Altered relationship between body fat and plasma adiponectin in end-stage renal disease

Patients with end-stage renal disease (ESRD) show an inverse association between body mass index and risk of death from cardiovascular disease. Paradoxical epidemiology may suggest some beneficial effects of body fat in ESRD. Because an antiatherogenic adipocytokine adiponectin is increased in uremic plasma, we tested a hypothesis that, in ESRD, plasma adipocytokine profile may be less atherogenic or that the relationship between body fat and adipocytokines may be altered. The subjects were 103 patients with ESRD undergoing hemodialysis and 166 healthy subjects comparable in age and sex. We measured body fat mass by dual-energy x-ray absorptiometry and plasma levels of adiponectin and leptin by enzyme-linked immunosorbent assay. The ESRD group showed a significant increase in plasma adiponectin, leptin, and adiponectin/leptin ratio than the healthy subjects. Although sex and fat mass were significant factors correlating with plasma adiponectin level in the healthy group, none of these were significantly associated with plasma adiponectin in the patients with ESRD. In contrast, leptin showed significant relationships with sex and fat mass regardless of the presence of ESRD. Plasma adiponectin correlated negatively with plasma triglycerides and positively with high-density lipoprotein cholesterol in both healthy and ESRD groups, suggesting that uremic adiponectin retains its actions in favor of its antiatherogenicity. Thus, plasma adipocytokine profile was altered in ESRD, and the effects of body fat and sex on adiponectin were less significant in the patients with ESRD.     

Infarct Size Limitation by Bradykinin Receptor Activation Is Mediated by the Mitochondrial But Not by the Sarcolemmal KATP Channel

Earlier studies have shown that activation of bradykinin B₂ receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B₂-receptor triggered pathway of PC is the ATP sensitive potassium (K_ATP) channel in the mitochondria (mito-K_ATP channel) or K_ATP channel in the sarcolemma (sarc-K_ATP channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 ± 2.9 (SE) of the untreated controls to 12.0 ± 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 mol/L), a selective mito-K_ATP channel blocker (% IS/AR = 44.2 ± 6.4). In contrast, a high dose of HMR1098 (20 mol/L), which is a newly developed sarc-K_ATP channel selective blocker with IC₅₀ of 0.6 mol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 ± 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 ± 3.8 and 35.1 ± 6.2, respectively). These results suggest that opening of the mito-K_ATP channel but not the sarc-K_ATP channel is involved in infarct size limitation by a mechanism triggered by bradykinin B₂ receptor activation.     

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5alpha-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1)), and androgen-producing enzymes (17betaHSD5 and 5alpha-reductase type 1 (5alphaRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5alphaRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.     

A case of hypersensitivity pneumonitis caused by Humicola fuscoatra

A 51-year-old housewife with hypersensitivity pneumonitis caused by Humicola fuscoatra is reported. The diagnosis was made by an inhalation challenge with H. fuscoatra antigen. She was admitted for diagnosis and treatment of a fever and productive cough. Auscultation of her lungs revealed inspiratory fine crackles. Her chest CT showed diffuse miliary nodules in a centri-lobular distribution with patchy ground glass opacities. Findings of transbronchial lung biopsy and BAL fluid were compatible with a hypersensitivity pneumonitis. Her symptoms worsened on returning home, which suggested the existence of some aetiological agent in the subject's house. H. fuscoatra, Penicillium decumbens and Aspergillus versicolor were isolated from a number of rooms. High titres of serum anti H. fuscoatra, P. decumbens and A. versicolor were detected. Inhalation challenge tests with both P. decumbens and A. versicolor antigen were negative, in contrast to that with H. fuscoatra which was positive. Based on these results, we advised the patient to cleanse her entire house. Since cleaning, her symptoms have not worsened upon returning home. This is the first report of hypersensitivity pneumonitis caused by H. fuscoatra antigen.     

Sinomenine and magnoflorine,major constituents of Sinomeni Caulis et Rhizoma,show potent protective effects against membrane damage induced by lysophosphatidylcholine in rat erythrocytes

The effects of the water extract of Sinomeni Caulis et Rhizoma (SCR-WE) and its major constituents, sinomenine (SIN) and magnoflorine (MAG), on moderate hemolysis induced by lysophosphatidylcholine (LPC) were investigated in rat erythrocytes and compared with the anti-hemolytic effects of lidocaine (LID) and propranolol (PRO) as reference drugs. LPC caused hemolysis at concentrations above the critical micelle concentration (CMC), and the concentration of LPC producing moderate hemolysis (60 %) was approximately 10 μM. SCR-WE at 1 ng/mL–100 μg/mL significantly inhibited the hemolysis induced by LPC. SIN and MAG attenuated LPC-induced hemolysis in a concentration-dependent manner from very low to high concentrations (1 nM–100 μM and 10 nM–100 μM, respectively). In contrast, the inhibiting effects of LID and PRO on LPC-induced hemolysis were observed at higher concentrations (1–100 μM) but not at lower concentrations (1–100 nM). Neither SIN nor MAG affected micelle formation of LPC, nor, at concentrations of 1 nM–1 μM, did they attenuate the hemolysis induced by osmotic imbalance (hypotonic hemolysis). Similarly, SCR-WE also did not modify micelle formation or hypotonic hemolysis, except at the highest concentration. These results suggest that SIN and MAG potently protect the erythrocyte membrane from LPC-induced damage and contribute to the beneficial action of SCR-WE. The protective effects of SIN and MAG are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.

     

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study

We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.