α-Adrenergic agonism enhances the growth hormone (GH) response to GH-releasing hormone through an inhibition of hypothalamic somatostatin release in normal men

The purpose of this study was to investigate the precise mechanism by which central a-adrenergic pathways modulate GH secretion in humans. In 10 normal subjects we compared the pattern of clonidine-induced GH release to that elicited by GH-releasing hormone (GHRH) given at a time of presumably similar responsiveness of the somatotrope. We also evaluated the effect of stimulation by GHRH (either endogenous, by administration of clonidine, or exogenous) on the GH response to a further exogenous GHRH stimulation. In 2 experiments the administration of clonidine (0.150 mg, orally) at 0 or 60 min was followed by a GHRH [GRF-(1-29); 1 µg/kg, iv] challenge at 180 min. In other experiments subjects received on separate occasions placebo or clonidine at 0 min, followed by GHRH at 60 min and again at 180 min. In a further experiment the administration of clonidine at 0 min was followed by 2 GHRH challenges (60 and 180 min later). The administration of clonidine 60 or 120 min, but not 180 min, before the GHRH bolus significantly (P <0.01) increased the GH responses to this challenge compared to those elicited by GHRH when given after placebo in a period of a similar somatotrope responsiveness. These, in turn, were significantly (P <0.05) higher than those elicited by clonidine alone. The close relationship between pre-GHRH plasma GH values and GHRH-elicited GH peaks, not observed for clonidine, was lost after pretreatment with this drug. These data indicate that clonidine was able to disrupt the intrinsic hypothalamic-somatotroph rhythm, suggesting that a-adrenergic pathways have a major inhibitory effect on somatostatin release. Our data also indicate that GH responses to a GHRH bolus administered 120 min after a prior GHRH challenge are dependent on two parameters: the intrinsic hypothalamic-somatotroph rhythm at the time of the second GHRH bolus, and the magnitude of GH secretion elicited by the previous somatotroph stimulation. In summary, a-adrenergic agonism appears to act primarily in GH control by inhibiting the hypothalamic release of somatostatin, rather than by stimulating GHRH secretion.

Using sketch-map coordinates to analyze and bias molecular dynamics simulations

When examining complex problems, such as the folding of proteins, coarse grained descriptions of the system drive our investigation and help us to rationalize the results. Oftentimes collective variables (CVs), derived through some chemical intuition about the process of interest, serve this purpose. Because finding these CVs is the most difficult part of any investigation, we recently developed a dimensionality reduction algorithm, sketch-map, that can be used to build a low-dimensional map of a phase space of high-dimensionality. In this paper we discuss how these machine-generated CVs can be used to accelerate the exploration of phase space and to reconstruct free-energy landscapes. To do so, we develop a formalism in which high-dimensional configurations are no longer represented by low-dimensional position vectors. Instead, for each configuration we calculate a probability distribution, which has a domain that encompasses the entirety of the low-dimensional space. To construct a biasing potential, we exploit an analogy with metadynamics and use the trajectory to adaptively construct a repulsive, history-dependent bias from the distributions that correspond to the previously visited configurations. This potential forces the system to explore more of phase space by making it desirable to adopt configurations whose distributions do not overlap with the bias. We apply this algorithm to a small model protein and succeed in reproducing the free-energy surface that we obtain from a parallel tempering calculation.

Corneal biomechanical properties in primary open angle glaucoma and normal tension glaucoma

PURPOSE: To determine and compare the corneal biomechanical properties between eyes with primary open angle glaucoma (POAG) and eyes with normal tension glaucoma (NTG). PATIENTS AND METHODS: Prospective cross-sectional study. Consecutive eligible POAG and NTG patients attending the Glaucoma Clinic had assessment of their corneal biomechanical properties-corneal hysteresis (CH) and corneal resistance factor (CRF)-using the Ocular Response Analyzer by an observer masked to the diagnosis. Exclusion criteria included previous intraocular surgery, corneal pathology, inflammatory connective tissue disease, and refraction of 5-dimensional or over. If both eyes were eligible, then the right eye was used for analysis. The main outcome measures were corneal hysteresis and CRF measurements. Data analysis was performed using the t test and general linear model. RESULTS: Eighty-one patients (80 whites) were analyzed. Forty had NTG, whereas 41 had POAG. Thirty-five were females. There was a statistically significant difference in mean CH (NTG 9.6±1.3 mm Hg; POAG 9.0±1.4 mm Hg; P=0.01), but not in mean CRF (NTG 9.9±1.4; POAG 10.8±1.7; P=0.06). The highest recorded Goldmann applanation intraocular pressure (IOP) was statistically significantly associated with lower CH (P=0.01) and higher CRF (P=0.02). CONCLUSIONS: There was a small but statistically significant difference in the mean CH between POAG and NTG (CH was higher in NTG). The highest recorded Goldmann applanation IOP was also statistically significantly correlated with lower CH and higher CRF, suggesting that alterations to the corneal biomechanical properties may occur as a result of chronic raised IOP in POAG. © 2008 by Lippincott Williams & Wilkins.

Comparative study between African-American and Caucasian Normal Tension Glaucoma patients

Purpose. To evaluate differences in optic disc and visual field damage between African-American and Caucasian Normal Tension Glaucoma (NTG) patients. Methods. We retrospectively selected 33 African-American patients with the diagnosis of NTG and age-matched them with 33 Caucasian patients with the same diagnosis. Three masked observers graded disc photographs and visual fields as being normal, globally damaged or focally damaged for both eyes of the subject. Chi-square test was used to evaluate statistically significant differences between groups. Results. The results of the visual fields showed that in the African-American group, 24% were graded normal, 30% showed global damage, and 46% showed focal damage. This data was compared with the Caucasian group which showed 41% normal graded eyes, 22% with global damage, and 37% with focal damage (p = 0.28). The results of the optic disc photos showed that in the African-American group, 25% were graded normal, 45% showed global damage, and 30% showed focal damage. This data was compared with the Caucasian group which showed 43% graded normal, 32% with global damage, and 25% with focal damage (p=0.16). Conclusions. In our study there was no difference in the frequency of globally damaged, focally damaged, and normal graded discs or visual fields between African-American and Caucasian NTG patients.

The short-term effect of topical dorzolamide compared with placebo on perimetry testing in normal subjects

Purpose. To study the effect of topical dorzolamide on retinal sensitivity in normal subjects. Methods. 20 normal subjects were prospectively randomized in a two period crossover study. Baseline threshold perimetry (HVF, program 24-2, Statpac analysis) was obtained. The study eye was randomly chosen and then was randomly assigned to receive either dorzolamide 2% or placebo one hour before repeat HVF. After at least two weeks washout the same eye was given the opposite drop one hour prior to repeat HVF. Global indices were compared using a paired T-test. Results. AFTER PLACEBO AFTER DORZOLAMIDE P-VALUE (mean±SD) (mean±SD) MD 0.12±1.4 0.16±1.4 0.82 PSD 1.83±0.6 1.66±0.4 0.04 SF 1.28±0.4 1.24±0.2 0.73 CPSD 1.05±0.9 0.84±0.6 0.35 Conclusion. In this population, topical dorzolamide had little effect on visual function.

Morphometric analysis of corneal endothelial giant cells in normal and traumatized corneas

Corneal endothelial cells from normal and traumatized human, primate, cat and rabbit eyes were studied by specular microscopy. Morphometric analysis was performed on micrographs of corneal endothelium using a semi-automated image analysis system. The results showed that under normal conditions the corneal endothelium of all four species exhibit major morphological similarities (mean cell areas: human 317 +/- 32 microns 2, primate 246 +/- 22 microns2, cat 357 +/- 25 microns 2, rabbit 308 +/- 35 microns 2). The normal corneal endothelium in man was found to be more polymegethous than that of the other species. Trauma to cat, primate and human corneas resulted in a long-term reduction in endothelial cell density and enhanced polymegethism. In contrast, the reparative response of the rabbit ensured the reformation of an essentially normal monolayer following injury. Endothelial giant cells were a normal inclusion in the rabbit corneal endothelium but were only significant in cat, primate and man following trauma. The presence of corneal endothelial giant cells in amitotic corneas may therefore represent a compensatory response in the absence of mitotic potential.

Stereological estimation of Weibel-Palade bodies in the retinal vasculature of normal and diabetic dogs

The absolute volume of Weibel-Palade (WP) bodies, the storage organelles of von Willebrand factor (vWF), was estimated by a stereological method in a known volume of central retina from normal and 5-year diabetic dogs. The results showed that the volume of WP bodies present in the endothelium of the retinal vasculature varies with blood vessel type and in diabetes. In both diabetic and normal dogs the endothelium of the retinal veins contained a higher volume of WP bodies than that of the retinal arteries. In dogs which had been diabetic for a duration of 5 years the volume of WP bodies present in the endothelium of retinal veins was significantly greater than in the endothelium of veins from the control animals. However, there was no significant difference in the volume of WP bodies present in the endothelium of retinal arteries or capillaries between the two groups of animals.

A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats

Cell loss and regeneration were investigated and compared in the retinal microvasculature of age- and sex-matched normal and streptozotocin diabetic rats. Selective pericyte loss in the diabetic rat was characterized by changes in the pericyte to endothelial cell ratio in retinal capillaries isolated for microscopy by the trypsin digest technique. A comparison of 3- and 9-month-old normal rats showed no significant change in the pericyte to endothelial cell ratio (1:2.7). In diabetic animals the ratio was reduced to 1:4.03, which was statistically significant (P less than .001). Premitotic retinal vascular cells in normal and diabetic rats were labelled with tritiated thymidine and the labelling indices calculated from cell counts of trypsin digest preparations. Methyl H3 thymidine was infused continuously over an eight-day period using osmotic mini pumps. The labelling index of endothelial cells (0.33%) in normal rats increased to 0.91% in diabetic animals (P less than .05). The labelling index of pericyte cells in normal animals (0.16%) did not increase significantly (P greater than .05) in diabetic animals (0.19%). A special stain was used to exclude labelled polymorphonuclear leukocytes from the cell counts.

A spectroscopically normal type Ic supernova from a very massive progenitor

We present observations of the Type Ic supernova (SN Ic) 2011bm spanning a period of about one year. The data establish that SN 2011bm is a spectroscopically normal SN Ic with moderately low ejecta velocities and with a very slow spectroscopic and photometric evolution (more than twice as slow as SN 1998bw). The Pan-STARRS1 retrospective detection shows that the rise time from explosion to peak was 40 days in the R band. Through an analysis of the light curve and the spectral sequence, we estimate a kinetic energy of 7-17 foe and a total ejected mass of 7-17 Mo, 5-10 Mo of which is oxygen and 0.6-0.7 Mo is 56Ni. The physical parameters obtained for SN 2011bm suggest that its progenitor was a massive star of initial mass 30-50 Mo. The profile of the forbidden oxygen lines in the nebular spectra show no evidence of a bi-polar geometry in the ejected material.

Spectroscopic Observations of SN 2012fr: A Luminous Normal Type Ia Supernova with Early High Velocity Features and Late Velocity Plateau

We present 65 optical spectra of the Type Ia supernova SN 2012fr, of which 33 were obtained before maximum light. At early times SN 2012fr shows clear evidence of a high-velocity feature (HVF) in the Si II 6355 line which can be cleanly decoupled from the lower velocity "photospheric" component. This Si II 6355 HVF fades by phase -5; subsequently, the photospheric component exhibits a very narrow velocity width and remains at a nearly constant velocity of v~12,000 km/s until at least 5 weeks after maximum brightness. The Ca II infrared (IR) triplet exhibits similar evidence for both a photospheric component at v~12,000 km/s with narrow line width and long velocity plateau, as well as a high-velocity component beginning at v~31,000 km/s two weeks before maximum. SN 2012fr resides on the border between the "shallow silicon" and "core-normal" subclasses in the Branch et al. (2009) classification scheme, and on the border between normal and "high-velocity" SNe Ia in the Wang et al. (2009a) system. Though it is a clear member of the "low velocity gradient" (LVG; Benetii et al., 2005) group of SNe Ia and exhibits a very slow light-curve decline, it shows key dissimilarities with the overluminous SN 1991T or SN 1999aa subclasses of SNe Ia. SN 2012fr represents a well-observed SN Ia at the luminous end of the normal SN Ia distribution, and a key transitional event between nominal spectroscopic subclasses of SNe Ia.

Investigation of moisture condition and Autoclam sensitivity on air permeability measurements for both normal concrete and high performance concrete

While on site measurement of air permeability provides a useful approach for assessing the likely long term durability of concrete structures, no existing test method is capable of effectively determining the relative permeability of high performance concrete (HPC). Lack of instrument sensitivity and the influence of concrete moisture are proposed as two key reasons for this phenomenon. With limited systematic research carried out in this area to date, the aim if this study was to investigate the influence of instrument sensitivity and moisture condition on air permeability measurements for both normal concrete and HPC. To achieve a range of moisture conditions, samples were dried initially for between one and 5 weeks and then sealed in polythene sheeting and stored in an oven at 50 C to internally distribute moisture evenly. Moisture distribution was determined throughout using relative humidity probe and electrical resistance measurements. Concrete air permeability was subsequently measured using standardised air permeability (Autoclam) and water penetration (BS EN: 12390-8) tests to assess differences between the HPCs tested in this study. It was found that for both normal and high performance concrete, the influence of moisture on Autoclam air permeability results could be eliminated by pre-drying (50 ± 1 C, RH 35%) specimens for 3 weeks. While drying for 5 weeks alone was found not to result in uniform internal moisture distributions, this state was achieved by exposing specimens to a further 3 weeks of sealed pre-conditioning at 50 ± 1 C. While the Autoclam test was not able to accurately identify relative HPC quality due to low sensitivity at associated performance levels, an effective preconditioning procedure to obtain reliable air permeability of HPC concretes was identified. © 2013 The Authors

SN 2009N: linking normal and subluminous Type II-P Sne

We present ultraviolet, optical, near-infrared photometry and spectroscopy of SN 2009N in NGC 4487. This object is a Type II-P supernova with spectra resembling those of subluminous II-P supernovae, while its bolometric luminosity is similar to that of the intermediate-luminosity SN 2008in. We created SYNOW models of the plateau phase spectra for line identification and to measure the expansion velocity. In the near-infrared spectra we find signs indicating possible weak interaction between the supernova ejecta and the pre-existing circumstellar material. These signs are also present in the previously unpublished near-infrared spectra of SN 2008in. The distance to SN 2009N is determined via the expanding photosphere method and the standard candle method as D = 21.6 ± 1.1 Mpc. The produced nickel-mass is estimated to be ∼0.020 ± 0.004 M⊙. We infer the physical properties of the progenitor at the explosion through hydrodynamical modelling of the observables. We find the values of the total energy as ∼0.48 × 1051 erg, the ejected mass as ∼11.5 M⊙, and the initial radius as ∼287 R⊙.

Intravitreal Injection of Normal Saline Induces Retinal Degeneration in the C57BL/6J Mouse

Purpose: To investigate the adverse effect of intravitreal injection of normal saline (NS) and phosphate buffered saline (PBS) in mouse eyes.

Methods: NS or PBS was injected intravitreally into C57BL/6J mouse eyes. Retinal lesions were monitored by fundus imaging, spectral-domain optical coherence tomography (SD-OCT), and histological investigations. Retinal immune gene expression was determined by real-time polymerase chain reaction (PCR). The toxic effect of NS and PBS or retinal protein from NS- or PBS-injected eyes on retinal pigment epithelium (RPE) was tested in B6-RPE-07 mouse RPE cell cultures.

Results: Intravitreal injection of NS dose-dependently induced localized retinal lesion in mice. Histological investigations revealed multiple vacuoles in photoreceptor outer segments and RPE cells. The lesions recovered over time and by 3 weeks post injection the majority of lesions vanished in eyes receiving 1 μl NS. Inflammatory genes, including TNF-α, IL-1β, IL-6, iNOS, and VEGF were upregulated in NS injected eyes. Intravitreal injection of PBS did not cause any pathology. The treatment of B6-RPE07 cells with 30% PBS or 30% NS did not affect RPE viability. However, incubation of 1-μg/ml retinal protein from NS-injected eyes, but not PBS-injected eyes induced RPE cell death.

Conclusion: NS is toxic to the C57BL/6J mouse retina and should not be used as a vehicle for intraocular injection. PBS is not toxic to the retina and is a preferred vehicle.

Translational Relevance: NS is not a physiological solution for intraocular injection in the C57BL/6J mice and questions its suitability for intraocular injection in other species, including human.