Concise review: Insights from normal bone remodeling and stem cell-based therapies for bone repair.

There is growing interest in the use of mesenchymal stem cells for bone repair. As a major reason for normal bone remodeling is the removal of fatigue microcracks, advances in our understanding of this process may inform approaches to enhance fracture healing. Increasing evidence now indicates that physiological bone remodeling occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells that differentiate into osteoblasts.

Coronary endothelial dysfunction in humans is associated with coronary retention of osteogenic endothelial progenitor cells.

Aims: Endothelial progenitor cells (EPC) may participate in the repair of injured coronary endothelium. We have recently identified EPC co-expressing the osteoblastic marker osteocalcin [OCN (+) EPC] and found that their numbers are increased in patients with early and late coronary atherosclerosis. The current study was designed to test the hypothesis that early coronary atherosclerosis is associated with the retention of osteogenic EPC within the coronary circulation.

The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?

Over a decade ago, we proposed a "unitary" model for the pathogenesis of osteoporosis that identified estrogen deficiency as the predominant cause of both the early, accelerated, and late slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. While this was a plausible model then, new data over the intervening years suggest a need to modify these concepts. Indeed, based largely on rodent studies, a "revisionist" view of the pathogenesis of osteoporosis has been proposed recently that attempts a paradigm shift from the estrogen-centric model to one in which bone loss is largely independent of estrogen deficiency and is driven instead by cell-autonomous age-related factors.

Placebo-controlled trials in osteoporosis--proceeding with caution.

This article presents one viewpoint on the issues surrounding placebo-controlled trials in osteoporosis. The other Sounding Board article in this issue presents an opposing view. At NEJM.

The DNA methyltranferase Dnmt2 participates in RNA processing during cellular stress.

The strong evolutionary conservation of the DNA methyltransferase, Dnmt2, is at odds with the absence of phenotypic defects in organisms lacking Dnmt2. The cellular processes where Dnmt2 has a role to play also remain largely undiscovered. Here we show that Dnmt2 is a part of RNA processing machinery during cellular stress.

How does the absence or presence of subglottal medialization affect glottal airflow?

Objectives: Our previous work has shown that the symmetric, smooth, convergent shape of the subglottis reduces turbulent airflow at the glottal entrance. Medialization thyroplasty may alter the glottal shape and is very likely to introduce some degree of glottal asymmetry, which could result in increased turbulence and a reduction in voice quality. This study reports the effects of medializing and not medializing the subglottis in silicone models of human cadaveric larynges.

Relation of age, gender, and bone mass to circulating sclerostin levels in women and men.

Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population-based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years.

Fat tissue, aging, and cellular senescence.

Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span.

Update on estrogens and the skeleton.

Context: The very clinical trial, the Women's Health Initiative, which definitely established the antifracture efficacy of estrogen therapy, led to the demise of estrogen treatment as a viable, long-term option for prevention of bone loss in postmenopausal women due to the well-publicized adverse effects of estrogen plus progestin therapy on a number of nonskeletal endpoints. Given the diminishing clinical use of estrogen, it is logical to question whether estrogen regulation of bone remains a relevant issue at a clinical or basic research level.

Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of the field.

Hypomethylation of the DNMT3L promoter in ocular surface squamous neoplasia.

Context: Cancer is known to have epigenetic inputs, with events like genomewide hypomethylation and gene-specific hypermethylation of DNA. The DNA methyltransferase enzymes act as effectors of this reprogramming. A previous study revealed that hypomethylation at the DNA methyltransferase 3-like (DNMT3L) promoter could be a potential biomarker in cervical tumors.

Trabecular bone deficits among Vietnamese immigrants.

Summary: Compared to white women, lower areal bone mineral density (aBMD) in middle-aged Vietnamese immigrants is due to reduced trabecular volumetric bone mineral density (vBMD), which in turn is associated with greater trabecular separation along with lower estrogen levels.

Introduction: The epidemiology of osteoporosis in Asian populations is still poorly known, but we previously found a deficit in lumbar spine aBMD among postmenopausal Southeast Asian women, compared to white women, that persisted after correction for bone size. This issue was revisited using more sophisticated imaging techniques.

Female reproductive system and bone.

The female reproductive system plays a major role in regulating the acquisition and loss of bone by the skeleton from menarche through senescence. Onset of gonadal sex steroid secretion at puberty is the major factor responsible for skeletal longitudinal and radial growth, as well as significant gain in bone density, until peak bone density is achieved in third decade of life. Gonadal sex steroids then help maintain peak bone density until menopause, including during the transient changes in skeletal mineral content associated with pregnancy and lactation.

Caffeine-related atrial fibrillation.

We present a case of caffeine-induced atrial fibrillation which spontaneously reverted to normal sinus rhythm. Caffeine is a methylxanthine alkaloid that can cause various supraventricular and ventricular arrhythmias. It is important to improve public awareness of the potential adverse effects of high consumption of caffeine-containing products as fatal and serious events can occur.

Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women.

Context: Intermittent PTH treatment stimulates bone formation, but the mechanism(s) of this effect remain unclear. Sclerostin is an inhibitor of Wnt signaling, and animal studies have demonstrated that PTH suppresses sclerostin production.

Objective: The objective of the study was to test whether intermittent PTH treatment of postmenopausal women alters circulating sclerostin levels.

Effects of suppression of follicle-stimulating hormone secretion on bone resorption markers in postmenopausal women.

Context: It has recently been proposed that the increase in bone resorption after the menopause may not be due principally to estrogen deficiency but rather to the concomitant increase in circulating FSH levels.

Objective: The objective of the study was to test whether suppression of FSH secretion in postmenopausal women reduces levels of bone resorption markers.

Design: This was a prospective study.

Physiology of bone loss.

The physiology of bone loss in aging women and men is largely explained by the effects of gonadal sex steroid deficiency on the skeleton. In women, estrogen deficiency is the main cause of early rapid postmenopausal bone loss, whereas hyperparathyroidism and vitamin D deficiency are thought to explain age-related bone loss later in life. Surprisingly, estrogen deficiency also plays a dominant role in the physiology of bone loss in aging men.

Human embryonic stem cell-derived CD34+ cells function as MSC progenitor cells.

Mesenchymal stem/stromal cells (MSCs) have been isolated from various tissues and utilized for an expanding number of therapies. The developmental pathways involved in producing MSCs and the phenotypic precursor/progenitor cells that give rise to human MSCs remain poorly defined. Human embryonic stem cells (hESCs) have the capability to generate functional hemato-endothelial cells and other mesoderm lineage cells.

Relation of vertebral deformities to bone density, structure, and strength.

Because they are not reliably discriminated by areal bone mineral density (aBMD) measurements, it is unclear whether minimal vertebral deformities represent early osteoporotic fractures. To address this, we compared 90 postmenopausal women with no deformity (controls) with 142 women with one or more semiquantitative grade 1 (mild) deformities and 51 women with any grade 2-3 (moderate/severe) deformities. aBMD was measured by dual-energy X-ray absorptiometry (DXA), lumbar spine volumetric bone mineral density (vBMD) and geometry by quantitative computed tomography (QCT), bone microstructure by high-resolution peripheral QCT at the radius (HRpQCT), and vertebral compressive strength and load-to-strength ratio by finite-element analysis (FEA) of lumbar spine QCT images.

Complete versus culprit only revascularization in acute ST elevation myocardial infarction: a meta-analysis.

Background: Current guidelines recommend against the revascularization of noninfarct related artery (complete revascularization [CR]) in patients with ST elevation myocardial infarction (STEMI) and no hemodynamic compromise, though level of evidence is C.

Aim: Our aim was to examine the available evidence to determine any advantage of CR over culprit only revascularization (COR).

Methods: We systematically searched medline using key words-"culprit coronary revascularization," "complete revascularization myocardial infarction," and "multivessel STEMI" for studies reporting outcomes after COR versus CR during primary procedure or index hospitalization published in English language and indexed before February 2010.

The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling to bone homeostasis.

Regulation of circulating sclerostin levels by sex steroids in women and in men.

Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels.

Effects of chronic estrogen treatment on modulating age-related bone loss in female mice.

While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate the effects of aging versus estrogen deficiency on age-related bone loss, we sham-operated, ovariectomized, or ovariectomized and estrogen-replaced female C57/BL6 mice at 6 months of age and followed them to age 18 to 22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies.

Effects of statins on progression of carotid atherosclerosis as measured by carotid intimal--medial thickness: a meta-analysis of randomized controlled trials.

Background: Carotid intimal-medial thickness (CIMT) as measured by B-mode ultrasonography is a surrogate marker for carotid atherosclerosis. Studies have found conflicting results for the effect of statins on carotid atherosclerosis progression by measuring CIMT. Hence, this meta-analysis was conducted to evaluate the impact of statin therapy on CIMT progression.

Effects of estrogen and testosterone on resting energy expenditure in older men.

The mechanisms by which sex hormones cause changes in body composition are unclear. Sex steroid deficiency might directly reduce energy expenditure/fat oxidation and thereby predispose to increased body fat. Alternatively, sex steroid deficiency could result in lean tissue loss and thus reduced energy expenditure.

Acoustic characteristics of phonation in "wet voice" conditions.

A perceptible change in phonation characteristics after a swallow has long been considered evidence that food and/or drink material has entered the laryngeal vestibule and is on the surface of the vocal folds as they vibrate. The current paper investigates the acoustic characteristics of phonation when liquid material is present on the vocal folds, using ex vivo porcine larynges as a model. Consistent with instrumental examinations of swallowing disorders or dysphagia in humans, three liquids of different Varibar viscosity ("thin liquid," "nectar," and "honey") were studied at constant volume.