Abstract Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because ...they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a “fracture,” with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients.
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of ...osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.
We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.
As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval CI, 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.
Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
ABSTRACT
Many manufacturing processes can induce residual stresses in components. These residual stresses influence the mean stress during cyclic loading and so can influence the fatigue life. ...However, the initial residual stresses induced during manufacturing may not remain stable during the fatigue life. This paper provides a broad and extensive literature survey addressing the stability of surface and near‐surface residual stress fields during fatigue, including redistribution and relaxation due to static mechanical load, repeated cyclic loads, thermal exposure and crack extension. The implications of the initial and evolving residual stress state for fatigue behaviour and life prediction are addressed, with special attention to fatigue crack growth. This survey is not a critical analysis; no detailed attempt is made to evaluate the relative merits of the different explanations and models proposed, to propose new explanations or models or to provide quantitative conclusions. Primary attention is given to the residual stresses resulting from four major classes of manufacturing operations: shot peening and related surface treatments, cold expansion of holes, welding and machining.
The circadian clock is known to regulate plant innate immunity but the underlying mechanism of this regulation remains largely unclear. We show here that mutations in the core clock component LUX ...ARRHYTHMO (LUX) disrupt circadian regulation of stomata under free running and Pseudomonas syringae challenge conditions as well as defense signaling mediated by SA and JA, leading to compromised disease resistance. RNA-seq analysis reveals that both clock- and defense-related genes are regulated by LUX. LUX binds to clock gene promoters that have not been shown before, expanding the clock gene networks that require LUX function. LUX also binds to the promoters of EDS1 and JAZ5, likely acting through these genes to affect SA- and JA-signaling. We further show that JA signaling reciprocally affects clock activity. Thus, our data support crosstalk between the circadian clock and plant innate immunity and imply an important role of LUX in this process.
Twelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in ...the human brain. Here, we identify 12 h rhythms in transcripts that either peak at sleep/wake transitions (approximately 9 AM/PM) or static times (approximately 3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia (SZ) lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in SZ, suggesting suboptimal timing of these essential processes.
Plants respond to ambient temperature changes over a series of timescales. Genetic and physiological studies over the last decades have revealed myriad thermally sensitive pathways in plants. A ...recent study provides a genetic and biochemical mechanistic description of how thermal changes can be transduced to influence gene expression. What remains to be revealed in this, and other thermally controlled responses, is a description of the primary temperature-sensing event. Cooling and warming alter membrane fluidity and elicit intracellular free-calcium elevations, a process that has been considered the primary event controlling plant responses to temperature. Such direct thermal sensors appear to process temperature information. Future efforts will be required to identify the effector proteins linking perception to response. This review considers the evidence for plant thermometers to date, provides a description of several notable physiological and developmental processes under ambient temperature control, and outlines major questions that remain to be addressed in the understanding of thermometers in plants.
ΔFosB is a unique transcription factor that plays an essential role in long-term adaptive changes in the brain associated with diverse conditions, such as drug addiction, Parkinson's disease, ...depression, and antidepressant treatment. It is induced in brain, in a region- and cell-type-specific manner by many types of chronic perturbations. Once induced, it persists for long periods of time due to its unusual stability. The transcriptional effects of ΔFosB are complex, because the protein can function as both a transcriptional activator and repressor. Progress has been made in identifying specific target genes for ΔFosB and in relating some of these genes to ΔFosB's cellular and behavioral actions. Future studies will help us to better understand the biochemical basis of ΔFosB's unique stability, as well as the precise molecular pathways through which this transcription factor produces its complex effects on neuronal plasticity and complex behavior.
In plants, iron (Fe) uptake and homeostasis are critical for survival, and these processes are tightly regulated at the transcriptional and posttranscriptional levels. Circadian clocks are endogenous ...oscillating mechanisms that allow an organism to anticipate environmental changes to coordinate biological processes both with one another and with the environmental day / night cycle. The plant circadian clock controls many physiological processes through rhythmic expression of transcripts. In this study, we examined the expression of three Fe homeostasis genes (IRON REGULATED TRANSPORTER1 IRT1, BASIC HELIX LOOP HELIX39, and FERRITIN1) in Arabidopsis (Arabidopsis thaliana) using promoter : LUCIF ERASE transgenic lines. Each these promoters showed circadian regulation of transcription. The circadian clock monitors a number of clock outputs and uses these outputs as inputs to modulate clock function. We show that this is also true for Fe status. Fe deficiency results in a lengthened circadian period. We interrogated mutants impaired in the Fe homeostasis response, including irt1-1, which lacks the major high-affinity Fe transporter, and fit-2, which lacks Fe deficiency-induced TRANSCRIPTION FACTOR1, a basic helix-loop-helix transcription factor necessary for induction of the Fe deficiency response. Both mutants exhibit symptoms of Fe deficiency, including lengthened circadian period. To determine which components are involved in this cross talk between the circadian and Fe homeostasis networks, we tested clock-or Fe homeostasis-related mutants. Mutants defective in specific clock gene components were resistant to the change in period length under different Fe conditions observed in the wild type, suggesting that these mutants are impaired in cross talk between Fe homeostasis and the circadian clock.
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