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1.  Small molecule annotation for the Protein Data Bank 
The Protein Data Bank (PDB) is the single global repository for three-dimensional structures of biological macromolecules and their complexes, and its more than 100 000 structures contain more than 20 000 distinct ligands or small molecules bound to proteins and nucleic acids. Information about these small molecules and their interactions with proteins and nucleic acids is crucial for our understanding of biochemical processes and vital for structure-based drug design. Small molecules present in a deposited structure may be attached to a polymer or may occur as a separate, non-covalently linked ligand. During curation of a newly deposited structure by wwPDB annotation staff, each molecule is cross-referenced to the PDB Chemical Component Dictionary (CCD). If the molecule is new to the PDB, a dictionary description is created for it. The information about all small molecule components found in the PDB is distributed via the ftp archive as an external reference file. Small molecule annotation in the PDB also includes information about ligand-binding sites and about covalent and other linkages between ligands and macromolecules. During the remediation of the peptide-like antibiotics and inhibitors present in the PDB archive in 2011, it became clear that additional annotation was required for consistent representation of these molecules, which are quite often composed of several sequential subcomponents including modified amino acids and other chemical groups. The connectivity information of the modified amino acids is necessary for correct representation of these biologically interesting molecules. The combined information is made available via a new resource called the Biologically Interesting molecules Reference Dictionary, which is complementary to the CCD and is now routinely used for annotation of peptide-like antibiotics and inhibitors.
doi:10.1093/database/bau116
PMCID: PMC4243272  PMID: 25425036
2.  Brain structural abnormalities in behavior therapy-resistant obsessive-compulsive disorder revealed by voxel-based morphometry 
Background
Although several functional imaging studies have demonstrated that behavior therapy (BT) modifies the neural circuits involved in the pathogenesis of obsessive-compulsive disorder (OCD), the structural abnormalities underlying BT-resistant OCD remain unknown.
Methods
In this study, we examined the existence of regional structural abnormalities in both the gray matter and the white matter of patients with OCD at baseline using voxel-based morphometry in responders (n=24) and nonresponders (n=15) to subsequent BT. Three-dimensional T1-weighted magnetic resonance imaging was performed before the completion of 12 weeks of BT.
Results
Relative to the responders, the nonresponders exhibited significantly smaller gray matter volumes in the right ventromedial prefrontal cortex, the right orbitofrontal cortex, the right precentral gyrus, and the left anterior cingulate cortex. In addition, relative to the responders, the nonresponders exhibited significantly smaller white matter volumes in the left cingulate bundle and the left superior frontal white matter.
Conclusion
These results suggest that the brain structures in several areas, including the orbitofrontal cortex, anterior cingulate cortex, and cingulate bundles, are related to the lack of a response to BT in patients with OCD. The use of a voxel-based morphometry approach may be advantageous to understanding differences in brain abnormalities between responders and nonresponders to BT.
doi:10.2147/NDT.S69652
PMCID: PMC4208702  PMID: 25349476
OCD; treatment resistance; orbitofrontal cortex
3.  Retention of the posterior cruciate ligament does not affect femoral rotational alignment in TKA using a gap-balance technique 
Purpose
Previous studies have evaluated the ability of the gap technique to achieve accurate rotational placement in both posterior cruciate ligament (PCL)-retaining and PCL-substituting total knee arthroplasty (TKA). The purpose of the present study was to determine (1) the accuracy of this technique in degrees and (2) whether retention of the PCL affects the rotational alignment of the femoral component relative to the transepicondylar axis during TKA. The hypothesis of this study was that retention of the PCL does not affect the femoral rotational alignment in TKA using a gap-balancing technique because both procedures are reported to have good long-term clinical outcomes.
Methods
The femoral rotation angle (FRA) relative to the transepicondylar axis was examined in 206 patients who underwent primary TKA using either PCL-retaining (104 knees) or PCL-substituting (102 knees) prostheses to determine the effect of PCL retention on FRA. Quantitative three-dimensional computed tomography was used to assess the FRA in both groups. All values are expressed as median (25th percentile, 75th percentile).
Results
Postoperative FRA in the PCL-retaining group was −1.1° (−2.8°, 2.2°) and in the PCL-substituting group was −0.1° (−2.5°, 2.8°). The groups were not statistically different. One outlier was found in the PCL-retaining group, and none was found in the PCL-substituting group.
Conclusions
The gap technique reliably allows accurate rotational alignment of the femoral component during TKA despite the retention of the PCL.
Level of evidence
Therapeutic study, Level II.
doi:10.1007/s00167-014-3218-8
PMCID: PMC4237913  PMID: 25119053
PCL retention; Femoral rotational alignment; TKA; Gap-balance technique
4.  Follicular Thyroid Carcinoma Characterized by Abundant Stromal Components with Chondroid and Osseous Metaplasia in a Dog 
ABSTRACT
A dog developed a cervical mass, and computed tomography verified a mass surrounding the trachea with some pulmonary masses. Histopathologically, the cervical mass was composed of malignant neoplastic cells showing follicular appearance which reacted positive for thyroglobulin on immunohistochemistry. A characteristic feature of the tumor was abundant and metaplastic stromal components. Anastomosed collagenous tissues connecting to capsule of the tumor were abundant in the stroma. In parts of the collagenous tissues, mature cartilages and bones were continuously formed. There was no cellular atypia or invasion in the components. We diagnosed this case as follicular thyroid carcinoma with metaplastic stroma. This is the first case report that characterizes stromal components with chondroid and osseous metaplasia in a canine thyroid carcinoma.
doi:10.1292/jvms.13-0529
PMCID: PMC4155200  PMID: 24805905
canine; chondroid metaplasia; follicular thyroid carcinoma; osseous metaplasia; tumor stroma
5.  Histological Characteristics of the Regression of Corpora Lutea in Wistar Hannover Rats: the Comparisons with Sprague-Dawley Rats 
Journal of Toxicologic Pathology  2014;27(2):107-113.
We examined the ovaries of 44 Wistar Hannover (RccHanTM:WIST) (WH) and 30 Sprague-Dawley (SD) rats at 32-weeks of age to determine whether the ovarian structure and formation/regression of the corpora lutea (CLs) differ between the two strains. The average ovary weight was higher in WH rats. The average number of all CLs, including currently formed and previously formed CLs, was higher in WH rats in all cycles; however, no appreciable difference was detected in the number of newly or currently formed CLs between the two strains. CLs regression characterized by degeneration and necrosis of luteal cells began to appear in diestrus in both strains; however, the distribution of degenerated/necrotic cells in CLs differed. Necrotic cells were scattered in SD rats but were focally observed in the center of the CL in WH rats. The reduction in size of previously formed CLs accompanied by regression started about 2 or more stages later in WH rats than in those of SD rats. In conclusion, the higher number of CLs in WH rats is considered to be due to slow CL regression compared with in SD rats.
doi:10.1293/tox.2013-0054
PMCID: PMC4110934  PMID: 25352711
Wistar Hannover; Sprague-Dawley; rat; ovary; corpora lutea; estrous cycle
6.  Profiles of Extracellular miRNAs in the Aqueous Humor of Glaucoma Patients Assessed with a Microarray System 
Scientific Reports  2014;4:5089.
Aqueous humor (AH) is one of the body fluids in the eye, which is known to be related with various ocular diseases, but the complete RNAs characteristic of the AH in patients is not yet known. The aim of this study was, with a microarray analysis, to reveal the disease-related extracellular miRNAs profiles in individual patients AH. 100 μl of AH was collected by anterior chamber paracentesis from 10 glaucoma, 5 cataract, and 5 epiretinal membrane patients. The extracted total RNAs were shorter than 200 nt, and their amount was 5.27 ± 0.41 ng in average. Among 530.5 ± 44.6 miRNA types detected in each sample with a microarray detectable 2019 types of matured miRNAs, 172 miRNAs were detected in all 10 glaucoma or control patients. From the glaucoma group, 11 significantly up-regulated and 18 significantly down-regulated miRNAs (P < 0.05 for both) were found to have areas under the curve better than 0.74 in a receiver operating characteristic analysis. They also formed a cluster composed only of glaucoma patients in a hierarchal cluster analysis. AH had a possibility of becoming a source of miRNA that can serve as a biomarker and a therapeutic target.
doi:10.1038/srep05089
PMCID: PMC4035584  PMID: 24867291
7.  Neural basis of three dimensions of agitated behaviors in patients with Alzheimer disease 
Background
Agitated behaviors are frequently observed in patients with Alzheimer disease (AD). The neural substrate underlying the agitated behaviors in dementia is unclear. We hypothesized that different dimensions of agitated behaviors are mediated by distinct neural systems.
Methods
All the patients (n=32) underwent single photon emission computed tomography (SPECT). Using the Agitated Behavior in Dementia scale, we identified the relationships between regional cerebral blood flow (rCBF) patterns and the presence of each of three dimensions of agitated behavior (physically agitated behavior, verbally agitated behavior, and psychosis symptoms) in AD patients. Statistical parametric mapping (SPM) software was used to explore these neural correlations.
Results
Physically agitated behavior was significantly correlated with lower rCBF values in the right superior temporal gyrus (Brodmann 22) and the right inferior frontal gyrus (Brodmann 47). Verbally agitated behavior was significantly associated with lower rCBF values in the left inferior frontal gyrus (Brodmann 46, 44) and the left insula (Brodmann 13). The psychosis symptoms were significantly correlated with lower rCBF values in the right angular gyrus (Brodmann 39) and the right occipital lobe (Brodmann 19).
Conclusion
Our results support the hypothesis that three different agitated behaviors may represent distinct neural networks in AD patients.
doi:10.2147/NDT.S57522
PMCID: PMC3933703  PMID: 24600224
physically agitated behavior; verbally agitated behavior; psychosis; SPECT
8.  Characteristics and significance of fever during 4 weeks after primary total knee arthroplasty 
Purpose
Most previous studies on postoperative fever (POF; ≥38 °C) after total knee arthroplasty (TKA) have reported findings from only the immediate postoperative days (PODs). The hypothesis of the current study is that 4 weeks of follow-up may reveal differences in the characteristics of POF and fever-related factors between a normal inflammatory response and an early acute infection-related response.
Methods
A total of 400 consecutive TKAs (314 patients) were retrospectively investigated. Patients were stratified into those who developed an early acute periprosthetic infection that required subsequent surgical treatment (STG; n = 5 TKAs) and those who did not (non-STG; n = 395 TKAs).
Results
Among the 400 knees, 149 (37 %) developed POF, with most reaching a maximum temperature (MT) on POD 0. In 13 TKA patients who had POF with a peak daily temperature ≥38 °C during postoperative weeks 2–4, the causes of POF were respiratory and urinary tract infections (n = 5 for each), superficial infection (n = 2), and periprosthetic infection (n = 1). The STG and non-STG differed significantly with regard to the rate of POF (p = 0.0205) and MT (p = 0.0003), including MTs less than 38 °C, during postoperative weeks 2–4. All five STG patients had elevated C-reactive protein levels and local symptomatic findings before the additional surgery.
Conclusions
The occurrence of POF and MT along with elevated C-reactive protein and local symptomatic findings at 2–4 weeks postoperatively may indicate the need for a positive fever workup to recognize early acute periprosthetic infection.
doi:10.1007/s00402-014-1949-0
PMCID: PMC3990857  PMID: 24522863
Total knee arthroplasty; Postoperative fever; Maximum temperature; Periprosthetic infection
9.  Anteroposterior Translation Does Not Correlate With Knee Flexion After Total Knee Arthroplasty 
Background
Stiffness after a TKA can cause patient dissatisfaction and diminished function, therefore it is important to characterize predictors of ROM after TKA. Studies of AP translation in conscious individuals disagree whether AP translation affects maximum knee flexion angle after implantation of a highly congruent sphere and trough geometry PCL-substituting prosthesis in a TKA.
Questions/purposes
We investigated whether AP translation correlated with maximum knee flexion angle (1) in patients who were awake, and (2) who were under anesthesia (to minimize the effects of voluntary muscle contraction) in a TKA with implantation of a PCL-substituting mobile-bearing prosthesis.
Methods
AP translation was examined under both conditions in 34 primary TKAs. Measurements under anesthesia were performed when the patients were having anesthesia for a contralateral TKA. Awake measurements were made within 4 days of that anesthetic session in patients who had no residual sedative effects. The average postoperative interval for the index TKA flexion measurements was 23 months (range, 6–114 months). AP translation was evaluated at 75° flexion using an arthrometer.
Results
There was no correlation between postoperative maximum knee flexion and AP translation at 75° during consciousness. There was no correlation between postoperative maximum knee flexion and AP translation under anesthesia.
Conclusion
AP translation at 75° flexion did not correlate with postoperative maximum knee flexion in either awake or anesthetized patients during a TKA with implantation of a posterior cruciate-substituting prosthesis.
Level of Evidence
Level II, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-013-3274-2
PMCID: PMC3890185  PMID: 24005980
10.  Corneal Mineralization in Wistar Hannover Rats 
Journal of Toxicologic Pathology  2013;26(3):275-281.
We have recently started using Wistar Hannover rats in Japan and are now collecting background data. We have been frequently observing corneal mineralization in Wistar Hannover rats of both the RccHanTM:WIST and Crl:WI (Han) strains. In this study, details of corneal mineralization in Wistar Hannover rats were histopathologically and ultrastructurally investigated. According to the results, Wistar Hannover rats had a much higher incidence of corneal mineralization compared with Sprague-Dawley rats. The incidence of corneal mineralization was higher in males than females. According to the histological examination, mineral deposits were positive for calcium by von Kossa’s method. Furthermore, in response to mineralization, keratocytes probably become active to play an important role against the mineralized substance.
doi:10.1293/tox.26.275
PMCID: PMC3787605  PMID: 24155560
Wistar Hannover rat; Background data; Cornea; Mineralization; Keratocyte
11.  Bacterial Pleuritis with Thickened Mesothelial Hyperplasia in a Young Beagle Dog 
Journal of Toxicologic Pathology  2013;26(3):313-317.
A five-month-old male beagle dog suddenly became moribund. Bloody fluid accumulated in the thoracic and abdominal cavities, and soft yellow flecks were floating in the thoracic fluid. The mediastinum and pericardium became dark reddish with villous thickening. Other parietal and pulmonary pleurae were rough, and the organs adhered to each other. Histologically, most mediastinal pleura formed papillary projections covered by a single layer of mesothelial cells. Many macrophages and neutrophils infiltrated the submesothelial connective tissue. At the mediastinum adjacent to the pericardium, cuboidal mesothelial cells proliferated solidly and formed a thick surface stratum. The flecks consisted of gram-negative filamentous or small bacillary (coccoid) bacteria. In the right posterior lobe of the lung, neutrophilic infiltration and a large encapsulated abscess including a bacterial colony were present. We diagnosed this case as “bacterial pleuritis with thickened mesothelial hyperplasia”. The cause of the pleuritis might be a chronic pleural infection spread via the lung abscess.
doi:10.1293/tox.26.313
PMCID: PMC3787610  PMID: 24155565
bacterial pleuritis; mesothelial hyperplasia; beagle dog; Escherichia coli; Serratia odorifera; Acinetobacter lwoffii
12.  Posterior Condylar Offset Does Not Correlate With Knee Flexion After TKA 
Background
Studies of medial and lateral femoral posterior condylar offset have disagreed on whether posterior condylar offset affects maximum knee flexion angle after TKA.
Questions/purposes
We asked whether posterior condylar offset was correlated with knee flexion angle 1 year after surgery in (1) a PCL-retaining meniscal-bearing TKA implant, or in (2) a PCL-substituting mobile-bearing TKA implant.
Methods
Knee flexion angle was examined preoperatively and 12 months postoperatively in 170 patients who underwent primary TKAs to clarify the effect of PCL-retaining (85 knees) and PCL-substituting (85 knees) prostheses on knee flexion angle. A quasirandomized design was used; patients were assigned to receive one or the other implant using chart numbers. A quantitative three-dimensional technique with CT was used to examine individual changes in medial and lateral posterior condylar offsets.
Results
In PCL-retaining meniscal-bearing knees, there were no significant correlations between posterior condylar offset and knee flexion at 1 year. In these knees, the mean (± SD) postoperative differences in medial and lateral posterior condylar offsets were 0.0 ± 3.6 mm and 3.8 ± 3.6 mm, respectively. The postoperative change in maximum knee flexion angle was −5° ± 15°. In PCL-substituting rotating-platform knees, similarly, there were no significant correlations between posterior condylar offset and knee flexion 1 year after surgery. In these knees, the mean postoperative differences in medial and lateral posterior condylar offsets were −0.5 ± 3.3 mm and 3.3 ± 4.2 mm, respectively. The postoperative change in maximum knee flexion angle was −2° ± 18°.
Conclusions
Differences in individual posterior condylar offset with current PCL-retaining or PCL-substituting prostheses did not correlate with changes in knee flexion 1 year after TKA. We should recognize that correctly identifying which condyle affects the results of the TKA may be difficult with conventional radiographic techniques.
Level of Evidence
Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-013-2999-2
PMCID: PMC3734430  PMID: 23609812
13.  Decreased white matter integrity before the onset of delusions in patients with Alzheimer’s disease: diffusion tensor imaging 
Background
The pathology of delusions in patients with Alzheimer’s disease (AD) associated with white matter (WM) abnormalities is poorly understood. In addition, whether the abnormalities in WM integrity that underlie the delusions develop before the onset of the delusions remains unclear. In this study, we used a diffusion tensor imaging approach to examine the existence of baseline abnormalities in WM integrity in AD patients who developed delusions and AD patients who did not develop delusions.
Methods
Using the Neuropsychiatric Inventory, we identified patients with AD who exhibit delusions during a 1-year period. All the patients underwent a magnetic resonance imaging (MRI) examination at baseline. We conducted fractional anisotropy using tract-based spatial statistics software and compared the results of AD patients who developed delusions with those who did not develop delusions.
Results
Compared with the AD patients who did not develop delusions (n = 15), the AD patients who developed delusions (n = 10) exhibited two relatively large clusters and one minimal cluster of significantly lower fractional anisotropy results. The first cluster was located in the left parieto-occipital region and included several fibers: the left inferior longitudinal fasciculus, the inferior fronto-occipital fasciculus, the posterior corona radiate, and the forceps major of the corpus callosum. The second cluster was located on the body of the corpus callosum. A third minimal cluster was located on the superior temporal gyrus white matter.
Conclusion
Abnormalities in WM integrity involving several fibers may be crucial to the development of delusions in AD patients.
doi:10.2147/NDT.S38942
PMCID: PMC3534309  PMID: 23293524
Alzheimer’s disease; white matter; DTI; delusions; tract-based spatial statistics
14.  Behavior management approach for agitated behavior in Japanese patients with dementia: a pilot study 
Background
Agitated behaviors are frequently observed in patients with dementia and can cause severe distress to caregivers. However, little evidence of the efficacy of nonpharmacological interventions for agitated behaviors exists for patients with dementia. The present pilot study aimed to evaluate a behavioral management program developed by the Seattle Protocols for patients with agitated behaviors in Japan.
Methods
Eighteen patients with dementia (Alzheimer’s disease, n = 14; dementia with Lewy bodies, n = 4) participated in an open study testing the effectiveness of a behavioral management program. The intervention consisted of 20 sessions over the course of 3 months. The primary outcomes were severity of agitation in dementia, as measured using the Agitated Behavior in Dementia scale (ABID) and the Cohen-Mansfield Agitation Inventory (CMAI).
Results
The behavioral management program resulted in significant reductions in total scores on both the ABID and CMAI. Although both physically agitated and verbally agitated behavior scores on the ABID improved significantly, symptoms of psychosis did not improve after the intervention.
Conclusion
The behavioral management technique may be beneficial to distressed caregivers of patients with dementia. In the future, a well designed study to develop the behavioral management program more fully is needed.
doi:10.2147/NDT.S38943
PMCID: PMC3533688  PMID: 23293522
Alzheimer’s disease; dementia with Lewy bodies; agitated behavior; behavioral management; Agitated Behavior in Dementia scale
15.  Neuroanatomical abnormalities before onset of delusions in patients with Alzheimer’s disease: a voxel-based morphometry study 
Background
Structural brain abnormalities associated with delusions in Alzheimer’s disease are poorly understood. In addition, whether the neural substrate underlying the delusions develops before the onset of the delusions is unclear. In this study, we used a voxel-based morphometry approach to examine the existence of regional structural abnormalities at baseline in patients with Alzheimer’s disease who did and who did not develop delusions.
Methods
Using the Neuropsychiatric Inventory, we identified patients with Alzheimer’s disease who exhibited delusions during a 2-year period. All the patients had undergone a magnetic resonance imaging examination at the start of the study period (baseline). We conducted a voxel-based morphometry analysis using statistical parametric mapping (SPM5) software and compared the results of patients with Alzheimer’s disease who did and did not develop delusions.
Results
Compared with the patients who did not develop delusions (n = 35), the patients who did develop delusions (n = 18) had significantly smaller gray matter volumes on both sides of the parahippocampal gyrus, the right posterior cingulate gyrus, the right orbitofrontal cortex, both sides of the inferior frontal cortex, the right anterior cingulate, and the left insula.
Conclusion
Structural brain abnormalities involving both the frontal and medial temporal lobes may be crucial to the expression of delusions in patients with Alzheimer’s disease.
doi:10.2147/NDT.S38939
PMCID: PMC3533692  PMID: 23293521
Alzheimer’s disease; delusions; structural brain abnormalities; voxel-based morphometry
16.  Age-related Histological Findings in the Pineal Gland of Crl:CD(SD) Rats 
Journal of Toxicologic Pathology  2012;25(4):287-291.
To provide background data as the pathologic basis, the pineal glands of 190 male and 193 female Crl:CD(SD) rats at ages of 0–7, 51–58, 70–85 and 111 weeks were examined histologically in this study. Mineralization and fibrosis were common findings in the aged rats, whereas they were rarely found in the young ones; mineralization was present in 7, 44, 67 and 79% of males and in 0, 32, 67 and 79% in females, and fibrosis was present in 0, 29, 48 and 44% of males and 0, 18, 40 and 35% of females at ages of 0–7, 51–58, 70–85 and 111 weeks, respectively. Striated muscle fiber appeared regularly in the fibrosis region from 51–58 weeks of age when fibrosis increased, while the origin of this fiber remained unclear. Vacuolation of pineal cells also increased with age in both sexes, though the total incidence was low. There was a low incidence of lymphocytic infiltration in both sexes, but this was not related to age.
doi:10.1293/tox.25.287
PMCID: PMC3517926  PMID: 23345933
pineal gland; spontaneous lesion; age-related finding; striated muscle fiber; rat
17.  Safety and efficacy of a new tourniquet system 
BMC Surgery  2012;12:17.
Background
In upper limb surgery, the pneumatic tourniquet is an essential tool to provide a clean, bloodless surgical field, improving visualization of anatomical structures and preventing iatrogenic failure. Optimal inflation pressure to accomplish these objects without injuring normal tissue and inducing complications is not yet established. Use of the minimum tourniquet pressure necessary to produce a bloodless surgical field is preferable in order to prevent injury to normal tissue. Various methods have been implemented in an effort to lower effective cuff pressure. The purpose of this study is to report clinical experience with a new tourniquet system in which pressure is synchronized with systolic blood pressure (SBP) using a vital information monitor.
Methods
We routinely used the tourniquet system in 120 consecutive upper limb surgeries performed under general anaesthesia in our operating room instead of our clinic. Cuff pressure was automatically regulated to additional 100 mmHg based on the SBP and was renewed every 2.5 minutes intervals.
Results
An excellent bloodless field was obtained in 119 cases, with the exception of one case of a 44-year-old woman who underwent internal screw fixation of metacarpal fracture. No complications, such as compartment syndrome, deep vein disorder, skin disorder, paresis, or nerve damage, occurred during or after surgery.
Conclusions
This new tourniquet system, synchronized with SBP, can be varied to correspond with sharp rises or drops in SBP to supply adequate pressure. The system reduces labor needed to deflate and re-inflate to achieve different pressures. It also seemed to contribute to the safety in upper limb surgery, in spite of rare unexpected oozing mid-surgery, by reducing tissue pressure.
doi:10.1186/1471-2482-12-17
PMCID: PMC3465201  PMID: 22894765
Tourniquet; Upper limb surgery; Systolic blood pressure; Autoregulation
18.  Continuous glucose monitoring system: Is it really accurate, safe and clinically useful? 
Abstract
The continuous glucose monitoring system (CGM) has been used for constant checking of glucose level by measuring interstitial glucose concentrations, since the early days of the 21st century. It can potentially improve diabetes care if used carefully with the understanding of the characteristics of this system. Although there is a time lag of approximately 5–15 min between blood and interstitial glucose levels, the system is considered the most suitable device for meticulous glucose control and prevention of hypoglycemia. A large number of studies have examined its accuracy, safety and clinical effectiveness. The continuous glucose‐error grid analysis (CG‐EGA), designed by WL Clarke, evaluates the clinical accuracy of CGM. It examines ‘temporal’ characteristics of the data, analyzing pairs of reference and sensor readings as a process in time represented by a ‘bidimensional’ time series and taking into account inherent physiological time lags. Investment in CG‐EGA is clearly meaningful, even though there are other methodologies for evaluation. The use of each method complementarily is the most effective way to prove the accuracy of the device. The device has improved gradually, and real‐time CGM, which allows real‐time monitoring of blood glucose level, is already available commercially. The use of real‐time CGM could potentially lead to over‐ or undertreatment with insulin. Patient education through proper and effective handling of the new device is essential to improve diabetes care. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00197.x, 2012)
doi:10.1111/j.2040-1124.2012.00197.x
PMCID: PMC4014941  PMID: 24843568
Continuous glucose monitoring system; Continuous glucose‐error grid analysis; Patient education
19.  Histopathology of Incidental Findings in Cynomolgus Monkeys (Macaca Fascicularis) Used in Toxicity Studies 
Journal of Toxicologic Pathology  2012;25(1):63-101.
The purpose of our publication is to widely communicate pictures of spontaneous findings occurring in cynomolgus monkeys. Focal lymphoplasmacytic infiltration is commonly seen in the general organs. The frequency and severity of these lesions may be influenced by the administration of drugs with an effect on the immune system. Lymphoplasmacytic infiltration in the lamina propria of the stomach is also frequently seen in cynomolgus monkeys, and it is caused mainly by a Helicobacter pylori infection. Various degrees of brown pigments are observed in various organs, and it is possible to distinguish the material of the pigments by its morphological features and site. A focal/segmental glomerular lesion is occasionally seen in a section of the kidney, and the minimal lesion has no influence on the urinalysis. We showed the common glomerular lesions in HE-stained sections, as well as in PAM- or PAS-stained sections, for understanding the details. Young and pubertal monkeys are usually used in toxicity studies; therefore, understanding various maturation stages of the genital system is important. In particular, the female genital system needs to be understood in the morphology, because their cyclic changes are different from other laboratory animals. Thus, we present the normal features of the cyclic changes of the female genital organs. Furthermore, we provide more information on spontaneous findings in cynomolgus monkeys for exact diagnoses in toxicity studies.
doi:10.1293/tox.25.63
PMCID: PMC3320159  PMID: 22481861
cynomolgus monkey; spontaneous; incidental; histopathology; background
20.  Histopathology of Incidental Findings in Beagles Used in Toxicity Studies 
Journal of Toxicologic Pathology  2012;25(1):103-134.
The purpose of our publication is to widely communicate the pictures of spontaneous findings occurring in beagles. Spontaneous arteritis occurs commonly in beagles. Frequent sites of arteritis are the heart, spleen, pancreas, epididymis and spinal cord. Morphological similarities between spontaneous and drug-induced arterial lesions may cause confusion when evaluating vascular toxicity of chemicals such as vasodilating agents. Focal and minimal inflammatory lesions are occasionally seen in the lung and may be associated with aspiration of food particles or of unknown causes. A cystic change with copious mucin production occurs occasionally in the mucosal epithelium of the gall bladder. Nesidioblastosis is seen rarely in the pancreas of beagles. C-cell complex and lymphocytic thyroiditis are common thyroid lesions. Spontaneous focal hypospermatogenesis and lobular Sertoli-cell-only seminiferous tubules occurring frequently in beagles must be distinguished from drug-induced damage of the seminiferous tubules in toxicity studies. The morphological differences of the female genital system in each cycle need to be understood; therefore, we present the normal features of the cyclic changes of the female genital organs. Further, we provide more information on spontaneous findings in beagles for exact diagnoses in toxicity studies.
doi:10.1293/tox.25.103
PMCID: PMC3320160  PMID: 22481862
beagle; spontaneous; incidental; histopathology; background
21.  Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia 
Background
The synapse-associated protein 97 gene (SAP97) encodes a regulatory scaffold protein for the localization of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) type glutamate receptors. We have recently demonstrated nominally significant associations between SAP97 gene and schizophrenia among Japanese males. The present study aimed to replicate these findings using an independent and larger sample.
Methods
We investigated seven SAP97 single nucleotide polymorphisms (SNPs) that displayed a significant association with schizophrenia in our preceding study in an independent Japanese population consisting of a total of 393 unrelated patients with schizophrenia (232 males and 161 females) and 393 unrelated control subjects (211 males and 182 females).
Results
The SNP rs9843659 showed a significant genotypic association with male patients in a recessive model (p = 0.037). The analysis of the combined data from the current and prior studies also demonstrated a significant association of this SNP (p = 0.0039). The meta-analysis for the allele frequency covering the two studies yielded an odds ratio of 1.38.
Conclusions
The present study replicated the previously reported male-selective genetic association between the SAP97 polymorphism and schizophrenia. These findings further support the possible involvement of the SAP97 gene variation in the susceptibility to schizophrenia in males and in the genetic basis for sex differences in the disorder.
doi:10.1186/1744-9081-8-2
PMCID: PMC3275478  PMID: 22225629
Schizophrenia; genetic association; single nucleotide polymorphisms; synapse-associated protein; scaffolding protein; SAP97; gender selective; glutamate
22.  Comparison of effects of azelnidipine and trichlormethiazide in combination with olmesartan on blood pressure and metabolic parameters in hypertensive type 2 diabetic patients 
Abstract
Aims/Introduction:  Angiotensin II type 1 receptor blockers (ARB) are regarded as first‐line treatment for type 2 diabetes with hypertension. However, lowering blood pressure to the target level often requires more than one antihypertensive agent as recommended by the guideline. In this open‐label, prospective, crossover clinical trial, we compared the effects of combination treatment of ARB with a calcium channel blocker (CCB) or with a low‐dose thiazide diuretic on blood pressure (BP) and various metabolic parameters in hypertensive patients with type 2 diabetes.
Materials and Methods:  A total of 39 Japanese type 2 diabetics with hypertension treated with olmesartan (20 mg/day) for at least 8 weeks were recruited to this study. At study entry, treatment was switched to either olmesartan (20 mg/day)/azelnidipine (16 mg/day) or olmesartan (20 mg/day)/trichlormethiazide (1 mg/day) and continued for 12 weeks. Then, the drugs were switched and treatment was continued for another 12 weeks. We measured clinical blood pressure and various metabolic parameters before and at the end of each study arm.
Results:  Compared with the olmesartan/trichlormethiazide treatment, treatment with olmesartan/azelnidipine achieved superior clinical blood pressure and pulse rate control. In contrast, the treatment with olmesartan/trichlormethiazide resulted in increased HbA1c, serum uric acid and worsening of estimated glomerular filtration rate, though there were no differences in other metabolic parameters including urine 8‐hydroxy‐2′‐deoxyguanosine, C‐reactive protein and adiponectin between the two treatments.
Conclusions:  Our results show that the combination of ARB with azelnidipine is more beneficial with regard to blood pressure control and metabolic outcome than the combination of olmesartan with low dose trichlormethiazide. This trial was registered with UMIN clinical trial registry (no. UMIN000005064). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00135.x, 2011)
doi:10.1111/j.2040-1124.2011.00135.x
PMCID: PMC4014909  PMID: 24843534
Calcium channel blocker; Thiazide diuretic; Angiotensin II type 1 receptor blockers
23.  Mixed Thymoma in a Young Cynomolgus Monkey (Macaca fascicularis) 
Journal of Toxicologic Pathology  2010;23(3):141-145.
A mass with a diameter of 1.5 cm was found in the thymus of a 4-year and 3-month-old male cynomolgus monkey. Microscopically, the mass consisted of two different patterns of proliferation, dense or fascicular proliferation of elongated spindle cells in a sporadic storiform pattern and dense proliferation of thymic cortex-like lymphoid cells in which the multifocal pale nests resembling the thymic medulla were distributed. In these pale nests, large dendriform cells sometimes forming Hassall’s corpuscles were present. The proliferating spindle cells were positive for cytokeratin. The lymphoid cells in the mass were positive for CD3. We concluded that the mass consisted of the neoplastic thymic epithelium with thymocytes proliferation containing medullary differentiation. The mass was diagnosed as a mixed thymoma according to the WHO classification of thymomas in humans. Mixed thymoma is characterized as a mixture of two types of proliferative lesions, spindle-shaped epithelial proliferation and a lymphocyte predominant lesion with or without medullary differentiation. To the best of our knowledge, this is the first report concerning thymoma in monkeys.
doi:10.1293/tox.23.141
PMCID: PMC3234617  PMID: 22272025
thymoma; thymus; monkey; mixed thymoma; medullary differentiation

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