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Background: Previous studies have shown that a donor/recipient body weight mismatch affects long-term graft survival and graft function after kidney transplantation. However, the mechanisms are not fully understood., Aim: To address the mechanisms, we compared the pathological and physiological features between patients with a donor/recipient body weight mismatch and those without a mismatch 1 yr after kidney transplantation. Furthermore, we investigated the correlation with the donor/recipient body weight ratio., Methods: We examined allograft biopsy specimens from 10 recipients with stable kidney function, with body weight mismatch (donor/recipient body weight ratio [D/R BWR] < 0.9), and compared them with samples from 13 patients without mismatch. We measured glomerular volume (GV) using the Weibel-Gomez method and glomerular density (GD) defined by nonsclerotic glomerular number/renal cortical area as pathological findings. The physiological parameters included estimated glomerular filtration rate and proteinuria (mg/day). These data were evaluated to identify a correlation with D/R BWR., Results: The pathological features showed that GV and GD were identical in the two groups. However, when glomerular enlargement was defined by ΔGV (GV at the 1-yr biopsy minus GV at baseline biopsy), ΔGV was higher in mismatch cases compared with that in cases without a mismatch (10.6 ± 4.6 vs. 5.5 ± 7.1 × 10(5) μm(3) ; P = 0.049). Furthermore, D/R BWR was significantly correlated with ΔGV (P = 0.03, r = -0.436). eGFR values were physiologically identical between the two groups, but the mismatch cases had significantly higher proteinuria levels than that of the cases without a mismatch at 1 yr after kidney transplantation., Conclusion: A donor/recipient body weight mismatch could affect glomerular enlargement and increased proteinuria 1 yr after kidney transplantation. How these two features affect long-term graft survival and function must be addressed in the future., (© 2015 Asian Pacific Society of Nephrology.)

Objective: To characterize bone fractures and the usefulness of micro-CT for imaging fractures in pet rabbits., Design: Retrospective case series., Animals: 210 client-owned rabbits with bone fractures., Procedures: Medical records of rabbits evaluated for bone fractures from 2007 through 2013 were examined. Information was collected on signalment and nature of fractures, and radiographic and micro-CT images of fractures were reviewed., Results: Almost half (n = 95 [47.7%]) of fractures were in rabbits < 3 years old. Accidental fall was the most common cause. Vertebral fracture was the most common type of fracture with a nonneoplastic cause (n = 46 [23.2%]) and was most common in the L4-L7 region. The tibia was the most common site for limb fracture among all fractures with a nonneoplastic cause (45 [22.7%]). Twelve (5.7%) fractures had a neoplastic cause, and 7 of these were associated with metastatic uterine adenocarcinoma. Females were significantly more likely to have a fracture caused by neoplasia than were males. Compared with radiography, micro-CT provided more detailed fracture information, particularly for complicated fractures or structures (eg, skull, pelvic, vertebral, and comminuted limb fractures)., Conclusions and Clinical Relevance: Findings were useful for understanding the nature of fractures in pet rabbits and supported the use of micro-CT versus radiography for fracture detection and evaluation.

During the last decade, multiphoton fluorescent microscopy has launched a new era in the field of biology. By using this advanced imaging technique we have established a system for visualizing the in situ behaviors of a diversity of living cells within intact tissues and organs. Among them we succeeded in visualizing the various dynamic phenomena within bones, a mysterious organ wherein various hematopoietic and immune cells are produced and functioning. However, these cell types are poorly understood with conventional methodologies such as histological analyses of decalcified bone sections. We have thus far focused on the behavior of osteoclasts, a type of specialized macrophage contributing to physiological turnover of bone tissues as well as pathological bone destruction, and have revealed novel mechanisms controlling the migration and function of osteoclasts in situ. Functional coupling between bone-destroying osteoclasts and bone-replenishing osteoblasts could also be visualized demonstrating a genuine mode of 'cross-talk' among these cell types. Furthermore, we have recently imaged in situ behaviors of different hematopoietic cells in bone marrow. Herein we present our latest data on cellular dynamics in the bone cavity, and discuss the applications of this novel methodology for future studies in the field of hematology.

Pseudomyxoma peritonei (PMP) is a condition characterized by production of a large amount of mucopolysaccharides by neoplastic epithelium, with intraabdominal cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) known to be viable treatment options. Pleural extension from an PMP is unusual and thought to be related to diaphragmatic perforation during surgery or transdiaphragmatic spreading of the disease through the lymphatic lacunae. Here, we report a patient with PMP with pleural extension of a mucinous tumor for whom CRS was performed twice. A 57-year-old female with PMP infiltrating the right chest cavity was scheduled for two separate CRS and hyperthermic chemotherapy procedures, because of the highly invasive characteristics of the surgery. For the first operation, we performed intra-abdominal surgery under general anesthesia combined with epidural anesthesia. To assess fluid and blood transfusion responsiveness, and reactions to vasoactive medication, we utilized an arterial pressure-based cardiac output monitor and central venous oximetry catheter. The second operation was performed 5 months later under general anesthesia with differential lung ventilation combined with epidural anesthesia. The operation and anesthesia for both surgical procedures were uneventful.

Osteoblasts are bone-forming cells and lately osteoblastic niche is getting a lot more attention as a candidate of hematopoietic niche. Although there have been many previous studies about osteoblasts, there are few studies about the dynamics of osteoblasts. Recent rapid advance of fluorescent imaging techniques enables us to observe cellular dynamics and there are some reports that osteoblasts were visualized in live bone by using intravital two-photon microscopy. Here we show past reports about live cell imaging of osteoblasts and our latest data of live cell imaging of osteoblasts in vivo and in vitro.

The anatomy of the lateral thoracic artery perforator flap remains controversial, but this region is extremely useful as a reconstructive donor site. In this report, we describe the usefulness of the preoperative color Doppler ultrasound evaluation for the harvesting of the lateral thoracic artery perforator flap, and we clarify its branching pattern. Twenty-seven patients underwent the preoperative color Doppler ultrasound assessment before perforator flaps were harvested. We evaluated the branching pattern and the diameter of the flaps by direct observation. All flaps were successfully transferred, and it was found that the branching pattern of the lateral thoracic perforator is divided into three groups: the superficial branch, the medial branch, and the deep branch. Their appearance ratios were 48.1% (13/27), 14.8% (4/27), and 81.5% (22/27), respectively. The lateral thoracic artery perforator flap has a great deal of anatomical variation, and vessels with relatively small diameters compared to those of other flaps. This is why flaps from this region are not currently popular. This study revealed the superiority of the color Doppler ultrasound for preoperative planning of the lateral thoracic artery perforator flap elevation. Furthermore, the branching pattern and the diameters of the different branches were specified., (Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Cigarette smoking, which is a well-known major risk factor for chronic obstructive pulmonary disease (COPD), causes both pulmonary and extrapulmonary abnormalities. Ghrelin is a gastric peptide that regulates energy homeostasis. In the present study, we investigated the effects of ghrelin on the catabolic changes, respiratory function and emphysema in an animal model of COPD induced by chronic exposure to cigarette smoke. Rats were exposed to cigarette smoke, and they were administered human ghrelin (0.1 or 1 mg/kg, subcutaneous, twice daily) for 12 weeks. Compared with air-exposed rats, body weight gain, food intake, food efficiency, tidal volume, peak expiratory flow rate, and forced expiratory volume at 100 ms were significantly lower, while functional residual capacity, lung capacity, and neutrophils in bronchoalveolar lavage fluid were significantly higher in cigarette smoke-exposed rats. These indicated that the systemic abnormalities associated with COPD developed after the exposure to cigarette smoke. Ghrelin significantly and dose-dependently increased the body weight gain and food efficiency in cigarette smoke-exposed rats. In ghrelin-treated rats, skeletal muscle strength, which tended to be lowered by cigarette smoke exposure, was improved. Ghrelin ameliorated respiratory function and emphysema in a dose-dependent manner, but did not inhibit the increase in neutrophils in the bronchoalveolar lavage fluid. The respiratory functional parameters and lung capacity were significantly correlated with body weight gain. These results suggest that ghrelin inhibited the development of the catabolic changes, respiratory dysfunction, and emphysema that were induced by cigarette smoke exposure in rats, at least in part, through the amelioration of nutritional status., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Bone is a highly dynamic organ in which several cell types function cooperatively. Among these, osteocytes have recently emerged as an important regulator of bone homeostasis, although their mechanism of regulation is unclear. Here, intravital bone imaging by two-photon excitation microscopy allowed us to directly visualize 'osteocytic osteolysis', or resorption of bone in the lacuno-canalicular system. Osteocyte lacunae and the canalicular network in the cortex of murine tibiae were imaged by in vivo calcein staining, and local acidification in these structures was monitored using a topically applied pH sensor. We also demonstrated that sciatic neurectomy causes significant acidification around osteocytic lacunae and enlargement of lacuno-canalicular areas. These results provide strong evidence for osteocytic osteolysis, and demonstrate that two-photon intravital microscopy is useful for analysis of this phenomenon., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Elucidation of the molecular mechanisms by which cancer cells overcome hypoxia is potentially important for targeted therapy. Complexation of hypoxia-inducible factors (HIFs) with aryl hydrocarbon receptor nuclear translocators can enhance gene expression and initiate cellular responses to hypoxia. However, multiple molecular mechanisms may be required for cancer cells to adapt to diverse microenvironments. We previously demonstrated that a physical interaction between the ubiquitously expressed transcription factor Sp1 and HIF2 is a major cause of FVII gene activation in poor prognostic ovarian clear cell carcinoma (CCC) cells under hypoxia. Furthermore, it was found that FVII activation is synergistically enhanced when serum-starved cells are cultured under hypoxic conditions. In this study, we investigated whether HIFs and transcription factor Sp1 cooperate to activate multiple genes in CCC cells under conditions of serum starvation and hypoxia (SSH) and then contribute to malignant phenotypes., Methods: To identify genes activated under hypoxic conditions in an Sp1-dependent manner, we first performed cDNA microarray analyses. We further investigated the molecular mechanisms of synergistic gene activations including the associated serum factors by various experiments such as real-time RT-PCR, western blotting and chromatin immunoprecipitation. The study was further extended to animal experiments to investigate how it contributes to CCC progression in vivo., Results: ICAM1 is one such gene dramatically induced by SSH and is highly induced by SSH and its synergistic activation involves both the mTOR and autonomously activated TNFα-NFκB axes. We identified long chain fatty acids (LCFA) as a major class of lipids that is associated with albumin, a serum factor responsible for synergistic gene activation under SSH. Furthermore, we found that ICAM1 can be induced in vivo to promote tumor growth., Conclusion: Sp1 and HIFs collaborate to activate genes required for the adaptation of CCC cells to severe microenvironments, such as LCFA starvation and hypoxia. This study highlights the importance of transcriptional regulation under lipid starvation and hypoxia in the promotion of CCC tumor growth.

Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt-Hogg-Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.

Background: Capsaicinoids, including capsaicin and its analogs, are responsible for the pungency of pepper (Capsicum species) fruits. Even though capsaicin is familiar and used daily by humans, the genes involved in the capsaicin biosynthesis pathway have not been well characterized. The putative aminotransferase (pAMT) and Pungent gene 1 (Pun1) proteins are believed to catalyze the second to last and the last steps in the pathway, respectively, making the Pun1 protein the putative capsaicin synthase. However, there is no direct evidence that Pun1 has capsaicin synthase activity., Results: To verify that the Pun1 protein actually plays a role in capsaicin production, we generated anti-Pun1 antibodies against an Escherichia coli-synthesized Pun1 protein and used them to antagonize endogenous Pun1 activity. To confirm the anti-Pun1 antibodies' specificity, we targeted Pun1 mRNA using virus-induced gene silencing. In the Pun1-down-regulated placental tissues, the accumulated levels of the Pun1 protein, which was identified on a western blot using the anti-Pun1 antibodies, were reduced, and simultaneously, capsaicin accumulations were reduced in the same tissues. In the de novo capsaicin synthesis in vitro cell-free assay, which uses protoplasts isolated from placental tissues, capsaicin synthesis was inhibited by the addition of anti-Pun1 antibodies. We next analyzed the expression profiles of pAMT and Pun1 in various pepper cultivars and found that high levels of capsaicin accumulation always accompanied high expression levels of both pAMT and Pun1, indicating that both genes are important for capsaicin synthesis. However, comparisons of the accumulated levels of vanillylamine (a precursor of capsaicin) and capsaicin between pungent and nonpungent cultivars revealed that vanillylamine levels in the pungent cultivars were very low, probably owing to its rapid conversion to capsaicin by Pun1 soon after synthesis, and that in nonpungent cultivars, vanillylamine accumulated to quite high levels owing to the lack of Pun1., Conclusions: Using a newly developed protoplast-based assay for de novo capsaicin synthesis and the anti-Pun1 antibodies, we successfully demonstrated that the Pun1 gene and its gene product are involved in capsaicin synthesis. The analysis of the vanillylamine accumulation relative to that of capsaicin indicated that Pun1 was the primary determinant of their accumulation levels.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN-associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp-cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA-IX. All clear cell RCCs were positively stained for CA-IX and negative for CK7. These data confirmed that mutant FLCN-associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp-cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri-nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA-IX, Ksp-cadherin, CD82 and CK7., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Pathophysiological features of chronic obstructive pulmonary disease (COPD) include systemic abnormalities, such as weight loss and skeletal muscle wasting. Although cigarette smoke (CS) is a major risk factor in COPD, the systemic effects of CS exposure remain to be elucidated. In this study, rats were exposed to CS or smoke-free air for 12 weeks. CS-exposed rats developed emphysema and had significantly lower body weight and food intake than control rats. The plasma ghrelin levels significantly increased with an upregulation of gastric ghrelin mRNA expression induced by CS exposure. Further, we observed low plasma insulin-like growth factor-1 levels and high tumor necrosis factor-α levels. A significant reduction of skeletal muscle strength and an increase in the mRNA expression of catabolic factors was observed in CS-exposed rats. These results indicated that chronic CS exposure induced not only pulmonary emphysema but also systemic abnormalities related to muscle catabolism associated with inflammatory responses., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Birt-Hogg-Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell carcinomas (RCC). Diagnostic markers that distinguish between FLCN-related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non-metastatic B (GPNMB) between FLCN-related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT-PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN-related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN-related RCCs was 23-fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work-up for BHD., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: Treating schizophrenia patients who fail to respond to antipsychotics is a major challenge, and the percentage of treatment-resistant patients is estimated to be 20-25 %. Recent studies indicate that yokukansan (YKS; D2 and 5HT1A partial agonist and 5HT2A and glutamate antagonist) to be safe and useful in treating behavioral and psychological symptoms associated with dementia and other neuropsychiatric conditions. We aimed at evaluating both the efficacy and safety of YKS in patients with treatment-resistant schizophrenia., Methods: This randomized, multicenter, double-blind, placebo-controlled study was conducted between May 2010 and August 2012. One hundred twenty antipsychotic-treated inpatients from 34 psychiatric hospitals in Japan were included. Patients were randomized to adjuvant treatment with YKS 7.5 g/day or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) with five factors [excitement/hostility (P4, P7, G8, and G14), depression/anxiety (G1, G2, G3, G4, and G6), cognition (P2, N5, N7, G5, G10, G11, G12, G13, and G15], positive (P1, P3, P5, P6, and G9), and negative (N1, N2, N3, N4, N6, G7, and G16]]. Other assessments included, Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The primary efficacy outcome was the change in PANSS five-factor scores. The secondary outcomes were changes in the scores of CGI-S. The analysis was made on a modified intention to treat basis with the help of a last observation carried forward method., Results: YKS showed a tendency of superiority to placebo in reducing total all PANSS five-factor scores in treatment-resistant schizophrenia, but the difference was not statistically significant in total, depression/anxiety, cognition, positive, and negative factors. However, compared to the placebo group, the YKS group showed statistically significant improvements in the PANSS excitement/hostility factor scores (p<0.05). No substantial side effects were recorded., Conclusion: The results of the present study indicate YKS to be a potential adjunctive treatment strategy for treatment-resistant schizophrenia, particularly to improve excitement/hostility symptoms.

Objectives. We aimed at evaluating both the efficacy and safety of TJ-54 (Yokukansan) in patients with treatment-resistant schizophrenia. This randomized, multicenter, double-blind, placebo-controlled study was conducted. Methods. One hundred and twenty antipsychotic-treated inpatients were included. Patients were randomized to adjuvant treatment with TJ-54 or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Results. TJ-54 showed a tendency of being superior to placebo in reduction total, positive, and general PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant in both per-protocol set (PPS) and intention-to-treat (ITT). However, in PPS analysis, compared to the placebo group, the TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores for lack of spontaneity and flow of conversation (TJ-54: -0.23 ± 0.08; placebo: -0.03 ± 0.08, P < 0.018), tension (TJ-54: -0.42 ± 0.09; placebo: -0.18 ± 0.09, P < 0.045), and poor impulse control (TJ-54: -0.39 ± 0.10; placebo: -0.07 ± 0.10, P < 0.037). Conclusions. The results of the present study indicate that TJ-54 showed a tendency of being superior to placebo in reduction PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant. However, compared to the placebo group, TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores.

Many children with cerebral palsy (CP) use a wheelchair during activities of daily living and often extend their hand upward and downward to reach objects in a seated position in a wheelchair. However, the effect of shoulder position on reaching movements of children with CP is not established. The purpose of this study was to determine the effect of the angle of shoulder flexion on the reach trajectory of children with spastic CP. Seven children with mild CP [Manual Ability Classification System (MACS) levels I-II], five children with severe CP (MACS levels III-V) and six typically developing (TD) children participated. We prepared the device to have a top board with variable tilting angle in order to reduce the effect of gravity imposing on reaching movements. By using this device, the subjects could extend their arm by sliding it on the board to push a target button. The reaching movements were performed with the more affected hand at three angles (60°, 90° and 120°) of shoulder flexion and captured using a camera motion analysis system. Subjects in the TD and mild CP groups reached the target at 60°, 90° and 120° of shoulder flexion. Subjects of the severe CP group reached the target at 60° and 90° of shoulder flexion, but two of the subjects could not reach the target at 120° of shoulder flexion. The TD and mild CP groups showed smooth and almost straight trajectories at all three angles of shoulder flexion; however, the reach trajectory in the subjects with severe CP changed with the angle of shoulder flexion. A large angle of shoulder flexion induced great outward deviation in the trajectory. These findings suggest that the difficulty of the reaching task is changed depending on the shoulder joint angle in children with severe CP and that therapeutic interventions for children with severe CP should be provided in a manner appropriate for the shoulder joint angle., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Canine lymphoma is a common cancer that has high rates of complete remission with combination chemotherapy. However, the duration of remission varies based on multiple factors, and there is a need to develop a method for early detection of recurrence. In this study, we compared the metabolites profiles in serum from 21 dogs with lymphoma and 13 healthy dogs using gas chromatography mass spectrometry (GC-MS). The lymphoma group was separated from the control group in an orthogonal projection to latent structure with discriminant analysis (OPLS-DA) plot using ions of m/z 100-600, indicating that the metabolites profiles in lymphoma cases differed from those in healthy dogs. The lymphoma group was also separated from the control group on OPLS-DA plot using 29 metabolites identified in all serum samples. Significant differences were found for 16 of these metabolites with higher levels in the lymphoma group for 15 of the metabolites and lower levels for inositol. An OPLS-DA plot showed separation of the lymphoma and healthy groups using these 16 metabolites only. These results indicate that metabolites profile with GC-MS may be a useful tool for detection of potential biomarker and diagnosis of canine lymphoma.

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.

Uterine superficial serous carcinoma (SSC) and serous endometrial intraepithelial carcinoma (SEIC) are unique malignancies found primarily in postmenopausal women. SSC and SEIC lesions measuring 1 cm or less are categorized as minimal uterine serous carcinoma (MUSC). Less well understood, however, the clinical behavior of SSC and SEIC lesions measuring more than 1 cm. We investigated 6 postmenopausal patients, aged 69-83 years, with SSC or SEIC and without hyperestrogenism. All but 1 patient had tumors originating from the surface of polyps, including 3 patients who each had an enormous polyp occupying the entire uterine cavity. Two patients had extensive SEICs measuring more than 1 cm; the others had SSCs, including 1 MUSC. The mesenchymal cells of the cancer-bearing polyps lacked the morphologic characteristics of endometrial stroma, and the cancer glands often immunostained negatively for estrogen receptors and progesterone receptors. Diffuse immunostaining for human epidermal growth factor receptor 2 was detected in 3 patients, and p53 was detected in all. Cyclin E, a downstream molecule of the F-box and WD repeat domain-containing 7 (FBXW7), was detected in all patients. Microdissected cancer glands showed p53 mutations in 2 patients and a FBXW7 mutation in 1 patient. These findings suggest that mutations of FBXW7 and p53 may contribute to the carcinogenesis of less invasive tumor subtypes. Pathologists and physicians should carefully evaluate SSC and SEIC lesions involving large polyps but lacking myometrial invasion.

Background: In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow., Methods: We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24., Results: Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT., Conclusions: In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose: In the present study, we compared 12- with 16-core biopsy in patients with prostate- specific antigen (PSA) levels of 4.0-20.0 ng/mL., Materials and Methods: Between 2003 and 2010, 332 patients whose serum PSA level was between 4.0 and 20.0 ng/mL underwent initial transrectal ultrasound (TRUS)-guided needle biopsy. Of those patients, 195 underwent 12-core biopsy and 137 underwent 16-core biopsy., Results: In the 12-core prostate biopsy group, 66 (33.8%) patients were found to have prostate cancer. On the other hand, in the 16-core prostate biopsy group of 137 patients, 61 (44.5%) were found to have prostate cancer. Among all patients, the prostate cancer detection rate was slightly higher in the 16-core biopsy group than in the 12-core biopsy group. Moreover, in patients with prostate volume > 30 mL or PSA density (PSAD) < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group. There was no significant difference in pathological tumor grade, indolent cancer probability, or biopsy complication rate between the two groups., Conclusion: In order to detect prostate cancer, 16-core prostate biopsy is safe and feasible for Japanese patients with serum PSA level of 4.0-20.0 ng/mL.

We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature., (© 2014 Asian Pacific Society of Nephrology.)

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder characterized by clinical features of skin lesions, pulmonary lesions and renal tumor. The gene responsible for this syndrome is located on chromosome 17p11.2 and designated as FLCN. In this article, we review renal tumors associated with BHDS with a focus on clinical and pathobiological aspects. Renal tumors often occur multifocally or bilaterally in the imaging analyses or gross examination. Histological examination of renal tumors includes a variety of subtypes such as hybrid oncocytic tumor, chromophobe renal cell carcinoma (RCC), oncocytoma, clear cell RCC and papillary RCC. The histologic discordance in multiple tumors seems to be characteristic of this syndrome. Oncocytosis is observed histologically in about half of the cases. Several investigations have elucidated that folliculin may be involved in the mammalian target of rapamycin (mTOR) pathway recently. Renal tumors composed of clear cells may behave in an aggressive fashion. However, renal tumors including hybrid oncocytic tumor, chromophobe RCC and oncocytoma behave mostly in an indolent fashion.

Objective: To examine the prevalence of torus mandibularis (TM) and identify clinical factors associated with its presence., Materials and Methods: A total of 664 Japanese adults over age 60 were studied by means of a questionnaire and clinical examination., Results: In all, 197 subjects (29.7%) had TM. We found a significant association between the presence of TM and torus palatinus (TP; 45.1% vs. 26.5%, p<0.001). Moreover, occlusal force with TM was significantly higher than without TM (p<0.05). Logistic regression adjusted for age and occlusal force revealed a significant relationship between TM and occlusal force and TP [p=0.005, odds ratio (OR)=2.44; p<0.001, OR=2.66, respectively]., Conclusion: This study suggests that there is a relationship between TM and factors related to occlusal factor., (© 2012 The Gerodontology Society and John Wiley & Sons A/S.)

In this article, we searched for the common histologic characteristic of renal tumors in patients with Birt-Hogg-Dubé syndrome (BHDS). We selected 6 patients with histologically confirmed renal tumor in BHDS. Germline FLCN gene mutation has been identified in 5 patients. Multifocality and bilaterality of the renal tumors were pathologically or radiologically confirmed in 5 and 2 cases, respectively. Histologic subtypes of the dominant tumor included 3 previously described hybrid oncocytic tumors, one composite chromophobe/papillary/clear cell renal cell carcinoma (RCC) and one unclassified RCC resembling hybrid chromophobe/clear cell RCC. In one case, chromophobe RCC and clear cell RCC were separately observed. Small papillary lesions located in the peripheral area of the tumor, which we designated as intratumoral peripheral small papillary tufts, were identified in all patients. In conclusion, multifocality/bilaterality of renal tumors, discordance of histologic subtypes, and the presence of intratumoral peripheral small papillary tufts may be important clues to identify BHDS-associated renal tumors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other., Methods: The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels., Results: Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors., Conclusions: Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes.

The junctional epithelium (JE) is an epithelial component that is directly attached to the tooth surface and has a protective function against periodontal diseases. In this study, we determined the origin of the JE using a bioengineered tooth technique. We transplanted the bioengineered tooth germ into the alveolar bone with an epithelial component that expressed green fluorescence protein. The reduced enamel epithelium from the bioengineered tooth fused with the oral epithelium, and the JE was apparently formed around the bioengineered tooth 50 days after transplantation. Importantly, the JE exhibited green fluorescence for at least 140 days after transplantation, suggesting that the JE was not replaced by oral epithelium. Therefore, our results demonstrated that the origin of the JE was the odontogenic epithelium, and odontogenic epithelium-derived JE was maintained for a relatively long period.

We describe a 76-year-old woman with cardiac tamponade who was admitted to our hospital. She underwent ascending and partial arch aortic replacement to treat acute type A aortic dissection. However, postoperative respiratory failure developed and a chest X-ray revealed right lung pneumothorax. The lung was finally expanded after difficulties with prolonged tube drainage. Chest computed tomography(CT) showed multiple cystic changes in the bilateral lungs. Her sister and her daughter also had a history of spontaneous pneumothorax. We finally diagnosed Birt-Hogg-Dube syndrome after deoxyribonucleic asid(DNA)sequencing of folliculin( FLCN) gene.

Background: Accumulating evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. We previously reported evidence of schizophrenia-like behaviors and microglial activation in Gunn rats. We concluded that the Gunn rat, which exhibits a high concentration of unconjugated bilirubin, may be useful as an animal model of schizophrenia. On the other hand, there have been numerous reports that minocycline is effective in treating schizophrenia., Methods: In the present study, we investigated the effects of minocycline on performance of behavioral tests (prepulse inhibition (PPI) and novel object recognition test (NORT)) after animals received either 40mg/kg/d of minocycline or vehicle by intraperitoneal (i.p.) injection for 14 consecutive days. Furthermore, we examined the effects of minocycline on microglial activation in the hippocampal dentate gyrus of Gunn rats and Wistar rats., Results: We found that administration of minocycline for 14days significantly increased the exploratory preference in retention sessions and tended to improve the PPI deficits in Gunn rats. Immunohistochemistry analysis revealed that microglial cells in the minocycline-treated Gunn rat group showed less expression of CD11b compared to vehicle-treated Gunn and Wistar groups., Conclusions: Our findings suggest that minocycline improves recognition memory and attenuates microglial activation in the hippocampal dentate gyrus of Gunn rats. Therefore, minocycline may be a potential therapeutic drug for schizophrenia., (Copyright © 2013. Published by Elsevier Inc.)

Background: Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01., Objective: To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population., Methods: A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01., Results: The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results., Conclusion: High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Endometrial stromal tumors (ESTs) are composed of cells resembling endometrial stroma, and are divided into benign and malignant types based on morphology. Endometrial stromal nodule (ESN) is a benign localized tumor, and endometrial stromal sarcoma (ESS) is an infiltrative and potentially metastatic neoplasm. A series of genetic aberrations contribute to pathological diagnosis of ESTs. At present, subsets of ESN and ESS-low grade (ESS-LG) are characterized as JAZF1-SUZ12/JJAZ1 gene fusion. The ESTs that show higher grade atypia but lack nuclear pleomorphism include YWHAE-FAM22 ESS. Here we report an unusual case of ESTs. Sudden colonic perforation occurred to the patient, and emergency surgery was performed. Pathological findings suggested metastatic ESS. Thorough medical examination of the genital organs detected a 1 cm-sized well-demarcated uterine tumor. Microscopically, the tumor lacked infiltrative features, conforming to the definition of ESN. Both lesions demonstrated identical cytology and shared JAZF1-SUZ12 gene fusion. Endometriosis was not found in any areas of the resected organs, strongly suggesting that the uterine orthotopic tumor metastasized. The current case uncovered the problems of differential diagnosis between ESN and ESS-LG. We demonstrate detailed pathological features of the two lesions, and discuss the possibility of orthotopic EST with limited infiltration to develop into ESS-LG., (© 2014 The Authors. Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Uterine tumors with sex cord-like elements are divided in two groups; uterine tumors resembling ovarian sex cord tumors (UTROSCT), and endometrial stromal tumors with sex cord-like elements (ESTSCLE). UTROSCT is currently defined as the neoplasm predominantly or exclusively composed of sex cord-like elements, and generally behaves in a benign fashion. We studied two unusual cases of UTROSCT with metastasis. One case was a 38-year-old multiparous woman presented with hypermenorrhea. The tumor grew as an intramural mass, and metastasized to a pelvic lymph node. Another case was a 57-year-old woman presented with genital bleeding. The tumor grew as a submucosal exophytic mass, and metastasized to the epiploic appendix. Microscopic examination of the 2 cases revealed that they were composed of sex cord-like cells, epithelioid cells and spindle cells. They exhibited solid pattern in predominance. Both solid and sex cord-like elements showed similar immunoreactivities for more than 3 sex cord markers, but simultaneously showed different staining patterns for some other markers. Characteristic features of endometrial stroma such as tongue-like infiltration and spiral arteries-like arterioles were not observed. RT-PCR analysis confirmed the absence of JAZF1-SUZ12 gene fusion, supporting the histopathological diagnosis of UTROSCT rather than ESTSCLE. The current cases warned the potential risk of UTROSCT whose biological behavior is still uncertain. We discuss histopathological, immunohistochemical and molecular findings of UTROSCT with metastasis.

Birt-Hogg-Dubé (BHD) syndrome is an inherited disease characterized by recurrent pneumothorax. We report some unusual clinicopathologic features of the lung in a Japanese family with this syndrome presenting with recurrent pneumothorax. Radiologic imaging did not show detectable lesions; however, at video-assisted thoracic surgery (VATS), multiple diffusely distributed microcysts were visible on the pleura. This characteristic morphologic feature was common to all affected family members. The proband underwent genetic testing and BHD syndrome was diagnosed. Although many patients with BHD syndrome with pneumothorax show obvious pulmonary cysts, this case suggests that radiologically indeterminate cysts have the potential to cause pneumothorax., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Although triple-negative breast cancer (TNBC) with epidermal growth factor receptor (EGFR) expression has been extensively studied, few studies have simultaneously examined EGFR expression and EGFR gene amplification. Here, we examined the correlations of EGFR expression with EGFR gene amplification, EGFR-activating mutations, and the expression of components of the Akt pathway., Methods: Tumor tissues were obtained from 84 patients with TNBC. We analyzed the expression of EGFR, phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and other relevant proteins using immunohistochemistry. We also analyzed EGFR gene and chromosome 7 copy numbers by dual-color in situ hybridization. DNA was extracted from formalin-fixed paraffin-embedded samples. Analysis of EGFR gene-activating mutations was performed using the smart amplification process version 2 assay., Results: Most TNBCs expressing EGFR are non-specialized invasive ductal carcinomas, whereas others are likely to be rare specialized carcinomas, such as typical medullary carcinoma, apocrine carcinoma, metaplastic carcinoma, and adenoid cystic carcinoma. EGFR was expressed in samples from 28 of 84 (33.3%) patients, but the EGFR gene was not amplified in any of the 84 samples. There were significant correlations between EGFR expression and the number of polysomic cells and the presence of high polysomy of chromosome 7. However, EGFR expression was not correlated with p-Akt or p-mTOR expression, nor with the other clinicopathological factors recorded in this study. We found no evidence of EGFR gene-activating mutations., Conclusions: EGFR gene amplification and EGFR-activating mutations might not be the mechanisms leading to the constitutive activation of EGFR in TNBC. Further investigation is needed to clarify the other molecular mechanisms for oncogenic activation of EGFR in TNBC.

Aims: Although there have been no conclusive pathophysiological findings in support of the degeneration theory in the etiology of schizophrenia to date, results of our neuroimaging studies suggest functional changes in the brains of schizophrenics. We evaluated age-related changes of brain perfusion in medicated patients with schizophrenia., Method: In this study, we evaluated age-related changes in brain perfusion in medicated schizophrenia patients (n = 44) and control subjects (n = 37) undergoing (99m)Tc-ethyl cysteinate dimer single-photon emission computed tomography., Result: Although the regional cerebral blood flow (rCBF) was found to be reduced in bilateral frontal lobes by analysis with age in the patients with schizophrenia, significant differences compared to controls in age effects on perfusion were found in the patients with schizophrenia in bilateral temporal lobes. Moreover, in multiple regression analysis including age, total time of treatment and overall neuroleptic dose, rCBF was found to be reduced in bilateral frontal and parietal lobes. As a result, cerebral perfusion in temporal lobes with schizophrenia might be related to age rather than medication., Conclusion: In this study, the patients with schizophrenia appeared to have significant bilateral temporal hypoperfusion related to age compared with controls. And bilateral temporal rCBF is decreased in patients with schizophrenia and even more in older schizophrenia patients. These changes might be consistent with degenerative changes observed in patients with schizophrenia and be a promising method for the efficient development of a treatment strategy by measuring temporal perfusion in patients with schizophrenia.

A 44-year-old man with type 2 diabetes of five years' duration was admitted for the management of poor glycemic control despite the administration of insulin therapy. On admission, he received vigorous treatment for a 28-year history of Crohn's disease and a 14-year history of a psychiatric disorder. His glycosylated hemoglobin A1c (HbA1c) level was 11.3%, his fasting blood glucose level was 567 mg/dL and his C-peptide level was 1.0 ng/mL. His quality of life (QOL) was severely impaired as a result of frequent episodes of hyperglycemia and hypoglycemia. Treatment with liraglutide was commenced in place of insulin, which improved the patient's glycemic control to an HbA1c level of 5.5% and markedly increased his QOL score with no hypoglycemia.

This paper examines the long and short term co-variability of QT and RR intervals for diabetic patients to explore if the QT-RR co-variability could yield a noble index for the stratification of clinical severity of the disease. Twenty four hour Holter ECG recordings are made for 19 type 2 diabetic (T2DM) patients and 25 normal subjects. RR and QT intervals are extracted from ECG signals sampled at 200 Hz and their co-variability has been examined. To see the long term QT-RR co-variability, correlation coefficients and mutual entropies between QT and RR intervals have been estimated for original beat to beat intervals and smoothed median interval series of successive one hundred beats. Mutual entropy for both beat-to-beat and smoothed median QT and RR interval series showed statistically significant differences between T2DM and control subjects whereas differences in correlation coefficients showed significant difference only for beat-to-beat intervals. Mutual entropy between both beat-to-beat and smoothed median QT-RR interval sequences showed the equally well separation between T2DM patients and control subjects: Mutual entropy and serial correlation coefficients for beat to beat intervals are respectively 1.42 ± 0.33 (bits), 0.856 ± 0.055 for control and 0.752 ± 0.23 (bits), 0.756 ± 0.10 for T2DM patients. Scatter diagram between RR and QT intervals show apparent nonlinearity which validate this result. Short term QT-RR co-variability has been examined by spline smoothed QTc series and sporadic changes have been observed for the control subjects whereas no such changes are found in diabetic patients. This new phenomenon could be a mean for the clinical characterization of diabetes.

Background: The pathophysiology of schizophrenia (SCZ) remains unclear, and its treatment is far from ideal. We have previously reported that yokukansan (YKS), which is a traditional Japanese medicine, is effective as an adjunctive therapy for SCZ. However, the mechanisms underlying the action of YKS have not yet been completely elucidated. A recent meta-analysis study has shown that adjuvant anti-inflammatory drugs are effective for SCZ treatment, and it has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Although certain ingredients of YKS have potent anti-inflammatory activity, no study has determined if YKS has anti-inflammatory properties., Methods: Using the Gunn rat, which has been reported as a possible animal model of SCZ, we investigated whether YKS affects cognitive dysfunction in an object-location test and the suppression of microglial activation and neurogenesis in the hippocampus., Results: We found that YKS ameliorated spatial working memory in the Gunn rats. Furthermore, YKS inhibited microglial activation and promoted neurogenesis in the hippocampal dentate gyrus of these rats. These results suggest that the ameliorative effects of YKS on cognitive deficits may be mediated in part by the suppression of the inflammatory activation of microglia., Conclusions: These findings shed light on the possible mechanism underlying the efficacy of YKS in treating SCZ.

The phylum Apicomplexa comprises obligate intracellular parasites that infect vertebrates. All invasive forms of Apicomplexa possess an apical complex, a unique assembly of organelles localized to the anterior end of the cell and involved in host cell invasion. Previously, we generated a chicken monoclonal antibody (mAb), 6D-12-G10, with specificity for an antigen located in the apical cytoskeleton of Eimeria acervulina sporozoites. This antigen was highly conserved among Apicomplexan parasites, including other Eimeria spp., Toxoplasma, Neospora, and Cryptosporidium. In the present study, we identified the apical cytoskeletal antigen of Cryptosporidium parvum (C. parvum) and further characterized this antigen in C. parvum to assess its potential as a target molecule against cryptosporidiosis. Indirect immunofluorescence demonstrated that the reactivity of 6D-12-G10 with C. parvum sporozoites was similar to those of anti-β- and anti-γ-tubulins antibodies. Immunoelectron microscopy with the 6D-12-G10 mAb detected the antigen both on the sporozoite surface and underneath the inner membrane at the apical region of zoites. The 6D-12-G10 mAb significantly inhibited in vitro host cell invasion by C. parvum. MALDI-TOF/MS and LC-MS/MS analysis of tryptic peptides revealed that the mAb 6D-12-G10 target antigen was elongation factor-1α (EF-1α). These results indicate that C. parvum EF-1α plays an essential role in mediating host cell entry by the parasite and, as such, could be a candidate vaccine antigen against cryptosporidiosis.