Mast cells are critical mediators of vaccine-induced Helicobacter clearance in the mouse model

BACKGROUND & AIMS: Despite the proven ability of immunization to prevent Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. METHODS: We explored the cellular events associated with Helicobacter clearance from the stomach following vaccination by flow cytometry analysis and histological and molecular studies. RESULTS: Kinetic studies showed that the infection is undetectable in vaccinated mice at day 5 postbacterial challenge. Flow cytometry analysis showed that the percentages of mast cells (CD3 - CD117 + ) increased in the lymphoid cells isolated from the stomach at day 4 postchallenge in urease + cholera toxin (CT)-vaccinated mice in comparison with mice administered with CT alone (9.4% +/- 4.4% and 3.1% +/- 1%, respectively, for vaccinated and CT administered, n = 5; P < .01). Quantitative PCR analysis showed an increased messenger RNA (mRNA) expression of the mast cell proteases 1 and 2 at day 5 postchallenge in the stomach of vaccinated mice. In contrast to wild-type mice, mast cell-deficient mice (W/W v mice) were not protected from H felis colonization after vaccination. Indeed only 1 out of 12 vaccinated W/W v mice showed a negative urease test. Remarkably, vaccinated W/W v mice reconstituted with cultured bone marrow-derived mast cells recovered the ability to clear the infection after vaccination (8 out of 10 mast cell-reconstituted mice showed negative urease tests [ P < .006 as compared with wild-type mice]). CONCLUSIONS: These experiments show that mast cells are, unexpectedly, critical mediators of anti- Helicobacter vaccination.     

Use of non-invasive cardiac investigations to predict clinical endpoints after coronary bypass graft surgery in coronary artery disease patients: results from the prognosis and evaluation of risk in the coronary operated patient (PERISCOP) study.

AIMS: Little is known about which patients who have undergone coronary bypass surgery are at risk of future clinical cardiovascular events and may benefit from further medical treatment. We sought to determine if routine non-invasive cardiac investigations performed early after surgery were able to stratify the risk of cardiovascular events in this population. METHODS: Two thousand and sixty-five consecutive patients were enrolled in a prospective multicenter study (PERISCOP). Exercise testing, echocardiography, and 24-h ambulatory ECG monitoring were performed at day 20+/-10 after coronary bypass surgery. Follow-up was performed 1 year after coronary bypass surgery. Causes of all hospitalisation and death occurring within 1 year were documented and classified by an End-point Committee. The principal endpoint was the combination of all-cause deaths and cardiovascular events requiring hospitalisation (myocardial infarction, unstable or severe angina, stroke, congestive heart failure). RESULTS: The 1-year frequency of first events was 155 (8%). In multivariate analysis, exercise duration <420s (RR=1.68; 95% CI: 1.13-2.49), exercise induced ST segment depression >1mm (RR=1.90; 95% CI: 1.18-3.05), and left ventricular (LV) dysfunction (wall motion index <1.15) (RR=1.97; 95% CI: 1.10-3.51) were independent predictors of cardiovascular events and deaths. Ambulatory ECG monitoring had no predictive value. CONCLUSIONS: Exercise testing and echocardiography performed early after coronary bypass surgery are able to identify high-risk patients who may benefit from intensive secondary prevention.     

High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation

BACKGROUND: Areas of complex fractionated atrial electrograms (CFAEs) have been implicated in the atrial substrate of atrial fibrillation (AF). The mechanisms underlying CFAE in humans are not well investigated. OBJECTIVES: The purpose of this study was to investigate the regional activation pattern associated with CFAE using a high-density contact mapping catheter. METHODS: Twenty patients with paroxysmal AF were mapped using a high-density multielectrode catheter. CFAE were mapped at 10 different sites (left atrium [LA]: inferior, posterior, roof, septum, anterior, lateral; right atrium [RA]: anterior, lateral, posterior, septum). Local atrial fibrillation cycle length (AFCL) was measured immediately before and after the occurrence of CFAE, and the longest electrogram duration (CFAEmax) was assessed. RESULTS: Longer electrogram durations were recorded in the LA compared with the RA (CFAEmax 118 +/- 21 ms vs 104 +/- 23 ms, P = .001). AFCL significantly shortened before the occurrence of CFAEmax compared with baseline (LA: 174 +/- 32 ms vs 186 +/- 32 ms, P = .0001; RA: 177 +/- 31 ms vs 188 +/- 31 ms, P = .0001) and returned to baseline afterwards. AFCL shortened by >or=10 ms in 91% of mapped sites. Two different local activation patterns were associated with occurrence of CFAEmax: a nearly simultaneous activation in all spines in 84% indicating passive activation, and a nonsimultaneous activation sequence suggesting local complex activation or reentry. CONCLUSION: Fractionated atrial electrograms during AF demonstrate dynamic changes that are dependent on regional AFCL. Shortening of AFCL precedes the development of CFAE; thus, cycle length is a major determinant of fractionation during AF. High-density mapping in AF may help to differentiate passive activation of CFAE from CFAE associated with an active component of the AF process.     

HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway

It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)     

Colonoscopy of acute colitis

Complications that might lead to surgery in severe attacks of ulcerative colitis have been found to be correlated with the depth of colonic ulcerations as measured by pathological examination of colectomy specimens. In order to evaluate the value of colonoscopy for the assessment of colonic ulcerations, we have reviewed the clinical, biological, colonoscopic, and anatomical findings in 85 consecutive patients with attacks of ulcerative colitis involving at least the rectosigmoid and part of the descending colon, seen in our center between 1981 and 1989. All had colonoscopy performed by a senior endoscopist at entry. Extensive deep colonic ulcerations were diagnosed in 46 of them, and moderate endoscopic colitis in 39. No complication related to colonoscopy occurred except for one colonic dilatation. Forty-three of the 46 patients with severe endoscopic colitis were operated upon: 38 of them failed to improve with high-dose corticosteroids and five had a toxic megacolon. Extensive ulcerations reaching at least the circular muscle layer were found at pathological examination of colectomy specimen in 42 of the 43 patients. Conversely, 30 of 39 patients with moderate endoscopic colitis went into clinical remission with medical treatment, and only nine patients needed further surgery because of medical treatment failure. Six of these nine patients underwent another colonoscopy prior to colectomy, and all six showed features of severe endoscopic colitis. Deep ulcerations reaching the circular muscle layer were found at pathological examination in five of these six patients and in one additional patient whose colonoscopy had been performed 21 days before colectomy. We conclude that, in expert hands, colonoscopy is safe and accurately selects patients with high risk of surgical complications who need early surgery in case of failure of medical treatment.     

Measurement of radiographic joint space width in the tibiofemoral compartment of the osteoarthritic knee: comparison of standing anteroposterior and Lyon schuss views

OBJECTIVE: To evaluate progression of joint space narrowing in radiographs of osteoarthritic (OA) knees imaged in both the standing anteroposterior (AP) and the Lyon schuss positions, using alternative methods to measure joint space width (JSW). METHODS: Standing AP (extended view) and Lyon schuss (posteroanterior [PA] view, with 20-30 degrees of flexion) radiographic images of 58 OA knees were obtained twice (at baseline and 2 years later). With both methods, fluoroscopy was used to align the anterior and posterior margins of the medial or lateral tibial plateau with the central x-ray beam. Minimum JSW, mean JSW, and joint space area (JSA) of the medial or lateral femorotibial joint space were measured using a new digital image analysis system. The effects of knee flexion versus extension and parallel versus nonparallel tibial plateau alignment were evaluated with respect to the reproducibility of JSW in repeated examinations (intraclass correlation coefficient [ICC]), the mean of within-knee standard deviations of repeated measurements (SD(m)), and the sensitivity to changes in JSW in serial radiographs (standardized response mean [SRM]). RESULTS: The performance of the new software, as assessed by the reproducibility of repeated measurements of minimum JSW on the same image, was excellent in both the standing AP (ICC = 0.98) and Lyon schuss radiographs (2 SD(m) = 0.5 mm, ICC = 0.98). The reproducibility in different radiographs of the same knee was not evaluated. However, over 2 years, the mean (+/- SD) decrease in the minimum JSW of OA knees was 0.17 +/- 0.75 mm in standing AP radiographs (P not significant) and 0.24 +/- 0.50 mm in Lyon schuss views (P = 0.007), with SRMs of 0.23 and 0.48, respectively. The quality of alignment of the tibial plateau was satisfactory (<1 mm between anterior and posterior margins of the medial tibial plateau) in 66% of the pairs of Lyon schuss radiographs and in 57% of the pairs of standing AP radiographs. In the Lyon schuss radiographs, SRM was highly dependent on tibial plateau alignment. Minimum JSW was more sensitive to change than was mean JSW or JSA, in paired Lyon schuss radiographs that exhibited satisfactory alignment. CONCLUSION: Compared with the standing AP radiograph, PA imaging of the knee in 20-30 degrees flexion (the schuss position) increases the reproducibility of radiographic JSW measurements in OA knees and the sensitivity to change in JSW in serial radiographs. Sensitivity to change in minimum JSW is notably increased by aligning the medial tibial plateau with the central x-ray beam in the Lyon schuss radiograph.     

AIDS-related cholangiopathy

Several types of biliary tract abnormality of undertermined origin have been described among AIDS patients. The aims of this study are (1) to evaluate whether biliary tree involvement is in fact one or several homogeneous morphological entities, (2) to specify the role of CMV orCryptosporidium sp. infection, and (3) to evaluate the possible efficacy of treatment. Since ultrasound had revealed abnormality in the biliary tree, 26 consecutive AIDS patients underwent cholangiography. Cholangiograms enabled us to distinguish between two types of biliary tract involvement: (1) gradual and regular stenosis of the terminal portion of the common bile duct associated with dilation but without irregularity of the intrahepatic biliary ducts was present in 27% of our cases, and (2) distal stenosis of the extrahepatic biliary ducts combined with diffuse irregularity of the caliber of the intrahepatic bile ducts was present in 73% of our cases. Concomitant infection by CMV orCryptosporidium sp. was significantly more frequent when intrahepatic duct irregularities were present (94%) than when absent (14%,P<0.001). Anti-CMV treatment and sphincterotomy were unsuccessful in treating anomalies of the intrahepatic biliary tract. Conversely, sphincterotomy caused rapid and lasting disappearance of pain in all our patients. In conclusion, biliary tract involvement in AIDS patients is of two types. CMV infection and infection byCryptosporidium sp. are most frequent when the large intrahepatic ducts are implicated.     

Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study

BACKGROUND: Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo biloba extracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated that because of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies have been published to date to test its efficacy in prevention of Alzheimer's disease. The potential association between use of C4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type was investigated. METHODS: A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years. Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive function remained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffer's test and whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-up period. In order to study the factors associated with the onset of dementia, the data concerning women with a score of > or = 8 on Pfeiffer's test at inclusion, indicating normal cognitive function, were analyzed. RESULTS: A multivariate analysis including potential confounding factors showed that fewer women who developed Alzheimer's dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio = 0.31, 95% confidence interval = 0.12-0.82, p =.018). Figures for EGb 761 alone were similar but did not reach statistical significance (odds ratio = 0.38, 95% confidence interval = 0.08-1.76, p =.22). CONCLUSION: These results suggest that C4A treatment may reduce the risk of developing Alzheimer's dementia in elderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. To establish a causal relationship, these findings have to be confirmed with prospective studies.