Scrotal Ulcers Arising during Treatment with All-trans Retinoic Acid for Acute Promyelocytic Leukemia

All-trans retinoic acid (ATRA) is effective in approximately 90% of the cases of acute promyelocytic leukemia (APL) with a low incidence of adverse effects. We report a patient with APL who developed skin ulcers of the scrotum concomitant with high fever during treatment that included ATRA. Severe fever was promptly alleviated with discontinuation of ATRA, while the ulcers improved gradually over 3 months. As the clinical features are similar to those of Sweet's syndrome, we should be aware of the possibility that this rare adverse effect may occur in the treatment with ATRA.     

Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21(CIP) but not that of p27(KIP). Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.     

Determinants of chronic hypercapnia in Japanese men with obstructive sleep apnea syndrome

STUDY OBJECTIVE: To identify the determinants of chronic hypercapnia (ie, PaCO(2), > or = 45 mm Hg) in men with obstructive sleep apnea syndrome (OSAS) without airflow obstruction. DESIGN: An analysis was conducted of 143 male patients with OSAS, which had been diagnosed by polysomnography (PSG), who had been referred to a university hospital. Patients were classified as hypercapnic (ie, PaCO(2), > or = 45 mm Hg) and normocapnic (ie, PaCO(2), < 45 mm Hg), and obese (ie, body mass index [BMI], > or = 30 kg/m(2)) or nonobese (ie, BMI, < 30 kg/m(2)). Patients with airflow obstruction (ie, FEV(1)/FVC ratio, < 70%) were excluded from the study. Baseline clinical characteristics, pulmonary function, PSG data, and blood gas data were compared between hypercapnic and normocapnic patients. Correlations between PaCO(2) and several anthropometric, respiratory, and polysomnographic variables were determined by stepwise multiple regression analysis. RESULTS: Fifty-five patients (38%) were hypercapnic. Hypercapnic patients were younger and heavier, and had more abnormalities on pulmonary and PSG testing. Stepwise multiple regression analysis revealed that the PaCO(2) level was influenced significantly by the mean level of arterial oxygen saturation (SaO(2)) during sleep and by the percent of vital capacity (%VC) (R(2) = 0.430; p < 0.0001), indicating that 43% of the total variance in the PaCO(2) could be explained by the mean SaO(2) and %VC in hypercapnic patients. In contrast, only 13% of the total variance in the PaCO(2) was accounted for by the mean SaO(2) and BMI in normocapnic patients (R(2) = 0.134; p = 0.0034). The mean SaO(2), %VC, and PaO(2) were selected as independent variables for predicting the PaCO(2) in obese patients. These variables explained 41% of the total variance in the PaCO(2) (R(2) = 0.407; p < 0.0001), whereas the mean SaO(2) only accounted for 13% of the total variance in PaCO(2) levels in nonobese patients (R(2) = 0.134; p = 0.0064). CONCLUSION: Nocturnal desaturation and restrictive pulmonary impairment play major roles in determining the PaCO(2) in hypercapnic and obese OSAS patients without airflow obstruction.     

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats

Background Portal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats.Methods PHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups.Results Portal venous pressure was significantly higher in cirrhotic rats compared with control rats (P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress.Conclusions These findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.     

Atorvastatin increases plasma soluble Fms-like tyrosine kinase-1 and decreases vascular endothelial growth factor and placental growth factor in association with improvement of ventricular function in acute myocardial infarction.

OBJECTIVES: This study examined whether atorvastatin increases plasma levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and reciprocally decreases vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels in patients with acute myocardial infarction (AMI). BACKGROUND: Statins exert cardioprotective actions partly through anti-inflammatory actions. By capturing VEGF and PlGF in plasma, sFlt-1 acts as a natural inhibitor of VEGF and PlGF, which have proinflammatory properties. METHODS: Left ventriculography and enzyme-linked immunosorbent assay of plasma levels of sFlt-1, VEGF, and PlGF were repeated after AMI in 50 consecutive patients with a first AMI. Patients were randomized to treatment with atorvastatin (10 mg/day; n=25) or placebo (n=25) within 3 days after AMI, and therapy was continued for 6 months. RESULTS: The sFlt-1 levels were low in the acute phase, followed by an increase at 2 weeks after AMI, whereas free VEGF and PlGF levels were high in the acute phase, followed by a decrease at 2 weeks. Atorvastatin increased sFlt-1 levels and reciprocally decreased VEGF and PlGF levels at 6 months compared with placebo. The increase in sFlt-1 levels and the decrease in VEGF and PlGF levels were correlated with improvement of left ventricular ejection fraction during the follow-up period. CONCLUSIONS: There was a reciprocal relationship between changes in sFlt-1 levels and changes in VEGF and PlGF levels after AMI; and atorvastatin increased sFlt-1 levels while decreasing VEGF and PlGF levels. These changes were associated with late improvement of post-MI ventricular function, and may represent an additional benefit of statin therapy.     

Effects of portal vein embolization before major hepatectomy

BACKGROUND/AIMS: Major hepatectomy can now be successfully performed after portal vein embolization, but the effects of portal vein embolization have not been clearly delineated. Our objective is to examine whether portal vein embolization really contributes to the success of major hepatectomy. METHODOLOGY: Thirty-eight patients underwent portal vein embolization and hepatectomy of two subsegments or more. They all belonged to a high-risk group according to a prognostic score. We selected 9 of 38 patients with liver metastases (PE-meta group) and 32 patients who had undergone hepatectomy without portal vein embolization (non-PE-meta group) during the study period to compare the serum levels of total bilirubin after hepatectomy. Fifteen of 38 patients had the levels of polymorphonuclear leukocyte elastase and thrombin-antithrombin complex examined after hepatectomy (PE group) and so did 20 patients without portal vein embolization (non-PE group). RESULTS: The maximum levels of total bilirubin in non-PE-meta group correlated with the percentage of hepatic parenchyma to be resected. In the patients receiving portal vein embolization, the pre-PE and post-PE levels were both below the regression. Similar shifts were seen in the graphs of polymorphonuclear leukocyte elastase and thrombin-antithrombin complex. CONCLUSIONS: The effects of preoperative portal vein embolization on safety in major hepatectomy were proved by its suppression of rise in total bilirubin, polymorphonuclear leukocyte elastase and thrombin-antithrombin complex after hepatectomy.     

Immunofluorescence staining of renal biopsy samples in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus using monoclonal antibody to reduced glycated lysine

This is the first report on immunofluorescence staining of renal biopsy samples in human diabetic nephropathy (DN) using monoclonal antibodies to reduced glycated lysine. In order to detect the localization of glycated lysine in the mesangial matrix and/or the glomerular basement membrane (GBM), we examined immunofluorescence staining using antibodies against reduced glycated lysine in the glomeruli of 16 patients with DN and ten age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls. In the early stage of DN, immunofluorescence microscopy revealed the presence of intense staining for reduced glycated lysine in the GBM as well as in part of the tubular basement membrane, but not in the mesangial area. In contrast, immunofluorescence microscopy revealed less staining for glycated lysine in the GBM in the advanced stage of DN, and no reaction with any part of the renal tissue in patients with DPGN. It was concluded that detection of reduced glycated lysine in GBM in the early stage of DN might be associated with the initial pathogenesis of this disease.     

The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis

Recent research progress indicates a close link between ghrelin, a natural ligand of GH secretagogues receptor (GHS-R), and both the metabolic balance and body composition. To clarify the involvement of ghrelin and GHS-R in the process of adipogenesis, we measured the expression of GHS-R and peroxisome proliferator-activated receptor gamma 2 (PPAR-gamma 2) mRNA in rat adipocytes using semiquantitative RT-PCR methods. The levels of GHS-R mRNA increased by up to 4-fold in adipose tissue from epididymal and parametrial regions as the rat aged from 4-20 wk and were significantly elevated during the differentiation of preadipocytes in vitro. Ghrelin (10(-8) M for 10 d) stimulated the activity of glycerol-3-phosphate dehydrogenase and the differentiation of rat preadipocytes in vitro. Ghrelin treatment also significantly increased the levels of PPAR-gamma 2 mRNA in primary cultured rat differentiated adipocytes. In addition, isoproterenol (10(-8) M, 40 min)-stimulated lipolysis was significantly reduced by simultaneous ghrelin treatment in a dose-dependent manner in vitro. In conclusion, the expression of GHS-R in rat adipocytes increases with the age and during adipogenesis. Ghrelin in vitro stimulates the differentiation of preadipocytes and antagonizes lipolysis. Ghrelin may therefore play an important role in the process of adipogenesis in rats.     

MRI findings of extranodal malignant lymphoma and squamous cell carcinoma in the head and neck regions

Objectives

To compare magnetic resonance imaging (MRI) findings between patients with malignant lymphoma (ML) and squamous cell carcinoma (SCC) in the head and neck regions, and to show the characteristic findings for ML.

Methods

We analyzed 10 lesions in nine patients with ML and 25 lesions in 25 patients with SCC. Diffusion-weighted imaging, T1-weighted imaging, and T2-weighted imaging were performed for all lesions. We estimated the apparent diffusion coefficients (ADCs) with b-factors of 0, 500, and 1000 s/mm², and obtained the means and standard deviations. In 29 cases, dynamic contrast-enhanced MRI (DCE-MRI) was performed and time–intensity curves were obtained. The peak time, maximum-to-initial ratio (MI ratio), end-to-maximum ratio, and end-to-initial ratio (EI ratio) were estimated. Receiver-operating characteristic analyses were performed to estimate the diagnostic power for these indices.

Results

The mean ADC for ML (0.762 ± 0.126 × 10^?3 mm²/s) was significantly lower than that for SCC (1.24 ± 0.22 × 10^?3 mm²/s, p < 0.0001). ML had a smaller MI ratio (2.13 ± 0.26) and smaller EI ratio (1.90 ± 0.29) than SCC (MI ratio: 2.46 ± 0.38, p = 0.033; EI ratio: 2.19 ± 0.29, p = 0.025). The area under the curve for the mean ADC (0.989) was higher than those for the MI ratio (0.779) and EI ratio (0.792).

Conclusions

The most characteristic findings for ML were extremely low ADCs. If the ADCs cannot be estimated because of severe susceptibility artifacts, DCE-MRI provides an alternative index for differentiating ML from SCC.

     

G-substrate gene promoter SNP (−1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindred

Background:   Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity.
Methods:   In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by 'modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of −1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers.
Results:   In the LDLR - mutation carriers, the plasma cholesterol levels were highest among −1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among −1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among −1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P  = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among −1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among −323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among −1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P  = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation.
Conclusion:   These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied.