Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method.

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels-Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.

Magnetic resonance elastography increases usefulness and safety of non-invasive screening for esophageal varices.

BACKGROUND AND AIMS: The Baveno VI criteria enable non-invasive screening for esophageal varices. However, these criteria were established based on studies examining a large proportion of patients with viral hepatitis and relatively few patients with non-alcoholic fatty liver disease (NAFLD). Furthermore, because vibration-controlled transient elastography (VCTE) has a high incidence of measurement error, improved criteria are needed. We aimed to develop criteria based on magnetic resonance elastography (MRE) even among patients with NAFLD. METHODS: We performed a cross-sectional analysis of patients who had undergone MRE and/or VCTE as well as an esophagogastroduodenoscopy. The patients were classified as having either a low risk or a high risk of varices. The optimal cut-offs for ruling out esophageal varices were calculated for the MRE and VCTE liver stiffness measurement (LSM), the platelet count in an estimation cohort, and the cut-offs were then evaluated using validation cohorts composed of patients who had undergone only MRE or VCTE. RESULTS: The study included 627 patients (39% with NAFLD). The optimal cut-off values for the MRE-LSM and the platelet count were 4.2 kPa and 18.0 × 104 /µL, respectively. An MRE-LSM of 4.2 kPa plus a platelet count of 18.0 × 104 /µL had a negative predictive value of 1.00 for both low-risk plus high-risk varices as well as for high-risk varices in a validation cohort, enabling the presence of varices to be ruled out. CONCLUSIONS: Magnetic resonance elastography might enable a safer avoidance of screening endoscopy, with a smaller measurement error, among patient populations with a high prevalence of NAFLD.

Caspase-Independent Apoptosis Induced by Reperfusion Following Ischemia without Bile Duct Occlusion in Rat Liver.

The contribution of caspases to hepatic ischemia/reperfusion (I/R)-induced apoptosis has not been completely understood yet. Several studies have demonstrated increased caspase activity during I/R and the protective effect of caspase inhibitors against I/R injuries. However, reports with opposing results also exist. Herein, we examined the contribution of caspases to the I/R-induced hepatic apoptosis in rats using caspase inhibitors and specific substrates of caspases. Hepatic I/R was induced via a 2-h occlusion of the portal vein and the hepatic artery, without conducting bile duct occlusion. DNA laddering and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL)-positive cells were increased at 3 h after reperfusion. Pretreatment with caspase inhibitors (Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp-cmk) 2 or 10 mg/kg intravenously (i.v.), 20 mg/kg intraperitoneally (i.p.), Z-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) 3 mg/kg i.v.) failed to reduce apoptosis induced by I/R. Interestingly, apoptosis induced by the portal triad (hepatic artery, portal vein, and bile duct) occlusion/reperfusion could be marginally attenuated using Z-Asp-cmk (2 mg/kg i.v.). The cleavage activity for Ac-DEVD-α-(4-methylcoumaryl-7-amide) (MCA), a caspase-3/7/8/9 substrate, was significantly increased by I/R. Conversely, the cleavage activities for Ac-DNLD-MCA and MCA-VDQVDGW[K-DNP]-NH2, specific substrates for caspase-3 and -7 respectively, were decreased by I/R. Protein expression of the cellular inhibitor of apoptosis protein 2 (c-IAP2), an endogenous caspase inhibitor, was increased by ischemia. Nuclear translocation of the apoptosis-inducing factor (AIF), an initiator protein of caspase-independent apoptosis, was also increased during I/R. These results suggest that caspases are inhibited by c-IAP2 induced during ischemia and that AIF may be involved in initiation of apoptosis induced by hepatic I/R without bile duct occlusion.

Intraoperative Identification of Colonic Tumor Sites Using a Near-Infrared Fluorescence Endoscopic Imaging System and Indocyanine Green.

BACKGROUND: This study aimed to investigate the feasibility of the PINPOINT® Endoscopic Fluorescence Imaging System (PINPOINT) for intraoperative identification of colonic tumor sites during laparoscopic colorectal surgery. METHODS: Eighty consecutive patients with colorectal cancer were prospectively enrolled. Preoperatively, 0.5 mL of indocyanine green (ICG; 2.5 mg/mL) was injected into the submucosal space only at the distal side of the tumor under colonoscopy. Intraoperatively, we identified the tumor site on a PINPOINT image in which near-infrared fluorescence was superimposed in pseudocolor on a white light image. We estimated the intraoperative visibility rate of the tumor site and safety of ICG injection and assessed the interobserver variability of visibility grade between 2 surgeons. RESULTS: The intraoperative visibility rate of the tumor site was 93.8% (75/80). The visibility rate at an interval between injection and surgery of <7 days was significantly better than that at an interval of ≥10 days (p < 0.001). The kappa value between 2 observers was 0.827 (95% CI 0.635-1.019) with an agreement rate of 92.5%. There were no preoperative adverse reactions to ICG or intraoperative complications. CONCLUSIONS: Using ICG with the PINPOINT for identifying colonic tumor sites was feasible without any adverse effects during laparoscopic colorectal surgery.

Does ß-hexosaminidase function only as a degranulation indicator in mast cells? The primary role of ß-hexosaminidase in mast cell granules.

ß-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of ß-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC ß-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of ß-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6-BMMC) or ß-hexosaminidase gene-deficient (hexb(-/-)-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-Kit(W)/Kit(W-v) [W/W(v)]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/W(v), BL/6-BMMC-reconstituted W/W(v), or hexb(-/-)-BMMC-reconstituted W/W(v) mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/W(v) and hexb(-/-)-BMMC-reconstituted W/W(v) mice than in BL/6 and BL/6-BMMC-reconstituted W/W(v) mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb(-/-)-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb(-/-)-BMMC lysate plus ß-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb(-/-)-BMMC lysate. These findings strongly suggest that MC granule ß-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of ß-hexosaminidase involves degradation of bacterial cell wall peptidoglycan.

Magnolol Enhances Hippocampal Neurogenesis and Exerts Antidepressant-Like Effects in Olfactory Bulbectomized Mice.

Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright © 2016 John Wiley & Sons, Ltd.

Nimodipine activates TrkB neurotrophin receptors and induces neuroplastic and neuroprotective signaling events in the mouse hippocampus and prefrontal cortex.

The L-type calcium channel blocker nimodipine improves clinical outcome produced by delayed cortical ischemia or vasospasm associated with subarachnoid hemorrhage. While vasoactive mechanisms are strongly implicated in these therapeutic actions of nimodipine, we sought to test whether nimodipine might also regulate neurotrophic and neuroplastic signaling events associated with TrkB neurotrophin receptor activation. Adult male mice were acutely treated with vehicle or nimodipine (10 mg/kg, s.c., 1.5 h) after which the phosphorylation states of TrkB, cyclic-AMP response element binding protein (CREB), protein kinase B (Akt), extracellular regulated kinase (ERK), mammalian target of rapamycin (mTor) and p70S6 kinase (p70S6k) from prefrontal cortex and hippocampus were assessed. Nimodipine increased the phosphorylation of the TrkB catalytic domain and the phosphoslipase-Cγ1 (PLCγ1) domain, whereas phosphorylation of the TrkB Shc binding site remained unaltered. Nimodipine-induced TrkB phosphorylation was associated with increased phosphorylation levels of Akt and CREB in the prefrontal cortex and the hippocampus whereas phosphorylation of ERK, mTor and p70S6k remained unaltered. Nimodipine-induced TrkB signaling was not associated with changes in BDNF mRNA or protein levels. These nimodipine-induced changes on TrkB signaling mimic those produced by antidepressant drugs and thus propose common mechanisms and long-term functional consequences for the effects of these medications. This work provides a strong basis for investigating the role of TrkB-associated signaling underlying the neuroprotective and neuroplastic effects of nimodipine in translationally relevant animal models of brain trauma or compromised synaptic plasticity.

Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders.

Compound 48/80, a Mast Cell Stimulator, Enhances Synthesis of IgE and IgG Induced by Intranasal Application of Ovalbumin in Mice.

Mast cells are well established effector cells of type I hypersensitivity reactions such as allergic rhinitis. However, recent studies have suggested that activated mast cells enhance local immunoglobulin E (IgE) synthesis in the nasal mucosa of allergic rhinitis patients. Therefore, we hypothesized that non-immunological mast cell activators may have the potential to enhance local IgE synthesis. Here, we examined the effect of compound 48/80 (C48/80), a mast cell activator, on IgE and immunoglobulin G (IgG) synthesis. Female Balb/c mice were intranasally administered a mixture of ovalbumin (OVA) (1-10 µg/nose) and C48/80 (1-100 µg/nose) on days 0, 7, 14 and 21 and on consecutive days from day 28 to day 42. Intranasal administration of C48/80 with OVA increased serum OVA-specific IgE and IgG. Double staining with fluorescent-labeled OVA and fluorescent-labeled IgE- or IgG-specific antibody demonstrated the presence of OVA-specific IgE- or IgG-producing cells in the nasal mucosa of sensitized mice. Moreover, intranasal administration of C48/80 with OVA increased the nasal mucosal interleukin (IL)-4 level and enhanced the OVA-induced symptom of sneezing. These results suggested that simultaneous activation of mast cells with antigen exposure enhances local IgE and IgG synthesis.

Evaluation of constituents of Piper retrofractum fruits on neurotrophic activity.

Three new compounds, 1-3, together with 22 known compounds, were isolated from the fruits of Piper retrofractum. The structures of the new compounds were elucidated on the basis of spectroscopic data analysis and comparison with literature values. Compound 1 was found to enhance the neurite outgrowth of NGF-mediated PC12 cells at concentrations ranging from 0.1 to 10 µM.

Linking Hypothermia and Altered Metabolism with TrkB Activation.

Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3ß (GSK3ß). Increased TrkB, GSK3ß, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

Influence of filtering on the effective concentration and sterility of a 2% cyclosporine ophthalmic solution: a quality improvement perspective.

BACKGROUND: Pharmaceutical companies do not sell formulations for all diseases; thus, healthcare workers have to treat some diseases by concocting in-hospital preparations. An example is the high-concentration 2% cyclosporine A (CyA) ophthalmic solution. Utilizing a filter in sterility operations is a general practice for concocting in-hospital preparations, as is the case for preparing a 2% CyA ophthalmic solution. However, whether filtering is appropriate concerning the active ingredient content and bacterial contamination according to the post-preparing quality control of a 2% CyA ophthalmic solution is yet to be verified. METHODS: We conducted particle size, preparation concentration, and bacterial contamination studies to clarify aforementioned questions. First, we measured the particle size of CyA through a laser diffraction particle size distribution. Next, we measured the concentration after preparation with or without a 0.45-µm filter operation using an electrochemiluminescence immunoassay. Finally, bacterial contamination tests were conducted using an automated blood culture system to prepare a 2% CyA ophthalmic solution without a 0.45 µm filtering. Regarding the pore size of the filter in this study, it was set to 0.45 µm with reference to the book (the 6th edition) with recipes for the preparation of in-hospital preparations edited by the Japanese Society of Hospital Pharmacists. RESULTS: CyA had various particle sizes; approximately 30% of the total particles exceeded 0.45 µm. The mean ± standard deviation of filtered and non-filtered CyA concentrations in ophthalmic solutions were 346.51 ± 170.76 and 499.74 ± 76.95ng/mL, respectively (p = 0.011). Regarding bacterial contamination tests, aerobes and anaerobes microorganisms were not detected in 14 days of culture. CONCLUSIONS: Due to the results of this study, the concentration of CyA may be reduced by using a 0.45-µm filter during the preparation of CyA ophthalmic solutions, and furthermore that the use of a 0.45-µm filter may not contribute to sterility when preparing CyA ophthalmic solutions.

Health-related quality of life in patients with colorectal cancer who receive oral uracil and tegafur plus leucovorin.

OBJECTIVE: Adjuvant chemotherapy with oral uracil/tegafur plus leucovorin has been acknowledged to be a standard treatment for Stage II or III cancer of the colon. The objective of the study was to examine the health-related quality of life during treatment in patients with colorectal cancer who receive oral uracil/tegafur plus leucovorin. METHODS: Health-related quality of life was assessed at baseline (pre-treatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires. Health-related quality of life data for five courses of treatment were then analyzed longitudinally. RESULTS: Ninety-four patients completed the baseline and post-treatment health-related quality of life assessments. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all the scales except cognitive function, dyspnea, insomnia, constipation and diarrhea. Role function and social function changed by 10 or more points considered clinically significant. Most of the scales in patients with Grade 0-1 toxicities were better than those with Grade 2-3 toxicities, but Grade 2-3 toxicities were not associated with post-treatment deteriorations in health-related quality of life. The development of Grade 3 toxicities negatively affected on the four scales at the next assessment, compared with Grade 1-2 toxicities. CONCLUSIONS: Overall health-related quality of life did not deteriorate during adjuvant chemotherapy with oral uracil/tegafur plus leucovorin in patients with colorectal cancer, despite the effect from surgical damage, whereas the development of Grade 3 toxicities negatively affected on short-term health-related quality of life. Further comparative studies are needed.

Health-related quality of life of colorectal cancer patients receiving oral UFT plus leucovorin compared with those with surgery alone.

BACKGROUND: Adjuvant chemotherapy of oral uracil/ftorafur (UFT) plus leucovorin (LV) has been accepted as the standard of care in the treatment of patients with stage II and III carcinoma of the colon. The objective of the study was to compare HRQOL reported by patients receiving oral UFT plus LV (UFT/LV group) versus no adjuvant treatment (control group) following surgery for colorectal cancer. METHODS: Ninety nine patients in the UFT/LV group and 83 in the control group participated. HRQOL was assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 and HRQOL data measured longitudinally following surgery were compared between the groups. RESULTS: Eighty-eight percent (87 of 99) received all scheduled doses of UFT plus LV during the first three cycles, and 82 percent (81 of 99) did so for five cycles. The most common type of toxicity in the UFT/LV group was fatigue, which was generally mild. Six patients each had grade 3 diarrhea or anorexia. There were significant differences in the scores for role function, and specific limitations such as fatigue, nausea, and vomiting, dyspnoea, appetite loss, and financial difficulties, which deteriorated in the UFT/LV group. CONCLUSIONS: HRQOL in colorectal cancer patients with adjuvant chemotherapy with oral UFT plus LV deteriorated during this phase of treatment compared with those with surgery alone, despite the biased stage of tumor between the groups. Symptom management and social support would improve HRQOL in such a group of patients.

Health-related quality of life in patients with advanced colorectal cancer: results from a phase II study of S-1 combined with irinotecan (CPT-11).

BACKGROUND: We carried out this study to examine the health-related quality of life (HRQOL) of patients with advanced colorectal cancer treated with the oral fluoropyrimidine S-1 plus irinotecan (CPT-11). METHODS: HRQOL was assessed at baseline (pretreatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires. The HRQOL data for 12 preselected scales and 21 courses of treatment were then analyzed longitudinally. RESULTS: Thirty-seven patients completed the baseline and post-treatment HRQOL assessments. Statistically significant differences between the baseline and post-treatment HRQOL scores were observed for the global QOL, social function, and pain scales (all QLQ-C30), as well as the body image, future perspective, gastrointestinal tract symptoms, weight loss, and chemotherapy side effects scales (all QLQ-CR38); favorable post-treatment results were observed for all the scales except for body image and chemotherapy side effects, for which post-treatment deteriorations were observed. The changes in body image, future perspective, weight loss, and chemotherapy side effects were each greater than ten points and seemed clinically significant. CONCLUSION: Combined treatment with S-1 plus CPT-11 resulted in an acceptable deterioration in HRQOL functioning and symptoms, compared with baseline levels.

Lipoteichoic acid improves the capability of mast cells in the host defense system against bacteria.

OBJECTIVES AND DESIGN: We investigated the effects of microbial components on the uptake of microbes by mast cells (MCs), and studied the change in cytokine production in MCs after bacterial uptake. MATERIAL OR SUBJECTS: LAD2 human mast cells, cord-blood and peripheral-blood derived MCs were employed to analyze their surface molecule expression and cytokine generation by flow cytometry. Bacterial internalization in these MCs was observed by confocal microscopy and flow cytometry. RESULTS: Complement receptor 3 expression was augmented by LTA but not by PGN or 3CpG-oligodeoxynucleotide. LTA also enhanced the uptake of opsonized bacteria (over twofold augmentation). After bacterial uptake, MCs augmented the production of chemoattractant cytokines for neutrophils, while Th1 and Th2 cytokine production showed little or no change. CONCLUSIONS: LTA increases the capability of the MC as a sentinel in the host immune response, and some bacterial components direct human MC function towards innate immunity after pathogen infection.

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-D-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N2O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinase-markers of neuronal excitability-were upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3ß (glycogen synthase kinase 3ß) became regulated only gradually upon N2O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3ß signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of α2-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3ß signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.

Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein.

The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Cav) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Cav channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Cav channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-γ1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Cav channels in FXS neural progenitors.

P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy.

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.

One-stage laparoscopy-assisted colectomy for synchronous double colorectal cancers.

Synchronous multiple malignant colorectal lesions are rare, and there have been very few studies about one-stage laparoscopic operations in these cases. Here, we evaluated the short-term outcomes of laparoscopy-assisted colectomy (LAC) for synchronous double colorectal cancers. Seven patients underwent one-stage LAC that required two resections and anastomoses in our hospital from 2010 to 2014. We retrospectively examined each patient's background and subsequent surgical outcomes. The median age of patients was 78 years, and the median BMI was 19.8 kg/m2 . The median operative time was 190 min, and blood loss was minimal. All resected specimens were extracted through a transumbilical incision. A radical operation was performed safely without procedural accidents or postoperative complications in all cases. The median postoperative hospital stay was 12.5 days. One-stage LAC is considered a safe and viable procedure for resecting synchronous double colorectal cancers. It involves minimal invasiveness and is similar to standard LAC.