Rationale: Pulmonary arterial hypertension (PAH) is a lethal, femalepredominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. Objectives: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor g coactivator 1-a (PGC1a), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. Methods: Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia1Sugen-5416 (CH1SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo. Measurements and Main Results: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1a; conversely, siPGC1a reduced PGC1a and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1a were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH1SU. In CH1SU, Ad-MFN2 improved walking distance (381 6 35 vs. 245 6 39 m; P , 0.05); decreased pulmonary vascular resistance (0.18 6 0.02 vs. 0.38 6 0.14 mm Hg/ml/min; P , 0.05); and decreased PA medial thickness (14.5 6 0.8 vs. 19 6 1.7%; P , 0.05). Lung vascularity was increased by MFN2. Conclusions: Decreased expression of MFN2 and PGC1a contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.Keywords: mitochondrial fission; peroxisome proliferator-activated receptor gamma coactivator-1 a; hypoxia-inducible factor-1 a; optic atrophy 1; female sex Pulmonary arterial hypertension (PAH) is a syndrome characterized by obstructive vascular remodeling, inflammation, and vasoconstriction of small pulmonary arteries. PAH is predominantly a disease of females (1). Recent advances in understanding the mechanism of PAH include the identification of mutations in the bone morphogenetic protein receptor 2 in familial PAH (2-4) and the recognition that increases in proliferation and apoptosisresistance of pulmonary arterial smooth muscle cells (PASMC), that have multifactorial etiology, contribute to vascular obstruction (reviewed in [5]). These discoveries have yet to be translated into approved therapies, and most PAH treatments are vasodilators. Perhaps because of this, the 1-year mortality rates remain high (z15%) (6). Although abnormalities of platelets, the endothelium, fibroblasts, and inflammatory cells contribute critically to the path...

Approximately 2.3% of patients hospitalized for HFrEF in a national registry were prescribed ARNI therapy in the first 12 months following Food and Drug Administration approval. Further study is needed to identify and overcome barriers to implementing new evidence into practice, such as ARNI use among eligible patients with HFrEF.

AIM:To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS:Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N 1 -methylnicotinamide on glucose metabolism, plasma H2O2 levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS:Diabetic subjects had significantly higher plasma N 1 -methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 ± 0.13 μmol/L vs 0.6 ± 0.13 μmol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N 1 -methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N 1 -methylnicotinamide. Moreover, cumulative exposure to N 1 -methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/ NADH ratio, and increased plasma H2O2 levels. Decrease in NAD/NADH ratio and increase in H2O2 generation were also observed in human erythrocytes after exposure to N 1 -methylnicotinamide in vitro . Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N 1 -methylnicotinamide clearance. CONCLUSION:These findings suggest that nicotinamide overload, which induced an increase in plasma N 1 -methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

Home-time, which can be readily calculated from administrative claims data, is substantially reduced for many patients following hospitalization for HF and is highly correlated with traditional time-to-event mortality and hospitalization outcomes. Home-time represents a novel, easily measured, patient-centered endpoint that may reflect effectiveness of interventions in future HF studies.

patients' experience, that feedback changes physicians' performance, and people will inevitably use the Internet to voice opinions, so why not capture this information in a useful form. 3 Arguments against using this data include the selection bias by those leaving reviews, the lack of meaningful data on technical quality of health care, and straining of physician-patient relationships. 2,5 Although our results do not counter all of these arguments against, they suggest that discretionary patient ratings, obtained through a Web site, may be a more useful tool than previously considered for both patients and health care workers. If patients are making choices based on this information, they can be reassured that the ratings are not entirely misleading and may be providing relevant information about health care quality. In his book The Wisdom of Crowds, James Surowiecki 7 argues that a diverse collection of "independently deciding individuals" is likely to make better predictions and decisions than single individuals or even experts. At least to an extent, the self-selecting crowd of patients appears to be wise. The use of Web-based patient ratings has become common in other industries such as hotels and restaurants, and consumers value these rankings in making choices. We believe that the information provided by these Web sites, although flawed, represents a potentially important development in the measurement of health care quality.

The MAC of intravenous anesthesia with 8% ILE was less than that of inhalation anesthesia with isoflurane vapor in dogs.

Although direct IV injection of liquid volatile anesthetics is usually lethal, anesthesia using emulsified halothane and isoflurane without adverse effects has been safely induced in animals. We identified the safe concentration of emulsified volatile anesthetic preparations and determined the dose-response relationship of IV emulsified isoflurane and propofol in rats. Liquid/gas partition coefficients of desflurane, sevoflurane, isoflurane, enflurane, and halothane in 20% and 30% Intralipid were measured and used to calculate their saturated concentrations. Unsaturated emulsified isoflurane was prepared by adding liquid isoflurane to 30% Intralipid. The loss of forepaw righting reflex was taken as induction of anesthesia, and disappearance of electrocardiogram was taken as death. The median effective induction dose (ED50) and median lethal dose (LD50) of emulsified isoflurane were 0.072 and 0.216 mL/kg liquid isoflurane, respectively. The ED50 and LD50 of propofol were 5.89 mg/kg and 18.19 mg/kg, respectively. Time to return of forepaw righting reflex after injection of emulsified isoflurane (38 +/- 18 s) was significantly shorter than with propofol (101 +/- 62 s; P < 0.05). Anesthesia was successfully induced in rats by IV emulsified isoflurane with a comparable safety index and certain safety factor as propofol. Recovery of anesthesia after IV emulsified isoflurane was faster than with propofol.

The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.