Osseointegration of porous titanium and tantalum implants in ovariectomized rabbits: A biomechanical study

BACKGROUNDToday, biological fixation of uncemented press-fit acetabular components plays an important role in total hip arthroplasty. Long-term stable fixation of these implants depends on the osseointegration of the acetabular cup bone tissue into the acetabular cup implant, and their ability to withstand functional loads.AIMTo compare the strength of bone-implant osseointegration of four types of porous metal implants in normal and osteoporotic bone in rabbits.METHODSThe study was performed in 50 female California rabbits divided into non-ovariectomized (non-OVX) and ovariectomized groups (OVX) at 6 mo of age. Rabbits were sacrificed 8 wk after the implantation of four biomaterials [TTM, CONCELOC, Zimmer Biomet''s Trabecular Metal (TANTALUM), and ATLANT] in a 5-mm diameter defect created in the left femur. A biomechanical evaluation of the femur was carried out by testing implant breakout force. The force was gradually increased until complete detachment of the implant from the bone occurred.RESULTSThe breakout force needed for implant detachment was significantly higher in the non-OVX group, compared with the OVX group for all implants (TANTALUM, 194.7 ± 6.1 N vs 181.3 ± 2.8 N; P = 0.005; CONCELOC, 190.8 ± 3.6 N vs 180.9 ± 6.6 N; P = 0.019; TTM, 186.3 ± 1.8 N vs 172.0 N ± 11.0 N; P = 0.043; and ATLANT, 104.9 ± 7.0 N vs 78.9 N ± 4.5 N; P = 0.001). In the OVX group, The breakout forces in TANTALUM, TTM, and CONCELOC did not differ significantly (P = 0.066). The breakout force for ATLANT in the OVX group was lower by a factor of 2.3 compared with TANTALUM and CONCELOC, and by 2.2 compared with TTM (P = 0.001). In the non-OVX group, the breakout force for ATLANT was significantly different from all other implants, with a reduction in fixation strength by a factor of 1.9 (P = 0.001).CONCLUSIONTANTALUM, TTM, and CONCELOC had equal bone-implant osseointegration in healthy and in osteoporotic bone. ATLANT had significantly decreased osseointegration (P = 0.001) in healthy and in osteoporotic bone.     

Anthropometry in 5- to 9-Year-Old Greenlandic and Ukrainian Children in Relation to Prenatal Exposure to Perfluorinated Alkyl Substances

Background

In some animal studies, perfluorinated alkyl substances are suggested to induce weight gain. Human epidemiological studies investigating these associations are sparse.

Objective

We examined pregnancy serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and the prevalence of offspring overweight (> 1 SD) and waist-to-height ratio (WHtR) > 0.5 at 5–9 years of age.

Methods

Sera from 1,022 pregnant women enrolled in the INUENDO cohort (2002–2004) from Greenland and Kharkiv (Ukraine) were analyzed for PFOA and PFOS using liquid chromatography–tandem mass spectrometry. Relative risks (RR) of being overweight and having WHtR > 0.5 in relation to continuous and categorized (tertiles) PFOA and PFOS were calculated at follow-up (2010–2012) using generalized linear models.

Results

Pooled PFOA median (range) was 1.3 (0.2–5.1) and PFOS median (range) was 10.8 (0.8–73.0) ng/mL. For each natural logarithm-unit (ln-unit) increase of pregnancy PFOA, the adjusted RR of offspring overweight was 1.11 [95% confidence interval (CI): 0.82, 1.53] in Greenlandic children. In Ukrainian children, the adjusted RR of offspring overweight was 1.02 (95% CI: 0.72, 1.44) for each ln-unit increase of pregnancy PFOA. Prenatal exposure to PFOS was not associated with overweight in country-specific or pooled analysis. The adjusted RR of having WHtR > 0.5 for each ln-unit increase of prenatal exposure to PFOA was 1.30 (95% CI: 0.97, 1.74) in the pooled analysis. For 1–ln-unit increase of prenatal exposure to PFOS, the adjusted RR of having a WHtR > 0.5 was 1.38 (95% CI: 1.05, 1.82) in the pooled analysis.

Conclusions

The results indicate that prenatal PFOA and PFOS exposures may be associated with child waist-to-height ratio > 0.5. Prenatal PFOA and PFOS exposures were not associated with overweight.

Citation

Høyer BB, Ramlau-Hansen CH, Vrijheid M, Valvi D, Pedersen HS, Zviezdai V, Jönsson BA, Lindh CH, Bonde JP, Toft G. 2015. Anthropometry in 5- to 9-year-old Greenlandic and Ukrainian children in relation to prenatal exposure to perfluorinated alkyl substances. Environ Health Perspect 123:841–846; http://dx.doi.org/10.1289/ehp.1408881     

Discovery of small molecule inhibitors that interact with γ-tubulin

Recent studies have shown an overexpression of γ-tubulin in human glioblastomas and glioblastoma cell lines. As the 2-year survival rate for glioblastoma is very poor, potential benefit exists for discovering novel chemotherapeutic agents that can inhibit γ-tubulin, which is known to form a ring complex that acts as a microtubule nucleation center. We present experimental evidence that colchicine and combretastatin A-4 bind to γ-tubulin, which are to our knowledge the first drug-like compounds known to interact with γ-tubulin. Molecular dynamics simulations and docking studies were used to analyze the hypothesized γ-tubulin binding domain of these compounds. The suitability of the potential binding modes was evaluated and suggests the subsequent rational design of novel targeted inhibitors of γ-tubulin.     

Time to pregnancy as a function of male and female serum concentrations of 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE)

BACKGROUND: Persistent organochlorine pollutants (POP) may affect both the female and male reproductive system in animals as well as in humans. METHODS: Blood samples were collected from pregnant women and their partners from Greenland, Warsaw and Kharkiv, and from a cohort of Swedish fishermen's wives. Blood samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE). Information on the participants' fertility, measured as time to pregnancy (TTP), was collected. In total, 778 men and 1505 women were included in the analyses. RESULTS: The data from Warsaw, Kharkiv and the Swedish fishermen's wives indicated no effect of either male or female exposure to POP on TTP. However, among men and women from Greenland, there seemed to be an association between serum concentrations of CB-153 and p,p'-DDE and prolonged TTP. Due to the strong intra-individual correlation between CB-153 and p,p'-DDE in the Greenlandic population, it was not possible to determine whether the risk was associated with CB-153 or p, p'-DDE or was an interaction between the two compounds. CONCLUSIONS: The overall results of the present study create a somewhat ambiguous pattern, but give some support to the idea that dietary POP exposure might be harmful for couple fertility.     

Experimental and Computational Study of the Interaction of Novel Colchicinoids with a Recombinant Human αI/βI‐Tubulin Heterodimer

The binding free energies on human tubulin of selected colchicine and thiocolchicine compounds were determined. Two methods were used for the determination of binding free energies: one is based on theoretical prediction simulating the dissociation of the compound from tubulin using a series of molecular dynamics simulations, and the other method involves a series of experiments that measured the affinity of the compound on a synthetically expressed and purified tubulin protein using a spectrofluorometric technique.     

Intermolecular transmission of superoxide dismutase 1 misfolding in living cells

Human wild-type superoxide dismutase-1 (wtSOD1) is known to coaggregate with mutant SOD1 in familial amyotrophic lateral sclerosis (FALS), in double transgenic models of FALS, and in cell culture systems, but the structural determinants of this process are unclear. Here we molecularly dissect the effects of intracellular and cell-free obligately misfolded SOD1 mutant proteins on natively structured wild-type SOD1. Expression of the enzymatically inactive, natural familial ALS SOD1 mutations G127X and G85R in human mesenchymal and neural cell lines induces misfolding of wild-type natively structured SOD1, as indicated by: acquisition of immunoreactivity with SOD1 misfolding-specific monoclonal antibodies; markedly enhanced protease sensitivity suggestive of structural loosening; and nonnative disulfide-linked oligomer and multimer formation. Expression of G127X and G85R in mouse cell lines did not induce misfolding of murine wtSOD1, and a species restriction element for human wtSOD1 conversion was mapped to a region of sequence divergence in loop II and β-strand 3 of the SOD1 β-barrel (residues 24-36), then further refined surprisingly to a single tryptophan residue at codon 32 (W32) in human SOD1. Time course experiments enabled by W32 restriction revealed that G127X and misfolded wtSOD1 can induce misfolding of cell-endogenous wtSOD1. Finally, aggregated recombinant G127X is capable of inducing misfolding and protease sensitivity of recombinant human wtSOD1 in a cell-free system containing reducing and chelating agents; cell-free wtSOD1 conversion was also restricted by W32. These observations demonstrate that misfolded SOD1 can induce misfolding of natively structured wtSOD1 in a physiological intracellular milieu, consistent with a direct protein-protein interaction.     

Using the CER Hub to ensure data quality in a multi-institution smoking cessation study

Comparative effectiveness research (CER) studies involving multiple institutions with diverse electronic health records (EHRs) depend on high quality data. To ensure uniformity of data derived from different EHR systems and implementations, the CER Hub informatics platform developed a quality assurance (QA) process using tools and data formats available through the CER Hub. The QA process, implemented here in a study of smoking cessation services in primary care, used the ‘emrAdapter’ tool programmed with a set of quality checks to query large samples of primary care encounter records extracted in accord with the CER Hub common data framework. The tool, deployed to each study site, generated error reports indicating data problems to be fixed locally and aggregate data sharable with the central site for quality review. Across the CER Hub network of six health systems, data completeness and correctness issues were prevalent in the first iteration and were considerably improved after three iterations of the QA process. A common issue encountered was incomplete mapping of local EHR data values to those defined by the common data framework. A highly automated and distributed QA process helped to ensure the correctness and completeness of patient care data extracted from EHRs for a multi-institution CER study in smoking cessation.     

Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells

The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor.