Box 1 | Prevailing attitudes of medical professionals emerging from public review and participant survey Agreement with goal of standardizing nomenclature, with acknowledgment of challenges Regarded multiplicity of terms and lack of adherence to established definitions as confusing and potentially leading to errors Anticipated that a standardized nomenclature would help foster consistency in trial design, execution, and reporting Judged consistency between terms used in scholarly and patient communities to be an important goal, but not one overriding the need for precision and efficiency Journal editors strongly agreed that having a more standardized nomenclature for kidney disease would be useful for their journals, but they anticipated time constraints of journal personnel to be the biggest barrier to implementation Qualified endorsement of replacing "renal" with "kidney" Felt that foregrounding "kidney" would be easier for patients and their families Perceived a greater likelihood of raising awareness, attracting funding, and influencing public policy with consistent use of "kidney" Cautioned against a wholesale switch because "renal" may be less awkward in some contexts and may be necessary in others (e.g., ESRD as a CMS definition) Dissatisfaction with "end-stage" as a descriptor of kidney disease Recognized that this wording can be demoralizing and stigmatizing for patients Considered the implication of imminent death to be outdated Frustrated by imprecision in its use (ranging from being a synonym for dialysis patients to a descriptor of patients with kidney failure with or without kidney replacement therapy) Recognition of the need for ongoing attention to nomenclature issues Noted that standardization of nomenclature is dependent on uptake of consensus definitions B where definitions are in flux or are more contentious, standardization of that nomenclature set may be premature B enhancing adoption of definitions requires continued effort Highlighted the need for harmonization with ongoing, broader-scope ontology efforts Expected that improved understanding of molecular mechanisms will lead to more-precise definitions and nomenclature CMS, Centers for Medicare & Medicaid Services; ESRD, end-stage renal disease.

Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4-or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2-to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four-to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.The group B coxsackieviruses (CVB; family Picornaviridae, genus Enterovirus, species group B coxsackievirus; six serotypes, CVB1 to -6) are among the best studied of human enteroviruses (102). The CVB genome is a single strand of positive sense RNA 7,400 nucleotides in length that encodes 11 proteins in a single open reading frame (89). The CVB have been associated with diverse human diseases, among the more serious of which are myocarditis, pancreatitis, and aseptic meningitis. The CVB have been soundly implicated as causes of human myocarditis (1, 26, 42, 60-62, 73, 74, 108, 109) and pancreatitis (2,41,54,58,66,107) and, furthermore, cause these diseases readily i...

Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB Â NZW)F 1 background, disruption of estrogen receptor-a (ERa or Esr1) attenuated glomerulonephritis and increased survival. ERa deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERa promotes loss of immunologic tolerance. Furthermore, ERa deficiency in (NZB Â NZW)F 1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERa may promote lupus, at least in part, by inducing interferon-g, an estrogen-regulated cytokine that impacts this disease. ERa deficiency in (NZB Â NZW)F 1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERa also modulates lupus in males. These studies demonstrate that ERa, rather than ERb, plays a major role in regulating autoimmunity in (NZB Â NZW)F 1 mice. Furthermore, our results suggest for the first time that ERa promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERa, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.

The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.

Eighty-four patients with insulin-dependent diabetes mellitus had studies of renal function and quantitative renal morphometry including mesangial volume fraction (Vvmes/glom), index of arteriolar hyalinosis, percentage of globally sclerosed glomeruli (%GS), and interstitial volume fraction for total renal cortex (Vvint/T). There was significant correlation among these four parameters, and all four structural parameters correlated with glomerular filtration rate and the log of urinary albumin excretion. Stepwise multiple regression analysis showed that Vvmes/glom and Vvint/T were additive, suggesting that they are partially independent. Arteriolar hyalinosis and %GS did not improve the correlations further. We hypothesize that Vvmes/glom, Vvint/T, arteriolar hyalinosis, and %GS represent multiple but probably interrelated pathologic mechanisms leading to the functional disturbances of diabetic nephropathy. Longitudinal studies of patients with diabetes and studies of patients with diseases producing interstitial expansion in the absence of glomerular disease may help clarify the independent role of interstitial expansion in the kidney disease of diabetes mellitus.