Mcculloughhoppe4176

Bone fragility and obesity are both diseases that are multifactorial in etiology and pathology. The contributing role of high fat diet (HFD) versus energy overconsumption on bone health is controversial. Exercise is often prescribed for improving bone health, but it is unclear whether HFD or overconsumption influences skeletal adaptations to exercise. Female and male Wistar rats were fed HFD or low fat diet (LFD) for 10 weeks, starting at 8 weeks of age. Within HFD, rats were labeled Obesity-Resistant (OR) or Obesity-Prone (OP) based on weight and fat gain. Within each diet and phenotype group, rats were randomized to treadmill exercise or sedentary control (SED) for the final 4 weeks. Selleck IWR-1-endo Femurs were assessed for fracture toughness. Cortical lamellar and nonlamellar bone microscale material behavior and chemistry were assessed using nanoindentation and Raman spectroscopy. Female bones had higher fracture toughness and mineral matrix ratio than male bones. Diet and energy overconsumption affected bone characteristics in a sex-dependent manner, where the divergence between OP and OR in response to HFD occurred more rapidly in males. Diet composition, in general, had a stronger effect on bone quality than overconsumption. HFD dramatically decreased bone size and lamellar mineralmatrix compared to LFD. Effects of short-term exercise training on microscale tissue properties were generally more robust with LFD. Exercise enhanced the contrast between lamellar and nonlamellar bone for nanoindentation modulus but decreased this contrast for plastic work. Our data demonstrate the complexities in the relationship between diet and obesity and highlight the importance of addressing both aspects when characterizing bone quality and fracture resistance.

Low energy availability causes disruption of hypothalamic gonadotropin-releasing hormone secretion leading to functional hypothalamic amenorrhea (FHA) and hypoestrogenism, which in turn contributes to decreased bone mineral density (BMD) and increased bone marrow adipose tissue (MAT). Transdermal estradiol administration in physiologic doses increases BMD in adolescents and adults with FHA. However, the impact of estrogen replacement on MAT in relation to changes in BMD has not been studied in adolescents and young adults. We hypothesized that physiologic estrogen replacement would lead to decreases in MAT, associated with increases in BMD.

We studied 15 adolescent and young adult females with FHA (14-25years). All participants received a17β- estradiol transdermal patch at a dose of 0.1mg/day (applied twice weekly) for 12months. Participants also received cyclic progestin for 10-12days each month. We quantified MAT (lipid/water ratio) of the fourth lumbar (L4) vertebral body and femoral diaphysis by single proton (1H)-magnetic resonance spectroscopy, and compartmental volumetric BMD of the distal radius and tibia using high-resolution peripheral quantitative computed tomography.

Transdermal estradiol therapy over 12months resulted in a decrease in MAT at the lumbar (L4) vertebra from 0.92±0.55 at baseline to 0.63±0.29 at 12-months (p=0.008), and an increase in radial and tibial cortical vBMD (p=0.006, p=0.0003). Changes in L4 MAT trended to be inversely associated with changes in radial cortical vBMD (rho=-0.47, p=0.08).

We show that in adolescent and young adult girls with FHA, MAT decreases following transdermal estrogen therapy and these changes are associated with increased cortical vBMD.

We show that in adolescent and young adult girls with FHA, MAT decreases following transdermal estrogen therapy and these changes are associated with increased cortical vBMD.Skeletal fluorosis (SF) is endemic primarily in regions with fluoride (F)-contaminated well water, but can reflect other types of chronic F exposure. Calcium (Ca) and vitamin D (D) deficiency can exacerbate SF. A 51-year-old man with years of musculoskeletal pain and opiate use was hypocalcemic with secondary hyperparathyroidism upon manifesting recurrent long bone fractures. He smoked cigarettes, drank large amounts of cola beverage, and consumed little dietary Ca. Then, after 5 months of Ca and D3 supplementation, serum 25(OH)D was 21 ng/mL (Nl, 30-100), corrected serum Ca had normalized from 7.8 to 9.4 mg/dL (Nl, 8.5-10.1), alkaline phosphatase (ALP) had decreased from 1080 to 539 U/L (Nl, 46-116), yet parathyroid hormone (PTH) had increased from 133 to 327 pg/mL (Nl, 8.7-77.1). Radiographs revealed generalized osteosclerosis and a cystic lesion in a proximal femur. DXA BMD Z-scores were +7.4 and +0.4 at the lumbar spine and "1/3" radius, respectively. Bone scintigraphy showed increased uptake in two ribs,reased to 248 U/L and 3.3 mg/L, respectively. Our experience combined with 15 publications in PubMed concerning unusual causes of non-endemic SF where the F source became known (19 cases in all) revealed 11 instances from high consumption of black tea and/or F-containing toothpaste, 1 due to geophagia of F-rich soil, and 7 due to "recreational" inhalation of F-containing vapors. Circulating PTH measured in 14 was substantially elevated in 2 (including ours) and mildly increased in 2. The severity of SF in the cases reviewed seemed to reflect cumulative F exposure, renal function, and Ca and D status. Several factors appeared to influence our patient's skeletal disease i) direct anabolic effects of toxic amounts of F on his skeleton, ii) secondary hyperparathyroidism from degradation-resistant fluorapatite bone crystals and low dietary Ca, and iii) impaired mineralization of excessive osteoid due to hypocalcemia.In oncology dose-finding clinical trials, the key to accurately estimating the maximum tolerated dose (MTD) is to use all data efficiently given small sample sizes. Currently, popular designs dichotomize adverse events of various types and grades that occur within the first treatment cycle into binary toxicity outcomes of dose-limiting toxicity (DLT) events. Such compression of toxicity data from multiple treatment cycles causes huge loss of information, often resulting in MTD estimation with large bias and variance. To improve this, a continuous endpoint (the total toxicity profile, TTP) was proposed to incorporate adverse event types and grades. The Bayesian Repeated Measures Design (RMD) was further developed by Yin et al. (2017) to account for the cumulative toxicity information from multiple treatment cycles. However, the existing RMD method selects the dose that minimizes the loss function based on point estimates, which may generate inconsistent results due to small sample sizes in phase I trials. To reduce the variability in dose escalation decision-making, we propose an improved repeated measures design with an interval-based decision rule that selects the dose with the highest posterior probability of falling in a pre-specified target toxicity interval.