European Best Practice Guidelines for Peritoneal Dialysis acknowledged by ISN.
Explore the source record for details and available documents.
Europe↗
Biomedical subjects
Richard Johnson
Publications and source records attributed to Richard Johnson.
The function of neurofascin155 in oligodendrocytes is regulated by metalloprotease-mediated cleavage and ectodomain shedding.
Formation of the paranodal axo-glial junction requires the oligodendrocyte-specific 155-kDa isoform of neurofascin (NF155). Here, we report the presence of two peptides in cultured oligodendrocytes, which are recognized by distinct NF155-specific antibodies and correspond to a membrane anchor of 30 kDa and a 125 kDa peptide, which is shed from the cells, indicating that it consists of the NF155 ectodomain. Transfection of OLN-93 cells with NF155 verified that both peptides originate from NF155 cleavage, and we present evidence that metalloproteases mediate NF155 processing. Interestingly, metalloprotease activity is required for NF155 transport into oligodendrocyte processes supporting the functional significance of NF155 cleavage. To further characterize NF155 cleavage and function, we transfected MDCK cells with NF155. Although ectodomain shedding was observed in polarized and non-polarized MDCK cells, surface localization of NF155 was restricted to the lateral membrane of polarized cells consistent with a role in cell-cell adhesion. Aggregation assays performed with OLN-93 cells confirmed that NF155 accelerates cell-cell adhesion in a metalloprotease-dependent manner. The physiological relevance of NF155 processing is corroborated by the presence of NF155 cleavage products in heavy myelin, suggesting a role of NF155 ectodomain shedding for the generation and/or stabilization of the nodal/paranodal architecture.
Animals↗
Is salt-wasting the long awaited answer to the hyperuricaemia seen in uromodulin storage diseases?
Explore the source record for details and available documents.
Animals↗
Prenatal cranial ultrasound features of duplication chromosome 3q(21-24).
Explore the source record for details and available documents.
Abnormalities, Multiple↗
An unusual case of an extra row of eyelashes in the superior eyelid skin crease.
A diabetic patient was referred to the office for assessment of anterior blepharitis and associated tear film complications. On examination, he was noted to have bilateral, symmetrical rows of extra cilia within both upper eyelid skin creases. Differential diagnoses of aberrant cilia are discussed.
Adult↗
Regulation of human vascular smooth muscle cell migration by beta-adrenergic receptors.
Migration and proliferation of vascular smooth muscle cells (VSMCs) are two events involved in atherosclerosis, restenosis after balloon angioplasty, and stenosis of grafted vessels. Platelet-derived growth factor (PDGF) found in stenotic vessels is known to induce migration of VSMCs. VSMCs express both alpha- and beta-adrenergic receptors on their surface, and blood vessels are innervated by the adrenergic nervous system and exposed to circulating epinephrine. We examined the role of these receptors on PDGF-induced migration of VSMCs. VSMCs were cultured from saphenous vein segments. Migration was stimulated by PDGF. Effect of pretreatment of VSMCs with the beta-agonist isoproterenol, the alpha-agonist phenylephrine, or forskolin on PDGF-induced migration was examined with a modified Boyden chamber. Cell migration was quantitated by spectrophotometry. Intracellular cyclic AMP was determined by radioimmunoassay. PDGF significantly induced VSMC migration. Isoproterenol (0.1 and 1.0 microM) inhibited PDGF-induced migration by 30 per cent and 50 per cent, respectively. Forskolin (10 microM) completely blocked PDGF-induced migration. The migration inhibition by isoproterenol or forskolin was associated with a significant elevation of intracellular cyclic AMP. In contrast, phenylephrine had no effect on PDGF-induced migration or on cyclic AMP. Activation of beta-adrenergic receptors and the consequent rise in intracellular cyclic AMP inhibits migration of VSMCs induced by PDGF. These results are consistent with the notion that adrenergic agonists with substantial beta-receptor affinity, such as isoproterenol, can inhibit smooth muscle cell migration.
Adrenergic beta-Agonists↗
Neurofascins are required to establish axonal domains for saltatory conduction.
Voltage-gated sodium channels are concentrated in myelinated nerves at the nodes of Ranvier flanked by paranodal axoglial junctions. Establishment of these essential nodal and paranodal domains is determined by myelin-forming glia, but the mechanisms are not clear. Here, we show that two isoforms of Neurofascin, Nfasc155 in glia and Nfasc186 in neurons, are required for the assembly of these specialized domains. In Neurofascin-null mice, neither paranodal adhesion junctions nor nodal complexes are formed. Transgenic expression of Nfasc155 in the myelinating glia of Nfasc-/- nerves rescues the axoglial adhesion complex by recruiting the axonal proteins Caspr and Contactin to the paranodes. However, in the absence of Nfasc186, sodium channels remain diffusely distributed along the axon. Our study shows that the two major Neurofascins play essential roles in assembling the nodal and paranodal domains of myelinated axons; therefore, they are essential for the transition to saltatory conduction in developing vertebrate nerves.
Animals↗
Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF.
A recently described form of synaptic plasticity results in dynamic changes in the calcium permeability of synaptic AMPA receptors. Since the AMPA receptor GluR2 subunit confers calcium permeability, this plasticity is thought to occur through the dynamic exchange of synaptic GluR2-lacking and GluR2-containing receptors. To investigate the molecular mechanisms underlying this calcium-permeable AMPA receptor plasticity (CARP), we examined whether AMPA receptor exchange was mediated by subunit-specific protein-protein interactions. We found that two GluR2-interacting proteins, the PDZ domain-containing Protein interacting with C kinase (PICK1) and N-ethylmaleimide sensitive fusion protein (NSF), are specifically required for CARP. Furthermore, PICK1, but not NSF, regulates the formation of extrasynaptic plasma membrane pools of GluR2-containing receptors that may be laterally mobilized into synapses during CARP. These results demonstrate that PICK1 and NSF dynamically regulate the synaptic delivery of GluR2-containing receptors during CARP and thus regulate the calcium permeability of AMPA receptors at excitatory synapses.
Animals↗
Blocking of monocyte chemoattractant protein-1 during tubulointerstitial nephritis resulted in delayed neutrophil clearance.
The chemokine monocyte chemoattractant protein (MCP)-1 has been implicated in the monocyte/macrophage infiltration that occurs during tubulointerstitial nephritis (TIN). We investigated the role of MCP-1 in rats with TIN by administering a neutralizing anti-MCP-1 antibody (Ab). We observed significantly reduced macrophage infiltration and delayed neutrophil clearance in the kidneys of TIN model rats treated with the anti-MCP-1 Ab. To exclude the possibility that an observed immune complex could affect the resolution of apoptotic neutrophils via the Fc receptor, TIN model rats were treated with a peptide-based MCP-1 receptor antagonist (RA). The MCP-1 RA had effects similar to those of the anti-MCP-1 Ab. In addition, MCP-1 did not affect macrophage-mediated phagocytosis of neutrophils in vitro. Deposition of the anti-MCP-1 Ab in rat kidneys resulted from its binding to heparan sulfate-immobilized MCP-1, as demonstrated by the detection of MCP-1 in both pull-down and immunoprecipitation assays. We conclude that induction of chemokines, specifically MCP-1, in TIN corresponds with leukocyte infiltration and that the anti-MCP-1 Ab formed an immune complex with heparan sulfate-immobilized MCP-1 in the kidney. Antagonism of MCP-1 in TIN by Ab or RA may alter the pathological process, most likely through delayed removal of apoptotic neutrophils in the inflammatory loci.
Animals↗
Knowledge of structured treatment interruption and adherence to antiretroviral therapy.
We conducted a survey of 106 HIV-infected patients on antiretroviral therapy at a community hospital in Lancaster, Pennsylvania, to determine the extent of patient knowledge and attitudes about structured treatment interruption (STI) and whether these were factors in adherence to antiretroviral regimens. Thirty-six percent of patients possessed knowledge of STI as a treatment option and four patients reported that they had stopped taking antiretroviral therapy without specific recommendation from their physician based on information they had heard or read about STI. There was no difference in median adherence based on whether a patient was aware of STI, however, in the group who had heard of STI, attitude that STI is very beneficial was correlated with greater adherence to medication. More than one third of HIV-infected patients on antiretroviral therapy possessed knowledge of STI, and this knowledge affected adherence to antiretroviral regimens. Providers caring for HIV-infected patients should routinely inquire about patient knowledge of STI as another factor in assessing adherence to antiretroviral therapy.
Adolescent↗
The impact of gender on progression of renal disease: potential role of estrogen-mediated vascular endothelial growth factor regulation and vascular protection.
Male gender is associated with a more rapid progression of renal disease independent of blood pressure, dietary protein intake, or serum lipid levels. Recently, we reported a key role for the intrarenal vasculature in progressive renal disease (Kang D-H, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of endothelium in progressive renal disease. J Am Soc Nephrol 2002, 13:806-816). We hypothesized that estrogen-mediated preservation of the renal vasculature could account for the better renal outcome in female rats. We analyzed micro- and macrovascular changes in the 5/6 remnant kidney (RK) models both in male (n = 24) and female (n = 24) Sprague-Dawley rats up to 12 weeks after renal mass reduction. At 12 weeks, male and female RK rats had equivalent blood pressure, glomerular tuft area, and RK/body weight, but male rats showed worse renal function, proteinuria, glomerulosclerosis (%), and tubulointerstitial fibrosis. At 12 weeks peritubular capillary (PTC) EC proliferation and PTC density were higher in female RK rats whereas macrovascular changes in preglomerular vessels (smooth muscle cell proliferation, medial wall thickening, and adventitial fibrosis) were less prominent. The expression of vascular endothelial growth factor (VEGF) and VEGF type 2 receptor (flk-1) in renal cortex assessed by immunostaining were higher in female RK rats. To dissect the mechanism of sex hormone-induced vascular remodeling and VEGF regulation, we investigated the in vitro effect of 17 beta-estradiol (17 beta E, 10 nmol/L) on proliferation and VEGF expression of renal tubular cells (rat proximal tubular cells), vascular smooth muscle cells (VSMCs), and human umbilical vein endothelial cells (HUVECs). 17 beta E directly stimulated the proliferation of HUVECs, whereas it inhibited serum-induced proliferation of VSMCs. 17 beta E stimulated VEGF mRNA expression both in renal tubular cells and VSMCs. However, when cells were pretreated with a nitric oxide donor to simulate the in vivo condition, 17 beta E inhibited VEGF mRNA expression and protein release in VSMCs. In conclusion, female RK rats developed less glomerulosclerosis and renal failure compared to male RK rats in association with greater preservation of PTC and less preglomerular arteriopathy. Estrogen stimulated basal VEGF expression in renal tubular cells. We propose that estrogen may protect female rats in progressive renal disease by stimulating VEGF expression and maintaining a healthy intrarenal vasculature.
Animals↗
Hepatic hydropericardium.
A 41-year-old man with chronic hepatitis C and cirrhosis presented with pericardial effusion and tamponade requiring pericardiocentesis. Nine liters of pericardial fluid was drained with complete resolution of his ascites. He represented with recurrent pericardial effusions despite salt restriction and diuretic therapy. Subsequent radionuclide scans demonstrated a direct connection between the peritoneal and pericardial spaces. A pericardial window was formed but despite this there was recurrence of pericardial effusion and pleural effusion. The patient underwent orthotopic liver transplantation 7 months later and no recurrence of pleural or pericardial effusion was observed following transplantation. We believe this is the first case report of pericardial effusion secondary to cirrhotic ascites and a communication between the peritoneal and pericardial cavities.
Adult↗
An appropriate increase in the transcription of Aspergillus nidulans uvsC improved gene targeting efficiency.
Gene targeting to knock out the activity of specific genes has become important due to recent progress in genomics research. But this technique is still unavailable for many organisms, including economically important microorganisms, due to the high background of ectopic integration during genetic transformation. Strategies to improve targeting efficiency have included manipulating the expression of genes that are involved in homologous recombination. In this study, transcription of Aspergillus nidulans uvsC was elevated using the promoter sequences of the glyceraldehyde-3-phosphate dehydrogenase and Taka-amylase A genes from A. nidulans and A. oryzea respectively. Although a several-fold increase in the efficiency of targeting was observed at 3 loci, mycelial growth was suppressed in strains that had higher levels of uvsC transcription. These results suggest that uvsC is a rate-limiting factor in gene targeting, and that the increased efficiency of this targeting is hindered by a negative effect of increased transcription on cell proliferation.
Aspergillus nidulans↗
A comparison of two methods of palliation of large bowel obstruction due to irremovable colon cancer.
INTRODUCTION: Untreated malignant large bowel obstruction is rapidly fatal. Short-term palliation of symptoms can be achieved by formation of a stoma in those patients for whom resection surgery is inappropriate. In the final months of life, a stoma represents a significant burden for both patients and carers. Palliative endoluminal stenting may therefore be an attractive alternative option for this poor prognostic group. PATIENTS: Thirty-six patients were studied of whom 18 had obstructing left-sided colon cancer relieved by placement of endoluminal stents. These were compared with 18 historical controls with similar clinicopathological features that were treated more conventionally with palliative stoma formation in the same hospital. RESULTS: Patients in the two groups had similar sex distribution (P = 0.5); however, patients undergoing palliative stoma formation were significantly younger than patients being stented (P = 0.0065). As well as being older, there was a trend towards greater co-morbidities, stent patients having higher ASA grades (P = 0.01). Both groups of patients gained relief of obstructive symptoms. There were no differences in survival (P = 0.5) or in hospital mortality (2 in each group). The median length of palliation is 92 days (42-infinity days) for stenting and 121 days (89-281 days) for palliative stoma formation. Formation of a stoma required a significantly longer stay in ITU (P = 0.003) but total hospital stay was similar. CONCLUSIONS: As an alternative to palliative surgery, selected patients benefit from colonic endoluminal stenting with relief of obstructive symptoms and no adverse effect on survival. They may be spared the potential problems associated with palliative stoma formation and the morbidity of surgery. Stenting can be offered to the very frail patient who would otherwise be managed conservatively.
Aged↗
Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study.
OBJECTIVE: To compare the tolerability of malaria chemoprophylaxis regimens in non-immune travellers. DESIGN: Randomised, double blind, study with placebo run-in phase. SETTING: Travel clinics in Switzerland, Germany, and Israel. MAIN OUTCOME MEASURE: Proportion of participants in each treatment arm with subjectively moderate or severe adverse events. PARTICIPANTS: 623 non-immune travellers to sub-Saharan Africa: 153 each received either doxycycline, mefloquine, or the fixed combination chloroquine and proguanil, and 164 received the fixed combination atovaquone and proguanil. RESULTS: A high proportion of patients reported adverse events, even in the initial placebo group. No events were serious. The chloroquine and proguanil arm had the highest proportion of mild to moderate adverse events (69/153; 45%, 95% confidence interval 37% to 53%), followed by mefloquine (64/153; 42%, 34% to 50%), doxycycline (51/153; 33%, 26% to 41%), and atovaquone and proguanil (53/164; 32%, 25% to 40%) (P = 0.048 for all). The mefloquine and combined chloroquine and proguanil arms had the highest proportion of more severe events (n = 19; 12%, 7% to 18% and n = 16; 11%, 6% to 15%, respectively), whereas the combined atovaquone and proguanil and doxycycline arms had the lowest (n = 11; 7%, 2% to 11% and n = 9; 6%, 2% to 10%, respectively: P = 0.137 for all). The mefloquine arm had the highest proportion of moderate to severe neuropsychological adverse events, particularly in women (n = 56; 37%, 29% to 44% versus chloroquine and proguanil, n = 46; 30%, 23% to 37%; doxycycline, n = 36; 24%, 17% to 30%; and atovaquone and proguanil, n = 32; 20%, 13% to 26%: P = 0.003 for all). The highest proportion of moderate or severe skin problems were reported in the chloroquine and proguanil arm (n = 12; 8%, 4% to 13% versus doxycycline, n = 5; 3%, 1% to 6%; atovaquone and proguanil, n = 4; 2%, 0% to 5%; mefloquine, n = 2; 1%, 0% to 3%: P = 0.013). CONCLUSIONS: Combined atovaquone and proguanil and doxycyline are well tolerated antimalarial drugs. Broader experience with both agents is needed to accumulate reports of rare adverse events.
Adolescent↗
Determination of the rate of reduction of oxyferrous cytochrome P450 2B4 by 5-deazariboflavin adenine dinucleotide T491V cytochrome P450 reductase.
The use of 5-deazaFAD T491V cytochrome P450 reductase has made it possible to directly measure the rate of electron transfer to microsomal oxyferrous cytochrome (cyt) P450 2B4. In this reductase the FMN moiety can be reduced to the hydroquinone, FMNH(2), while the 5-deazaFAD moiety remains oxidized [Zhang, H., et al. (2003) Biochemistry 42, 6804-6813]. The rate of electron transfer from 5-deazaFAD cyt P450 reductase to oxyferrous cyt P450 was determined by rapidly mixing the ferrous cyt P450-2-electron-reduced 5-deazaFAD T491V reductase complex with oxygen in the presence of substrate. The 5-deazaFAD T491V reductase which can only donate a single electron reduces the oxyferrous cyt P450 and oxidizes to the air-stable semiquinone, with rate constants of 8.4 and 0.37 s(-1) at 15 degrees C. Surprisingly, oxyferrous cyt P450 turns over more slowly with a rate constant of 0.09 s(-1), which is the rate of catalysis under steady-state conditions at 15 degrees C (k(cat) = 0.08 s(-1)). In contrast, the rate constant for electron transfer from ferrous cyt b(5) to oxyferrous cyt P450 is 10 s(-1) with oxyferrous cyt P450 and cyt b(5) simultaneously undergoing spectral changes. Quantitative analyses by LC-MS/MS revealed that the product, norbenzphetamine, was formed with a coupling efficiency of 52% with cyt b(5) and 32% with 5-deazaFAD T491V reductase. Collectively, these results suggest that during catalysis a relatively stable reduced oxyferrous intermediate of cyt P450 is formed in the presence of cyt P450 reductase but not cyt b(5) and that the rate-limiting step in catalysis follows introduction of the second electron.
Aryl Hydrocarbon Hydroxylases↗
Substrate specificity and inducibility of TACE (tumour necrosis factor alpha-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity.
Tumour necrosis factor alpha (TNF alpha)-converting enzyme (TACE/ADAM-17, where ADAM stands for a disintegrin and metalloproteinase) releases from the cell surface the extracellular domains of TNF and several other proteins. Previous studies have found that, while purified TACE preferentially cleaves peptides representing the processing sites in TNF and transforming growth factor alpha, the cellular enzyme nonetheless also sheds proteins with divergent cleavage sites very efficiently. More recent work, identifying the cleavage site in the p75 TNF receptor, quantifying the susceptibility of additional peptides to cleavage by TACE and identifying additional protein substrates, underlines the complexity of TACE-substrate interactions. In addition to substrate specificity, the mechanism underlying the increased rate of shedding caused by agents that activate cells remains poorly understood. Recent work in this area, utilizing a peptide substrate as a probe for cellular TACE activity, indicates that the intrinsic activity of the enzyme is somehow increased.
ADAM Proteins↗
Role of TGF-beta signaling in extracellular matrix production under high glucose conditions.
BACKGROUND: Hyperglycemia has been shown to play an important role in diabetic renal and vascular complications. Some studies show that high glucose may mediate diabetic complications by stimulating extracellular matrix (ECM) production. We hypothesize that this may be mediated by activating transforming growth factor-beta (TGF-beta)/Smads signaling. METHODS: Renal and vascular cells were cultured under high glucose conditions in the presence or absence of a neutralizing TGF-beta antibody and examined for activation of Smad signaling and collagen production. The regulating role of Smad signaling in high glucose-induced collagen synthesis was determined by inducing overexpression of the inhibitory Smad7 in a stable Smad7-expressing tubular cell line. RESULTS: Activation of Smad signaling, as evidenced by Smad2 and Smad3 nuclear translocation and phosphorylation, was found in renal and vascular cells at 24 hours after high glucose stimulation (up to 55% increased). This was associated with de novo synthesis of collagen I at day 3 by all cell types. High glucose-induced activation of Smad signaling and collagen synthesis were TGF-beta-dependent since these were associated with a significant increase in TGF-beta production at 24 hours (P < 0.01) and were blocked by a neutralizing TGF-beta antibody. Importantly, overexpression of Smad7 resulted in marked inhibition of high glucose-induced Smad2 and Smad3 activation and type I collagen synthesis, suggesting that Smad signaling is a key pathway in high glucose-mediated renal and vascular scarring. CONCLUSION: High glucose acts by activating the TGF-beta dependent Smad signaling pathway to stimulate collagen synthesis by renal and vascular cells. Smad signaling plays a critical role in regulating high-glucose-mediated diabetic renal and vascular complications.
Animals↗