Small dense LDL cholesterol is a robust therapeutic marker of statin treatment in patients with acute coronary syndrome and metabolic syndrome

BackgroundSmall dense low-density lipoprotein (sd-LDL) is an atherogenic LDL subfraction and often increased in metabolic syndrome (MetS). This study aimed to determine whether sd-LDL cholesterol (sd-LDL-C) is a therapeutic marker of statin treatment in patients with acute coronary syndrome (ACS) and MetS.MethodsWe examined 71 patients with ACS and 50 non-ACS subjects with normal coronary arteries (controls). The patients with ACS were treated with life-style modifications (n = 36) or those plus 20 mg atorvastatin daily (n = 35) for 6 months. We measured sd-LDL-C by a novel detergent-based homogenous assay and calculated buoyant LDL-C (b-LDL-C).ResultsThe patients with ACS had higher sd-LDL-C than did the controls (30 ± 14 vs. 22 ± 8 mg/dl, p < 0.001). Furthermore, sd-LDL-C was higher in the patients with ACS and MetS (n = 31) than in those without MetS (n = 40) (35 ± 17 vs. 27 ± 11 mg/dl, p < 0.05). Atorvastatin reduced LDL-C and sd-LDL-C by 31% (102 ± 23 to 70 ± 28 mg/dl, p < 0.0001) and 24% (29 ± 15 to 22 ± 13 mg/dl, p < 0.01). The reduction in sd-LDL-C by atorvastatin was 5.5-fold greater in the patients with ACS and MetS than in those without MetS (p < 0.001). Contrary, that in b-LDL-C was similar between the groups.Conclusionssd-LDL-C is a superior therapeutic marker of statin treatment in patients with ACS and MetS.     

Prediction of metabolic syndrome using artificial neural network system based on clinical data including insulin resistance index and serum adiponectin

Objective

This study aimed to predict the 6-year incidence of metabolic syndrome (MetS) using an artificial neural network (ANN) system and multiple logistic regression (MLR) analysis based on clinical factors, including the insulin resistance index calculated by homeostasis model assessment (HOMA-IR).

Design

Subjects were recruited from participants in annual health check-ups in both 2000 and 2006. A total of 410 Japanese male teachers and other workers at Keio University, 30–59 years of age at baseline, participated in this retrospective cohort study.

Measurements

Clinical parameters were randomly divided into a training dataset and a validation dataset, and the ANN system and MLR analysis were applied to predict individual incidences. The leave some out cross validation method was used for validation.

Results

The sensitivity of the prediction was 0.27 for the MLR model and 0.93 for the ANN system, while specificities were 0.95 and 0.91, respectively. Sensitivity analysis employing the ANN system identified BMI, age, diastolic blood pressure, HDL-cholesterol, LDL-cholesterol and HOMA-IR as important predictors, suggesting these factors to be non-linearly related to the outcome.

Conclusion

We successfully predicted the 6-year incidence of MetS using an ANN system based on clinical data, including HOMA-IR and serum adiponectin, in Japanese male subjects.     

Paget’s disease of bone resembling bone metastasis from gastric cancer

A 74-year-old man had an endoscopic type 0′-IIc tumor in the upper gastric body on the greater curvature and biopsy showed the tumor to be a well-differentiated adenocarcinoma (Group 5). He was referred to us for endoscopic submucosal dissection (ESD). Endoscopy revealed fold convergency, fold swelling, and fusion of the fold, indicating tumor invasion into the submucosa, which was outside the indications for ESD. In addition, there was an increase of serum bone-type alkaline phosphatase (ALP-III and ALP-IV) and urinary cross-linked N-terminal telopeptide of type I collagen (a bone metabolism marker), while ¹⁸F-fluorodeoxyglucose positron emission tomography showed increased uptake in the left pelvis and Th10, suggesting bone metastases. We first diagnosed gastric cancer with bone metastases; however, the symptoms suggested pathological bone fracture and no bone pain. Therefore, a computed tomography-guided aspiration bone biopsy was performed to exclude the possibility of Paget’s disease of bone. Biopsy specimens revealed no tumor and a mosaic pattern. No increased uptake of ¹⁸F-FAMT (L-[3-¹⁸F] α-methyltyrosine) supported a diagnosis of no bone metastases from gastric cancer. We finally diagnosed gastric cancer accompanied by Paget’s disease of bone and performed a laparoscopy-assisted proximal gastrectomy. The pathological diagnosis was U less 0-IIb, and U post 0-IIc ypT1a (M) N0H0P0M0 yp stage IA. In gastric cancer patients with suspected bone metastasis, we also need to consider Paget’s disease of bone.     

Iron chelator deferasirox rescued mice from Fas‐induced fulminant hepatitis

Aim: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long–Evans cinnamon rats was prevented by feeding an iron‐deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once‐daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. Methods: Human primary hepatocytes undergoing Fas‐stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas‐stimulation. Results: The apoptosis‐inducing activity of anti‐Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas‐induced production of reactive oxygen species (ROS) and the activation of caspase‐3, both of which were also suppressed by antioxidant, N‐acetyl‐L‐cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas‐induced fulminant hepatitis. Conclusion: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase‐3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.     

Nicotine ameliorates impairment of working memory in methamphetamine-treated rats

Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.     

Effects of valsartan on neuroprotection and neurogenesis after ischemia

Experimental and clinical studies have revealed that angiotensin II type 1 receptor blocker has protective effects against ischemic brain injury, but the mechanism is still obscure. Angiotensin II type 1 receptor blocker may also have effects on neurogenesis through the activation of unblocked angiotensin II type 2 receptors. In this study, we showed that valsartan significantly suppressed superoxide production and cytochrome C release into the cytosol after transient forebrain ischemia and consequently attenuated ischemic neuronal damage without affecting the blood pressure in rats. However, valsartan has none of the expected effects on neurogenesis after ischemia. These results suggest that valsartan has neuroprotective effects on ischemic injury through the suppression of oxidative stress and mitochondrial injury.