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991.
Background and objectives: The objective of this study was to investigate the effects of desensitization protocols using intravenous Ig with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention of antibody-mediated rejection and downregulation of donor-specific antibodies.Design, setting, participants, & measurements: Thirty-five complement-dependent cytotoxicity T cell cross-match–negative but complement-dependent cytotoxicity B cell and/or flow cytometry cross-match–positive kidney transplant recipients were treated with high-dosage intravenous Ig plus Thymoglobulin induction treatment. Donor-specific antibody strength was stratified as strong, medium, or weak by Luminex flow beads. Group 1 patients had weak/moderate and group 2 strong donor-specific antibodiesResults: Whereas no group 1 patients had acute rejection, 66% of group 2 had acute rejection (44% antibody-mediated rejection, 22% cellular rejection). The protocol was then changed to the addition of peritransplantation plasmapheresis to patients with strong donor-specific antibodies (group 3). This change resulted in a dramatic decrease in the acute rejection rate to 7%. During a median 18 mo of follow-up, patient survival was 100, 100, and 93% and graft survival was 100, 78, and 86% in groups 1, 2, and 3, respectively. During follow-up, 17 (52%) patients lost donor-specific antibodies completely, and 10 (30%) lost some of donor-specific antibodies and/or decreased the strength of existing donor-specific antibodies.Conclusions: These results indicated that in patients with strong donor-specific antibodies, the addition of plasmapheresis to high-dosage intravenous Ig decreases the incidence of acute rejection. The majority of the patients, whether they received intravenous Ig alone or with plasmapheresis, lost their donor-specific antibodies during follow-up.Donor-specific anti-HLA antibodies (DSA) in patients who are sensitized through pregnancy, previous blood transfusions, or organ transplantation is an important obstacle in kidney transplantation. Sensitized patients wait longer on the deceased-donor transplantation list, may not receive a transplant, and may have greater morbidity and mortality. Some sensitized patients may have living donor candidates, but transplantation cannot be performed because of cross-match positivity. Recent desensitization protocols using the combination of plasmapheresis (PP) or immunoadsorption to remove DSA and/or intravenous Ig (IVIG) and rituximab to downregulate antibody-mediated immune responses have made kidney transplantation feasible by abrogating complement-dependent cytotoxicity (CDC) T cell cross-match positivity. In previous studies, two protocols were examined: High-dosage IVIG (2.0 g/kg) (13) and PP with low-dosage IVIG (100 mg/kg after each PP session) (48); however, acute antibody-mediated rejection (AMR) continued to be an important barrier and was still observed in at least 30 to 40% of the recipients included in these desensitization protocols, even when rituximab was added to the protocol.Whereas CDC T cell cross-match positivity is an absolute contraindication to kidney transplantation, the clinical significance of CDC B cell or flow cytometry (FC) T and/or B cell cross-match positivity are less clear. Most studies have demonstrated that CDC T cell cross-match–negative but CDC B or FC T/B cell cross-match–positive patients with DSA are at higher risk for developing acute cellular, antibody-mediated, and chronic rejection and graft loss (9,10). The role of desensitization protocols for these patients has not been studied in a large cohort. We previously reported our initial experience using low-dosage IVIG (300 mg/kg) and Thymoglobulin induction treatment in 15 patients (11,12). Because of early AMR in three patients, the IVIG dosage was increased to a total of 2.0 mg/kg in subsequent patients. Now, we present our experience in CDC T cell–negative but CDC B cell or FC T and/or B cell cross-match–positive kidney transplant recipients with DSA, who were stratified according to mean fluorescence indices of Luminex flow beads. The results showed that patients with strong DSA were at much higher risk for developing acute AMR early after transplantation, and the addition of peritransplantation PP to high-dosage IVIG and Thymoglobulin treatment significantly decreased the incidence of AMR. The majority of the patients, whether they received IVIG alone or with PP, lost DSA during follow-up.  相似文献   
992.

Aims/hypothesis

Validated biomarkers are needed to monitor the effects of immune intervention in individuals with type 1 diabetes. Despite their importance, few options exist for monitoring antigen-specific T cells. Previous reports described a combinatorial approach that enables the simultaneous detection and quantification of multiple islet-specific CD8+ T cell populations. Here, we set out to evaluate the performance of a combinatorial HLA-A2 multimer assay in a multi-centre setting.

Methods

The combinatorial HLA-A2 multimer assay was applied in five participating centres using centralised reagents and blinded replicate samples. In preliminary experiments, samples from healthy donors were analysed using recall antigen multimers. In subsequent experiments, samples from healthy donors and individuals with type 1 diabetes were analysed using beta cell antigen and recall antigen multimers.

Results

The combinatorial assay was successfully implemented in each participating centre, with CVs between replicate samples that indicated good reproducibility for viral epitopes (mean %CV = 33.8). For beta cell epitopes, the assay was very effective in a single-centre setting (mean %CV = 18.4), but showed sixfold greater variability across multi-centre replicates (mean %CV = 119). In general, beta cell antigen-specific CD8+ T cells were detected more commonly in individuals with type 1 diabetes than in healthy donors. Furthermore, CD8+ T cells recognising HLA-A2-restricted insulin and glutamate decarboxylase epitopes were found to occur at higher frequencies in individuals with type 1 diabetes than in healthy donors.

Conclusions/interpretation

Our results suggest that, although combinatorial multimer assays are challenging, they can be implemented in multiple laboratories, providing relevant T cell frequency measurements. Assay reproducibility was notably higher in the single-centre setting, suggesting that biomarker analysis of clinical trial samples would be most successful when assays are performed in a single laboratory. Technical improvements, including further standardisation of cytometry platforms, will likely be necessary to reduce assay variability in the multi-centre setting.
  相似文献   
993.
BACKGROUND: Heart rate variability (HRV) is reported as a surrogate index for clinical outcome in trials of secondary prevention strategies for coronary artery disease (CAD), but a standardized guide for interpreting HRV change is not established. DESIGN: We evaluated HRV change in trials with CAD patients who received conventional medications (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors), biobehavioral treatment (psychotropics, biofeedback, relaxation) or exercise training. METHODS: Medline, Pubmed, Psycinfo, the Cochrane database, and Embase were searched until July 2007, without language restriction. We identified 33 randomized controlled trials. Two reviewers independently abstracted all trials using a standardized form. A hierarchy of frequency and time domain HRV indices defined outcome. RESULTS: A random-effects model yielded an overall pooled standardized mean difference (SMD) between treatment and control groups of moderate magnitude across treatment classes, based on a composite of time and frequency domain indices (SMD=0.40, P<0.0001), or only time or frequency indices (SMD=0.37 and 0.43, respectively, both P<0.0001). This change was equivalent to an increase in standard deviation of all normal-to-normal RR intervals of 9.0 ms (95% Confidence Interval, CI, 7.3, 10.7 ms) or a relative increase of 15.9% (95% CI, 13.2, 18.6%). To detect HRV change of this magnitude, a hypothetical trial would require a sample size of 660 patients for conventional medications or 1232 patients for all treatment classes. CONCLUSION: Pharmacologic, biobehavioral and exercise strategies for secondary prevention of CAD significantly increase HRV. This review provides a framework to assist efforts to evaluate the contribution of HRV change to CAD prognosis.  相似文献   
994.
995.
On the national level in Ecuador in 1982 roughly 61 percent of elderly people 60 years and over lived in complex family households, but this was 70 percent in the Coastal region (Costa) compared with only 54 percent in the Mountain region (Sierra), these two regions comprising over 95 percent of Ecuador's 1982 population. The regional difference could not be explained by standard demographic or socioeconomic characteristics available in the 1982 Census, either among all elderly people or unmarried women elderly. Rather, the regional difference may reflect underlying value and attitude differences not measured in the Census. As the marital structure of the adult population in the two areas has been quite different, consensual union being much more common in the Costa than the Sierra, we are left to wonder if there might be two different family systems at play. Such speculation will need to be addressed by future research.  相似文献   
996.
OBJECTIVE: To explore the differences between oscillometric and auscultatory measurements. METHOD: From a simulator evaluation of a non-invasive blood pressure (NIBP) device regenerating 242 oscillometric blood pressure waveforms from 124 subjects, 10 waveforms were selected based on the differences between the NIBP (oscillometric) and auscultatory pressure measurements. Two waveforms were selected for each of five criteria: systolic over and underestimation; diastolic over and underestimation; and close agreement for both systolic and diastolic pressures. The 10 waveforms were presented to seven different devices and the oscillometric-auscultatory pressure differences were compared between devices and with the oscillometric waveform shapes. RESULTS: Consistent patterns of waveform-dependent over and underestimation of systolic and diastolic pressures were shown for all seven devices. The mean and standard deviation, for all devices, of oscillometric-auscultatory pressure differences were: for the systolic overestimated waveforms, 36 +/- 28/-6 +/- 3 and 23 +/- 2/-1 +/- 3 mmHg (systolic/diastolic differences); for systolic underestimated waveforms, -21 +/- 5/-4 +/- 3 and -11 +/- 4/-3 +/- 3 mmHg; for diastolic overestimated waveforms, 3 +/- 4/12 +/- 5 and 17 +/- 6/10 +/- 2 mmHg; for diastolic underestimated waveforms, 1 +/- 4/-22 +/- 4 and -9 +/- 6/-29 +/- 4 mmHg; and for the two waveforms with good agreement, 0 +/- 6/0 +/- 3 and -2 +/- 4/-4 +/- 3 mmHg. Waveforms for which devices showed good oscillometric and auscultatory agreement had smooth envelopes with clearly defined peaks, compared with the broader plateau and complex shapes of those waveforms for which devices over or underestimated pressures. CONCLUSION: By increasing the understanding of the characteristics and limitations of the oscillometric method and the effects of waveform shape on pressure measurements, simulator evaluation should lead to improvements in NIBP devices.  相似文献   
997.
Cyanobacteria can generate molecules hazardous to human health, but production of the known cyanotoxins is taxonomically sporadic. For example, members of a few genera produce hepatotoxic microcystins, whereas production of hepatotoxic nodularins appears to be limited to a single genus. Production of known neurotoxins has also been considered phylogenetically unpredictable. We report here that a single neurotoxin, beta-N-methylamino-L-alanine, may be produced by all known groups of cyanobacteria, including cyanobacterial symbionts and free-living cyanobacteria. The ubiquity of cyanobacteria in terrestrial, as well as freshwater, brackish, and marine environments, suggests a potential for wide-spread human exposure.  相似文献   
998.
OBJECTIVE: There is an urgent need for biomarkers with which to monitor disease activity in patients with systemic lupus erythematosus (SLE). We recently showed that abnormal levels of C4d, an activation-derived fragment of complement component C4, are deposited on the surface of erythrocytes from patients with SLE. This study focused on reticulocytes, the youngest and shortest-lived erythrocytes (lifespan 24-48 hours), with the objective of testing our hypothesis that when reticulocytes emerge from the bone marrow, they are immediately exposed to and acquire C4d at levels proportionate to the extent of complement activation at that time, thereby reflecting disease activity in SLE. METHODS: We conducted a cross-sectional study of 156 patients with SLE, 140 patients with other diseases, and 159 healthy controls. Levels of C4d on the surface of reticulocytes were examined using a 2-color flow cytometric assay. The results were analyzed for correlations with SLE disease activity. RESULTS: A wide range of increased levels of reticulocyte C4d was specifically detected in SLE patients. These levels fluctuated in SLE patients and correlated with clinical disease activity, as determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus Activity Measure (SLAM). Specifically, in cross-sectional analyses, patients with reticulocyte C4d levels in the highest quartile compared with those in the lowest quartile had significantly higher SELENA-SLEDAI (P = 0.00002) and SLAM (P = 0.02) scores. Longitudinal observation demonstrated that the reticulocyte C4d levels changed in relation to the clinical course in individual patients. CONCLUSION: These findings support our hypothesis that C4d-bearing reticulocytes may serve as biomarkers of disease activity in patients with SLE.  相似文献   
999.
OBJECTIVES: The purpose of this research was to determine if sex and gender differences in the management of acute coronary syndromes (ACS) are associated with differences in prognosis after ACS. BACKGROUND: Previous investigators have reported sex/gender differences in the management of patients with ACS, but the impact of these differences on prognosis is unclear. METHODS: We analyzed data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which enrolled 4,836 women and 7,726 men with ACS. Patients were classified into risk strata using the Thrombolysis In Myocardial Infarction (TIMI) score. RESULTS: Women underwent fewer invasive procedures including angiography, angioplasty, and coronary artery bypass graft (CABG) surgery (47.6% vs. 60.5%; p = 0.0001) compared to men. No significant differences in cardiovascular death, myocardial infarction (MI), or stroke were observed (9.8% vs. 10.9%; p = 0.04), although women were more likely than men to develop refractory ischemia and to be rehospitalized for chest pain during follow-up (16.6% vs. 13.9%; p = 0.0001). These differences were particularly evident among TIMI high-risk women. A significant interaction between TIMI risk and gender for the outcome of refractory angina and rehospitalization for angina was present. CONCLUSIONS: Compared to men, high-risk women with ACS undergo less coronary angiography, angioplasty, and CABG surgery, and while they do not have higher incidence cardiovascular death, recurrent MI, or stroke, they suffer an increased rate of refractory ischemia and rehospitalization. All high-risk women and men with ACS should receive optimal medical management, and be considered for coronary angiography with possible revascularization if their coronary anatomy warrants it.  相似文献   
1000.
Background: Invasive pneumococcal disease is a significant cause of morbidity and mortality in the United States. Despite availability of an effective vaccine, many patients refuse vaccination.
Objective: To investigate patient characteristics and features of the patient–provider relationship associated with pneumococcal vaccine refusal.
Design: Case–control study using chart review.
Patients: Five hundred adults from the medical clinics of a 1,000-bed inner-city teaching hospital.
Measurements and Main Results: Independent risk factors for pneumococcal vaccine refusal included patient–provider gender discordance (odds ratio (OR)=2.09, 95% confidence interval (CI) 1.07 to 4.09); a visit to a not-usual provider at the time of vaccine offering (OR=2.26, 95% CI 1.13 to 4.49); never having received influenza vaccination (OR=7.44, 95% CI 3.76 to 14.76); prior pneumococcal vaccine refusals (OR=3.45, 95% CI 1.60 to 7.43); and a history of ever having refused health maintenance tests (OR=2.86, 95% CI 1.40 to 5.84).
Conclusions: We have identified both patient factors and factors related to the patient–provider relationship that are risk factors for pneumococcal vaccine refusal. By identifying patients at risk for pneumococcal vaccine refusal, efforts to increase vaccination rates can be better targeted.  相似文献   
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