Potential for neural regeneration after neurotoxic injury in the adult mammalian retina

It has long been believed that the retina of mature mammals is incapable of regeneration. In this study, using the N-methyl-D-aspartate neurotoxicity model of adult rat retina, we observed that some Müller glial cells were stimulated to proliferate in response to a toxic injury and produce bipolar cells and rod photoreceptors. Although these newly produced neurons were limited in number, retinoic acid treatment promoted the number of regenerated bipolar cells. Moreover, misexpression of basic helix-loop-helix and homeobox genes promoted the induction of amacrine, horizontal, and rod photoreceptor specific phenotypes. These findings demonstrated that retinal neurons regenerated even in adult mammalian retina after toxic injury. Furthermore, we could partially control the fate of the regenerated neurons with extrinsic factors or intrinsic genes. The Müller glial cells constitute a potential source for the regeneration of adult mammalian retina and can be a target for drug delivery and gene therapy in retinal degenerative diseases.     

Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion

Chromosomal translocations that involve the monocytic leukemia zinc finger (MOZ) gene are typically associated with human acute myeloid leukemia (AML) and often predict a poor prognosis. Overexpression of HOXA9, HOXA10, and MEIS1 was observed in AML patients with MOZ fusions. To assess the functional role of HOX upregulation in leukemogenesis by MOZ–TIF2, we focused on bromodomain-PHD finger protein 1 (BRPF1), a component of the MOZ complex that carries out histone acetylation for generating and maintaining proper epigenetic programs in hematopoietic cells. Immunoprecipitation analysis showed that MOZ–TIF2 forms a stable complex with BRPF1, and chromatin immunoprecipitation analysis showed that MOZ–TIF2 and BRPF1 interact with HOX genes in MOZ–TIF2-induced AML cells. Depletion of BRPF1 decreased the MOZ localization on HOX genes, resulting in loss of transformation ability induced by MOZ–TIF2. Furthermore, mutant MOZ–TIF2 engineered to lack histone acetyltransferase activity was incapable of deregulating HOX genes as well as initiating leukemia. These data indicate that MOZ–TIF2/BRPF1 complex upregulates HOX genes mediated by MOZ-dependent histone acetylation, leading to the development of leukemia. We suggest that activation of BRPF1/HOX pathway through MOZ HAT activity is critical for MOZ–TIF2 to induce AML.     

Non-high-density lipoprotein cholesterol and the development of coronary heart disease and stroke subtypes in a general Japanese population: The Hisayama Study

Background and purpose

It has not been fully determined whether non-high-density lipoprotein cholesterol (non-HDLC) levels are involved in vascular events, especially stroke, in general Asian populations. We evaluated the association between non-HDLC levels and the risk of type-specific cardiovascular disease in a prospective cohort study in Japan.

Methods

A total of 2452 community-dwelling Japanese subjects aged ≥40 years were followed prospectively for 24 years.

Results

The age- and sex-adjusted incidence of coronary heart diseases (CHD) significantly increased with elevating non-HDLC levels (P for trend < 0.001), but no such association was observed for ischemic and hemorrhagic strokes. With regard to ischemic stroke subtypes, the age- and sex-adjusted incidence of lacunar infarction significantly increased with elevating non-HDLC levels (P for trend < 0.01), and such tendency was seen for atherothrombotic infarction (P for trend = 0.098), while a significant inverse association was observed for cardioembolic infarction (P for trend = 0.007). After adjustment for confounders, namely, age, sex, diabetes, body mass index, systolic blood pressure, electrocardiogram abnormalities, current drinking, current smoking, and regular exercise, the associations remained significant for CHD [adjusted hazard ratio (HR) for a 1 standard deviation of non-HDLC concentrations = 1.17, 95% confidence interval (CI) = 1.02 to 1.35], atherothrombotic infarction (adjusted HR = 1.39, 95% CI = 1.09 to 1.79), and cardioembolic infarction (adjusted HR = 0.64, 95% CI = 0.47 to 0.85).

Conclusions

Our findings suggest that elevated non-HDLC levels are a significant risk factor for the development of atherothrombotic infarction as well as CHD but reduce the risk of cardioembolic infarction in the general Japanese population.     

Low molecular weight pentastarch is more effective than crystalloid solution in goal-directed fluid management in patients undergoing major gastrointestinal surgery

Background

This prospective observational study compared the volume effect between hydroxyethyl starch (HES) and crystalloid solution and its context dependency in intraoperative goal-directed fluid management.

Methods

With institutional review board (IRB) approval, 35 patients undergoing major gastrointestinal surgery were enrolled. Fluid challenge consisting of 250 ml of either bicarbonate Ringer solution (BRS) or low molecular weight pentastarch (HES 70/0.5) was given to maintain stroke volume index >35 ml/m². The context of fluid challenge was classified as related to either epidural block (EB) or blood loss (BL) or as nonspecific. The primary end point was the interval between index fluid challenge and the next fluid challenge, and the secondary end point was the hemodynamic parameter at the end of fluid challenge. Differences in these parameters in each clinical context were compared between BRS and HES 70/0.5. A p value <0.05 was considered statistically significant.

Results

Eighty-eight, 77, and 127 fluid challenges were classified as related to EB and BL and as nonspecific, respectively. In the nonspecific condition, the median (range) interval after fluid challenge with HES 70/0.5 and BRS was 45 (11–162) min and 18 (8–44) min, respectively, and the difference was statistically significant. Also, mean arterial pressure and stroke volume index significantly increased, whereas stroke volume variation significantly decreased after fluid challenge with HES 70/0.5 compared with BRS. Such differences were not observed in the other situations.

Conclusions

HES 70/0.5 exerted larger volume effects than did crystalloid under nonspecific conditions. However, similar volume effects were observed during volume loss and extensive sympathetic blockade.     

The safety and effectiveness profile of daily teriparatide in a prospective observational study in Japanese patients with osteoporosis at high risk for fracture: interim report

This postmarketing surveillance study assessed the safety and effectiveness of daily teriparatide treatment in patients with osteoporosis in a Japanese clinical setting. In this prospective, multicenter, observational study, patients with osteoporosis at high risk for fracture received subcutaneous injections of teriparatide (20 μg/day) for a maximum of 24 months. For this interim report, data from 1,671 patients were eligible for analysis at the cutoff date. The mean age was 75.3 years; 93 % of patients (1,552/1,671 patients) were women. There were 117 adverse drug reactions (ADRs) reported in 101 of 1,671 patients (6.04 %); the most common reported ADRs were nausea, dizziness, headache, and palpitations. No clinically significant safety issues were identified, although 5 serious ADRs were reported in 4/1,671 (0.24 %) patients. At 12 months, 71.9 % of patients remained on teriparatide treatment. From 1 month, there were rapid increases in the biomarkers of bone formation P1NP and, to a lesser extent, BAP. In contrast, increases in the biomarkers of bone resorption, serum NTX, urinary NTX, and TRACP5b, were smaller. After 12 months of treatment, there was an increase in bone mineral density at the lumbar spine, femoral neck, and total hip, and a decrease in the Visual Analog Scale score for back pain. The incidence of new vertebral and nonvertebral fractures was 1.21 % and 3.18 %, respectively. In conclusion, the favorable safety profile and effectiveness of teriparatide observed in this population of Japanese patients with osteoporosis were accompanied by relatively high persistence with treatment, which is a key factor in the success of osteoporosis treatment.     

Glucocorticoid receptor and serum‐ and glucocorticoid‐induced kinase‐1 in esophageal adenocarcinoma and adjacent Barrett's esophagus

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation‐associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum‐ and glucocorticoid‐induced kinase‐1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.     

Various significant connections of the male pelvic floor muscles with special reference to the anal and urethral sphincter muscles

The male pelvic floor is a complex structure formed by several muscles. The levator ani muscle and the perineal muscles are important components of the pel     

Association of glycated hemoglobin at an early stage of pregnancy with the risk of gestational diabetes mellitus among non‐diabetic women in Japan: The Japan Environment and Children’s Study

Aims/IntroductionGestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is associated with adverse pregnancy outcomes. This study aimed to explore the associations between glycated hemoglobin (HbA1c) levels at the early stage of pregnancy and the GDM risk among non‐diabetic women in a nationwide study in Japan. In addition, the relationship between GDM and adverse pregnancy outcomes was also analyzed.Materials and MethodsThis cohort study (n = 89,799) used data from the Japan Environment and Children’s Study. We stratified the participants into four groups according to HbA1c levels at an early stage of pregnancy. We investigated the association of HbA1c at an early stage of pregnancy with the risk of GDM, and of GDM with the risk of some representative adverse pregnancy outcomes, using the multiple logistic regression model with adjustment for potential confounders.ResultsThe adjusted odds ratio for GDM per 0.1 percentage point increase in HbA1c (%) was 1.20. The adjusted odds ratio for developing GDM was significantly increased in women from the HbA1c 5.0–5.4% category. GDM significantly increased the adjusted odds ratio for adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, polyhydramnios and premature birth.ConclusionsHigh‐normal HbA1c levels at the early stage of pregnancy are significantly associated with GDM risk in women in Japan. GDM was significantly associated with adverse pregnancy outcomes.     

Role of aldosterone in left ventricular hypertrophy in hypertension

BACKGROUND: Aldosterone induces cardiac fibrosis in experimental animal models, but only limited information is available on the association between aldosterone and left ventricular (LV) hypertrophy in human beings. The aim of the present study was to determine the role of aldosterone in LV geometry and to investigate other types of target organ damage in hypertensive patients. METHODS: A total of 25 patients with primary aldosteronism caused by Conn's adenoma, 29 patients with renovascular hypertension, and 29 patients with essential hypertension (EHT) were included in the present study. Echocardiographic examinations and 24-h ambulatory blood pressure (BP) monitoring were conducted in all subjects. RESULTS: The mean 24-h systolic and diastolic BP in primary aldosteronism and renovascular hypertension were found to be comparable to those in EHT. However, LV mass index adjusted by age, sex, mean 24-h systolic BP, mean 24-h pulse rate, body mass index, and duration of hypertension was significantly increased in the patients with primary aldosteronism and renovascular hypertension compared with values in patients with EHT (150.2 +/- 7.7, 142.3 +/- 7.2, and 115.2 +/- 7.2 g/m(2), respectively). Hypertensive organ damages, such as proteinuria and hypertensive retinopathy, were more pronounced in the patients with renovascular hypertension; however, LV hypertrophy was especially exaggerated in patients with primary aldosteronism. CONCLUSIONS: These results indicate that aldosterone may induce LV hypertrophy in human beings as well as in experimental animals, and that angiotensin II and aldosterone may differentially participate in causing hypertensive target organ damage.