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A 30-year-old woman with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation (HSCT) derived from her HLA-matched sister six years previously. She received preconditioning total body irradiation with renal shielding and was subsequently administered cyclosporin A (CyA) as prophylaxis against graft-versus-host disease (GVHD). Four months after HSCT, asymptomatic proteinuria and glomerular hematuria developed during CyA tapering without obvious extrarenal involvements of GVHD, and persisted for six years. A renal biopsy revealed endothelial injury in the glomeruli, and the deposition of C4d was detected diffusely on glomerular capillaries and focally on peritubular capillaries, suggesting that nephropathy involved antibody- or complement-associated immune reactions.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disease caused by GATA3 mutations. Although several cases with variable renal features have been reported, the presence of histological changes within the glomeruli in adult patients is unclear. We herein report an adult case of HDR syndrome with a novel p.C288W (TGC>TGG) missense mutation in GATA3. His renal histology showed a membranoproliferative glomerulonephritis-like glomerular lesion. Additional renal histological analyses of HDR syndrome patients will be needed to clarify the role of GATA3 in both the developing and adult kidney.

We investigated the expression of the semaphorin family member, Sema3D, in the developing dorsal root ganglia of the rat. Sema3D expression was observed in a subpopulation of dorsal root ganglion (DRG) neurons. The expression peaked at E15 and thereafter it declined. The change in Sema3D expression between E13 and E20 was analyzed by comparison to the expression of TrkA, TrkC and Neuropilin-1 by in situ hybridization. The expression pattern of Sema3D in DRG was similar to that of TrkC and was different from that of TrkA or Neuropilin-1. Double immunohistochemical analysis revealed that Sema3D expression was confined to neurons that expressed TrkC and Runx3, which mediate proprioception, but not to nociceptive neurons that express TrkA. Functionally distinct DRG neurons have different projection patterns in the spinal cord, therefore, Sema3D may regulate the axonal navigation of the large diameter DRG neurons.

Background/Aims: Peritoneal fibrosis can lead to the discontinuation of continuous ambulatory peritoneal dialysis. The present study investigated the direct effect of aldosterone, which influences tissue fibrosis, and its cellular mechanism using cultured rat peritoneal mesothelial cells (RPMCs). Materials andMethods: The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors, 11β-hydroxysteroid dehydrogenase 2, serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and connective tissue growth factor (CTGF) was evaluated using reverse transcriptase-polymerase chain reaction and Western blot. The ability of RPMCs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA of SGK1 was transfected to determine the role of SGK1. Results: CYP11B2, mineralocorticoid receptors and 11β-hydroxysteroid dehydrogenase 2 were expressed in RPMCs. The release of aldosterone from RPMCs into the culture medium was confirmed. Stimulation of RPMCs with the addition of aldosterone significantly increased SGK1 expression and phosphorylation and CTGF upregulation, and these effects were completely inhibited by the mineralocorticoid receptor antagonist spironolactone. SGK1 gene silencing abrogated aldosterone-induced CTGF expression. Conclusion: The local aldosterone system exists and acts directly as a profibrotic factor in the peritoneal mesothelium.

The preoptic area (POa) of the rostral diencephalon supplies the neocortex and the amygdala with GABAergic neurons in the developing mouse brain. However, the molecular mechanisms that determine the pathway and destinations of POa-derived neurons have not yet been identified. Here we show that Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-induced expression of Neuropilin-2 (Nrp2) and its down-regulation control the destination of POa-derived GABAergic neurons. Initially, a majority of the POa-derived migrating neurons express COUP-TFII and form a caudal migratory stream toward the caudal subpallium. When a subpopulation of cells steers toward the neocortex, they exhibit decreased expression of COUP-TFII and Nrp2. The present findings show that suppression of COUP-TFII/Nrp2 changed the destination of the cells into the neocortex, whereas overexpression of COUP-TFII/Nrp2 caused cells to end up in the medial part of the amygdala. Taken together, these results reveal that COUP-TFII/Nrp2 is a molecular switch determining the pathway and destination of migrating GABAergic neurons born in the POa.

Latexin, the endogenous protein inhibitor of the A/B subfamily of metallocarboxypeptidases, is expressed in small nociceptive neurons in sensory ganglia and in a subset of neurons in the telencephalon. In this study, we generated latexin-deficient mice that exhibited increased tail-flick latency compared to wild-type animals upon noxious heat stimulation. The reduced pain sensitivity in the mutants was rescued by the systemic administration of a plant carboxypeptidase inhibitor that inhibits the A/B subfamily of metallocarboxypeptidases. These findings suggest that latexin is involved in the transmission of pain.

A 70-year-old woman developed anemia and kidney injury 10 months after mitral valve (MV) repair. Serological findings and Doppler echocardiography suggested hemolytic anemia due to mitral regurgitation jet collision with an annuloplasty ring (MRCR). Since kidney injury persisted even without exacerbation of anemia over 10 months, we performed an MV replacement. The anemia improved rapidly after the surgery; however, the renal function remained chronic kidney disease (CKD) after reoperation. Kidney injury was thought to be due to iron deposition and decreased renal perfusion that caused tubular injury. A comprehensive literature review shows that hemolysis due to MRCR in the early postoperative phase (within 3 postoperative months) can be often ameliorated with endothelialization without the need for reoperation; however, hemolysis in the late postoperative phase can persist even for a long period without reoperation. Chronic hemolysis can lead to kidney injury and progress to CKD even without clinical evidence of exacerbation of anemia. Therefore, in cases of late postoperative phase hemolysis, reoperation should be considered for better management of kidney injury and hemolytic anemia.

Neurons expressing latexin, a carboxypeptidase A inhibitor, are restricted to lateral areas in the cerebral cortex of adult and early postnatal rats. To address the precise timing of cortical regional specification at the cellular level, we monitored latexin expression in developing cortical cells under specific conditions in vitro. Individual cortical cells were labeled with 5-bromo-2′-deoxyuridine in vivo, dissociated and exposed to a defined new environment in a monolayer or a reaggregated-cell culture system. While a substantial fraction of early progenitor cells derived from the lateral cerebral wall became latexin-expressing neurons in both systems, far fewer progenitors from dorsal cortex did so under the same environmental conditions, indicating early establishment of cortical regional specification at the progenitor cell level. Furthermore, it was shown that the probability for postmitotic cells within lateral cortex to become latexin-expressing neurons was influenced by temporally regulated regional environmental signals. These findings suggest that developing cortical cells are progressively specified for a regional molecular phenotype during both their proliferative and postmitotic periods.

Most of the smaller diameter neurons of dorsal root and trigeminal ganglia in adult rats expressed latexin, which has the inhibitor activity of carboxypeptidase A. Most of the dorsal root ganglion (DRG) neurons containing either calcitonin gene-related peptide (CGRP), substance P (SP) or somatostatin (SST) coexpressed latexin. Latexin was widely distributed in the cytoplasm of the cell body and in axonal fibers of cultured DRG neurons which were sensitive to capsaicin. In addition, latexin-immunoreactivity was observed throughout lamina II of the spinal cord in normal animals, but was lost following sciatic nerve-axotomy, suggesting the presence of latexin-immunoreactive axonal fibers and/or terminals from DRG neurons. Immunoelectron microscopy indeed revealed latexin-immunoreactive axonal terminals and thinly myelinated and unmyelinated axonal fibers within the dorsal horn. These observations suggest that latexin may be involved in nociceptive information transmission or its modulation.

Mechanisms intrinsic to the early cerebral cortex have been implicated in the establishment of cortical area identity. However, the extent to which the cortical protomap contributes to the formation of highly complex intrahemispheric connections remains obscure. Mechanisms by which postmitotic neurons establish correct corticocortical connections later in corticogenesis also remain to be elucidated. Here, we used a new transplantation method, employing donor tissue harvested from enhanced green fluorescent protein-expressing rats, to show that cortical progenitors are regionally specified for connectional potential and that this controls the development of specific intrahemispheric projections. The acquisition of connectional capacity relies on positional cues within the cortical primordium, but is independent of thalamic inputs. In addition, since cortical neurons developing in organotypic slice culture extended axons more prominently into their normal cortical target tissues than into non-target tissues, we suggest that cortical neurons respond to specific signals derived from their cortical targets.

The developmental mechanism that contributes to the highly organized axonal connections within the cerebral cortex is not well understood. This is partly due to the lack of molecular markers specifically expressed in corticocortical associative neurons during the period of circuit formation. We have shown previously that latexin, a carboxypeptidase A inhibitor, is expressed in intrahemispheric corticocortical neurons from the second postnatal week in the rat (Arimatsu et al. [1999] Cereb. Cortex 9:569-576). In the present study, we first demonstrate in the adult rat that the orphan nuclear receptor Nurr1 is coexpressed in latexin-expressing neurons located in layer V, sublayer VIa, and the white matter of the lateral sector of the neocortex, and also in latexin-negative early born neurons in sublayer VIb of the entire neocortex. Virtually all Nurr1-expressing neurons exhibit immunoreactivity for phosphate-activated glutaminase but not for gamma-aminobutyric acid, suggesting that they are glutamatergic-excitatory neurons. By combining Nurr1 immunohistochemistry and 5-bromo-2'-deoxyuridine-birthdating, we then show that Nurr1 is expressed in (early born) subplate neurons and (later born) presumptive latexin-expressing neurons from embryonic day 18 onward. Finally, by combination of Nurr1 immunohistochemistry and retrograde tracing, we show that Nurr1-expressing neurons, including those in sublayer VIb, contribute predominantly to long-range intrahemispheric corticocortical projections. These results raise the possibility that Nurr1 plays a role in the establishment and maintenance of normal corticocortical circuitry and function.

Latexin, a carboxypeptidase A inhibitor, is expressed in a subset of neurons in the infragranular layers of the lateral cortex in the rat. We here show that latexin-expressing neurons exhibit ultrastructural features common to cortical pyramidal neurons. We show in combined retrograde tracing and immunofluorescent experiments that latexin-expressing neurons contribute to specific corticocortical pathways. Thus, injections of the retrograde tracer fluorogold into either the primary somatosensory (SI) or the primary motor (MI) cortical area labeled many latexin-expressing neurons in the infragranular layers of the secondary somatosensory (SII) and visceral sensory (Vi) areas. In contrast, tracer injections involving the thalamus, striatum, or contralateral SII and Vi exclusively labeled latexin-nonexpressing neurons in both the SII and Vi. Finally, we show that the correct corticocortical projections can be formed in organotypic slice cultures in vitro from latexin-expressing neurons: when slices of developing SII were cocultured with those from the SI and the thalamus, latexin-immunoreactive neurons in the SII projected preferentially to their normal SI target. The specific connectivity formed in vivo and in vitro by this molecularly distinct neuronal population reveals its characteristic manner of cortical organization and provides a unique model system to analyze mechanisms underlying the formation of precise corticocortical pathways.

The exact timing of regional patterning in the developing cerebral cortex and other telencephalic structures remains to be elucidated. In the present study, we addressed this issue by comparing the distribution and density of neuronal population expressing latexin in the adult rat telencephalon, with the regional pattern in the fetal cerebral wall as to the potential to generate latexin-expressing neurons. Immunohistochemical analyses on adult animals have shown that latexin-expressing neurons are restricted to a lateral cortical field, within which they are most abundant at the middle level, decreasing in number rostrally and caudally. Substantial numbers of latexin-immunopositive neurons were recorded in the claustrum and endopiriform nuclei, both of which are located from rostral to middle level in the lateral telencephalon. By examining the number and density of latexin-immunopositive neurons in organotypic slice cultures from various portions of the developing rat cerebral wall, it has been shown that the regional pattern within the early cerebral wall as to the potential to generate latexin-expressing neurons matches well the distribution and density of latexin-expressing neurons in the adult telencephalon. Thus, in cultures derived from either embryonic day 13 or 16 fetuses, latexin-immunopositive neurons appeared most prominently in those from rostral-to-middle portions of the lateral cerebral wall, decreasing in number rostrally and caudally. In cultures from the dorsal cerebral wall, the number was generally very low. In light of our previous finding that most prospective latexin-expressing neurons are still dividing at embryonic day 13, it can be concluded that some kind of pattern formation event occurs within the early cerebral wall even prior to the genesis of the postmitotic neurons that would be later allocated in a region-specific manner.