Bone tissue engineering in osteoporosis

Osteoporosis is a polygenetic, environmentally modifiable disease, which precipitates into fragility fractures of vertebrae, hip and radius and also confers a high risk of fractures in accidents and trauma. Aging and the genetic molecular background of osteoporosis cause delayed healing and impair regeneration. The worldwide burden of disease is huge and steadily increasing while the average life expectancy is also on the rise. The clinical need for bone regeneration applications, systemic or in situ guided bone regeneration and bone tissue engineering, will increase and become a challenge for health care systems. Apart from in situ guided tissue regeneration classical ex vivo tissue engineering of bone has not yet reached the level of routine clinical application although a wealth of scaffolds and growth factors has been developed. Engineering of complex bone constructs in vitro requires scaffolds, growth and differentiation factors, precursor cells for angiogenesis and osteogenesis and suitable bioreactors in various combinations. The development of applications for ex vivo tissue engineering of bone faces technical challenges concerning rapid vascularization for the survival of constructs in vivo. Recent new ideas and developments in the fields of bone biology, materials science and bioreactor technology will enable us to develop standard operating procedures for ex vivo tissue engineering of bone in the near future. Once prototyped such applications will rapidly be tailored for compromised conditions like vitamin D and sex hormone deficiencies, cellular deficits and high production of regeneration inhibitors, as they are prevalent in osteoporosis and in higher age.     

[18F]-JK-PSMA-7 PET/CT Under Androgen Deprivation Therapy in Advanced Prostate Cancer

Purpose

PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [¹⁸F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [¹⁸F]-JK-PSMA-7 under ADT.

Procedures

We examined the performance of [¹⁸F]-JK-PSMA-7 in 70 patients (first cohort) with increasing or detectable PSA values under ADT (PSA < 2 ng/ml for 21/70 patients). We further analyzed 58 independent patients with PSA levels < 2 ng/ml under ADT, who were imaged with [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL (second cohort). Finally, we compared detection rates between [¹⁸F]-JK-PSMA-7, [⁶⁸Ga]PSMA-11, and [¹⁸F]DCFPyL.

Results

In the first cohort, we detected [¹⁸F]-JK-PSMA-7-positive lesions in 63/70 patients. In patients with PSA levels ≥ 2 ng/ml, the detection rate was 100 % (49/49). In patients with PSA < 2 ng/ml, the detection rate was significantly lower (66.7 %, 14/21, p = 9.7 × 10^?5) and dropped from 85.7 % (12/14, PSA levels between 0.3 and 2.0 ng/ml) to 28.6 % (2/7) for PSA levels < 0.3 ng/ml (p = 1.73 × 10^?2). In the second cohort (PSA < 2 ng/ml), the detection rate was 79.3 % (46/58) for [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL. Again, the detection rate was significantly higher (p = 1.1 × 10^?2) for patients with PSA levels between 0.3 and 2.0 ng/ml (87.0 %, 40/46) relative to those with PSA levels < 0.3 ng/ml (50 %, 6/12). No significant difference was found between [¹⁸F]-JK-PSMA-7 and [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL in patients with PSA levels < 2 ng/ml (p = 0.4295).

Conclusion

[¹⁸F]-JK-PSMA-7 PET showed a high detection rate in patients with PSA levels ≥ 0.3 ng/ml under ADT. The lower PSA threshold of 0.3 ng/ml for high detection rates was consistent across the three PSMA ligands. Thus, PSMA imaging is suitable for clinical follow-up of patients with increasing PSA levels under ADT.

     

G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade

OBJECTIVES: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity. METHODS: We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay). RESULTS: With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect. CONCLUSION: According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.     

Effect on enamel shear bond strength of adding microsilver and nanosilver particles to the primer of an orthodontic adhesive

Background

The objective of this study was to determine whether the addition of microsilver or nanosilver particles to an orthodontic primer affects shear bond strength (SBS) and bracket/adhesive failure.

Methods

Bovine incisors were randomly divided into six groups with 16 specimens in each: In group 1 (control), brackets were bonded with Transbond? XT primer. In the experimental groups, microsilver (groups 2 and 3) and nanosilver (groups 4–6) particles of different sizes were added to Transbond XT primer and light cured for 15 seconds [group 2: 0.1% (w/w) microsilver particle size 3.5–18 μm; group 3: 0.3% (w/w) microsilver particle size 3.5–18 μm; group 4: 0.11% (w/w) nanosilver particle size 12.6–18.5 nm; group 5: 0.18% (w/w) nanosilver particle size 12.6–18.5 nm; group 6: 0.33% (w/w) nanosilver particle size 12.6–18.5 nm]. Thereafter, brackets were bonded by light curing the adhesive for 20 seconds. After 24 hours of storage in distilled water at 37°C, SBS was measured with a Zwicki 1120 testing machine. The adhesive remnant index and the prevalence of silver spots on the specimen surface were determined under 10× magnification. Statistical two-way analysis of variance was performed to compare SBS, and a chi-square test was used to compare ARI scores and the prevalence of silver spots.

Results

No significant differences in SBS (control: 16.59?±?6.82 MPa; group 2: 20.6?±?4.19 MPa; group 3: 16.98?±?4.84 MPa; group 4: 17.15?±?5.92 MPa; group 5: 20.09?±?3.35 MPa; group 6: 16.44?±?4.51 MPa; p?>?0.665) and ARI scores (p?=?0.901) were found between the control group and any experimental group. Only experimental groups with nanosilver particles revealed statistically more silver spots on the remaining adhesive.

Conclusions

Addition of small concentrations of microsilver or nanosilver particles affects neither SBS nor ARI scores. Addition of nanosilver particles results in silver spots in the remaining primer visible under 10× magnification. Further studies are needed to investigate the anti-caries potential and clinical performance of conventional orthodontic primer with incorporated nanosilver or microsilver particles.

     

Control strategies for active lower extremity prosthetics and orthotics: a review

Technological advancements have led to the development of numerous wearable robotic devices for the physical assistance and restoration of human locomotion. While many challenges remain with respect to the mechanical design of such devices, it is at least equally challenging and important to develop strategies to control them in concert with the intentions of the user.This work reviews the state-of-the-art techniques for controlling portable active lower limb prosthetic and orthotic (P/O) devices in the context of locomotive activities of daily living (ADL), and considers how these can be interfaced with the user’s sensory-motor control system. This review underscores the practical challenges and opportunities associated with P/O control, which can be used to accelerate future developments in this field. Furthermore, this work provides a classification scheme for the comparison of the various control strategies.As a novel contribution, a general framework for the control of portable gait-assistance devices is proposed. This framework accounts for the physical and informatic interactions between the controller, the user, the environment, and the mechanical device itself. Such a treatment of P/Os – not as independent devices, but as actors within an ecosystem – is suggested to be necessary to structure the next generation of intelligent and multifunctional controllers.Each element of the proposed framework is discussed with respect to the role that it plays in the assistance of locomotion, along with how its states can be sensed as inputs to the controller. The reviewed controllers are shown to fit within different levels of a hierarchical scheme, which loosely resembles the structure and functionality of the nominal human central nervous system (CNS). Active and passive safety mechanisms are considered to be central aspects underlying all of P/O design and control, and are shown to be critical for regulatory approval of such devices for real-world use.The works discussed herein provide evidence that, while we are getting ever closer, significant challenges still exist for the development of controllers for portable powered P/O devices that can seamlessly integrate with the user’s neuromusculoskeletal system and are practical for use in locomotive ADL.     

Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis

Polyreactive innate-type B cells account for many B cells expressing self-reactivity in the periphery. Improper regulation of these B cells may be an important factor that underlies autoimmune disease. Here we have explored the influence of self-reactive innate B cells in the development of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis. We show that splenic marginal zone (MZ), but not B-1 B cells exhibit spontaneous IgM reactivity to autologous collagen II in naïve mice. Upon immunization with heterologous collagen II in complete Freund''s adjuvant the collagen-reactive MZ B cells expanded rapidly, while the B-1 B cells showed a modest anti-collagen response. The MZ B cells were easily activated by toll-like receptor (TLR) 4 and 9-ligands in vitro, inducing proliferation and cytokine secretion, implying that dual engagement of the B-cell receptor and TLRs may promote the immune response to self-antigen. Furthermore, collagen-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitro and induction of IgG anti-collagen antibodies in vivo. MZ B cells that were deficient in complement receptors 1 and 2 demonstrated increased proliferation and cytokine production, while Fcγ receptor IIb deficiency of the cells lead to increased cytokine production and antigen presentation. In conclusion, our data highlight self-reactive MZ B cells as initiators of the autoimmune response in CIA, where complement and Fc receptors are relevant in controlling the self-reactivity in the cells.