Effects of long‐term transdermal hormone replacement therapy on the renin–angiotensin– aldosterone system,plasma bradykinin levels and blood pressure in normotensive postmenopausal women

Aim: This study was designed to investigate the effects of 24‐month long‐term transdermal hormone replacement therapy (HRT) on the circulating levels of components of the renin–angiotensin–aldosterone system (RAAS) and bradykinin, blood pressure (BP) and lipid profile in normotensive postmenopausal women (PMW). Methods: Twenty‐two normotensive PMW were randomized to receive transdermal HRT (continuous 17‐β estradiol patch at 36 µg/day plus cyclic oral medroxyprogesterone acetate 2.5 mg/day for 12 days/month) (n = 12) or control (n = 10). The plasma renin activity (PRA), serum angiotensin‐converting enzyme (ACE) activity, plasma angiotensin (Ang) I, Ang II, aldosterone, bradykinin, and BP were measured before, and 12 and 24 months after, the start of the HRT. Results: In the HRT group, the diastolic BP and mean BP were significantly decreased at 12 and 24 months (both P < 0.05) after the start of therapy, however, no significant change of the systolic BP was noted during the study period. No changes in the RAAS components or lipid profile were noted in either group. The plasma bradykinin levels were significantly reduced at 12 (P < 0.05) and 24 months (P < 0.01), while no changes were observed in the control group. Conclusion: More than 12 months of long‐term transdermal HRT kept diastolic BP, mean BP and plasma bradykinin levels decreased in normotensive PMW, without influencing any of the components of the RAAS. This therapy may allow optimal blood pressure control and prevent elevation of the cardiovascular risk.     

CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input

Rapid induction of CD8⁺ cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4⁺ T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naïve precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4⁺ T cells in early phases of the immune response. We show that CD4⁺ T cells help optimal CTL expansion by facilitating entry of naïve polyclonal CD8⁺ T cells into the draining lymph node (dLN) early after infection or immunization. CD4⁺ T cells also facilitate input of naïve B cells into reactive LNs. Such “help” involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen- and CD40-dependent manner, CD4⁺ T cells activate dendritic cells to support naïve lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4⁺ T-cell help, whereby they increase the input of naïve lymphocytes to the relevant LN for efficient screening of cognate CD8⁺ T cells.     

Administration of angiotensin-converting enzyme inhibitors is associated with slow progression of mild aortic stenosis in Japanese patients

It is almost unknown which demographic factors or medications affect the progression of aortic stenosis (AS) in Japanese patients with mild AS. We identified a total of 194 patients with native tricuspid valvular AS, defined as a continuous-wave Doppler determined peak aortic valve jet velocity of ≥ 2.0 m/s, in whom echo Doppler studies were repeated at an interim of at least 6 months. Annualized change in peak jet velocity was calculated, and effects of age, sex, diabetes mellitus, blood pressure, serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels, and use of statins and antihypertensive agents on the progression of AS were retrospectively evaluated. Peak aortic valve jet velocity was 2.36 ± 0.79 m/s (mean ± SD) and annualized increase in peak aortic valve jet velocity was 0.17 ± 0.32 m/s/year for all the studied patients. The increase in peak aortic valve jet velocity was lower in patients taking angiotensin-converting enzyme inhibitors (ACE-Is) than in those not taking ACE-Is (0.04 ± 0.22 vs. 0.20 ± 0.32 m/s/year, P < 0.05). Such protective associations were not observed for other first-line antihypertensive agents and statins. Multiple linear regression analysis revealed that ACE-I treatment, decrease in left ventricular ejection fraction, and higher peak aortic valve jet velocity at the first echocardiogram were associated with slower progression of AS. Administration of ACE-Is was associated with the slow progression of mild AS in Japanese patients. Prospective study to assess this hypothesis is needed.     

Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats

We have generated rats bearing an oxytocin (OXT)-monomeric red fluorescent protein 1 (mRFP1) fusion transgene. The mRFP1 fluorescence was highly visible in ventral part of the supraoptic nucleus (SON) and the posterior pituitary in a whole mount. mRFP1 fluorescence in hypothalamic sections was also observed in the SON, the paraventricular nucleus (PVN), and the internal layer of the median eminence. Salt loading for 5 d caused a marked increase in mRFP1 fluorescence in the SON, the PVN, the median eminence, and the posterior pituitary. In situ hybridization histochemistry revealed that the expression of the mRNA encoding the OXT-mRFP1 fusion gene was observed in the SON and the PVN of euhydrated rats and increased dramatically after chronic salt loading. The expression of the endogenous OXT and the arginine vasopressin (AVP) genes were significantly increased in the SON and the PVN after chronic salt loading in both nontransgenic and transgenic rats. These responses were not different between male and female rats. Compared with nontransgenic rats, euhydrated and salt-loaded male and female transgenic rats showed no significant differences in plasma osmolality, sodium concentration, OXT, and AVP levels. Finally, we succeeded in generating a double-transgenic rat that expresses both the OXT-mRFP1 fusion gene and the AVP-enhanced green fluorescent protein fusion gene. Our new transgenic rats are valuable new tools to study the physiology of the hypothalamo-neurohypophysial system.     

A case of unilocular serous cystic neoplasm mimicking mucinous cystic neoplasm

A 40's woman had a cystic lesion in the tail of the pancreas that had grown over a 1.5-year period. Endoscopic ultrasound revealed a partition structure and "cyst-in-cyst" like lesion, and a diagnosis of mucinous cystic neoplasm was made. The patient underwent distal pancreatectomy with splenectomy. Following histological examination, our final diagnosis was revised to unilocular serous cystic neoplasm since the increase in cysts was due to hemorrhage and the partition structure was in fact granulation tissue. We here discuss this rare case with reference to previous published reports.     

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure. The aim of this study was to investigate the role of cardiac Fstl1 in the remodeling response to pressure overload. Cardiac myocyte-specific Fstl1-KO mice were constructed and subjected to pressure overload induced by transverse aortic constriction (TAC). Although Fstl1-KO mice displayed no detectable baseline phenotype, TAC led to enhanced cardiac hypertrophic growth and a pronounced loss in ventricular performance by 4 wk compared with control mice. Conversely, mice that acutely or chronically overexpressed Fstl1 were resistant to pressure overload-induced hypertrophy and cardiac failure. Fstl1-deficient mice displayed a reduction in TAC-induced AMP-activated protein kinase (AMPK) activation in heart, whereas Fstl1 overexpression led to increased myocardial AMPK activation under these conditions. In cultured neonatal cardiomyocytes, administration of Fstl1 promoted AMPK activation and antagonized phenylephrine-induced hypertrophy. Inhibition of AMPK attenuated the antihypertrophic effect of Fstl1 treatment. These results document that cardiac Fstl1 functions as an autocrine/paracrine regulatory factor that antagonizes myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload, possibly through a mechanism involving the activation of the AMPK signaling axis.     

Angiopoietin balance in septic shock patients with acute lung injury: effect of direct hemoperfusion with polymyxin B-immobilized fiber

Acute lung injury (ALI) in sepsis is characterized by an increase in microvascular permeability, resulting in pulmonary edema. Several studies have suggested that angiopoietin-1 and -2 play a contributory role in the pathogenesis of ALI. Polymyxin B-immobilized fiber column hemoperfusion is effective for sepsis-induced ALI. We investigated the angiopoietin levels before and after direct hemoperfusion with polymyxin B-immobilized fiber column (PMX) therapy. Enzyme-linked immunoassay was used to measure the serum angiopoietin-1 and -2 levels in 25 patients with septic shock treated with PMX. Eleven of the 25 patients were diagnosed with ALI. There was a significant positive correlation between the angiopoietin-1 level and the PaO(2) /FiO(2) ratio, but there was a significant inverse correlation between the angiopoietin-2 level and the PaO(2) /FiO(2) ratio. The mean angiopoietin-1 level before PMX therapy in the ALI group was significantly lower and the mean angiopoietin-2 level was significantly higher than in the non-ALI group. The mean angiopoietin-1 level of the ALI patients in response to PMX therapy was increased during PMX therapy, but that of the non-ALI patients with newly occurring ALI showed a decreased angiopoietin-1 level. On the other hand, the mean angiopoietin-2 level of the responders was decreased during PMX therapy, but that of patients with newly occurring ALI showed an increased angiopoietin-2 level. This result suggested that each angiopoietin-1 and -2 level may play a role in the pathogenesis of ALI and that PMX therapy ameliorates the angiopoietin balance in patients with ALI in sepsis.     

Molecular epidemiological study of Bacillus anthracis isolated in Mongolia by multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA-8)

The incidence of anthrax, which is caused by Bacillus anthracis, in the human and animal population of Mongolia has increased recently, and control of this infection is a nationwide concern. In this study, 29 isolates obtained from animals and various regions in Mongolia from 2001 to 2007 were analyzed by performing multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA-8) to understand the genetic relationship between the Mongolian B. anthracis isolates. We found that all the Mongolian isolates can be classified into A3 cluster along with the Japanese and the Chinese B. anthracis isolates. Our data revealed that MLVA-8 is useful for studying the molecular epidemiology of the Mongolian B. anthracis isolates and would help characterize B. anthracis infections in Mongolia.     

Nationwide antimicrobial susceptibility survey of Neisseria gonorrhoeae isolates in Japan

In a nationwide antimicrobial susceptibility survey of 494 Nesseria gonorrhoeae isolates collected from February 2008 to December 2009 in 3 regions of Japan, 112 (22.7%) were collected from western Japan (Kinki, Chugoku, Shikoku, and Kyushu), 277 (56.1%) from mid-eastern Japan (Kanto), and 105 (21.1%) from eastern Japan (Tokai, Hokuriku, Koushinetsu, Tohoku, and Hokkaido). Resistance to ciprofloxacin (CPFX) was 72.8%, to penicillin G (PCG) 19.8%, and to tetracycline (TC) 18.2%. Intermediate resistance to CPFX was 1.8%, to PCG 73.7%, and to TC 43.7%. These results indicate that both types of resistance to the 3 agents were very high. Intermediate resistance to cefixime (CFIX) was 38.1% and to cefozidim (CDZM) 13.4%. Resistance to CFIX was only 0.4% and to CDZM 0%. Susceptibility to azithromycin was 96.6%, to ceftriaxone 99.8%, and to spectinomycin 100%. No significant difference in resistance was seen to different antimicrobial agent classes tested in the 3 regions, although intermediate resistance to CFIX in western Japan was significantly higher than in mid-eastern Japan.