Cobalt chromium alloys in fixed prosthodontics: Investigations of mechanical properties and microstructure.

STATEMENT OF PROBLEM: Cobalt chromium (Co-Cr) alloys possess beneficial mechanical properties because alloys, even in thin sections, can resist high mastication forces and exhibit an acceptable bond to the surface porcelain layer. Traditional manufacturing techniques of Co-Cr alloys such as casting have been replaced with newer fabrication techniques, such as milling, laser melting, and presintered milling. Despite scarce documentation, these new manufacturing techniques are being used to fabricate dental and implant constructions. PURPOSE: This in vitro study investigates the hardness, yield strength, elastic modulus, and microstructure of the most commonly used Co-Cr alloys for fixed prosthodontics based on manufacturing technique. In addition, this study investigates the effect of heat treatment on the mechanical properties and microstructure of these materials. MATERIAL AND METHODS: Five Co-Cr alloys were included (dumbbell and rectangular shaped) based on four manufacturing techniques: cast, milled, laser melted, and presintered milled. Commercially pure titanium grade 4 and titanium-6 aluminum-4 vanadium ELI (extra low interstitial) were included for comparison, and yield strength and elongation after fracture were evaluated. The specimens were tested for hardness using the Vickers test and for elastic modulus using a nondestructive impulse excitation technique. The microstructure of selected specimens was analyzed using focused ion beam-scanning electron microscopy (FIB-SEM) and energy dispersive X-ray spectroscopy (EDS). RESULTS: The mechanical properties depend on the manufacturing technique used; the laser-melted and presintered Co-Cr specimens demonstrated the highest mechanical properties, followed by the milled and cast groups. Both the laser-melted and the presintered milled Co-Cr specimens showed smaller grain size compared with the cast and milled Co-Cr specimens. The titanium-6 aluminum-4 vanadium ELI demonstrated higher hardness and yield strength compared to commercially pure titanium grade 4. No major differences were observed for the selected materials regarding the mechanical properties and microstructural appearance after heat treatment. CONCLUSIONS: The laser melting and presintered milling techniques produced higher mechanical properties compared with the cast and milled Co-Cr. These findings were confirmed through microstructural analysis with respect to the grain size, precipitation, and number of pores.

Identification and analyses of inhibitors targeting apolipoprotein(a) kringle domains KIV-7, KIV-10, and KV provide insight into kringle domain function.

Increased plasma concentrations of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular disease. Lp(a) is composed of apolipoprotein(a) (apo(a)) covalently bound to apolipoprotein B of low-density lipoprotein (LDL). Many of apo(a)'s potential pathological properties, such as inhibition of plasmin generation, have been attributed to its main structural domains, the kringles, and have been proposed to be mediated by their lysine-binding sites. However, available small-molecule inhibitors, such as lysine analogs, bind unselectively to kringle domains and are therefore unsuitable for functional characterization of specific kringle domains. Here, we discovered small molecules that specifically bind to the apo(a) kringle domains KIV-7, KIV-10, and KV. Chemical synthesis yielded compound AZ-05, which bound to KIV-10 with a Kd of 0.8 µm and exhibited more than 100-fold selectivity for KIV-10, compared with the other kringle domains tested, including plasminogen kringle 1. To better understand and further improve ligand selectivity, we determined the crystal structures of KIV-7, KIV-10, and KV in complex with small-molecule ligands at 1.6-2.1 Å resolutions. Furthermore, we used these small molecules as chemical probes to characterize the roles of the different apo(a) kringle domains in in vitro assays. These assays revealed the assembly of Lp(a) from apo(a) and LDL, as well as potential pathophysiological mechanisms of Lp(a), including (i) binding to fibrin, (ii) stimulation of smooth-muscle cell proliferation, and (iii) stimulation of LDL uptake into differentiated monocytes. Our results indicate that a small-molecule inhibitor targeting the lysine-binding site of KIV-10 can combat the pathophysiological effects of Lp(a).

Early Cup Loosening After Metal-on-Metal Total Joint Replacement of the Trapeziometacarpal Joint: A Retrieval Study.

PURPOSE: To investigate the possible mechanisms behind early cup loosening in a metal-on-metal trapeziometacarpal joint replacement. METHODS: The trapezia from 5 female patients were removed as part of a salvage procedure after a median of 22 months (range, 7-43 months) after implantation. Three osteoarthritic patients with symptomatic cup loosening and 2 with instability had a median age of 62 years (range, 59-65 years) at primary surgery. The trapezia with cups in situ were preserved and processed for histomorphometry. Studies with laser ablation inductively coupled plasma mass spectrometry and scanning electron microscopy with energy dispersive x-ray spectroscopy were also performed on 2 of the specimens. RESULTS: In all 5 specimens, osteolytic lesions undermined the cups and were also seen at the cup edges, completely surrounding the loose cups. Large amounts of dark particular material were seen in the periprosthetic tissues, mostly internalized by macrophages. The presence of chrome and cobalt in these regions was confirmed. Four of the 5 cups showed marked or complete loss of hydroxyapatite. CONCLUSIONS: We have found several possible explanations for the poor performance of this cup, including its cannulated design and metal-on-metal bearing. The changes seen are early and advanced, raising serious concerns about the implant and particularly the articulation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Bone tissue response following local drug delivery of bisphosphonate through titanium oxide nanotube implants in a rabbit model.

OBJECTIVES: The objective of this study was to evaluate whether surface chemistry-controlled TiO2 nanotube structures may serve as a local drug delivery system for zoledronic acid improving implant-bone support. METHODS: Twenty-four screw-shaped Ti implants with surface chemistry-controlled TiO2 nanotube structures were prepared and divided into a zoledronic acid-formatted test and a native control group. The implants were inserted into contra-lateral femoral condyles in 12 New Zealand White rabbits. Bone support was evaluated using resonance frequency analysis (RFA) and removal torque (RTQ), as well as histometric analysis following a 3-weeks healing interval. RESULTS: Zoledronic acid-formatted TiO2 nanotube test implants showed significantly improved implant stability and osseointegration measured using RFA and RTQ compared with control (p < 0.05), and showed significantly enhanced new bone formation within the root of the threads compared with control (p < 0.05). CONCLUSIONS: TiO2 nanotube implants may prove to be a significant delivery system for drugs or biologic agents aimed at supporting local bone formation. Additional study of candidate drugs/agents, optimized dosage and release kinetics is needed prior to evaluation in clinical settings.

Improved osseointegration and interlocking capacity with dual acid-treated implants: a rabbit study.

AIM: To investigate how osseointegration is affected by different nano- and microstructures. The hypothesis was that the surface structure created by dual acid treatment (AT-1), applied on a reduced topography, might achieve equivalent biomechanical performance as a rougher surface treated with hydrofluoric acid (HF). MATERIALS AND METHODS: In a preclinical rabbit study, three groups (I, II, and III) comprised of test and control implants were inserted in 30 rabbits. The microstructures of the test implants were either produced by blasting with coarse (I) or fine (II) titanium particles or remained turned (III). All test implants were thereafter treated with AT-1 resulting in three different test surfaces. The microstructure of the control implants was produced by blasting with coarse titanium particles thereafter treated with HF. The surface topography was characterized by interferometry. Biomechanical (removal torque) and histomorphometric (bone-implant contact; bone area) performances were measured after 4 or 12 weeks of healing. RESULTS: Removal torque measurement demonstrated that test implants in group I had an enhanced biomechanical performance compared to that of the control despite similar surface roughness value (Sa ). At 4 weeks of healing, group II test implants showed equivalent biomechanical performance to that of the control, despite a decreased Sa value. Group III test implants showed decreased biomechanical performance to that of the control. CONCLUSIONS: The results of the present study suggest that nano- and microstructure alteration by AT-1 on a blasted implant might enhance the initial biomechanical performance, while for longer healing time, the surface interlocking capacity seems to be more important.

Inflammatory cytokine release is affected by surface morphology and chemistry of titanium implants.

To investigate in vitro cellular cytokine expression in relation to commercially pure titanium discs, comparing a native surface to a fluorinated oxide nanotube surface. Control samples pure titanium discs with a homogenous wave of the margins and grooves and an often smeared-out surface structure. Test samples pure titanium discs with a fluorinated titanium oxide chemistry and surface morphology with nanopore/tube geometry characterized by ordered structures of nanotubes with a diameter of ≈ 120 nm, a spacing of ≈ 30 nm, and a wall thickness of ≈ 10 nm. Cross-section view showed vertically aligned nanotubes with similar lengths of ≈ 700 nm. Peripheral blood mononuclear leucocytes were cultured for 1, 3, and 6 days according to standard procedures. BioPlex Pro™ assays were used for analysis and detection of cytokines. Selected inflammatory cytokines are reported. A pronounced difference in production of the inflammatogenic cytokines was observed. Leucocytes exposed to control coins produced significantly more TNF-α, IL-1ß, and IL-6 than the test nanotube coins. The effect on the TH2 cytokine IL-4 was less pronounced at day 6 compared to days 1 and 3, and slightly higher expressed on the control coins. The morphology and surface chemistry of the titanium surface have a profound impact on basic cytokine production in vitro. Within the limitations of the present study, it seems that the fluorinated oxide nanotube surface results in a lower inflammatory response compared to a rather flat surface that seems to favour inflammation.

Characterization of a small molecule inhibitor of plasminogen activator inhibitor type 1 that accelerates the transition into the latent conformation.

A novel class of small molecule inhibitors for plasminogen activator inhibitor type 1 (PAI-1), represented by AZ3976, was identified in a high throughput screening campaign. AZ3976 displayed an IC(50) value of 26 µm in an enzymatic chromogenic assay. In a plasma clot lysis assay, the compound was active with an IC(50) of 16 µm. Surprisingly, AZ3976 did not bind to active PAI-1 but bound to latent PAI-1 with a K(D) of 0.29 µm at 35 °C and a binding stoichiometry of 0.94, as measured by isothermal calorimetry. Reversible binding was confirmed by surface plasmon resonance direct binding experiments. The x-ray structure of AZ3976 in complex with latent PAI-1 was determined at 2.4 Å resolution. The inhibitor was bound in the flexible joint region with the entrance to the cavity located between α-helix D and ß-strand 2A. A set of surface plasmon resonance experiments revealed that AZ3976 inhibited PAI-1 by enhancing the latency transition of active PAI-1. Because AZ3976 only had measurable affinity for latent PAI-1, we propose that its mechanism of inhibition is based on binding to a small fraction in equilibrium with active PAI-1, a latent-like prelatent form, from which latent PAI-1 is then generated more rapidly. This mode of action, with induced accelerated latency transition of active PAI-1 may, together with supporting x-ray data, provide improved opportunities for small molecule drug design in the hunt for therapeutically useful PAI-1 inhibitors.

A randomized and controlled clinical trial of two different compositions of deproteinized bovine bone and autogenous bone used for lateral ridge augmentation.

OBJECTIVE: The aim of the study was to radiologically and histologically evaluate the graft healing and volumetric changes after lateral augmentation with two different compositions of deproteinized bovine bone (DPBB) and autogenous bone (AB). MATERIAL AND METHODS: Thirteen patients with a mean age of 59.6 ± 12.1 years (six men and seven women) were included in this randomized and controlled trial, designed as a split-mouth study. Ten edentulous and four partially edentulous jaws with an alveolar ridge width of ≤4 mm were laterally augmented with a graft composition of 60 : 40 (DPBB/AB) on one side and 90 : 10 (DPBB/AB) on the contralateral side. Cone beam computed tomography (CB/CT) was obtained immediately postoperatively and after a healing period of 7.5 months. Width changes were measured on CB/CT scans. After a mean healing period of 8.1 months (range, 7.9-8.3), biopsies were retrieved perpendicular to the crest from each graft by means of a trephine bur. Histomorphometry was performed, and the following variables were recorded: Ingrowth of new bone (percentage of total graft width), percentage of DPBB, bone and soft tissue, and percentage of DPBB particles in contact with bone. RESULTS: The mean gained width of the alveolar crest after 7.5 months was significantly more for the 60 : 40 mixture compared with the 90 : 10 mixture, 3.5 (±1.3) mm and 2.9 (±1.3) mm, respectively. There was a significant difference in graft width reduction between 60 : 40 and 90 : 10 after 7.5 months, 37 (±19.9)% and 46.9 (±23.5)%, respectively. New bone ingrowth had occurred in 82.1 (±23.3)% and 82.3 (±26.6)% of the graft, respectively. There were no statistical differences between fractions of different tissues between the 90 : 10 and 60 : 40 compositions. However, there were significantly more soft tissue and less new bone formation closer to the periosteum compared with the graft portion closer to the residual bone in both 60 : 40 and 90 : 10 compositions. CONCLUSIONS: There was significantly less graft width reduction with a mixture of 60 : 40 (DPBB/AB) compared with a mixture of 90 : 10 composition, but the results from the histomorphometry showed no statistical differences comparing the groups.

The histological evaluation of osseointegration of surface enhanced microimplants immediately loaded in conjunction with sinuslifting in humans.

OBJECTIVE: The aim was to investigate histomorphometrically whether or not implant surface nanotopography improves the bone response under immediate loading simultaneous to sinus grafting. MATERIALS AND METHODS: Dual acid-etched titanium microimplants with/without crystalline surface deposition of calcium phosphate particles were placed in bilateral sinuslift areas grafted with a mixture of iliac crest bone and BioOss. Surface topography of microimplants was characterized using interferometry. Loaded microimplants (MsL) were immobilized in a provisional bridge supported by four normal size implants. Some patients had unloaded microimplants as controls (MsU). Biopsies were trephined after 2 or 4 months and histomorphometric analysis of bone area (BA) and bone-to-implant contact (BC) was performed. Nonparametric methods for dependent data were used to compare effect of surface modification, and healing time (2 vs. 4 months). RESULTS: A total of 53 biopsies were available from 13 patients. A total of 4/28 and 1/11 MsL failed after resp. 2 and 4 months vs. 0/6 and 1/5 MsU. Many loaded biopsies were damaged at the apical portion and showed no bone adhesion. MsL decreased in BA from coronal to apical from 2 to 4 months; Coronal > Middle (P = 0.047), Coronal > Apical (P < 0.001) and Middle > Apical (P < 0.001). This gradual decrease was not observed for BC; Coronal < Middle and Middle > Apical (P < 0.001). Only the middle part showed significant bone contact after 2 months. For MsL there was no statistically significant difference between surface or time indicating that improvement of osseointegration over time due to maturation of the graft was poor. The MsU did not show any difference between Osseotite and Nanotite for BIC and BA (P > 0.05) but doubled both their BA and BIC (P < 0.05) between 2 and 4 months. CONCLUSIONS: Osseointegration in sinus-grafted bone mixed with BioOss was poor irrespective of healing time or nanotopographical surface modification. The apex of MsL showed minimal bone contact suggesting that the graft does not add to the loading capacity. Surface enhancement was not beneficial despite the enlarged surface area. Overloading, most critical coronally of an implant, increases risks for implant failure and jeopardizes bone healing especially under immediate loading conditions with high load.

Experimental evidence for interfacial biochemical bonding in osseointegrated titanium implants.

OBJECTIVES: (i) To identify and quantify an interfacial biochemical bond and the bonding strength of osseointegrated implants with bioactive titanium oxide chemistry, ATiO(x)B (A, metal cations; TiO(x) , titanium oxides/hydroxides; B, non-metal anions) and (ii) to provide quantitative evidence for the biochemical bond theory of osseointegration proposed by Sul et al. for description and explanation of why and how the implants with ATiO(x) B surface oxide chemistry may exhibit a significantly stronger bone response, in spite of the fact that the roughness values approached zero, or were equivalent to or significantly lower than those of the control implants. MATERIALS AND METHODS: We applied a newly developed biochemical bond measurement (BBM) method to model implant surfaces that were "perfectly" smooth nanotopography near-zero roughness as the constant parameter, and used the bioactive surface chemistry of titanium oxide, ATiOx B chemistry as a variable parameter in rabbit tibiae for 10 weeks. In this manner, we determined an interfacial biochemical bond and quantified its bonding strength. RESULTS: The increase in biochemical bond strengths of the test implant relative to the control implant was determined to be 0.018 (±0.008) MPa (0.031 vs 0.021 MPa, n = 10) for tensile strength and 8.9 (±6.1) Ncm (33.0 vs 24.1 Ncm, n = 10) for removal torque. Tensile and removal torque show strong correlation in the Pearson test (r = 0.901, P ≤ 0.001). In addition, histomorphometric measurements including bone-to-metal-contact (BMC, P = 0.007), bone area and newly formed bone showed significant increases in the mean values for ATiO(x) B chemistry (P = 0.007, n = 10). Biochemical bond theory states that the surface oxide chemistry, ATiO(x) B must have more electrical and chemical molecular polarity that fractionally charges the surfaces denoted as δ(+) and δ(-) and leads to electrostatic and electrodynamic interactions with the bone healing cascade, eventually leading to the formation of biochemical bonding at the bone/implant interface. CONCLUSIONS: The present study has provided quantitative evidence for biochemical bond theory of osseointegration of implants with bioactive surface oxide chemistry, ATiO(x) B. The theory of biochemical bonds may provide a scientific rationale pertinent to recent emerging trends and technologies for surface chemistry modifications of implants.

Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication.

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that binds DNA and assembles co-regulator complexes to regulate gene transcription. GR agonists are widely prescribed to people with inflammatory and autoimmune diseases. Here we present high-resolution, multidomain structures of GR in complex with ligand, DNA and co-regulator peptide. The structures reveal how the receptor forms an asymmetric dimer on the DNA and provide a detailed view of the domain interactions within and across the two monomers. Hydrogen-deuterium exchange and DNA-binding experiments demonstrate that ligand-dependent structural changes are communicated across the different domains in the full-length receptor. This study demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore, provides a platform to build a new level of understanding of how receptor modifications can drive disease progression and offers key insight for future drug design.

Enhanced implant integration with hierarchically structured implants: a pilot study in rabbits.

AIM: To investigate bone-to-implant bonding for some novel surface modifications with a hierarchic structure and to correlate the in vivo results with surface roughness parameters. MATERIALS AND METHODS: Newly developed implants surfaces were tested in rabbits and compared with the commercially available OsseoSpeed™ (OS) implant. The blasted test samples were subjected to treatment in oxalic acid (AT-II), followed by subsequent etching in hydrofluoric acid (AT-I). Scanning electron microscopy and X-ray photoelectron spectroscopy were used to characterize the surface topography and chemical composition of the implants. Biomechanical testing after 6 weeks of healing was complemented with the quantification of fluorochromes and the results were subjected to a multivariate statistical analysis. RESULTS: The results show, both with biomechanical- and with histomorphometrical tests, that the AT-I implants with different surface roughness at the micro (blasting), submicro (shallow cavities) and nanolevels (precipitates) have a greater bone tissue integration compared with the AT-II- and OS implants. The 2D bone-to-implant contact (BIC) data were in accordance with the 3D removal torque (RTQ) results even if the former were deduced from implants located in spongeous-type bone and the latter in cortical bone. The increase in RTQ values for the test samples AT-I and AT-II compared with the reference complies with the slightly higher S(a) values for these surfaces. CONCLUSIONS: Using a combination of conventional methods with novel quantification of florochrome and multivariate analysis, the influence of surface roughness on different levels could be discriminated. The RTQ and BIC values show that the most hierarchical structure with submicro cavities and nanoscale precipitates possesses the most favourable osseointegration properties.

The biological response to three different nanostructures applied on smooth implant surfaces.

OBJECTIVE: To evaluate the biological effects of three calcium phosphate (CaP) coatings with nanostructures on relatively smooth implant surfaces. MATERIAL AND METHODS: Stable CaP nanoparticle suspensions of different particle sizes and structures were coated onto implants by immersion and subsequent heat treatment. An uncoated implant was used as the control. After topographical and chemical characterizations, implants were randomly inserted into rabbit tibiae for removal torque (RTQ) testing. To confirm the biological reaction, implants were placed in the bilateral femurs of three rabbits. RESULTS: The topographical characterization showed that each surface had different nanostructural characteristics and X-ray photon spectroscopy showed various CaP compositions. The control and test groups had different nanotopographies; however, the differences among the test groups were only significant for Surfaces B and C and the rest were insignificant. The RTQ tests showed significantly higher values in two test groups (Surface A and Surface C). Histologically, no adverse effects were seen in any group. Histomorphometrical evaluation showed comparable or better osseointegration along the implant threads in the test groups. CONCLUSION: The three different CaP coatings with nanostructures on the implant surfaces had enhancing effects on osseointegration. Along with the surface nanotopography, the CaP chemistry might have influenced the biological outcomes.

The effect of calcium ion concentration on the bone response to oxidized titanium implants.

AIM: To investigate the effect of calcium concentration on the bone tissue response to Ca-incorporated titanium implants. MATERIALS AND METHODS: Two titanium surfaces containing 4.2% and 6.6% calcium were prepared using the micro-arc oxidation process. The implants were inserted in the tibia of nine New Zealand White rabbits. After 6 weeks of healing, the bone response to the implants was quantitatively compared by biomechanical and histomorphometrical measurements. RESULTS: Ca 4.2% and Ca 6.6% containing implants revealed no distinctive differences in their qualitative surface chemistry; chemical bonding state of Ca in titanium oxide was mainly calcium titanates. No significant differences were observed between two implants in peak removal torque and shear strength comparisons (P>0.05). Histomorphometrical analyses presented no significant differences in bone-metal contact, bone area and newly formed bone measurements between two implants (P>0.05). CONCLUSIONS: From biomechanical and histomorphometrical measurements, the two calcium concentrations in this study did not differ significantly with respect to their influence on the bone tissue response. This similar bone response in rabbit tibiae may be explained by the similarity of the qualitative Ca chemistry in titanium surfaces.

Chronic pain in older adults: a controlled pilot trial of a brief cognitive-behavioural group treatment.

BACKGROUND: Chronic pain is a common condition among older adults. While cognitive behaviour therapy (CBT) has been tested in numerous studies on adults and children there are fewer studies on older persons. The objective of this study was to investigate the effects of a six-session CBT group treatment for older persons with chronic pain. As a secondary aim we investigated whether treatment credibility was associated with outcome. METHOD: We included 21 persons (mean age = 72.0 years) who were randomly allocated to either a waitlist condition or treatment consisting of applied relaxation, with the addition of problem solving, assertiveness, communication strategies, sleep management, and relapse prevention. RESULTS: Few statistically significant effects were found on measures of pain, mood, anxiety, and quality of life; however, a significant treatment effect with a between group effect size of d = 1.0 was observed with respect to perceived ability to function despite the discomfort of pain. CONCLUSION: The study provides some preliminary support for the use of group-based CBT with a focus on applied relaxation for older adults with chronic pain.

Biopsies from the Distal Radius after Implantation of Calcium Phosphate Cement.

Background: Calcium Phosphate (CaP) bone cement is gradually replaced by new bone when used as a gap-filler. Details of the re-modelling process are still unclear. Uncertainty is also present as to the possible release of cement particles during the resorption phase causing local soft tissue reactions. The objective of this study was to perform a comprehensive histological investigation of the injectable CaP bone cement used as a void filler in corrective radius osteotomies and adjacent tissue reactions. Methods: Fourteen patients, median age 56 years (18-72), 4 men/10 women, underwent removal of distal radius plates (11 dorsal/3 volar) due to tenosynovitis-like symptoms. Eleven study patients went through corrective osteotomies with CaP bone cement and three were control patients. Previous surgery in three controls consisted in (1) corrective osteotomy with bone graft (dorsal plate), and (2) plated distal radius fractures (1 dorsal/1 volar plate). Biopsies were taken of bone-cement-bone junctions (11), bone-bone graft-bone junctions (1), bone (2) and juxtaposing soft tissue (14). The interval from corrective CaP cement surgery to biopsy was median 1.1 (0.6-2.3) years. Results: Biopsies of bone-cement junctions showed the different stages of new bone formation from CaP to immature bone and later mature well-organised bone. The cement showed signs of osteoclast-mediated resorption. Cement particles, macrophages, multinucleated giant cells (MNGC) and plasma cells were observed in most soft tissue biopsies. MNGC with internalised particles were seen. Macrophages were found along and/or within tendon sheaths in all patients in both groups, but rarely containing cement particles. Conclusions: Gradual re-modelling of the cement into well-organised bone was observed confirming osteoclast-osteoblast coupling. There was no indication that cement particles were the cause of the tenosynovitis-like symptoms.

Gender differences in caregiver's use of spoken language with young children who are hard-of-hearing.

PURPOSE: Shared parenting among caregivers of different gender is common in the Swedish society. It is unclear if this includes shared contribution for children's language development. The objective of this cross-sectional study was to explore the natural language environment of children who were hard-of-hearing compared to typically hearing controls. METHODS: Seventy-two families with children aged 7-35 months participated; 22 children who were hard-of-hearing (Cochlear implants, n=11; Hearing aids, n=11) and 50 controls with typical hearing. The majority of caregivers had higher education background level, especially in the control group. Families conducted a daylong recording with the Language Environment Analysis technology, when both parents were present at home. An Interpreted Time Segmental analysis was performed to extract information about female versus male caregivers quantitative word use. RESULTS: The results showed significant gender differences related to number of adult words, with less male words than female words (p <0.001). Male caregivers of children who were hard-of-hearing contributed with around 27 % of adult words during the recordings while males in the control group contributed with 37 %. There was a larger variation in number of female words in the study group than for controls, especially in mothers of children with cochlear implants. CONCLUSIONS: Female caregivers talk significantly more close to young children than male caregivers, and especially in the subgroup of children with cochlear implants. Children who are hard-of-hearing are dependent on a rich language environment, and might be especially vulnerable if male caregivers are less involved as language facilitators. More studies are needed to explore caregiver gender differences, both related to quantitative and qualitative language stimulation.

Discovery by Virtual Screening of an Inhibitor of CDK5-Mediated PPARγ Phosphorylation.

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the ob/ob diabetic mouse model.

Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.

Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC50, 1.5 nM in vitro) and selectivity (>450-fold vs thyroid peroxidase in vitro), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2b/3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

Principal component analysis: a novel analysis to evaluate the characteristics of osseointegration of different implant surfaces.

OBJECTIVE: To apply a new statistical method (principle component analysis; PCA) to evaluate osseointegration. MATERIALS AND METHODS: Two different commercially available implants were selected for the study. Twenty implants, 10 of each type, were placed in the rabbit tibiae (n = 10). The fluorochromes (FLCs) alizarin complexone and calcein green were administered after 20 days and 4 days before sacrifice for labeling. On the day of implantation and retrieval (6 weeks), implant stability was measured with a resonance frequency analyzer (RFA). The retrieved samples were ground sectioned for histomorphometric and FLC quantification. The collected data were analyzed by a PCA software program (Qlucore Omics Explorer, Lund, Sweden) to explore and determine the correlation between different study variables and to analyze the differences between different implants. RESULTS: The RFA presented no significant differences at either time point. The bone-to-implant contact was significantly higher for the TiUnite (NobelBiocare, Gothenburg, Sweden); however, the bone area and FLC quantification showed higher values for the Osseotite (3i Implant Innovation, FL). Consistent with these results, the PCA indicated a strong correlation between TiUnite and high bone-to-implant contact values and between Osseotite and high bone area and FLC values. No correlation between RFA and the biological responses were found. CONCLUSION: The application of the PCA analysis may help interpret and correlate results obtained from numerous evaluations.