Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a pathological condition that involves diffuse lung injury and severe hypoxemia caused by pulmonary and systemic diseases. We have established a mouse model of severe ARDS, developed by intratracheal injection of α-galactosylceramide (α-GalCer), an activator of natural killer T (NKT) cells, followed by LPS. In the present study, we used this model to investigate the regulatory mechanism in the early inflammatory response during acute lung injury. In α-GalCer/LPS-treated mice, the number of CD4+ CD25+ Foxp3+ regulatory T (Treg) cells and the expression of a Treg cell-tropic chemokine, secondary lymphoid-tissue chemokine (SLC), in the lungs was significantly lower than in mice treated with LPS alone. Giving recombinant (r)SLC increased the number of Treg cells in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced the expression of SLC and the accumulation of Treg cells in the lungs of α-GalCer/LPS-treated mice, whereas giving recombinant (r)IFN-γ reduced the number of Treg cells in mice treated with LPS alone. IL-10 production was significantly lower in α-GalCer/LPS-treated mice than in mice treated with LPS alone. Giving rIL-10 prolonged survival and attenuated lung injury as a result of reduced production of inflammatory cytokines (such as IL-1ß, IL-6, TNF-α, and IFN-γ) and chemokines (including MCP-1, RANTES, IP-10, Mig, MIP-2, and KC) in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced IL-10 production in α-GalCer/LPS-treated mice. These results suggest that the attenuated accumulation of Treg cells may be involved in the development of severe ARDS through a reduction in the synthesis of IL-10.

Outcome of the Sauvé-Kapandji procedure for distal radioulnar joint disorder with rheumatoid arthritis or osteoarthritis: Results of one-year follow-up.

OBJECTIVES: We performed the Sauvé-Kapandji procedure for treating disorders of the distal radioulnar joint (DRUJ) in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). This study aimed to compare and clarify the results of the SK procedure between RA and OA patients. We report the one-year follow-up results of patients who underwent the SK procedure to correct the DRUJ disorder caused by RA or OA. METHODS: The study included 22 wrists of 19 patients with RA and 10 wrists of nine patients with OA. Pain, grip strength and range of motion of the wrist were examined clinically. For the evaluation of the stability of the carpus, ulnar stump and bone union, parameters were measured using radiographs. Shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH) was used for functional evaluation. RESULTS: Wrist pain reduced in all cases, and bone union was achieved in all wrists. The QuickDASH score significantly improved in both patients with RA and OA. In patients with RA, the range of motion increased significantly with regard to supination but decreased significantly with regard to palmar flexion. Carpal alignment and ulnar stump stability were maintained well at one-year follow-up. CONCLUSION: The Sauvé-Kapandji procedure for treating disorders of the distal radioulnar joint DRUJ showed good results clinically and radiographically, irrespective of RA or OA.

Dectin-2-dependent host defense in mice infected with serotype 3 Streptococcus pneumoniae.

BACKGROUND: Streptococcus pneumoniae, a major causative bacterial pathogen of community-acquired pneumonia, possesses a thick polysaccharide capsule. Host defense against this bacterium is mediated by activation of innate immune cells that sense bacterial components. Recently, C-type lectin receptors (CLRs) have garnered much attention in elucidating the recognition mechanism of pathogen-derived polysaccharides. METHODS: In the present study, we first compared the clinical course and neutrophil accumulation in the lungs of Dectin-2 knock-out (KO) and wild type (WT) mice. Mice were infected intratracheally with a serotype 3 strain of S. pneumoniae, and S. pneumoniae bacterial engulfment by neutrophils and inflammatory cytokine and anti-pneumococcal polysaccharide-specific IgG levels were evaluated in bronchoalveolar lavage fluid (BALF). We also examined the effect of Dectin-2 deficiency on interleukin (IL)-12 production by bone marrow-derived dendritic cells (BM-DCs) stimulated with the bacterial components. RESULTS: S. pneumonia-infected Dectin-2KO mice had a shorter survival time, larger bacterial burden and lower interferon gamma (IFN-γ) production in the lungs than WT mice. Although neutrophilic infiltration in the lungs was equivalent between Dectin-2KO mice and WT mice, S. pneumonia engulfment by neutrophils was attenuated in Dectin-2KO mice compared to WT mice. The anti-pneumococcal polysaccharide-specific IgG and IgG3 levels in BALF were lower in Dectin-2KO mice than in WT mice. When BM-DCs were stimulated with S. pneumoniae culture supernatant or its Concanavalin A (ConA)-bound fraction, IL-12 production was abrogated in Dectin-2KO mice compared to WT mice. CONCLUSIONS: We demonstrated that Dectin-2 is intimately involved in the host defense against infection with a serotype 3 strain of S. pneumoniae. Dectin-2-dependent IL-12 production may contribute to IFN-γ synthesis and subsequent production of serotype-specific anti-capsular polysaccharide IgG after S. pneumoniae infection, which may promote S. pneumoniae bacterial opsonization for engulfment.

Etoposide and Corticosteroid Combination Therapy Improves Acute Respiratory Distress Syndrome in Mice.

Excessive inflammation reactions with a cytokine storm in the lungs have historically been thought as the primary cause of fatal acute respiratory distress syndrome (ARDS). However, interruption of inflammatory cytokine activation failed to attenuate ARDS, suggesting that other therapies are required to treat this illness and improve survival. Etoposide (ET), a cytotoxic agent, and prednisolone (PSL), a corticosteroid with strong anti-inflammatory activity, have been used to treat other disease involving similar cytokine-activated macrophages and hemophagocytic activity. However, they have not been previously tested as ARDS therapeutics alone or in combination. In the present study, we used a fatal ARDS mouse model induced via administration of α-galactosylceramide and lipopolysaccharide, which resulted in the development of severe lung injury with hypercytokinemia and hemophagocytosis, all of which were observed in ARDS patients infected with highly pathogenic respiratory viruses. The ET and PSL combination therapy, but not ET or PSL alone, reduced the recruitment and activation of inflammatory cells including macrophages, natural killer T cells, and neutrophils, and significantly improved the survival rate in this model. Furthermore, whereas ET alone improved lung edema, it did not increase the survival rate, indicating the necessity of PSL in the treatment of ARDS. Surprisingly, combination therapy did not reduce the production of cytokines and chemokines in the lungs, demonstrating that inflammatory cells, rather than hypercytokinemia, are the direct target of these compounds and primary cause of ARDS-related death. Thus, combination therapy with ET and PSL that targets inflammatory cells has the potential to attenuate fatal ARDS.

Comparison of Median Nerve Cross-sectional Area on 3-T MRI in Patients With Carpal Tunnel Syndrome.

This study correlated morphologic abnormalities of idiopathic carpal tunnel syndrome (CTS) with the severity of CTS using 3-T magnetic resonance imaging (MRI). The relationship of the severity of CTS and the cross-sectional area of the median nerve (CSA) was assessed at several levels. Seventy wrists of 35 patients (27 women and 8 men) with unilateral idiopathic CTS underwent nerve conduction study and 3-T MRI of the wrist. The CSA at 4 levels (distal radioulnar joint, body of scaphoid, tubercule of scaphoid, and hook of hamate) and the thickness of the transverse carpal ligament at 3 levels in both affected and unaffected hands were measured using 3-T MRI and correlated with the severity of CTS assessed with distal motor latency. The CSA in the affected hand at the scaphoid body level was significantly higher than in the unaffected hand. The CSA at the scaphoid body level was positively correlated with distal motor latency in the affected hand. The CSA in the affected hand at the scaphoid tubercule level was significantly lower than in the unaffected hand. The CSA had a negative correlation with distal motor latency at the scaphoid tubercule level. The CSA at the distal radioulnar joint and the hamate hook was not significantly different between the affected hand and the unaffected hand. The CSA at the distal radioulnar joint level and hook level were not correlated significantly with distal motor latency in the affected hand. The mean CSA of the affected hand at the scaphoid body level was highest in 4 levels. [Orthopedics. 2017; 40(1):e77-e81.].

Computed tomographic features of bilateral coronoid process hyperplasia with special emphasis on patients without interference between the process and the zygomatic bone.

OBJECTIVE: To reveal computed tomography (CT) features of patients with coronoid process hyperplasia without interference between the process and the zygomatic bone. STUDY DESIGN: A case-control study was designed. Thirteen cases without interference (2 male and 11 female, 28-56 years old) and 65 controls were sampled from a patient database. Differences in CT features were analyzed between the 2 groups regarding the following 7 points of 5 regions: configuration of the coronoid process, vertical level of the coronoid process, the distance between the bilateral zygomatic arches, thickness of the temporal muscle, anteroposterior width of the temporal muscle, thickness of the temporal muscle tendon, and thickness of the masseter muscle. Cluster analysis was applied to differentiate between individuals. RESULTS: All cases had bilateral hyperplastic change of the coronoid process. Differences were found between the cases and controls in 6 of 7 CT features with the exception of temporal muscle thickness. All incidences of significant difference showed larger values in the cases. All cases were clustered into the same group and were differentiated from the controls. CONCLUSION: CT features appeared to be effective for diagnosis of this condition, and these patients should be put into the same category under the diagnosis of coronoid process hyperplasia.

Involvement of Gr-1 dull+ cells in the production of TNF-α and IL-17 and exacerbated systemic inflammatory response caused by lipopolysaccharide.

Systemic inflammatory response syndrome (SIRS) is a life-threatening disease. Recent reports have demonstrated that the immunoregulatory cells that express Gr-1, a granulocyte surface antigen, play a critical role in various pathological conditions. In the present study, we have established a mouse model of SIRS and addressed the possible contribution of Gr-1+ cells in this model. C57BL/6 mice were injected intraperitoneally with anti-Gr-1 mAb or control IgG 1 day before administration of lipopolysaccharide (LPS). All of the mice that received anti-Gr-1 mAb and LPS died early as a result of hypothermia and severe emaciation, whereas mice treated with control IgG and LPS survived the observation period. In mice treated with anti-Gr-1 mAb and LPS, acute inflammatory changes with alveolar hemorrhage were observed in the lung and proximal convoluted tubule necrosis was observed in the kidney. Serum TNF-α and IL-17A levels were markedly increased in anti-Gr-1 mAb-pretreated mice compared with those in control IgG-treated mice at 1 and 3 h after LPS administration, respectively. Flow cytometric analysis revealed an increase in TNF-α and IL-17A expression in Gr-1 dull+ cells in the peripheral blood mononuclear cells. Neutralization of TNF-α by a specific mAb almost completely reversed the clinical course and inhibited the increased production of IL-17A. In addition, IL-17A KO mice were less susceptible to the lethality in this model. Thus, we established a mouse model of severe SIRS and suggested that Gr-1 dull+ cells may play a critical role in the development of this pathological condition.

Dectin-2-dependent NKT cell activation and serotype-specific antibody production in mice immunized with pneumococcal polysaccharide vaccine.

Although thymus-independent type 2 antigens generally do not undergo Ig class switching from IgM to IgG, pneumococcal polysaccharide vaccine (PPV) induces the production of serotype-specific IgG. How this happens remains unclear, however. In the present study, PPV immunization induced production of IgG as well as IgM specific for a serotype 3-pneumococcal polysaccharide in the sera of wild-type (WT) mice, but this phenomenon was significantly reduced in Dectin-2 knockout (KO) mice. Immunization with PPV caused IL-12p40 production in WT mice, but this response was significantly reduced in Dectin-2KO mice. Likewise, immunization with PPV activated natural killer T (NKT) cells in WT mice but not in Dectin-2KO mice. Furthermore, administration of α-galactosylceramide, recombinant (r)IL-12 or rIFN-γ improved the reduced IgG levels in Dectin-2KO mice, and treatment with neutralizing anti-IFN-γ mAb resulted in the reduction of IgG synthesis in PPV-immunized WT mice. Transfer of spleen cells from PPV-immunized WT mice conferred protection against pneumococcal infection on recipient mice, whereas this effect was cancelled when the transferred spleen cells were harvested from PPV-immunized Dectin-2KO mice. These results suggest that the detection of PPV antigens via Dectin-2 triggers IL-12 production, which induces IFN-γ synthesis by NKT cells and subsequently the production of serotype-specific IgG.

Palmar plating system for Colles' fractures--a preliminary report.

PURPOSE: To present our results of the palmar plating system that we developed for the treatment of Colles' fractures. METHODS: By using the palmar plating system that we developed a consecutive series of 40 acute Colles' fractures were treated surgically. There were 12 men and 28 women with a mean age of 57 years at the time of the injury (range, 25-90 y). All patients had internal fixation using the trans-flexor carpi radialis tendon approach. The system has 3 main features. First, the plate is small in size, being 1.1 mm in thickness and 47 mm in length. Only a 3- to 4-cm skin incision is required for application of the plate. Second, the screw is cannulated and cancellous in type, with a low-profile head. Subchondral screw fixation is achieved both easily and safely by using a guidewire. Third, the plate has a window through which injectable bone cement can be placed. RESULTS: Union was achieved in all patients. The palmar tilt, radial inclination, radial length, and ulnar variance were maintained after surgery. According to the Gartland and Werley rating scale that was modified by Sarmiento there were 12 excellent and 28 good results. There were no extensor tendon injuries that could occur when the dorsal approach was used. CONCLUSIONS: This palmar plating system can make fixation of the distal radius easy, safe, and effective in the treatment of unstable Colles' fractures.