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.     

Vitamin K2 and bone quality

Effects of vitamin K(2) (menatetrenone) and alendronate on bone mineral content and bone mechanical property in rats fed a low-magnesium diet. Recent clinical studies have shown that the occurrence of new fractures does not always depend on bone mineral density. Therefore bone quality has become an important issue in osteoporosis research. No animal model for evaluating bone quality has been established. In this study, we found that the treatment of rats with a low-magnesium (Mg) diet reduced their bone strength without decreasing bone mineral content (BMC), so the low Mg diet model is considered to be a good model for examining bone quality. Using this model, we investigated the effects of vitamin K(2) (V.K(2)) and alendronate (ALN). V.K(2) increased maximum load and elastic modulus without influencing BMC. ALN increased maximum load with increasing BMC. By using Fourier transform infrared microscopic analysis, the low-Mg diet treatment increased the mineral/matrix ratio of bones, and V.K(2) suppressed the increase in this ratio. These findings suggest that the mineral/matrix ratio may be a factor involved in bone quality, and that V.K(2) may improve bone quality.     

Optimal therapeutic range for oral anticoagulants in Japanese patients with prosthetic heart valves: a preliminary report from a single institution using conversion from thrombotest to PT-INR

The thrombotest (TT) technique has been widely used in Japan for monitoring oral anticoagulant therapy (OAT). The therapeutic range was originally recommended to be 10%–25%. However, the International Committee for Standardization in Hematology/International Committee on Thrombosis and Hemostasis (ICSH/ICTH) recommended using the international normalized ratio of prothrombin time (PT-INR) for monitoring OAT. It is necessary to use a universal standard measure for monitoring OAT in accordance with the ICSH/ISTH recommendation. We simultaneously measured TT and PT in blood samples from 1 157 patients on long-term warfarin therapy, and studied the correlation between TT and PT-INR. An excellent linear correlation was obtained between TT-INR and PT-INR with the regression equation PT-INR = 1.0420 TT-INR − 0.0987 (r = 0.905, P < 0.001). We also examined the correlation between the incidence of thromboembolism in 170 patients receiving warfarin therapy after prosthetic valve replacement; 50.5% received concomitant antiplatelet therapy. Thromboembolism occurred in 9 of 170 patients during a mean follow-up period of 2.44 years. The average TT values in patients with and without thromboembolism were 26.4% (PT-INR: 1.53) and 21.1% (1.73), respectively (P < 0.01). The incidence of thromboembolism did not differ significantly between patients on warfarin alone (average TT: 22.2%) and those on warfarin and antiplatelet agent (average TT: 20.9%). Our results suggest that the incidence of thromboembolism is low in Japan despite a less intensive regimen having been adopted. Received: June 22, 2000 / Accepted: October 4, 2000     

Immunocytochemical study of peptidylarginine deiminase: localization of its immunoreactivity in prolactin cells of female rat pituitaries

We have performed an immunocytochemical study of peptidylarginine deiminase (EC 3.5.3.15) in rat pituitaries. Male and female rat pituitaries were fixed by brief transcardial perfusion of Bouin Hollande Sublimate solution. Immunoperoxidase staining of cryosections obtained from female pituitaries with an antiserum to rat skeletal muscle peptidylarginine deiminase yielded specific staining of numerous cells in the pars distalis. In contrast, few immunopositive cells were noted in the pars distalis of male pituitaries. At least some of the immunopositive cells in female pars distalis were also stained with an antiserum to rat PRL. No such coincidence of immunoreactivities was noted when antisera to other anterior pituitary hormones were used. Biochemical and immunocytochemical examination of peptidylarginine deiminase during the pregnant period revealed its marked depletion on day 7 and its substantial restoration on day 14, showing apparently negative correlation with the known changes in the secretory activities of lactotrophs. This and the female-dominant occurrence of peptidylarginine deiminase in lactotrophs suggest significant involvement of the enzyme in the function of lactotrophs.     

Granulocytic sarcoma of the colon in chronic myelomonocytic leukemia

A 59-year-old man with a six-month history of chronic myelomonocytic leukemia (CMML) was admitted to the Kitasato University Hospital because of melena in September 2000. Colonofiberscopy and barium enema demonstrated an ulcerated tumorous lesion in the transverse colon. The histopathologic findings of the ulcer bed revealed diffuse infiltration of granulocytes at each stage of differentiation. The diagnosis of granulocytic sarcoma (GS) was made. Surgical resection was not indicated, because thrombocytopenia was hardly improved enough to allow surgery despite repetitive transfusion of platelet concentrates. CMML developed to refractory anemia with excess of blast in transformation in February 2001. Two courses of low dose cytarabine plus aclarubicin were ineffective on the GS in spite of a decrease in the peripheral blood blasts. Progression to acute myeloid leukemia eventually broke out, in July 2001. The patient died of leukemia complicated with pneumonia and intestinal obstruction. At present, nine cases of GS in the colon have been reported. However, these cases did not include CMML. This is the first report describing GS in the colon associated with CMML.