Studies on the interaction between the estrogen and vitamin D endocrine system

Estrogen deficiency and vitamin D deficiency play key roles in the pathogenesis of postmenopausal osteoporosis. Aim of the studies in this thesis is to extend our knowledge on the interaction between E2 and 1,25-(0H)2D3 and thereby to provide more insight into the significance of E, for 1,25-(0H)2D3 mediated processes in calcium and bone metabolism. Furthermore the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR genotypes in relation to BMD and fracture risk are studied. The first part of the thesis focuses on the effect of E2 on 1,25-(0H)2D3 mediated processes. In chapters 2 and 3 the effect of E, deficiency and E2 repletion on 1,25-(0H),D, synthesis and 1,25-(0H)2D3 mediated intestinal calcium absorption in a rat model for postmenopausal osteoporosis is described. An important bone anabolic factor is IGF-1. Both 1,25-(0H)2D3 as well as Ez have been shown to regulate IGF-I expression in vitro. Chapter 4 describes the effect of E, deficiency and E2 repletion on IGF-I levels in bone in vivo in relation to bone metabolism. The effect of E2 on bone mineralization is discussed in Chapter 5. The second part of the thesis considers the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR gene polymorphisms in relation to BMD and fracture risk. Chapter 6 describes a pilot study addressed to whether differences in rates of bone turnover between women with either extremely low or extremely high BMD can be ascribed to genetic variations of the VDR. Furthermore, the biochemical response to short-term substitution of 1,25-(0H)2D3 in both BMD groups was related to VDR gene polymorphisms. In chapter 7 functional consequences of VDR gene polymorphisms in vitro are studied. Chapter 8 discusses the association between ERa gene polymorphism and fracture risk in postmenopausal women. Moreover, the interaction between ERa gene and VDR gene polymorphisms on fracture risk is described. In chapter 9 the results are discussed and suggestions for future research are made. Finally, the main findings are summarized in Chapter 10

A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensivity in a patient with xeroderma pigmentosum

Background: Radiotherapy-induced DNA double-strand breaks (DSBs) are critical cytotoxic lesions. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma, exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA DSB repair. Aim: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells. Methods: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and g-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed. Results: Transfer of chromosome 8 (location of DNAPKcs gene) and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249-bp deletion (between base pairs 3656 and 3904) encompassing exon 31 of the gene. Conclusion: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability

Nearshore movement ecology of a medium-bodied shark, the creek whaler Carcharhinus fitzroyensis

Background: The movement and habitat use patterns of medium-bodied nearshore sharks are poorly understood. However, these species face some of the highest levels of exposure to anthropogenic development. The habitat and space use strategies species exhibit affect their role within communities and how they respond to environmental change. The present study used passive acoustic telemetry to evaluate the residency, space use, and habitat use patterns of the creek whaler Carcharhinus fitzroyensis in a nearshore embayment in Queensland, Australia. Results: Individuals were monitored for approximately 18 months. Half of the monitored population were highly resident to the bay. In contrast, several individuals spent less than 2 weeks in the bay, suggesting that broader movements may occur in a portion of the population. Size had no effect on residency. Activity space size varied between months and time of day but was also not affected by animal size. All C. fitzroyensis spent the majority of time in seagrass habitat (70%) and deep water (>5 m) mud substrate (20%). Shallow mudflat, sandy inshore, and reef habitats were rarely used (7%). Although the sample size of immature individuals was relatively small, results indicated immature and mature C. fitzroyensis shared space and habitats. Conclusions: Overall, C. fitzroyensis used a combination of nearshore movement patterns typically exhibited by small- and large-bodied species. The movement patterns exhibited by C. fitzroyensis suggest that this species has a moderately high degree of seagrass habitat specialisation. Seagrass habitat is typically highly productive and may be an important foraging habitat for this species. Given the consistent use of seagrass habitat, C. fitzroyensis are likely vulnerable to population decline as a result of seagrass habitat loss. Future research should continue to investigate the unique movements of medium-bodied sharks

Interface state contribution to the photovoltaic effect in organic phototransistors:Photocapacitance measurements and optical sensing

Made available in DSpace on 2018-12-11T16:50:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Instituto Nacional de Ciência e Tecnologia em Eletrônica OrgânicaWe report the results of an investigation into the contribution that trapping in interface states makes to the photovoltaic effect observed in organic phototransistors. To isolate this effect from other processes that occur in the transistor structure when under illumination, we focus attention on the photo-response of metal-insulator-semiconductor (MIS) capacitors - the core structure of transistors. The capacitors comprised poly(3-hexylthiophene), (P3HT), as the active semiconductor in combination with one of three insulators, namely, poly(amide-imide), (PAI), SU-8 photoresist and polysilsesquioxane (PSQ). Following initial characterization in the dark, the capacitor response was measured both during and after irradiation with light in the wavelength range 400–700 nm. Three different approaches were employed to study the photo-response, each providing a different insight into the processes occurring. Capacitance-voltage sweeps before, during and after illumination provided direct evidence supporting the view that the photovoltaic effect occurred as a result of electron trapping in interface states of density up to ∼2 × 1012 cm−2 in the P3HT/PAI combination but lower for SU-8 and PSQ. The dynamic photo-response, in which device capacitance was held constant by changing the applied bias, showed a fast component related to optically induced photoconduction in the semiconductor and a slower component reflecting the dynamics of interface electron trapping. Finally, photo-induced capacitance changes occurring with constant applied voltage were used to demonstrate a simple 3 × 3 imaging array.School of Electronic Engineering Bangor University, Dean StreetBrazilian Nanotechnology National Laboratory (LNNano) Brazilian Centre of Research in Energy and Materials (CNPEM)Department of Physics São Paulo State University (UNESP), PO Box 266Institute of Physics of São Carlos University of São Paulo (USP), PO Box 369Catarinense Federal Institute of Education Science and Technology, PO Box 21Department of Physics São Paulo State University (UNESP), PO Box 26

Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside—a Comprehensive Review

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions

Serum vitamin D levels are associated with structural and functional properties of the carotid artery in older men and women

Background and aims: This cross-sectional study aimed to assess the relationship between serum vitamin D levels and carotid and brachial artery distensibility in patients older than 55 years, referred to the outpatient clinic of the department of internal medicine and geriatric medicine of the Erasmus Medical Center, in Rotterdam. Methods and results: From April to July 2006 we consecutively enrolled 49 elder patients (21 men and 28 women, mean age 78 ± 8 years) without a cardiovascular event within 6 weeks before the visit. Carotid and brachial artery distensibility coefficients and serum 25(OH)D levels (mean 50 ± 28.8 nmol/L) were assessed. Multivariate analysis (with linear regression model) was performed to investigate the relation between these parameters: carotid artery distensibility coefficient was associated with serum 25(OH)D levels (β = 0.112; 95% CI 0.053 0.172; p = 0.001). Moreover, a negative association was also observed between carotid artery distensibility coefficient and mean arterial pressure (β = −0.279; 95% CI, −0.339 −0.159; p = 0.0001). On the contrary, brachial artery distensibility has shown no association with 25(OH)D levels, being negatively linked to LDL-cholesterol levels and heart rate. An association was also observed between serum 25(OH)D level and carotid artery intima–media thickness. Conclusion: Our results revealed that serum 25(OH)D levels of older men and women were associated with both structural and functional properties of the carotid artery. No association was found with the brachial artery distensibility

Case report: tracking data from foraging hawksbill turtles in the northern Red Sea

Background: Hawksbill turtles (Eretmochelys imbricata) are Critically Endangered throughout their global range, and concerningly little is known about this species in the Red Sea. With large-scale coastal development projects underway in the northern Red Sea, it is critical to understand the movement and habitat use patterns of hawksbill turtles in this environmentally unique region, so that effective conservation strategies can be implemented. We satellite tagged three hawksbill turtles, one 63 cm curved carapace length adult male captured near Wahlei Island, one 55 cm turtle captured in the Gulf of Aqaba, and one 56 cm turtle suffering from a floating syndrome which was captured at Waqqadi Island, rehabilitated, and released at Waqqadi Island. Turtles were tracked for 156, 199, and 372 days between October 2020 and November 2021. Results: We calculated the home ranges and core use areas of hawksbill turtles using kernel-density estimations and found that each turtle showed high fidelity to their foraging sites. Home ranges calculated with GPS-derived locations ranged between 13.6 and 2.86 km2, whereas home ranges calculated with Argos-derived locations ranged from 38.98 to 286.45 km2. GPS-derived locations also revealed a higher proportion of time spent in coral and rock habitats compared to Argos, based on location overlap with the Allen Coral Reef Atlas. We also found that turtles were making shallow dives, usually remaining between 0 and 5 m. Conclusions: While the number of tracked turtles in this study was small, it represents an important contribution to the current understanding of spatial ecology among foraging hawksbill turtles globally, and provides the first-ever reported hawksbill turtle tracking data from the Red Sea. Our results suggest that protecting coral reef habitats and implementing boating speed limits near reefs could be effective conservation measures for foraging hawksbill turtles in the face of rapid coastal development

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density