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1.  Neuroblastoma at the trigeminal nerve in a cynomolgus monkey (Macaca fascicularis) 
Journal of Toxicologic Pathology  2016;29(3):191-194.
A male cynomolgus monkey (Macaca fascicularis) of 5 years and 11 months of age from the vehicle control group of a 4-week repeated oral dose toxicity study had a spontaneously occurring mass lesion directly attached to the proximal part of the left trigeminal nerve. Histologically, the mass was characterized by a multifocal nodular appearance. Nodular zones showed low to moderate cellularity and were composed of small round cells exhibiting nuclear uniformity. On the other hand, inter-nodular zones were composed of nerve fiber containing septa and closely aggregated highly pleomorphic cells. Immunohistochemically, the small round cells were strongly immunopositive for synaptophysin, neuN, and class III beta-tubulin, while the highly pleomorphic cells were weakly immunopositive for neuN and occasionally immunopositive for class III beta-tubulin and doublecortin, suggesting that the tumor had originated from a neuronal lineage cell. Based on these findings, the mass was diagnosed as a neuroblastoma at the trigeminal nerve.
PMCID: PMC4963618  PMID: 27559245
cynomolgus monkey; trigeminal nerve; neuroblastoma
2.  Accumulation of brown pigment-laden macrophages associated with vascular lesions in the lungs of cynomolgus monkeys(Macaca fascicularis) 
Journal of Toxicologic Pathology  2016;29(3):181-184.
Accumulation of macrophages containing brown pigments in the lungs is a well-known spontaneous lesion found in cynomolgus monkey. However, its pathogenesis has not been clearly described. In our survey, brown pigment-laden macrophages were found in the lungs of 4 out of 43 cases. Brown pigments were mostly found in the macrophages of the perivascular interstitium, which proved to be hemosiderin. Some small- to medium-sized vessels that exhibited prominent accumulation of brown pigment-laden macrophages showed degeneration and necrosis of the smooth muscle cells of tunica media. Furthermore, ruptures of the internal and external elastic laminae were seen in some of the vessels. These findings suggested that partial fragmentation of the vascular elastic lamina followed by degeneration and necrosis of the tunica media caused blood leakage leading to the accumulation of hemosiderin-laden macrophages in the perivascular interstitium of the lungs.
PMCID: PMC4963612  PMID: 27559243
brown pigmentation; hemosiderin; vascular lesions; lung; cynomolgus monkey
3.  The Reduced Cochlear Output and the Failure to Adapt the Central Auditory Response Causes Tinnitus in Noise Exposed Rats 
PLoS ONE  2013;8(3):e57247.
Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input.
PMCID: PMC3596376  PMID: 23516401
4.  Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals 
SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including β-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC90s of ≤1 μg/ml. Unlike tebipenem (MIC50, 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC50, ≥128 μg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase I. SM-368589 and SM-375769, which are medoxomil esters of SM-295291 and SM-369926, respectively, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.
PMCID: PMC3553697  PMID: 23147735
5.  Splenic Hemangiosarcoma in a Young Sprague-Dawley Rat 
Journal of Toxicologic Pathology  2012;25(4):273-276.
The present report describes a rare case of spontaneous hemangiosarcoma in a nine-week-old male Sprague-Dawley rat. At necropsy, multiple white nodules of various sizes were observed on and within the enlarged spleen and liver and were histopathologically determined to be composed of spindle- to oval-shaped cells that showed invasive growth without encapsulation and were arranged solidly but partially in whorls or faint alveolar patterns with vascular-like spaces containing small clefts or erythrocytes in the tumor mass. Immunohistochemical analysis revealed that most of the tumor cells were strongly positive for vimentin, von Willebrand factor (vWF) and CD34 but negative for podoplanin. In addition, electron microscopic examination revealed the presence of Weibel-Palade bodies in the cytoplasm of the tumor cells. Based on these findings, this case was diagnosed as a hemangiosarcoma. The splenic masses were larger than the hepatic ones, with tumor cells mainly observed at periportal regions with tumor embolism in the liver, suggesting that primary hemangiosarcoma initially developed in the spleen before metastasizing.
PMCID: PMC3517923  PMID: 23345930
rat; young; spontaneous; hemangiosarcoma; Weibel-Palade bodies
6.  Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer 
BMC Urology  2011;11:7.
Primary androgen deprivation therapy (ADT) is a treatment option not only for advanced but also for localized prostate cancer. However, the appropriate duration for primary ADT for localized prostate cancer has not been defined and few studies have addressed this issue. In this study, we aimed to determine the appropriate duration of ADT for localized prostate cancer.
Sixty-eight consecutive patients with localized prostate cancer who underwent a prostatectomy following neoadjuvant ADT were retrospectively reviewed. Factors associated with pT0, which is regarded as serious cancer cell damage or elimination, were investigated.
Of the 68 males, 24 (35.3%) were classified as pT0. The median duration of neoadjuvant ADT in the pT0 and non-pT0 groups was 9 months and 7.5 months, respectively (p = 0.022). The duration of neoadjuvant ADT from when PSA reached < 0.2 ng/ml to surgery was longer in the pT0 group than that in the non-pT0 group (median 5 months against 3 months, p = 0.011). pT0 was achieved in 5 of 6 patients (83.3%) who received ADT for ≥10 months after PSA reached < 0.2 ng/ml. No other clinical characteristics predicted conversion to pT0.
Continuous ADT for ≥10 months after PSA reached < 0.2 ng/ml induced serious prostate cancer cell damage in most patients (> 80%) and may be sufficient to treat localized prostate cancer.
PMCID: PMC3116482  PMID: 21569574
7.  A Case of Spontaneous Malignant Hibernoma in a Crl:CD(SD)IGS Rat 
Journal of Toxicologic Pathology  2009;22(3):205-208.
A firm, tan, well-circumscribed mass that measured 25 × 30 × 35 mm was observed in the thoracic cavity of a 53-week-old male Crl:CD(SD) IGS rat. Histologically, the mass was encapsulated by fibrous tissue and contained fibrovascular septae. Tumor cells were compactly arranged, and most were oval to polygonal in shape with multivacuolated cytoplasm and a centrally located nucleus. In some parts of the tumor, marked cellular atypia and frequent mitoses were evident. Vacuoles in cytoplasm were positive for oil red O. The tumor cells were characterized ultrastructurally by abundant, round to oval mitochondria with transverse closely-packed cristae. Tumor cells were immunohistochemically positive for uncoupling protein 1 (UCP-1). Several thrombi and hemorrhagic or necrotic foci were also observed within the tumor mass. Vascular invasion of the tumor capsule was observed; however, invasion of surrounding tissues or metastases were not observed. Based on the pathology findings, this case was diagnosed as a malignant hibernoma.
PMCID: PMC3252043  PMID: 22271996
rat; spontaneous; malignant hibernoma; cellular atypia; vascular invasion; UCP-1
8.  Relation between psychosocial variables and the glycemic control of patients with type 2 diabetes: A cross-sectional and prospective study 
This cross-sectional and prospective study used a variety of psychological inventories to evaluate the relationship between psychosocial factors and the glycemic control of patients with type 2 diabetes.
Participants were 304 patients with type 2 diabetes who were treated as outpatients at diabetes clinics. All participants were assessed for HbA1c and completed the following self-report psychological inventories: 1) Diabetes Treatment Satisfaction Questionnaire (DTSQ), 2) Problem Areas in Diabetes Survey (PAID), 3) Well-being Questionnaire 12 (W-BQ12), 4) Self-Esteem Scale (SES), 5) Social Support Scale, and 6) Self-Efficacy Scale. HbA1c was again measured one year later. The relationships between the psychosocial variables obtained by analysis of the psychological inventories and baseline or one-year follow-up HbA1c were determined.
Baseline HbA1cwas significantly correlated with age, diet treatment regimen, number of microvascular complication of diabetes, and the total scores of DTSQ, W-BQ12, PAID, SES and the Self-Efficacy Scale. Hierarchical stepwise multiple regression revealed that significant predictors of baseline HbA1c were total DTSQ and PAID scores, along with age, diet treatment regimen, and number of microvascular complication of diabetes after adjustment for demographic, clinical and other psychosocial variables. Two hundred and ninety patients (95.4% of 304) were followed and assessed one year after baseline. Hierarchical stepwise multiple regression analysis showed the significant predictors of follow-up HbA1c to be total DTSQ and PAID scores, along with age and diet treatment regimen. However, the correlation between baseline and follow-up HbA1c was so high that the only other variable to retain significance was diet treatment regimen once baseline HbA1c was included in the regression of follow-up HbA1c.
The DTSQ and the PAID predicted both current and future HbA1c to a similar and significant degree in patients with type 2 diabetes.
PMCID: PMC2667542  PMID: 19298645
9.  Double-balloon endoscopy in the diagnosis and management of GI tract diseases: Methodology, indications, safety, and clinical impact 
AIM: To prospectively evaluate the indications, methodology, safety, and clinical impact of double-balloon endoscopy.
METHODS: A total of 60 patients with suspected or documented small- or large-bowel diseases were investigated by double balloon endoscopy. A total of 103 procedures were performed (42 from the oral route, 60 from the anal route, and 1 from the stoma route). The main outcome measurements were the time of insertion and the entire examination, complications, diagnostic yields, and the ability to successfully perform treatment.
RESULTS: Observation of the entire small intestine was possible in 10 (40%) of 25 patients with total enteroscopy. The median insertion time was 122 min (range, 74-199 min). Observation of the entire colon was possible in 13 (93%) of 14 patients after failure of total colonoscopy using a conventional colonoscope. Small-intestine abnormalities were found in 20 (43%) of 46 patients with indications of suspected or documented small bowel diseases, obscure GI tract bleeding, or a history of ileus. Endoscopic procedures including tattooing (n = 33), bite biopsy (n = 17), radiographic examination (n = 7), EUS (n = 5), hemostasis (n = 1), polypectomy (n = 5), balloon dilatation (n = 1), endoscopic mucosal resection (n = 1) and lithotripsy (n = 1) were all successfully performed. No relevant technical problems or severe complications were encountered.
CONCLUSION: Double balloon endoscopy is a feasible technique that allows adequate small and large bowel examination and potentially various endoscopic procedures of small-intestinal lesions. It is safe, useful, and also provides a high clinical impact.
PMCID: PMC4088048  PMID: 17171795
Double-balloon endoscopy; GI tract disease; Endoscopic therapy
10.  Safety advantage of endocut mode over endoscopic sphincterotomy for choledocholithiasis 
AIM: To evaluate whether an automatically controlled cut system (endocut mode) could reduce the complication rate of endoscopic sphincterotomy (EST) and serum hyperamylasemia after EST compared to the conventional blended cut mode.
METHODS: From January 2001 to October 2003, 134 patients with choledocholithiasis were assigned to either endocut mode group or conventional blended cut mode group at the time of sphincterotomy. The two groups were retrospectively compared for the complications after EST and serum amylase level before and 24 h after the procedure.
RESULTS: Of the 134 patients treated, 79 were assigned to conventional blended cut mode group and 55 to endocut mode group. There was no significant difference in age, sex, and serum amylase level before EST between the two groups. Complications were found in 5 patients of the endocut mode group (9%): hyperamylasemia (5 times higher than normal) in 4 and moderate pancreatitis in 1. Complications were found in 13 patients of the conventional blended cut mode group (16%): hyperamylasemia in 12 and moderate pancreatitis in 1. Serum amylase levels were elevated in both groups 24 h after EST (P < 0.02). The average serum amylase level 24 h after EST in the conventional blended cut mode group was significantly higher than that in the endocut mode group (P < 0.05).
CONCLUSION: Endocut mode offers a safety advantage over conventional blended cut mode for pancreatitis after EST by reducing hyperamylasemia.
PMCID: PMC4087690  PMID: 16610062
Endocut mode; Endoscopic sphincterotomy; Choledocholithiasis
11.  Role of Nerve Growth Factor in Cutaneous Wound Healing: Accelerating Effects in Normal and Healing-impaired Diabetic Mice  
Four full-thickness skin wounds made in normal mice led to the significant increase in levels of nerve growth factor (NGF) in sera and in wounded skin tissues. Since sialoadenectomy before the wounds inhibited the rise in serum levels of NGF, the NGF may be released from the salivary gland into the blood stream after the wounds. In contrast, the fact that messenger RNA and protein of NGF were detected in newly formed epithelial cells at the edge of the wound and fibroblasts consistent with the granulation tissue produced in the wound space, suggests that NGF was also produced at the wounded skin site. Topical application of NGF into the wounds accelerated the rate of wound healing in normal mice and in healing-impaired diabetic KK/Ta mice. This clinical effect of NGF was evaluated by histological examination; the increases in the degree of reepithelialization, the thickness of the granulation tissue, and the density of extracellular matrix were observed. NGF also increased the breaking strength of healing linear wounds in normal and diabetic mice. These findings suggested that NGF immediately and constitutively released in response to cutaneous injury may contribute to wound healing through broader biological activities, and NGF improved the diabetic impaired response of wound healing.
PMCID: PMC2212117  PMID: 9449710

Results 1-11 (11)