16 research outputs found
The Prevalence and Volumetry of Pituitary Cysts in Children with Growth Hormone Deficiency and Idiopathic Short Stature
Background
Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS).
Methods
Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented.
Results
Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%+/-12.8 vs. 7.1%+/-8.0). Observers were blinded to patient groups.
Conclusions
GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure
Femtosecond Stimulated Raman Study of the Photoactive Flavoprotein AppABLUF
Femtosecond stimulated Raman Spectroscopy (FSRS) is applied to study the photocycle of a blue light using flavin (BLUF) domain photoreceptor, AppABLUF. It is shown that FSRS spectra are sensitive to the light adapted state of the protein and probe its excited state dynamics. The dominant contribution to the most sensitive excited state Raman active modes is from flavin ring modes. However, TD-DFT calculations for excited state structures indicate that reproduction and assignment of the experimentally observed spectral shift will require high level calculations on the flavin in its specific protein environment
Histone deacetylase inhibitors modulate KATP subunit transcription in HL-1 cardiomyocytes through effects on cholesterol homeostasis
Histone deacetylase inhibitors (HDIs) are under investigation for the treatment of a number of human health problems. HDIs have proven therapeutic value in refractory cases of cutaneous T-cell lymphoma,. Electrocardiographic ST segment morphological changes associated with HDIs were observed during development. Because ST segment morphology is typically linked to changes in ATP sensitive potassium (KATP) channel activity, we tested the hypothesis that HDIs affect cardiac KATP channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20 fold increase in SUR2 (Abcc9) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (Abcc8) expression. Moreover, the effect was cell specific as neither HDI markedly altered KATP subunit expression in MIN6 pancreatic β-cells. We observe significant enrichment of the H3K9Ac histone mark specifically at the SUR2 promoter consistent with the conclusion that chromatin remodeling at this locus plays a role in increasing SUR2 gene expression. Unexpectedly, however, we also discovered that HDI-dependent depletion of cellular cholesterol is required for the observed effects on SUR2 expression. Taken together, the data in the present study demonstrate that KATP subunit expression can be epigenetically regulated in cardiomyocytes, defines a role for cholesterol homeostasis in mediating epigenetic regulation and suggests a potential molecular basis for the cardiac effects of the HDIs
Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD)
Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: Role of the Na+-glucose cotransporter
Contribution of Cytosolic Ionic and Energetic Milieu Change to Ischemia- and Reperfusion-Induced Injury in Guinea Pig Heart: Fluorometry and Nuclear Magnetic Resonance Studies
Real-world effects of using a phone while driving on lateral and longitudinal control of vehicles
Mechanism of the AppA<sub>BLUF</sub> Photocycle Probed by Site-Specific Incorporation of Fluorotyrosine Residues: Effect of the Y21 p<i>K</i><sub>a</sub> on the Forward and Reverse Ground-State Reactions
The
transcriptional antirepressor AppA is a blue light using flavin
(BLUF) photoreceptor that releases the transcriptional repressor PpsR
upon photoexcitation. Light activation of AppA involves changes in
a hydrogen-bonding network that surrounds the flavin chromophore on
the nanosecond time scale, while the dark state of AppA is then recovered
in a light-independent reaction with a dramatically longer half-life
of 15 min. Residue Y21, a component of the hydrogen-bonding network,
is known to be essential for photoactivity. Here, we directly explore
the effect of the Y21 p<i>K</i><sub>a</sub> on dark state
recovery by replacing Y21 with fluorotyrosine analogues that increase
the acidity of Y21 by 3.5 pH units. Ultrafast transient infrared measurements
confirm that the structure of AppA is unperturbed by fluorotyrosine
substitution, and that there is a small (3-fold) change in the photokinetics
of the forward reaction over the fluorotyrosine series. However, reduction
of 3.5 pH units in the p<i>K</i><sub>a</sub> of Y21 increases
the rate of dark state recovery by 4000-fold with a Brønsted
coefficient of ∼1, indicating that the Y21 proton is completely
transferred in the transition state leading from light to dark adapted
AppA. A large solvent isotope effect of ∼6–8 is also
observed on the rate of dark state recovery. These data establish
that the acidity of Y21 is a crucial factor for stabilizing the light
activated form of the protein, and have been used to propose a model
for dark state recovery that will ultimately prove useful for tuning
the properties of BLUF photosensors for optogenetic applications
Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial
BACKGROUND: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs).
OBJECTIVES: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD.
METHODS: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy.
RESULTS: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life.
CONCLUSIONS: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)