IQ in high school as a predictor of midlife alcohol drinking patterns.

AIMS: The aim of the present study was to assess the relationship between adolescent IQ and midlife alcohol use and to explore possible mediators of this relationship. METHODS: Study data were from 6300 men and women who participated in the Wisconsin Longitudinal Study of high-school students graduating in 1957. IQ scores were collected during the participants' junior year of high school. In 2004, participants reported the number of alcoholic beverages consumed (past 30 days) and the number of binge-drinking episodes. A multinomial logistic regression was conducted to determine the relationship between adolescent IQ and future drinking pattern (abstainer, moderate drinker, or heavy drinker), and Poisson regression was used to examine the number of binge-drinking episodes. Two mediators-income and education-were also explored. RESULTS: Every one-point increase in IQ score was associated with a 1.6% increase in the likelihood of reporting moderate or heavy drinking as compared to abstinence. Those with higher IQ scores also had significantly fewer binge-drinking episodes. Household income, but not education, partially mediated the relationship between IQ and drinking pattern. CONCLUSIONS: The present study suggests that higher adolescent IQ may predict a higher likelihood of moderate or heavy drinking in midlife, but fewer binge-drinking episodes. The study also suggests that this relationship is mediated by other psychosocial factors, specifically income, prompting future exploration of mediators in subsequent studies.

When Are "Paraphernalia" Critical Medical Supplies?

Evidence of harm reduction interventions' morbidity and mortality benefits is abundant and of high quality, so there are good reasons for regional and national groups to advocate for more widespread distribution of legally regulated "drug paraphernalia," including needles, syringes, and fentanyl test strips. But lack of consistency among states' laws means that patients' interstate travel can subject them to being charged with possession of illegal items. This commentary on a case offers guidance to clinicians looking to help patients understand legal risks of interstate travel with supplies that are prescribed or recommended to reduce harms of their drug use and explores the ethical responsibilities of physicians in jurisdictions that legally prohibit these harm reduction interventions.

Peripheral refraction and image blur in four meridians in emmetropes and myopes.

INTRODUCTION: The peripheral refractive error of the human eye has been hypothesized to be a major stimulus for the development of its central refractive error. AIM: The purpose of this study was to investigate the changes in the peripheral refractive error across horizontal, vertical and two diagonal meridians in emmetropic and low, moderate and high myopic adults. SUBJECTS AND METHODS: Thirty-four adult subjects were recruited and aberration was measured using a modified commercial aberrometer. We then computed the refractive error in power vector notation from second-order Zernike terms. Statistical analysis was performed to evaluate the statistical differences in refractive error profiles between the subject groups and across all measured visual field meridians. RESULTS: Small amounts of relative myopic shift were observed in emmetropic and low myopic subjects. However, moderate and high myopic subjects exhibited a relative hyperopic shift in all four meridians. Astigmatism J0 and J45 had quadratic or linear changes dependent on the visual field meridians. Peripheral Sphero-Cylindrical Retinal Image Blur increased in emmetropic eyes in most of the measured visual fields. CONCLUSION: The findings indicate an overall emmetropic or slightly relative myopic periphery (spherical or oblate retinal shape) formed in emmetropes and low myopes, while moderate and high myopes form relative hyperopic periphery (prolate, or less oblate, retinal shape). In general, human emmetropic eyes demonstrate higher amount of peripheral retinal image blur.

In-Vivo Evaluation of Peripheral Refraction Changes with Single Vision and Multifocal Soft Contact Lenses.

This study investigated in-vivo changes of peripheral refraction with commercially available single vision and multifocal soft contact lenses, utilizing different designs and various corrective power values. Starting at the fovea, wave-front aberrations were measured up to 30o nasal retinal eccentricity, in 10o increments, using a commercially available Shack-Hartmann aberrometer. Three different types of contact lenses were fitted in an adult subject's right eye: Acuvue Oasys Single Vision (ASV), Proclear Multifocal D with 2.50 diopters (D) add power (PMD), and ArtMost SoftOK (SOK). Each lens type was fitted in corrective power values of -2.00 D, -4.00 D, and -6.00 D. Refractive errors were computed in power vector notation: The spherical equivalent (M), the Cartesian Jackson-Cross-Cylinder (J0), and the oblique Jackson Cross Cylinder (J45) from measured second order Zernike terms. Acuvue Oasys Single Vision lenses produced a slight myopic shift at 30o retinal periphery (-0.32 D ± 0.05) without significant differences between the various lens power values. Proclear Multifocal D lenses did not create clinically significant myopic shifts of at least -0.25 D. All SOK lenses produced clinically significant relative myopic shifts at both 20o (-0.61 D ± 0.08) and 30o (-1.42 D ± 0.15) without significant differences between the various lens power values. For all lens types and power values, off-axis astigmatism J0 was increased peripherally and reached clinical significance beyond 20o retinal eccentricity. The increased amount of off-axis astigmatism J0 did not show a significant difference for the same type of lenses with different dioptric power. However, at 30o retinal eccentricity, SOK lenses produced significantly higher amounts of off-axis astigmatism J0, compared with ASV and PMD lenses (SOK versus ASV versus PMD: -1.67 D ± 0.09, -0.81 D ± 0.07, and -0.72 D ± 0.15). Both ASV and SOK lenses showed no clinically significant differences in the amount of introduced astigmatic retinal image blur, with various lens power values. Proclear Multifocal D lenses showed a systematic increase of astigmatic retinal image blur with an increase of add power. At 30o retinal eccentricity, -6.00 D SOK lenses introduced 0.73 D astigmatic retinal image blur, while PMD and ASV lenses introduced 0.54 D and 0.37 D, respectively. In conclusion, relative peripheral refractions, measured in-vivo, were independent of the contact lenses central corrective power. The SOK contact lenses demonstrated a stronger capability in rendering relative peripheral myopic defocus into far periphery, compared to the other lens designs used in this study. This was accompanied by higher amounts of introduced astigmatic retinal image blur.

Optical Rehabilitation of a Patient with Keratoconus and Nystagmus.

Keratoconus is a progressive corneal disease characterized by bilateral yet usually asymmetric thinning of the cornea with an onset typically in teenage years. While it often presents as an isolated condition, keratoconus may also be associated with many systemic and/or ocular diseases, such as connective tissue and chromosomal disorders. Its association with nystagmus has been described in Leber's congenital amaurosis, where patients also exhibit abnormal pupillary responses, early-onset retinal dystrophy, mental developmental delays, and eventual blindness. The case described here, however, was a high-functioning teenager with keratoconus and infantile nystagmus, and oscillopsia on left gaze and a compensatory head turn to the patient's left. The initial distance visual acuities of 20/60 and 20/150 in the right and left eye, respectively improved to 20/25 and 20/40 by the use of corneal rigid gas permeable contact lenses. In addition, the patient's neck strain and overall gait were eased by yoked prism spectacles.

Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.

Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3'-triiodo-L-thyronine.

Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype beta (TRbeta) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRbeta stimulation. For these studies, the TRbeta selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED(50) = 190 nmol/kg x d) approximately 30 times more potently than it induced tachycardia (ED(15) = 5451 nmol/kg x d). T(3) showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED(5) = 477 nmol/kg x d) relative to tachycardia compared with T(3), which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T(3) and GC-1, whereas no tachycardia was observed for GC-1, unlike T(3). T(3) and GC-1 caused a significant (approximately 4%) reduction in body weight in these animals. Therefore, selective TRbeta activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).

N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation.

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.

The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice.

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.

Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability.

Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR beta subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR alpha appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR beta activation on metabolic rate and HR with either TR alpha 1-/- mice or the selective TR beta agonist KB-141 in mice, rats, and monkeys. 3,5,3'-triiodi-l-thyronine (T3) had a greater effect on increasing HR in WT than in TR alpha-/- mice (ED15 values of 34 and 469 nmol/kg/day, respectively). T3 increased metabolic rate [whole body oxygen consumption (MVO2)] in both WT and TR alpha-/- mice, but the effect in the TR alpha 1-/- mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2 is likely due to both TR alpha and -beta. T3 had equivalent potency for cholesterol reduction in WT and TR alpha-/- mice. KB-141 increased MVO2 with selectivities of 16.5- and 11.2-fold vs. HR in WT and TR alpha 1-/- mice, respectively. KB-141 also increased MVO2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR beta-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).