Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.     

A sensitive sandwich ELISA for measuring thrombopoietin in human serum: serum thrombopoietin levels in healthy volunteers and in patients with haemopoietic disorders

A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) has been established to estimate serum thrombopoietin (TPO) concentrations in healthy volunteers and patients with haemopoietic disorders. The ELISA uses a mouse monoclonal antibody (Ab) as the capture Ab and a biotinylated rabbit polyclonal Ab as the detector. The ELISA was reproducible, highly sensitive and specific for human TPO. The coefficients of intra- and inter-assay variation were from 3.0% to 4.9% and from 5.9% to 6.1%, respectively. The quantitative limit of the ELISA was 0.09 fmol/ml in serum. The quantitative limit was lower than the normal level. The dose–response curves of serum samples from healthy volunteers and patients with haemopoietic disorders were parallel to the standard curves. The ELISA did not cross-react with a variety of blood components and cytokines to produce false-positive results.
The serum TPO concentrations from 29 normal males and 21 females were 0.79 ± 0.35 and 0.70 ± 0.26 fmol/ml, respectively. Serum TPO levels in patients with aplastic anaemia (AA), acute lymphocytic leukaemia (ALL) and essential thrombocythaemia (ET) were measured using the ELISA. The serum TPO levels in the patients with ET ( n  = 6, 2.80 ± 1.55 fmol/ml) were higher than the normal level. The patients with AA ( n  = 7, 18.53 ± 12.37 fmol/ml) and ALL ( n  = 5, 10.36 ± 5.57 fmol/ml) had significantly higher serum TPO levels than normal individuals. These results indicate that the ELISA specific to TPO should prove useful in measuring the TPO concentration in serum samples.     

Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration: role in preventing lung injury and fibrosis in bleomycin-challenged mice

BACKGROUND AND OBJECTIVE: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and the injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis by antineutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effects of 14-MRMLs on an experimental model of bleomycin-induced acute lung injury and subsequent fibrosis in mice. METHODS: Bleomycin was administered IV to ICR mice. At 28 days after bleomycin injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were assessed by overall comparison between control (normal saline solution [NS] alone), untreated (bleomycin alone), and treated (bleomycin plus 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in BAL fluid and induction of messenger RNA (mRNA) of adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) in lung tissues were examined at 0 to 13 days after bleomycin treatment. These parameters were also compared with those for the control (NS alone), 14-MRML untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML pretreated) groups. RESULTS: Bleomycin-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after bleomycin injection in ICR mice, especially those pretreated with 14-MRMLs. Hydroxyproline content in lung tissues was also decreased in the 14-MRML-pretreated groups. The number of neutrophils in BAL fluid significantly increased, with two peaks at 1 day and 9 days (from 6 to 11 days) after bleomycin administration. 14-MRMLs significantly inhibited both peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leukocyte migration into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate that of ICAM-1 mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA. CONCLUSION: These findings indicate that attenuation of inflammatory cell migration into the airspace by 14-MRMLs, especially of neutrophils and macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14-MRMLs clearly attenuated the expression of VCAM-1 mRNA during the early phase of bleomycin-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This may be one mechanism of the anti-inflammatory and antifibrotic effects of 14-MRMLs. These findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.     

Disuse atrophy of the left ventricle in chronically bedridden elderly people.

In the elderly cardiac size and function are determined by their level of physical activity. In this study, we assessed by echocardiography, the anatomic and physiologic changes of the heart in 28 elderly patients who had no cardiac disease and who were chronically bedridden. The data obtained were compared to those obtained from a control group of 38 age and sex matched elderly people whose activities had not been restricted. Chronically bedridden patients had markedly smaller left ventricular dimensions in both end-diastole and end-systole and smaller left atrial dimensions than did control subjects (3.7 +/- 0.7 vs 4.7 +/- 0.6 cm, p less than 0.001, 2.4 +/- 0.8 vs 2.9 +/- 0.7 cm, p less than 0.02 and 3.2 +/- 0.5 vs 3.8 +/- 0.9 cm, p less than 0.01, respectively). Though the wall thickness of the interventricular septum did not differ between the study groups, the left ventricular posterior walls of the bedridden group were significantly thinner than in the control group (0.8 +/- 0.2 vs 1.0 +/- 0.2 cm, p less than 0.01). The bedridden group had a significantly lower stroke index (26.9 +/- 6.2 vs 47.0 +/- 11.1 ml/m2, p less than 0.001) and cardiac index (1.84 +/- 0.52 vs 3.15 +/- 0.63 l/min/m2, p less than 0.001) than did the control group. Left ventricular mass index and left ventricular systolic stress were significantly lower in bedridden patients than in control subjects (88.0 +/- 18.1 vs 143.5 +/- 30.9 g/m2, p less than 0.001, and 135.9 +/- 4.9 vs 186.6 +/- 35.7 10(3) dynes/cm2, p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved survival of idiopathic dilated cardiomyopathy in the 1990s

To analyze the recent change in the long-term survival of patients with dilated cardiomyopathy (DCM), the present study comprised consecutive 111 patients with ejection fraction <50% and left ventricular end-diastolic diameter >58 mm. who were admitted to hospital from January 1983 to December 1994. The patients were divided into 2 groups: group A who were diagnosed before 1989 and group B diagnosed after 1990. Basic characteristics at diagnosis, including age, NYHA functional class, left ventricular end-diastolic diameter and ejection fraction, were similar between these 2 groups. Calculated survival rate at 5 years was 90.0% in group B in contrast to 62.3% in group A. Event-free survival also improved in group B. In group B, beta-blockers and angiotensin converting enzyme inhibitors were more frequently used than in group A (p<0.0001) whereas digitalis and other positive inotropic agents were significantly less used. Left ventricular ejection fraction was significantly improved during the follow-up period in patients treated with beta-blockers compared with those not treated with beta-blockers. These data indicate a significant improvement in the survival of patients with dilated cardiomyopathy after 1990, which may be explained by the change of medical treatment, especially the use of beta-blockers.     

A new mutation in exon 12 of the gp91-phox gene leading to cytochrome b- positive X-linked chronic granulomatous disease

We have previously reported a patient with cytochrome b-positive X- linked chronic granulomatous disease. Although the O2- production of neutrophils from the patient was completely defective, we presented data suggesting that the patient's cytochrome b was present at a normal level and possibly had normal spectroscopic features. Thus, to look for a mutation in the cytochrome b heavy chain (gp91-phox) gene, DNA analysis of gp91-phox cDNA derived from this patient was performed. As a result, we found that five nucleotides (1521 through 1525) within exon 12 were deleted, and a new sequence of eight nucleotides was inserted. This mutation converted Gln507-Lys508-Thr509 into His-Ile-Trp- Ala. Mismatched polymerase chain reaction showed that the mother has both wild and mutated alleles, confirming that this case was transmitted in an X-linked fashion. This mutation is different from those previously reported by others. The translocation of p47-phox and p67-phox to the membrane fraction occurred, indicating the complete formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. We conclude that this case suggests that the structure encoded on exon 12 of gp91-phox is important for electron transfer.     

Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.     

Potential Usefulness of Early Potassium Supplementation for Preventing Severe Hypokalemia Induced by Liposomal Amphotericin B in Hematologic Patients: A Retrospective Study

Purpose

Liposomal amphotericin B (L-AMB) is an essential antifungal agent for patients with hematologic diseases; however, the drug causes severe hypokalemia at a high frequency. Meanwhile, there is little evidence regarding the risk factors for L-AMB–induced severe hypokalemia, and the prevention protocol has not been established. The goal of this study was to identify the risk factors related to severe hypokalemia induced by L-AMB in hematologic patients.

Infectious mononucleosis in Japan: Comparison with acute viral hepatitis type A

In order to clarify the characteristics of infectious mononucleosis hepatitis (IMH) in Japan, 20 cases with IMH treated at Kamo Hospital during the past 6 years (Group I) were analysed in comparison with cases of acute viral hepatitis, especially type A. The test for heterophil antibody was positive in only two cases. During the same period 209 cases were treated for acute viral hepatitis (type A: 77 cases = Group A; type B: 61 cases; type non-A, non-B: 71 cases). In Group I the common clinical symptoms and signs were headache, sore throat and lymph node swelling; jaundice was not as common as in Group A. GOT and GPT activities increased moderately in the acute stage, but they were significantly lower than those in Group A. LDH, AP, GGT and LAP activities were disproportionately higher to GPT activity in Group I. Liver biopsy in the convalescent stage showed that lipofuscin deposition and sinusoidal mononuclear cell infiltration were more prominent in Group I, while sinusoidal neutrocyte infiltration and focal necrosis at periportal areas were more common in Group A. Differential diagnosis of the two diseases could be made using these clinical features and histological findings. However, immunological differentiation is required for specific diagnosis because some features such as fever, prolonged elevation of thymol turbidity test, atypical lymphocytes in peripheral blod and predilection for young people were observed in both groups. Furthermore, the present study indicated that IMH is no longer rare and most cases do not demonstrate heterophil antibody in Japan.