Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Twelve tips for developing,implementing, and sustaining medical education fellowship programs: Building on new trends and solid foundations

Medical education fellowship programs (MEFPs) are a form of faculty development contributing to an organization’s educational mission and participants’ career development. Building an MEFP requires a systematic design, implementation, and evaluation approach which aligns institutional and individual faculty goals. Implementing an MEFP requires a team of committed individuals who provide expertise, guidance, and mentoring. Qualified MEFP directors should utilize instructional methods that promote individual and institutional short and long term growth. Directors must balance the use of traditional design, implementation, and evaluation methodologies with advancing trends that may support or threaten the acceptability and sustainability of the program. Drawing on the expertise of 28 MEFP directors, we provide twelve tips as a guide to those implementing, sustaining, and/or growing a successful MEFP whose value is demonstrated by its impacts on participants, learners, patients, teaching faculty, institutions, the greater medical education community, and the population’s health.     

Effects of laundry detergents on Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Euroglyphus maynei.

BACKGROUND: House-dust mites in clothing and bedding are the source of major allergens. Based on studies of Dermatophagoides pteronyssinus only, weekly washing in hot water is recommended to kill dust mites and remove allergens from clothing and bedding. However, in the United States, washing is most often done in warm or cold water, and other mite species are involved. OBJECTIVE: The purpose of this study was to investigate the lethal effects of various temperatures of hot water alone and hot, warm, and cold water containing detergents and chlorine bleach on Dermatophagoidesfarinae, D. pteronyssinus, and Euroglyphus maynei. METHODS: Mites were soaked in test solutions at various temperatures and for various lengths of time, allowed time to recover, and then analyzed for survival. RESULTS: D. farinae was the most temperature-sensitive and chlorine bleach-sensitive of the three species. In 50 degrees C water alone, 100% mortality for D. farinae was obtained in 10 minutes, whereas most D. pteronyssinus and E. maynei survived. However, 53 degrees C-soaks for 12 and 5 minutes were needed to kill all D. pteronyssinus and E. maynei, respectively. Laundry detergents at their recommended and doubled concentrations and chlorine bleach generally increased mite mortalities over water alone for the three species. Soaking for 4 hours in warm water containing various detergents alone induced mortalities of 19 to 50%, 2 to 35%, and 14 to 46% for D. farinae, D. pteronyssinus, and E. maynei, respectively. CONCLUSIONS: Washing bed linens weekly in warm water with a 4-hour presoak containing most detergents and bleach will kill most D. farinae and, depending on the detergent brand, moderate numbers of D. pteronyssinus. Four-hour soaks in warm water containing the recommended concentrations of various detergents alone also kills moderate numbers of D. farinae, D. pteronyssinus, and E. maynei. Therefore, the cumulative effect of weekly washing with long presoaks should significantly reduce mite levels over time in bed linens, particularly when mattresses and pillows are encased to prevent reinfestation.     

Soft tissue healing after parasagittal palatal incisions in segmental maxillary surgery: a review of 311 patients.

PURPOSE: This study retrospectively evaluated the soft tissue healing after using parasagittal soft tissue incisions for surgical segmental maxillary expansion. PATIENTS AND METHODS: The records of 311 patients (224 females, 87 males), with an average age of 28.5 years (range, 12 to 62 years) who had transverse maxillary hypoplasia, were retrospectively evaluated. All patients underwent segmental maxillary osteotomies, surgical maxillary expansion greater than 5 mm, and placement of midpalatal porous block hydroxyapatite (PBHA). Parasagittal palatal soft tissue incisions were used to facilitate expansion, minimize soft tissue damage, and maintain soft tissue coverage over the PBHA implants. At postoperative follow-up visits, any signs or symptoms of complications associated with the use of the parasagittal incisions were recorded. RESULTS: Average patient follow-up was 3.4 years (range, 1.0 to 7.2 years). In 293 patients (94%), the palates healed uneventfully without complications. Eighteen patients (6%) had complications; 9 (2.9%) had infections associated with the midpalatal implants, 8 (2.6%) had oronasal communications, and 1 (0.3%) had problems associated with a palatal wire. Six patients with midpalatal implant problems required removal of the implant, 4 patients required closure of their oronasal communications, and 1 patient required removal of a palatal wire. Therefore, 11 patients (3.5%) required minor secondary surgical procedures. No teeth or alveolar bone were lost in any of the cases. CONCLUSIONS: The use of parasagittal palatal incisions appears to be a safe technique for soft tissue management during large surgical maxillary expansions associated with segmental maxillary osteotomies and midpalatal placement of PBHA implants.     

Comparing histological data from different brains: Sources of error and strategies for minimizing them

The recent development of brain atlases with computer graphics templates, and of huge databases of neurohistochemical data on the internet, has forced a systematic re-examination of errors associated with comparing histological features between adjacent sections of the same brain, between brains treated in the same way, and between brains from groups treated in different ways. The long-term goal is to compare as accurately as possible a broad array of data from experimental brains within the framework of reference atlases. Main sources of error, each of which ideally should be measured and minimized, include intrinsic biological variation, linear and nonlinear distortion of histological sections, plane of section differences between each brain, section alignment problems, and sampling errors. These variables are discussed, along with approaches to error estimation and minimization in terms of a specific example—the distribution of neuroendocrine neurons in the rat paraventricular nucleus. Based on the strategy developed here, the main conclusion is that the best long-term solution is a high-resolution 3D computer graphics model of the brain that can be sliced in any plane and used as the framework for quantitative neuroanatomy, databases, knowledge management systems, and structure–function modeling. However, any approach to the automatic annotation of neuroanatomical data—relating its spatial distribution to a reference atlas—should deal systematically with these sources of error, which reduce localization reliability.     

Tooth movement and cytokines in gingival crevicular fluid and whole blood in growing and adult subjects.

INTRODUCTION: Tooth movement has been studied largely with respect to the force required for tipping when pressure distribution varies along the length of the periodontal ligament. But important factors for effective canine translation include the nature and magnitude of applied stress and the patient's cell biology. The purpose of this research was to test 3 hypotheses: (1) the velocity of tooth translation (v(t)) is related to applied stress and growth status, (2) a threshold of stress accounts for the lag phase, and (3) v(t) is correlated with the ratio (AI) of 2 cytokines (IL-1beta, IL-1RA) measured in gingival crevicular fluid (GCF) and stimulated whole blood (SWB). METHODS: Continuous maxillary canine retraction stresses of 13 kPa and 4, 26, or 52 kPa were applied bilaterally in 6 growing and 4 adult subjects for 84 days. Dental models and GCF samples were collected at 1- to 14-day intervals. Cytokines were measured in GCF and SWB cell cultures. RESULTS: V(t) was positively related to stress and was higher in growing subjects (P = .001). It was also related to AI(GCF) in growers (R2= 0.56) and nongrowers (R2= 0.72). Canines moved with 52 kPa showed a lag phase, and postlag phase AI(GCF) was twice that of lag phase AI(GCF). Mean v(t) and associated AI(GCF) during the postlag phase were nearly double the values for canines moved with 13 and 26 kPa. SWB production of cytokines was dose-dependent. For growing subjects, SWB IL-1RA was correlated with v(t) (R = 0.70-0.72), and AI(SWB) and IL-1beta concentrations were correlated with AI(GCF) (R = 0.73-0.78). CONCLUSIONS: V(t) varied with growth status and stresses < or = 52 kPa; stresses of < 52 kPa showed no lag phase; and equivalent stresses yielded subject-dependent differences in v(t), which correlated with cytokines in GCF and SWB.     

Three-dimensional spinal curvature in idiopathic scoliosis

Scoliosis is usually considered as a deformity of the spine in the frontal plane, without reference to curvatures in other planes. In this study, the three-dimensional shape of the spine of 104 patients with untreated idiopathic scoliosis (5-55 degrees Cobb) was studied by means of stereo radiographs to determine relationships between curvature of the spine in the frontal plane view, in the lateral view, and in the intermediate views. There was a weak but statistically significant correlation (r = 0.2) relating greater scoliosis with lesser kyphosis or greater lordosis. In the thoracic region, the sagittal plane spinal curvature was less than that measured in a population without scoliosis (mean difference, 7.72 +/- 9.9 degrees). Seventy-four of 76 scolioses in the upper region of the spine with lateral curvature greater than 5 degrees Cobb were kyphotic. Sixty-four of 84 curves greater than 5 degrees Cobb in the lower region were lordotic. Measuring curvatures in the plane of symmetry of the rotated apical vertebra altered these ratios to 69 of 76 kyphotic in the upper region and 68 of 84 lordotic in the lower region. The plane of maximum curvature of sections of the spine with scoliosis was not related to the plane of symmetry of the rotated apical vertebra, for in kyphotic regions of the spine the rotations of these two planes were in opposite directions. In all cases, the magnitudes of the rotations were quite different, i.e., by a factor of -0.22 for curves in thoracic region and by a factor of 0.24 for curves in the lumbar region. This implies that mechanical measures to correct this spinal deformity or to prevent progression should apply different rotations to the apex from those applied to the curve as a whole and, in opposite senses, in curves in kyphotic regions. There was no evidence of an abnormality of sagittal curvature of a magnitude to implicate it in the etiology or in the treatment.     

PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes.

Scintigraphic imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has demonstrated extensive losses of cardiac sympathetic neurons in idiopathic Parkinson's disease (IPD). In contrast, normal cardiac innervation has been observed in (123)I-MIBG studies of multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP). Consequently, it has been hypothesized that cardiac denervation can be used to differentiate IPD from MSA and PSP. We sought to test this hypothesis by mapping the distribution of cardiac sympathetic neurons in patients with IPD, MSA, and PSP by using PET and (11)C-meta-hydroxyephedrine ((11)C-HED). Also, the relationship between cardiac denervation and nigrostriatal denervation was investigated by measuring striatal presynaptic monoaminergic nerve density with PET and (11)C-dihydrotetrabenazine ((11)C-DTBZ). METHODS: (11)C-HED and (11)C-DTBZ scans were obtained for patients with IPD (n = 9), MSA (n = 10), and PSP (n = 8) and for age-matched control subjects (n = 10). Global and regional measurements of (11)C-HED retention were obtained to assess the extent of cardiac sympathetic denervation. (11)C-DTBZ binding was measured in the caudate nucleus, anterior putamen, and posterior putamen. RESULTS: As expected, extensive cardiac denervation was observed in several of the patients with IPD. However, substantial cardiac denervation was also seen in some patients with MSA and PSP. (11)C-DTBZ studies demonstrated striatal denervation in all patients with IPD and in most patients with MSA and PSP. No correlation was found between cardiac (11)C-HED retention and striatal (11)C-DTBZ binding. CONCLUSION: Cardiac sympathetic denervation was found to occur not only in IPD but also in other movement disorders, such as MSA and PSP. This finding implies that scintigraphic detection of cardiac sympathetic denervation cannot be used independently to discriminate IPD from other movement disorders, such as MSA and PSP. Cardiac sympathetic denervation was not correlated with striatal denervation, suggesting that the pathophysiologic processes underlying cardiac denervation and striatal denervation occur independently in patients with parkinsonian syndromes. These findings provide novel information about central and peripheral denervation in patients with neurodegenerative disorders.