Relationship between hemoglobin levels and vancomycin clearance in patients with sepsis.

PURPOSE: It is important to accurately estimate accurate vancomycin (VCM) clearance (CLvcm) for appropriate VCM dosing in the treatment of patients with sepsis. However, the pathophysiology of sepsis can make CLvcm prediction less accurate. Clearance of hydrophilic antibiotics is disturbed by organ dysfunction, and hemoglobin levels are negatively correlated with sequential organ function assessment scores. We investigated whether hemoglobin levels are associated with CLvcm in sepsis patients. METHODS: We performed a retrospective cohort study of patients treated with VCM in the Emergency and Critical Care Center of Nihon University Itabashi Hospital between 2005 and 2015. We enrolled 72 patients after exclusion of patients who received renal replacement therapy or surgery, had a change in hemoglobin levels more than 2 g/dL or received an erythrocyte infusion during the interval between initial VCM administration and measurement of initial trough levels, had a serum baseline creatinine level of ≥ 2 mg/dL, or were under 18 years old. RESULTS: Enrolled patients consisted of 13 non-sepsis patients and 59 sepsis patients. In sepsis patients, although CLvcm was correlated with CrCl in HGB ≥ 9 group as well as in non-sepsis patients, its correlation was not observed in HGB < 9 group. Hemoglobin levels were correlated with CLvcm in sepsis patients but not in non-sepsis patient. Multiple linear regression analysis also indicated that lower CLvcm was associated with lower hemoglobin and CrCl. CONCLUSION: Lower hemoglobin levels influence a relationship between CLvcm and CrCl in sepsis patients. We propose that VCM dosing should be adjusted for hemoglobin levels in sepsis patients.

Relationship Between Initial Vancomycin Trough Levels and Early-Onset Vancomycin-Associated Nephrotoxicity in Critically Ill Patients.

BACKGROUND: Appropriate initial dosing of vancomycin (VCM) is important in improving survival and in preventing nephrotoxicity in critically ill patients, but the potential relationship between initial VCM trough levels and early-onset nephrotoxicity remains unclear. We examined the relationship between initial VCM trough levels and early-onset VCM-associated nephrotoxicity. METHODS: We performed a retrospective study of patients who had therapeutic drug monitoring of VCM with initial trough levels within 4 days after the beginning of VCM administration. We excluded patients who received renal replacement therapy from 2 days before to 7 days after the beginning of VCM administration, were younger than 18 years, or had renal dysfunction before the beginning of VCM administration. Early-onset VCM-associated nephrotoxicity was defined as an increase in serum creatinine level of ≥0.5 mg/dL (44.2 µmol/L) or 50% above baseline for 2 or more consecutive days within 7 days after the beginning of VCM administration. RESULTS: Among 109 enrolled patients, 13 patients had early-onset VCM-associated nephrotoxicity. Its incidence rate was 31.3% in patients with initial trough levels of ≥20g/mL, which was significantly higher than 6.3% in patients with initial trough levels of <10 mg/L. Multiple logistic regression analysis demonstrated that early-onset VCM-associated nephrotoxicity was associated with initial trough levels of ≥20 mg/L (odds ratio, 5.0; 95% confidence interval, 1.3-19.1) and with vasopressor use (odds ratio, 5.0; 95% confidence interval, 1.3-19.1). Kaplan-Meier analysis showed that the probability of nonnephrotoxicity for patients with initial VCM trough levels of ≥20 mg/L was lower compared with patients with trough levels of <15 mg/L. CONCLUSIONS: Initial trough levels of ≥20 mg/L but not ≥15 mg/L were associated with early-onset VCM-associated nephrotoxicity in critically ill patients. Future prospective studies are needed to examine outcomes in critically ill patients achieving initial VCM trough levels of 15-20 mg/L.

Stereochemically controlled asymmetric 1,2-reduction of enones mediated by a chiral sulfoxide moiety and a lanthanum(III) ion.

Enantiomerically pure (Z)-ß-sulfinyl allylic alcohols of either handedness can be readily prepared from (Z)-ß-sulfinyl enones using NaBH(4) or DIBAL reductants in the presence of LaCl(3) as a chelating agent. A chiral sulfoxide auxiliary induces the remote 1,2-asymmetric reduction (1,4-induction) to afford various chiral allylic alcohols in high yields with excellent stereoselectivities (up to 100% de).

Visualization of volatile substances in different organelles with an atmospheric-pressure mass microscope.

We have developed a mass microscope (mass spectrometry imager with spatial resolution higher than the naked eye) equipped with an atmospheric pressure ion-source chamber for laser desorption/ionization (AP-LDI) and a quadrupole ion trap time-of-flight (QIT-TOF) analyzer. The optical microscope combined with the mass spectrometer permitted us to precisely determine the relevant tissue region prior to performing imaging mass spectrometry (IMS). An ultraviolet laser tightly focused with a triplet lens was used to achieve high spatial resolution. An atmospheric pressure ion-source chamber enables us to analyze fresh samples with minimal loss of intrinsic water or volatile compounds. Mass-microscopic AP-LDI imaging of freshly cut ginger rhizome sections revealed that 6-gingerol ([M + K](+)at m/z 333.15, positive mode; [M - H](-) at m/z 293.17, negative mode) and the monoterpene ([M + K](+) at m/z 191.09), which are the compounds related to pungency and flavor, respectively, were localized in oil drop-containing organelles. AP-LDI-tandem MS/MS analyses were applied to compare authentic signals from freshly cut ginger directly with the standard reagent. Thus, our atmosphere-imaging mass spectrometer enabled us to monitor a quality of plants at the organelle level.

Effect of cell differentiation for neuroblastoma by vitamin k analogs.

BACKGROUND: Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation. METHODS: In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells. RESULTS: VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation. CONCLUSIONS: Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.

Hospital-pharmacy cooperative training and drug-taking compliance in outpatients with chronic pain: a case-control study.

Purpose: Chronic pain is a common symptom that is suffered by 20% of the overall population in Japan. Although pharmacotherapy is critical for the treatment of chronic pain, there are no reports on the pharmacies. In the present study, we examined the effect of hospital-community pharmacy cooperative training on improving drug-taking compliance, pain relief, anxiety, insomnia, and motor function in patients with chronic pain. Patients and methods: The subject sample included 87 patients with chronic pain who were examined for the first time at the outpatient services department of Nihon University Itabashi Hospital. Patients were interviewed to obtain information regarding drugs used before and after the treatment, habitually used community pharmacies, presence of cooperative training with Itabashi Hospital, drug-taking compliance, and side effects. We compared treatment outcomes before and after consultation using the Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS), EuroQol Group measure (EQ-5D) for quality of life, Athens Insomnia Scale, and Locomo 25 scale for motor function. Results: In patients who used community pharmacies that perform training, drug-taking compliance was significantly better, and a significant improvement was observed in the scores of BPI, HADS Anxiety, Athens Insomnia, and Locomo 25. Conclusion: Pharmacotherapy is essential for the treatment of chronic pain. To this end, appropriate drugs with proper drug management guidance are indispensable. In this study, the use of community pharmacies that have undergone cooperative training with hospitals improves pain and anxiety. This is achieved through proper drug management guidance, shared awareness of drug information, and achievement of better drug-taking compliance. To improve the quality of treatment for chronic pain, involvement of community pharmacies such as by providing accurate information is essential. In the future, expanding cooperative training with hospitals may further help reassure patients, facilitate drug-taking, and improve the quality of treatment for chronic pain.

Multicharged iron ions produced by using induction heating vapor source.

Multiply charged Fe ions are produced from solid pure material in an electron cyclotron resonance (ECR) ion source. We develop an evaporator by using induction heating with an induction coil which is made of bare molybdenum wire partially covered by ceramic beads in vacuum and surrounding and heating directly the pure Fe rod. Heated material has no contact with insulators, so that outgas is minimized. The evaporator is installed around the mirror end plate outside of the ECR plasma with its hole grazing the ECR zone. Helium or argon gas is usually chosen for supporting gas. The multicharged Fe ions up to Fe(13+) are extracted from the opposite side of mirror and against the evaporator, and then multicharged Fe ion beam is formed. We compare production of multicharged iron ions by using this new source with our previous methods.

[Assessment of the Relationship between Hypnotics and Delirium Using the Japanese Adverse Drug Event Report (JADER) Database].

　The Japanese Adverse Drug Event Report (JADER) database was used to examine the risk of delirium and the time of its onset with various hypnotics, including 10 benzodiazepines (BZDs), 3 non-benzodiazepines (non-BZDs), 1 melatonin receptor agonist (MRTA), and 1 orexin receptor inhibitor (OXRI). Data entered in the JADER database between April 1, 2004 and February 1, 2016 were analyzed. The index for safety signal detection, the reporting odds ratio (ROR), was the odds ratio for adverse drug reaction reporting. The ROR for each drug was calculated; a signal was considered present if the lower bound of the 95% confidence interval of the ROR was greater than 1. The time to onset of delirium was calculated for drugs for which the number of days from the start of drug administration to delirium onset was reported. During the period examined in the analysis, a total of 621114 adverse drug reaction reports were seen, and the total number of delirium reports was 1417 after redundant cases were excluded. A signal was detected for 5 of the 10 BZDs and all 3 non-BZDs, with no signal for the MRTA and the OXRI. The time of delirium onset varied widely even for drugs classified as being in the same action duration group, and no correlation was seen for delirium onset time. The results of this study suggested that delirium risk varies depending on the hypnotic. Thus, hypnotics can be selected according to their delirium risk.

Optimal timing for pegfilgrastim administration in Japanese breast cancer patients receiving intermediate-risk chemotherapies.

Background Pegfilgrastim is widely used for prophylaxis of febrile neutropenia (FN) in cancer patients receiving chemotherapies. However, the optimal timing of pegfilgrastim administration has not been established. Objective We investigated the effect of the timing of pegfilgrastim administration on the prevention of FN in patients with breast cancer undergoing intermediate-risk chemotherapies. Method We retrospectively analysed the incidence of FN in patients with breast cancer treated at our institution with intermediate-risk chemotherapies and primary or secondary prophylactic pegfilgrastim between 2015 and 2017. The impact of the timing of pegfilgrastim administration on the incidence of FN was evaluated by univariate and multivariate logistic regression analyses. Results Overall, 87 patients received a total of 318 chemotherapy cycles with pegfilgrastim, and 14 patients (16%) experienced FN. In univariate analyses, day 2 pegfilgrastim administration, age of > 65 years, baseline haemoglobin < 12 g/dL, prior history of FN, and presence of recurrent/metastatic disease trended toward an association with FN. Adjustment for these confounding risk factors revealed that day 2 pegfilgrastim administration was associated with a significantly increased risk of FN (odds ratio 11.0, p = 0.009). Conclusion Administrating pegfilgrastim on day 3 or later may prevent FN more effectively among Japanese breast cancer patients receiving intermediate-risk chemotherapies.

A clinical prediction model for infusion-related reactions to rituximab in patients with B cell lymphomas.

Background Infusion-related reactions (IRRs) are a major adverse event of rituximab. Objective To develop a prediction model for IRRs to rituximab among patients with B cell non- Hodgkin's lymphomas (B-NHL). Setting A 1000-bed university hospital in Tokyo. Methods Patients with B-NHL treated with rituximab at our institution from 2004 to 2014 were retrospectively analysed. Chills, fever, rash, nausea, asthenia, headache, cardiovascular symptoms, and respiratory symptoms of any grade, in association with rituximab infusion, were identified as IRRs. Risk factors for IRRs to rituximab found in the intergroup analysis were subsequently evaluated by using multivariate analysis. Main outcome measure Occurrence of IRRs to rituximab. Results A total of 140 patients with various types of B-NHL, including 74% with diffuse large Bcell lymphoma, were analysed. Among them, 55 and 85 patients were assigned to the IRR group and the non-IRR group, respectively. Indolent histological subtypes, bulky disease (>10 cm), B symptoms, higher serum soluble interleukin-2 receptor concentration, and bone marrow involvement were more common in the IRR group. The multivariate logistic regression analysis identified low-grade lymphomas [odds ratio (OR) 2.81, p = 0.017] and bulky disease (OR 2.52, p = 0.037) as independent risk factors for IRRs to rituximab. The incidence rates of IRRs to rituximab among patients with neither, one, or both of these risk factors were 26, 54, and 78%, respectively (χ2 = 16.4, p < 0.001). Conclusions A simple combination of histopathological subtype and bulkiness of disease could predict the risk of IRRs to rituximab among patients with B-NHL.

A case of nasopharyngeal actinomycosis leading to otitis media with effusion.

Nasopharyngeal actinomycosis is extremely rare, and to our knowledge, only seven cases have previously been reported. Diagnosis of actinomycosis is made by clinical finding, observation of the bacteria and histopathological examination. Treatment for actinomycosis is surgical debridement and administration of antibioticus, especially penicillin for several weeks with good prognosis. We report a case of nasopharyngeal actinomycosis, which lead to otitis media with effusion. Endoscopic surgery and prolonged penicillin administration for 2 months were effective for treatment of actinomycosis in the nasopharynx.

Involvement of Pharmacists in Medical Care in Emergency and Critical Care Centers.

Emergency and critical care centers provide multidisciplinary therapy for critically ill patients by centralizing the expertise and technology of many medical professionals. Because the patients' conditions vary, different drug treatments are administered along with surgery. Therefore, the role of pharmacists is important. Critically ill patients who receive high-level invasive treatment undergo physiological changes differing from their normal condition along with variable therapeutic effects and pharmacokinetics. Pharmacists are responsible for recommending the appropriate drug therapy using their knowledge of pharmacology and pharmacokinetics. Further, pharmacists need to determine the general condition of patients by understanding vital signs, blood gas analysis results, etc. It is therefore necessary to conduct consultations with physicians and nurses. The knowledge required for emergency medical treatment is not provided during systematic training in pharmaceutical education, meaning that pharmacists acquire it in the clinical setting through trial and error. To disseminate the knowledge of emergency medical care to pharmacy students, emergency care training has been started in a few facilities. I believe that medical facilities and universities need to conduct joint educational sessions on emergency medical care. Moreover, compared with other medical fields, there are fewer studies on emergency medical care. Research-oriented pharmacists must resolve this issue. This review introduces the work conducted by pharmacists for clinical student education and clinical research at the Emergency and Critical Care Center of Nihon University Itabashi Hospital and discusses future prospects.

Producing multicharged fullerene ion beam extracted from the second stage of tandem-type ECRIS.

We have been constructing the tandem-type electron cyclotron resonance ion source (ECRIS). Two ion sources of the tandem-type ECRIS are possible to generate plasma individually, and they also confined individual ion species by each different plasma parameter. Hence, it is considered to be suitable for new materials production. As the first step, we try to produce and extract multicharged C60 ions by supplying pure C60 vapor in the second stage plasma because our main target is producing the endohedral fullerenes. We developed a new evaporator to supply fullerene vapor, and we succeeded in observation about multicharged C60 ion beam in tandem-type ECRIS for the first time.

Duration of Systemic Inflammatory Response Syndrome Influences Serum Vancomycin Concentration in Patients With Sepsis.

PURPOSE: Vancomycin (VCM) is used in the treatment of methicillin-resistant Staphylococcus aureus infection. The dosage of VCM must be adjusted by using therapeutic drug monitoring because of the drug's narrow therapeutic concentration window. Although optimal administration based on population pharmacokinetic (PPK) analysis and/or a Bayesian method has improved prediction accuracy, serum concentrations of VCM in patients with sepsis often deviate significantly from predicted values. We investigated factors influencing prediction errors with PPK analysis in VCM dosing. METHODS: This retrospective cohort study included patients treated with VCM. Their clinical data were recorded, and there were 27 nonseptic patients and 68 septic patients. VCM concentrations were predicted by using PPK analysis and data compared with observed concentrations. FINDINGS: Patients with sepsis had a higher mean absolute error than nonseptic patients, indicating a deviation of VCM concentrations from predicted values in the septic patients. To determine factors influencing prediction errors, we classified patients with sepsis into 3 subgroups according to the mean absolute error value (2.17) for the nonseptic patients: "lower" group (prediction errors, below -2.17), "upper" group (>2.17), and "no change" group (-2.17 to 2.17). In a comparison of clinical characteristics of the 3 groups, significant differences were found in the duration of systemic inflammatory response syndrome (SIRS), SIRS score, disseminated intravascular coagulation score, and levels of creatinine clearance (CrCl), hemoglobin, and diastolic blood pressure. Multiple logistic regression analysis identified SIRS duration and CrCl as factors associated with VCM concentrations in the lower and/or upper groups of septic patients. Shorter and longer SIRS duration were associated with VCM concentrations in the lower group and the upper group, respectively, compared with predicted values in patients with sepsis. According to receiver-operating characteristic curve analysis, the optimal cutoff value of SIRS duration for the lower group was 2 days; for the upper group, it was 6 days. VCM clearance in patients with an SIRS duration <2 days was higher than that for patients with an SIRS duration ≥6 days. IMPLICATIONS: SIRS duration was identified as influencing VCM concentration in patients with sepsis. This study has 2 limitations. First, we performed blood sampling only for trough concentrations. Repeated blood sampling for both peak and trough concentrations should be performed for more accurate pharmacokinetic evaluation in critically ill patients. Second, we determined CrCl by using the Cockcroft-Gault formula, which may not be accurate in critically ill patients. Modifying VCM dosing according to SIRS duration will improve prediction accuracy of VCM concentration based on therapeutic drug monitoring.

[Influence of systemic inflammatory response syndrome on the pharmacokinetics of vancomycin].

Therapeutic drug monitoring (TDM) of vancomycin (VCM) is recommended to minimize its nephrotoxicity and maximize efficacy. Recently, the concept of systemic inflammatory response syndrome (SIRS) has been introduced to describe a clinical state resulting from the actions of complex intrinsic mediators in an acute-phase systemic response. However, there are few reports on the pharmacokinetics of VCM in patients with SIRS. This study investigated the effect of SIRS on the pharmacokinetics of VCM by analyzing the predictability of TDM and pharmacokinetic parameters in 31 non-SIRS patients and 52 SIRS patients, with stratification by SIRS score. The mean prediction error (ME) and mean absolute prediction error in SIRS score 2 and 3 patients differed from those in non-SIRS patients. The ME in the score 4 group showed a negative value. In the comparison of pharmacokinetic parameters by SIRS score, a significantly lower CL(vcm) value was observed at score 4 compared with scores 2 and 3, a higher Vd value was observed at score 4 compared with non-SIRS and at score 3, and a longer T1/2 was observed at score 2. In the comparison of patient characteristics by SIRS score, albumin, aspartate aminotransferase, and alanine aminotransferase levels showed differences among the scores. However, no correlation was observed between VCM pharmacokinetics and these three laboratory parameters. These findings suggest that the pharmacokinetics of VCM may be affected by the pathology of SIRS rather than by patient characteristics.

Magnetic responses of human visual cortex to illusory contours.

To examine the neural mechanism underlying illusory-contour perception, we measured the magnetic responses of the human visual cortex to an abutting-line grating inducing illusory contours (test stimulus) and a non-abutting-line grating (control stimulus) using the technique of magnetoencephalography (MEG). In the initial latency period of 60-80 ms, the MEG response to the test stimulus was nearly identical with that to the control stimulus, but in the subsequent period of 80-150 ms, the former was larger than the latter. The origin of the peak MEG response to the test stimulus was estimated to be in the vicinity of striate cortex/extrastriate visual cortex for two of the four subjects. These results suggest that, in accord with those of the previous electrophysiological and functional magnetic resonance imaging studies, illusory-contour signals are generated in the very early stage(s) of processing in the primate visual cortex.

Surround suppression in the human visual cortex: an analysis using magnetoencephalography.

The responses of neurons in the primate and cat primary visual cortices (V1s) to the stimuli within their classical receptive fields (CRFs) are markedly suppressed by the surrounding stimuli outside CRFs. In the present study, we show that a similar suppressive effect occurs for visually evoked magnetic responses in the human visual cortex. The initial peak amplitude of the magnetic response (at a latency of around 90 ms) to a test grating accompanied by high-contrast surround gratings was smaller than that for the test without the surround. Current source localization with a single dipole model indicated that the initial response originated from cortical activity near the occipital pole in the contralateral hemisphere to the visual stimulation. The peak amplitude for the test decreased with increasing surround contrast, and increased with increasing test contrast. The contrast dependence and the early development of the surround suppression were in agreement with the results of the V1 single-cell studies of monkeys and cats. We suggest that the surround suppression of the initial peak amplitude of the magnetic response may be ascribed to the inhibition of the neural activity at the early processing stage(s), presumably at V1, in the human visual cortex.

A solitary fibrous tumor in the external auditory meatus.

We herein describe a rare case of a spindle-cell neoplasm arising in the external auditory canal. A 38-year-old man presented with a progressive swelling of the entrance of left external auditory meatus. The patient underwent a surgical removal of the tumor. A light microscopic study showed a spindle-cell proliferation with a collagenous stroma and a staghorn-like vascular pattern. The tumor cells were immunohistochemically positive for vimentin and CD34. The tumor was thereafter diagnosed to be a solitary fibrous tumor (SFT). SFTs most commonly occur in the pleura and are supposed to originate from submesothelial connective tissue. Although, several cases of extrapleural SFT have been reported, no SFT arising in the entrance of left external auditory canal have ever been reported in the literature. As a basically benign tumor, it occasionally relapses or metastasizes after excision, and therefore a careful follow up is necessary.

Laryngeal solitary multiple mucosal neuromas without multiple endocrine neoplasia (MEN) type 2B.

The first case of laryngeal solitary multiple mucosal neuromas (MMN) was reported. A 73-year-old man who had complained of hoarseness and abnormal prickly sensation in the throat for 3 months visited our hospital. Many small whitish-yellow nodules were observed in the laryngeal mucosa from the right arytenoid to the interarytenoid region. Using laryngomicroscopy biopsy was performed twice. The pathological study showed neurogenic nodular lesions consisting of regularly arranged nerve bundles with many axons and Schwann cell proliferation, and so MMN was finally diagnosed. As MMN is regarded as a constant component of multiple endocrine neoplasia (MEN) type 2B, screening of MEN type 2B was performed, however, they were all within normal limits. This case was, therefore, diagnosed as a laryngeal solitary MMN without MEN type 2B.

Oropharyngeal dysphagia in a case of Huntington's disease.

The aim of this study is to analyze dysphagic symptoms of a patient with Huntington's disease (HD) who had having difficulty in swallowing. The patient was a 66-year-old female with HD. Inspection of self-feeding at bedside and videofluorographic swallowing assessment were performed. The features at self-feeding were the tendency of rapid eating, inability for smooth transportation of food to oral cavity, weak lip closure, which resulted in falling of food and eating it again. The videofluorography indicated clumsy tongue movement and postural instability by chorea which caused discoordination between oral and pharyngeal stage. Those ended in spill of liquid to the pharynx and retention of bolus in the oral cavity and vallecula, and aspiration did not occur. Pudding was carefully chewed because of the patient's alertness to the examination. The cognitive disturbance and choreic movement caused dysphagia at the preparatory and oral stages, and chorea also produced the discoordication between the oral and pharyngeal stage. The change of the shape of cups and stable posture were advised to lessen the chance of her aspiration.