Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. Introduction: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. Methods: We performed nested case–control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800–829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). Results: Meta-analysis of the two nested case–control studies showed pooled odds ratios of 0.98 (0.91–1.05, p = 0.52), 1.04 (0.97–1.12, p = 0.28), and 1.16 (0.83–1.62, p = 0.38) for the associations betwee

Mapping the multicausality of Alzheimer's disease through group model building

Alzheimer's disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD.Neuro Imaging Researc

Categorizing Different Approaches to the Cosmological Constant Problem

We have found that proposals addressing the old cosmological constant problem come in various categories. The aim of this paper is to identify as many different, credible mechanisms as possible and to provide them with a code for future reference. We find that they all can be classified into five different schemes of which we indicate the advantages and drawbacks. Besides, we add a new approach based on a symmetry principle mapping real to imaginary spacetime.Comment: updated version, accepted for publicatio

Surgery and radiotherapy in vulvar cancer.

Item does not contain fulltextThe majority of patients with vulvar cancer have squamous cell carcinomas (SCC). The cornerstone of the treatment is surgery. Radical vulvectomy with "en bloc" inguinofemoral lymphadenectomy has led to a favorable prognosis but with impressive morbidity. Nowadays, treatment is more individualized with wide local excision with uni- or bilateral inguinofemoral lymphadenectomy via separate incisions as the standard treatment for early stage patients with SCC of the vulva with depth of invasion >1 mm without suspicious groins. In case of more than one intranodal lymph node metastasis and/or extranodal growth, postoperative radiotherapy on the groins and pelvis is warranted. Until now there is a limited role for primary radiotherapy on the vulva and/or groins in early stage disease. The sentinel lymph node (SLN) procedure with the combined technique (preoperative lymphoscintigraphy with a radioactive tracer and intraoperative blue dye) is a promising staging technique for patients with early stage vulvar cancer. The safety of clinical implementation of the SLN procedure and the role of additional histopathological techniques of the SLNs need to be further investigated before its wide-scale application. Patients with advanced vulvar cancer are difficult to treat. One of the problems in patients with locally advanced vulvar cancer is the high incidence of concomitant bulky lymph nodes in the groin(s). Ultraradical surgery in case of resectable disease will lead to impressive morbidity because of the exenterative-type procedure. (Chemo)radiation with or without surgery should be regarded as the first choice for patients with locally advanced vulvar cancer only when primary surgery will necessitate performance of a stoma. Further studies are needed to determine the optimal combined modality treatment in these patients. Due to the fact that vulvar cancer is a rare disease, further clinical studies will only be possible, when international collaborative groups will join forces in order to perform clinical trials, in which different treatment options such as SLN procedure, primary radiotherapy on the groins and multimodality treatment for advanced disease will be investigated

Current controversies in the management of patients with early-stage vulvar cancer.

Contains fulltext : 87921.pdf (publisher's version ) (Closed access)PURPOSE OF REVIEW: The purpose of this review is to outline current controversies in management of early-stage vulvar cancer. The main focus will be on the procedures for assessing the sentinel node and the treatment of those with evidence of metastatic involvement. RECENT FINDINGS: Assessment of the sentinel node has recently been introduced into the standard treatment of early-stage squamous cell vulvar cancer. The combination of a radioactive tracer and blue dye is the most accurate technique for sentinel node detection. Preoperative imaging is recommended to rule out gross nodal involvement and ultrasound with fine needle aspiration cytology by an experienced radiologist appears to have the highest sensitivity/specificity for detecting metastases, although large comparative studies are not available. All patients with sentinel node metastases require additional treatment to the groin, independent of the size of metastasis in the sentinel node and currently this involves inguinofemoral lymphadenectomy. Further research is ongoing to investigate the role of radiotherapy instead of lymphadenectomy. The little experience there is of sentinel node biopsy in vulvar melanoma suggests that the procedure is feasible and inclusion criteria should follow those of cutaneous melanoma. SUMMARY: Sentinel node biopsy is safe in treatment of early-stage vulvar cancer. Ongoing studies are investigating the optimal additional treatment for patients with a positive sentinel node in terms of efficacy and morbidity.1 september 201