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.     

NATURAL SKIN REDUCTION AND BREAST RECOVERY USING A TISSUE EXPANDER AFTER ENUCLEATION OF A GIANT BREAST TUMOUR

We report a new use of the tissue expander for reshaping a breast after resection of a giant tumour. After resection of giant fibroadenomas, two patients had expanders inserted into the tissue defect and gradually reduced in size over five months. This facilitated healing and natural skin shrinkage and resulted in a natural shape and size.     

Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology

Regional progression of neurofibrillary tangles (NFTs) around the hippocampus was traced on thick sections double immunofluorolabeled with RD3 and RD4 antibodies, specific for three- and four-repeat tau, respectively. As reported, the cubic density of all tau-positive neurons was predominant in the entorhinal cortex and cornu ammonis (CA)1, and decreased progressively to the CA2–4 subregions. Among the three isoform profiles (RD3+/4?, RD3+/4+, and RD3?/4+), this regional gradient was replicated with RD3+/4? and RD3+/4+ neurons, while RD3?/4+ neurons exhibited the reverse gradient. Comparison of the subregion pairs confirmed a consistent profile shift along this gradient in every case regardless of the abundance of NFTs. To clarify the underlying mechanism of this regional profile shift, intraneuronal intensity of RD3 and RD4 immunoreactivity (IR) was quantified. Although their intensities were both lower in dendrites than in the soma, this gradient was steeper with RD4, leaving RD3 IR in dendrites. Dendritic arborization was abundant in RD3?/4+ pretangles, attenuated in RD3+/4+ neurons, and further attenuated in RD3+/4? ghost tangles. These findings suggest that dendritic RD4 IR retracts first, leaving RD3 IR in the dendrites. Taken together, this dendrite-oriented retraction initiates the gradual shift from RD3?/4+ pretangle neurons to RD3+/4? ghost tangles by way of RD3+/4+ NFTs. This intraneuronal profile shift may be a basis for the regional gradation featured by the similar profile shift during progression of NFT pathology.