Faculty Bibliography

OBJECTIVE: Neonatal lupus (NL) occurs in fetuses exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, although the mothers themselves may not manifest any clinical disease. A focus on transmission of risk factors for NL from maternal grandparents to mothers of children with NL may yield dividends toward understanding the aggregation of autoantibodies and genetic factors in affected families. This study was perforned to determine the role of maternal grandparents in the development of the autoimmune phenotype of mothers of children with NL. METHODS: Fifty-one mothers of children with cardiac and/or cutaneous NL, 48 maternal grandmothers, and 35 maternal grandfathers in the Research Registry for Neonatal Lupus were interrogated for clinical symptoms by questionnaire and underwent laboratory assessments, including determination of anti-SSA/Ro and anti-SSB/La antibody status (by enzyme-linked immunosorbent assay) and genotype at rs1800629 (TNFalpha) and rs7775397 (C6orf10) (allelic discrimination). The transmission disequilibrium test (TDT) was computed to test for nonrandom transmission from maternal grandparents to mothers of children with NL. RESULTS: The common phenotypic feature in mothers of children with NL was the autoantibody and not the clinical profile; 7 had lupus, 14 had Sjogren's syndrome, 7 had both, and 23 were asymptomatic. Mothers of children with NL were significantly enriched for the risk alleles at both TNFalpha and C6orf10. The grandparents of children with NL carried minimal burden for autoimmune disease or abnormal antibody production and were not enriched in the genetic risk factors. However, the TDT analysis showed significant excess transmission of the risk alleles at both TNFalpha (odds ratio [OR] 6.67, P = 3.93 x 10(-4) ) and C6orf10 (OR 35.0, P = 3.74 x 10(-5) ) to mothers of children with NL. CONCLUSION: Mothers of children with NL are enriched for the TNFalpha and C6orf10 risk alleles, which are preferentially inherited from the asymptomatic maternal grandparents. These findings support the hypothesis that the development of NL and genetic etiology are multigenerational.

Background- Cardiac manifestations of neonatal lupus include conduction disease and, rarely, an isolated cardiomyopathy. This study was initiated to determine the mortality and morbidity of cardiac neonatal lupus and associated risk factors in a multi-racial/ethnic US-based registry to provide insights into the pathogenesis of antibody-mediated injury and data for counseling. Methods and Results- Three hundred twenty-five offspring exposed to maternal anti-SSA/Ro antibodies with cardiac neonatal lupus met entry criteria. Maternal, fetal echocardiographic, and neonatal risk factors were assessed for association with mortality. Fifty-seven (17.5%) died, 30% in utero. The probability of in utero death was 6%. The cumulative probability of survival at 10 years for a child born alive was 86%. Fetal echocardiographic risk factors associated with increased mortality in a multivariable analysis of all cases included hydrops and endocardial fibroelastosis. Significant predictors of in utero death were hydrops and earlier diagnosis, and of postnatal death were hydrops, endocardial fibroelastosis, and lower ventricular rate. Isolated heart block was associated with a 7.8% case fatality rate, whereas the concomitant presence of dilated cardiomyopathy or endocardial fibroelastosis quadrupled the case fatality rate. There was a significantly higher case fatality rate in minorities compared with whites, who were at a lower risk of hydrops and endocardial fibroelastosis. Pacing was required in 70%; cardiac transplantation was required in 4 children. Conclusion- Nearly one fifth of fetuses who develop cardiac neonatal lupus die of complications predicted by echocardiographic abnormalities consistent with antibody-associated disease beyond the atrioventricular node. The disparity in outcomes observed between minorities and whites warrants further investigation

Background. The hepatitis C virus is a major cause of hepatocellular carcinoma. Extrahepatic manifestations of hepatitis C include mixed cryoglobulinemia which can result in ischemic damage to multiple organs. The management of these sequelae in posthepatectomy patients is unclear. Case Report. A 49-year-old male with hepatitis C was found to have a 4 cm hepatocellular carcinoma on surveillance imaging. He underwent portal vein embolization followed by hepatectomy. His postoperative course was complicated by the development of splenic infarcts, small bowel ischemia, skin lesions, and liver damage. Findings of elevated cryocrit and elevated rheumatoid factor suggested the diagnosis of cryoglobulin-related vasculitis. The patient improved on supportive care. Conclusion. Cryoglobulinemia is associated with hepatitis C and may complicate the care of this patient population. The treatment of cryoglobulinemia posthepatectomy patients is complicated by concerns over how medications may affect the regenerating liver. Steroids should be used with caution in this setting. Summary. Brief report of hepatectomy complicated by vasculitis in the context of hepatocellular carcinoma secondary to hepatitis C addresses the management of mixed cryoglobulinemia in post-hepatectomy patients

Purpose: The classic cardiac manifestations of neonatal lupus (cardiac-NL) include a spectrum of conduction dysfunction (1^st, 2^nd, or 3^rd degree heart block (CHB)) and more rarely cardiomyopathy which can be absent any conduction disease. This study was undertaken to update the mortality data of cardiac-NL in a large US based cohort and identify associated risk factors to further understand the pathogenesis of anti-SSA/Ro mediated injury and provide evidence based data for counseling women with these antibodies. Methods: Three hundred and one children with cardiac-NL (295 with CHB and 6 with isolated cardiomyopathy) enrolled in the Research Registry for Neonatal Lupus (RRNL) had sufficient medical records for review. The RRNL database was analyzed for the following potential mortality maternal risk factors: age at pregnancy, race/ethnicity, anti-SSB/La antibody status, health status and fetal risk factors: time of diagnosis, exposure to maternal non-fluorinated and fluorinated steroids during pregnancy, method of delivery, and gender. In addition, morbidity was assessed by the frequency of pacemaker placement and cardiac transplant. Results: Follow up of the children ranged from in utero death to adulthood. Of the 301 children with cardiac-NL, 53 (17.6%) died. Thirty percent died in utero or at birth, 41% died prior to six months of postnatal life and the remaining 29% died after 6 months. Mortality was higher among children born to non-Caucasian mothers compared to Caucasian mothers (33% vs 15% p=.0003). Maternal age was equivalent between the groups (29.1 dead vs 29.7 live). The maternal presence of anti-SSB/La antibodies was 74% for those whose children died and 63% for those whose children survived, which was not significant. A maternal diagnosis of Sjorgen's Syndrome and/or Systemic Lupus Erythematosus was not significantly associated with cardiac-NL death (53% in death vs 44%) suggesting that prior knowledge of maternal antibody status did not influence mortality. With regard to fetal factors, 86% of those who died were diagnosed with cardiac-NL during pregnancy compared to 85% who survived. For those diagnosed during pregnancy there was a trend towards early gestational diagnosis for those children that died compared to those that survived (21 vs 23.5 weeks p=.09). There was also a trend toward higher exposure to maternal fluorinated steroids after the diagnosis in children that died (53% vs 40% p=.09), however there was no difference in maternal use of non-fluorinated steroids in those that died vs those that survived (19% vs 16%). Most fetuses were delivered by C-section and this was not significantly associated with death (70% dead vs 75% live). Female gender was also not associated with outcome (49% who died were female vs 52% live). Eighty-five percent of children received a pacemaker, 43% within 9 days of birth, 20% between 9 days and one year. Five children (2%) received a heart transplant. Conclusion: Based on data from this large cohort, 17.6% of children born with cardiac-NL die from complications of the disease. Eighty-five percent required pacing and two percent required cardiac transplantation. Mortality was more prevalent in children born to non Caucasian mothers

BACKGROUND: The cellular basis of long term radiation damage in the brain is not fully understood. METHODS AND FINDINGS: We administered a dose of 25Gy to adult rat brains while shielding the olfactory bulbs. Quantitative analyses were serially performed on different brain regions over 15 months. Our data reveal an immediate and permanent suppression of SVZ proliferation and neurogenesis. The olfactory bulb demonstrates a transient but remarkable SVZ-independent ability for compensation and maintenance of the calretinin interneuron population. The oligodendrocyte compartment exhibits a complex pattern of limited proliferation of NG2 progenitors but steady loss of the oligodendroglial antigen O4. As of nine months post radiation, diffuse demyelination starts in all irradiated brains. Counts of capillary segments and length demonstrate significant loss one day post radiation but swift and persistent recovery of the vasculature up to 15 months post XRT. MRI imaging confirms loss of volume of the corpus callosum and early signs of demyelination at 12 months. Ultrastructural analysis demonstrates progressive degradation of myelin sheaths with axonal preservation. Areas of focal necrosis appear beyond 15 months and are preceded by widespread demyelination. Human white matter specimens obtained post-radiation confirm early loss of oligodendrocyte progenitors and delayed onset of myelin sheath fragmentation with preserved capillaries. CONCLUSIONS: This study demonstrates that long term radiation injury is associated with irreversible damage to the neural stem cell compartment in the rodent SVZ and loss of oligodendrocyte precursor cells in both rodent and human brain. Delayed onset demyelination precedes focal necrosis and is likely due to the loss of oligodendrocyte precursors and the inability of the stem cell compartment to compensate for this loss.