IgG alloantibody responses to donor-specific blood transfusion in different rat strain combinations as a predictor of renal allograft survival.

Donor-specific blood transfusion prolongs the survival of fully allogeneic ACI (RT1a) renal allografts in PVG (RT1c) recipients from 7-10 days to greater than 100 days. We have observed significant differences in the alloantibody (Ab1) responses to ACI renal allografts in control and DSBT-treated PVG recipients: DSBT is associated with decreased IgG and IgM alloantibody circulating in serum, deposited in the allograft, and produced in culture by splenocytes. In the present studies the effects of DSBT on alloantibody production and renal allograft survival were extended to examine other recipient strains: F344 (RT1lv1), BN (RT1n), W/F (RT1u) and LEW (RT1l). Animals of each recipient strain were injected i.v. with 0.5 ml of ACI blood alone or followed by a renal allograft. Studies on the kinetics of IgM and IgG alloantibody responses were performed by flow cytometry on lymphocytes from donor ACI, PVG, and PVG.R1 (RT1.Aa class I MHC antigen on PVG background) rats. In F344 and PVG rats, DSBT from ACI rats elicited a transient IgM response that peaked at day 7 and was not followed by a switch to IgG. In control PBS transfused F344 recipients, an ACI renal allograft stimulated both IgM and IgG alloantibody production. DSBT pretreatment significantly decreased circulating IgG alloantibody following ACI renal transplantation and prolonged graft survival in F344 recipients. In DSBT-treated F344 recipients that rejected ACI renal allografts acutely, small amounts of IgG (5-12 mode channel shift) were detected in sera harvested 7 days after transplantation, whereas almost no IgG was detected in the sera from DSBT treated F344 rats that accepted their renal allografts indefinitely. In contrast, DSBT alone from ACI to BN, W/F, or LEW strains elicited a transient IgM response that peaked at day 7 and was followed by a strong IgG response that peaked on days 10-14 and remained high through day 21. DSBT failed to prolong ACI renal allograft survival in any of these strains (survival less than 11 days in control and DSBT rats). The alloantibody response to DSBT in all five recipient strains examined was directed primarily to RT1.Aa class I MHC antigens, as determined by binding studies on lymphocytes from ACI, PVG and PVG.R1 rats and alloantibody blocking studies using biotinylated rat monoclonal antibodies to distinct epitopes of the RT1.Aa antigen. The relative magnitude of blocking of R2/10P and R2/15S binding by sera from BN, W/F, and LEW rats was: control allograft recipients greater than DSBT pretreated allograft recipients greater than DSBT alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Association of donor-specific blood transfusion enhancement of rat renal allografts with accelerated development of antiidiotypic antibodies and reduced alloantibody responses

Pretransplant donor-specific blood transfusion (DSBT) has been shown to enhance renal allograft survival in man and indefinitely prolong renal transplants among various MHC-disparate rat strains. Using PVG (RT1c) recipients and ACI (RT1a) donor-strain rats, DSBT alone was found to elicit complement-dependent cytotoxic IgM antibody (Ab) to donor class I (RT1.Aa) alloantigens that peaked at 7 days. An enzyme-linked immunosorbent assay was developed to measure host Ab against allospecific (idiotypic) determinants on the anti-RT1.Aa monoclonal Ab R2/10P, R2/15S, and YR1/100. Following DSBT alone, antiidiotypic Ab were detected in the circulation within 7-11 days after transfusion. Transplantation of a donor strain kidney in the presence of antiidiotypic Ab at day 7 or 11 post-DSBT resulted in enhanced graft survival and a rapid decline in circulating alloantibody, such that by days 4-6 posttransplantation little IgM or IgG alloantibody was detected. In contrast, all 6 PVG rats that were transplanted 4 days after DSBT (prior to development of detectable antiidiotypic Ab) rejected their grafts within 30 days, and 4 of 6 showed elevated alloantibody titers within 3 days posttransplantation. Control PVG rats receiving autologous blood transfusion (ABT) alone developed no alloantibody response but developed high titers of donor-specific alloantibody by 6 days posttransplantation, at the time of irreversible rejection. ABT alone did not elicit antiidiotypic Ab and ABT pretreated graft recipients developed antiidiotypic Ab only after the onset of rejection at day 4. In both DSBT and ABT groups, the antiidiotypic Ab were primarily IgM, IgG1, and IgG2c. These findings indicate that DSBT induces production of cytotoxic alloantibodies followed by an antiidiotypic Ab response at days 7-11, during which time transplanted renal allografts are not rejected and there is a reduction in circulating alloantibody. In contrast, renal allografts placed in DSBT-treated rats prior to antiidiotypic Ab development (less than or equal to 4 days) or in ABT-treated rats that do not develop any antiidiotypic Ab, elicit a rapid rise in alloantibody and are rejected.     

Pellucid marginal degeneration and scleroderma

Systemic scleroderma is a progressive multi‐system connective tissue disease. Ocular involvement includes keratoconjunctivitis sicca, progressive shallowing of conjunctival fornices, peripheral ulcerative keratitis and eyelid tightness. No association has been reported between scleroderma and pellucid marginal degeneration, which is a rare bilateral corneal ectasia. Pellucid marginal degeneration is characterised by noninflammatory and progressive peripheral corneal thinning inferiorly, often with high against‐the‐rule astigmatism. We report a case of a 55‐year‐old woman with systemic scleroderma who presented with rapidly progressing against‐the‐rule astigmatism. The differential diagnosis of peripheral corneal thinning and the challenge of the surgical management of pellucid marginal degeneration are briefly discussed.     

Cardiovascular magnetic resonance for the assessment of patients undergoing transcatheter aortic valve implantation: a pilot study

Background

Before trans-catheter aortic valve implantation (TAVI), assessment of cardiac function and accurate measurement of the aortic root are key to determine the correct size and type of the prosthesis. The aim of this study was to compare cardiovascular magnetic resonance (CMR) and trans-thoracic echocardiography (TTE) for the assessment of aortic valve measurements and left ventricular function in high-risk elderly patients submitted to TAVI.

Methods

Consecutive patients with severe aortic stenosis and contraindications for surgical aortic valve replacement were screened from April 2009 to January 2011 and imaged with TTE and CMR.

Results

Patients who underwent both TTE and CMR (n = 49) had a mean age of 80.8 ± 4.8 years and a mean logistic EuroSCORE of 14.9 ± 9.3%. There was a good correlation between TTE and CMR in terms of annulus size (R² = 0.48, p < 0.001), left ventricular outflow tract (LVOT) diameter (R² = 0.62, p < 0.001) and left ventricular ejection fraction (LVEF) (R² = 0.47, p < 0.001) and a moderate correlation in terms of aortic valve area (AVA) (R² = 0.24, p < 0.001). CMR generally tended to report larger values than TTE for all measurements. The Bland-Altman test indicated that the 95% limits of agreement between TTE and CMR ranged from -5.6 mm to + 1.0 mm for annulus size, from -0.45 mm to + 0.25 mm for LVOT, from -0.45 mm² to + 0.25 mm² for AVA and from -29.2% to 13.2% for LVEF.

Conclusions

In elderly patients candidates to TAVI, CMR represents a viable complement to transthoracic echocardiography.     

Left ventricular reverse remodeling after transcatheter aortic valve implantation: a cardiovascular magnetic resonance study

Background

In patients with severe aortic stenosis, left ventricular hypertrophy is associated with increased myocardial stiffness and dysfunction linked to cardiac morbidity and mortality. We aimed at systematically investigating the degree of left ventricular mass regression and changes in left ventricular function six months after transcatheter aortic valve implantation (TAVI) by cardiovascular magnetic resonance (CMR).

Methods

Left ventricular mass indexed to body surface area (LVMi), end diastolic volume indexed to body surface area (LVEDVi), left ventricular ejection fraction (LVEF) and stroke volume (SV) were investigated by CMR before and six months after TAVI in patients with severe aortic stenosis and contraindications for surgical aortic valve replacement.

Results

Twenty-sevent patients had paired CMR at baseline and at 6-month follow-up (N=27), with a mean age of 80.7±5.2 years. LVMi decreased from 84.5±25.2 g/m² at baseline to 69.4±18.4 g/m² at six months follow-up (P<0.001). LVEDVi (87.2±30.1 ml /m²vs 86.4±22.3 ml/m²; P=0.84), LVEF (61.5±14.5% vs 65.1±7.2%, P=0.08) and SV (89.2±22 ml vs 94.7±26.5 ml; P=0.25) did not change significantly.

Conclusions

Based on CMR, significant left ventricular reverse remodeling occurs six months after TAVI.     

A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis

OBJECTIVES: This study examined the effect of aspirin on the risk of embolic events in infective endocarditis (IE). BACKGROUND: Embolism is a major complication of IE, and studies in animal models have shown that platelet inhibition with aspirin can lead to more rapid vegetation resolution and a lower rate of embolic events. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial of aspirin treatment (325 mg/day) for four weeks in patients with IE to test the hypothesis that the addition of aspirin would reduce the incidence of clinical systemic embolic events. Patients with perivalvular abscess were excluded. Serial cerebral computed tomograms and transesophageal echocardiograms were obtained in a subset of patients. RESULTS: During the four-year study period, 115 patients were enrolled: 60 assigned to aspirin and 55 assigned to placebo. Embolic events occurred in 17 patients (28.3%) on aspirin and 11 patients (20.0%) on placebo, with an odds ratio (OR) of 1.62 (95% confidence interval [CI] 0.68 to 3.86, p = 0.29). There was a trend toward a higher incidence of bleeding in the patients taking aspirin versus placebo (OR 1.92, 95% CI 0.76 to 4.86, p = 0.075). Development of new intracranial lesions was similar in both groups. Aspirin had no effect on vegetation resolution and valvular dysfunction. CONCLUSIONS: In endocarditis patients already receiving antibiotic treatment, the addition of aspirin does not appear to reduce the risk of embolic events and is likely associated with an increased risk of bleeding. Aspirin is not indicated in the early management of patients with IE.     

Enhanced co-stimulatory ability of synovial fluid accessory cells in rheumatoid arthritis

We have established in vitro assays that allow the examination of co- stimulatory function of rheumatoid arthritis (RA) antigen-presenting cells (APC). Synovial fluid (SF) and peripheral blood (PB) APC co- stimulatory ability was compared in the activation of peptide-specific human T-cell clones. T-cell receptor (TCR) stimulation by peptide or anti-CD3 antibody allowed the direct comparison of SF and PB APC co- stimulatory activity, separately from their ability to process antigen. SF APC from 15 RA patients consistently enhanced T-cell proliferation when compared to their PB counterparts. Moreover, increasing the numbers of PB APC present resulted in only a minor increase in T-cell proliferation, failing to achieve levels stimulated by SF APC. We propose that the enhanced co-stimulatory function of synovial APC may be a significant factor in the persistence of local immune responses in RA.      

In vitro analysis of colour Doppler flow with the use of proximal isovelocity surface area: improved flow estimates using a nonhemispherical model

OBJECTIVE: To examine the geometry of the proximal isovelocity surface area (PISA) envelope and its associated isotach, and to evaluate the accuracy of two models of calculating volumetric flow by using the PISA technique. DESIGN: A new model for determining isotach geometry from the PISA envelope was developed and tested in an in vitro simulation. SETTING: Echocardiography Laboratory, Hotel Dieu Hospital, Kingston, Ontario. MATERIALS AND METHODS: PISA envelopes were visualized using an in vitro flow simulator with a series of sharp-edged orifices (2.5 to 16 mm diameter) at a range of flow rates (10 to 110 mL/s). INTERVENTIONS: Flow calculations based on the traditional hemispherical geometric assumption for the isotach and the new model were made and compared with measured flow rates. MAIN RESULTS: The hemispherical model systematically and significantly underestimated flow. The nonhemispherical model, which requires measurement of both the height (a) and lateral width (2d) of the PISA envelope, provided improved estimates of flow. CONCLUSIONS: The nonhemispherical model provides a better estimate of flow through an orifice. Flow rate Q can be calculated directly from the size of the PISA envelope and the aliasing velocity (VA) by using the relationship Q = (3.14d2 + 5.97da + 1.37a2)VA or can be read from a nomogram.     

High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy

Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an induction failure (IF); this subset of patients has an extremely poor outcome with further conventional therapy. Since 1985, we have entered 30 IF patients into protocols using conditioning with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) followed by autologous stem cell transplantation (ASCT) with bone marrow (19 patients), peripheral blood stem cells (PBSCs; 8 patients), or both (3 patients). All except 2 patients had previously received chemotherapy regimens for HD that contained at least 7 drugs, and 9 had received prior radiotherapy (RT). After documentation of IF, the majority of patients received some cytoreductive therapy as specified by protocol (local RT in 9, two cycles of conventional chemotherapy in 2, both modalities in 2, or high-dose cyclophosphamide to enhance PBSC collection in 11) before CBV +/- P. Five treatment-related deaths occurred, all before day 150 posttransplant. Eleven patients have had progressive HD at a median of 6 months (range, 0.1 to 45 months) after ASCT. The actuarial progression-free survival (PFS) at a median follow- up of 3.6 years (range, 0.2 to 8.2 years) is 42% (95% confidence intervals, 21% to 61%). The statistical analysis identified only prior clinical bleomycin lung toxicity as an adverse risk factor for PFS, mainly because of the increased nonrelapse mortality seen in these patients. CBV +/- P and ASCT can produce durable remission in a substantial proportion of IF HD patients who otherwise have a poor survival, and we believed ASCT approaches represent the best therapy currently available for these patients. Additional measures are needed to reduce the primary problem of disease progression despite high-dose chemotherapy and stem cell transplantation.     

Antitrypanosomal potentials of the extract and fractions of Abrus precatorius seeds

ObjectiveTo evaluate the in vivo trypanocidal activity of the methanol extract and fractions of Abrus precatorius seeds in mice.MethodsParasiteamia was induced unto mice by intraperitoneal injection of 1.25×10⁵ Trypanosoma in normal saline. Five days when a high level of parasiteamia was established treatment commenced until ten days. The mice were treated with 10, 20 and 40 mg/kg bt. of the extract and 5 and 10 mg/kg bt. of the fraction (F₂), respectively for 5 days. Diminazene aceturate at the dose of 3.5 mg/kg bt. for two days was used as the reference drug. The level of parasitaemia and packed cell volume (PCV) of the animals estimated.ResultsAt doses of 10, 20 and 40 mg/kg the crude extract showed a sharp reduction in the level of parasitaemia in mice compared with the untreated group. The mice treated with F₂ at doses of 5 and 10 mg/kg showed a sharp reduction in the level of parasitamia to zero in day 9, and a gradual recovery from the 12th day of treatment. This effect is comparable to that of the mice treated with 7 mg/kg of standard drug diminazene aceturate. The PCV of the treated showed a gradual decrease with time, but not as much as the untreated group. Phytochemical screening revealed the presence of glycosides, alkaloids, carbohydrates, tannins and proteins in the Abrus precatorius powder while F₂ was rich in alkaloids.ConclusionsThis study shows that both the extract and the fractions of Abrus precatorius seeds exhibited a promising trypanocidal property. Alkaloids may be responsible for the observed activity.