, adenovirus, Coxsackievirus) and this correlated with increased responses to live attenuated viral vaccines and certain autoantigens. This high group was more likely to be associated with gestational diabetes and an older age. Genetic analyses identified polymorphisms in the IL2RB, TNFSF4, and INS genes in two high responder individuals that were associated with their elevated cytokine levels and clinical history of eczema and asthma.

Conclusion

Serum IgG profiling of toddlers reveals correlations between the magnitude of the antibody responses towards viruses, live attenuated vaccines, and certain autoantigens. A low responder group had much weaker responses overall, including against vaccines. The serum antibody screen also identifies individuals with IgG responses to less common infections (West Nile virus, parvovirus, tuberculosis). The characterization of the antibody responses in combination with the identification of genetic risk alleles provides an opportunity to identify children with increased risk of clinical disease.

     

Inhibin- A and Pro-αC Are Elevated in Preeclamptic Pregnancy and Correlate with Human Chorionic Gonadotropin

PROBLEM: Serum concentrations of the heterodimeric glycoprotein inhibin-A (α-β_A) and its α-subunit increase during pregnancy. The placenta is the predominant source of inhibin during pregnancy, and a paracrine role in the trophoblast has been suggested. Elevated serum concentrations of inhibin α-subunit as well as the glycoprotein human chorionic gonadotropin (hCG) have been described in preeclamptic pregnancy. The objectives of this investigation were to compare serum concentrations of inhibin-A and inhibin pro-αC in preeclamptic and normotensive pregnancy, and to examine the relationship of hCG and inhibin-A in those pregnancies. METHOD OF STUDY: A case-control design using 32 patients with preeclampsia with a single fetus at 32–40 weeks of gestation and 34 gestation age-matched normotensive control subjects was used for this investigation. Solid-phase enzyme-linked immunosorbent assays were used to measure inhibin-A and inhibin pro-αC in sera. An immunoradiometric assay was used to measure intact hCG. RESULTS: Inhibin-A and inhibin pro-αC concentrations were significantly elevated in the sera of women with preeclampsia compared with those concentrations in normotensive control subjects (P < 0.05). A relationship of inhibin-A or pro-αC with severity of preeclampsia was not observed. There was a significant positive correlation of serum hCG with both inhibin-A and pro-αC (P < 0.05). CONCLUSIONS: Levels of inhibin-A and the subunit pro-αC are increased in pregnancies complicated by preeclampsia. These findings are potentially the effect of a paracrine role of inhibin-A in the development and proliferation of the trophoblast.     

Characterization of Monoclonal Antibodies to Calpain 3 and Protein Expression in Muscle from Patients with Limb-Girdle Muscular Dystrophy Type 2A

Monoclonal antibodies were raised to two regions of calpain 3 (muscle-specific calcium-activated neutral protease), which is the product of the gene that is defective in limb-girdle muscular dystrophy type 2A. The antibodies produced characteristic patterns of bands on Western blots: normal calpain 3 protein was represented by bands at 94 kd, plus additional fragments at ~60 or 30 kd, according to the antibody used. Specificity was confirmed by the loss of all bands in patients with null gene mutations. The “normal” profile of bands was observed in muscle from 33 control subjects and 70 disease-control patients. Calpain 3 protein was found to be extremely stable in fresh human muscle, with full-size protein being detected 8 hours after the muscle had been removed. Blots of muscle from nine limb-girdle muscular dystrophy type 2A patients with defined mutations showed variation in protein expression, with seven showing a clear reduction in the abundance of protein detected. No simple relationship was found between the abundance and clinical severity. Two patients showed normal expression of the full-size 94 kd band accompanied by a clear reduction in the smaller fragments. This pattern was also observed in one patient with an undefined form of limb-girdle dystrophy. These results indicate that immunodiagnosis is feasible, but caution will need to be exercised with the interpretation of near-normal protein profiles.     

Elevated Serum Resistin in Juvenile IdiopathicArthritis: Relation to Categories and Disease Activity

Background

Juvenile Idiopathic Arthritis (JIA) is one of the more common chronic diseases of childhood that often persists into adulthood and can result in significant long-term morbidity, including physical disability. The aim of the present study was to assess the serum level of resistin in JIA patients and compare its levels according to the categories, clinical manifestations and disease activity.

Methods

Sixty-eight JIA patients and 33 age and sex matched control children were included in the present study. All patients included in this study were subjected to full history taking, clinical examination. Juvenile arthritis disease activity score in 27 joints (JADAS-27) was calculated and Childhood Health Assessment Questionnaire (CHAQ) was used to measure the functional status. Serum resistin levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results

The mean serum resistin was significantly higher in the JIA patients (4.01?±?2.46 ng/ml) compared to the control (2.08?±?1.23 ng/ml) (p?<?0.001) especially those with systemic-onset. Its level was significantly higher in those receiving steroids and those with a positive antinuclear antibody. Resistin significantly correlated with the JADAS27 (r 0.26, p 0.035) and CHAQ (r 0.4, p 0.001). The JIA patients were 50 females and 18 males; however, the level of resistin was insignificantly different according to the gender although there was a tendency to be higher in females.

Conclusion

Our results reinforce the proposition of an important role for resistin in JIA and may be considered an interesting biomarker for disease activity especially those with systemic onset.     

Lung Chitinolytic Activity and Chitotriosidase Are Elevated in Chronic Obstructive Pulmonary Disease and Contribute to Lung Inflammation

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and emphysematous alveolar destruction. In this study, we have investigated whether chitotriosidase (ChTRase) and acidic mammalian chitinase, two chitinases with chitinolytic activity, are selectively augmented in COPD and contribute to its pathogenesis. We found that smokers with COPD, but not asthmatics, had higher chitinolytic activity and increased levels of ChTRase in bronchoalveolar lavage, more ChTRase-positive cells in bronchial biopsies, and an elevated proportion of alveolar macrophages expressing ChTRase than smokers without COPD or never-smokers. ChTRase accounted for approximately 80% of bronchoalveolar lavage chitinolytic activity, while acidic mammalian chitinase was undetectable. Bronchoalveolar lavage chitinolytic activity and ChTRase were associated with airflow obstruction and emphysema and with the levels of interleukin (IL)−1β, IL-8, tumor-necrosis factor (TNF)-α, and its type II soluble receptor. Tumor necrosis factor-α stimulated ChTRase release only from alveolar macrophages from smokers with COPD, and exposure of these cells to ChTRase promoted the release of IL-8, monocyte-chemoattractant protein-1, and metalloproteinase-9. Finally, ChTRase overexpression in the lung of normal mice promoted macrophage recruitment and the synthesis of the murine homologue of IL-8, keratinocyte-derived cytokine, and of monocyte-chemoattractant protein-1. We conclude that pulmonary ChTRase overexpression may represent a novel important mechanism involved in COPD onset and progression.Chronic obstructive pulmonary disease (COPD), a debilitating respiratory condition, is a significant cause of morbidity, mortality, and health care costs worldwide and its global burden is increasing.¹ The defining feature of COPD is irreversible airflow limitation measured during forced expiration, caused by either an increase in airway resistance, or in lung compliance due to emphysematous lung destruction, or both.¹ A dominant hallmark of COPD is an abnormal inflammatory response to inhaled particles and this has the potential to produce lung injury.^1,2,3 Recent data suggest that emphysema results from an exaggerated synthesis, predominantly by neutrophils and macrophages, of serine and cysteine proteases and matrix-degrading metalloproteinases (MMPs), enzymes that promote cell activation and injury and that degrade connective tissue components.^3,4,5Recently, a family of enzymes named chitinases has been identified in humans and rodents.⁶ These enzymes are endo-β-1,4-N-acetylglucosamidases that degrade chitin, an abundant wall- and exoskeleton-derived polysaccharide that protects nematodes, fungal cells, and insects from the animal and plant hosts that they invade.^7,8 Although chitin does not have a mammalian counterpart, elevated chitinolytic activity and prominent expression of the two chitinases that catalyze the hydrolysis of chitin, namely chitotriosidase (ChTRase) and acidic mammalian chitinase (AMCase), have been associated with pathological conditions that are characterized by tissue inflammation and remodeling, including atherosclerosis and asthma.^9,10,11In the present study, we investigated whether chitinolytic activity and the expression of ChTRase and AMCase are augmented in the airways of patients with COPD and whether they contribute to inflammatory and remodeling responses by activating alveolar macrophages, an important orchestrator of these responses.⁵ We found that chitinolytic activity was elevated in the airways of patients with COPD, and that the majority of this activity was accountable by ChTRase, but not AMCase. Moreover, ChTRase activated the synthesis of pro-inflammatory and remodeling chemokines and metalloproteinases by alveolar macrophages and its overexpression in the airways of normal mice induced macrophage recruitment and up-regulated the levels of pro-inflammatory and fibrogenic chemokines that have been implicated in the pathogenesis of COPD. Taken together, these findings demonstrate that COPD is characterized by elevated levels of ChTRase and suggest that this chitinase contributes to disease pathogenesis and progression.     

Increased Myeloperoxidase Activity and Protein Nitration Are Indicators of Inflammation in Patients with Chagas' Disease

In this study, we investigated whether inflammatory responses contribute to oxidative/nitrosative stress in patients with Chagas'' disease. We used three tests (enzyme-linked immunosorbent assay, immuno-flow cytometry, and STAT-PAK immunochromatography) to screen human serum samples (n = 1,481) originating from Chiapas, Mexico, for Trypanosoma cruzi-specific antibodies. We identified 121 subjects who were seropositive for T. cruzi-specific antibodies, a finding indicative of an 8.5% seroprevalence in the rural population from Chiapas. Seropositive and seronegative subjects were examined for plasma levels of biomarkers of inflammation, i.e., myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and xanthine oxidase (XOD), as well as for oxidative (advanced oxidation protein products [AOPPs]) and nitrosative (3-nitrotyrosine [3NT]) biomarkers. The seropositive subjects exhibited a significant increase in MPO activity and protein level, the indicator of neutrophil activation. Subsequently, a corresponding increase in AOPP contents, formed by MPO-dependent hypochlorous acid and chloramine formation, was noted in seropositive subjects. The plasma level of 3NT was significantly increased in seropositive subjects, yet we observed no change in XOD activity (O₂⁻ source) and nitrate/nitrite contents (denotes iNOS activation and NO production), which implied that direct peroxynitrite formation does not contribute to increased nitrosative damage in chagasic subjects. Instead, a positive correlation between increased MPO activity and protein 3NT formation was observed, which suggested to us that MPO-dependent formation of nitrylchloride that occurs in the presence of physiological NO and O₂⁻ concentrations contributes to protein nitration. Overall, our data demonstrate that T. cruzi-induced neutrophil activation is pathological and contributes to MPO-mediated collateral protein oxidative and nitrosative damage in human patients with Chagas'' disease. Therapies capable of suppressing MPO activity may be useful in controlling the inflammation and oxidative/nitrosative pathology in chagasic cardiomyopathy.Trypanosoma cruzi, the causative agent of Chagas’ disease, is reported to infect 28 million individuals throughout Latin America (47). Infected individuals, after immune control of acute parasitemia, remain seropositive and clinically asymptomatic. Several years after infection, ∼30% of infected patients develop symptomatic chronic disease, which presents with a progressive cardiac and/or digestive pathology (31). The mechanism(s) of evolution of the clinical form of Chagas’ disease is not known (19).In vitro and in vivo studies with experimental models have shown that infection by T. cruzi elicits both proinflammatory responses and reactive oxygen species (ROS) that appear essential for control of the parasite (reviewed in references 14 and 48). Reactive oxidants are generated as a consequence of an “oxidative burst” of phagocytic cells (e.g., macrophages and neutrophils) activated by T. cruzi infection (8). NADPH oxidase, activated in all phagocytic cells, produces superoxide (O₂⁻) (1, 11). Endothelial activation of xanthine oxidase (XOD) in response to T. cruzi infection also results in increased O₂⁻ production via oxidation of hypoxanthine to xanthine and uric acid (3, 17). Superoxide spontaneously recombines with other molecules to produce other free radicals (e.g., H₂O₂ and OH) that exert cytotoxic effects via modifications of DNA, protein, and lipids (7, 23). Myeloperoxidase (MPO), a heme enzyme, is released by activated neutrophils into the extracellular milieu, where it uses H₂O₂ and chloride anion (Cl⁻), forming hypochlorous acid (HOCl) (20, 44). HOCl is a powerful oxidant and reacts with amines to form chloramines.Besides ROS, activated macrophages produce nitric oxide (NO) via the inflammatory activation of inducible nitric oxide synthase (iNOS) in response to T. cruzi infection (27). NO, produced in abundance by iNOS, directly reacts with O₂⁻ to form peroxynitrite (ONOO⁻) and peroxynitrous acid (ONOOH), which have been shown to kill T. cruzi (36). Alternatively, nitrite (NO₂⁻), a major product derived from NO, may be oxidized by MPO to nitrogen dioxide (NO₂), which may further react with HOCl to form the highly reactive compound nitryl chloride (NO₂Cl) (5).The cytotoxic ROS and reactive nitrogen species cause collateral damage to host cellular components. For example, ONOO⁻-mediated increased protein 3-nitrotyrosine (3NT) formation is detected in the plasma and heart of mice infected by T. cruzi (13, 27). We have found increased plasma and cardiac levels of protein carbonyls and malonyldialdehydes (MDA; lipid peroxidation markers) in mice and rats infected by T. cruzi (13, 40). A substantial increase in the plasma level of MDA, in association with inefficient glutathione antioxidant defense, has been documented for seropositive patients with Chagas'' disease (12, 41).In this study, we have investigated the role of inflammatory mediators (e.g., MPO, XOD, and iNOS) in the elicitation/sustenance of oxidative/nitrosative stress in human patients with Chagas'' disease. Our data demonstrate that the activated expression and activity of MPO are positively correlated with increased protein oxidation and nitration in seropositive subjects and suggest that MPO is the major cause of collateral damage through protein modification in humans with Chagas'' disease.     

Increased Levels of Antibodies to IFN-γ in Human and Experimental African Trypanosomiasis

In African trypanosomiasis the occurrence of antibodies to interferon-γ (IFN-γ) was studied in both humans and experimental rats. Sera from patients infected with Trypanosoma brucei gambiense showed increased levels of antibodies to IFN-γ as compared with controls from the same regions in Africa. In Sprague-Dawley rats infected with Trypanosoma brucei brucei an early appearance of IFN-γ-producing spleen cells was observed, followed by an increase in levels of antibodies against IFN-γ in the sera. Previously, IFN-γ has been found to play a crucial role in trypanosome infections in rats by promoting proliferation of Trypanosoma brucei brucei . The appearance of antibodies to IFN-γ in humans, as in rats, indicates that this cytokine is produced also in the human infection. Its parasitic growthstimulating and pathophysiological effects on the organism may be reduced by the antibodies.     

Serum Antibodies Positivity to 12 Helicobacter pylori Virulence Antigens in Patients with Benign or Malignant Gastroduodenal Diseases – Cross-sectional Study

Aim

To investigate the association of gastric histological and endoscopic findings in patients with Helicobacter pylori (H. pylori), according to presence of seropositivity to 12 bacterial virulence antigens.

Methods

This is a cross-sectional single-center study of 360 consecutive outpatients referred in the period of one year to upper gastrointestinal endoscopy because of dyspeptic complaints. Patients sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens – p120 (CagA – cytotoxin-associated antigen), p95 (VacA – vacuolating cytotoxin), p67 (FSH – flagellar sheath protein), p66 (UreB – urease enzyme heavy subunit), p57 (HSP homologue – heath shock protein homologue), p54 (flagellin), p33, p30 (OMP – outer membrane protein), p29 (UreA – urease enzyme light subunit), p26, p19, and p17. Upper gastrointestinal endoscopy was performed, endoscopic diagnosis recorded, and 4 mucosal biopsy samples were obtained and assessed according to Updated Sydney protocol.

Results

The sera of 207 patients were analyzed. Thirty patients had gastric adenocarcinoma, 126 peptic ulcers, and 51 normal finding. p120 (CagA) seropositivity was significantly more often present in patients with higher activity grade in the antrum (P = 0.025), p30 in patients with greater inflammation in the antrum (P = 0.025) and the corpus (P = 0.010), p33 in patients with greater inflammation in the corpus (P = 0.050), and p19 (OMP) in patients with lower intestinal metaplasia grades in the corpus (P = 0.025). Seroreactivity to all other bacterial proteins showed no association with the histological status of the stomach mucosa. Except for the seropositivity to protein p95 (VacA), which was more often present in patients with duodenal ulcer (P = 0.006), there was no difference in seroreactivity to other bacterial proteins and upper gastrointestinal endoscopic findings.

Conclusions

p120 (CagA), p33, p 30 (OMP), and p19 (OMP) seropositivity was more often present in patients with higher grades of the histological parameters of gastritis and seropositivity to protein p95 (VacA) with endoscopic presence of duodenal ulcer. Histological parameters of gastritis are more associated with bacterial virulence than endoscopic findings.Helicobacter pylori (H. pylori) is recognized as a major gastric pathogen with worldwide distribution (1). Estimated prevalence of H. pylori infection in Croatia is 60.4% (2). The persistent colonization induces gastritis and in some patients peptic ulcer disease, atrophic gastritis, or gastric carcinoma (3). However, most of patients infected with H. pylori never develop cancer or ulcer disease and there is a need to identify additional factors that may influence the risk for development of such diseases. The outcome of H. pylori infection is associated with specific (virulence associated) bacterial genotypes, environmental factors, and host’s immune status (4). A number of putative virulence factors for H. pylori infection have been identified, including CagA (cytotoxin-associated antigen), VacA (vacuolating cytotoxin), IceA (induced by epithelium antigen), BabA (blood-group antigen-binding adhesin), etc. It is likely that every other factor that results in increased inflammation will also consequently increase the risk of a disease occurrence.Presently, the only reliable way to identify the disease associated with H. pylori infection remains endoscopic examination combined with histological assessment of the gastric mucosa (5). The bacterial virulence antigens elicit specific antibodies during infection. However, the value of these antibodies as predictive factors for the severity of the disease remains controversial (6-15). So far, several investigations on the subject have been done, such as detecting the level, specificity, or presence of isotypes of serum H. pylori antibodies (16-22). Because disease outcome depends on both the strain characteristics and the host’s response, the serum antibody response to virulence antigens could provide clues in predicting the presence and severity of associated diseases (23,24). On the other hand, since subjects without manifest disease also have strains bearing this or other virulence antigens, it seems that the disease could not be attributed to one virulence antigen alone. Thus, other virulence antigens may also be important. The exact role of other bacterial virulence antigens – p67 (FSH – flagellar sheath protein), p66 (UreB – urease enzyme heavy subunit), p57 (HSP homologue – heath shock protein homologue), p54 (flagellin), p33, p30 (OMP – outer membrane protein), p29 (UreA – urease enzyme light subunit), p26, p19 (OMP), and p17 in the pathogenesis of gastrointestinal diseases is still unclear.In this study, we aimed to investigate the association of gastric histological and endoscopic findings in H. pylori-positive patients according to presence of seropositivity to 12 bacterial virulence antigens. Since both bacterial virulence antigens and pattern of H. pylori gastritis may contribute to development of clinically relevant gastroduodenal disease, we wanted to determine the antibodies which are most associated with higher grades of histology findings of gastritis, atrophy, or intestinal metaplasia and different clinical diseases (peptic ulcer, gastric cancer, and non-ulcer dyspepsia).     

Increased inflammation and lethality of Dusp1−/− mice in polymicrobial peritonitis models

The mitogen-activated protein kinase phosphatase Dusp1 (also known as MKP-1) is essential for control of the inflammatory response to systemic challenge with the lipopolysaccharide of Gram-negative bacteria. Here, we have investigated the consequences of Dusp1-deficiency in colon ascendens stent peritonitis (CASP) and caecal ligation and puncture (CLP), two mouse models of septic peritonitis. Following CASP, Dusp1^−/− mice had increased serum levels of CCL4, interleukin-10 (IL-10) and IL-6, with differences from wild-type mice being dependent on severity of sepsis. These cytokines, along with inducible nitric oxide synthase messenger RNA, were also expressed at higher levels in spleen and liver. Similar over-production of these cytokines was detected in the CLP model, with even larger differences from wild-type mice. Despite the increased inflammatory response, bacterial clearance was impaired in Dusp1^−/− mice subjected to CASP and CLP. Dusp1^−/− mice suffered increased lethality in both peritonitis models. Together our data indicate that exaggerated inflammatory responses to gut bacteria introduced into the peritoneum in the absence of Dusp1 do not help to control bacterial replication but are detrimental for the host.     

血清尿酸在冠心病患者中的变化及意义

目的 探讨血清尿酸水平与冠心病的关系.方法 经冠状动脉造影确诊的冠心病患者(冠心病组)95例和非冠心病患者(对照组)72例,冠心病组又分为单支病变亚组(40例)、双支病变亚组(32例)和三支病变亚组(23例),均测定血清尿酸水平.结果 冠心病组血清尿酸水平显著高于对照组(P＜0.01),双支病变亚组和三支病变亚组血清尿酸水平均显著高于单支病变亚组(P＜0.05;P＜0.01).结论 血清尿酸水平与冠心病密切相关,且随冠心病病情严重程度而增加,高尿酸血症是冠心病的一个危险因素.     

Elevated Serum Anti-Saccharomyces cerevisiae, Anti-I2 and Anti-OmpW Antibody Levels in Patients with Suspicion of Celiac Disease

OBJECTIVES: Expression of anti-Saccharomyces cerevisiae antibodies (ASCA) identifies patients and individuals at risk for Crohn's disease and has also been reported in 40-60% of celiac disease (CD) cases, suggesting a role of host response to enteric microbiota in the development of inflammatory lesions. In this prospective study in patients with suspicion of CD, we evaluate the frequency and association of ASCA to serological responses for other host microbial targets formally associated with Crohn's disease, including the Pseudomonas fluorescens associated sequence I2 and a Bacteroides caccae TonB-linked outer membrane protein, OmpW. METHODS: Small bowel mucosal biopsies were taken from 242 patients with suspicion of CD, their sera were tested for antibodies to tissue transglutaminase (tTG), ASCA, I2, and OmpW. Eighty adult healthy blood donors were used as controls. RESULTS: The diagnosis of CD was confirmed on biopsy in 134 cases. The occurrence of ASCA and I2 positivity was significantly higher in adult CD patients than in patients with non-CD disease. Anti-I2 levels in the sera were significantly higher in adult CD patients than in non-CD disease or the controls and anti-OmpW levels in CD and non-CD patients when compared to controls. Positive seroreactivity to OmpW seemed to increase with age. Of the CD patients, 90% were seropositive for at least one microbial antigen tested. CONCLUSIONS: This study demonstrates a mosaic of disease-related serological responses to microbial antigens in patients with CD. Immune responses to commensal enteric bacteria may play a role in the small intestine mucosal damage in CD.