Genetic control of bone density and turnover: Role of the collagen 1α1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Suggestive linkage of the parathyroid receptor type 1 to osteoporosis

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1α (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p ≤0.05) at markers close to or within the candidate genes IL- 1α, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.

Identification of a novel fusion transcript between human relaxin-1 (RLN1) and human relaxin-2 (RLN2) in prostate cancer

Simultaneous expression of highly homologous RLN1 and RLN2 genes in prostate impairs their accurate delineation. We used PacBio SMRT sequencing and RNA-Seq in LNCaP cells in order to dissect the expression of RLN1 and RLN2 variants. We identified a novel fusion transcript comprising the RLN1 and RLN2 genes and found evidence of its expression in the normal and prostate cancer tissues. The RLN1-RLN2 fusion putatively encodes RLN2 isoform with the deleted secretory signal peptide. The identification of the fusion transcript provided information to determine unique RLN1-RLN2 fusion and RLN1 regions. The RLN1-RLN2 fusion was co-expressed with RLN1 in LNCaP cells, but the two gene products were inversely regulated by androgens. We showed that RLN1 is underrepresented in common PCa cell lines in comparison to normal and PCa tissue. The current study brings a highly relevant update to the relaxin field, and will encourage further studies of RLN1 and RLN2 in PCa and broader.

Moving on (part 1): The physics of power and curriculum history

This is the first of two papers that map (dis)continuities in notions of power from Aristotle to Newton to Foucault. They trace the ways in which bio-physical conceptions of power became paraphrased in social science and deployed in educational discourse on the child and curriculum from post-Newtonian times to the present. The analyses suggest that, amid ruptures in the definition, role, location and meaning given 'power' historically in various 'physical' and 'social' cosmologies, the naming of 'power' has been dependent on 'physics', on the theorization of motion across 'Western' sciences. This first paper examines some (dis)continuities in regard to histories of motion and power from Aristotelian 'natural science' to Newtonian mechanics.

The geometry of Bi nanolines on Si(0 0 1)

A study of the Bi nanoline geometry on Si(0 0 1) has been performed using a combination of ab initio theoretical technique and scanning tunnelling microscopy (STM). Our calculations demonstrate decisively that the recently proposed Haiku geometry is a lower energy configuration than any of the previously proposed line geometries. Furthermore, we have made comparisons between STM constant-current topographs of the lines and Tersoff–Haman STM simulations. Although the Haiku and the Miki geometries both reproduce the main features of the constant-current topographs, the simulated STM images of the Miki geometry have a dark stripe between the dimer rows that does not correspond well with experiment.

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.

GABAAα1 and GABAAρ1 subunits are expressed in cultured human RPE cells and GABAA receptor agents modify the intracellular calcium concentration.

Purpose: Gamma-aminobutyric acid A (GABAA) receptors (GABAARs), which are ionotropic receptors involving chloride channels, have been identified in various neural (e.g., mouse retinal ganglion cells) and nonneural cells (e.g., mouse lens epithelial cells) regulating the intracellular calcium concentration ([Ca(2+)]i). GABAAR β-subunit protein has been isolated in the cultured human and rat RPE, and GABAAα1 and GABAAρ1 mRNAs and proteins are present in the chick RPE. The purpose of this study was to investigate the expression of GABAAα1 and GABAAρ1, two important subunits in forming functional GABAARs, in the cultured human RPE, and further to explore whether altering receptor activation modifies [Ca(2+)]i. Methods: Human RPE cells were separately cultured from five donor eye cups. Real-time PCR, western blots, and immunofluorescence were used to test for GABAAα1 and GABAAρ1 mRNAs and proteins. The effects of the GABAAR agonist muscimol, antagonist picrotoxin, or the specific GABAAρ antagonist 1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA) on [Ca(2+)]i in cultured human RPE were demonstrated using Fluo3-AM. Results: Both GABAAα1 and GABAAρ1 mRNAs and proteins were identified in cultured human RPE cells; antibody staining was mainly localized to the cell membrane and was also present in the cytoplasm but not in the nucleus. Muscimol (100 μM) caused a transient increase of the [Ca(2+)]i in RPE cells regardless of whether Ca(2+) was added to the buffer. Muscimol-induced increases in the [Ca(2+)]i were inhibited by pretreatment with picrotoxin (300 μM) or TPMPA (500 μM). Conclusions: GABAAα1 and GABAAρ1 are expressed in cultured human RPE cells, and GABAA agents can modify [Ca(2+)]i.

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgenindependent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

A cryptographic analysis of the TLS 1.3 handshake protocol candidates

The Internet Engineering Task Force (IETF) is currently developing the next version of the Transport Layer Security (TLS) protocol, version 1.3. The transparency of this standardization process allows comprehensive cryptographic analysis of the protocols prior to adoption, whereas previous TLS versions have been scrutinized in the cryptographic literature only after standardization. This is even more important as there are two related, yet slightly different, candidates in discussion for TLS 1.3, called draft-ietf-tls-tls13-05 and draft-ietf-tls-tls13-dh-based. We give a cryptographic analysis of the primary ephemeral Diffie–Hellman-based handshake protocol, which authenticates parties and establishes encryption keys, of both TLS 1.3 candidates. We show that both candidate handshakes achieve the main goal of providing secure authenticated key exchange according to an augmented multi-stage version of the Bellare–Rogaway model. Such a multi-stage approach is convenient for analyzing the design of the candidates, as they establish multiple session keys during the exchange. An important step in our analysis is to consider compositional security guarantees. We show that, since our multi-stage key exchange security notion is composable with arbitrary symmetric-key protocols, the use of session keys in the record layer protocol is safe. Moreover, since we can view the abbreviated TLS resumption procedure also as a symmetric-key protocol, our compositional analysis allows us to directly conclude security of the combined handshake with session resumption. We include a discussion on several design characteristics of the TLS 1.3 drafts based on the observations in our analysis.

Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in Type 1 diabetes

OBJECTIVE This study determined if deficits in corneal nerve fiber length (CNFL) assessed using corneal confocal microscopy (CCM) can predict future onset of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS CNFL and a range of other baseline measures were compared between 90 nonneuropathic patients with type 1 diabetes who did or did not develop DPN after 4 years. The receiver operator characteristic (ROC) curve was used to determine the capability of single and combined measures of neuropathy to predict DPN. RESULTS DPN developed in 16 participants (18%) after 4 years. Factors predictive of 4-year incident DPN were lower CNFL (P = 0.041); longer duration of diabetes (P = 0.002); higher triglycerides (P = 0.023); retinopathy (higher on the Early Treatment of Diabetic Retinopathy Study scale) (P = 0.008); nephropathy (higher albumin-to-creatinine ratio) (P = 0.001); higher neuropathy disability score (P = 0.037); lower cold sensation (P = 0.001) and cold pain (P = 0.027) thresholds; higher warm sensation (P = 0.008), warm pain (P = 0.024), and vibration (P = 0.003) thresholds; impaired monofilament response (P = 0.003); and slower peroneal (P = 0.013) and sural (P = 0.002) nerve conduction velocity. CCM could predict the 4-year incident DPN with 63% sensitivity and 74% specificity for a CNFL threshold cutoff of 14.1 mm/mm2 (area under ROC curve = 0.66, P = 0.041). Combining neuropathy measures did not improve predictive capability. CONCLUSIONS DPN can be predicted by various demographic, metabolic, and conventional neuropathy measures. The ability of CCM to predict DPN broadens the already impressive diagnostic capabilities of this novel ophthalmic marker.

Queensland pharmacist immunisation pilot phase 1 pharmacist vaccination - Influenza final report

The results of the pilot demonstrated that a pharmacist delivered vaccinations services is feasible in community pharmacy and is safe and effective. The accessibility of the pharmacist across the influenza season provided the opportunity for more people to be vaccinated, particularly those who had never received an influenza vaccine before. Patient satisfaction was extremely high with nearly all patients happy to recommend the service and to return again next year. Factors critical to the success of the service were: 1. Appropriate facilities 2. Competent pharmacists 3. Practice and decision support tools 4. In-­‐store implementation support We demonstrated in the pilot that vaccination recipients preferred a private consultation area. As the level of privacy afforded to the patients increased (private room vs. booth), so did the numbers of patients vaccinated. We would therefore recommend that the minimum standard of a private consultation room or closed-­‐in booth, with adequate space for multiple chairs and a work / consultation table be considered for provision of any vaccination services. The booth or consultation room should be used exclusively for delivering patient services and should not contain other general office equipment, nor be used as storage for stock. The pilot also demonstrated that a pharmacist-­‐specific training program produced competent and confident vaccinators and that this program can be used to retrofit the profession with these skills. As vaccination is within the scope of pharmacist practice as defined by the Pharmacy Board of Australia, there is potential for the universities to train their undergraduates with this skill and provide a pharmacist vaccination workforce in the near future. It is therefore essential to explore appropriate changes to the legislation to facilitate pharmacists’ practice in this area. Given the level of pharmacology and medicines knowledge of pharmacists, combined with their new competency of providing vaccinations through administering injections, it is reasonable to explore additional vaccines that pharmacists could administer in the community setting. At the time of writing, QPIP has already expanded into Phase 2, to explore pharmacists vaccinating for whooping cough and measles. Looking at the international experience of pharmacist delivered vaccination, we would recommend considering expansion to other vaccinations in the future including travel vaccinations, HPV and selected vaccinations to those under the age of 18 years. Overall the results of the QPIP implementation have demonstrated that an appropriately trained pharmacist can deliver safely and effectively influenza vaccinations to adult patients in the community. The QPIP showed the value that the accessibility of pharmacists brings to public health outcomes through improved access to vaccinations and the ability to increase immunisation rates in the general population. Over time with the expansion of pharmacist vaccination services this will help to achieve more effective herd immunity for some of the many diseases which currently have suboptimal immunisation rates.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-)(9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-)(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-)(5), permuted threshold for genome-wide significance 7.7 x 10(-)(5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Strong evidence for a novel schizophrenia risk locus on chromosome 1p31.1 in homogeneous pedigrees from Tamil Nadu, India

OBJECTIVE: The study of ethnically homogeneous populations may help to identify schizophrenia risk loci. The authors conducted a genomewide linkage scan for schizophrenia in an Indian population. METHOD: Participants were 441 individuals (262 affected probands and siblings) who were recruited primarily from one ethnically homogeneous group, the Tamil Brahmin caste, although individuals from other geographically proximal castes also participated. Genotyping of 124 affected sibling pair pedigrees was performed with 402 short tandem repeat polymorphisms. Linkage analyses were conducted using nonparametric exponential LOD (logarithm of the odds ratio for linkage) scores and parametric heterogeneity LOD scores. Parametric heterogeneity scores were calculated using simple dominant and recessive models, correcting for multiple statistics. The data were examined for evidence of consanguinity. Genomewide significance levels were determined using 10,000 gene dropping simulations. RESULTS: These findings revealed genomewide significant linkage to chromosome 1p31.1, through the use of both exponential and heterogeneity LOD scores, incorporating correction for multiple statistics and mild consanguinity. The estimated sibling recurrence risk associated with this putative locus was 1.95. Analysis for heterogeneity LOD scores also detected suggestive linkage to chromosomes 13q22.1 and 16q12.2. Using 117 tag single nucleotide polymorphisms (SNPs), family-based association analyses of phosphodiesterase 4B (PDE4B), the closest schizophrenia candidate gene, detected no convincing evidence of association, suggesting that the chromosome 1 peak represents a novel risk locus. CONCLUSIONS: This is the first study-to the authors' knowledge-to report significant linkage of schizophrenia to chromosome 1p31.1. Further investigation of this chromosome region in diverse populations is warranted to identify underlying sequence variants.

Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 × 10−28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 × 10−14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 × 10−9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.