Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability

We demonstrated recently that chronic administration of aldosterone to rats induces glomerular mesangial injury and activates mitogen-activated protein kinases including extracellular signal-regulated kinases 1/2 (ERK1/2). We also observed that the aldosterone-induced mesangial injury and ERK1/2 activation were prevented by treatment with a selective mineralocorticoid receptor (MR) antagonist, eplerenone, suggesting that the glomerular mesangium is a potential target for injuries induced by aldosterone via activation of MR. In the present study, we investigated whether MR is expressed in cultured rat mesangial cells (RMCs) and involved in aldosterone-induced RMC injury. MR expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. Cell proliferation and micromechanical properties were determined by [3H]-thymidine uptake measurements and a nanoindentation technique using an atomic force microscope cantilever, respectively. ERK1/2 activity was measured by Western blotting analysis with an anti-phospho-ERK1/2 antibody. Protein expression and immunostaining revealed that MR was abundant in the cytoplasm of RMCs. Aldosterone (1 to 100 nmol/L) dose-dependently activated ERK1/2 in RMCs with a peak at 10 minutes. Pretreatment with eplerenone (10 micromol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation and decreased the elastic modulus, indicating cellular proliferative and deforming effects of aldosterone, respectively. These aldosterone-induced changes in cellular characteristics were prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor, PD988059 (100 micromol/L). The results indicate that aldosterone directly induces RMC proliferation and deformability through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.     

Acute Nicotine Administration Increases BOLD fMRI Signal in Brain Regions Involved in Reward Signaling and Compulsive Drug Intake in Rats

Background:

Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine.

Methods:

Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03–0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated.

Results:

A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal.

Conclusions:

These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure

The pathophysiologic role of atrial natriuretic factor and other neuroendocrine variables in relation to serum sodium and renal function was evaluated in 15 conscious dogs with severe chronic ventricular pacing-induced heart failure (250 beats/min for 5.1 +/- 0.4 weeks). Six sham-operated dogs observed over an 8 week period served as controls. Development of heart failure was characterized by a progressive increase in plasma norepinephrine, renin activity and aldosterone from control values of 293 +/- 15 pg/ml, 1.4 +/- 0.4 ng/ml per h and 124 +/- 42 pg/ml, respectively, to 1,066 +/- 96 pg/ml, 10.2 +/- 2.4 ng/ml per h and 577 +/- 151 pg/ml (all p less than 0.01), respectively, at severe heart failure. In contrast to other neuroendocrine variables, plasma atrial natriuretic factor increased from a control level of 243 +/- 74 pg/ml to a peak concentration of 724 +/- 149 pg/ml (p less than 0.01) at 2 weeks, then declined and plateaued at twice the level of the control value as severe heart failure developed. At severe heart failure, serum sodium decreased from 147 +/- 0.6 to 141.8 +/- 2.1 mmol/liter (p less than 0.05), whereas urea increased from 6.0 +/- 0.5 to 7.8 +/- 0.6 mmol/liter (p less than 0.05). The change in serum sodium concentration correlated with plasma renin activity and aldosterone (r = -0.77, -0.88, respectively, both p less than 0.01), but not with norepinephrine or atrial natriuretic factor. When sinus rhythm was restored, 14 dogs were observed for 48 to 72 h and 8 dogs were followed up for another 4 weeks after cessation of pacing.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure

OBJECTIVES: The role of atrial myocytes and extracellular matrix (ECM) changes in atrial chamber remodeling was studied in a canine model of heart failure (HF). BACKGROUND: Cardiac remodeling is a key process mediating the progression of HF. Studies of the structural mechanisms of cardiac remodeling have been limited to the left ventricle. The structural alterations associated with atrial chamber remodeling in evolving HF have not been studied. METHODS: Age- and weight-matched dogs were subjected to right ventricular pacing (240 beats/min) for one and three weeks to produce early and severe HF, respectively. Atrial tissues were assessed for myocyte and ECM changes. RESULTS: Right atrial and left atrial (LA) pressures were significantly increased in early and severe HF. The LA wall tension index was significantly increased at both HF stages by 116% and 443%, respectively. Atrial collagen synthesis and degradation were significantly increased in severe HF. Gelatinase activity was significantly increased at both early and severe stages of HF. Gelatin zymography showed increased matrix metalloproteinases (MMP)-9 with early HF and increased MMP-2 with severe HF. The LA wall tension index was significantly correlated with gelatinase activity and collagen synthesis. Although total atrial collagen content was not changed, disarray of collagen fibers was observed. Atrial myocyte hypertrophy without evidence of apoptosis was also present in severe HF. CONCLUSIONS: There is marked atrial chamber remodeling in canine pacing-induced HF, which is characterized by myocyte hypertrophy and dynamic collagen turnover. Atrial remodeling may contribute to the development of atrial arrhythmias and pulmonary hypertension and could offer a novel therapeutic target.     

Development of Epstein-Barr virus-associated gastric cancer: Infection,inflammation, and oncogenesis

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.     

HIV transmission in sexual partners of persons with HIV/AIDS attending the Infectious Diseases Hospital, Yangon

A study was conducted in the Infectious Diseases Hospital, Yangon, for one year from August 1996 to 1997, to assess the extent and the factors related to HIV transmission among sexual partners of HIV/AIDS cases. It was a cross-sectional comparative study on 67 (61 males, 6 females) HIV positive individuals with or without AIDS, and their sexual partners. Separate interviews of index cases and partners were done, and clinical examination and laboratory tests for HIV and sexually transmitted diseases (STDs) were performed. HIV transmission was found in 41.8% of the partners. Male-to-female transmission was 39.3% (n=61) and female to male transmission was 66.7% (n=6), Seven and one half percent of the partners were suffering from AIDS. There were 4 (6.6%) pregnant mothers and 1 (25%) was HIV positive. Though 75% of the partners did not use condoms during their married life, HIV transmission was significantly reduced in the condom users (odds ratio (OR) = 0.18, 95% confidence interval (CI) 0.02-0.98 p = < 0.05). The seropositive men who were less than 30 years of age had greater HIV transmission (OR = 5.67, 95% CI 1.13-36.46). However, socio-demographic factors, number of marital partners and age of first sex partners, duration of marriage, number of sexual relationships between these couples, duration of HIV positivity and AIDS infection, immunological status of the index group and STD positivity among partners had no significant association with the transmission of HIV. This study demonstrated that the transmission of HIV was high among the sexual partners of persons with HIV infection. It also highlighted the requirement of effective counseling and preventive measures against HIV infection among the couples.     

Neisseria meningitidis infections in Northern Norway: an epidemic in 1974-1975 due mainly to group B organisms.

A severe epidemic of disease due to Neisseria meningitidis has been occurring in northern Norway since 1974. Based on bacteriological and clinical examination of cases during the 18 months between January 1, 1974 and June 30, 1975, an overall attack rate of 26.3 cases per 100,000 population per year has been calculated. The attack rates were highest in 1975 (total, 37.4 cases per 100,000 population; Troms County, 54.5) and in children younger than four years (total, 173.6; Troms County, 328.9). The epidemic shows a total case-fatality ratio of 14.1%. The highest case fatality ratio was recorded for patients older than 20 years (25.0%). Among the youngest children, cases were distinctly more frequent in males than females; in older children and adults, male patients had a clearly higher case-fatility ratio than female patients. Of the three serogroups of N. meningitidis, group B caused more cases of infection that groups A and C together. In addition, the causative meningococcal strains were almost uniformly resistant to high concentrations of sulfonamide. Both of these traits appear to have developed in northern Norway at or shortly before the time when the epidemic began.