Aldosterone-producing adrenocortical adenoma (APA) is responsible for the majority of cases clinically diagnosed as primary aldosteronism. Aldosterone synthase (CYP11B2) is one of the enzymes that play essential roles in aldosterone synthesis and is involved in the pathogenesis of APA. Recent studies have demonstrated that various factors and regulators influence the expression and function of CYP11B2 in APA. In particular, somatic mutations, such as gain-of-function and loss-of-function mutations, have been identified in several genes, each of which encodes a pivotal protein that affects the calcium signaling pathway, the expression of CYP11B2, and aldosterone production. The gain-of-function mutations were reported in KCNJ5 that encodes G-protein activated inward rectifier K+ channel 4 (Kir3.4) and in CACNA1D, encoding calcium channel, voltage-dependent, L type, alpha subunit Cav1.3. The loss-of-function mutations were found in ATP1A1 that encodes Na+/K+ ATPase α subunit and in ATP2B3, encoding Ca2+ ATPase. Furthermore, the aberrant expression of gonadotropin-releasing hormone receptor is associated with the overexpression of CYP11B2 and overproduction of aldosterone in APA with activating mutations in CTNNB1 encoding β-catenin. On the other hand, CYP11B2 also catalyzes the conversion of cortisol to 18-hydroxycortisol and subsequently converts 18-hydroxycortisol to 18-oxocortisol. The recent studies have identified 18-oxocortisol as an important and distinct biomarker to diagnose primary aldosteronism. In this review, we summarize the recent findings on CYP11B2 and discuss the molecular pathogenesis of APA and the clinical significance of CYP11B2.
Brugada syndrome is characterized by distinguishing electrocardiogram (ECG) patterns (coved and saddle-back types with day-to-day variation) and occurrence of lethal tachy-arrhythmias. The appearance of coved type ECG (type 1) is required for the diagnosis of Brugada syndrome, whereas the significance of saddle-back type ECG (type 2), which is inadequate for the diagnosis, has not been fully established. We enrolled 34 consecutive patients with type 2 ECG on outpatient-clinic. Among them, 7 patients were ventricular fibrillation (VF) survivors who were diagnosed as Brugada syndrome with transient appearance of type 1 ECG, and showed type 2 ECG on their first outpatient-clinic visit after the VF event (VF group). The remaining 27 were asymptomatic and never showed type 1 ECG on repeated ECG examinations (control group). The VF group showed significantly longer RJ intervals in leads V1 and V2 and QTc intervals in lead V2 compared with the control group (P < 0.030, P < 0.017, and P < 0.030, respectively). Late potentials, detected on the signal-averaged ECG (SA-ECG), reflect conduction abnormalities and are known as one of the risk markers of arrhythmic events. Among the 34 patients, late potentials were negative in 12 patients belonging to the control group. In conclusion, the SA-ECG could be helpful to identify high-risk patients for its high negative predictive value as the first step, and ECG parameters, including RJ intervals in leads V1 and V2 and QTc interval in lead V2, could be useful for further risk stratification in patients with type 2 Brugada ECG.
Mucosal immunity may play a key role in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). IgAVN is characterized by the presence of non-thrombocytopenic palpable purpura, associated with glomerulonephritis with IgA-dominant immune deposits. Recent studies have shown the up-regulation of Toll-like receptors (TLRs) in patients with IgAN or IgAVN. Among TLRs that mediate innate immune reactions, TLR2, TLR4, and TRL5 recognize bacterial components, while TLR3, TLR7, and TLR9 recognize viral components. Here we compared the expression levels of TLR mRNAs in peripheral blood mononuclear cells (PBMCs) from 49 IgAN patients, 20 IgAVN patients, and 20 patients with thin basement membrane nephropathy (TBMN), unrelated to immune-mediated pathogenesis, as a control. The real-time RT-PCR analysis revealed the significantly higher expression levels of TLR2, TLR3, TLR5, TLR7, and TLR9 mRNAs in PBMCs of IgAN and IgAVN patients, compared to TBMN patients. Importantly, TLR4 mRNA levels were significantly higher in IgAN patients than in IgAVN patients, while its expression levels were comparable in IgAVN patients and TBMN patients. In contrast, TLR5 and TLR9 mRNA levels were significantly higher in IgAVN patients than in IgAN patients. In IgAN patients, expression levels of TLR2, TLR3, TLR5, or TLR9 mRNA were correlated with proteinuria levels, and TLR4 mRNA levels were correlated with serum IgA levels. In IgAVN patients, however, there was no such correlation. The up-regulated expression of TLR mRNAs in PBMCs may be related to the development of IgAN and IgAVN. The distinct expression patterns between these two diseases may reflect their different pathogenetic mechanisms.
Dry form of age-related macular degeneration (AMD) constitutes 90% of AMD cases, and it is characterized by the formation of drusen under the retina and the slow breakdown of the light-sensing cells in the macula, which causes a gradual loss of central vision. Since oxidative stress is involved in the pathogenesis of dry AMD, α-lipoic acid (LA) with antioxidant properties was selected, and its effect on anti-oxidative markers and visual quality in patients with dry AMD was assessed. A total of 100 dry AMD patients (60-83 years old) were randomly assigned to LA treatment group (n = 50) and placebo control group (n = 50). We measured the serum superoxide dismutase (SOD) activity, an important marker of antioxidant defense, best-corrected visual acuity (BCVA), contrast sensitivity, and Chinese-Version Low Vision Quality of Life (CLVQOL) before and after LA or placebo intervention. Pearson correlation coefficients were calculated to explore the relationship between contrast sensitivity values and CLVQOL scores. There was a statistically significant increase in serum SOD activity after LA intervention. The CLVQOL score was improved significantly after LA treatment. The contrast sensitivity measured at middle and low spatial frequency was significantly higher after LA treatment. CLVQOL scores were positively correlated with contrast sensitivity at low spatial frequency (3 cyc/degree) in LA-treated group. These results indicate that LA treatment improves vision-related quality of life in patients with dry AMD probably by increasing antioxidant activity. Thus, LA can be regarded as a promising agent for the treatment of AMD.
The mechanisms of fetal semi-allograft acceptance by the mother’s immune system have been the target of many immunological studies. Early pregnancy factor (EPF) is a molecule present in the serum of pregnant mammals soon after conception that has been reported to have immunomodulatory effects. In the present study, we aimed to determine whether immune cells such as CD4+CD25+ regulatory T cells (Tregs) are involved in the suppressive mechanism of EPF. Accordingly, CD4+CD25– T cells were isolated from spleens of female C57BL/6 mice and stimulated with anti-CD3 antibody, anti-CD28 antibody and IL-2 in the presence or absence of EPF. Flow cytometry was used to analyze the differentiation of CD4+CD25– T cells to CD4+CD25+ Tregs. We thus found a remarkable rise in the Treg ratio in the EPF-treated cells. Higher mRNA and protein levels of fork head box P3 (Foxp3), a marker of the Treg lineage, were also observed in cells treated with EPF. Furthermore, the effect of EPF on Treg immunosuppressive capacity was evaluated. EPF treatment induced the expression of interleukin-10 and transforming growth factor β1 in Tregs. The suppressive capacity of Tregs was further measured by their capability to inhibit T cell receptor-mediated proliferation of CD4+CD25– T cells. We thus found that EPF exposure can enhance the immunosuppressive functions of Tregs. Overall, our data suggest that EPF induces the differentiation of Tregs and increases their immunosuppressive activities, which might be an important mechanism to inhibit immune responses during pregnancy.
Handgrip strength (HGS) is a useful measure of health-related quality of life and general muscle strength. Serum total bilirubin (T-B) may present potential beneficial effects in preventing oxidative changes which are associated with a risk of metabolic syndrome and the development of cardiovascular disease. Limited information is available regarding whether HGS is an independent confounding factor for serum T-B. The study participants were 214 men aged 71 ± 8 (mean ± standard deviation) years and 302 women aged 71 ± 7 years that were enrolled consecutively from among paticipants aged ≥ 50 years through an annual check-up process. We evaluated the relationship between serum T-B and confounding factors within each sex. HGS related significantly with serum T-B in both men (r = 0.156, p = 0.023) and women (r = 0.173, p = 0.003). Multiple linear regression analysis showed that in men, HGS (β = 0.173) as well as smoking status (β = −0.147), exercise habit (β = 0.138), low-density lipoprotein cholesterol (β = 0.146), and hemoglobin A1c (HbA1c) (β = −0.198) were significantly and independently associated with serum T-B. In women, HGS (β = 0.159) as well as smoking status (β = −0.116), high-density lipoprotein cholesterol (β = 0.159), and HbA1c (β = −0.161) were significantly and independently associated with serum T-B. Multivariate-adjusted serum T-B levels were significantly lower in subjects with the lowest HGS level in both sexes. Increased HGS is strongly associated with increased serum T-B, independent of confounding factors in both sexes.
In Japan, aspiration pneumonia is common among the elderly and patients are often treated by temporary discontinuation of meals. However, there are few published studies on the fasting duration for aspiration pneumonia treatment. Therefore, we conducted the present study to assess the opinions of clinicians regarding the fasting duration for the treatment of patients with aspiration pneumonia and the actual medical practice with regard to oral ingestion in hospitalized patients with aspiration pneumonia. We targeted hospitals with internal medicine and respiratory medicine departments across Japan. A questionnaire regarding the fasting duration for aspiration pneumonia treatment and oral ingestion in hospitalized patients with aspiration pneumonia was mailed to physicians treating patients with pneumonia at 2,490 hospitals. We received appropriate responses from 350 facilities (response rate, 14.1%). Most clinicians (78.3%) responded that it best to keep the fasting duration for treatment as short as possible and considered that fasting is absolutely unnecessary. Regarding oral ingestion in hospitalized patients, more than 25% of clinicians restricted oral intake for a certain number of days. The majority of these clinicians (53.3%) preferred prolonged fasting for 3 to 7 days. Although most physicians preferred the fasting duration to be as short as possible, there was a difference between the ideal and actual scenarios in reintroducing oral intake early in patients with aspiration pneumonia. Improving physicians’ knowledge and experience will bridge the gap between the ideal situation and what currently occurs. Further studies should investigate the acceptable fasting duration for the treatment of aspiration pneumonia.
Traditional Japanese (Kampo) medicine has been widely applied in general medicine in Japan. In 2001, the model core curriculum for Japanese medical education was revised to include Kampo medicine. Since 2007, all 80 Japanese medical schools have incorporated it within their programs. However, postgraduate training or instruction of Kampo medicine has not been recognized as a goal for the clinical training of junior residents by Japan’s Ministry of Health, Labour and Welfare; little is known about postgraduate Kampo medicine education. This exploratory study investigated attitudes about Kampo medicine among junior residents in Japanese postgraduate training programs. A questionnaire survey was administered to junior residents at five institutions in the Tohoku area of Japan. Questions evaluated residents’ experiences of prescribing Kampo medicines and their expectations for postgraduate Kampo education and training. As a result, 121 residents responded (response rate = 74%). About 96% of participants had previously received Kampo medicine education at their pre-graduate medical schools and 64% had prescribed Kampo medications. Specifically, daikenchuto was prescribed to prevent ileus and constipation after abdominal surgery and yokukansan was prescribed to treat delirium in the elderly. Residents received on-the-job instruction by attending doctors. Over 70% of participants indicated that there was a need for postgraduate Kampo medicine education opportunities and expected lectures and instruction on how to use it to treat common diseases. In conclusion, we have revealed that junior residents require Kampo medicine education in Japanese postgraduate training programs. The programs for comprehensive pre-graduate and postgraduate Kampo education are expected.
Chagas disease is a parasitic infection mainly found in Latin America; it is transmitted by a triatomine, also known as assassin bug or kissing bug. In humans, the parasite causes mostly cardiac disorders. Two-thirds of the Mexican territory are regarded as risk areas for vector transmission of Trypanosoma cruzi, the causal agent. The parasite can be found as a blood-borne trypomastigote or as an intracellular amastigote. The progression and severity of lesions could be due to frequent reinfections or to infection by highly virulent strains. A total of 3,327 individuals younger than 18 years old, living in risk areas for this disease in the rural setting of the States of Queretaro, San Luis Potosi, and Veracruz, underwent a seroepidemiological study. Among them, 37 subjects were seropositive for T. cruzi, and were studied to look for signs of cardiac pathology, which has only been reported in adults. A clinical record was prepared for all included individuals, and electrocardiography (ECG) and echocardiography (ECHO) studies were performed; 25 cases showed lesions compatible with the onset of Chagas cardiomyopathy. The other 12 patients showed either normal ECG and ECHO data or showed abnormal parameters that were not regarded as significant. Lesions found in the onset of Chagas cardiomyopathy in children are herein reported, along with 14 cases of cardiac pathology compatible with Chagas disease. Our results indicate that patients younger than 18 years can show a cardiac pathology similar to that observed in adults.
Alport syndrome is a progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes that encode collagen type IV alpha 3, alpha 4, and alpha 5 chains, respectively. Because of abnormal collagen chain, glomerular basement membrane becomes fragile and most of the patients progress to end-stage renal disease in early adulthood. COL4A5 mutation causes X-linked form of Alport syndrome, and two mutations in either COL4A3 or COL4A4 causes an autosomal recessive Alport syndrome. Recently, renin-angiotensin-aldosterone system (RAAS) blockade has been shown to attenuate effectively disease progression in Alport syndrome. Here we present three Japanese siblings and their father all diagnosed with autosomal recessive Alport syndrome and with different clinical courses, suggesting the importance of the early initiation of RAAS blockade. The father was diagnosed with Alport syndrome. His consanguineous parents and his wife were healthy. All three siblings showed hematuria since infancy. Genetic analysis revealed that they shared the same gene mutations in COL4A3 in a compound heterozygous state: c.2330G>A (p.Gly777Ala) from the mother and c.4354A>T (p.Ser1452Cys) from the father. Although RAAS blockade was initiated for the older sister and brother when their renal function was already impaired, it did not attenuate disease progression. In the youngest brother, RAAS blockade was initiated during normal renal function stage. After the initiation, his renal function has been normal with the very mild proteinuria to date at the age of 17 years. We propose that in Alport syndrome, RAAS blockade should be initiated earlier than renal function is impaired.