Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

Infection with hepatitis B virus genotype A in Tokyo, Japan during 1976 through 2001

Background Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan.Methods We examined clinical and virological features of the 66 Japanese patients who admitted Toranomon Hospital in Tokyo, Japan, between 1976 and 2001, who were found to have HBV/A infection. HBV genotype A was classified into subtype A (European type) and A (South African type) by phylogenetic analysis of the preS1 and preS2 regions, and the S gene sequences.Results Of the 66 patients infected with HBV/A, 14 (21%) were asymptomatic carriers, 26 (39%) presented with acute hepatitis, 22 (33%) with chronic hepatitis, and 4 (6%) with liver cirrhosis. HBV/A infection persisted for more than 6 months in 5 of the 26 (19%) patients with acute hepatitis. The frequency of acute hepatitis in patients infected with HBV/A was higher after than before 1991 (2/22 [9%] vs 24/44 [55%]; P < 0.0001). The frequency of nucleotide 1858 of T was higher in asymptomatic carriers than in patients with acute hepatitis in whom infection was resolved (5/14 [36%] vs 0/21 [0%]; P = 0.008). Of the 57 patients for whom subtypes of genotype A were determined, subtype A was identified in 53 (93%) and subtype A in only 4 (7%). All patients infected with subtype A were persistently infected with HBV.Conclusions HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, and subtype A is uncommon in the Tokyo metropolitan area.     

Toll-like receptors stimulate human neutrophil function

The first immune cell to arrive at the site of infection is the neutrophil. Upon arrival, neutrophils quickly initiate microbicidal functions, including the production of antimicrobial products and proinflammatory cytokines that serve to contain infection. This allows the acquired immune system enough time to generate sterilizing immunity and memory. Neutrophils detect the presence of a pathogen through germ line-encoded receptors that recognize microbe-associated molecular patterns. In vertebrates, the best characterized of these receptors are Toll-like receptors (TLRs). We have determined the expression and function of TLRs in freshly isolated human neutrophils. Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10-all the TLRs except TLR3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels. The agonists of all TLRs expressed in neutrophils triggered or primed cytokine release, superoxide generation, and L-selectin shedding, while inhibiting chemotaxis to interleukin-8 (IL-8) and increasing phagocytosis of opsonized latex beads. The response to the TLR9 agonist nonmethylated CpG-motif-containing DNA (CpG DNA) required GM-CSF pretreatment, which also enhanced the response to the other TLR agonists. Finally, using quantitative polymerase chain reaction (QPCR), we demonstrate a chemokine expression profile that suggests that TLR-stimulated neutrophils recruit innate, but not acquired, immune cells to sites of infection.     

Effect of infarcted myocardium on diagnostic accuracy of exercise echocardiography for detecting noninfarct-related coronary artery lesions

Background The utility of exercise echocardiography for evaluating remote ischemia due to noninfarct-related artery (n-IRA) lesions in patients with prior myocardial infarction has not been established.Methods Quantitative coronary angiography and treadmill exercise echocardiography were performed within 2 weeks in 115 patients with prior myocardial infarction (>6 weeks) and 224 patients without myocardial infarction. Coronary lumen diameter stenosis ≥50% (by angiography) and the lack of a hyperdynamic response on exercise echocardiography were considered significant. Myocardial infarction size was defined as the number of myocardial segments with severe hypokinesis, akinesis, or dyskinesis on echocardiography at rest.Results For detection of n-IRA lesions in patients with prior myocardial infarction, the sensitivity of exercise echocardiography was similar (78% vs 79%, P = not significant), however, the specificity was significantly lower (77% vs 91%, P < .01) than for detection of significant stenoses in patients without prior myocardial infarction. Angiographic percent-diameter stenosis, presence of collateral vessel, achieved exercise level, and presence of peri-infarct ischemia did not affect the specificity of exercise echocardiography. However, the specificity of exercise echocardiography was significantly lower (69% vs 84%, P < .05) in patients with echocardiographically large infarction (infarction size ≥2) than in patients with small infarction (infarction size <2).Conclusion In patients with prior myocardial infarction, exercise echocardiography showed low specificity for detection of noninfarct-related artery lesions, especially in patients with echocardiographically large myocardial infarction. These characteristics of treadmill exercise echocardiography should be considered when this technique is applied for patients with healed myocardial infarction. (Am Heart J 2003;145:162-8.)     

A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukaemia in complete remission

We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease-free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT.     

Detection and monitoring of methotrexate-associated lung injury using serum markers KL-6 and SP-D in rheumatoid arthritis

The applicability of monitoring concentrations of serum KL-6 and serum surfactant protein-D (SP-D) in the detection of methotrexate-associated lung injury (MTX pneumonitis) in patients with rheumatoid arthritis (RA) was investigated. The concentrations of these markers, sequentially measured in two patients with RA complicated with MTX pneumonitis, were increased in accordance with the severity of MTX pneumonitis. Conversely, the concentrations of these markers were decreased with the improvement of MTX pneumonitis, suggesting that the monitoring of these markers could be applicable not only for detecting the onset of MTX pneumonitis, but also for detecting the therapeutic response of MTX pneumonitis.     

Effect of nicorandil on coronary spasm

In patients in whom dynamic coronary obstruction plays a predominant role in the pathogenesis of angina pectoris, dilatation of large coronary arteries and relief of coronary spasm account for the main mechanism of action of antianginal drugs. In this study, the acute vasodilating effects of nicorandil, a newly developed antianginal drug, were assessed in 10 patients who had spontaneous and ergonovine-evoked coronary spasms. The prompt, complete relief of both spontaneous and evoked coronary spasms was obtained in all of 10 patients with nicorandil. The coronary spasmolytic effect of nicorandil in the present series is thus considered to be beneficial to the treatment of coronary spasm.