A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity

Case report: Transient lactate elevation by intravenous insulin infusion therapy for diabetic ketoacidosis in a patient with mitochondrial DNA 3243 A > G mutation: A glycolysis rebooting syndrome?

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed

Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches

BACKGROUND: For over 150 years, pathologists have relied on histomorphology to classify and diagnose neoplasms. Their success has been stunning, permitting the accurate diagnosis of thousands of different types of neoplasms using only a microscope and a trained eye. In the past two decades, cancer genomics has challenged the supremacy of histomorphology by identifying genetic alterations shared by morphologically diverse tumors and by finding genetic features that distinguish subgroups of morphologically homogeneous tumors. DISCUSSION: The Developmental Lineage Classification and Taxonomy of Neoplasms groups neoplasms by their embryologic origin. The putative value of this classification is based on the expectation that tumors of a common developmental lineage will share common metabolic pathways and common responses to drugs that target these pathways. The purpose of this manuscript is to show that grouping tumors according to their developmental lineage can reconcile certain fundamental discrepancies resulting from morphologic and molecular approaches to neoplasm classification. In this study, six issues in tumor classification are described that exemplify the growing rift between morphologic and molecular approaches to tumor classification: 1) the morphologic separation between epithelial and non-epithelial tumors; 2) the grouping of tumors based on shared cellular functions; 3) the distinction between germ cell tumors and pluripotent tumors of non-germ cell origin; 4) the distinction between tumors that have lost their differentiation and tumors that arise from uncommitted stem cells; 5) the molecular properties shared by morphologically disparate tumors that have a common developmental lineage, and 6) the problem of re-classifying morphologically identical but clinically distinct subsets of tumors. The discussion of these issues in the context of describing different methods of tumor classification is intended to underscore the clinical value of a robust tumor classification. SUMMARY: A classification of neoplasms should guide the rational design and selection of a new generation of cancer medications targeted to metabolic pathways. Without a scientifically sound neoplasm classification, biological measurements on individual tumor samples cannot be generalized to class-related tumors, and constitutive properties common to a class of tumors cannot be distinguished from uninformative data in complex and chaotic biological systems. This paper discusses the importance of biological classification and examines several different approaches to the specific problem of tumor classification

δ¹⁸O and δ¹³C record of Paragloborotalia siakensis and Dentoglobigerina venezuelana from IODP Hole 321-U1337A

Knowledge of the equatorial thermocline is essential for understanding climate changes in the tropical Pacific. Multispecies planktic foraminiferal analyses provide a way to examine temperature distributions and thus the structure of the thermocline. Although the secular thermocline development has been documented back to the late Miocene, the early to middle Miocene interval has rarely been examined. In addition, relationships with the dynamic Antarctic ice sheets remain unclear. Here we investigate the vertical thermal gradient in the upper water column at Integrated Ocean Drilling Program Site U1337 in the eastern equatorial Pacific (EEP) throughout the early to middle Miocene (23.1 to 11.7 Ma). The gradient increased over the Miocene Climatic Optimum, whereas it decreased during the East Antarctic Ice Sheet Expansion (EAIE). Comparison of the EEP record with its western equatorial Pacific (WEP) counterpart suggests that sea surface temperature was more stable in the WEP than in the EEP. We further estimated equatorial thermocline from two diagonal gradients between the EEP and the WEP: thermocline shoaled from 16.7 to 15.7 Ma and tilt weakened between 16.5 and 13.8 Ma. The onset of the "Monterey Excursion" and the reduced Antarctic ice sheet volume would have affected thermocline depth and tilt, respectively. Thermocline depth was likely much deeper compared to Pliocene‐to‐modern conditions. Furthermore, a 4‐point‐based distribution of isotherms (4DI index) was used as a metric of the evenness or unevenness of the isotherm distributions. The 4DI index considerably reduced at around the EAIE and other Mi‐events, reflecting the evenly distributed isotherms under a more glaciated Antarctica

Planktic foraminiferal δ¹⁸O and δ¹³C record from IODP Hole 320-U1334A

Understanding planktic foraminiferal depth habitat along with consistent taxonomic concepts is key to accurate reconstruction of paleoceanographic records. The Oligocene‐Pliocene long‐ranging and widely distributed species Dentoglobigerina venezuelana lived in the mixed layer (shallower) during the early Oligocene, whereas the same species calcified at thermocline or subthermocline depths (deeper) during the late Oligocene and Miocene. The exact timing of the species' depth habitat change and its possible relationships with Oligocene climate dynamics remain unknown. Here we reveal isotopic records of D. venezuelana along with the Paragloborotalia siakensis group (a mixed‐layer dweller) by using sediments at Integrated Ocean Drilling Program Site U1334 in the eastern equatorial Pacific throughout the Oligocene. A two‐step depth habitat change of D. venezuelana is apparent: (1) from upper to lower mixed layer (~27.4 Ma) and (2) from lower mixed layer to thermocline depth (~26.3 Ma). In addition, the planktic foraminiferal faunal assemblage experienced a marked change from dominantly thermocline (deeper) species to abundant mixed‐layer (shallower) species, suggesting that depth habitat shifts of D. venezuelana were clearly related to thermocline deepening in the eastern equatorial Pacific. Comparison of the first isotopic shift (~27.4 Ma) at multiple sites (U1334, U1333, and 1218) revealed a southward depth habitat change of D. venezuelana within ~200 kyr, implying overall thermocline deepening with reduced steepness in the eastern equatorial Pacific. We consider that global warming conditions during the late Oligocene likely caused thermocline deepening with upwelling decrease in the eastern equatorial Pacific, guiding D. venezuelana to adapt to greater depths in the water column

Stratigraphic distribution and the number of planktic foraminifera from IODP Hole 320-U1334A

Understanding planktic foraminiferal depth habitat along with consistent taxonomic concepts is key to accurate reconstruction of paleoceanographic records. The Oligocene‐Pliocene long‐ranging and widely distributed species Dentoglobigerina venezuelana lived in the mixed layer (shallower) during the early Oligocene, whereas the same species calcified at thermocline or subthermocline depths (deeper) during the late Oligocene and Miocene. The exact timing of the species' depth habitat change and its possible relationships with Oligocene climate dynamics remain unknown. Here we reveal isotopic records of D. venezuelana along with the Paragloborotalia siakensis group (a mixed‐layer dweller) by using sediments at Integrated Ocean Drilling Program Site U1334 in the eastern equatorial Pacific throughout the Oligocene. A two‐step depth habitat change of D. venezuelana is apparent: (1) from upper to lower mixed layer (~27.4 Ma) and (2) from lower mixed layer to thermocline depth (~26.3 Ma). In addition, the planktic foraminiferal faunal assemblage experienced a marked change from dominantly thermocline (deeper) species to abundant mixed‐layer (shallower) species, suggesting that depth habitat shifts of D. venezuelana were clearly related to thermocline deepening in the eastern equatorial Pacific. Comparison of the first isotopic shift (~27.4 Ma) at multiple sites (U1334, U1333, and 1218) revealed a southward depth habitat change of D. venezuelana within ~200 kyr, implying overall thermocline deepening with reduced steepness in the eastern equatorial Pacific. We consider that global warming conditions during the late Oligocene likely caused thermocline deepening with upwelling decrease in the eastern equatorial Pacific, guiding D. venezuelana to adapt to greater depths in the water column

Structure, Stability and Binding Properties of Collagen-Binding Domains from <i>Streptococcus mutans</i>

Collagen-binding proteins (CBP), Cnm and Cbm, from Streptococcus mutans are involved in infective endocarditis caused by S. mutans because of their collagen-binding ability. In this study, we focused on the collagen-binding domain (CBD), which is responsible for the collagen-binding ability of CBP, and analyzed its structure, binding activity, and stability using CBD domain variants. The CBD consists of the N1 domain, linker, N2 domain, and latch (N1-N2~) as predicted from the amino acid sequences. The crystal structure of the Cnm/CBD was determined at a 1.81 Å resolution. N1_linker_N2 forms a ring structure that can enfold collagen molecules, and the latch interacts with N1 to form a ring clasp. N1 and N2 have similar immunoglobulin folds. The collagen-binding activities of Cbm/CBD and its domain variants were examined using ELISA. N1-N2~ bound to collagen with KD = 2.8 μM, and the latch-deleted variant (N1-N2) showed weaker binding (KD = 28 μM). The linker-deleted variant (N1N2~) and single-domain variants (N1 and N2) showed no binding activity, whereas the domain-swapped variant (N2-N1~) showed binding ability, indicating that the two N-domains and the linker are important for collagen binding. Thermal denaturation experiments showed that N1-N2 was slightly less stable than N1-N2~, and that N2 was more stable than N1. The results of this study provide a basis for the development of CBD inhibitors and applied research utilizing their collagen-binding ability