Histone deacetylase inhibitors: a novel class of therapeutic agents in diabetic nephropathy

Histone deacetylase (HDAC) inhibitors are currently being tested as anticancer agents in clinical trials. Chromatin remodeling, such as through histone acetylation, is a fundamental phenomenon in eukaryotic cell biology, bearing implications to numerous physiological and pathological phenomena. Here, we discuss recent data from our own laboratory and those of others demonstrating antifibrotic and renoprotective effect of HDAC inhibitors in diabetic kidneys, and the possible mechanisms including the role of reactive oxygen species. HDAC inhibitors may prove to be a novel class of multitarget agents in the treatment of diabetic nephropathy.     

Nardostachys jatamansi extract protects against cytokine-induced β-cell damage and streptozotocin-induced diabetes

AIM: To investigate the anti-diabetogenic mechanism of Nardostachys jatamansi extract (NJE). METHODS: Mice were injected with streptozotocin viaa tail vein to induce diabetes. Rat insulinoma RINm5F cells and isolated rat islets were treated with interleukin1β and interferon-γ to induce cytotoxicity. RESULTS: Treatment of mice with streptozotocin resulted in hyperglycemia and hypoinsulinemia, which was conf irmed by immunohistochemical staining of the islets. The diabetogenic effects of streptozotocin were c...     

Active immunization against de novo hepatitis B virus infection in pediatric patients after liver transplantation

The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc (+) donors. HBIG and/or lamivudine are recommended for the prevention of de novo HBV infection in naive patients, but there are attendant problems, such as mutant strain emergence and high cost. Active immunization presents a better alternative than the use of HBIG or lamivudine, if it can be proven to be effective. Accordingly, we investigated the outcome of HBV vaccination in pediatric hepatic transplant recipients. Between July 1999 and October 2001, 19 pediatric recipients were administered HBV vaccinations after liver transplantation at Seoul National University Hospital. Nine patients received a graft from anti-HBc (+) donors and 10 from anti-HBc (-) donors. When steroid was withdrawn, recombinant HBV vaccine was administered. The median follow-up period after vaccination was 10.0 +/- 5.2 months. Seventeen of the 19 patients showed a positive response to vaccination. In 9 patients who received grafts from anti-HBc (+) donors, 2 patients showed no response, 4 patients low response (peak HBsAb titer <1,000 IU/L), and 3 patients high response (peak HBsAb titer >/=1,000 IU/L). De novo HBV infection developed in 1 of 2 patients who showed no response to vaccination. In 10 patients who received grafts from anti-HBc (-) donors, 5 showed a low response and 5 a high response. In conclusion, HBV vaccination in pediatric patients after liver transplantation appeared to exhibit some effectiveness at protecting young children that received a graft from anti-HBc (+) donors from de novo HBV infection.     

Characteristics of cytomegalovirus enterocolitis in patients with or without inflammatory bowel diseases

Objectives: Cytomegalovirus (CMV) disease is more common in immunocompromised patients but may occur in people with normal immune function. In addition, CMV enterocolitis can aggravate inflammatory bowel diseases (IBD), but there was little knowledge of differences in clinical and endoscopic features of CMV enterocolitis between patients with IBD and without IBD. The aim of this study was to determine the difference in clinical implication in CMV enterocolitis between the IBD patients and non-IBD patients.

Methods: This was a retrospective study of 82 patients with CMV enterocolitis based on the pathologic findings at two tertiary referral hospitals from 2003 to 2013. Clinical and endoscopic characteristics and clinical course were analyzed according to the presence of IBD.

Results: Of the 82 patients, 25 (30.5%) had IBD and 57 (69.5%) did not have IBD. Hematochezia was more common in IBD patients (84.0% vs. 35.1%; p = .001), but fever and positive CMV antigenemia were more common in non-IBD patients (50.9% vs. 12.0%; p = .001; 54.4% vs. 28.0; p = .027). Endoscopic findings showed more ulcer with inflammation in IBD patients (68.0% vs. 35.2%; p = .005). Sixty-four patients were treated with antiviral agents and 12 patients who did not receive antiviral agents recovered spontaneously. All naturally healed patients were in normal immune status.

Conclusions: Hematochezia is more common in IBD patients and fever/CMV antigenemia is more common in patients without IBD. In patients without IBD, the natural resolution of CMV enterocolitis is expected at least in normal immune function.     

Two cases of polymorphic ventricular tachycardia induced by the administration of verapamil against paroxysmal supraventricular tachycardia

Verapamil is widely used for the termination of paroxysmal supraventricular tachycardia (PSVT) with little proarrhythmic effect. We describe two cases of PSVT that changed to non-sustained polymorphic ventricular tachycardia after administration of verapamil. Electrophysiological study revealed atrioventricular nodal reentrant tachycardia in the first case, and atrioventricular reentrant tachycardia due to a concealed left lateral accessory pathway in the second case. Catecholamine-induced automaticity was one of the possible mechanisms of VT in the first case, but the mechanism is unknown in the second case.     

Cruciate ligament integrity in osteoarthritis of the knee

OBJECTIVE: To evaluate, using magnetic resonance imaging (MRI), the prevalence of anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) rupture in knees with symptomatic osteoarthritis (OA) compared with those without OA, and the relationship to pain and recalled injury. METHODS: MRI and plain radiography of the knee were performed in a group of 360 subjects with painful knee OA (cases; 66.7% male, mean age 67.1 years) and 73 without knee pain (controls; 57.5% male, mean age 66.1 years). MRIs were read for the presence or absence of complete or partial ACL or PCL tear. Subjects with knee pain were asked to quantify severity of pain on a visual analog scale and to report whether they could recall a significant knee injury (requiring use of a cane or crutches). We compared the prevalence of ACL and PCL rupture in those with and those without knee pain and also evaluated whether, in cases, there was any association with recalled knee injury. RESULTS: The proportion of cases who had complete ACL rupture was 22.8%, compared with 2.7% of controls (P = 0.0004). PCL rupture was rare both in cases (0.6%) and in controls (0%). Cases with ACL rupture had more severe radiologic OA (P < 0.0001) and were more likely to have medial joint space narrowing (P < 0.0001) than cases with intact ACLs, but did not have higher pain scores. Among cases, only 47.9% of those with complete ACL tears reported a previous knee injury, compared with 25.9% of those without complete ACL tears (P = 0.003). CONCLUSION: ACL rupture is more common among those with symptomatic knee OA compared with those without knee OA. Fewer than half of subjects with ACL rupture recall a knee injury, suggesting that this risk factor for knee OA is underrecognized.     

Familial protein S deficiency with a variant protein S molecule in plasma and platelets

A protein S deficient family presenting a variant protein S molecule in plasma and platelets is described. The propositus, age 20, and two brothers suffered from venous thrombotic disease. The propositus, the only family member studied while taking oral anticoagulants, had a protein S antigen (ag) level of 17% and undetectable activity. As demonstrated by immunoblotting both the propositus and one clinically affected brother (42% ag, 7% activity) presented variant protein S molecules of 65,000 molecular weight (mol wt) while the other clinically affected brother (64% ag, 11% activity) had only protein S with normal electrophoretic mobility of 70,000 mol wt. The mother had normal protein S levels (93% ag, 100% activity) but had both normal and variant protein S molecules and based on her functional protein S data a normal anticoagulant activity of the variant molecule is suggested. One asymptomatic but protein S deficient sister (68% ag, 9% activity) as well as the asymptomatic protein S deficient father (59% ag, 10% activity) had only protein S molecules of 70,000 mol wt. The variant protein S bound to C4b-binding protein in plasma, and differed from normal protein S in carbohydrate content. Platelets of each family member contained the same immunoblotting pattern of normal and variant protein S forms as found in plasma, consistent with the hypothesis that protein S gene expression involves codominant expression of two alleles that is similar in cells that control the synthesis of both platelet and plasma forms of protein S.     

Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils

In four healthy volunteers, we analyzed in detail the immediate in vivo effects on circulating neutrophils of subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF). Neutrophil activation was assessed by measurement of degranulation. Mobilization of secretory vesicles was shown by a decrease in leukocyte alkaline phosphatase content of the circulating neutrophils. Furthermore, shortly postinjection, Fc gamma RIII was found to be upregulated from an intracellular pool that we identified by immunoelectron microscopy as secretory vesicles. Intravascular release of specific granules was shown by increased plasma levels of lactoferrin and by upregulation of the expression of CD66b and CD11b on circulating neutrophils. Moreover, measurement of fourfold elevated plasma levels of elastase, bound to its physiologic inhibitor alpha 1- antitrypsin, indicated mobilization of azurophil granules. However, no expression of CD63, a marker of azurophil granules, was observed on circulating neutrophils. G-CSF--induced mobilization of secretory vesicles and specific granules could be mimicked in whole blood cultures in vitro, in contrast to release of azurophil granules. Therefore, we postulate that the most activated neutrophils leave the circulation, as observed shortly postinjection, and undergo subsequent stimulation in the endothelial microenvironment, resulting in mobilization of azurophil granules. Our data demonstrate that G-CSF should be regarded as a potent immediate activator of neutrophils in vivo.