Combination of magnetic hyperthermia and immunomodulators to drive complete tumor regression of poorly immunogenic melanoma.

Hyperthermia using magnetic nanoparticles enables tumor-specific heating and can destroy tumor tissues. This approach works as in situ vaccination with tumor antigens released from dying tumor cells. However, in situ vaccination caused by magnetic hyperthermia is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment. In this study, we explored a novel strategy for immunotherapy using magnetic hyperthermia to regress poorly immunogenic melanoma. Magnetic hyperthermia induced tumor cell death in a B16-F10 melanoma mouse model. After hyperthermia treatment, we found elevated levels of HMGB1, which is known to be released from dying cells to promote inflammation, and the proinflammatory cytokine TNF-α was increased in serum of the mice. Systemic administration of glycyrrhizin, an HMGB1 inhibitor, reduced the levels of TNF-α in serum and successfully delayed the regrowth of tumors after magnetic hyperthermia. To achieve complete tumor regression, TLR9 activation by intratumor injection of CpG was combined with systemic administration of anti-PD-1 antibody and anti-CTLA-4 antibody. The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors. These findings have important implications for the development of novel cancer immunotherapy using magnetic hyperthermia for poorly immunogenic tumors.

[Severe neuropsychiatric disorder developing during busulfan-containing regimen for stem cell transplantation].

Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.

Prevalence of sarcopenia in patients with gynecological cancer.

BACKGROUND: The aim of the study was to investigate a prevalence of sarcopenia in patients with gynecological cancer in accordance with current diagnostic criteria of sarcopenia. METHODS: A series of 513 patients with gynecological cancer who were intended to newly receive initial or salvage treatment were recruited in a prospective study. Eligible patients were examined with dual energy X-ray absorptiometry and underwent handgrip strength test and the Short Physical Performance Battery before treatment. Sarcopenia was defined as both low skeletal muscle mass (skeletal muscle mass index) and low muscle strength (handgrip strength of <18.0 kg) or both low skeletal muscle mass index and low physical performance (Short Physical Performance Battery score of ≤9). RESULTS: A total of 475 patients (92.6%) were completely assessed in this study. Eligible patients' median age was 60 years (range: 29-89 years). Frequencies of patients with low skeletal muscle mass index, low hand grip strength and low Short Physical Performance Battery were 118 (24.8%), 70 (14.7%) and 80 (16.8%), respectively. Sarcopenia was finally identified in 45 patients (9.5%), which accounted for 38.1% of patients with low skeletal muscle mass index, 64.3% of the patients with low hand grip strength and 56.3% of the patients with low physical performance, respectively. CONCLUSIONS: The prevalence of sarcopenia of 9.5% in patients with gynecological malignancy who were scheduled to newly receive an initial or a salvage treatment. A large-scale, nation-wide study might be planned to elucidate an accurate prevalence of sarcopenia among gynecologic cancer patients.

Role of insulin-like growth factor 1, sex and corticosteroid hormones in male major depressive disorder.

BACKGROUND: Hormones of the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-somatotropic (HPS) axes are potentially involved in major depressive disorder (MDD), but these hormones have not been simultaneously investigated in male patients with MDD. We investigated the association between male MDD symptoms and estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF1). METHODS: Serum estradiol, testosterone, cortisol, DHEAS, and IGF1 levels were measured in 54 male patients with MDD and 37 male controls and were compared with clinical factors. We investigated the associations between hormone levels and Hamilton Depression Rating Scale (HAM-D) scores. The correlations among hormones were also investigated. RESULTS: Patients had significantly lower estradiol levels than controls (22.4 ± 8.4 pg/mL vs. 26.1 ± 8.5 pg/mL, P = 0.040). Serum estradiol levels were negatively correlated with HAM-D scores (P = 0.000094) and positively correlated with Global Assessment of Functioning scores (P = 0.000299). IGF1 levels and the cortisol:DHEAS ratio were higher in patients than in controls (IGF1: 171.5 ± 61.8 ng/mL vs. 144.1 ± 39.2 ng/mL, P = 0.011; cortisol:DHEAS ratio: 0.07 ± 0.05 vs. 0.04 ± 0.02, P = 0.001). DHEAS levels were lower in patients than in controls (227.9 ± 108.4 µg/dL vs. 307.4 ± 131.2 µg/dL, P = 0.002). IGF1, cortisol:DHEAS ratio, and DHEAS were not significantly correlated with HAM-D scores. Cortisol and testosterone levels were not significantly different between patients and controls. Serum estradiol levels were positively correlated with DHEAS levels (P = 0.00062) in patients, but were not significantly correlated with DHEAS levels in controls. CONCLUSION: Estradiol may affect the pathogenesis and severity of patients with MDD in men, and other hormones, such as those in the HPA and HPS axes, may also be involved in male MDD. Additionally, a correlation between estradiol and DHEAS may affect the pathology of MDD in men.

Lower Prolactin Levels in Patients Treated With Aripiprazole Regardless of Antipsychotic Monopharmacy or Polypharmacy.

BACKGROUND: Hyperprolactinemia is a troublesome adverse effect of antipsychotics. Aripiprazole (ARP), which is one of second-generation antipsychotics, has been reported to lower serum prolactin (PRL) levels. However, few studies have compared the effect of ARP on plasma PRL levels between monopharmacy and polypharmacy with antipsychotics. METHODS: We conducted a large-scale investigation of the physical risk for inpatients with schizophrenia using a questionnaire covering demographic data, the number, dose and type of antipsychotics, and serum PRL levels. RESULTS: Sufficient data to conduct an assessment of the effect on PRL levels between antipsychotic monopharmacy and polypharmacy were obtained from 316 of the inpatients. Serum PRL levels in ARP combination group were lower than non-ARP combination group, regardless of antipsychotic monopharmacy or polypharmacy. CONCLUSIONS: The present study suggests that ARP lowers serum PRL levels regardless of monopharamacy or polypharmacy with antipsychotics.

Correction to: Awake fiberoptic intubation with an epidural catheter in a morbidly obese patient.

In the original publication of the article, the acknowledgment section was not included and provided in this correction.

Awake fiberoptic intubation with an epidural catheter in a morbidly obese patient.

We report successful awake intubation in a morbidly obese patient (body mass index of 61.2) using an epidural catheter inserted through the external forceps channel of the fiberscope for delivery of local anesthetic. Direct application of local anesthetic to the pharyngolaryngeal area and proximal tracheal, through the use of a relatively firm epidural catheter. We conclude that awake intubation can be achieved by this method which spares the subsequent use of any sedative drugs.

Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder.

BACKGROUND: Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. METHODS: Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Subjects included 59 men and 32 women with an average age of 44.1 ± 13.1 years (mean ± SD). The blood IGF-I level was 152.0 ± 50.0 ng/mL, the cortisol level was 10.1 ± 4.6, and the DHEAS level was 201.3 ± 112.7 µg/dL. The mean HAM-D score was 13.9 ± 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R = 0.200, P < 0.001; adjusted R = 0.273, P < 0.001). CONCLUSIONS: Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey.

BACKGROUND: Patients with schizophrenia have an increased prevalence of metabolic disturbances compared with the general population. However, the mechanisms underlying the metabolic side effects of antipsychotics are unknown. The aim of the present study was to compare the levels of high-density lipoprotein (HDL)-cholesterol in Japanese schizophrenia patients medicated with olanzapine, risperidone, or aripiprazole monotherapy. METHODS: This study was a post-hoc analysis of a nationwide survey, which included 433 Japanese outpatients with schizophrenia and 674 inpatients. A brief questionnaire was compiled that covered demographic data, systolic blood pressure, diastolic blood pressure, and HDL-cholesterol after reviewing the relevant literature and guidelines. To compare demographic and clinical characteristics, analysis of variance was performed for continuous variables and the chi-square test was performed for categorical variables. For comparisons of HDL-cholesterol levels among the three antipsychotic groups, analysis of covariance was carried out with age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference as confounding variables after stratification by body mass index (BMI) for each outpatient group and inpatient group. RESULTS: The mean age was 57.9 ± 14.0 years and the mean BMI was 23.4 ± 4.5 kg/m2. HDL-cholesterol levels when stratified by BMI differed significantly (p = 0.019) between the three antipsychotic groups after age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference in inpatients. A significant difference in HDL-cholesterol levels was only found in the overweight inpatient group, and no significant differences in HDL-cholesterol levels were found among the three antipsychotics for outpatients of all BMI stratifications or inpatients that were underweight or of normal weight. For post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group (p = 0.023). CONCLUSIONS: This study reveals a difference in HDL-cholesterol levels in overweight Japanese inpatients with schizophrenia resulting from the use of different antipsychotics. In the post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group. Further studies incorporating more detailed evaluations, including diet and physical activity, are needed to clarify the differences in HDL-cholesterol according to antipsychotic use.

Effect of GWAS-Identified Genetic Variants on Maximum QT Interval in Patients With Schizophrenia Receiving Antipsychotic Agents: A 24-Hour Holter ECG Study.

BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Estimation of Evolutionary Rates of Mitochondrial DNA in Two Japanese Wood Mouse Species Based on Calibrations with Quaternary Environmental Changes.

Reliable estimates of evolutionary rates of mitochondrial DNA might allow us to build realistic evolutionary scenarios covering broad time scales based on phylogenetic inferences. In the present study, we sought to obtain estimates of evolutionary rates in murine rodents using calibrations against historical biogeographic events. We first assumed that land-bridge-like structures that appeared intermittently at glacial maxima with 100,000-year intervals shaped the divergence patterns of cytochrome b (Cytb) sequences (1140 bp) of the larger Japanese wood mouse Apodemus speciosus. The comparison of sequences from peripheral remote islands that are separated from one another by deep straits allowed us to estimate mitochondrial DNA evolutionary rates (substitutions/site/million years) to be 0.027 to 0.036, with presumed calibrations from 140,000, 250,000, 350,000, and 440,000 years ago. Second, we addressed rapid expansion events inferred from analyses of the Cytb sequences of the lesser Japanese wood mouse A. argenteus. We detected five expansion signals in the dataset and established three categories based on the expansion parameter tau values: 3.9, 5.6-5.7, and 7.8-8.1. Considering that the climate became warmer 15,000, 53,000, and 115,000 years ago after preceding periods of rapid cooling, we calculated evolutionary rates to be 0.114, 0.047, and 0.031, respectively. This preliminary concept of the evolutionary rates on a time scale from 15,000 to 440,000 years ago for the wood mouse should be refined and tested in other species of murine rodents, including mice and rats.

Echocardiography findings in a case with Ballantyne syndrome.

Marked fluid retention occurs in Ballantyne syndrome, but few reports are available on changes in cardiac morphology in this syndrome. A woman with generalized edema, dyspnea, fetal hydrops (skin edema and ascites), thickened placenta, and elevated plasma B-type natriuretic peptide level (344 pg/mL) was admitted to our hospital at gestational week (GW) 20+3 . Blood pressure remained within the normal range. However, acute increases in left atrial volume index, pulmonary artery systolic pressure, and hyperdynamic left ventricular function (as evidenced by increased left ventricular ejection fraction to 74% with cardiac index of 5.1 L/min/m2 ) occurred preceding fetal death at GW 21+4 in the presence of increased inferior vena cava diameter (23 mm) and relatively low systemic vascular resistance of 752 dyn·s/cm5 . These findings suggested life-threatening heart failure and required cesarean delivery at GW 21+5 resulting in complete recovery. The placenta suggested cytomegalovirus infection.

[The Safety of Using Long-acting Injections : From an Opposing Position-Is It Better to Administer Long-acting Injections?].

While long-acting injections (LAI) have arrived in Japan as a second-generation antipsy- chotic drug and LAI therapy for the symptom-stabilization phase is garnering attention, deaths associated with paliperidone (PAL) -LAI were sensationally reported, attracting interest regarding the safety of LAIs. In writing this report, an opportunity to oppose LAI usage was provided, so we raise the following three issues concerning the usage of the second-generation antipsychotic LAI for the symptom-stabilization phase. 1) Particularly notable adverse reactions of LAI are those acutely developed and in some cases fatal, including malignant syndrome, diabetic ketoacidosis, torsade de pointes due to pro- longed electrocardiogram QT, and leukopenia. All antipsychotic drugs come with the risk of such adverse reactions, and since the occurrence of adverse reactions cannot be predicted prior to administration, once they have developed, the offending drugs should be immediately reduced or discontinued to remove the drug from the body ; however, since this process can- not be followed with LAIs, such fatal adverse reactions may be protracted. Moreover, in the US, adverse reactions from post injection delirium/sedation syndrome (PDSS) have been reported in relation with olanzapine (OLZ) -LAI. This is a disease state in which the drug rap- idly flows into the blood following LAI intramuscular administration along with an acute increase in blood level, leading to significant sedation (lethargy in some cases) and/or serious symptoms accompanied by delirium ; therefore, in order to minimize these risks, the US FDA has made it mandatory to use a monitoring system referred to as REMS (Risk Evaluation and Mitigation Strategy)for OLZ-LAI. Whether or not the phenomenon occurs only with OLZ-LAI remains to be seen, so careful attention must be paid. 2) In Japanese psychiatric clinical sites, the current situation is that monitoring of adverse reactions for antipsychotic drugs, particularly with outpatients, is not sufficiently carried out Under such circumstances, there remain doubts when it comes to advocating -looking to replace oral drugs with LAI in the symptom-stabilization phase. 3) Replacing oral drugs with LAI in the symptom-stabilization phase significantly increases treatment costs as well as increasing the number of hospital visits. This increase in treatment cost and number of visits may have a large impact on the adherence of the patients to the drugs.

[Long QT Syndrome Induced by Antidepressants].

A diagnosis of drug-induced long QT syndrome is made when the QT interval corrected for heart rate (QTc) is 500 msec or above or is prolonged 60 msec or more after initiating, substituting, or increasing the dose of the drug, and it is considered that the risk of severe ventricular arrhythmia, referred to as torsade de pointes (TdP), increases under these condi- tions. Long QT syndrome is divided into the two broad categories of congenital or secondary, and among drug-induced long QT syndrome, which is classified as secondary, antipsychotic drugs are considered to be the most frequent cause of TdP, excluding anti-arrhythmic drugs. At the same time, escitalopram, which became commercially available in 2011, garnered attention in Japan due to administration contraindication in patients with prolonged QT. The guidelines of the International Conference on Harmonization of Technical Requirements for Regis- tration of Pharmaceuticals for Human Use (ICH) (E14) requires a detailed QT prolongation effect evaluation study (Thorough QT/QTc study) for new drugs, and in Japan, this has been adapted to drugs applied for on and after Nov 1, 2010. As a result of the study, escitalopram demonstrated a maximum of 11.8 msec prolongation from baseline when administered at 30 mg, which is the approved dosage overseas, and thus became contraindicated in patients with prolonged QT ; however, since the approved dosage of escitalopram in Japan is 20 mg/day, and since the study at our site indicated that other antipsychotic drugs may have a QT prolongation effect greater than escitalopram, our findings suggest the necessity to determine inter- drug differences and dose dependency of the antidepressant drugs and antipsychotic drugs that were commercially available before 2010 and are still used today, by conducting QT prolongation effect evaluation studies. Furthermore, the factors prolonging the QT intervals include a female sex, hypokalemia, hypomagnesaemia, bradyarrhythmia, various cardiac diseases, central nerve system diseases, drug interactions, and gene mutations; wherein, drug-induced long QT syndrome occurs due to the additive and synergistic effects of these factors, making it difficult to predict QT prolongation. Therefore, careful electrocardiogram monitoring is required in clinical settings.

Estimating the molecular evolutionary rates of mitochondrial genes referring to Quaternary ice age events with inferred population expansions and dispersals in Japanese Apodemus.

BACKGROUND: Determining reliable evolutionary rates of molecular markers is essential in illustrating historical episodes with phylogenetic inferences. Although emerging evidence has suggested a high evolutionary rate for intraspecific genetic variation, it is unclear how long such high evolutionary rates persist because a recent calibration point is rarely available. Other than using fossil evidence, it is possible to estimate evolutionary rates by relying on the well-established temporal framework of the Quaternary glacial cycles that would likely have promoted both rapid expansion events and interisland dispersal events. RESULTS: We examined mitochondrial cytochrome b (Cytb) and control region (CR) gene sequences in two Japanese wood mouse species, Apodemus argenteus and A. speciosus, of temperate origin and found signs of rapid expansion in the population from Hokkaido, the northern island of Japan. Assuming that global warming after the last glacial period 7-10 thousand years before present (kyr BP) was associated with the expansion, the evolutionary rates (sites per million years, myr) of Cytb and CR were estimated as 11-16 % and 22-32 %, respectively, for A. argenteus, and 12-17 % and 17-24 %, respectively, for A. speciosus. Additionally, the significant signature of rapid expansion detected in the mtDNA sequences of A. speciosus from the remaining southern main islands, Honshu, Shikoku, and Kyushu, provided an estimated Cytb evolutionary rate of 3.1 %/site/myr under the assumption of a postglacial population expansion event long ago, most probably at 130 kyr BP. Bayesian analyses using the higher evolutionary rate of 11-17 %/site/myr for Cytb supported the recent demographic or divergence events associated with the Last Glacial Maximum. However, the slower evolutionary rate of 3.1 %/site/myr would be reasonable for several divergence events that were associated with glacial periods older than 130 kyr BP. CONCLUSIONS: The faster and slower evolutionary rates of Cytb can account for divergences associated with the last and earlier glacial maxima, respectively, in the phylogenetic inference of murine rodents. The elevated evolutionary rate seemed to decline within 100,000 years.

GIPR Gene Polymorphism and Weight Gain in Patients With Schizophrenia Treated With Olanzapine.

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.

[The Effectiveness of Combining Remifentanil with Propofol to Achieve Seizure Adequacy in a Patient Undergoing Modified Electroconvulsive Therapy].

A patient with medication resistant schizophrenia underwent modified electroconvulsive therapy (12 sessions). Propofol was chosen as a hypnotic agent and the adjustment of its dose and stimulus intensity was attempted. However, despite using propofol of a dose minimally required for hypnosis, adequate seizures could not be induced even with the maximum stimulation. Assuming that propofol was preventing the induction of seizures, it was decided to reduce its dose and at the same time to combine it with remifentanil 100 µg starting from the fifth session. This allowed to reach the seizure adequacy during the next and the four subsequent sessions. Although from the tenth session on, adequate seizures could no longer be induced (possibly due to the development of resistance to propofol), the patient's symptoms showed improvement after completion of all 12 sessions.

Cardiovascular pharmacodynamics of donepezil hydrochloride on the PR and QT intervals in patients with dementia.

OBJECTIVE: Although several case reports suggested that donepezil hydrochloride can induce bradycardia or atrioventricular block, the details remain unclear. We implemented a study of the impact of donepezil hydrochloride administration on PR, RR, and QT intervals. METHODS: The subjects were 18 patients who were diagnosed with either dementia or cognitive disorder (DSM-IV-TR) and were hospitalized between January 2011 and December 2012. After hospitalization, they were treated with donepezil hydrochloride. Clinical parameters and electrocardiograms before and after the administration of donepezil hydrochloride were retrieved from the patients' medical records. RESULTS: After the administration of donepezil hydrochloride, the mean PR interval significantly increased from 177.3 ± 30.9 to 186.8 ± 38.4 ms (p<0.001). And the mean RR interval also significantly increased from 850.3 ± 112.5 to 886.7 ± 136.4 ms (p=0.014). The mean difference in the PR interval before and after the administration of donepezil hydrochloride was 9.5 ± 17.1 (range=-21.0-44.0) ms. The QT intervals were unaffected by the administration of donepezil hydrochloride. CONCLUSIONS: Care should be taken when administering donepezil to patients with atrioventricular block, or patients taking other drugs that can prolong the PR interval. Copyright © 2014 John Wiley & Sons, Ltd.