Rationale: Possible beneficial effects of Growth Differentiation Factor 11 (GDF11) on the normal, diseased, and aging heart have been reported, including reversing aging induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload induced pathological hypertrophy. Objective: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload induced cardiac hypertrophy. Methods and Results: 12–13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post TAC, these mice received recombinant GDF11 at one of 3 doses: 0.5 mg/kg, 1.0 mg/kg, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at one-week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by HW/TL ratio, myocyte cross sectional area, and LV mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. Conclusions: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.

Microarray results demonstrated that only 347 transcripts of the 47 231 were significantly different by 2-fold or greater in the ZF and ZR. ZF had 195 transcripts with 2-fold or greater increase compared with its paired ZR, whereas ZR was found to have 152 transcripts with 2-fold or greater higher expression than in ZF. Microarray and qPCR analysis of transcripts encoding steroidogenic enzymes (n = 10) demonstrated that only 3β-hydroxysteroid dehydrogenase, steroid sulfotransferase, type 5 17β-hydroxysteroid dehydrogenase, and cytochrome b5 were significantly different. Immunohistochemistry and qPCR studies confirmed that the ZF had an increased expression of lymphoid enhancer-binding factor 1 and nephroblastoma overexpressed, whereas ZR showed an increased expression of solute carrier family 27 (fatty acid transporter) (SLC27A2), member 2 and TSPAN12 (tetraspanin 12) CONCLUSION: Microarray revealed several novel candidate genes for elucidating the molecular mechanisms governing the ZF and ZR, thereby increasing our understanding of the functional zonation of these two adrenocortical zones.

Background: This study compared patient preference for Humalog® KwikPen™ 200 units/mL (insulin lispro; hereafter, IL 200 pen; Eli Lilly and Company, Indianapolis, IN) versus the Humalog KwikPen 100 units/mL (insulin lispro; hereafter, IL 100 pen; Eli Lilly and Company, Indianapolis, IN) in patients with diabetes requiring >20 units of mealtime insulin and diabetes caregivers. This study also determined which attributes had the greatest influence on pen preference selection. Methods: In this 2-period, crossover, simulated-use study, 106 participants were randomized to 1 of 8 sequences that varied the pen order (IL 100 pen or IL 200 pen) and dosing order (15 units = low dose or 50 units = high dose) for a total of 4 simulated injections. Participants then completed a self-administered questionnaire to select their overall preference between the 2 pens and then rated the importance of 11 pen attributes in contributing to their overall preference. Results: Of the 90 participants expressing an overall preference, significantly more preferred the IL 200 pen to the IL 100 pen (IL 200 pen: 80 respondents; IL 100 pen: 10 respondents; 95% confidence interval [0.81, 0.94], P < .0001). The total amount of insulin in the pen, the ease in pressing the injection button, and the amount of fluid injected were key attributes influencing IL 200 pen preference. Conclusions: Based on these key attributes, the IL 200 pen was significantly preferred over the IL 100 pen by patients with diabetes who require >20 daily mealtime insulin units or diabetes caregivers and may improve the injection experience for these patients.

The prevalence of ISH increased correspondingly with advanced stages of CKD, which may partially contribute to the increased cardiovascular mortality during the progress of CKD.

Objective To explore correlations between body mass index (BMI), preoperative systemic immune-inflammation index (SII) and endocrine therapy resistance, and evaluate BMI and SII as predictors of resistance, in patients with luminal breast cancer. Methods This retrospective study included patients with luminal breast cancer who underwent endocrine therapy at Hebei General Hospital. Relationships between BMI and SII subgroups, and clinicopathological parameters were analysed using χ2-tests. Disease-free survival was assessed using Log-rank statistics. Multivariate analysis of factors related to disease progression were analysed using Cox proportional hazards model. Results Out of 161 patients, those with normal BMI and low SII had significantly lower endocrine resistance rates versus those with high BMI and SII, and BMI was significantly positively correlated with SII. High BMI or SII was associated with significantly lower disease-free survival rates. Hazard ratios for disease progression risk were 6.036, 3.508 and 1.733, for SII, BMI and TNM stage, respectively. Conclusion In patients with luminal breast cancer, high BMI (>23 kg/m2) and SII (>518 × 109/L) levels may predict high endocrine resistance rates. BMI, SII and TNM stage were independent prognostic factors for endocrine therapy resistance.

Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL.

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Cardiomyocyte hypertrophy induced by phenylepherine (PE) is accompanied by depression of cytochrome c oxidase (COX) activity. Vascular endothelial growth factor (VEGF) recovers the suppressed COX activity and reverses cardiomyocyte hypertrophy. Because PE causes intracellular copper (Cu) depletion and COX activity is Cu-dependent, the present study was undertaken to test the hypothesis that VEGF recovers suppressed COX activity by restoring Cu availability. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of 100 µmol/L in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to VEGF at a final concentration of 20 ng/mL in cultures for 24 h. Atomic absorption spectrometry analysis revealed that VEGF restored PE-depleted Cu concentrations in hypertrophic cardiomyocytes along with the recovery of COX activity. Western blot analysis showed that protein contents of COX subunit COX-IV and Cu chaperones for COX (COX17, COX11, and SCO2) were decreased in response to PE treatment, and recovered after VEGF treatment. In addition, VEGF treatment suppressed PE-induced accumulation of reactive oxygen species (ROS) and the relevant elevation of homocysteine, which has been shown to form complexes with Cu to restrict Cu availability. This study thus demonstrates that VEGF recovers PE-suppressed COX activity by restoring Cu availability and VEGF suppression of ROS accumulation and homocysteine elevation would contribute to the increased Cu availability.