Intermittent treatment with parathyroid hormone (PTH) increases bone mass in experimental animals and humans. In vitro studies have suggested that the anabolic effect of PTH may be mediated by local growth factors. However, the relevance of these findings to in vivo situations remains unclear. In this study, we examined a time course of daily s.c. injections of hPTH(1-34) on the skeletal concentration of insulin-like growth factor (IGF)-I, IGF-II, and transforming growth factor (TGF-.3) in the proximal tail vertebrae of male rats. PTH caused a time and dose-dependent increase in the bone mineral density of the lumbar spine. This anabolic effect on bone mass was accompanied by progressive increases in bone matrix-associated IGF-I and TGF-fl1. Increases in IGF-I and TGF-1i1 became apparent after four and eight weeks of PTH treatment respectively and persisted through week 12. PTH had no effect on circulating IGF-I, suggesting that the increase of bone matrix IGF-I was due to the local effect of PTH on bone tissue directly rather than to an increase of circulating IGF-I. These data are consistent with the hypothesis that IGF-I and TGF-f81 may play a role as local mediators of the anabolic effects of PTH on bone metabolism. (J. Clin. Invest. 1995. 96:767-774.)

Autosomal recessive bestrophinopathy (ARB) and vitelliform macular dystrophy (VMD) are distinct phenotypes, typically inherited through recessive and dominant patterns, respectively. Recessively inherited VMD (arVMD) has been reported, suggesting that dominant and recessive BEST1-related retinopathies represent a single disease spectrum. This study compares adVMD, arVMD, and ARB to determine whether a continuum exists and to define clinical and genetic features to aid diagnosis and management. METHODS.One arVMD patient and nine ARB patients underwent standard ophthalmic examination, imaging, electrophysiology, and genetic assessments. A meta-analysis of reported BEST1 variants was compiled, and clinical parameters were analyzed with regard to inheritance and phenotype.RESULTS. Among 10 patients with biallelic BEST1 variants, three novel ARB variants (p.Asp118Ala, p.Leu224Gln, p.Val273del) were discovered. A patient with homozygous p.Glu35Lys was clinically unique, presenting with VMD, including hyperautofluorescence extending beyond the macula, peripheral punctate lesions, and shortened axial-length. A tritan-axis color vision deficit was seen in three of six (50%) of ARB patients. Attempts to distinguish recessively-inherited ARB and dominantly-inherited VMD genotypically, by variant frequency and residue location, did not yield significant differences. Literature meta-analysis with principle component analysis of clinical features demonstrated a spectrum of disease with arVMD falling between adVMD and ARB.CONCLUSIONS. This study suggests that arVMD is part of a continuum of autosomal recessive and dominant BEST1-related retinopathies. Detailed clinical and molecular assessments of this cohort and the literature are corroborated by unsupervised analysis, highlighting the overlapping heterogeneity among BEST1-associated clinical diagnoses. Tritan-axis color vision deficit is a previously unreported finding associated with ARB.

Oculocutaneous albinism (OCA) encompasses a set of autosomal recessive genetic conditions that affect pigmentation in the eye, skin, and hair. OCA patients display reduced best-corrected visual acuity, reduced to absent ocular pigmentation, abnormalities in fovea development, and/or abnormal decussation of optic nerve fibers. It has been hypothesized that improving eye pigmentation could prevent or rescue some of the vision defects. The goal of the present study was to develop an in vitro model for studying pigmentation defects in human retinal pigment epithelium (RPE). We developed a ''disease in a dish'' model for OCA1A and OCA2 types using induced pluripotent stem cells to generate RPE. The RPE is a monolayer of cells that are pigmented, polarized, and polygonal in shape, located between the neural retina and choroid, with an important role in vision. Here we show that RPE tissue derived in vitro from OCA patients recapitulates the pigmentation defects seen in albinism, while retaining the apical-basal polarity and normal polygonal morphology of the constituent RPE cells.

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Study Objective: We developed a novel, quick, easy to use electrocardiogram (ECG) screening criterion (Seamens’ Sign) for left ventricular hypertrophy (LVH). This new criterion was defined as the presence of QRS complexes touching or overlapping in two contiguous precordial leads. Methods: This study was a retrospective chart review of 2184 patient records. The primary outcome was whether Seamens’ Sign was noninferior in confirming LVH compared to other common criteria. Test characteristics were calculated for each of the LVH criteria. Inter-rater agreement was assessed on a random sample using Cohen’s Kappa. Results: Median age was 63, 52% of patients were male and there was a 35% prevalence of LVH by transthoracic echocardiogram (TTE). Nine percent were positive for LVH on ECG based on Seamens’ Sign. Seamens’ Sign had a specificity of 0.92. Tests assessing noninferiority indicated Seamens’ Sign was non-inferior to all criteria (p < 0.001) except for Cornell criterion for women (p = 0.98). Seamens’ Sign had 90% (0.81-1.00) inter-rater agreement, the highest of all criteria in this study. Conclusion: When compared to both the Sokolow-Lyon criteria and the Cornell criterion for men, Seamens’ Sign is noninferior in ruling in LVH on ECG. Additionally, Seamens’ Sign has higher inter-rater agreement compared to both Sokolow-Lyon criteria as well as the Cornell criteria for men and women, perhaps related to its ease of use.

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