It has been demonstrated that inhibitors of advanced glycation end products (AGE), such as aminoguanidine, can suppress peritoneal AGE in rats on peritoneal dialysis (PD). However, it is unknown whether late administration of a putative cross-link breaker, alagebrium, could reverse peritoneal AGE. We therefore compared alagebrium with aminoguanidine in their ability to reverse peritoneal AGE in rats on PD. Male Sprague-Dawley rats were randomly divided into 3 groups: group I dialyzed with 4.25% glucose solution for all exchanges; group II dialyzed with 4.25% glucose solution containing aminoguanidine, and group III dialyzed with 4.25% glucose solution containing alagebrium for last 8 weeks of 12-week dialysis period. Dialysis exchanges were performed 2 times a day for 12 weeks. Immunohistochemistry was performed using a monoclonal anti-AGE antibody. One-hour PET was performed for comparison of transport characteristics. The immunolabelling of AGE in peritoneal membrane was markedly decreased in the alagebrium group. Consistent with this, the alagebrium group exhibited significantly higher D/Do glucose and lower D/P urea, suggesting low peritoneal membrane transport. But there were no significant differences between the control and the aminoguanidine group. These results suggest that the alagebrium may be the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in rats on PD.
Advanced Glycation End Products; Aminoguanidine; Alagebrium; Peritoneal Dialysis
Bordetella (B) bronchiseptica is a common veterinary pathogen, but has rarely been implicated in human infections. Most patients with B. bronchiseptica infections are compromised clinically such as in patients with a malignancy, AIDS, malnutrition, or chronic renal failure. We experienced a case of relapsing peritonitis caused by B. bronchiseptica associated with continuous ambulatory peritoneal dialysis (CAPD). A 56-yr-old male, treated with CAPD due to end stage renal disease (ESRD), was admitted with complaints of abdominal pain and a turbid peritoneal dialysate. The culture of peritoneal dialysate identified B. bronchiseptica. The patient was treated with a combination of intraperitoneal antibiotics. There were two further episodes of relapsing peritonitis, although the organism was sensitive to the used antibiotics. Finally, the indwelling CAPD catheter was removed and the patient was started on hemodialysis. This is the first report of a B. bronchiseptica human infection in the Korean literature.
Bordetella Bronchiseptica; Peritonitis; Peritoneal Dialysis, Continuous Ambulatory
Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulation of synaptic plasticity. CaM binding dynamically regulates mGluR5 surface expression; however, the mechanisms linking CaM to mGluR5 trafficking are not clear. Recent studies showed that CaM binding to mGluR7 regulates its trafficking in a phosphorylation-dependent manner by disrupting the binding of PICK1. The E3 ligase seven in absentia homolog (Siah)-1A binds to mGluR5 and competes with CaM binding making it an intriguing molecule to regulate phosphorylation-dependent trafficking of mGluR5. In the present study, we find that CaM competes with Siah-1A for mGluR5 binding in a phosphorylation-dependent manner in rat hippocampal neurons. Specifically, phosphorylation of mGluR5 S901 favors Siah-1A binding by displacing CaM. We identified critical residues regulating Siah-1A binding to mGluR5 and showed that binding is essential for the Siah-1A effects on mGluR5 trafficking. Siah-1A binding decreases mGluR5 surface expression and increases endosomal trafficking and lysosomal degradation of mGluR5. Thus CaM-regulated Siah-1A binding to mGluR5 dynamically regulates mGluR5 trafficking. These findings support a conserved role for CaM in regulating mGluR trafficking by PKC-dependent regulation of receptor binding proteins.
Keyhole craniotomy is a modification of pterional craniotomy that allows for use of a minimally invasive approach toward cerebral aneurysms. Currently, mini-pterional (MPKC) and supraorbital keyhole craniotomies (SOKC) are commonly used. In this study, we measured and compared the geometric configurations of surgical exposure provided by MPKC and SOKC.
Nine patients underwent MPKC and four underwent SOKC. Their postoperative contrast-enhanced brain computed tomographic scans were evaluated. The transverse and longitudinal diameters and areas of exposure were measured. The locations of the anterior communicating artery, bifurcation of the middle cerebral artery (MCAB), and the internal carotid artery (ICA) terminal were identified, and the working angles and depths for these targets were measured.
No significant differences in the transverse diameters of exposure were observed between MPKC and SOKC. However, the longitudinal diameters and the areas were significantly larger, by 1.5 times in MPKC. MPKC provided larger operable working angles for the targets. The angles by MPKC, particularly for the MCAB, reached up to 1.9-fold of those by SOKC. Greater working depths were required in order to reach the targets by SOKC, and the differences were the greatest in the MCAB by 1.6-fold.
MPKC provides larger exposure than SOKC with a similar length of skin incision. MPKC allows for use of a direct transsylvian approach, and exposes the target in a wide working angle within a short distance. Despite some limitations in exposure, SOKC is suitable for a direct subfrontal approach, and provides a more anteromedial and basal view. MCAB and posteriorly directing ICA terminal aneurysms can be good candidates for MPKC.
Cerebral aneurysm; Craniotomy; Minimally invasive; Mini-pterional; Supraorbital; Surgical exposure
Infraoptic anterior cerebral artery (ACA) is an extremely rare congenital anomaly. This anomalous artery usually arises from the intradural internal carotid artery (ICA) near the level of the ophthalmic artery (OA) or rarely from the extradural ICA. This anomaly frequently harbors a cerebral aneurysm, and may involve other coexisting vascular anomalies. In the case of this anomaly, surgical treatment of the aneurysm at the proximal ACA or anterior communicating artery (ACoA) may sometimes be difficult, because the veiled proximal ACA by the optic nerve would make proximal control inconvenient and the vertical midline segment of the proximal ACA would frequently form a superiorly directing aneurysm with a relatively high position. We report on an extremely rare case of a ruptured aneurysm at the infraoptic azygous ACA, possibly having an extradural origin, accompanied by contralateral ICA agenesis, and also introduce a feasible method for treatment by Y-stent assisted coil embolization.
Infraoptic; Anterior cerebral artery; Y-stent
Tubulin glutamylation is a post-translational modification (PTM) occurring predominantly on ciliary axonemal tubulin and has been suggested to be important for ciliary function 1,2. However, its relationship to disorders of the primary cilium, termed ‘ciliopathies’, has not been explored. Here, in Joubert syndrome (JBTS) 3, we identify the JBTS15 locus and the responsible gene as CEP41, encoding a centrosomal protein of 41 KDa 4. We show that CEP41 is localized to the basal body/primary cilium, and regulates the ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme 5. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mouse, and induces cilia axonemal glutamylation defects. Our data identify loss of CEP41 as a cause of JBTS ciliopathy and highlight involvement of tubulin PTM in pathogenesis of the ciliopathy spectrum.
A fenestrated middle cerebral artery (MCA) is a rare congenital anomaly, and is related to interference in the normal embryonic development of the MCA. Fenestrated MCA has been regarded to have no clinical significance other than a rare event of hemorrhage from associated aneurysm. However, the fenestration within the arterial trunk can be an obstacle against thrombus migration and may be associated with a major cerebral infarction. Moreover, the presence of this anomaly can be hardly detected prior to thrombolytic procedures, and emergent treatments are proceeded without any information of anatomical configurations. Therefore, the recanalization procedures would carry a high risk of intraprocedural complications. We report a rare case of MCA territory infarction from occlusion of fenestrated M1 segment, and also introduce a safe method of mechanical thrombolysis using coil.
Cerebral infarction; Middle cerebral artery; Fenestration
Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.
Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse U.S. populations. We measured luciferase activities of the six common promoter haplotypes of MATE1 using in vitro and in vivo reporter assays. Haplotypes that contain the most common variant (mean allele frequency in four ethnics: 0.322), g.−66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, AP-1 and AP-2rep, were predicted to bind to the promoter in the region of g.−66T>C. Results from electrophoretic mobility shift assays showed that the g.−66T allele, exhibited greater binding to AP-1 than the g.−66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.−66T>C. These data suggest that the reduced transcriptional activity of g.−66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.−66T>C in comparison to samples from individuals who were homozygous for the g.−66T allele. Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.−66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.
MATE1; Haplotype; Promoter; AP-1; AP-2rep; Transcriptional activity; Pharmacogenomics; Membrane transporters; SLC47A1; Polymorphisms
The “ciliopathies” are a newly defined group of disorders characterized by defects in the structure or function of the cellular primary cilium. Patients with these disorders display variably expressive fibrocystic renal disease, retinal blindness, polydactyly, obesity, and brain dysgenesis as well as neurocognitive impairments. Joubert syndrome is a ciliopathy defined by cerebellar vermis hypoplasia, oculomotor apraxia, intermittent hyperventilation, and mental retardation. Recent evidence suggests important roles for the primary cilium in mediating a host of extracellular signaling events such as morphogen, mitogen, homeostatic and polarity signals. Based upon the clinical features of ciliopathies and cilia mediated signaling pathways, the data support a role for the primary cilium in modulating neurogenesis, cell polarity, axonal guidance and possibly adult neuronal function.
Ciliopathy; Joubert syndrome; Neuronal function; Primary cilia
The tubby mouse is characterized by progressive retinal and cochlear degeneration and late-onset obesity. These phenotypes are caused by a loss-of-function mutation in the tub gene and are shared with several human syndromes, suggesting the importance of tubby protein in central nervous system (CNS) functioning. Although evidence suggests that tubby may act as a transcription factor mediating G-protein coupled receptor (GPCR) signaling, any downstream gene regulated by tubby has yet to be identified. To explore potential target genes of tubby with region-specific transcription patterns in the brain, we performed a microarray analysis using the cerebral cortex and hypothalamus of tubby mice. We also validated the changes of gene expression level observed with the microarray analysis using real-time RT-PCR. We found that expression of erythroid differentiation factor 1 (Erdr1) and caspase 1 (Casp1) increased, while p21-activated kinase 1 (Pak1) and cholecystokinin 2 receptor (Cck2r) expression decreased in the cerebral cortex of tubby mice. In the hypothalamic region, Casp 1 was up-regulated and µ-crystallin (CRYM) was down-regulated. Based on the reported functions of the differentially expressed genes, these individual or grouped genes may account for the phenotype of tubby mice. We discussed how altered expression of genes in tubby mice might be understood as the underlying mechanism behind tubby phenotypes.
Tubby; Microarray; Gene expression; Cerebral cortex; Hypothalamus
Heparin is a well-known anticoagulant widely used in various clinical settings. Interestingly, recent studies have indicated that heparin also has anti-inflammatory effects on neuroinflammation-related diseases, such as Alzheimer's disease and meningitis. However, the underlying mechanism of its actions remains unclear. In the present study, we examined the anti-inflammatory mechanism of heparin in cultured cerebral endothelial cells (CECs), and found that heparin inhibited the tumor necrosis factor α(TNFα)-induced and nuclear factor kappa B (NF-κB)-dependent expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which are crucial for inflammatory responses. Heparin selectively interfered with NF-κB DNA-binding activity in the nucleus, which is stimulated by TNFα. In addition, non-anticoagulant 2,3-O desulfated heparin (ODS) prevented NF-κB activation by TNFα, suggesting that the anti-inflammatory mechanism of heparin action in CECs lies in heparin's ability to inhibit the expression of cell adhesion molecules, as opposed to its anticoagulant actions.
Heparin; NF-κB; ICAM-1; VCAM-1; Cerebral endothelial cells; Anti-inflammation