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.     

Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4⁺ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection.METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4⁺ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment.RESULTS. Frequencies of Mtb-specific IFN-γ⁺CD4⁺ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38⁺IFN-γ⁺, HLA-DR⁺IFN-γ⁺, and Ki-67⁺IFN-γ⁺, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4⁺ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure.TRIAL REGISTRATION. Registration is not required for observational studies.FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.     

Caring for the Digital Generation: Understanding Electronic Aggression

We live in a technology-saturated world, evidenced by widespread, global use of the Internet and other forms of technology. Technology offers nearly limitless connectivity, information-sharing, and communication. Unfortunately, with these opportunities come risks, especially for children, and pediatric healthcare providers have a responsibility to be aware and informed of these risks and how to respond. This article provides a breakdown of the broad phenomenon of electronic aggression and offers practice implications for healthcare providers.     

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.