Inhibition of Complement Regulation Is Key to the Pathogenesis of Active Heymann Nephritis

Crry (complement receptor 1–related protein/gene y) is a key cellular complement regulator in rodents. It is also present in Fx1A, the renal tubular preparation used to immunize rats to induce active Heymann nephritis (HN), a model of membranous nephropathy. We hypothesized that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development of injury in HN by neutralizing the complement regulatory activity of Crry. Rats immunized with Fx1A lacking Crry remained free of proteinuria and glomerular deposits of C3 during a 10-wk follow-up despite typical granular immunoglobulin (Ig)G deposits in glomeruli. Anti-Fx1A auto-Abs were present in their sera at levels that were not different from sera pooled from proteinuric rats with HN induced with nephritogenic Fx1A. Passive administration of sheep anti-Crry Abs to rats immunized with Crry-deficient Fx1A led to proteinuria and glomerular C3 deposition, which were not seen in such rats injected with preimmune IgG, nor in rats with collagen-induced arthritis injected with anti-Crry IgG. To directly examine the role of Crry in HN, rats were immunized with Crry-deficient Fx1A reconstituted with rCrry. This led to typical HN, with 8 out of 15 rats developing proteinuria within 14 wk. Moreover, the extent of glomerular C3 deposition correlated with proteinuria, and anti-Crry Abs were present in glomerular eluates. Thus, Crry is a key nephritogenic immunogen in Fx1A. Formation of neutralizing auto-Abs to Crry impairs its function, leading to unrestricted complement activation by Abs reactive with the HN antigenic complex on the epithelial cell surface.     

Transplant ureteral obstruction masquerading as recurrent rejection episodes: management by percutaneous antegrade balloon dilatation

We report a 52-year-old male renal transplant recipient who had three "rejection episodes." The first of these responded to conventional antirejection therapy; however, the next two episodes showed incomplete responses to treatment for rejection. At subsequent presentation with deteriorating renal function, ureteral obstruction was evident and was relieved with percutaneous antegrade balloon dilatation with a return of his plasma creatinine to normal. Obstruction of the ureter was a major component in our patient's course given the lack of response to conventional antirejection therapy and the normalization of renal function with relief of the documented ureteral stenosis. This case illustrates that ureteral obstruction can mimic rejection in the renal transplant recipient. Management of ureteral stenosis in transplant patients with percutaneous antegrade balloon dilatation appears to be an effective procedure and can supplant the need for open surgical procedures.     

Autochthonous dermal leishmaniasis in Texas.

Over a 2-year period two cases of dermal leishmaniasis of special interest were recognized in Texas. The first occurred in 1972 in a 74-year-old woman who had residences in Dilworth and Gahzales, Gonzales County, and the other was in a 56-year-old man from Kenedy, Karnes County, in 1974. Both cases were biopsy- and culture-positive, and the second patient exhibited anti-Leishmania antibodies by indirect immunofluorescent antibody and direct agglutination tests. Epidemiologic investigation revealed no association between the two cases and suggested that both patients had acquired their infections locally in southern Texas. Moreover, serologic evidence of Leishmania infection was uncovered in a neighbor of the second case and in 3 dogs living nearby. Potential sylvatic reservoirs and arthropod vectors of the disease are resident in the area. Epidemiologic data suggest that dermal leishmaniasis is endemic in south-central Texas.     

Absence of functional alternative complement pathway alleviates lupus cerebritis

The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB-/-MRL/lpr) compared to fB-sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16+/-0.02 vs. 0.35+/-0.13, p<0.03) was increased, while expression of p-PTEN (0.40+/-0.06 vs. 0.11+/-0.07, p<0.05) was decreased in fB-/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB-/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.     

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.     

Determinants of altered anxiety after abnormal maternal serum alpha-fetoprotein screening

With maternal serum alpha-fetoprotein testing, large numbers of previously "low-risk" patients are now considered high risk and are offered genetic testing. Anecdotally, these patients have been perceived as more highly anxious than other second-trimester patients referred for genetic testing because of advanced maternal age. Thus we have studied patient demographics, true genetic risks, the perceptions of risk, and state (situational) and trait (constitutional) anxiety for these patients and their partners. Significantly increased state anxiety was noted for mothers as compared with fathers both in the group of women referred for testing because of maternal serum alpha-fetoprotein levels and in those referred due to advanced maternal age. State anxiety was increased in the women referred for maternal serum alpha-fetoprotein levels as compared with women referred for advanced maternal age. True genetic risks were comparable between the groups. Some critics have argued that maternal serum alpha-fetoprotein screening engenders unnecessary anxiety. Our data show that patients undergoing genetic testing due to maternal serum alpha-fetoprotein levels have higher state anxiety than women undergoing testing because of advanced maternal age, but that indication is much less a factor than are partner differences. Therefore, increased anxiety after abnormal maternal serum alpha-fetoprotein testing results cannot be reasonably used as an argument against such testing.     

Dual epileptic foci in a single patient express distinct temporal patterns dependent on limbic versus nonlimbic brain location

How timing information is transferred from the suprachiasmatic nucleus to other regions of the brain to mediate activity, either physiological or pathological, is largely unclear. A patient with medically refractory epilepsy and a well-documented, long-term seizure diary provided a unique means to demonstrate how susceptibility to chronobiological modulation varies with brain region. Evaluation for epilepsy surgery disclosed two independent epileptic foci, one limbic and the other nonlimbic. Seizures from both foci occurred periodically with a dominant period of 24 hours but were out of phase with each other. Temporal lobe seizures occurred maximally in the light portion of the daily light-dark cycle, and parietal lobe seizures occurred nocturnally and out of phase with limbic seizures. These data suggest that neuronal excitation and inhibition, depending on the anatomical system involved in epilepsy, may be differently affected by circadian modulation.     

Distribution of seizure precipitants among epilepsy syndromes

PURPOSE: Previous studies of patient-reported seizure precipitants have not evaluated whether different epilepsy syndromes are differentially affected. METHODS: Patients of a tertiary-care epilepsy center were consecutively surveyed with the use of a standardized questionnaire that lists precipitants that might trigger or exacerbate seizures (alcohol, caffeine, fasting, fatigue, fever or illness, flashing lights, heat or humidity, menstrual cycle, sleep, sleep deprivation, emotional stress, unknown, or other). Patients were classified into epilepsy syndromes according to International League Against Epilepsy criteria. Age and gender within groups defined by major precipitants were compared. Pearson's correlation was performed to evaluate common patterns of precipitants. RESULTS: Of 400 patients, 62% cited at least one precipitant. In order of frequency, stress (30%), sleep deprivation (18%), sleep (14%), fever or illness (14%), and fatigue (13%) were noted by at least 10% of patients. Stress, fatigue, and sleep deprivation positively correlated, but sleep tended to negatively correlate with other major precipitants. Rankings of precipitants varied within epilepsy syndromes, with patients with temporal lobe epilepsy citing sleep infrequently compared with patients with other epilepsy syndromes. Menstrual effects were ranked highly within major precipitants among women over age 12 and were especially noted by women with temporal lobe epilepsy (28%). CONCLUSIONS: Most patients with epilepsy identify a precipitant that triggers or exacerbates seizures. The high correlation of stress, sleep deprivation, and fatigue suggests that they act through common mechanisms to worsen seizure control. Through identification of the effect of both endogenous and exogenous precipitants among syndromes, more research and counseling can be directed to specific precipitants.