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Background This study aimed to evaluate the quality of life (QOL) of older adults using cochlear implants (CIs) by focusing on how individual characteristics and speech perception are related to generic QOL ratings and utilizing the Health Utilities Index Mark III (HUI3) for assessment. Methodology A cross-sectional study was conducted with 19 participants aged ≥60 years, who were within one to five years post-implant activation. Data were obtained through self-administered questionnaires, including the HUI3 for generic QOL assessment and disease-specific indexes. Speech perception tests and chart reviews provided personal characteristic data. Statistical analysis was performed using the Mann-Whitney U-test, one-way analysis of variance, and Pearson's correlation coefficient. Results In total, 18 patients responded to the study. This study revealed that the generic QOL in older adult CI users was lower than that in the general older adult population. There was no significant association between QOL and variables such as sex, duration of implant usage, or age. However, a longer duration of hearing loss before receiving an implant was associated with higher generic QOL scores. Additionally, a strong correlation was observed between the hearing-related QOL score and utility scores. Conclusions Longer pre-implantation hearing loss correlated with better post-implantation QOL. Additionally, a reduced QOL, specifically within the hearing attribute, a subdomain of the HUI3, was associated with a lower overall generic QOL. The results suggest that generic QOL cannot be evaluated based on hearing ability alone and that cochlear implantation does not completely improve generic QOL. This study represents an important first step in understanding the QOL of older adult CI users from a variety of backgrounds., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of the Jikei University School of Medicine issued approval 33-425(11050). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This research was supported by a research grant from the Japanese Society for Rehabilitation Coordination Science. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Imagawa et al.)

This study aimed to develop and validate a simple scoring system to determine the high-risk group for pancreatic cancer (PC) in the asymptomatic general population. The scoring system was developed using data from PC cases and randomly selected non-PC cases undergoing annual medical checkups between 2008 and 2013. The performance of this score was validated for participants with medical checkups between 2014 and 2016. In the development set, 45 PC cases were diagnosed and 450 non-PC cases were identified. Multivariate analysis showed three changes in clinical data from 1 year before diagnosis as independent risk factors: ΔHbA1c ≥ 0.3%, ΔBMI ≤ -0.5, and ΔLDL ≤ -20 mg/dL. A simple scoring system, incorporating variables and abdominal ultrasound findings, was developed. In the validation set, 36 PC cases were diagnosed over a 3-year period from 32,877 participants. The AUROC curve of the scoring system was 0.925 (95%CI 0.877-0.973). The positive score of early-stage PC cases, including Stage 0 and I cases, was significantly higher than that of non-PC cases (80% vs. 6%, p = 0.001). The simple scoring system effectively narrows down high-risk PC cases in the general population and provides a reasonable approach for early detection of PC.

Objectives: In patients with unresectable malignant hilar biliary obstruction (UMHBO), drainage of ≥ 50% liver volume correlates with better clinical outcomes. Accurately measuring the liver volume to be drained by biliary stents is required. We aimed to develop a novel method for calculating the drained liver volume (DLV) using a 3D volume analyzer (3D volumetry), and assess the usefulness for drainage in patients with UMHBO., Methods: Three-dimensional volumetry comprises the following steps: (1) manual tracing of bile duct using 3D imaging system; (2) 3D reconstruction of bile duct and liver parenchyma; and (3) calculating DLV according to the 3D distribution of bile ducts. Using 3D volumetry, we reviewed data of patients who underwent biliary drainage for UMHBO, calculated the DLV, and determined the association between DLV and biliary drainage outcome., Results: There were 104 eligible cases. The mean DLV was 708 ± 393 ml (53% ± 21%). and 65 patients (63%) underwent drainage of   ≥50% liver volume. The clinical success rate was significantly higher in patients with DLV ≥ 50% than in patients with DLV < 50% (89% vs. 28%, P < 0.001). The median time to recurrence of biliary obstruction (TRBO) and survival time were significantly longer in patients with DLV ≥ 50% than in patients with DLV < 50% (TRBO, 292 vs. 119 days, P = 0.03; survival, 285 vs. 65days, P = 0.004, log-rank test, respectively)., Conclusions: Three-dimensional volumetry, a novel method to calculate DLV accurately according to bile duct distribution was useful for drainage in UMHBO patients., (© 2024. The Author(s).)

Additive manufacturing techniques are being used in the medical field. Orthopedic hip prostheses and denture bases are designed and fabricated based on the patient's computer-aided design (CAD) data. We attempted to incorporate this technique into dental implant bone augmentation. Surgical simulation was performed using patient data. Fourteen patients underwent bone augmentation using a selective laser melting (SLM) titanium mesh plate. The results showed no evidence of infection in any of the 14 patients. In 12 patients, only one fixation screw was used, and good results were obtained. The SLM titanium mesh plate was good adaptation in all cases, with bone occupancy greater than 90%. The average bone resorption of the marginal alveolar bone from the time of dental implant placement to the time of the superstructure placement was 0.69 ± 0.25 mm. Implant superstructures were placed in all cases, and bone augmentation with SLM titanium mesh plates was considered a useful technique.

Background and Objectives : Understanding the relationships between subjective shoulder stiffness, muscle hardness, and various factors is crucial. Our cross-sectional study identified subgroups of shoulder stiffness based on symptoms and muscle hardness and investigated associated factors. Materials and Methods : measures included subjective stiffness, pain, muscle hardness, and factors like physical and psychological conditions, pressure pain threshold, postural alignment, heart rate variability, and electroencephalography in 40 healthy young individuals. Results : Three clusters were identified: Cluster 1 with high stiffness, pain, and muscle hardness; Cluster 2 with low stiffness and pain but high muscle hardness; and Cluster 3 with low levels of all factors. Cluster 1 had significantly higher central sensitization-related symptoms (CSS) scores than Cluster 2. Subjective stiffness is positively correlated with psychological factors. Conclusions : our results suggest that CSS impacts subjective symptom severity among individuals with similar shoulder muscle hardness.

Objectives: Resonance properties of the nasal and sinus cavities are involved in the individuality of speech. However, detailed information on how alterations in the nasal cavity morphology affect voice quality is lacking. The aim of the present study was to investigate the effects of structural changes in the nasal cavity on voice production by spraying a topical adrenaline solution with a vasoconstrictive effect into the nasal cavity, causing nasal mucosal contraction., Study Design: Prospective., Methods: Overall, 51 adult volunteers were recruited from the Otorhinolaryngology Outpatient Department of the Jikei University Hospital from June to September 2022. Among them, 20 completed acoustic rhinometry and voice recordings before and after adrenaline spraying. The nasal consonant [N] uttered with the mouth completely closed was recorded for 5 seconds. The remaining 31 volunteers completed all auditory experiments. This was conducted to determine whether the changes in voice before and after adrenaline spraying could be discriminated against by the participants., Results: The nasal volume had increased 5 and 10 minutes after spraying compared to that before spraying, reaching a significance at 10 minutes (P = 0.06). It had increased at 2 and 5 cm from the external nostrils compared to that within 3 cm of the external nostrils (P = 0.04). Among the 31 volunteers in the auditory experiments, 30 had a discrimination rate >90%, with a mean of 96.3% (standard error, 3.2). The spectral envelope of the 16 frequency bands varied significantly at 500-Hz increments (P = 0.0006). In particular, changes in the high-frequency bands were larger between 4500 and 6000 Hz., Conclusions: Nasal enlargement with 0.02% topical adrenaline affects the spectral envelope, particularly in the high-frequency bands between 4500 and 6000 Hz, and perceptibly alters the voice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Stretching is an effective exercise for increasing body flexibility and pain relief. This study investigates the relationship between stretching intensity and relaxation effects, focusing on brainwaves and autonomic nervous system (ANS) activity. We used a crossover design with low- and high-intensity conditions to elucidate the impact of varying stretching intensities on neural activity associated with relaxation in 19 healthy young adults. Participants completed mood questionnaires. Electroencephalography (EEG) and plethysmography measurements were also obtained before, during, and after stretching sessions. The hamstring muscle was targeted for stretching, with intensity conditions based on the Point of Discomfort. Data analysis included wavelet analysis for EEG, plethysmography data, and repeated-measures ANOVA to differentiate mood, ANS activity, and brain activity related to stretching intensity. Results demonstrated no significant differences between ANS and brain activity based on stretching intensity. However, sympathetic nervous activity showed higher activity during the rest phases than in the stretch phases. Regarding brain activity, alpha and beta waves showed higher activity during the rest phases than in the stretch phases. A negative correlation between alpha waves and sympathetic nervous activities was observed in high-intensity conditions. However, a positive correlation between beta waves and parasympathetic nervous activities was found in low-intensity conditions. Our findings suggest that stretching can induce interactions between the ANS and brain activity.

The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) may require a somewhat invasive pathological examination and steroid responsiveness. This retrospective study assessed the complemental diagnosis of AIP and IgG4-SC using submandibular gland (SG) ultrasonography (US) in 69 patients, including 54 patients with AIP, 2 patients with IgG4-SC, and 13 patients with both AIP and IgG4-SC. The data from the physical examination and US of SGs to diagnose AIP ( n = 67) and IgG4-SC ( n = 15) were analyzed. The steroid therapy efficacy in resolving hypoechoic lesions in SGs was evaluated in 36 cases. The presence of IgG4-related pancreaticobiliary disease with multiple hypoechoic lesions in SGs was reduced from 31 to 11 cases after steroid therapy, suggesting that multiple hypoechoic lesions in SGs are strongly associated with IgG4-positive cell infiltrations. Multiple hypoechoic lesions in SGs were observed in 53 cases, whereas submandibular swelling on palpation was observed in 21 cases of IgG4-related pancreaticobiliary diseases. A complemental diagnosis of IgG4-related pancreaticobiliary diseases without a histological diagnosis and steroid therapy was achieved in 57 and 68 cases without and with multiple hypoechoic lesions in SGs, respectively. In conclusion, multiple hypoechoic lesions in SGs are useful for the complemental diagnosis of IgG4-related pancreaticobiliary diseases.

The HCO 3 - concentration in venous serum ([HCO 3 - ] s ) is a factor commonly used for detecting the body pH and metabolic conditions. To exactly detect [HCO 3 - ] s , the venous CO 2 pressure should be kept as it is in the vein. The [HCO 3 - ] s measurement is technically complicated to apply for huge numbers of almost heathy persons taking only basic medical examinations. The summation of [HCO 3 - ] s and the venous serum Cl - concentration ([Cl - ] s ) is approximately constant; therefore, we studied if [Cl - ] s could be a marker detecting metabolic conditions instead of [HCO 3 - ] s . Venous blood was obtained from persons taking basic medical examinations (the number of persons = 107,630). Older persons showed higher values of [Cl - ] s , fasting blood sugar (FBS), and glycated hemoglobin (HbA1c) than younger ones. [Cl - ] s showed positive correlation to age and negative correlation to FBS and HBA1c. The negative correlation of [Cl - ] s to FBS/HbA1c was obvious in persons with high FBS/HbA1c, leading us to an idea that persons with high FBS/HbA1c show high [HCO 3 - ] s , which might be caused by low activity of carbonic anhydrase in the lung observed in persons with diabetes mellitus under acidotic conditions. Taken together, an easily measured serum electrolyte, [Cl - ] s , could be a useful marker estimating metabolic conditions.

Jaw reconstruction using an additive-manufacturing titanium artificial bone (AMTAB) has recently attracted considerable attention. The synthesis of a titanium artificial bone is based on three-dimensional computed tomography images acquired before surgery. A histological evaluation of porous AMTAB (pAMTAB) embedded in rat calvarial bone defects was conducted. This study examined three groups: rats implanted with mixed-acid and heat-treated pAMTAB, rats implanted with untreated pAMTAB, and rats with no implant. In both pAMTAB groups, bone defects were created in rat calvarial bones using a 5-mm trephine bar, followed by pAMTAB implantation. The pAMTAB was fixed to the defect using the fitting force of the surrounding bones. The rats were sacrificed at 4, 8, and 16 weeks after implantation, and the skull was dissected. Undecalcified ground slides were prepared and stained with Villanueva Goldner. Compared with the no implant control group, both pAMTAB groups exhibited new bone formation inside the defect, with greater bone formation in the mixed-acid and heat-treated pAMTAB group than in the untreated pAMTAB group, but the difference was not significant. These data suggest that pAMTAB induces bone formation after implantation in bone defects. Bone formation appears to be enhanced by prior mixed-acid and heat-treated pAMTAB.

The additive manufacturing (AM) technique has attracted attention as one of the fully customizable medical material technologies. In addition, the development of new surface treatments has been investigated to improve the osteogenic ability of the AM titanium (Ti) plate. The purpose of this study was to evaluate the osteogenic activity of the AM Ti with mixed-acid and heat (MAH) treatment. Fully customized AM Ti plates were created with a curvature suitable for rat calvarial bone, and they were examined in a group implanted with the MAH-treated Ti in comparison with the untreated (UN) group. The AM Ti plates were fixed to the surface of rat calvarial bone, followed by extraction of the calvarial bone 1, 4, 8, and 12 weeks after implantation. The bonding between the bone and Ti was evaluated mechanically. In addition, AM Ti plates removed from the bone were examined histologically by electron microscopy and Villanueva-Goldner stain. The mechanical evaluation showed significantly stronger bone-bonding in the MAH group than in the UN group. In addition, active bone formation was seen histologically in the MAH group. Therefore, these findings indicate that MAH resulted in rapid and strong bonding between cortical bone and Ti.

Objective: This study investigated factors related to the satisfaction level of cochlear implants for the elderly., Methods: A survey was conducted by sending an anonymous self-reported questionnaire to medical facilities specializing in cochlear implantation throughout Japan and members of cochlear implant self-help groups aged 65 years and older. The subjects were divided into two age-based groups (under 75 and 75 years and older) to analyze the usage of cochlear implants. Binary logistic regression was performed to analyze factors related to the satisfaction level of the recipients with hearing improvements provided by cochlear implants (p<0.05)., Results: Responses were received from 60 cochlear implant users. The mean age of the respondents was 74.9±6.87 (mean ± 1SD) years. The mean cochlear implant use was 12.4 ± 4.0 (mean ± 1SD) hours per day. Regarding satisfaction with the cochlear implants, 93.3% responded "somewhat satisfactory" or better, indicating at least moderate satisfaction. However, fewer respondents in the 75-years and older group reported feeling "satisfactory" or better (chi-square test, p<0.05). Concerning device operation and management, difficulties including volume adjustment, switching between program, and exchanging cables, were reported. Among the patient-reported indices of postoperative hearing improvements studied, their ability to hear and comprehend conversations with family members and information provided at reception desks were most associated with user satisfaction with cochlear implants., Conclusion: Many elderly patients were satisfied with their cochlear implants; however, respondents in the 75-years and older group had lower levels of satisfaction compared to those in respondents in the under-75-years group. Elderly patients had problems with more complex operations and management of their cochlear implants. Moreover, they were satisfied with their ability to comprehend familiar, everyday conversations. These factors related to satisfaction level may be useful in providing valuable rehabilitation for elderly patients with cochlear implants., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Presarcopenia is a prognostic factor in patients with hepatocellular carcinoma (HCC). The Japan integrated staging (JIS) score is a prognostic method that combines the Child-Turcotte-Pugh classification and the tumor-node-metastasis (TNM) staging for HCC. We investigated the relationship between presarcopenia, the JIS score, and prognosis in patients with primary HCC. This retrospective study included 153 patients with primary HCC who were hospitalized from October 2011 to March 2018 at Municipal Hospital of Kofu. The skeletal muscle mass was measured using simplified psoas muscle mass index (PMI) based on CT imaging, and PMI using the volume analyzer SYNAPSE VINCENT ver3.0. We diagnosed presarcopenia based on the cut off value according to the assessment criteria for sarcopenia in liver disease defined by the Japan Society of Hepatology. Forty-three patients (28%) were diagnosed with presarcopenia. The median event-free survival was significantly worse in patients with presarcopenia than those without presarcopenia (P = 0.016). In multivariate analysis, presence of presarcopenia, JIS score ≥3, alpha-fetoprotein ≥200 ng/ml, and prothrombin induced by vitamin K absence-II ≥ 200 mAU/ml were significant prognostic factors. Among the patients with JIS scores ≥3, there was no difference in the event occurrence rate with presence of presarcopenia (P = 0.96). Among the patients with JIS scores ≤2, the median event-free-survival was significantly shorter in those with presarcopenia than those without presarcopenia (P = 0.045). Presarcopenia was an independent prognostic factor in patients with primary HCC. In patients with JIS scores ≤2, the median event-free survival was significantly shorter in those with presarcopenia compared to those without presarcopenia. In the patients with JIS scores ≥3, there was no difference in the event occurrence rates in those with and without presarcopenia.

Purpose: For patients receiving palliative care, information about prognosis is important to help them set priorities and expectations for care and to assist clinicians in decision-making. The purpose of this study was to investigate prognostic models applicable to the terminal stage of gastrointestinal cancer, especially in terms of accuracy of prediction regarding 3-week survival., Methods: We validated retrospectively the accuracy of a prognosis prediction model for 354 end-stage gastrointestinal cancer patients who underwent palliative care at our hospital. Using receiver operating characteristic analysis and the area under the curve (AUC), we selected the cut-off value for 3-week survival and evaluated the predictive ability using sensitivity, specificity, positive predictive value, negative predictive value, and accurate diagnosis rate., Results: In our analysis of various models, Palliative Prognostic Index (PPI) and Biological Prognostic Score (BPS) version 3 showed excellent predictive performance with AUCs of 0.85 and 0.83, respectively, and accurate diagnosis rates of 80.0 and 79.0, respectively. BPS version 2 showed fair predictive performance with an AUC of 0.76 and an accurate diagnosis rate of 72.0. Using these models, stratification of prognostic prediction was possible., Conclusions: PPI and BPS were found to be accurate prediction models for short-term survival of terminal gastrointestinal cancer patients.

Objective: We evaluated the characteristics of patients with diverticular bleeding in whom emergency endoscopy should be proactively performed and those in whom it is unnecessary for spontaneous hemostasis following conservative treatment., Methods: This study involved 132 patients in whom diverticular bleeding was diagnosed on lower gastrointestinal endoscopy. We evaluated the rate of identification of the bleeding diverticulum during endoscopy and the rate of spontaneous hemostasis following conservative treatment., Results: In 26 patients (20%), bleeding diverticulum was identified during endoscopy. Extravasation or fluid collection on CT imaging was an important factor of successful identification of the bleeding source on endoscopy. Of the 104 patients in the conservative treatment group, 91 (87%) were able to be discharged after spontaneous hemostasis. Univariate analysis revealed a high rate of spontaneous hemostasis in patients without extravasation and fluid collection on CT imaging, those without adhesion of blood during endoscopy, those without diabetes, and those with a hemoglobin level ≥10 g/dL., Conclusion: In patients with colonic diverticular bleeding, extravasation or fluid collection on CT is an important factor related to the identification of the bleeding diverticulum. Patients without characteristic CT findings had a high rate of spontaneous hemostasis after conservative treatment., Background: Diverticular bleeding is the most frequent cause of lower gastrointestinal bleeding accounting for 20%-40% of all cases in Japan and 20%-48% of all those in the Western countries[1, 2]. The prevalence of colonic diverticula tends to increase with age; thus, the overall prevalence of diverticular bleeding is expected to increase in the future. In Japan, the Japanese Gastroenterological Association published guidelines on colonic diverticulitis in 2017; these guidelines recommend the performance of lower gastrointestinal endoscopic examination within 24 h in patients with lower gastrointestinal bleeding suspected to be diverticular bleeding[3]. It has been reported that, for patients with lower gastrointestinal bleeding, urgent endoscopy helps avoid embolotherapy, colectomy, massive blood transfusion, and repeat bleeding[1, 4, 5]. However, it is often difficult to identify the bleeding point [6]; further, there are many challenging cases wherein it is difficult to decide whether urgent endoscopy should be performed in situations where there is insufficient medical staff, such as during nighttime and on holidays. Bleeding is reported to stop spontaneously with conservative treatment alone in 70% of diverticular bleeding cases[7, 8]. In particular, when determining the treatment policy for diverticular bleeding and in the case of patients at high risk of complications following endoscopy, such as older patients, those with poor performance status or cardiovascular disease, and those in whom spontaneous hemostasis can be expected, urgent endoscopy should be avoided, and elective endoscopy should be selected. Therefore, the type of cases wherein urgent endoscopy is effective and the type wherein it is unnecessary need to be clarified. Thus far, there have been very few reports of the characteristics of patients with diverticular bleeding in whom spontaneous hemostasis was achieved. We aimed to assess the characteristics of patients in whom emergency endoscopy should be proactively performed and those for whom it is unnecessary. Thus, we retrospectively analyzed the identification rate for the responsible diverticulum in patients with diverticular bleeding and the rate of spontaneous hemostasis following conservative treatment., Competing Interests: The authors have declared that no competing interests exist.

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Lepr fa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague-Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor-positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non-ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome., (© 2019 John Wiley & Sons Australia, Ltd.)

Purpose: We carried out guided bone regeneration of cranial bone defects in rats using the bovine bone substitute Bio-Oss and a collagen membrane and performed histological observations of the bone repair process., Materials and Methods: Bone defects were created in the cranial bones of 30 15-week-old Sprague-Dawley rats. We made 3 groups. A is unfilled, B is Bio-Oss, and C is Bio-Oss plus a collagen membrane. At 4 or 8 weeks postoperatively, tissue samples were taken. The Kawamoto technique was used for histological evaluation., Results: There was no new bone formation in group A. In groups B and C, new bone formation was evident around the Bio-Oss. In group C, new bone formation was evident in the centers of the bone defects, detached from the cut edge of the cranial bone., Conclusion: Our results suggested that the Bio-Oss acts as a scaffold for bone repair, and the use of a collagen membrane may anchor the Bio-Oss closely to the cranial bone and assist the bone repair response.

Hyalinizing trabecular tumour (HTT) immunohistochemically shows cell membranous immunoreactivity for MIB-1. This aberrant immunoreactivity is an important factor for the diagnosis of HTT. However, fully automated stainers frequently fail to confirm the immunoreactivity. The aim of this study is to investigate the cause of false negative cell membranous immunoreactivity for MIB-1 in HTT using fully automated stainers, to determine potential reasons for the problem, and to establish methods confirming cell membranous immunoreactivity for MIB-1 in HTT. Six participating institutions examined immunoreactivity for MIB-1 in 10 HTT cases using two approaches: fully automated and semi-automated methods. In the latter, antigen retrieval was carried out using manual methods adopted for routine assays at each institute. The autostainers used included the BOND-MAX, BOND-III, Benchmark XT, and Omnis systems. Using fully automated methods, institute E showed cell membranous MIB-1 positivity in all HTT cases. In contrast, at institute D, all HTT cases were negative. The positive rates of the remaining four institutes ranged from 10% to 20%. The incidence of positive cases using semi-automated methods was 100%, 90%, 90%, 30%, 80%, and 100% at institutes A, B, C, D, E, and F, respectively. We assert that antigen retrieval should be conducted manually for diagnosis of HTT; furthermore, definitively diagnosed HTT should be prepared as the external positive control.

A 77-year-old woman with mild dilatation (4mm) of the main pancreatic duct was referred to our hospital. Contrast-enhanced computed tomography revealed segmental dilatation of the main pancreatic duct in the pancreatic tail, but no mass was noted in the pancreas. Endoscopic ultrasonography showed low papillary lesions in the dilated pancreatic duct. Cytological analysis of the pancreatic juice revealed adenocarcinoma. Distal pancreatectomy was performed for a diagnosis of main duct-intraductal papillary mucinous cancer (MD-IPMC) of the pancreatic tail. Histological findings indicated pancreatobiliary (PB)-type non-invasive IPMC. Although the patient did not meet the diagnostic criteria for intraductal papillary mucinous neoplasms (IPMNs), her final diagnosis was PB-type non-invasive IPMC. Because PB-type IPMNs display poor mucin production, pancreatic duct dilatation is sometimes mild and requires careful assessment for accurate diagnosis.

The M-type phospholipase A2 receptor (PLA2R1) was identified recently as a specific target antigen in idiopathic membranous nephropathy. However, the influence of different sample preparation techniques on the immunostaining of PLA2R1 is unclear. Previous studies have identified IgG4 as the dominant subclass of PLA2R1 antibodies. However, it remains unclear whether the IgG subclass profiles of the glomerular immune complexes of PLA2R1-positive and -negative idiopathic membranous nephropathy cases are similar. To address these questions, we conducted the present study of 58 idiopathic membranous nephropathy cases. The PLA2R1 positivity rate for the paraffin-embedded sections was 61%, whereas that for the frozen sections was 65%. Nonspecific background staining was observed in the frozen sections. Discrepancies between different sample preparations occurred in three cases (6%); two cases were PLA2R1-positive in paraffin sections and PLA2R1-negative in frozen sections and one case was PLA2R1-negative in paraffin sections and PLA2R1-positive in frozen sections. Regarding the IgG subclass profile, 89% of the PLA2R1-positive cases demonstrated the IgG4-dominant/codominant phenotype versus 31% of the PLA2R1-negative cases (p < 0.001). Clinical characteristics and pathological findings did not significantly differ between PLA2R1-positive and -negative cases. In summary, the PLA2R1 immunofluorescence results were not affected by the different sample preparation techniques, although paraffin-embedded sections were preferred for the histological detection of PLA2R1 because of the nonspecific background staining observed in frozen sections. The observed lower frequency of the non-IgG4-dominant/codominant phenotype in PLA2R1-negative idiopathic membranous nephropathy cases may suggest that there are heterogeneous subgroups of this disease.

We have recently developed a new method called the immunohistochemistry-based cell cycle detection (iCCD), which allows the determination of cell cycle phases on a cell-by-cell basis. This automated procedure can be performed on tissue sections and involves triple immunostaining for geminin, cdt1, and γ H2A.X, which are nuclear proteins expressed sequentially, with a few overlaps, during the cell cycle. In the current study, we applied this technique to resected specimens of colorectal neoplasm to determine the usefulness of iCCD for the pathological examination of colorectal cancers. We examined 141 cases of colorectal cancers. Normal mucosa and adenomas were analyzed as controls. In nonneoplastic mucosa, we observed a pattern of distribution of the cells positive for these cell cycle markers. Adenomas showed a slight distortion in this pattern, the geminin-positive cells, indicative of S/G2/M phase, were localized in the upper one-third region of the crypts. In neoplastic mucosa, the marker expression pattern was disorganized. Compared with normal mucosa, colorectal neoplasms showed an increased proportion of geminin-positive cells and decreased percentages of cdt1-positive cells (G1 phase). However, we did not find significant difference in the expression pattern between adenomas and carcinomas. Cellular proportions were correlated with clinicopathological parameters such as microscopic vascular invasion and pT stages. In cases of preoperative adjuvant therapy, the proportion of geminin-positive cells decreased, whereas that of γ H2A.X-positive cells (indicative of apoptosis/degeneration) increased significantly. We believe that this novel method can be applied to clinical samples to evaluate cell cycle kinetics and the effects of preoperative adjuvant therapy in colorectal cancers.

The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables the single-step construction of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, in a five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple bond-forming events, and provides a reliable catalytic process for the asymmetric synthesis of densely functionalized pyrrolidines.

For pancreatic islet transplantation, maintaining organ viability after pancreas procurement is critical and a major determinant for better graft function and survival. University of Wisconsin (UW) solution is currently the gold standard for abdominal organ preservation and the pancreas in particular. However, in the use of UW preservation solution for islet transplantation, there are disadvantages to be overcome, such as the inhibition of collagenase activity during pancreatic digestion. In this study, we compared UW solution with HN-1 solution in pancreas preservation for islet isolation. Islet yield was significantly greater in the HN-1 group than the UW group both before and after purification. In the in vitro assay, the adenosine triphosphate content in cultured islets was significantly higher in the HN-1 group than in the UW group. Furthermore, in streptozotocin-induced diabetic nude mice, the islet graft function of the HN-1 group was superior to that of the UW group. We concluded that the use of HN-1 solution is a promising approach for optimal pancreas preservation in islet transplantation.

For pancreatic islet transplantation, one of the most important steps of islet isolation is islet purification. The most common method of islet purification is density gradient centrifugation because there are differences in density between islets and acinar tissue. However, the density of islets/acinar tissue depends on several conditions, such as the incubation time before purification and the osmolality of the preincubation solution. In this study, we evaluated the impact of using two different preincubation solutions before purification. We used the University of Wisconsin (UW) solution and a new preservation solution (HN-1), which we recently developed. There were no significant differences between the two solutions in terms of the islet yield, rate of viability, and purity or stimulation index after purification. There were also no differences in the attainability and suitability of posttransplantation normoglycemia. Our study shows that the HN-1 solution is equivalent to the UW solution for preincubation before islet purification.

Our aim was to determine whether or not non-small-cell lung cancer is squamous cell carcinoma (SQCC); even in small samples, it is essential in view of the side effects attendant on new therapeutics. Lung adenocarcinoma (ADC) with the EML4-ALK fusion gene has been described as demonstrating mucinous cribriform/acinar growth and signet-ring cells, sometimes partially simulating SQCC. We investigated the relation among morphology, anaplastic lymphoma kinase (ALK) rearrangement, and immunophenotype in 321 ADCs by tissue microarray using SQCC markers cytokeratin (CK)5/6, CK14, desmocollin-3, desmoglein-3, p40, p63 versus ADC markers thyroid transcription factor (TTF)-1 and napsin A. Unlike 312 ALK-negative ADCs, 9 ALK-positive cases were negative for 4 SQCC markers. Only 1 ALK-positive ADC showing assertive morphology was positive for CK5/6 and p63 as well as for TTF-1 and napsin A. Coexpression of TTF-1/p40 was not observed, unlike that of TTF-1/p63 reported previously. There was no statistically significant difference between ALK-negative and ALK-positive ADC by immunohistochemical profiling.

Carcinogenesis is widely believed to occur when regulatory systems governing cellular proliferation and differentiation are compromised. To date, various methods have been devised to determine cell cycle. However, these methods have not gained popularity in the diagnostic field. We developed a multiplex immunohistochemical method that can simultaneously stain cells in the G1 and S/G2/M phases and those undergoing apoptosis with the 3 markers Cdt1, geminin, and gamma H2A.X. The staining procedure can be performed using an autoimmunostainer. The nuclei of cells in the G1 phase stain red with the antibody for Cdt1, those in the S/G2/M phases stain blue with the antibody for geminin, and the nuclei of cells undergoing apoptosis stain brown with the antibody for H2A.X. The present method enables accurate cell cycle assessments using paraffin-embedded tissue specimens, which are superior to other forms of specimens in terms of morphologic observation.

The current Food and Drug Administration-approved standard treatment for non-small cell carcinomas consists of carboplatin/taxol/avastin. However, nowadays more specialized protocols, depending on tumor subtype, are being used for lung cancer patients. Therefore, accurate differentiation between adenocarcinoma and squamous cell carcinoma is essential for the selection of appropriate therapies. We designed a rapid multiplex immunostaining method using a novel 4-antibody cocktail, YANA-4. This antibody cocktail consists of the following monoclonal antibodies: rabbit for thyroid transcription factor 1(TTF-1), mouse for napsin A, mouse l for p63, and rabbit for CK14. All procedures can be completed within 3 hours. This method labels the nuclei of adenocarcinomas as brown with TTF-1, and cytoplasm as blue with napsin A. Squamous cell carcinomas could be differentiated from adenocarcinomas with an inverse staining pattern: blue nuclei with p63 and brown cytoplasm with CK14. In this study, 97.4% (38 of 39) of adenocarcinomas showed brown nuclei (TTF-1) and/or blue cytoplasm (napsin A), with 4 cases showing positivity only for brown nuclei (TTF-1) and 1 case only for blue cytoplasm (napsin A). None of the squamous cell carcinoma cases showed these staining patterns. Positivity for blue nuclei (p63) and/or brown cytoplasm (CK14) was detected in 100% (25 of 25) of squamous cell carcinomas, with 1 case showing positivity only for brown cytoplasm (CK14) and 2 cases only for blue nuclei (p63). None of the adenocarcinoma cases showed these patterns. This rapid immunohistochemical method can thus be considered highly specific and sensitive for differentiating adenocarcinomas and squamous cell carcinomas.

Aim: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined., Methods: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests., Results: JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher., Conclusions: These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.

Cytochalasin D (CD) induced production of the superoxide radical (O(2)(-)) in guinea pig polymorphonuclear leukocytes (PMNs). The protein kinase C (PKC) inhibitor GF109203X (GFX) was rarely without effect on CD-induced O(2)(-) production. CD as well as PMA induced the translocation of p47(phox) to the membrane fraction, and this translocation was slightly decreased by GFX. Moreover, the inhibitory effect of a PKCzeta antagonist with sequences based on the endogenous PKCzeta pseudosubstrate region was weaker than the inhibitory effect on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced O(2)(-) production. On the other hand, the production of O(2)(-) induced by CD was more strongly suppressed by the PLD inhibitor ethanol and phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin than that induced by fMLP, and the activation of phospholipase D (PLD) by CD was restrained by wortmannin. These findings suggest that NADPH oxidase is activated by CD through a PKC-independent signaling pathway in PMNs, and this pathway involves the activation of PLD through PI3-K.

Phorbol myristate acetate (PMA)-induced superoxide radical (O(2)(-))-production in guinea pig peritoneal polymorphonuclear leukocytes (PMNs) was significantly lower than that in peripheral cells. To determine the role of phosphotyrosine proteins in the lower O(2)(-) production, the effect of ST638 and genistein, tyrosine kinase inhibitors, on PMA-induced O(2)(-) production in peritoneal PMNs was examined. PMA-induced O(2)(-)-production of the cells was increased by the pretreatment with ST638 or genistein, the increment depending on the inhibitor concentration. The p47phox level in the plasma membrane of PMA-stimulated PMNs was increased by the pretreatment with ST638, although the phosphorylated p47phox level in the cells was not altered by ST638. On the other hand, PMA-induced O(2)(-)-production of peripheral PMNs was not affected by the pretreatment with ST638, but that of cytochalasin B (CB)-primed peripheral PMNs significantly increased by further treatment with ST638. The phosphotyrosine protein level of peritoneal PMNs was higher than that of the peripheral cells, especially in cytosolic proteins including 50-60 and 70-85 kDa proteins, and that of the CB-primed peripheral cells was also higher than that of the intact cells in similar cytosolic proteins to those above. Further treatment of CB-primed peripheral cells with ST638 resulted in a lower level of phosphotyrosine proteins. These findings suggest that phosphorylation of some protein(s) at specific tyrosine residues inhibits the translocation of p47phox to the plasma membrane from the cytosol, resulting in lower O(2)(-)-generation in casein-induced peritoneal exudate PMNs.

PTP-BAS is a membrane-associated protein tyrosine phosphatase containing a band-4.1 homology region and five PDZ (PSD-95 Dlg ZO-1) [discs-large homology region ('DHR')/Gly-Leu-Gly-Phe ('GLGF')] domains. The second and fourth PDZ domains were reported to associate with Fas/CD95. By using the first PDZ domain as a bait in yeast two-hybrid screening, we have identified IkappaBalpha as a binding protein. IkappaBalpha associated with PDZ1 through the stretch of the N-terminal three ankyrin repeats. The association was also confirmed in HeLa cells by co-immunoprecipitation experiments. Inhibition of PTP-BAS by expression of dominant-negative PTP-BAS mutant resulted in tyrosine-phosphorylation of IkappaBalpha. Tyrosine-phosphorylation of IkappaBalpha is a key event in activation of nuclear factor (NF)-kappaB during reoxygenation. PTP-BAS may thus play a regulatory role in activation of NF-kappaB under high oxidative stress.

Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.