WSX-1 plays a significant role for the initiation of experimental autoimmune uveitis

WSX-1 is a subunit of the IL-27R, which plays a critical role in the initiation of T(h)1 responses. Murine experimental autoimmune uveitis (EAU) is a model of human autoimmune uveitis, in which a T(h)1 response predominates in the pathogenetic process. To explore the role of WSX-1 in this model, WSX-1(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 to induce EAU. We found that the EAU clinical and histological scores were lower in the WSX-1(-/-) mice up to day 21, whereas after day 21, the EAU scores were the same between the wild-type (WT) and WSX-1(-/-) mice with both declining at the same rate. In contrast to T lymphocytes from WT mice, WSX-1(-/-) T lymphocytes on day 9 after immunization failed to produce IFN-gamma. Similarly, expression of T(h)1-related chemokines, such as regulated on activation, normal T cell expressed and secreted and IP-10, in the eye was reduced in WSX-1(-/-) mice compared with WT mice on day 13 after immunization. In addition, sub-retinal transfer of lymphocytes from WSX-1(-/-) mice on day 9 after immunization did not induce EAU in the recipient mice. Importantly, IFN-gamma production, chemokine expression and the transferability of disease by lymphocytes became comparable for WSX-1(-/-) and WT mice at later stages. Thus, IL-27/WSX-1 affects the early development of EAU, and might be a target for therapy during the onset of autoimmune uveitis in humans.     

Continuous infusion of lipoic acid rapidly reduces plasma beta-hydroxybutyrate with elevation of non-esterified fatty acids in broiler chickens

The present study was conducted to determine the effects of alpha-lipoic acid (ALA) on fatty acid mobilisation and ketone body production in female broiler chickens. In the first experiment, chickens received an intravenous infusion of ALA (0,25 or 50 mg/kg per h) for 90 min. Blood was drawn at 30 min intervals, and plasma glucose, NEFA, free glycerol and hydroxybutyrate were analysed. In the second experiment, ALA (100 mg/kg per h) was continuously infused to chickens fed or fasted for at least 24 h. Changes in plasma metabolites for 90 min were determined. In the first experiment, as shown by the response area, ALA infusion did not affect plasma glucose but increased (P<0 x 05) plasma NEFA, regardless of the dose level. In contrast, plasma hydroxybutyrate was reduced at the lower infusion rate (P<0 x 05). No significant changes in plasma free glycerol were observed. In experiment 2, ALA stimulated both plasma glucose (P<0 x 01) and NEFA (P<0 x 001) and the responses were greater than those of controls, regardless of the feeding state. The interaction between ALA and the feeding condition had a significant effect on plasma hydroxybutyrate (P<0 x 01). ALA reduced plasma hydroxybutyrate, and this response was greater in the fasted birds than in those fed. Therefore, the present study found a lowering effect of ALA on plasma hydroxybutyrate level and suggests that the ALA-induced plasma NEFA increment was attributable to decreased hepatic fatty acid oxidation in chickens.     

Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men

To evaluate the effect of lactulose on calcium (Ca) and magnesium (Mg) absorption, we performed a clinical trial with a double-blind, randomized, crossover design in 24 healthy adult male volunteers. The absorptions of Ca and Mg were evaluated by a single-labeling method using stable isotopes. The test foods, containing lactulose at a dose of 0 g (placebo), 2 g (low-dose), or 4 g (high-dose) together with 300 mg of Ca containing 20 mg of 44Ca, and 150 mg of Mg containing 28 mg of 25Mg, were administered orally. Urine samples were collected for 8 h after the ingestion of the test food. The ratios of stable isotopes in urine (44Ca/40Ca and 25Mg/24Mg) were measured by ICP-MS (inductively coupled plasma-mass spectrometry). The urinary stable-isotopes ratios (44Ca/40Ca and 25Mg/24Mg) increased with lactulose dosage. Significant differences were observed in the Ca ratio between placebo and high-dose lactulose (p<0.01), and in the Mg ratio between placebo and low-dose lactulose and between placebo and high-dose lactulose (p<0.01). Lactulose ingestion did not change the levels of bone-resorption markers (type I collagen cross-linked N-telopeptide and deoxypyridinoline) in urine. The test foods did not cause any side effects. This study demonstrates that lactulose enhances the absorptions of Ca and Mg in adult men.     

High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis

Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the autoantibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (K(AV) = 20.0 +/- 7.5 pM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease.     

Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. METHODS AND RESULTS: The serum MCP-1 concentrations and the intimal - medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemically in radial arterial tissues obtained from the HD patients. IMT and the serum concentration of MCP-1 in the HD patients were both significantly greater than in controls. Multiple regression analysis revealed that the serum concentration of MCP-1 was an independent factor influencing IMT. Tissue immunostaining showed that MCP-1 is expressed in both endothelial and smooth muscle cells and that its level of expression correlates with the serum concentration of MCP-1. CONCLUSIONS: An increase in MCP-1 may be an important factor in the progression of atherosclerosis in non-diabetic HD patients.     

A Novel Guide-Wire Technique for Repositioning a Nasobiliary Catheter from Mouth to Nostril without Using a Nelaton Tube

Objective

We aimed to assess the usefulness of a novel guide-wire technique for repositioning without the use of a Nelaton tube and to compare this to the conventional technique.

Subjects and Methods

A total of 50 patients who underwent endoscopic nasobiliary drainage (ENBD) at the Yachiyo Medical Center, Chiba, Japan, were enrolled into the study. The patients were randomly divided into 2 groups according to the use of a novel guide-wire technique (n = 28) or the conventional technique (n = 22). The ENBD catheters were repositioned from the mouth to the nose. The primary end point was the procedural time from the insertion of the Nelaton tube or guide wire into the nostril until the ENBD catheter had been repositioned in the nose. The secondary end point was the success rate of the procedure.

Results

The mean procedure time of our technique (120.8 s) was shorter than the traditional technique (131.9 s), but this difference was not statistically significant (p = 0.56). Our technique did not involve the use of the Nelaton tube, and so could save the cost of USD 1.17 per patient. The novel technique did not require the removal of the mouthpiece with a laryngoscope or the use of a Nelaton tube, and no postural change was necessary. A single operator performed the novel procedure unassisted. No adverse events were observed relating to either the novel or the traditional technique.

Conclusions

The novel guide-wire technique for repositioning ENBD catheters was effective and is recommended for use.Key Words: Guide wire, Nelaton tube, Endoscopic nasobiliary drainage, Endoscopic retrograde cholangiopancreatography     

Various Neurological Symptoms by Neurolymphomatosis as the Initial Presentation of Primary Testicular Lymphoma

Neurological symptoms induced by the infiltration of malignant lymphoma into the nervous systems are subsumed under the term neurolymphomatosis (NL). Here, we report the case of a 30-year-old Japanese man with primary testicular lymphoma complicated, as seen in various neurological findings, by secondary NL prior to testicular swelling. Painless right scrotal enlargement was noticed more than 1 month after the appearance of neurological complications such as right upper extremity numbness, dysarthria, facial palsy, and diplopia. Proactive investigation and biopsies of extranodal sites at high risk of central nervous system infiltration of malignant lymphoma, such as the testes, should be considered when secondary NL is suspected based on imaging findings.Key Words: Neurolymphomatosis, Primary testicular lymphoma, Diffuse large B-cell lymphoma, Central nervous system infiltration     

Combination of Factor H Mutation and Properdin Deficiency Causes Severe C3 Glomerulonephritis

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation.Complement is a component of the innate immune system that plays a key role in recognizing and fighting pathogenic infections.^1,2 Three main pathways exist to initiate complement activation: the classic pathway, the lectin pathway, and the alternative pathway (AP). The classic and lectin pathways are initiated by antigen–antibody complexes and microbial sugar molecules, respectively. The AP is constitutively active at a low level caused by spontaneous C3 tick-over and capable of self-amplification on foreign surfaces that lack regulatory control.^1,2 Although complement plays a physiologic role in host defense and homeostasis, inappropriately activated complement can lead to serious tissue injury. In particular, AP dysregulation has been implicated in many complement-mediated human autoimmune disorders.^3–6AP complement activation is regulated by several membrane-bound and fluid-phase proteins. Among them, factor H (fH) is an abundant plasma regulator that works to restrict the activity of the C3 convertase C3bBb both on the cell surface and in the fluid phase.^7–9 It is a glycoprotein composed of 20 short consensus repeat (SCR) domains, and it inhibits the AP C3 convertase C3bBb by decay acceleration and cofactor activity for factor I (fI)-mediated proteolytic cleavage of C3b. The C-terminal SCR domains of fH interact with surface-deposited C3b and polyanionic molecules on eukaryotic cells, and they play a critical role in determining its affinity for host tissues.^10,11 The N-terminal 1–4 SCRs of fH are responsible for its complement-regulating activity. Opposing the activities of fH and other membrane complement regulators, factor properdin (fP) is a plasma protein that facilitates AP complement activation. It stabilizes the labile AP C3 convertase C3bBb, significantly extending its half-life.¹² Recent studies have shown that fP may also work as an initiator of AP complement on certain activating surfaces.^13–18 In contrast to the multitude of negative regulators, fP is the only known positive regulator of the complement cascade.Mutations in fH in animals and man are associated with several kidney pathologies, including C3 GN, dense deposit disease (DDD), and atypical hemolytic uremic syndrome (aHUS).^9,19–21 Development of these diseases has also been linked to other abnormalities in AP complement regulation, such as the presence of nephritic factors and mutations in C3, factor B (fB), membrane cofactor protein, and fI.^22–24 Many of these disease-causing defects, including fH mutations, lack complete penetrance, and presently it is not well understood how disease phenotypes associated with these defects might be affected by other modifier genes or abnormalities. Here, we provide a striking example in mice, where loss of fP activity, while expected to be therapeutic, surprisingly converted a mild C3 GN phenotype of an fH mutant mouse to lethal C3 GN resembling human DDD. Our results shed new light on the pathogenesis of fH-related kidney diseases and have therapeutic implications for human C3 glomerulopathy patients.     

An Overview of Regular Dialysis Treatment in Japan (As of 31 December 2010)

A nationwide statistical survey of 4226 dialysis facilities was conducted at the end of 2010, and 4166 facilities (98.6%) responded. The number of new patients introduced into dialysis was 37 512 in 2010. This number has decreased for two consecutive years since it peaked in 2008. The number of patients who died in 2010 was 28 882, which has been increasing every year. The number of patients undergoing dialysis at the end of 2010 was 298 252, which is an increase of 7591 (2.6%) compared with that at the end of 2009. The number of dialysis patients per million at the end of 2010 was 2329.1. The crude death rate of dialysis patients in 2010 was 9.8%, and has been gradually increasing. The mean age of the new patients introduced into dialysis was 67.8 years and the mean age of the entire dialysis patient population was 66.2 years. Regarding the primary disease of the new patients introduced into dialysis, the percentage of patients with diabetic nephropathy was 43.6%, which is a slight decrease from that in the previous year (44.5%). Patients with diabetic nephropathy as the primary disease accounted for 35.9% of the entire dialysis patient population, which approaches the percentage of patients with chronic glomerulonephritis as the primary disease (36.2%). The percentage of patients who had undergone carpal tunnel release surgery (CTx) was 4.3%, which is a slight decrease from that at the end of 1999 (5.5%). The decrease in the percentage of patients who had undergone CTx was significant among the patients with dialysis durations of 20–24 years (1999, 48.0%; 2010, 23.2%). A total weekly Kt/V attributable to peritoneal dialysis and their residual functional kidney was 1.7 or higher for 59.4% of patients who underwent peritoneal dialysis.