A murine cytomegalovirus-neutralizing monoclonal antibody exhibits autoreactivity and induces tissue damage in vivo.

The autoreactivity of murine cytomegalovirus (MCMV)-neutralizing monoclonal antibody (mAb) AC1 was examined in vitro and in vivo. Both mAb AC1 and a human antiserum reactive with U1-small nuclear ribonucleoprotein (U1-snRNP) stained uninfected mouse embryo fibroblasts (MEF) in a speckled nuclear pattern and reacted with 70,000 molecular weight (MW) MEF nuclear antigens by immunoblotting, suggesting that mAb AC1 cross-reacted with the 70,000 MW component of U1-snRNP. However, only mAb AC1 cross-reacted with an additional epithelial cytoplasmic autoantigen present in cultured HEp2 cells. On tissue sections from uninfected mice, mAb AC1 predominantly reacted with a component of central and peripheral nervous systems, although cross-reactivity with the stratum spinosum of the skin and the outer sheath of hair follicles was also observed. Immunoblotting revealed that mAb AC1 reacted with phosphorylated epitopes present on a 98,000 MW MCMV structural protein and the 200,000 MW mouse neurofilament protein (NFP). Treatment of uninfected mice with mAb AC1 resulted in a severe interstitial pneumonia with greatly thickened and congested alveolar septa. Severe oedema of the hypodermis and a mild mesangial proliferative glomerulonephritis were also observed. These results demonstrate that a mAb reacting with a MCMV structural phosphoprotein which can protect mice against the dissemination of MCMV, can also promote the development of autoimmune disease. Therefore, the production of such cross-reactive antibodies may be an important mechanism in the development of autoimmunity following viral infection.     

Anulus fibrosus in bulging intervertebral disks

In this investigation the association of radial tears of the anulus fibrosus and bulging of the intervertebral disk was studied. An index of disk bulging was measured in sagittal anatomic sections in 149 lumbar disks from 31 cadavers. The indexes of disk bulging were correlated with stages of disk development and the presence of an annular tear. The largest disk-bulging indexes were always associated with radial tears of the anulus. Eighty-four percent of the disks with radial tears had disk-bulging indexes greater than 2.5 mm. Most normal adult disks had an index of less than 2.5 mm. The results challenge the concept that the anulus fibrosus is intact in bulging disks, although ruptured in herniated disks.     

Short-term suppression of plasma free fatty acids fails to improve insulin sensitivity when intramyocellular lipid is elevated.

AIMS: Metabolic responses to manipulation of the plasma free fatty acid (FFA) concentration were assessed in six healthy men via cross-over design to determine whether FFAs independently influence insulin sensitivity. METHODS: Intramyocellular lipid (IMCL) was measured by proton magnetic resonance spectroscopy and insulin sensitivity via frequently sampled intravenous glucose tolerance test (IVGTT) after 67 h of two identical low carbohydrate/high fat (LC) diets which were used to elevate IMCL and plasma FFAs. To uncouple the influence of FFAs and IMCL on insulin sensitivity, FFAs were suppressed 30 min prior to and during IVGTT in one treatment [LC + nicotinic acid (NA)] by NA ingestion. RESULTS: Vastus lateralis IMCL was significantly elevated in LC (13.3 +/- 1.1 x 10(-3)) and LC + NA (13.5 +/- 1.1 x 10(-3)) (P < 0.01 for both), but was not different between conditions (P > 0.05). Plasma FFAs were raised in LC (0.79 +/- 0.08 mmol/l) and LC + NA (0.80 +/- 0.11 mmol/l) (P < 0.01 for both) and were significantly reduced by NA ingestion prior to (0.36 +/- 0.05 mmol/l, P < 0.01) and during IVGTT (P < 0.05) in LC + NA. Despite marked differences in plasma FFA availability, insulin sensitivity and glucose tolerance were not different between LC and LC + NA (P > 0.05 for both). CONCLUSIONS: Plasma FFAs appear to exert no immediate effect on insulin sensitivity/glucose tolerance independent of their action on intracellular lipid moieties. Further research is required to elucidate the duration of FFA suppression required to restore insulin sensitivity following lipid-induced insulin resistance.     

adaptive fourier threshold filtering: A method to reduce noise and incoherent artifacts in high resolution cardiac images

We introduce an image processing method which reduces white noise and random artifacts in sets of high resolution, time resolved images. At each pixel, the processing consists of: (1) the isolation of a time intensity curve (TIC), (2) Fourier transformation of each TIC, (3) application of a threshold to remove low intensity coefficients, (4) inverse transformation to generate noise reduced TICS which are recombined to form images with improved signal-to-noise ratio (SNR). Noise filtering by Fourier thresholding is demonstrated on a set of cardiac images, resulting in a reduction of the noise energy by approximately 90%.     

Identifying High Risk Groups and Quantifying Absolute Risk of Cancer After Kidney Transplantation: A Cohort Study of 15 183 Recipients

Transplant recipients have increased cancer risk, but data on risk variation across different patient groups are sparse. Rates and standardized rate ratios (SRR) of cancer (all sites, excluding nonmelanocytic skin and lip cancer) compared to the general population were calculated, using Australia and New Zealand Dialysis and Transplant Registry data. Within the transplant population, risk factors were identified (hazard ratios: HR; 95% CI) and absolute risk estimated for recipient groups. A total of 1642 (10.8%) of 15 183 recipients developed cancer. Risk was inversely related to age (SRR 15-30 children, 2 if >65 years). Females aged 25-29 had rates equivalent to women aged 55-59 from the general population. Age trend for lymphoma, colorectal and breast risk was similar; melanoma showed less variability across ages, prostate showed no risk increase. Within the transplanted population, risk was affected by age differently for each sex (p = 0.007), elevated by prior malignancy (HR 1.40; 1.03-1.89), white race (HR 1.36; 1.12-1.89), but reduced by diabetic end-stage kidney disease (ESKD) (HR 0.67; 0.50-0.89). Cancer rates in kidney recipients are similar to nontransplanted people 20-30 years older, but absolute risk differs across patient groups. Men aged 45-54 surviving 10 years have cancer risks varying from 1 in 13 (non-white, no prior cancer, diabetic ESKD) to 1 in 5 (white, prior cancer, other ESKD).     

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.