Inflammatory Bone Loss in Experimental Periodontitis Induced by Aggregatibacter actinomycetemcomitans in Interleukin-1 Receptor Antagonist Knockout Mice

The interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-α) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-κB ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1α mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.     

Up‐regulation of Rac1 in the bronchial smooth muscle of murine experimental asthma

There has been considerable research on the involvement of RhoA/Rho kinase signalling in smooth muscle contractions. However, only a few reports have addressed the specific role of Rac1, which is a member of the Rho GTPase superfamily. Therefore, this study investigated the role of Rac1‐related pathways in bronchial smooth muscle (BSM) contractions. Bronchial rings isolated from mice were suspended in an organ bath, and the isometric contractions of circular smooth muscles were monitored. The phosphorylation of myosin light chains (MLCs) was analysed by immunoblotting. The Rac1 inhibitor EHT1864 inhibited carbachol (CCh)‐induced BSM contractions, although high K⁺ depolarization‐induced BSM contractions were not significantly attenuated by EHT1864. Moreover, high K⁺‐ and phorbol 12,13‐dibutyrate (PDBu; PKC activator)‐induced contractions were not attenuated by Rac1 inhibition, whereas sodium fluoride (NaF)‐induced force development was inhibited by EHT1864. The gene and protein expression of Rac1 was increased in the BSM of a murine model with antigen‐induced airway hyper‐responsiveness (AHR). In addition, an increased force of the BSM contractions in AHR was suppressed by EHT1864 treatment, suggesting that the up‐regulation of Rac1 is involved in AHR. These findings suggest that an increase in Rac1‐mediated signalling is involved in the augmented contractions of BSMs in antigen‐induced AHR mice.     

A case of paracoccidioidomycosis with severe adrenal insufficiency

Paracoccidioidomycosis (PCM) is the most common systemic fungal disease in central-south America, but is rare in Japan. We experiensed a case of PCM in a patient, who came from Bolivia and presented with mouth pain and reduced dietary intake but no fever. Adrenal insufficiency was diagnosed with extremely high serum adrenocorticotropic hormone (ACTH) and was resolved with hormone supplementation. The PCM was treated with trimethoprim-sulfamethoxazole which was switched to itraconazole and improvement was achieved.     

Comparison of short- and long-term outcomes after early versus late liver retransplantation: a single-center experience

Background

As the survival of patients after liver transplantation (LT) improves, the requirement of liver retransplantation (reLT) for late graft failure has grown. Although some have reported that the short-term outcome of late reLT was comparable with that of early reLT, it remains unknown whether long-term survival of late reLT is inferior to that of early reLT patients.

Materials and methods

We reviewed early (<6 mo after primary LT) and late (≥6 mo after primary LT) reLT cases performed between January 2000 and December 2010.

Results

Sixteen early and 32 late reLT cases were analyzed. There was no significant difference regarding the number of units of red blood cells transfused during the transplantation between the groups, whereas operative time was significantly longer in the late reLT cases. Graft loss within 3 mo after early and late reLT was 18.6% and 15.6%, respectively. Patient and graft survival rates after 1, 3, 5, and 10 y in the late reLT group were 80.6%, 73.3%, 73.3%, and 67.7% and 80.7%, 69.1%, 63.3%, and 54.3%, respectively, whereas those in the early reLT group were 75.0%, 75.0%, 64.3%, and 64.3% and 81.3%, 75.0%, 64.3%, and 32.1%, respectively. There was no significant difference in patient or graft survival rates between the groups (P = 0.91 and 0.91, respectively).

Conclusions

Acceptable short- and long-term survival were provided in early and late reLT. The time between the primary LT and reLT does not seem to play significant role in the prognosis of reLT in the long term.     

Fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation

T. Mori, Y. Nakamura, J. Kato, K. Sugita, M. Murata, K. Kamei, S. Okamoto. Fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation.
Transpl Infect Dis 2011. All rights reserved Abstract: Rhodotorula species have been increasingly recognized as emerging pathogens, particularly in immunocompromised patients. We herein report on a patient with myelodysplastic syndrome who developed fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. He developed severe acute graft‐versus‐host disease requiring high‐dose steroids, and had serially been administered fluconazole and micafungin for the prophylaxis of fungal infection. Although several cases of Rhodotorula infection after HSCT have been reported, all of them were recipients of autologous HSCT, not allogeneic HSCT. A review of all the reported cases of Rhodotorula infection after HSCT revealed that all patients had received fluconazole or echinocandins before the onset of infection. The findings suggest that Rhodotorula species could be causative yeasts, particularly in patients receiving fluconazole or echinocandins, both of which are inactive against the species.     

Impact of glutathione S-transferase T1 gene polymorphisms on acute cellular rejection in living donor liver transplantation

It has previously been demonstrated that glutathione S-transferase T1 (GSTT1) genetic mismatch between recipient and donor is a risk factor for developing immune-mediated hepatitis following liver transplantation and for antibody-mediated rejection in renal transplantation. Little is known whether the GSTT1 gene polymorphism affects the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Patients underwent LDLT at Nagoya University or Kyoto University, Japan, between 2004 and 2009. Genotyping of GSTT1 genes (null or present genotype) was conducted in recipients and donors. A total of 155 LDLT cases were examined. Forty-seven recipients (30.3%) developed early ACR. There was no association of recipient GSTT1 genotype with ACR incidence. However, ACR incidence was significantly higher in recipients transplanted from GSTT1 present genotype donors than in those transplanted from GSTT1 null genotype donors [odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.12–5.83, p = 0.016]. Moreover, GSTT1 recipient/donor genotype mismatch (present/null or null/present) was significantly associated with ACR development (OR = 2.28, 95% CI = 1.12–4.61, p = 0.022). The genotyping of GSTT1 in recipients and donors might be useful to stratify the liver transplant recipients according to risk of ACR.     

In vivo bioluminescence imaging of magnetically targeted bone marrow‐derived mesenchymal stem cells in skeletal muscle injury model

The purpose of this study is to clarify the kinetics of transplanted mesenchymal stem cells (MSCs) in rat skeletal muscle injury model and the contribution of the magnetic cell delivery system to muscle injury repair. A magnetic field generator was used to apply an external magnetic force to the injury site of the tibia anterior muscle, and 1 × 10⁶ MSCs labeled with ferucarbotran–protamine complexes, which were isolated from luciferase transgenic rats, were injected into the injury site. MSCs were injected with and without an external magnetic force (MSC M+ and MSC M? groups, respectively), and phosphate‐buffered saline was injected into injury sites as a control. In vivo bioluminescence imaging was performed immediately after the transplantation and, at 12, 24, and 72 h, and 1 and 4 weeks post‐transplantation. Also, muscle regeneration and function were histologically and electromechanically evaluated. In vivo bioluminescence imaging showed that the photon of the MSC M+ group was significantly higher than that of the MSC M? group throughout the observation period. In addition, muscle regeneration and function in the MSC M+ group was histologically and functionally better than that of the MSC M? group. The results of our study indicated that magnetic cell delivery system may be of use in directing the transplanted MSCs to the injury site to promote skeletal muscle regeneration. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 754–759, 2013     

Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome

Background

Rituximab, an anti-CD20 antibody that targets B cells, is a promising agent against steroid-dependent and steroid-resistant nephrotic syndrome in children.

Case-Diagnosis/Treatment

We report a 3-year-old boy who presented with atypical Pneumocystis jiroveci pneumonia (PCP) following administration of rituximab for refractory nephrotic syndrome. He had received cyclosporine and daily prednisolone for over 1?year. Following rituximab therapy, a hazy shadow was observed on his chest X-ray. Chest-computed tomography revealed multiple nodular lesions in bilateral lungs, although his clinical symptoms were subtle. PCR analysis demonstrated the presence of Pneumocystis DNA in his bronchoalveolar lavage. Lung wedge resection of the nodular lesion exhibited granulomas containing a few cysts of P. jiroveci that primarily consisted of T cells and histiocytes and lacked B cells. A deficiency of B cells following rituximab treatment suggests a dramatic effect on the immune response and, therefore, could result in granulomatous PCP. Nodular granulomatous lesions of PCP comprise an emerging concept previously reported in adults with hematological disease, bone marrow transplant, or treatment with rituximab. We report the first pediatric case of nodular PCP. Granulomatous PCP can be life-threatening. Moreover, bronchoalveolar lavage often fails to demonstrate the presence of P. jiroveci DNA. Wedge biopsy is warranted for definitive diagnosis. Our patient fully recovered with sulfamethoxazole/trimethoprim treatment because of early detection.

Conclusions

The indication of rituximab for refractory nephrotic syndrome has increased recently. Therefore, recognition of the risk of atypical PCP is important. Our findings suggest that PCP prophylaxis should be considered following rituximab therapy.