Alternative Leader-Exon Usage in Mouse IGF-I mRNA Variants: Class 1 and Class 2 IGF-I mRNAs

The mouse IGF-I gene contains six exons, and exon 1 and exon 2 gene are considered to be leader exons. The regulatory mechanism of alternative usage of the leader exons is unclear in mice. The present study, was aimed at clarifying changes in class 1 (derived from exon 1) and class 2 (derived from exon 2) IGF-I mRNA expression in mice under various conditions. Both class 1 and class 2 IGF-I mRNAs were expressed in the mouse uterus, liver and kidney, and class 1 IGF-I mRNA was the major transcript in all organs studied. In the uterus, both class 1 and class 2 IGF-I mRNA expression changed markedly during the estrous cycle, with the highest level at proestrus, but in the liver and kidney there were no significant changes in IGF-I mRNA expression during the estrous cycle. Estrogen treatment increased both class 1 and class 2 IGF-I mRNA levels in the uterus of ovariectomized mice, but class 1 mRNA expression increased more in response to estrogen treatment than class 2 mRNA expression. These findings suggest that estrogen stimulates IGF-I gene expression in, uterine cells, and that a promoter involved in transcription of class 1 IGF-I mRNA is more responsive to estrogen. In conclusion, the present study revealed that two leader exons of mouse IGF-I gene are used in the uterus, liver and kidney. IGF-I mRNA levels of both classes changed during the estrous cycle in the uterus, but not in the liver or kidney. Estrogen increased IGF-I mRNA levels of both classes in the uterus

Mild Hypobaric Hypoxia Enhances Post-exercise Vascular Responses in Young Male Runners

It has been reported that sustained post-exercise vasodilation may be linked to exercise-induced angiogenesis. The present study aimed to evaluate whether mild hypobaric hypoxia enhances the post-exercise reduction in systemic vascular resistance in young male runners. Seven male intercollegiate runners (aged 19–21 years) performed maximal incremental treadmill running under conditions of hypobaric hypoxia (corresponding to 2,200 m above sea level, hereinafter referred to as HH) and normobaric normoxia (corresponding to sea level, hereinafter referred to as NN). A third exercise test was performed under NN conditions, consisting of submaximal exercise with the same absolute exercise volume as was achieved during HH (submaximal exercise under NN conditions, hereinafter referred to as NNsubmax). Blood pressure and cardiac output (CO) were measured before and at 15, 30, and 60 (p60) minutes after exercise. Compared with NN, exercise time was shorter in HH and NNsubmax conditions (p < 0.05). Systolic blood pressure and mean blood pressure (MBP) were lower after exercise in HH conditions (p < 0.05). No condition-related differences were found in CO. Total peripheral resistance (TPR, defined as the ratio of MBP to CO) was significantly lower after exercise compared to baseline for all conditions (p < 0.05). However, the decrease in TPR was maintained longer after exercise in HH compared with NN and NNsubmax conditions (p < 0.05). At p60, TPR was lower than baseline for HH conditions (p < 0.05), whereas after exercise in NN, and NNsubmax conditions, TPR recovered to baseline by p60. Decreases in systemic vascular resistance after exercise were maintained longer under mild HH conditions compared with NN despite the lower exercise volume of the former

A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index.

First published online: April 2, 2015[Objective] Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. [Methods] A retrospective cohort study was performed in two hospitals in Japan (2007–13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. [Results] A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624–0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725–0.874). [Conclusions] This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis

Organ-Specific and Age-Dependent Expression of Insulin-like Growth Factor-I (IGF-I) mRNA Variants: IGF-IA and IB mRNAs in the Mouse

Insulin-like growth factor-I (IGF-I) gene generates several IGF-I mRNA variants by alternative splicing. Two promoters are present in mouse IGF-I gene. Each promoter encodes two IGF-I mRNA variants (IGF-IA and IGF-IB mRNAs). Variants differ by the presence (IGF-IB) or absence (IGF-IA) of a 52-bp insert in the E domain-coding region. Functional differences among IGF-I mRNAs, and regulatory mechanisms for alternative splicing of IGF-I mRNA are not yet known. We analyzed the expression of mouse IGF-IA and IGF-IB mRNAs using SYBR Green real-time RT-PCR. In the liver, IGF-I mRNA expression increased from 10 days of age to 45 days. In the uterus and ovary, IGF-I mRNA expression increased from 21 days of age, and then decreased at 45 days. In the kidney, IGF-I mRNA expression decreased from 10 days of age. IGF-IA mRNA levels were higher than IGF-IB mRNA levels in all organs examined. Estradiol-17 beta (E2) treatment in ovariectomized mice increased uterine IGF-IA and IGF-IB mRNA levels from 3 hr after injection, and highest levels for both mRNAs were detected at 6 hr, and relative increase was greater for IGF-IB mRNA than for IGF-IA mRNA. These results suggest that expression of IGF-I mRNA variants is regulated in organ-specific and age-dependent manners, and estrogen is involved in the change of IGF-I mRNA variant expression

Acute cardiovascular response after maximal cycling exercise in endurance- and strength-trained men

Background: Post-exercise hypotension is an important regulator of ambulatory blood pressure—an independent risk factor for cardiovascular disease. Although post-exercise hypotension may be associated with aerobic exercise capacity in male athletes, it has not been explored whether muscular strength or strength training affects post-exercise hypotension. To elucidate whether the cardiovascular responses after exercise differ between endurance- and strength-trained men, this study investigated cardiovascular indices (e.g., blood pressure, cardiac output, total peripheral resistance) before and after maximal cycling exercise in male long-distance runners, weightlifters, and sedentary peers. Methods: Ten male intercollegiate long-distance runners, nine weightlifters, and 10 sedentary peers performed maximal incremental cycling. Cardiovascular indices were measured before and at 15, 30, 60, and 90 min after the exercise. Results: The runners had remodeled hearts and higher maximal oxygen uptake, and the weightlifters had a higher resting systolic blood pressure. Blood pressure decreased after exercise in all groups. Although the weightlifters showed higher systolic blood pressure than the sedentary men throughout the experiment, the changes from baseline showed no intergroup differences in blood pressure. Cardiac output increased and total peripheral resistance decreased after exercise relative to baseline in all groups; there were no intergroup differences in changes in these measures. Conclusions: The mode of habitual exercise training may affect post-exercise hypotension similarly in endurance- and strength-trained male athletes in spite of their different cardiovascular adaptations

Interleukin-18 (IL-18) mRNA Expression and Localization of IL-18 mRNA-Expressing Cells in the Mouse Uterus

Interleukin-18 (IL-18) belongs to the interleukin-1 family and was identified as an interferon gamma inducing factor. We investigated IL-18 mRNA-expressing cells in the mouse uterus. By RNase protection assay, IL-18 mRNA and a subunit of IL-18 receptor mRNA were detected in the uterus. In the uterus, IL-18 mRNA levels increased during sexual maturation. In situ hybridization analysis demonstrated IL-18 mRNA-expressing cells in the mouse uterus of different ages. At 21 days of age, IL-18 mRNA-expressing cells were detected in the luminal epithelial cells and stromal cells although the IL-18 mRNA signal was weak. At 42 days of age, IL-18 mRNA signal was mainly detected in the stromal cells located near the myometrium, and in some of the luminal and glandular epithelial cells. In the uterus of 63-day-old adult mice, a strong hybridization signal for IL-18 mRNA was detected at estrus, but was weak at diestrus. IL-18 mRNA was mainly detected in the glandular epithelial cells and stromal cells. The effect of estradiol-17 beta (E-2) on IL-18 mRNA-expressing cells in the uterus was examined in ovariectomized mice. In oil-treated mice IL-18 mRNA signal was localized in luminal epithelial cells and stromal cells, while in E-2-treated mice IL-18 mRNA signal was localized in stromal cells alone. These results suggest that the mouse uterus has an IL-18 system, and IL-18 exerts a physiological role within the uterus in a paracrine manner, and that IL-18 gene expression is regulated by estrogen