Language：Japanese   Publisher：(一社)日本緩和医療薬学会  

リドカインゼリーを混合したワセリンを塗布することで放射線皮膚炎による激しい疼痛を明瞭に軽減できた症例を報告する。今回の症例では、放射線皮膚炎の疼痛にオピオイドやステロイド外用剤を用いたが、疼痛コントロールに苦慮していた。リドカイン混合ワセリンは、放射線皮膚炎による難治性の疼痛を軽減(NRS9→3)する。(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Although the dosage of oral antibiotics (OA) for the mandibular third molar extraction (MTME) varies among the administration periods according to the current guideline, our previous reports suggested that it might be possible to further shorten the administration period without increasing the incidence of surgical site infection (SSI). In the present study, we retrospectively evaluated the relationship between the incidence of SSI and the administration period of OA in patients who underwent the MTME in our hospital. This retrospective cohort study included 348 patients who underwent the MTME in our dental outpatient clinic from June 2020 to March 2022. The administrated antibiotic was amoxicillin (AMPC) in all patients. Patients were divided into two groups based on the administration period of AMPC single and three times before the surgery. The following information was collected: (1) patient factors (age, gender, body mass index, diagnosis, mandibular third molar status); (2) surgical factors (operation time, presence/absence of wound closure, presence/absence of hemostat, experience of surgeons); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. There were 217 cases in the single group and 131 cases in the three times group. The incidence of SSI was 1.1% (4/348), with 1.4% (3/217) in the single group and 0.8% (1/131) in the three times group; there was no significant difference between the two groups. Our result suggests that single administration of AMPC before the MTME would be sufficient for the prevention of SSI in Japanese patients without risk factors.

DOI： 10.1248/yakushi.22-00163

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Oral mucositis (OM) is a common side effect in patients with cancer receiving chemotherapy and radiotherapy; however, no salivary mediator is known to be associated with OM. We aimed to determine candidate salivary inflammatory mediators potentially associated with OM in patients with cancer. To this end, we compared the relationships between OM grade, oral mucosal dryness, and inflammatory mediators (Interleukin (IL)-1β, IL-6, IL-10, IL-12p70, tumor necrosis factor (TNF), prostaglandin E2, and vascular endothelial growth factor) in patients with cancer and in healthy volunteers (HV). We collected saliva samples from 18 patients with cancer according to the following schedule: 1) within 14 days of treatment initiation, 2) within 3 days of OM occurrence, 3) when OM was improved or got worsened, and 4) within 7 days after chemotherapy completion. The oral care support team determined the OM grade at each sample collection point based on CTCAE version 5.0. Salivary inflammatory mediator concentrations were detected using cytometric bead array or enzyme-linked immunoassay. We compared oral mucosal dryness in pre- and post-index patients with cancer to that in HV (n = 33) using an oral moisture-checking device. Fourteen of eighteen patients experienced OM (four, grade 3 OM; four, grade 2 OM; six, grade 1 OM). IL-6, IL-10, and TNF salivary concentrations were significantly increased in the post-index group compared to those in the pre-index group (p = 0.0002, p = 0.0364, and p = 0.0160, respectively). Additionally, salivary IL-6, IL-10, and TNF levels were significantly higher in the post-index group than in the HV group (p < 0.0001, p < 0.05, and p < 0.05, respectively). Significant positive correlations were observed between OM grade and salivary IL-6, IL-10, and TNF levels (p = 0.0004, r = 0.4939; p = 0.0171, r = 0.3394; and p = 0007, r = 0.4662, respectively). Oral mucosal dryness was significantly higher in the HV than in the pre- and post-index groups (p < 0.001). Our findings suggest that salivary IL-6, IL-10, and TNF levels may be used as biomarkers for OM occurrence and grade in patients with cancer. Furthermore, monitoring oral mucosal dryness and managing oral hygiene before cancer treatment is essential.

DOI： 10.1371/journal.pone.0267092

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INTRODUCTION: According to the guidelines, the dosage for mandibular wisdom tooth extraction (MWTE) varies within the administration period. There is a 24-fold difference between the minimum and maximum doses. If an appropriate antimicrobial can be administered without increasing incidence of surgical site infection (SSI), it may lead to a global action plan on antimicrobial resistance (AMR). Therefore, we prospectively surveyed incidence of SSI post-operatively and use of oral antibiotics (OA) for MWTE. METHODS: Subjects were patients who underwent MWTE in our dental outpatient clinic from May 2019 to April 2020. Two groups were formed depending on type of administration period they received: 24 h and 48 h after surgery. The following information was collected: (1) patient factors (age, gender, body mass index, presence/absence of preoperative medication, diagnosis, impacted wisdom tooth status; (2) surgical factors (operative time, presence/absence of closure, presence/absence of hemostat, doctor career, type and frequency of painkiller); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. RESULTS: Three hundred forty subjects were analyzed, all of which used amoxicillin. There were 106 cases in 24 h group and 234 cases in 48 h group. The total incidence of SSI was 1.1% (4/340 cases), with 0.9% (1/106 cases) in 24 h group and 1.3% (3/234 cases) in 48 h group; there was no difference between the two groups. CONCLUSION: Our study suggests that amoxicillin (250 mg/dose every 8 h x 3 doses beginning 1 h before surgery) might be sufficient in preventing SSI in Japanese dental patients without SSI risk factors.

DOI： 10.1016/j.jiac.2021.01.018

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INTRODUCTION: We investigated the use of oral antibiotics (OA) and surgical site infection (SSI) related to extractions of ordinary teeth and mandibular wisdom teeth in a dental outpatient clinic from January 2015 to December 2019. METHODS: The following information were surveyed: (1) presence/absence of OA, (2) timing, (3) type, (4) administration period, and (5) SSI rates. RESULTS: The use of OA during ordinary tooth extraction decreased from 68.3% to 41.3%, but SSI rate did not change during this period of time. Total SSI rate was 0.8% (122/14,832) on average. For mandibular wisdom tooth extraction, preoperative administration of third-generation cephalosporins decreased from 70.4% to 0.3% while that of penicillin (AMPC) increased from 0% to 98%. SSI rate was not changed after these improvements. Total SSI rate was 3.5% (180/5106) on average. The duration of OA was slightly decreased to two days in 2018 and 2019, and it was found that there was no significant difference in SSI rates between 2- and 3-day durations. Preoperative administration had 0.37 odds ratio (OR) (95% confidence interval (95%CI): 0.22-0.63) of SSI compared with postoperative administration. AMPC had 0.76 OR (95% CI: 0.55-1.04) of SSI compared with Third-generation cephalosporins and others. Timing of OA was P < 0.01. CONCLUSIONS: SSI rates did not change over time, administration period of OA decreased and the use of AMPC increased. Therefore, it seems necessary to continue to investigate the effects of SSI risk factors proactively in the future and to make efforts in the advocacy of appropriate antimicrobial use.

DOI： 10.1016/j.jiac.2020.08.022

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OBJECTIVES: This retrospective study examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for oral mucositis (OM) affected head-and-neck cancer (HNC) patients receiving concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint. The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. RESULTS: The group managed by PEMT had significantly lower weight loss and a significantly lower incidence of local anesthetic and opioid use and switch to tape compared with the group not managed by PEMT (p<0.05). The two groups showed no significant difference in OM (yes/no) or OM severity. The PEMT group had significantly shorter LOD at 57 (53-64) days compared with the non-PEMT group at 63.5 (57-68) days (p<0.05). CONCLUSIONS: Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, the PEMT group had a lower incidence of grades 3 and 4 OM than the non-PEMT group, although not significantly. In addition, PEMT contributed to oral pain relief and the lowering of the risk for OM by reduction in weight loss.

DOI： 10.1371/journal.pone.0260026

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Introduction: Postoperative infection is a major cause of morbidity and prolonged hospitalization in patients undergoing gastrointestinal surgery. This observational study aimed to investigate the risk factors associated with postoperative infection and to develop a prediction model for postoperative infections that occur after gastrointestinal surgery. Methods: The study population comprised 1637 patients who underwent gastrointestinal surgery at Niigata University Medical and Dental Hospital between June 2013 and May 2017. Observational data from 1883 surgical procedures were used in the statistical analyses (including 198 patients who underwent several operations). Results: The generalized estimating equation (GEE) was used to detect significant risk factors, including older age, history of smoking, body temperature greater than 38 °C, non-endoscopic surgical procedures, surgery in the thoracic or lower gastrointestinal tract, and use of medical nutritional products during surgery. The sensitivity and specificity of the GEE model were 88.2% and 55.1%, respectively. Conclusion: This study established a predictable GEE model, incorporating the data of patients who were hospitalized several times into a prediction analysis, even though the sensitivity was not sufficiently high. The GEE model, which is considered clinically useful, can be constructed using a variety of variables, including those obtained from electronic health records.

DOI： 10.3390/gastroent11020007

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Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.

DOI： 10.1007/s13691-019-00394-2

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INTRODUCTION: Because of the increasing age of the general population, there is an increasing number of older patients with lung cancer. Cancer chemotherapy often causes severe hematological toxicity in older patients. OBJECTIVE: This study aimed to explore the risk factors affecting the hematological toxicity of cytotoxic anticancer drugs in patients with lung cancer. METHODS: Data were retrospectively collected from 194 patients with lung cancer at Niigata University Medical and Dental Hospital, Japan, between April 2011 and March 2016, when the patients underwent their first round of cytotoxic chemotherapy. The patients were divided into three groups on the basis of age: <65, 65-74, and ≥75 years. Physiological functions and laboratory data before treatment, as well as hematological adverse events following chemotherapy, were compared among the groups. RESULTS: Patients aged ≥75 years were significantly more likely to experience grade 3 or 4 neutropenia, compared with patients aged <65 years. However, there were no differences in the incidence of anemia or thrombocytopenia among the age groups. The frequency of febrile neutropenia tended to increase with age. Multivariate analysis showed that age ≥75 years, male sex, and a performance status of ≥2 were independent factors for grade 3 or 4 neutropenia. Patients with 2 or 3 of these factors had a significantly higher frequency of neutropenia, compared with patients who had 0 or 1 of these factors. CONCLUSION: We found that age ≥75 years, male sex, and a performance status of ≥2 were independent risk factors for grade 3 or 4 neutropenia.

DOI： 10.1159/000507864

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Language：Japanese   Publisher：(一社)医薬品相互作用研究会  

当院歯科領域では周術期患者に対し、術後感染予防として注射用抗菌薬セファゾリン(CEZ)が推奨されているが、CEZ投与終了翌日から経口抗菌薬へ切り替えて投与する治療(経口スイッチ療法)が経験的に行われる場合がある。「術後感染予防抗菌薬適正使用のための実践ガイドライン」では、推奨投与期間を超えた経口抗菌薬の追加は不要であるとされている。そこで今回、経口スイッチ療法の必要性について検討するため、2015年1月～6月に当院歯科領域でCEZを使用された患者213例を対象とし、経口スイッチ療法実施群(111例)と非実施群(102例)に分けて諸データの群間比較を行った。結果、実施群の背景として、「入院期間の短縮」や「剤形変更による費用削減」などを期待して経口スイッチ療法が行われていたと考えられたが、実際には「入院期間の短縮」「費用削減」とも認められなかった。このことから経口スイッチ療法の必要性は低い可能性が示唆された。

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Language：Japanese   Publisher：(一社)日本病院薬剤師会  

これまで新潟大学医歯学総合病院歯科領域では予防的抗菌薬として、経験的にセフォチアム(cefotiam:以下、CTM)が使用されていたが、院内感染制御チーム(infection control team:以下、ICT)が2011年7月に介入し、セファゾリン(cefazolin:以下、CEZ)へ変更となった。今回、予防的抗菌薬変更による手術部位感染(surgical site infection:以下、SSI)発生率と医療費への影響を評価することを目的に後ろ向きに調査した。その結果、対象患者1,081名中、CTM使用患者は486名、CEZ使用患者は595名で、SSI発生率に差はなかった。一人当たりの平均投与費用は9,946円から2,169円へと減少し、SSI発生阻止率から算出した費用対効果比は10,016.3から2,204.5に改善されていた。以上のことから、ICTの介入による予防的抗菌薬変更はSSI発生率に差は認められず、医療費削減の点からも推奨される取り組みであったと考えられた。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J04451&link_issn=&doc_id=20170612190005&doc_link_id=%2Fdg4hppha%2F2017%2F005306%2F002%2F0671-0674%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2017%2F005306%2F002%2F0671-0674%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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OBJECTIVES: The adenosine triphosphate assay using peripheral lymphocytes may be useful to evaluate the risks of acute rejection and infection in kidney transplant patients. We used the adenosine triphosphate assay to evaluate differences between recipients who were treated with cyclosporine- or tacrolimus-based immunosuppressive therapy. MATERIALS AND METHODS: Adenosine triphosphate levels were measured in peripheral CD4+ cells before and after transplant and were correlated with clinical outcomes in 45 kidney transplant recipients. These recipients received immunosuppressive therapy with either cyclosporine (23 patients) or tacrolimus (22 patients). RESULTS: Adenosine triphosphate levels were significantly lower in the cyclosporine- than tacrolimus-based therapy groups from 2 to 6 weeks after transplant. Adenosine triphosphate levels were similar between these groups before and 1 week after transplant. The frequency of cytomegalovirus infection was greater in the recipients who received cyclosporine (17 patients [74%]) than tacrolimus (6 patients [27%]; P ≦ .003). The frequency of acute rejection episodes was similar between the cyclosporine and tacrolimus groups. CONCLUSIONS: These observations suggest that cyclosporine-based immunosuppressive therapy causes excessive immunosuppression compared with tacrolimus-based therapy, evidenced by the lymphocyte adenosine triphosphate levels. The adenosine triphosphate assay using peripheral CD4+ cells may be a useful method for predicting the occurrence of cytomegalovirus infections in kidney transplant recipients.

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The lymphocyte immunosuppressant sensitivity test (LIST) with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay procedure has been used to predict the pharmacological efficacy of immunosuppressive agents to prevent acute rejection episodes for renal transplant recipients. In this study, mycophenolic acid (MPA) pharmacological efficacies were evaluated by LIST at both prior to and just after renal transplantation. We compared the efficacies to the clinical outcome of these recipients. MPA's pharmacological efficacy was evaluated by LIST not only before the operation but also at 2, 4, and 6 weeks after transplantation in 16 renal transplant recipients. These recipients were divided into high- and low-sensitivity groups according to peripheral blood mononuclear cell (PBMC) sensitivity to MPA in vitro. The MPA sensitivities were compared to cytomegalovirus (CMV) infection and acute rejection episodes in these recipients under MPA immunosuppressive therapy. The rate of CMV infection episodes in the low-MPA pharmacological efficacy group categorized at 2 weeks after renal transplantation was 5/6 (83.3%), which was significantly higher than the rate of 1/10 (10.0%) (p < 0.01) in the high-MPA sensitivity group. However, the MPA pharmacological efficacy evaluated both before and after transplantation had no relationship with the incidence of rejection episodes. These findings suggest that the MPA pharmacological efficacy evaluated by LIST at 2 weeks after operation is a useful biomarker for predicting the following occurrence of CMV infection episodes in renal transplant recipients.

DOI： 10.3727/215517913X674216

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The lymphocyte immunosuppressant sensitivity test (LIST) using patient peripheral lymphocytes can predict the therapeutic efficacy of immunosuppressive drugs used in renal transplantation. We have evaluated the pharmacological efficacy of drugs by using the LIST with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, which measures the cellular mitochondrial activity. The LIST with the MTT assay requires a relatively large amount of blood. As such, we developed a new assay for examining drug sensitivity with a CellTiter-Glo assay, which measures the amount of cellular ATP to help increase the assay's sensitivity and reduce the amount of blood needed. Renal transplant recipients generally receive either cyclosporine or tacrolimus, in addition to mycophenolate mofetil and methylprednisolone, as an immunosuppressive therapy to prevent acute rejection. We evaluated the pharmacological efficacy of these immunosuppressive agents with both the MTT and CellTiter-Glo assays using the peripheral blood mononuclear cells of 21 healthy volunteers. Furthermore, we also examined the relationship between these immunosuppressive agents' pharmacological efficacy and the results of the MTT and CellTiter-Glo assays. The IC50 values for cyclosporine, tacrolimus, mycophenolic acid, and methylprednisolone were significantly correlated between the MTT and CellTiter-Glo assays. The amount of blood cells required for LIST with the CellTiter-Glo assay was able to be reduced to 25% of the amount required for the previously established LIST with the MTT assay procedure. We concluded from these observations that the LIST with the CellTiter-Glo assay should be used instead of the MTT assay for carrying out individualized immunosuppressive therapy in renal transplantation patients.

DOI： 10.3727/215517913X674207

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The lymphocyte immunosuppressant sensitivity test (LIST) with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay procedure can predict the pharmacological efficacy of immunosuppressive agents. A previous study reported the pharmacological efficacy of tacrolimus evaluated by LIST just before renal transplantation significantly correlated with the incidence of acute rejection episodes. However, the pharmacological efficacy of tacrolimus has not been estimated after renal transplantation. Therefore, the present study evaluated the pharmacological efficacy of tacrolimus by LIST using the MTT assay procedure before and 1, 3, and 12 months after transplantation in 17 renal transplant recipients that received tacrolimus-based immunosuppressive therapy. The tacrolimus pharmacological efficacies before and after the procedure were also compared with incidence of acute rejection and cytomegalovirus (CMV) infection episodes. The individual values of tacrolimus 50% inhibition of lymphocyte proliferation (IC50) varied widely before transplantation, and the mean value of the IC50 was 126.4 ± 337.7 ng/ml. The patients were divided into two groups according to the tacrolimus IC50 values evaluated before transplantation. The rate of acute rejection episodes in the tacrolimus high-sensitivity group was significantly lower than that in the tacrolimus low-sensitivity group (p = 0.005). The tacrolimus IC50 deviation between patients expanded further at one and three months after surgery. However, the sensitivity deviation almost converged at 1 year after surgery. Moreover, the pharmacological efficacy of tacrolimus evaluated at 1, 3, and 12 months after transplantation did not significantly correlate with the incidence of acute rejection episodes. The pharmacological efficacies of tacrolimus evaluated at both before and after surgery were not significantly correlated with the episodes of CMV infection. These findings suggest that the pharmacological efficacy of tacrolimus evaluated with LIST before surgery is a useful biomarker for predicting the occurrence of acute allograft rejection in renal transplantation.

DOI： 10.3727/215517912X639360

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Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.

DOI： 10.3727/096368911X605493

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Language：Japanese   Publishing type：Research paper (scientific journal)  

It is obvious that pharmacists play a critical role as risk managers in the healthcare system, especially in medication treatment. Hitherto, there is not a single multicenter-survey report describing the effectiveness of clinical pharmacists in preventing medical errors from occurring in the wards in Japan. Thus, we conducted a 1-month survey to elucidate the relationship between the number of errors and working hours of pharmacists in the ward, and verified whether the assignment of clinical pharmacists to the ward would prevent medical errors between October 1-31, 2009. Questionnaire items for the pharmacists at 42 national university hospitals and a medical institute included the total and the respective numbers of medication-related errors, beds and working hours of pharmacist in 2 internal medicine and 2 surgical departments in each hospital. Regardless of severity, errors were consecutively reported to the Medical Security and Safety Management Section in each hospital. The analysis of errors revealed that longer working hours of pharmacists in the ward resulted in less medication-related errors; this was especially significant in the internal medicine ward (where a variety of drugs were used) compared with the surgical ward. However, the nurse assignment mode (nurse/inpatients ratio: 1 : 7-10) did not influence the error frequency. The results of this survey strongly indicate that assignment of clinical pharmacists to the ward is critically essential in promoting medication safety and efficacy.

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The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of immunosuppressive agents. We herein estimated the mycophenolic acid efficacy using LIST before and 1, 3, and 12 months after the operation in 15 renal transplant recipients. The pharmacological efficacy of mycophenolic acid as assessed before transplantation showed small individual variations, whereas the variability greatly increased at 1 and 3 months after transplantation. Furthermore, the individual IC50 variation among these subjects at 1-year after operation was closely similar to that observed before surgery. No significant implications of these individual differences in the mycophenolic acid sensitivity were noted in regard to the clinical courses of these recipients.

DOI： 10.3109/08923970903490478

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The lymphocyte immunosuppressant-sensitivity test (LIST) has been reported extensively as being able to estimate the pharmacological efficacy of immunosuppressive drugs in individual patients. This study measured the IC50 values for 6 drugs, cyclosporine, tacrolimus, methylprednisolone, 6-mercaptopurine, mycophenolic acid, and mizoribine, against mitogen-induced proliferation of peripheral-blood lymphocytes in 29 renal transplant recipients. We also examined relationship between the IC50 values and 4 factors; age, duration of dialysis, percentage of lymphocytes in total white blood cells, and blastogenesis stimulation index by mitogen. There were no significant correlations between the IC50 values and these factors, except that the tacrolimus IC50 value was correlated weakly with the stimulation index (p<0.05, r=-0.429). It was concluded that the pharmacological efficacy of immunosuppressive drugs cannot be inferred from the patient characteristics or their laboratory data. LIST is an effective method to elucidate the pharmacodynamic properties of immunosuppressive agents in individual renal transplant recipients without being influenced by the recipient clinical data.

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The physiological function of the prion protein (PrP) remains enigmatic despite its established involvement in the pathogenesis of spongiform encephalopathies. PrP is a glycolipid-anchored membrane protein, which constitutively recycles between the cell surface and an endosomal compartment. The N-terminal region of PrP contains a four tandem repeat (OP4) of the octapeptide PHGGGWGQ (OP) that binds and reduces Cu(II) ions. We have examined the kinetic properties of the OP4-mediated Cu(II) reduction and found that OP4 exhibits the highest reduction activity around pH 6.5, close to the pH in early endosomes. All four OP units and at least one tryptophan side chain are essential for Cu(II) reduction. The reaction is described by an uncompetitive substrate inhibition mechanism involving a 1:1 Cu(II)-OP4 active intermediate. Structural analysis by Raman spectroscopy has revealed that the Cu(II) ion is coordinated by four histidine Ntau atoms in the active intermediate and the feasibility of formation of this intermediate correlates with the Cu(II) reduction over a pH range from 5.0 to 8.2. Molecular mechanics calculations suggest that two tryptophan residues of OP4 are located near the Cu(II) site, being consistent with the importance of redox-active tryptophan in the Cu(II) reduction. PrP has been proposed to capture Cu(II) ions in the extracellular space and release them in the endosome. The results of this study strongly suggest that PrP also plays a role in the reduction of captured Cu(II) ions prior to their transfer to Cu(I)-specific intracellular copper trafficking proteins.

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Language：English   Publisher：AMER CHEMICAL SOC  

Cu-Zn superoxide dismutase (SOD) contains a conserved, metal-free His residue at an opening of the backbone beta-barrel in addition to six Cu- and/or Zn-bound His residues in the active site. We examined the protonation and hydrogen bonding state of the metal-free His residue (His41) in bovine SOD by UV Raman spectroscopy. Analysis of the His Raman intensity at 1406 cm(-1) in a D2O solution has shown that His41. has a pK(a) of 9.4, consistent with the NMR and X-ray structures at acidic to neutral pH, in which two imidazole nitrogen atoms of cationic His41 are hydrogen bonded to the main chain C=O groups of Thr37 and His118. Upon deprotonation of His41 at pH 9.4, the Thr37-His41-His118 hydrogen bond bridge breaks on the His118 side and SOD loses 70% of its activity. Concomitantly, hydrogen-deuterium exchange is accelerated for amide groups of beta-strands, indicating an increased conformational fluctuation of the beta-barrel. Thr37 and His41 are in direct contact with Leu36, whose hydrophobic side chain closes off the opening of the beta-barrel, while His118 is indirectly connected to Arg141 that assists the docking of superoxide to Cu. These Raman findings strongly suggest that the His41-mediated hydrogen bond bridge plays a crucial role in keeping the protein structure suitable for highly efficient catalytic reactions. The catalytic and structural role of His41 is consistent with the observation that the mutation of His43 in human SOD (equivalent to His41 in bovine SOD) to Arg largely reduces the dismutase activity and the protein structural stability.

DOI： 10.1021/bi049767k

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Cu-Zn superoxide dismutase (SOD) contains a conserved, metal-free His residue at an opening of the backbone beta-barrel in addition to six Cu- and/or Zn-bound His residues in the active site. We examined the protonation and hydrogen bonding state of the metal-free His residue (His41) in bovine SOD by UV Raman spectroscopy. Analysis of the His Raman intensity at 1406 cm(-1) in a D2O solution has shown that His41. has a pK(a) of 9.4, consistent with the NMR and X-ray structures at acidic to neutral pH, in which two imidazole nitrogen atoms of cationic His41 are hydrogen bonded to the main chain C=O groups of Thr37 and His118. Upon deprotonation of His41 at pH 9.4, the Thr37-His41-His118 hydrogen bond bridge breaks on the His118 side and SOD loses 70% of its activity. Concomitantly, hydrogen-deuterium exchange is accelerated for amide groups of beta-strands, indicating an increased conformational fluctuation of the beta-barrel. Thr37 and His41 are in direct contact with Leu36, whose hydrophobic side chain closes off the opening of the beta-barrel, while His118 is indirectly connected to Arg141 that assists the docking of superoxide to Cu. These Raman findings strongly suggest that the His41-mediated hydrogen bond bridge plays a crucial role in keeping the protein structure suitable for highly efficient catalytic reactions. The catalytic and structural role of His41 is consistent with the observation that the mutation of His43 in human SOD (equivalent to His41 in bovine SOD) to Arg largely reduces the dismutase activity and the protein structural stability.

DOI： 10.1021/bi049767k

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Molecular dynamics analyses were performed to examine conformational changes in the C-domain of calmodulin and the N-domain of troponin C induced by binding of Ca2+ ions. Analyses of conformational changes in calmodulin and troponin C indicated that the shortening of the distance between Ca2+ ions and Ca2+ binding sites of helices caused widening of the distance between Ca2+ binding sites of helices on opposite sides, while the hydrophobic side chains in the center of helices hardly moved due to their steric hindrance. This conformational change acts as the clothespin mechanism. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(04)00114-0

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Molecular dynamics analyses were performed to examine conformational changes in the C-domain of calmodulin and the N-domain of troponin C induced by binding of Ca2+ ions. Analyses of conformational changes in calmodulin and troponin C indicated that the shortening of the distance between Ca2+ ions and Ca2+ binding sites of helices caused widening of the distance between Ca2+ binding sites of helices on opposite sides, while the hydrophobic side chains in the center of helices hardly moved due to their steric hindrance. This conformational change acts as the clothespin mechanism. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(04)00114-0

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Isotope-edited Raman spectroscopy, a combination of site-selective isotopic labeling and Raman difference spectroscopy, is a useful method for studying the structure and interaction of individual nucleic acid residues in oligonucleotides. To obtain basic data for applying isotope-edited Raman spectroscopy to guanine residues, we studied the vibrational modes of UV resonance Raman bands of the C8-deuterated guanine ring by examining the wavenumber shifts upon seven isotopic substitutions (2-C-13, 2-N-15, 6-O-18, 7-N-15 8-C-13, 9-N-15 and 1'-C-13). The hydrogen bond sensitivities of the Raman bands were also investigated by comparing the Raman spectra recorded in several solvents of different hydrogen bonding properties. Some of the Raman bands were found to be markers of hydrogen bonding at specific donor or acceptor sites on the guanine ring. The Raman bands, which shift on C8-deuteration, remain in the difference spectrum between the unlabeled and C8-deuterated guanine rings. Among them, a negative peak around 1525 cm(-1) and a strong positive/negative peak pair around 1485/1465 cm(-1) serve as markers of hydrogen bonding at N7 and C6=O, respectively. Another weak positive/negative peak pair around 1025/1040 cm(-1) is sensitive to hydrogen bonding at the proton donor sites (N1-H and N2-H-2). The applicability of the hydrogen bond markers has been tested by using a 22-mer oligonucleotide duplex containing eight guanine residues and its analog in which a single guanine residue is C8-deuterated. The difference spectrum shows that the hydrogen bonding state of the guanine residue at the labeled position is consistent with the Watson-Crick base pair structure of DNA. Isotope-edited Raman spectroscopy is a useful tool for studying the hydrogen bonding state of selected guanine residues in oligonucleotides. Copyright (C) 2002 John Wiley Sons, Ltd.

DOI： 10.1002/jrs.899

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Isotope-edited Raman spectroscopy, a combination of site-selective isotopic labeling and Raman difference spectroscopy, is a useful method for studying the structure and interaction of individual nucleic acid residues in oligonucleotides. To obtain basic data for applying isotope-edited Raman spectroscopy to guanine residues, we studied the vibrational modes of UV resonance Raman bands of the C8-deuterated guanine ring by examining the wavenumber shifts upon seven isotopic substitutions (2-C-13, 2-N-15, 6-O-18, 7-N-15 8-C-13, 9-N-15 and 1'-C-13). The hydrogen bond sensitivities of the Raman bands were also investigated by comparing the Raman spectra recorded in several solvents of different hydrogen bonding properties. Some of the Raman bands were found to be markers of hydrogen bonding at specific donor or acceptor sites on the guanine ring. The Raman bands, which shift on C8-deuteration, remain in the difference spectrum between the unlabeled and C8-deuterated guanine rings. Among them, a negative peak around 1525 cm(-1) and a strong positive/negative peak pair around 1485/1465 cm(-1) serve as markers of hydrogen bonding at N7 and C6=O, respectively. Another weak positive/negative peak pair around 1025/1040 cm(-1) is sensitive to hydrogen bonding at the proton donor sites (N1-H and N2-H-2). The applicability of the hydrogen bond markers has been tested by using a 22-mer oligonucleotide duplex containing eight guanine residues and its analog in which a single guanine residue is C8-deuterated. The difference spectrum shows that the hydrogen bonding state of the guanine residue at the labeled position is consistent with the Watson-Crick base pair structure of DNA. Isotope-edited Raman spectroscopy is a useful tool for studying the hydrogen bonding state of selected guanine residues in oligonucleotides. Copyright (C) 2002 John Wiley Sons, Ltd.

DOI： 10.1002/jrs.899

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The imidazole ring of histidine exists in two tautomeric forms in neutral-to-basic aqueous solution, and the tautomerism of the histidine residue sometimes plays a key role in catalytic reactions of enzymes. We have investigated the molecular vibrations of two tautomers of 4-methylimidazole (4-Melm), a model compound for the histidine side chain, by Raman spectroscopy and ab initio calculations based on the density functional theory (DFT) approach. Examination of the temperature dependence of Raman intensity revealed nine pairs of bands characteristic of the N1-protonated and the N3-protonated tautomers of 4-Melm at 1576/1596, 1452/1427, 1304/1344, 1265/1259, 1229/1234, 1165/1149, 1088/1104, 996/1014, and 942/934 cm(-1). Five to six pairs of tautomerism-sensitive Raman bands were also identified for each of the C2-, N-, and C2,N-deuterated analogues of 4-Melm. The observed Raman wavenumbers were used to determine nine scaling factors for the in-plane force constants derived from DFT calculations using the 6-311+G(2d, p) basis set. The force field finally obtained reproduces the experimental vibrational wavenumbers of four additional isotopomers (C5-, C5,N-, C2,C5-, and C2,C5,N-deuterated 4-Melm) as well. The vibrational modes calculated for 4-Melm are useful in understanding the origins of the previously proposed tautomer marker bands of histidine at 1568/1585, 1282/1260, 1090/1105, and 983/1004 cm(-1). A pair of Raman bands at 1320/1354 cm(-1) is suggested to be a new tautomer marker of histidine.

DOI： 10.1021/jp0124185

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The imidazole ring of histidine exists in two tautomeric forms in neutral-to-basic aqueous solution, and the tautomerism of the histidine residue sometimes plays a key role in catalytic reactions of enzymes. We have investigated the molecular vibrations of two tautomers of 4-methylimidazole (4-Melm), a model compound for the histidine side chain, by Raman spectroscopy and ab initio calculations based on the density functional theory (DFT) approach. Examination of the temperature dependence of Raman intensity revealed nine pairs of bands characteristic of the N1-protonated and the N3-protonated tautomers of 4-Melm at 1576/1596, 1452/1427, 1304/1344, 1265/1259, 1229/1234, 1165/1149, 1088/1104, 996/1014, and 942/934 cm(-1). Five to six pairs of tautomerism-sensitive Raman bands were also identified for each of the C2-, N-, and C2,N-deuterated analogues of 4-Melm. The observed Raman wavenumbers were used to determine nine scaling factors for the in-plane force constants derived from DFT calculations using the 6-311+G(2d, p) basis set. The force field finally obtained reproduces the experimental vibrational wavenumbers of four additional isotopomers (C5-, C5,N-, C2,C5-, and C2,C5,N-deuterated 4-Melm) as well. The vibrational modes calculated for 4-Melm are useful in understanding the origins of the previously proposed tautomer marker bands of histidine at 1568/1585, 1282/1260, 1090/1105, and 983/1004 cm(-1). A pair of Raman bands at 1320/1354 cm(-1) is suggested to be a new tautomer marker of histidine.

DOI： 10.1021/jp0124185

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Cyclic AMP (cAMP) receptor protein (CRP) forms 1:1 and 1:2 complexes with cAMP, and the former complex is considered to be the most active form of CRP in binding to specific DNA sequences and in modulating gene transcription by RNA polymerases. We examine the cAMP binding modes and structural changes of CRP upon cAMP binding by UV resonance Raman spectroscopy. The Raman spectra of CRP-(cAMP)(1) and CRP-(cAMP)(2) extracted from those of CRP- cAMP mixtures at varied mixing ratios clearly show that the hydrogen bonding state and the conformation of cAMP in both complexes in solution are very similar to those found in the X-ray crystal structure of CRP-(cAMP)(2), which is evidence that the cAMP binding mode does not differ between the two complexes. The environmental hydrophobicity of Trp85 monitored by UV resonance Raman intensity shows a significant decrease upon binding of the first cAMP molecule, whereas no further change occurs in the second cAMP binding step. The environmental change of Trp85 suggests an opening of the cleft between the N-terminal cAMP and C-terminal DNA binding domains in the process of CRP activation by binding of a single cAMP molecule. (C) 2002 Wiley Periodicals, Inc.

DOI： 10.1002/bip.10081

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Cyclic AMP (cAMP) receptor protein (CRP) forms 1:1 and 1:2 complexes with cAMP, and the former complex is considered to be the most active form of CRP in binding to specific DNA sequences and in modulating gene transcription by RNA polymerases. We examine the cAMP binding modes and structural changes of CRP upon cAMP binding by UV resonance Raman spectroscopy. The Raman spectra of CRP-(cAMP)(1) and CRP-(cAMP)(2) extracted from those of CRP- cAMP mixtures at varied mixing ratios clearly show that the hydrogen bonding state and the conformation of cAMP in both complexes in solution are very similar to those found in the X-ray crystal structure of CRP-(cAMP)(2), which is evidence that the cAMP binding mode does not differ between the two complexes. The environmental hydrophobicity of Trp85 monitored by UV resonance Raman intensity shows a significant decrease upon binding of the first cAMP molecule, whereas no further change occurs in the second cAMP binding step. The environmental change of Trp85 suggests an opening of the cleft between the N-terminal cAMP and C-terminal DNA binding domains in the process of CRP activation by binding of a single cAMP molecule. (C) 2002 Wiley Periodicals, Inc.

DOI： 10.1002/bip.10081

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Raman spectroscopy has been combined with site-selective isotopic labeling techniques to obtain structural information on a selected nucleic acid residue in oligonucleotides. In the difference spectrum between the unlabeled and site-selectively labeled oligonucleotides, the Raman signals from the residue at the labeled position show up, while the signals from the residues at unlabeled positions are canceled out. To demonstrate the utility of this new method, we have prepared a self-complementary tetradecamer DNA, d(AGTGCTCGAGCACT)(2), containing single C8-deuterated adenine at position 9 (A9) or 12 (A12). UV (257 nm) resonance Raman difference spectra between the unlabeled and labeled oligonucleotides in solution reveal slightly different microenvironments around A9 and A 12 as expected for a double-stranded helical structure of the tetradecamer DNA. In the presence of an antitumor antibiotic, actinomycin D, which intercalates into the 5'-GC-3' sequence of DNA, the Raman signals of A9 on the 5'-side of the intercalation site become significantly weaker, indicating an increased base stacking with adjacent guanine bases. In contrast, the Raman signals of A12 on the 3'-side are not affected by the binding of actinomycin D. This observation provides the first experimental evidence that the intercalation of actinomycin D induces an asymmetric structural alteration of DNA in solution. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-2860(01)00808-0

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Raman spectroscopy has been combined with site-selective isotopic labeling techniques to obtain structural information on a selected nucleic acid residue in oligonucleotides. In the difference spectrum between the unlabeled and site-selectively labeled oligonucleotides, the Raman signals from the residue at the labeled position show up, while the signals from the residues at unlabeled positions are canceled out. To demonstrate the utility of this new method, we have prepared a self-complementary tetradecamer DNA, d(AGTGCTCGAGCACT)(2), containing single C8-deuterated adenine at position 9 (A9) or 12 (A12). UV (257 nm) resonance Raman difference spectra between the unlabeled and labeled oligonucleotides in solution reveal slightly different microenvironments around A9 and A 12 as expected for a double-stranded helical structure of the tetradecamer DNA. In the presence of an antitumor antibiotic, actinomycin D, which intercalates into the 5'-GC-3' sequence of DNA, the Raman signals of A9 on the 5'-side of the intercalation site become significantly weaker, indicating an increased base stacking with adjacent guanine bases. In contrast, the Raman signals of A12 on the 3'-side are not affected by the binding of actinomycin D. This observation provides the first experimental evidence that the intercalation of actinomycin D induces an asymmetric structural alteration of DNA in solution. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-2860(01)00808-0

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UV resonance Raman spectra of guanosine and its seven isotope-substituted analogs (2-C-13, 2-N-15 6-O-18, 7-N-15, 8-C-13, 9-N-15 and 1'-C-13) were measured with 257 mn excitation in H2O and D2O solutions, In-plane vibrations of the guanine ring were selectively enhanced in the UV resonance Raman spectra, and most Raman bands showed significant wavenumber shifts upon isotopic substitution. The observed isotope shifts were used to assign the Raman bands to vibrations of the peripheral sites (N1-H, C2-NH2 and C6=O), the pyrimidine ring and/or the imidazole ring. Previous assignments for some Raman bands were shown to be inconsistent with the isotopic data and they were revised. Relationships between the vibrational modes and the sensitivities to hydrogen bonding or conformation are discussed for known Raman marker bands. Each hydrogen bond marker arises from a vibration that involves, at least partly, the proton donor or acceptor atom, All the marker bands of glycosidic bond orientation and ribose ring puckering actually involve atomic displacements around the N9-C1' moiety connecting the guanine ring to ribose, permitting vibrational coupling between them. The isotopic wavenumber shifts reported here may be useful in improving the force field for the 9-substituted guanine ring and in interpreting the vibrational spectra of guanine nucleoside and nucleotides. Copyright (C) 1999 John Wiley & Sons, Ltd.

DOI： 10.1002/(SICI)1097-4555(199908)30:8<623::AID-JRS407>3.0.CO;2-9

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UV resonance Raman spectra of guanosine and its seven isotope-substituted analogs (2-C-13, 2-N-15 6-O-18, 7-N-15, 8-C-13, 9-N-15 and 1'-C-13) were measured with 257 mn excitation in H2O and D2O solutions, In-plane vibrations of the guanine ring were selectively enhanced in the UV resonance Raman spectra, and most Raman bands showed significant wavenumber shifts upon isotopic substitution. The observed isotope shifts were used to assign the Raman bands to vibrations of the peripheral sites (N1-H, C2-NH2 and C6=O), the pyrimidine ring and/or the imidazole ring. Previous assignments for some Raman bands were shown to be inconsistent with the isotopic data and they were revised. Relationships between the vibrational modes and the sensitivities to hydrogen bonding or conformation are discussed for known Raman marker bands. Each hydrogen bond marker arises from a vibration that involves, at least partly, the proton donor or acceptor atom, All the marker bands of glycosidic bond orientation and ribose ring puckering actually involve atomic displacements around the N9-C1' moiety connecting the guanine ring to ribose, permitting vibrational coupling between them. The isotopic wavenumber shifts reported here may be useful in improving the force field for the 9-substituted guanine ring and in interpreting the vibrational spectra of guanine nucleoside and nucleotides. Copyright (C) 1999 John Wiley & Sons, Ltd.

DOI： 10.1002/(SICI)1097-4555(199908)30:8<623::AID-JRS407>3.0.CO;2-9

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Ultraviolet (UV) resonance Raman spectra of an acetyl derivative of adenosine and its C8-deuterated analog were measured in solvents with varied hydrogen bonding properties. The Raman spectrum of the acetyl derivative in H2O solution is almost identical to that of adenosine in H2O solution, indicating that the acetyl derivative is a good model for the adenine nucleotide in DNA, Most of the Raman bands increase or decrease in wavenumber upon hydrogen bonding at the proton-donor (C6-NH2) and proton-acceptor sites (N1, N3 and N7) of the adenine ring. Among them, the nu(1), nu(2), nu(3), nu(5) and nu(9) bands of the adenine ring and the nu(1)', nu(2)', nu(3)', nu(5)', nu(7)' and nu(9)' bands of the C8-deuterated adenine ring show wavenumber shifts larger than 5 cm(-1). Relative intensities of some Raman bands change as well. The wavenumber and intensity changes can be used as markers of hydrogen bonding at the proton donor and/or acceptor sites of the adenine ring. The Raman spectral difference between the nondeuterated and C8-D labeled adenine rings reflects the hydrogen-bonding state very sensitively and is expected to be useful in studying the hydrogen-bonding state of a particular adenine residue in oligonucleotides by a combination of site-selective C8-D labeling and UV resonance Raman spectroscopy. (C) 1998 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-2860(98)00301-9

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Ultraviolet (UV) resonance Raman spectra of an acetyl derivative of adenosine and its C8-deuterated analog were measured in solvents with varied hydrogen bonding properties. The Raman spectrum of the acetyl derivative in H2O solution is almost identical to that of adenosine in H2O solution, indicating that the acetyl derivative is a good model for the adenine nucleotide in DNA, Most of the Raman bands increase or decrease in wavenumber upon hydrogen bonding at the proton-donor (C6-NH2) and proton-acceptor sites (N1, N3 and N7) of the adenine ring. Among them, the nu(1), nu(2), nu(3), nu(5) and nu(9) bands of the adenine ring and the nu(1)', nu(2)', nu(3)', nu(5)', nu(7)' and nu(9)' bands of the C8-deuterated adenine ring show wavenumber shifts larger than 5 cm(-1). Relative intensities of some Raman bands change as well. The wavenumber and intensity changes can be used as markers of hydrogen bonding at the proton donor and/or acceptor sites of the adenine ring. The Raman spectral difference between the nondeuterated and C8-D labeled adenine rings reflects the hydrogen-bonding state very sensitively and is expected to be useful in studying the hydrogen-bonding state of a particular adenine residue in oligonucleotides by a combination of site-selective C8-D labeling and UV resonance Raman spectroscopy. (C) 1998 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-2860(98)00301-9

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Ultraviolet resonance Raman spectra of 2'-deoxy-3',5'-bis(triisopropylsilyl)guanosine (TPS-dGuo) were recorded in non-hydrogen bonding, proton acceptor, and proton donor/acceptor solvents. Raman spectral changes observed on going from inert to proton acceptor solvents were ascribed to the hydrogen bonding at the proton donor sites of the guanine ring(N1-H and C2-NH2), and the spectral changes associated with the solvent change from proton acceptor to donor/acceptor were ascribed to the hydrogen bonding at the proton acceptor sites (N3, C6=0, and N7). A Raman band appearing at 1624 cm(-1) in inert solvents is assigned mainly to the NH2 scissors mode and its frequency changes to approximate to 1640 cm(-1) in acceptor solvents, reflecting the hydrogen bonding at C2-NH2. Another band at 1581 cm(-1), arising largely from the N1-H bend, shows an upshift of approximate to 10 cm(-1) upon hydrogen bonding at either N1-H or acceptor sites. Hydrogen bonding at the acceptor sites also produces frequency shifts of other Raman bands (at 1710, 1565, 1528, 1481, and 1154 cm(-1) in 1,2-dichloroethane solution). Among the Raman bands listed above, the 1710 cm(-1) band due to the C6=0 stretch decreases in frequency, whereas the others increase. The downshift of the C6=0 stretching frequency is correlated with the strength of hydrogen bonding at C6=O. The frequency of the 1481 cm(-1) band increases with a decrease of the C6=O stretching frequency, indicating that the 1481 cm(-1) band is also a marker of hydrogen bonding at C6=O. This finding is in sharp contrast to the previously proposed correlation with the hydrogen bonding at N7. The 1565 cm(-1) band is assigned to a vibration mainly involving the N1-C2=N3 linkage, and its frequency increases with increasing strength of the hydrogen bond at N3. Three bands around 1315, 1 180, and 1030 cm(-1), which are known to be sensitive to the ribose ring puckering and glycosidic bond orientation, also show small frequency changes upon hydrogen bonding. The Raman marker bands for the hydrogen bonds at C2-NH2, N1-H, C6=0, and N3 are expected to be useful in studying the structures of nucleic acids and nucleic acid-protein complexes containing guanine residues.

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Ultraviolet resonance Raman spectra of 2'-deoxy-3',5'-bis(triisopropylsilyl)guanosine (TPS-dGuo) were recorded in non-hydrogen bonding, proton acceptor, and proton donor/acceptor solvents. Raman spectral changes observed on going from inert to proton acceptor solvents were ascribed to the hydrogen bonding at the proton donor sites of the guanine ring(N1-H and C2-NH2), and the spectral changes associated with the solvent change from proton acceptor to donor/acceptor were ascribed to the hydrogen bonding at the proton acceptor sites (N3, C6=0, and N7). A Raman band appearing at 1624 cm(-1) in inert solvents is assigned mainly to the NH2 scissors mode and its frequency changes to approximate to 1640 cm(-1) in acceptor solvents, reflecting the hydrogen bonding at C2-NH2. Another band at 1581 cm(-1), arising largely from the N1-H bend, shows an upshift of approximate to 10 cm(-1) upon hydrogen bonding at either N1-H or acceptor sites. Hydrogen bonding at the acceptor sites also produces frequency shifts of other Raman bands (at 1710, 1565, 1528, 1481, and 1154 cm(-1) in 1,2-dichloroethane solution). Among the Raman bands listed above, the 1710 cm(-1) band due to the C6=0 stretch decreases in frequency, whereas the others increase. The downshift of the C6=0 stretching frequency is correlated with the strength of hydrogen bonding at C6=O. The frequency of the 1481 cm(-1) band increases with a decrease of the C6=O stretching frequency, indicating that the 1481 cm(-1) band is also a marker of hydrogen bonding at C6=O. This finding is in sharp contrast to the previously proposed correlation with the hydrogen bonding at N7. The 1565 cm(-1) band is assigned to a vibration mainly involving the N1-C2=N3 linkage, and its frequency increases with increasing strength of the hydrogen bond at N3. Three bands around 1315, 1 180, and 1030 cm(-1), which are known to be sensitive to the ribose ring puckering and glycosidic bond orientation, also show small frequency changes upon hydrogen bonding. The Raman marker bands for the hydrogen bonds at C2-NH2, N1-H, C6=0, and N3 are expected to be useful in studying the structures of nucleic acids and nucleic acid-protein complexes containing guanine residues.

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Infrared, Raman and UV resonance Raman spectra of adenosine and its 1,3-N-15(2), 2-C-13, and 8-C-13 isotopic analogues were measured in neutral aqueous solution (Raman and UV Raman) and in the crystalline state (infrared and Raman). The observed isotopic wavenumber shifts are useful in distinguishing adenine ring vibrations from ribose vibrations. In-plane modes of the adenine ring are selectively enhanced in UV resonance Raman spectra, which facilitates the assignment of the in-plane vibrations. In addition to the in-plane modes, a ribose vibration coupled with adenine in-plane vibrations was identified in the UV resonance Raman spectra. The fundamental wavenumbers for 22 in-plane normal modes of the 9-substituted adenine ring of adenosine in the 1700-250 cm-1 region are proposed. Although the fundamental wavenumbers of adenosine correspond well with those of adenine above 1350 cm-1 and below 800 cm-1, the vibrations in the 1350-800 cm-1 region are appreciably affected by the presence of the N-9-C-1' glycosidic bond and the couplings between ribose and adenine ring vibrational motions. The adenosine fundamental wavenumbers and their isotopic shifts reported here may be useful in analysing vibrational spectra of adenine nucleosides and nucleotides and in improving the force field of the 9-substituted adenine ring.

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Infrared, Raman and UV resonance Raman spectra of adenosine and its 1,3-N-15(2), 2-C-13, and 8-C-13 isotopic analogues were measured in neutral aqueous solution (Raman and UV Raman) and in the crystalline state (infrared and Raman). The observed isotopic wavenumber shifts are useful in distinguishing adenine ring vibrations from ribose vibrations. In-plane modes of the adenine ring are selectively enhanced in UV resonance Raman spectra, which facilitates the assignment of the in-plane vibrations. In addition to the in-plane modes, a ribose vibration coupled with adenine in-plane vibrations was identified in the UV resonance Raman spectra. The fundamental wavenumbers for 22 in-plane normal modes of the 9-substituted adenine ring of adenosine in the 1700-250 cm-1 region are proposed. Although the fundamental wavenumbers of adenosine correspond well with those of adenine above 1350 cm-1 and below 800 cm-1, the vibrations in the 1350-800 cm-1 region are appreciably affected by the presence of the N-9-C-1' glycosidic bond and the couplings between ribose and adenine ring vibrational motions. The adenosine fundamental wavenumbers and their isotopic shifts reported here may be useful in analysing vibrational spectra of adenine nucleosides and nucleotides and in improving the force field of the 9-substituted adenine ring.

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Ultraviolet resonance Raman spectra of ribosyl C(1')-deuterated guanosine and adenosine were measured. Most in-plane vibrations of the purine rings in the 1420-1100-cm-1 region showed frequency upshifts upon C(1')-deuteration, while those in the 1100-700-cm-1 region showed downshifts. The purine ring vibrations above 1450 cm-1 were unaffected. The frequency shifts associated with the C(1')-deuteration are explained by assuming couplings of the purine vibrations with a ribose C(1')-H bending mode, which involves a hydrogen motion in the plane of N(9)-C(1')-H. The purine vibrations that showed upshifts in the 1420-1100-cm-1 region are originally lowered in frequency by coupling with the ribosyl bending mode alpha(CH) around 1420 cm-1 and restore their intrinsic frequencies upon shifting of alpha(CH) to alpha(CD) around 1100 cm-1 in the C(1')-D isotopomers. Some of the upshifted vibrations may be further pushed up by coupling with alpha(CD). On the other hand, the downshifted purine modes in the 1100-700-cm-1 region do not interact with alpha(CH) because of large frequency separations from alpha(CH) and retain their intrinsic frequencies in the C(1')-H species. In the C(1')-D species, however, alpha(CD) couples with these modes and pushes their frequencies downward. The observed C(1')-D frequency shifts provide direct evidence of vibrational coupling between the base and ribose rings, suggesting that the purine base vibrations may be affected by the ribose ring puckering and glycosidic bond orientation. Actually, most of the purine vibrations that showed significant C(1')-D shifts are known or proved to be conformational markers of purine nucleosides and nucleotides. The conformational sensitivity of purine vibrations really arises from vibrational coupling between the base and ribose rings.

DOI： 10.1021/ja00077a005

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Ultraviolet resonance Raman spectra of ribosyl C(1')-deuterated guanosine and adenosine were measured. Most in-plane vibrations of the purine rings in the 1420-1100-cm-1 region showed frequency upshifts upon C(1')-deuteration, while those in the 1100-700-cm-1 region showed downshifts. The purine ring vibrations above 1450 cm-1 were unaffected. The frequency shifts associated with the C(1')-deuteration are explained by assuming couplings of the purine vibrations with a ribose C(1')-H bending mode, which involves a hydrogen motion in the plane of N(9)-C(1')-H. The purine vibrations that showed upshifts in the 1420-1100-cm-1 region are originally lowered in frequency by coupling with the ribosyl bending mode alpha(CH) around 1420 cm-1 and restore their intrinsic frequencies upon shifting of alpha(CH) to alpha(CD) around 1100 cm-1 in the C(1')-D isotopomers. Some of the upshifted vibrations may be further pushed up by coupling with alpha(CD). On the other hand, the downshifted purine modes in the 1100-700-cm-1 region do not interact with alpha(CH) because of large frequency separations from alpha(CH) and retain their intrinsic frequencies in the C(1')-H species. In the C(1')-D species, however, alpha(CD) couples with these modes and pushes their frequencies downward. The observed C(1')-D frequency shifts provide direct evidence of vibrational coupling between the base and ribose rings, suggesting that the purine base vibrations may be affected by the ribose ring puckering and glycosidic bond orientation. Actually, most of the purine vibrations that showed significant C(1')-D shifts are known or proved to be conformational markers of purine nucleosides and nucleotides. The conformational sensitivity of purine vibrations really arises from vibrational coupling between the base and ribose rings.

DOI： 10.1021/ja00077a005

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Language：English   Publisher：JAPAN ACAD  

Infrared spectra of an oriented fiber made from 1200 kDa fragment of rabbit skeletal muscle connectin (titin) showed an abundance of beta-sheet structures. Infrared dichroism revealed that the beta-sheets were alligned with their mainchain axes parallel to the fibre axis. This conclusion is in good agreement with the results of chicken breast muscle beta-connectin (Uchida, K. et al., FEBS Lett., 295, 35-38 (1991)). A model of molecular structure of connectin is presented.

DOI： 10.2183/pjab.69.224

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Language：English   Publisher：JAPAN ACAD  

Infrared spectra of an oriented fiber made from 1200 kDa fragment of rabbit skeletal muscle connectin (titin) showed an abundance of beta-sheet structures. Infrared dichroism revealed that the beta-sheets were alligned with their mainchain axes parallel to the fibre axis. This conclusion is in good agreement with the results of chicken breast muscle beta-connectin (Uchida, K. et al., FEBS Lett., 295, 35-38 (1991)). A model of molecular structure of connectin is presented.

DOI： 10.2183/pjab.69.224

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：AMER SOC PHOTOBIOLOGY  

Ultraviolet resonance Raman spectra of phytochrome in the red light-absorbing form (Pr) and the far-red light-absorbing form (Pfr) are reported. The spectra excited at 240-nm provide structural information about the protein part of phytochrome. The protein contains only a very small amount of beta-sheet structure and most of the tyrosine side chains are located in hydrophobic environments. Indole rings of tryptophan (Trp) interact with neighboring groups in the Pr form and these interactions become weaker with the conversion from Pr to Pfr. Some Trp side chains of Pfr are surrounded by aliphatic groups but such is not the case in Pr. These changes in the environment occur at the same time as changes in orientation of Trp side chains. Our observations suggest that interactions between Trp residues and the tetrapyrrolic chromophore occur in the Pr form and that the strength of these interactions diminishes in the Pfr form.

DOI： 10.1111/j.1751-1097.1993.tb02307.x

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：AMER SOC PHOTOBIOLOGY  

Ultraviolet resonance Raman spectra of phytochrome in the red light-absorbing form (Pr) and the far-red light-absorbing form (Pfr) are reported. The spectra excited at 240-nm provide structural information about the protein part of phytochrome. The protein contains only a very small amount of beta-sheet structure and most of the tyrosine side chains are located in hydrophobic environments. Indole rings of tryptophan (Trp) interact with neighboring groups in the Pr form and these interactions become weaker with the conversion from Pr to Pfr. Some Trp side chains of Pfr are surrounded by aliphatic groups but such is not the case in Pr. These changes in the environment occur at the same time as changes in orientation of Trp side chains. Our observations suggest that interactions between Trp residues and the tetrapyrrolic chromophore occur in the Pr form and that the strength of these interactions diminishes in the Pfr form.

DOI： 10.1111/j.1751-1097.1993.tb02307.x

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja00009a071

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja00009a071

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Language：English   Publisher：ELSEVIER SCIENCE BV  

Ultraviolet resonance Raman spectra (266-nm excitation) were studied for adenine, uracil and thymine derivatives in several solvents at low concentrations (0.5-10 mM) where hydrogen bonding between solute molecules is negligible. The Raman spectral patterns depend critically on the proton-accepting/donating properties of the solvents. Raman bands which show large solvent effects are expected to be useful in studying the hydrogen-bonding states of the nucleic acid bases.

DOI： 10.1016/0022-2860(91)87129-6

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Language：English   Publisher：ELSEVIER SCIENCE BV  

Ultraviolet resonance Raman spectra (266-nm excitation) were studied for adenine, uracil and thymine derivatives in several solvents at low concentrations (0.5-10 mM) where hydrogen bonding between solute molecules is negligible. The Raman spectral patterns depend critically on the proton-accepting/donating properties of the solvents. Raman bands which show large solvent effects are expected to be useful in studying the hydrogen-bonding states of the nucleic acid bases.

DOI： 10.1016/0022-2860(91)87129-6

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Language：English   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ic00310a012

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Language：English   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ic00310a012

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