Comparing α7 nicotinic acetylcholine receptor binding,amyloid‐β deposition,and mitochondria complex‐I function in living brain: A PET study in aged monkeys

This study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7‐nAChR) binding, amyloid‐β (Aβ) deposition, and mitochondrial complex I (MC‐I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [¹¹C](R)‐MeQAA, [¹¹C]PIB, and [¹⁸F]BCPP‐EF were conducted in monkeys in a conscious condition. [¹¹C](R)‐MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BP_ND), [¹¹C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [¹⁸F]BCPP‐EF binding was determined by Logan graphical analysis to calculate total distribution volume (V_T) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [¹¹C](R)‐MeQAA, while being lower in the cerebellum. Significant age‐related reduction of [¹¹C](R)‐MeQAA binding to α7‐nAChR was determined only in the occipital cortex. The plot of Vt of [¹⁸F]BCPP‐EF against BP_ND of [¹¹C](R)‐MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [¹¹C]PIB against BP_ND of [¹¹C](R)‐MeQAA showed a positive correlation. The in vivo binding of [¹¹C](R)‐MeQAA could reflect the upregulation of α7‐nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC‐I activity in living brain. Synapse 69:475–483, 2015. © 2015 Wiley Periodicals, Inc.     

CD11c‐positive cells from brain,spleen, lung,and liver exhibit site‐specific immune phenotypes and plastically adapt to new environments

The brain's immune privilege has been also attributed to the lack of dendritic cells (DC) within its parenchyma and the adjacent meninges, an assumption, which implies maintenance of antigens rather than their presentation in lymphoid organs. Using mice transcribing the green fluorescent protein under the promoter of the DC marker CD11c (itgax), we identified a juxtavascular population of cells expressing this DC marker and demonstrated their origin from bone marrow and local microglia. We now phenotypically compared this population with CD11c/CD45 double‐positive cells from lung, liver, and spleen in healthy mice using seven‐color flow cytometry. We identified unique, site‐specific expression patterns of F4/80, CD80, CD86, CX3CR1, CCR2, FLT3, CD103, and MHC‐II. Furthermore, we observed the two known CD45‐positive populations (CD45^high and CD45^int) in the brain, whereas liver, lung, and spleen exhibited a homogeneous CD45^high population. CD11c‐positive microglia lacked MHC‐II expression and CD45^high/CD11c‐positive cells from the brain have a lower percentage of MHC‐II‐positive cells. To test whether phenotypical differences are fixed by origin or specifically develop due to environmental factors, we transplanted brain and spleen mononuclear cells on organotypic slice cultures from brain (OHSC) and spleen (OSSC). We demonstrate that adaption and ramification of MHC‐II‐positive splenocytes is paralleled by down‐regulation of MHC‐II, whereas brain‐derived mononuclear cells neither ramified nor up‐regulated MHC‐II in OSSCs. Thus, brain‐derived mononuclear cells maintain their MHC‐II‐negative phenotype within the environment of an immune organ. Intraparenchymal CD11c‐positive cells share immunophenotypical characteristics of DCs from other organs but remain unique for their low MHC‐II expression. GLIA 2015;63:611–625     

ICD coding for epilepsy: Past,present, and future—A report by the International League Against Epilepsy Task Force on ICD codes in epilepsy

The World Health Organization (WHO) International Classification of Diseases (ICD) has been used to classify causes of morbidity and mortality such as epilepsy for more than 50 years. The aims of this critical commentary are to do the following: (1) Introduce the ICD classification, summarize the ICD‐9 and ICD‐10 codes for epilepsy and seizures, and discuss the challenges of mapping epilepsy codes between these two versions; (2) discuss how the ICD‐9 and ICD‐10 relate to the revised International League Against Epilepsy (ILAE) terminology and concepts for classification of seizures and epilepsies; (3) discuss how ICD‐coded data have been used for epilepsy care and research and briefly examine the potential impact of the international ICD‐10 clinical modifications on research; (4) discuss the upcoming ICD‐11 codes and the role of the epilepsy community in their development; and (5) discuss how the ICD‐11 will conform more closely to the current ILAE terminology and classification of the epilepsies and seizures and its potential impact on clinical care, surveillance, and public health and research.     

Classical type and blastoid variant mantle cell lymphoma in the same lymph node: Histology and cytological findings from a touch imprint specimen

Blastoid variant (BV) is one of the aggressive variants of mantle cell lymphoma (MCL). BV‐MCL is defined by its blastic cytomorphology. Previous studies using sequential biopsies in cases with MCL have demonstrated that classical type MCL (C‐MCL) often transforms or relapses as an aggressive variant, but a histopathological transition from C‐MCL to an aggressive MCL variant in the same pathological specimen has been shown in only a limited number of the cases. We present a case of MCL in which a histological transition between C‐MCL and BV‐MCL was observed in the same lymph node. A 53‐year‐old man presented with a submandibular tumor. Touch imprint cytology revealed a monotonous proliferation of large blastic lymphoid cells. Histology revealed a transition between a large lymphoid cell component and small foci of small‐ to medium‐sized cell component within the tumor. Both components were CD5(+), CD10(−), CD20(+), cyclin D1(+), and SOX11(+) on immunohistochemistry. Fluorescent in situ hybridization revealed the translocation of IgH/BCL1 locus. These findings led to a final diagnosis of BV‐MCL with coexistent C‐MCL. The present case suggests the existence of a pathogenetic pathway of MCL from C‐MCL to BV‐MCL. Because it is important to accurately identify BV‐MCL for prognostication, appropriate ancillary diagnostic tools should be used in suspected cases. Diagn. Cytopathol. 2017;45:364–370. © 2016 Wiley Periodicals, Inc.     

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the “supernumerary” group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X‐linked nuclear‐encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early‐onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.     

Molecular mechanisms and functions of pyroptosis,inflammatory caspases and inflammasomes in infectious diseases

Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicates that cell death contributes to immune defense against infectious diseases. Pyroptosis is a form of inflammatory programmed cell death pathway activated by human and mouse caspase-1, human caspase-4 and caspase-5, or mouse caspase-11. These inflammatory caspases are used by the host to control bacterial, viral, fungal, or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore-forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro-inflammatory cytokines IL-1β and IL-18, alarmins and endogenous danger-associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.     

Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER–Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N‐ and O‐glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.