Experience-dependent functional plasticity and visual response selectivity of surviving subplate neurons in the mouse visual cortex.

Subplate neurons are early-born cortical neurons that transiently form neural circuits during perinatal development and guide cortical maturation. Thereafter, most subplate neurons undergo cell death, while some survive and renew their target areas for synaptic connections. However, the functional properties of the surviving subplate neurons remain largely unknown. This study aimed to characterize the visual responses and experience-dependent functional plasticity of layer 6b (L6b) neurons, the remnants of subplate neurons, in the primary visual cortex (V1). Two-photon Ca2+ imaging was performed in V1 of awake juvenile mice. L6b neurons showed broader tunings for orientation, direction, and spatial frequency than did layer 2/3 (L2/3) and L6a neurons. In addition, L6b neurons showed lower matching of preferred orientation between the left and right eyes compared with other layers. Post hoc 3D immunohistochemistry confirmed that the majority of recorded L6b neurons expressed connective tissue growth factor (CTGF), a subplate neuron marker. Moreover, chronic two-photon imaging showed that L6b neurons exhibited ocular dominance (OD) plasticity by monocular deprivation during critical periods. The OD shift to the open eye depended on the response strength to the stimulation of the eye to be deprived before starting monocular deprivation. There were no significant differences in visual response selectivity prior to monocular deprivation between the OD changed and unchanged neuron groups, suggesting that OD plasticity can occur in L6b neurons showing any response features. In conclusion, our results provide strong evidence that surviving subplate neurons exhibit sensory responses and experience-dependent plasticity at a relatively late stage of cortical development.

The third nationwide surveillance of antimicrobial susceptibility against Neisseria gonorrhoeae from male urethritis in Japan, 2016-2017.

Neisseria gonorrhoeae is one of the important pathogens of sexually transmitted infections. N. gonorrhoeae is rapidly becoming antimicrobial resistant, and there are few drugs that are effective in the initial treatment of gonorrhea. To understand the trends of antimicrobial susceptibility of N. gonorrhoeae, the Surveillance Committee of the Japanese Society of Infectious Diseases, the Japanese Society for Chemotherapy, and the Japanese Society of Clinical Microbiology conducted the third nationwide antimicrobial susceptibility surveillance of N. gonorrhoeae isolated from male urethritis. The specimens were collected from male patients with urethritis at 30 facilities from May 2016 to July 2017. From the 159 specimens collected, 87 N. gonorrhoeae strains were isolated, and 85 were tested for susceptibility to 21 antimicrobial agents. All strains were non-susceptible to penicillin G. Seven strains (8.2%) were ß-lactamase-producing strains. The rates of susceptibility to cefixime and cefpodoxime were 96.5% and 52.9%, respectively. Three strains were non-susceptible with a minimum inhibitory concentration (MIC) of 0.5 mg/L for cefixime. None of the strains were resistant to ceftriaxone or spectinomycin. The susceptibility rate for ciprofloxacin was 23.5% (20 strains), and no strains showed intermediate susceptibility. The susceptibility rate against azithromycin was 81.2%, with one strain isolated with a MIC of 8 mg/L against azithromycin. The results of this surveillance indicate that ceftriaxone and spectinomycin, which are currently recommended for gonococcal infections in Japan, appear to be effective. It will be necessary to further expand the scale of the next surveillance to understand the current status of drug-resistant N. gonorrhoeae in Japan.

The role of early visual experience in the development of spatial-frequency preference in the primary visual cortex.

KEY POINTS: The mature functioning of the primary visual cortex depends on postnatal visual experience, while the orientation/direction preference is established just after eye-opening, independently of visual experience. In this study, we find that visual experience is required for the normal development of spatial-frequency (SF) preference in mouse primary visual cortex. We show that age- and experience-dependent shifts in optimal SFs towards higher frequencies occurred similarly in excitatory neurons and parvalbumin-positive interneurons. We also show that some excitatory and parvalbumin-positive neurons preferentially responded to visual stimuli consisting of very high SFs and posterior directions, and that the preference was established at earlier developmental stages than the SF preference in the standard frequency range. These results suggest that early visual experience is required for the development of SF representation and shed light on the experience-dependent developmental mechanisms underlying visual cortical functions. ABSTRACT: Early visual experience is crucial for the maturation of visual cortical functions. It has been demonstrated that the orientation and direction preferences in individual neurons of the primary visual cortex are well established immediately after eye-opening. The postnatal development of spatial frequency (SF) tuning and its dependence on visual experience, however, has not been thoroughly quantified. In this study, macroscopic imaging with flavoprotein autofluorescence revealed that the optimal SFs shift towards higher frequency values during normal development in mouse primary visual cortex. This developmental shift was impaired by binocular deprivation during the sensitive period, postnatal 3 weeks (PW3) to PW6. Furthermore, two-photon Ca2+ imaging revealed that the developmental shift of the optimal SFs, depending on visual experience, concurrently occurs in excitatory neurons and parvalbumin-positive inhibitory interneurons (PV neurons). In addition, some excitatory and PV neurons exhibited a preference for visual stimuli consisting of particularly high SFs and posterior directions at relatively early developmental stages; this preference was not affected by binocular deprivation. Thus, there may be two distinct developmental mechanisms for the establishment of SF preference depending on the frequency values. After PW3, SF tuning for neurons tuned to standard frequency ranges was sharper in excitatory neurons and slightly broader in PV neurons, leading to considerably attenuated SF tuning in PV neurons compared to excitatory neurons by PW5. Our findings suggest that early visual experience is far more important than orientation/direction selectivity for the development of the neural representation of the diverse SFs.

MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment.

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin-G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.

Second nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by Japanese Surveillance Committee from 2015 to 2016: antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus.

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16-40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum ß-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan.

Explaining the ocean's richest biodiversity hotspot and global patterns of fish diversity.

For most marine organisms, species richness peaks in the Central Indo-Pacific region and declines longitudinally, a striking pattern that remains poorly understood. Here, we used phylogenetic approaches to address the causes of richness patterns among global marine regions, comparing the relative importance of colonization time, number of colonization events, and diversification rates (speciation minus extinction). We estimated regional richness using distributional data for almost all percomorph fishes (17 435 species total, including approximately 72% of all marine fishes and approximately 33% of all freshwater fishes). The high diversity of the Central Indo-Pacific was explained by its colonization by many lineages 5.3-34 million years ago. These relatively old colonizations allowed more time for richness to build up through in situ diversification compared to other warm-marine regions. Surprisingly, diversification rates were decoupled from marine richness patterns, with clades in low-richness cold-marine habitats having the highest rates. Unlike marine richness, freshwater diversity was largely derived from a few ancient colonizations, coupled with high diversification rates. Our results are congruent with the geological history of the marine tropics, and thus may apply to many other organisms. Beyond marine biogeography, we add to the growing number of cases where colonization and time-for-speciation explain large-scale richness patterns instead of diversification rates.

[A Case of Malignant Peritoneal Mesothelioma Treated with Cisplatin and Pemetrexed].

A 65-year-old man was admitted to our hospital complaining of general malaise, anorexia and weight loss. A computed tomography(CT)scan showed massive ascites and multiple peritoneal masses. Although adenocarcinoma was suspected based on the cytology of the ascites, we were unable to determine the site of origin. We next performed a laparoscopy and a biopsy of the tumor on the omentum. The laparoscopy showed small, white, hard nodules that were disseminated throughout the abdominalcavity, and histologicaldiagnosis confirmed malignant peritonealmesothel ioma. The patient was administered chemotherapeutic treatment of cisplatin and pemetrexed. After treatment, the ascites decreased; however, tumor regression was not observed. The patient's performance status gradually decreased, and he died on hospital day 104. Prognosis of malignant peritoneal mesothelioma remains poor, and malignant peritoneal mesothelioma should be considered when diagnosing peritoneal tumors.

Relationship between white matter integrity and serum cortisol levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.

BACKGROUND: Higher daytime cortisol levels because of a hyperactive hypothalamic-pituitary-adrenal axis have been reported in patients with major depressive disorder (MDD). The elevated glucocorticoids inhibit the proliferation of the oligodendrocytes that are responsible for myelinating the axons of white matter fibre tracts. AIMS: To evaluate the relationship between white matter integrity and serum cortisol levels during a first depressive episode in drug-naive patients with MDD (MDD group) using a tract-based spatial statistics (TBSS) method. METHOD: The MDD group (n = 29) and a healthy control group (n = 47) underwent diffusion tensor imaging (DTI) scans and an analysis was conducted using TBSS. Morning blood samples were obtained from both groups for cortisol measurement. RESULTS: Compared with the controls, the MDD group had significantly reduced fractional anisotropy values (P<0.05, family-wise error (FWE)-corrected) in the inferior fronto-occipital fasciculus, uncinate fasciculus and anterior thalamic radiation. The fractional anisotropy values of the inferior fronto-occipital fasciculus, uncinate fasciculus and anterior thalamic radiation had significantly negative correlations with the serum cortisol levels in the MDD group (P<0.05, FWE-corrected). CONCLUSIONS: Our findings indicate that the elevated cortisol levels in the MDD group may injure the white matter integrity in the frontal-subcortical and frontal-limbic circuits.

Elevated levels of CYP94 family gene expression alleviate the jasmonate response and enhance salt tolerance in rice.

The plant hormone jasmonate and its conjugates (JAs) have important roles in growth control, leaf senescence and defense responses against insects and microbial attacks. JA biosynthesis is induced by several stresses, including mechanical wounding, pathogen attacks, drought and salinity stresses. However, the roles of JAs under abiotic stress conditions are unclear. Here we report that increased expression of the Cyt P450 family gene CYP94C2b enhanced viability of rice plants under saline conditions. This gene encodes an enzyme closely related to CYP94C1 that catalyzes conversion of bioactive jasmonate-isoleucine (JA-Ile) into 12OH-JA-Ile and 12COOH-JA-Ile. Inactivation of JA was facilitated in a rice line with enhanced CYP94C2b expression, and responses to exogenous JA and wounding were alleviated. Moreover, salt stress-induced leaf senescence but not natural senescence was delayed in the transgenic rice. These results suggest that bioactive JAs have a negative effect on viability under salt stress conditions and demonstrate that manipulating JA metabolism confers enhanced salt tolerance in rice.

RELATIONSHIP BETWEEN THE CORTICAL THICKNESS AND SERUM CORTISOL LEVELS IN DRUG-NAÏVE, FIRST-EPISODE PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A SURFACE-BASED MORPHOMETRIC STUDY.

OBJECTIVE: In major depressive disorder (MDD) patients, higher morning cortisol levels due to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis have been reported. The aim of the present study was to evaluate the relationship between cortical thinning and the serum cortisol levels during the first depressive episode in drug-naïve MDD patients using an automated surface-based morphometry (SBM) method. METHODS: The institutional review board approved this prospective study. MR imaging data were obtained using a 3T scanner by a three-dimensional fast-spoiled gradient recalled acquisition with steady state (3D-FSPGR). Thirty drug-naïve patients with MDD and 41 age- and gender-matched healthy subjects (controls) were enrolled. We then used the SBM method (Freesurfer) to generate cortical thickness maps, and measured the cortical thickness in each subject. Morning blood samples were drawn from all participants for cortisol measurements. RESULTS: We found the serum cortisol levels were significantly higher in the MDD patients than in the controls. The MDD patients manifested significant thinning of the left lateral orbitofrontal cortex compared with the controls. There was a significant negative linear correlation between the thickness of the left lateral orbitofrontal cortex and the serum cortisol levels in the MDD patients. CONCLUSIONS: In the early stage of MDD, the thickness of the lateral orbitofrontal cortex was significantly reduced, and also showed a significant inverse correlation with the serum cortisol levels. Since the lateral orbitofrontal cortex contains a high concentration of glucocorticoid receptor, glucocorticoid receptor-mediated signaling transductions could contribute to neurotoxicity, which might occur when there are high cortisol levels in patients with MDD.

Epithelial protein lost in neoplasm modulates platelet-derived growth factor-mediated adhesion and motility of mesangial cells.

Mesangial cell migration, regulated by several growth factors, is crucial after glomerulopathy and during glomerular development. Directional migration requires the establishment of a polarized cytoskeletal arrangement, a process regulated by coordinated actin dynamics and focal adhesion turnover at the peripheral ruffles in migrating cells. Here we found high expression of the actin cross-linking protein EPLIN (epithelial protein lost in neoplasm) in mesangial cells. EPLIN was localized in mesangial angles, which consist of actin-containing microfilaments extending underneath the capillary endothelium, where they attach to the glomerular basement membrane. In cultured mesangial cells, EPLIN was localized in peripheral actin bundles at focal adhesions and formed a protein complex with paxillin. The MEK-ERK (extracellular signal-regulated kinase) cascade regulated EPLIN-paxillin interaction and induced translocalization of EPLIN from focal adhesion sites to peripheral ruffles. Knockdown of EPLIN in mesangial cells enhanced platelet-derived growth factor-induced focal adhesion disassembly and cell migration. Furthermore, EPLIN expression was decreased in mesangial proliferative nephritis in rodents and humans in vivo. These results shed light on the coordinated actin remodeling in mesangial cells during restorative remodeling. Thus, changes in expression and localization of cytoskeletal regulators underlie phenotypic changes in mesangial cells in glomerulonephritis.

Sex differences in the prevalence, progression, and improvement of chronic kidney disease.

BACKGROUND/AIMS: We examined sex differences in prevalence, progression, and improvement in early-stage chronic kidney disease (CKD). METHODS: We analyzed data from 533 participants who took 4 consecutive annual CKD detection tests. RESULTS: Urine albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and hemoglobin (Hb) at baseline in men with and without CKD and in women with and without CKD were 8.3±6.1, 149.2±310.4, 10.2±5.8, and 96.7±246.8 mg/g Cr; 83.4±14.7, 63.8±18.8, 79.9±13.0, and 69.4±20.0 mL/min/1.73 m2; and 14.8±1.2, 14.3±1.4, 13.0±1.0, and 13.0±1.2 mg/dL, respectively. ACR levels decreased significantly over time in men and women with CKD and they increased significantly over time in men and women without CKD. eGFR levels in men and women with CKD did not significantly change over time, but they decreased significantly over time in men and women without CKD. CKD prevalence and progression rate were not significantly different between sexes. Among the CKD participants, significantly more women had a "cured" status at 3 years (39.1% vs. 19.4%, P<0.01). Most whose eGFR increased to >60 mL/min/1.73 m2 at 3 years had values just below those at baseline. Regression analysis showed that change in eGFR correlated significantly with ACR in men with CKD (change in eGFR = -1.707+0.022×ACR, P<0.001, r2=0.201) and with Hb and ACR in women with CKD (change in eGFR = 48.870-3.803×Hb + 0.018×ACR, P<0.05, r2=0.134). CONCLUSIONS: These results suggest that the slight decrease of Hb within a normal range and mild anemia can be managed in women with early-stage CKD. The key baseline for eGFR is 60 mL/min/1.73 m2.

Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.

A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.

[Current situation and problems associated with inactivation of microorganisms in water using copper].

OBJECTIVES: The current situation and problems associated with inactivation of microorganisms in water using copper were elucidated. METHODS: A literature review was conducted regarding the history and mechanisms of inactivation technology using copper, the variety of microorganisms shown to be inactivated by these methods in previous experiments, and the efficacy of such technologies for the inactivation of microorganisms in water. RESULTS: The use of copper for inactivation of microorganisms has a long history. Although the use of copper was discontinued temporarily owing to the advent of antibiotics in the 1930s, the occurrence of antibiotic-resistant bacteria has resulted in the need for different approaches to control pathogenic microorganisms. One such alternative is the use of copper. Although the mechanisms underlying the efficacy of copper inactivation technology have not yet been elucidated in detail, it has been suggested that pathogenic bacteria are inactivated due to the toxicity of copper ions and strong oxidation effects of reactive oxygen species. Copper inactivation technology is effective against many pathogenic microorganisms that pose a risk to public health, such as Legionella pneumophila, Salmonella enterica, and Mycobacterium tuberculosis. In recent years, copper inactivation technology has been used in various water-related devices, especially water supply pipes in buildings. Previous studies have demonstrated that microorganisms can be sufficiently inactivated by copper even at concentrations below that specified in the Water Quality Standard for Drinking Water. However, some previous studies have indicated that the inactivation effect of copper is short-lived. Therefore, the development of techniques to maintain a long-term inactivation effect is a key concern. In addition, it has been reported that the use of copper pipes triggers chlorine decay and results in the formation of chlorine disinfection byproducts. Hence, further studies should aim at assessing the risks and benefits associated with the use of copper. CONCLUSION: Although the practical issues regarding copper inactivation technology are persistent, this method has been demonstrated to be efficacious. Therefore, this technology could be expected to be used in many devices such as water supply systems in hospitals in the near future.

[Tracheal intubation using Airtraq optical laryngoscope in an adult patient with Goldenhar syndrome].

A 23-year-old woman with Goldenhar syndrome and conductive deafness was scheduled for tympanoplasty. Goldenhar syndrome is a developmental disorder characterized by ear malformation, mandibular hypoplasia, and vertebral anomalies. Furthermore, she had micrognathia, trismus, and mandibular hypoplasia. Awake taracheal intubation was attempted to prevent airway obstruction, because we had anticipated her difficult airway (micrognathia, trismus, and mandibular hypoplasia). The vocal cords were visualized with a Cormac and Lehane grade I, using the Airtraq optical laryngoscope Small (Size 2), under sedation. Then, an endotracheal tube was inserted after induction of general anesthesia. This is the first case report on the successful orotracheal intubation using Airtraq in an adult with Goldenhar syndrome.

Maintenance of dendritic spine morphology by partitioning-defective 1b through regulation of microtubule growth.

Dendritic spines are postsynaptic structures that receive excitatory synaptic input from presynaptic terminals. Actin and its regulatory proteins play a central role in morphogenesis of dendritic spines. In addition, recent studies have revealed that microtubules are indispensable for the maintenance of mature dendritic spine morphology by stochastically invading dendritic spines and regulating dendritic localization of p140Cap, which is required for actin reorganization. However, the regulatory mechanisms of microtubule dynamics remain poorly understood. Partitioning-defective 1b (PAR1b), a cell polarity-regulating serine/threonine protein kinase, is thought to regulate microtubule dynamics by inhibiting microtubule binding of microtubule-associated proteins. Results from the present study demonstrated that PAR1b participates in the maintenance of mature dendritic spine morphology in mouse hippocampal neurons. Immunofluorescent analysis revealed PAR1b localization in the dendrites, which was concentrated in dendritic spines of mature neurons. PAR1b knock-down cells exhibited decreased mushroom-like dendritic spines, as well as increased filopodia-like dendritic protrusions, with no effect on the number of protrusions. Live imaging of microtubule plus-end tracking proteins directly revealed decreases in distance and duration of microtubule growth following PAR1b knockdown in a neuroblastoma cell line and in dendrites of hippocampal neurons. In addition, reduced accumulation of GFP-p140Cap in dendritic protrusions was confirmed in PAR1b knock-down neurons. In conclusion, the present results suggested a novel function for PAR1b in the maintenance of mature dendritic spine morphology by regulating microtubule growth and the accumulation of p140Cap in dendritic spines.

PAR-1/MARK: a kinase essential for maintaining the dynamic state of microtubules.

The serine/threonine kinase, PAR-1, is an essential component of the evolutionary-conserved polarity-regulating system, PAR-aPKC system, which plays indispensable roles in establishing asymmetric protein distributions and cell polarity in various biological contexts (Suzuki, A. and Ohno, S. (2006). J. Cell Sci., 119: 979-987; Matenia, D. and Mandelkow, E.M. (2009). Trends Biochem. Sci., 34: 332-342). PAR-1 is also known as MARK, which phosphorylates classical microtubule-associated proteins (MAPs) and detaches MAPs from microtubules (Matenia, D. and Mandelkow, E.M. (2009). Trends Biochem. Sci., 34: 332-342). This MARK activity of PAR-1 suggests its role in microtubule (MT) dynamics, but surprisingly, only few studies have been carried out to address this issue. Here, we summarize our recent study on live imaging analysis of MT dynamics in PAR-1b-depleted cells, which clearly demonstrated the positive role of PAR-1b in maintaining MT dynamics (Hayashi, K., Suzuki, A., Hirai, S., Kurihara, Y., Hoogenraad, C.C., and Ohno, S. (2011). J. Neurosci., 31: 12094-12103). Importantly, our results further revealed the novel physiological function of PAR-1b in maintaining dendritic spine morphology in mature neurons.

Plasma levels of metabolites of catecholamine in nicotine-dependent patients treated with varenicline.

INTRODUCTION: Our hypothesis is that varenicline decreases the plasma levels of catecholamine metabolites; such a decrease is associated with the main mechanisms of smoking cessation and leads to a depressive state. To confirm the hypothesis, we investigated the association of plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with nicotine dependence in comparison with nonsmokers. METHODS: To confirm the hypothesis, we investigated the association of plasma HVA and MHPG levels in patients with nicotine dependence in comparison with nonsmokers. In addition, we also examined the plasma HVA and MHPG levels before (T0) and 8 weeks after the varenicline treatment (T8). RESULTS: Seventeen of 20 smokers (85.0%) stopped smoking during the 12 weeks of treatment. Plasma HVA levels and MHPG levels in the patients at T0 (HVA 5.1 ± 2.1 ng/ml, MHPG 2.2 ± 0.6 ng/ml) were significantly higher than those of the control group (HVA 3.0 ± 1.0 ng/ml, MHPG 1.6 ± 1.4 ng/ml; HVA p = .0012, MHPG p = .0069). In this study, the plasma HVA and MHPG levels were not changed after treatment with varenicline, although the smokers had already quit. CONCLUSIONS: These results suggest that varenicline sustains higher catecholamine levels. The findings that the treatment with varenicline did not decrease the plasma levels of catecholamine metabolites can explain why none of the smokers had become depressed after the varenicline treatment.

Serum levels of brain-derived neurotrophic factor (BDNF), BDNF gene Val66Met polymorphism, or plasma catecholamine metabolites, and response to mirtazapine in Japanese patients with major depressive disorder (MDD).

OBJECT: We investigated an association between the polymorphism of brain-derived neurotrophic factor (BDNF) gene Val66Met and the response to mirtazapine in Japanese patients with major depressive disorder (MDD). We also examined mirtazapine's effects on the serum BDNF and plasma levels of catecholamine metabolites in these patients. METHODS: Eighty-four patients who met the DSM-IV-TR criteria for MDD were treated with only mirtazapine for 4 weeks. The BDNF Val66Met polymorphism was detected by direct sequencing in the region, and serum BDNF levels and plasma levels of catecholamine metabolites were measured by ELISA and HPLC-ECD, respectively. RESULTS: Mirtazapine treatment for 4 weeks significantly increased serum BDNF levels in the responders, whereas nonresponders showed significant decreases. No association was found between either of the two genotypes (Val/Val vs. Met-carriers) and the response to mirtazapine at T4 or the serum BDNF levels at T0. Mirtazapine did not alter the plasma levels of homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG). Discussion The dynamics of serum BDNF levels, but not plasma levels of HVA and MHPG, reflect the response to mirtazapine treatment; the BDNF Val66Met polymorphism in patients with depression is, however, associated with neither a particular response to mirtazapine treatment nor baseline serum BDNF levels. CONCLUSION: Serum BDNF levels, but not plasma levels of HVA or MHPG, and BDNF Val66Met polymorphism are related to the mirtazapine response in MDD.

Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients.

OBJECTIVE: We investigated the effects of aripiprazole on plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in first-episode untreated schizophrenia patients. METHODS: The subjects were 50 Japanese first-episode untreated schizophrenia patients who met the Diagnostic and Statistical Manual of Mental Disorders Text Revision criteria and were treated with aripiprazole monotherapy. Twenty-nine were males, and 21 were females. The age ranged from 21 to 42 years (mean ± SD; 30.8 ± 5.3 years). Plasma BDNF and catecholamine metabolites were measured by ELISA and HPLC, respectively. Psychiatric symptoms were evaluated using by Positive and Negative Syndrome Scale. RESULTS: Treatment with aripiprazole for 8 weeks significantly increased plasma BDNF levels. It also changed plasma levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. A negative correlation was also observed between duration of psychosis and plasma BDNF levels. No correlation was observed however between plasma BDNF levels and the dose of aripiprazole. CONCLUSIONS: To the best of our knowledge, this is the first report showing that aripiprazole increases plasma BDNF levels in first-episode untreated schizophrenia patients. Furthermore, the BDNF Val66Met polymorphism was independent of the response to aripiprazole.