Roles of the kallikrein/kinin system in the adaptive immune system

This review deals with the effects of kinins, a family of octa- to decapeptides structurally related to bradykinin (BK), in adaptive immune responses. Herein, we discuss the experimental evidence that kinins may exert influence on multiple players of the immune system (i.e. macrophages, dendritic cells, T and B lymphocytes), and modulate the activation, proliferation, migration and effector functions of these cells. We also give an overview of the possible impact of kinins in human autoimmune diseases and corresponding animal models, with special emphasis on autoimmune neuroinflammation and arthritis. These studies indicate a possible immunomodulatory capacity of kinins beyond our current knowledge of kinin actions regarding the vascular system, and thus the way towards future therapeutic approaches.     

A pilot study of risk-based prevention in private practice

BACKGROUND: Risk-based prevention is a means of ensuring that patients receive preventive treatment appropriate for their risk of disease. While straightforward, its application in private practice has not been examined. METHODS: Volunteer clinicians in 15 offices participated in a six-month pilot study to test methods for a larger, risk-based prevention demonstration study operated by a dental insurer. Concomitant with oral examinations for patients of this insurer, clinicians identified patients at elevated risk of developing dental caries and periodontitis. For these patients, the reasons for elevated risk (risk indicators), as well as planned preventive treatment in response to that risk, were recorded and transmitted to the insurer via the claim form. RESULTS: The clinicians identified relatively small percentages of patients as being at high risk of developing caries (4 percent) and periodontitis (7 percent), with little variation across the 15 offices. Larger proportions of patients were identified as being at moderate risk of developing caries (29 percent) and periodontitis (30 percent), with more extensive variation across offices. In general, patients classified as being at elevated risk had received more disease-related treatment than patients at low risk before the classification, which provided some validation for the accuracy of risk assessment. CONCLUSIONS: The results of this pilot study suggest that formal, risk-based prevention can be accomplished in dental offices. Clinicians' reported risk assignments and indicators, together with their planned preventive treatments, demonstrate a good understanding of risk-based prevention. CLINICAL IMPLICATIONS: Researchers may need to clarify the criteria used to assess moderate risk of developing dental caries, and clinicians may need to emphasize greater use of fluorides and more frequent recall visits for adults at elevated risk of developing dental caries.     

Risk indicators for posterior tooth fracture

BACKGROUND: Identifying posterior teeth that are at heightened risk of developing cusp fracture is an inexact science. Risk indicators based on controlled observations are not available, and dentists' assessments vary. METHODS: The authors conducted a case-control study of cusp fracture in restored posterior teeth. They evaluated 39 potential risk indicators identified in previous uncontrolled studies for an association with fracture in 200 patients with fractures and 252 patients without fractures. These risk indicators delineated patients' clinical characteristics and behaviors, as well as clinical characteristics of individual teeth. The authors used logistic regression to develop models identifying risk indicators associated with fracture, both between case and control subjects and between case and comparison teeth in case subjects. RESULTS: Two risk indicators appeared in both models. The presence of a fracture line and an increase in the proportion of the volume of the natural tooth crown occupied by the restoration substantially increased the odds of fracture (P < .001). Additional risk indicators were unique to the case subject-control subject model, including subject age and other measures related to the relative size of the restoration or to loss of dentinal support. Neither patient behaviors such as clenching, grinding and biting hard objects nor occlusal characteristics such as guidance, cusp anatomy and general wear patterns were strong predictors of fracture risk. CONCLUSIONS: Among posterior teeth with restorations, two clinical features were strongly associated with the risk of cusp fracture: presence of a fracture line in the enamel and proportional volume of the restoration. CLINICAL IMPLICATIONS: Dentists assessing the risk of fracture should consider a detectable fracture line or a high ratio of restoration-to-total-crown volume as important indicators of elevated risk.     

Tempromandibular joint (TMJ) response to intra-articular dexamethasone injection following mechanical arthropathy: a histological study in rats

The purpose of this study was to evaluate as well as to compare the effect of intra-articular versus intra-peritoneal injection of dexamethasone on synovitis induced by trauma to the rat's TMJ. Twenty-seven male Wister rats were included in the present study. Induced forced condylar hypermobility achieved through opening the rat's mouth manually 10 times for 10 consecutive days. Rats were randomized into three groups (3 rats in the control group, and 24 rats in both experimental groups). Group I (control group): Rats of this group were left without any treatment after induction of synovitis. Group II: Rats were injected with a single dose of 1.2 mg/kg dexamethasone intra-articularly (after 10 days). Group III: Rats were injected with a single intra-peritoneal injection of 1.2 mg/kg dexamethasone (after 10 days). Control rats were sacrificed at 6 weeks, while rats in Groups II and III were sacrificed at 1 and 6 weeks after drug injection, then joints were dissected and processed for histological study. The condylar head of the rats injected with intra-articular dexamethasone showed resorption with active osteoclastic activity, although the drug was given only once. This might be an alarming sign of the severe adverse effect(s) of the local injection of dexamethasone.     

The influence of different cultivation conditions on the metabolic functionality of encapsulated primary hepatocytes

The clinical application of bioartificial liver support systems (BALS) is still limited because of technical problems associated with the storage, transport and scale-up of common systems. The encapsulation of primary hepatocytes could solve these problems since the scale-up depends only on the number of the beads and encapsulation leads to protection of the cells during the process of freezing and thawing. Many efforts have been made to find an appropriate material for the encapsulation of primary hepatocytes in terms of mechanical resistance as well as appropriate bio- and hemo-compatibility. This study focuses on the improvement of the metabolic functionality of encapsulated primary hepatocytes. A comparison between two different cultivation models showed that dynamic cultivation conditions lead to a 20.4-fold increase in the albumin production and a 5.21-fold increase in the urea synthesis of encapsulated hepatocytes. Furthermore, the influence of different ratios of the number of the cells to the volume of the media was analyzed. Encapsulated hepatocytes cultured with a high amount of medium were characterized by a significantly higher metabolic activity compared to encapsulated hepatocytes cultured with a low level of medium. Interestingly, the cell concentration per mL alginate has no significant influence on the metabolic activity of encapsulated hepatocytes. In conclusion, different optimization strategies are discussed and, finally, the functionality of encapsulated hepatocytes is compared to the standard model of hepatocyte culture, the collagen sandwich.     

KIF16B is a candidate gene for a novel autosomal‐recessive intellectual disability syndrome

Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%–3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease‐causing variant (16%–55%), with the genetic involvement increasing as intelligence quotient decreases. WES has also accelerated novel disease gene discovery in this field. We identified a novel biallelic variant in the KIF16B gene (NM_024704.4:c.3611T > G) in two brothers that may be the cause of their phenotype.     

Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model

Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the “2-pathway” stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4⁺?FoxP3⁺ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic.