Human and rat microsomal metabolites of N-tert-butoxycarbonylmethamphetamine and its urinary metabolites in rat

Forensic Toxicology - N-tert-Butoxycarbonylmethamphetamine (BocMA), a masked derivative of methamphetamine (MA), converts into MA under acidic condition and potentially acts as a precursor to MA...     

Overexpression of PGC1α and accumulation of p62 in apocrine carcinoma of the breast

Apocrine carcinoma is categorized as a special type of breast carcinoma because of its specific morphological features. To clarify the characteristics of apocrine carcinoma from the point of view of the mitochondrial profile, we conducted a comparative study between apocrine and non‐apocrine carcinomas. The expressions of mitochondrial related factors (PGC1α, Nrf1, Nrf2, mtTFA and COX4) were examined in a testing set of breast cancer tissue. Apocrine carcinomas showed a clear tendency towards higher mRNA expression levels of PGC1α than non‐apocrine carcinomas. The expression of the selected factor, PGC1α, as well as that of p62 was further examined. The results revealed that apocrine carcinomas showed a higher immunohistochemical positivity rate for PGC1α (21.3% vs. 3.2%; P = 0.008), and that the mRNA expression level of PGC1α was significantly higher in apocrine carcinoma than in non‐apocrine carcinoma (P = 0.007). The immunohistochemical positivity rate for p62 protein was also higher in apocrine carcinomas (44.7% vs. 21.0%; P = 0.015), although no significant difference in the p62 mRNA expression level was detected between the two types of carcinoma (P = 0.633). In conclusion, this study revealed that apocrine carcinoma overexpressed PGC1α contributing to mitochondrial biogenesis, and also p62 protein accumulation.     

Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule

We studied the influence of IL-6 on chemokine production from peripheral blood mononuclear cells (PBMC), fibroblastic synovial cells and human umbilical vessel endothelial cells (HUVEC). Moreover, we examined the effect of IL-6 on the adhesion of U937 cells to HUVEC. For chemokine production, PBMC, fibroblastic synovial cells and HUVEC were cultured with IL-6 or IL-6 + soluble IL-6R (sIL-6R) for 24 h and then the production of MCP-1 and IL-8 were measured in supernatants. IL-6 and IL-6 + sIL-6R induced production of both MCP-1 and IL-8 in PBMC and synovial cells, respectively. In HUVEC, IL-6 + sIL-6R induced MCP-1 production, but inhibited IL-8 production. For adhesion molecule expression, the production of soluble form of adhesion molecules in HUVEC culture supernatant were measured by ELISA and the expression of adhesion molecules on cell surface were examined by flow cytometry analysis. Soluble ICAM-1 was detectable in IL-6 + sIL-6R-treated HUVEC and IL-6 + sIL-6R-induced ICAM-1 expression on cell membrane of HUVEC. In addition, U937 cells were added to HUVEC, which were pre-treated with IL-6 + sIL-6R for 24 h, and 3 h later attached U937 cells were counted. The adhesion of U937 cells to HUVEC was augmented when HUVEC was pretreated by IL-6 + sIL-6R. This adhesion was suppressed by anti-ICAM-1 antibody and anti-IL-6R antibody, but not by antibodies against VCAM-1 or E-selectin. In conclusion, IL-6 signaling plays an important role in inflammatory cell migration by increasing the rate of cell adhesion and by inducing chemokine production in inflamed joints.     

Spontaneous migration of a metal clip into renal pelvis after laparoscopic pyeloplasty: a case report

Migration of surgical materials into the urinary tract is very rare. We present a case of spontaneous migration of a metal clip into renal pelvis after laparoscopic pyeloplasty. A 44-year-old woman who had a long history of multiple sclerosis presented with symptomatic left hydronephrosis due to ureteropelvic junction (UPJ) obstruction. Since antegrade endopyelotomy was unsuccessful, the patient underwent laparoscopic Anderson-Hynes pyeloplasty. The UPJ was wrapped with thick inflammatory tissue and a crossing vessel that firmly adhered to the UPJ was found and dissected. Metal clips were used for hemostasis. Although the hydronephrosis was improved and flank pain was completely dissolved, a stone was identified in the pelvis 22 months after the surgery. The stone was formed around a metal clip that had been possibly migrated into the renal pelvis. Transureteral lithotripsy was performed using an 8F ureterofiberscope and a clip was removed.     

Coenzyme Q10-Binding/Transfer Protein Saposin B also Binds gamma-Tocopherol

gamma-Tocopherol, the major form of dietary vitamin E, is absorbed in the intestine and is secreted in chylomicrons, which are then transferred to liver lysosomes. Most gamma-tocopherol is transferred to liver microsomes and is catabolized by cytochrome p450. Due to the hydrophobicity of gamma-tocopherol, a binding and transfer protein is plausible, but none have yet been isolated and characterized. We recently found that a ubiquitous cytosolic protein, saposin B, binds and transfers coenzyme Q10 (CoQ10), which is an essential factor for ATP production and an important antioxidant. Here, we report that saposin B also binds gamma-tocopherol, but not alpha-tocopherol, as efficiently as CoQ10 at pH 7.4. At acidic pH, saposin B binds gamma-tocopherol preferentially to CoQ10 and alpha-tocopherol. Furthermore, we confirmed that saposin B selectively binds gamma-tocopherol instead of CoQ10 and alpha-tocopherol at every pH between 5.4 and 8.0 when all three lipids are competing for binding. We detected gamma-tocopherol in human saposin B monoclonal antibody-induced immunoprecipitates from human urine, although the amount of gamma-tocopherol was much smaller than that of CoQ10. These results suggest that saposin B binds and transports gamma-tocopherol in human cells.     

Increased number of CD16CD56 NK cells in peripheral blood mononuclear cells after allogeneic cord blood transplantation

In the present study, we investigated subpopulations of natural killer (NK) cells and the expression of stimulatory and inhibitory NK receptors after adult blood and bone marrow transplantation (BBMT) and cord blood transplantation (CBT). There were significant increases in CD16⁺CD56^dim cell proportion and in absolute number in peripheral blood mononuclear cells (PBMC) during a period of 4–9 months after CBT compared with these in normal PBMC, cord blood (CB), and in PBMC after BBMT. Also, increased numbers of CD16⁺CD56^dim NK cells were sustained in some patients until 4 years after CBT. This CD16⁺CD56^dim cell subset after CBT exhibited decreased expression of NKG2A compared with that in CB and increased expression of NKG2C. Purified CD16⁺CD56^dim cells from patients 8–9 months after CBT exhibited significantly higher levels of cytolytic activity against K562 than did purified CD16⁺CD56^bright cells and also whole PBMC. The CD16⁺CD56^dim cell subset with a high level of cytolytic activity significantly increased after CBT, and these cells may be responsible for NK cell–mediated immunity after CBT.     

Treatment of idiopathic gustatory rhinorrhea by resection of the posterior nasal nerve

We herein describe a case of 44-year old female who presented with a chief complaint of gustatory rhinorrhea from childhood, in which gustatory stimuli caused bilateral excessive, watery nasal secretion. No abnormality of taste acuity was observed. This disorder was presumably caused by faulty regenerated parasympathetic nerve fibers reaching the nasal mucosa or possibly, by a congenital condition. Nasal pretreatment with an anti-cholinergic drug clinically blocked the positive sugar-induced rhinorrhea, thus indicating that the gustatory rhinitis in this case was produced by foods that stimulate muscarinic receptors sensitive to atropine (probably on submucosal nasal glands). Although this syndrome can be treated prophylactically by the use of topical atropine, the patient preferred to undergo radical therapy and a resection of the posterior nasal nerve was performed through the middle meatus under endoscopic control. The resection of the nerve on both sides resulted in an almost complete inhibition of the sugar-induced rhinorrhea without serious complications. Although this disease is not life-threatening, it is socially embarrassing and troublesome to patients and surgical therapy is one of the accepted modalities.     

α2-Antiplasmin Is Associated with the Progression of Fibrosis

Systemic sclerosis results in tissue fibrosis due to the activation of fibroblasts and the ensuing overproduction of the extracellular matrix. We previously reported that the absence of α2-antiplasmin (α2AP) attenuated the process of dermal fibrosis; however, the detailed mechanism of how α2AP affects the progression of fibrosis remained unclear. The goal of the present study was to examine the role of α2AP in fibrotic change. We observed significantly higher levels of α2AP expression in the skin of bleomycin-injected systemic sclerosis model mice in comparison with the levels seen in control mice. We also demonstrated that α2AP induced myofibroblast differentiation, and the absence of α2AP attenuated the induction of myofibroblast differentiation. Moreover, we found that connective tissue growth factor induced the expression of α2AP through both the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways in fibroblasts. Interestingly, α2AP also induced transforming growth factor-β expression through the same pathways, and the inhibition of ERK1/2 and JNK slowed the progression of bleomycin-induced fibrosis. Our findings suggest that α2AP is associated with the progression of fibrosis, and regulation of α2AP expression by the ERK1/2 and JNK pathways may be an effective antifibrotic therapy for the treatment of systemic sclerosis.Systemic sclerosis (SSc) affects the skin and the internal organs, resulting in tissue fibrosis. Although the disease process involves immunological mechanisms, vascular damage, and activation of fibroblasts, the pathogenesis of SSc remains to be further elucidated. Fibrotic diseases are characterized by excessive scarring due to excessive production, deposition, and contraction of the extracellular matrix (ECM). This process usually occurs over many months and years, and can lead to organ dysfunction or death. Connective tissue growth factor (CTGF) is constitutively overexpressed in fibrotic lesions such as in scleroderma,¹ liver,² renal,^3,4 lung,⁵ and pancreatic fibrosis.⁵ CTGF acts as a downstream effecter of at least some of the profibrotic effects of transforming growth factor-β (TGF-ß),⁶ and promotes fibroblast proliferation, myofibroblasts differentiation, matrix production, and granulation tissue formation.^7,8Human and murine α2-antiplasmin (α2AP) are serpins (serine protease inhibitors) with a molecular weight of 65 to 70 kd,⁹ which rapidly inactivate plasmin, resulting in the formation of a stable inactive complex, plasmin-α2AP.¹⁰ Tissue fibrosis is generally considered to arise due to a failure of the normal wound healing response to terminate.¹¹ Previous our studies show that α2AP is associated with the wound healing and the fibrosis.^12,13 In addition, it has been reported that the level of plasmin-α2AP complex in plasma is elevated in SSc patients.¹⁴ These findings suggest that α2AP may be associated with the progression of fibrotic disease, but the physiological roles of α2AP are not precisely understood. We herein report that α2AP plays an important role in the progression of fibrosis.     

Dysuria therapeutic agents as an independent prognostic factor for the primary recurrence of non-muscle invasive bladder cancer: a propensity score matching study

ObjectiveTo investigate if the use of therapeutic agents for dysuria is a risk factor for the primary recurrence of non-muscle invasive bladder cancer (NMIBC).MethodsFirst, patients with NMIBC were divided into two groups: the non-recurrence group and the recurrence group. Patient characteristics were compared between both groups. The risk factors of recurrence that were statistically different between the two groups were identified by multivariate analysis. Second, we divided the patients into risk and non-risk groups, and differences in the recurrence-free survival (RFS) between the two groups were analyzed before and after propensity score matching (PSM).ResultsA total of 162 patients were included, with 84 patients in the non-recurrence group and 78 patients in the recurrence group. In the multivariate analysis, the intake of dysuria agents and bacillus Calmette–Guérin (BCG) therapy were independent factors. The RFS results in terms of the intake of dysuria agents were statistically significant before and after PSM analysis, but no factors were significantly different between the BCG and non-BCG groups after PSM.ConclusionsTherapeutic agents for dysuria might be at an independent risk factor for NMIBC recurrence. This trial is registered with the UMIN Clinical Trials Registry under the number UMIN000036097 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno = R000041122).