Osteoporosis case finding in the general practice: phalangeal radiographic absorptiometry with and without risk factors for osteoporosis to select postmenopausal women eligible for lumbar spine and hip densitometry

Mass screening for osteoporosis using DXA measurements at the spine and hip is presently not recommended by health authorities. Instead, risk factor questionnaires and peripheral bone measurements may facilitate the selection of women eligible for axial bone densitometry. The aim of this study was to validate a case finding strategy for postmenopausal women who would benefit most from subsequent DXA measurement by using phalangeal radiographic absorptiometry (RA) alone or in combination with risk factors in a general practice setting. The sensitivity and specificity of this strategy in detecting osteoporosis (T-score ≤2.5SD at the spine and/or the hip) were compared with those of the current reimbursement criteria for DXA measurements in Switzerland. Four hundred and twenty-three postmenopausal women with one or more risk factors for osteoporosis were recruited by 90 primary care physicians who also performed the phalangeal RA measurements. All women underwent subsequent DXA measurement of the spine and the hip at the Osteoporosis Policlinic of the University Hospital of Berne. They were allocated to one of two groups depending on whether they matched with the Swiss reimbursement conditions for DXA measurement or not. Logistic regression models were used to predict the likelihood of osteoporosis versus "no osteoporosis” and to derive ROC curves for the various strategies. Differences in the areas under the ROC curves (AUC) were tested for significance. In women lacking reimbursement criteria, RA achieved a significantly larger AUC (0.81; 95% CI 0.72-0.89) than the risk factors associated with patients' age, height and weight (0.71; 95% C.I. 0.62-0.80). Furthermore, in this study, RA provided a better sensitivity and specificity in identifying women with underlying osteoporosis than the currently accepted criteria for reimbursement of DXA measurement. In the Swiss environment, RA is a valid case finding tool for patients with risk factors for osteoporosis, especially for those who do not qualify for DXA reimbursemen

Claudin-12 is not required for blood-brain barrier tight junction function

Background The blood-brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown. Methods We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant. Results Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12(lacZ/lacZ) C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12(lacZ/lacZ) C57BL/6J mice. Conclusions Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12(lacZ/lacZ) C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss

A Binding Potency Assay for Pritumumab and Ecto-Domain Vimentin.

Pritumumab, a natural human IgG1kappa mAb, was isolated from the regional lymph node of a patient with cervical cancer. This antibody has been reported to bind the cytoskeletal protein vimentin, and to cell surface expressed vimentin referred to as ecto-domain vimentin (EDV). Here, we report details of the development of a potency of binding assay for pritumumab as a prerequisite before pursuing clinical trials. The enzyme linked immunosorbent assay (ELISA) to detect antibody-binding antigen can serve as a potency assay for release of manufactured samples to be used in clinical studies. Several layers of controls for this assay along with suitability testing for reagents and components of the assay must be developed before the assay can be incorporated for stability testing and release of manufatured samples

First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes