Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for ...sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.
Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of ...antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans.
•Local resonances of metamaterial panels lead to further sound absorption improvement.•Effective medium method is used to model finite metamaterial panels.•Full multiphysical simulation model ...considers vibroacoustic coupling and end effects.
To further improve the sound absorption enhancement of flexible micro-perforated panels (FMPPs), a new sort of perforated sound absorbers – metamaterial-based micro-perforated panels (MMPPs) – is proposed by combining a micro-perforated host panel and local resonators (LRs) attached on a sub-wavelength scale, targeting the flexural waves. Theoretical and numerical models show that MMPPs are able to further enhance sound absorption in a wide frequency range. The theoretical model is developed based on the effective medium method as the structural wavelength in the host panel is much larger than the distance between the LRs, and the full simulation model, including visco-thermal effects, is conducted by utilizing multi-physical coupling integrated in COMSOL. Besides, a structural finite element unit cell method is used to evaluate the stop band behavior of the MMPP. Good agreement is achieved between the theoretically predicted acoustical properties and the simulation results for both conventional FMPPs and the proposed MMPPs, validating the numerical and theoretical models. Both models reveal that the sound absorption enhancement of the MMPP stems from the resulting acoustic surface impedance improvement, caused by the sub-wavelength attached local resonances. The effect of key properties of the LRs (i.e. mass, damping and multiple resonances) on the sound absorption performance of MMPPs is then analyzed by applying the theoretical model and effective frequency-adjustability of the absorption enhancement performance is found. The proposed MMPP shows great potential for the noise reduction industry.
Anterior cruciate ligament (ACL) injury is an important risk factor for development of knee osteoarthritis (OA). To identify those ACL injured patients at increased risk for knee OA, it is necessary ...to understand risk factors for OA.
To summarise the evidence for determinants of (1) tibiofemoral OA and (2) patellofemoral OA in ACL injured patients.
MEDLINE, EMBASE, Web of Science and CINAHL databases were searched up to 20 December 2013. Additionally, reference lists of eligible studies were manually and independently screened by two reviewers. 2348 studies were assessed for the following main inclusion criteria: ≥20 patients; ACL injured patients treated operatively or non-operatively; reporting OA as outcome; description of relationship between OA outcome and determinants; and a follow-up period ≥2 years. Two reviewers extracted the data, assessed the risk of bias and performed a best-evidence synthesis.
Sixty-four publications were included and assessed for quality. Two studies were classified as low risk of bias. Medial meniscal injury/meniscectomy showed moderate evidence for influencing OA development (tibiofemoral OA and compartment unspecified). Lateral meniscal injury/meniscectomy showed moderate evidence for no relationship (compartment unspecified), as did time between injury and reconstruction (tibiofemoral and patellofemoral OA).
Medial meniscal injury/meniscectomy after ACL rupture increased the risk of OA development. In contrast, it seems that lateral meniscal injury/meniscectomy has no relationship with OA development. Our results suggest that time between injury and reconstruction does not influence patellofemoral and tibiofemoral OA development. Many determinants showed conflicting and limited evidence and no determinant showed strong evidence.
To enhance the sound insulation performance of double panel partitions at their mass-air-mass resonance frequency, novel compact and low-mass solutions are sought. This paper investigates the use of ...the locally resonant vibro-acoustic metamaterial concept as a possible solution. The metamaterial solution is applied to one panel of a double panel partition in order to enhance the sound transmission loss at the mass-air-mass resonance. To design the metamaterial solution and predict its sound transmission loss performance, an extension of the multiple reflection theory is proposed, incorporating the dynamic mass of a metamaterial panel. The latter is obtained from the metamaterial plate dispersion curves, calculated using finite element based unit cell modeling. The designed metamaterial solution is manufactured and its insertion loss is measured. The novel design outperforms the original double panel and an equivalent total mass double panel configuration in the targeted mass-air-mass resonance frequency region. The predictions obtained with the proposed method are in good agreement with the experimentally obtained results. This demonstrates the potential of the metamaterial solution to enhance the acoustic insulation at the mass-air-mass resonance and indicates that the proposed method allows a fast, simple and representative indication of their acoustic insulation performance.
•Double panel STL is enhanced at the mass-air-mass frequency using locally resonant metamaterials.•A unit cell based dynamic mass calculation based on the dispersion curves is proposed.•Fast STL prediction method is proposed using the multiple reflection theory combined with the dynamic mass.•A transparent metamaterial double panel partition is designed, manufactured and tested experimentally.•Good agreement between proposed method and experimental results.
It remains unclear how interleukin-21 receptor (IL-21R) contributes to type 1 diabetes. Here we have shown that dendritic cells (DCs) in the pancreas required IL-21R not for antigen uptake, but to ...acquire the chemokine receptor CCR7 and migrate into the draining lymph node. Consequently, less antigen, major histocompatibility complex (MHC) class II, and CD86 was provided to autoreactive effector cells in Il21r−/− mice, impairing CD4+ T cell activation, CD40:CD40L interactions, and pancreatic infiltration by autoreactive T cells. CD40 crosslinking restored defective CD4+ cell expansion and CD4 independently expanded autoreactive CD8+ cells, but CD8+ cells still required CD4+ cells to reach the pancreas and induce diabetes. Diabetes induction by transferred T cells required IL-21R-sufficient host antigen-presenting cells. Transferring IL-21R-sufficient DCs broke diabetes resistance in Il21r−/− mice. We conclude that IL-21R controls both antigen transport by DCs and the crucial beacon function of CD4+ cells for autoreactive CD8+ cells to reach the islets.
► Il21r−/− DCs fail to acquire CCR7 and MHC II upon antigen uptake in the pancreas ► Antigen shuttling from the pancreas to the draining LN is impaired in Il21r−/− mice ► CD4+ T cells need IL-21R to assist CD8+ T cells to infiltrate pancreatic islets ► CD40 stimulation and IL-21R+ DCs break diabetes resistance in Il21r−/− mice
Vitamin D is a steroid hormone that is acquired via diet or synthesized in the skin upon UV exposure and needs subsequent hydroxylation steps to become activated as 1,25-dihydroxyvitamin D. While ...widely known for its role in maintaining bone health, vitamin D receptors have also been identified in different immune cell types. Many immune cells can also convert vitamin D into its bioactive form, thus enhancing the locally available concentrations to those required for the immunomodulatory effects of vitamin D. In this review, we summarize the genetic and epidemiologic data potentially linking vitamin D to autoimmune, infectious and allergic diseases. We also discuss how vitamin D influences the immune responses in each of those conditions based on the data generated using patient samples or preclinical models of each of these diseases.
Background:
Semitendinosus and gracilis tendons may regenerate after harvesting for ligament reconstruction procedures. However, predictive factors of tendon regeneration and the extent of functional ...recovery remain unclear.
Purpose:
To identify predictive factors for hamstring tendon regeneration and to examine the morbidity of nonregenerated hamstring tendons.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
Of the 154 patients who were included in a prospective follow-up study, 79 underwent reconstruction of the anterior cruciate ligament entailing the hamstring tendons and met the following inclusion criteria: (1) anterior cruciate ligament rupture diagnosed by physical examination and magnetic resonance imaging (MRI), (2) MRI within 6 months after trauma, (3) age between 18 and 45 years, and (4) 2-year follow-up MRI data available. Hamstring tendon regeneration was assessed as complete if a tendon-like structure could be visualized at the level of the joint line or more cranially. Patient characteristics—such as age, sex, body mass index, alcohol/nicotine use, activity level (Tegner scores), and functional instability (1-legged hop test)—were evaluated preoperatively and at 2 years to determine predictive factors for tendon regeneration or examine functional recovery of hamstring tendon regeneration.
Results:
At 2 years’ follow-up, 67.1% of the patients showed regeneration of semitendinosus tendons, 81.0% of gracilis tendons, and 59.5% of both tendons. The likelihood of semitendinosus tendon regeneration significantly decreased with aging (odds ratio OR, 0.92 change per year of age; 95% CI, 0.84-0.99; P = .03) and smoking (OR, 0.20; 95% CI, 0.05-0.77; P = .02). No predictive factor was found for gracilis tendon regeneration. Regeneration of the semitendinosus and gracilis tendons was negatively related with smoking (OR, 0.22; 95% CI, 0.06-0.79; P = .02). Patients without regeneration showed similar postoperative visual analog scale scores during physical activity, similar Tegner scores, and a significant decrease of the upper leg circumference, as compared with their preoperative results. Regardless of the regeneration status, 1-legged hop test results significantly increased at 2-year follow-up.
Conclusion:
Hamstring tendon regeneration occurs less frequently in older patients and in smokers. However, absence of regenerated tendons does not seem to cause a loss of function.
The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the ...treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4+ CD25high CD127low regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D3 1,25(OH)2D3 and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4+ CD25high CD127low regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH)2D3 and TX527 treatment inhibit the production of effector cytokines IFN-γ, IL-9, and IL-17. Importantly, 1,25(OH)2D3 and TX527 promote the induction of IL-10-producing CD4+ CD25high CD127low T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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