Developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. This article provides an introduction to some of the literature addressing the effects of these toxicologic exposures on the developing brain. This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities. The developing brain is uniquely susceptible to permanent impairment by exposure to environmental substances during time windows of vulnerability. Lead, mercury, and polychlorinated biphenyls (PCBs) have been extensively studied and found to impair development at levels of exposure currently experienced by significant portions of the general population. High-dose exposures to each of these chemicals cause catastrophic developmental effects. More recent research has revealed toxicity at progressively lower exposures, illustrating a "declining threshold of harm" commonly observed with improved understanding of developmental toxicants. For lead, mercury, and PCBs, recent studies reveal that background-population exposures contribute to a wide variety of problems, including impairments in attention, memory, learning, social behavior, and IQ. Unfortunately, for most chemicals there is little data with which to evaluate potential risks to neurodevelopment. Among the 3000 chemicals produced in highest volume (over 1 million lbs/yr), only 12 have been adequately tested for their effects on the developing brain. This is a matter of concern because the fetus and child are exposed to untold numbers, quantities, and combinations of substances whose safety has not been established. Child development can be better protected by more precautionary regulation of household and environmental chemicals. Meanwhile, health care providers and parents can play an important role in reducing exposures to a wide variety of known and suspected neurodevelopmental toxicants that are widely present in consumer products, food, the home, and wider community.

This review focuses on the osteogenic differentiation of mesenchymal stem cells (MSC), bone formation and turn-over in good and ill skeletal fates. The interacting molecular pathways which control bone remodeling in physiological conditions during a lifelong process are described. Then, alterations of the molecular pathways regulating osteogenesis are addressed. In the aging process, as well as in glucocorticoid-induced osteoporosis, bone loss is caused not only by an unbalanced bone resorption activity, but also by an impairment of MSCs’ commitment towards the osteogenic lineage, in favour of adipogenesis. Mutations affecting the expression of key genes involved in the control of bone development occur in several heritable bone disorders. A few examples are described in order to illustrate the pathological consequences of perturbation in different steps of osteogenic commitment, osteoblast maturation, and matrix mineralization, respectively. The involvement of abnormal MSC differentiation in cancer is then discussed. Finally, a brief overview of clinical applications of MSCs in bone regeneration and repair is presented.

The acute-phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen-containing bisphosphonates (N-BPs). It has been demonstrated in vitro that N-BPs stimulate gd T-cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25-hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N-BP-naive osteoporotic women (63.7 AE 10.6 years of age) were stratified for the occurrence of APR (APR þ ) or not (APR -) and quantified by body temperature and

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Vitamin D deficiency is highly prevalent among children and adults worldwide. Agreement exists that vitamin D deficiency should be corrected. However, the definitions of vitamin deficiency and effective vitamin D replacement therapy are inconsistent in the literature. Not only is the dosing regimen still under debate, but also the time and period of administration (i.e., daily vs. monthly dose). In pediatric as well as elderly subjects, dosing regimens with high vitamin D doses at less frequent intervals were proposed to help increase compliance to treatment: these became widespread in clinical practice, despite mounting evidence that such therapies are not only ineffective but potentially harmful, particularly in elderly subjects. Moreover, in the elderly, high doses of vitamin D seem to increase the risk of functional decline and are associated with a higher risk of falls and fractures. Achieving good adherence to recommended prophylactic regimens is definitely one of the obstacles currently being faced in view of the wide segment of the population liable to the treatment and the very long duration of prophylaxis. The daily intake for extended periods is in fact one of the frequent causes of therapeutic drop-outs, while monthly doses of vitamin D may effectively and safely improve patient compliance to the therapy. The aim of our paper is a quasi-literature review on dosing regimens among children and elderly. These two populations showed a particularly significant beneficial effect on bone metabolism, and there could be different outcomes with different dosing regimens.

The topical application of lactic acid bacteria (LAB) is recognized as a useful approach to improve skin health. This work aims to characterize by a multidisciplinary approach, the wound healing, anti-inflammatory, anti-pathogens and proteomic effects of six LAB lysates, belonging to the genus Lactobacillus. Our results demonstrated that the lysates of tested LAB stimulated the proliferation of keratinocytes, and that L. plantarum SGL 07 and L. salivarius SGL 19 accelerated the re-epithelization by inducing keratinocyte migration. The bacterial lysates also reduced the secretion of specific pro-inflammatory mediators from keratinocytes. Furthermore, viable L. salivarius SGL 19 and L. fermentum SGL 10 had anti-pathogenic effects against S. aureus and S. pyogenes, while L. brevis SGL 12 and L. paracasei SGL 04 inhibited S. aureus and S. pyogenes, respectively. The tested lactobacilli lysates also induced specific proteome modulation of the exposed keratinocytes, involving dysregulation of proteins (such as interleukin enhancer-binding factor 2 and ATP-dependent RNA helicase) and pathways (such as cytokine, NF-kB, Hedgehog, and RUNX signaling) associated with their specific wound healing and anti-inflammatory effects. This study indicates the different potential of selected lactobacilli, suggesting that they may be successfully used in the future together with conventional therapies to bring relief from skin disorders. Abbreviations LAB Lactic acid bacteria TNF-α Tumor necrosis factor-alpha IFN-γ Interferon-gamma PBS Phosphate buffered saline DMEM Dulbecco's modified Eagle's medium MCP-1 Monocyte chemoattractant protein-1 RANTES Regulated on activation, normal T cell expressed and secreted LC-MS/MS Liquid chromatography-tandem mass spectrometry SWATH Sequential window acquisition of all theoretical mass spectra The skin, considered the largest organ of the body, is involved in a variety of functions and acts primarily as a protective barrier preventing the entry of potential pathogens. In particular, skin homeostasis is regulated by microorganisms, the so called skin microbiota, which act on keratinocytes and on their cytokine release, ensuring

The apparent paradox of bone fragility in acromegaly patients with a normal BMD can be explained by increased cortical thickness and porosity and reduced trabecular thickness with increased trabecular separation. These structural and microarchitectural abnormalities persist in the controlled phase of acromegaly despite bone turnover normalization. The main determinant of bone disease after hormonal control is severe osteoblastic dysfunction.

BackgroundWarfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification.MethodsRats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically.ResultsHistomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries.ConclusionsThese findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients.