Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Histological and Immunohistochemical Features of Normal Histiocytes and Langerhans Cells, and Histiocytic Sarcomas in Four-Toed Hedgehogs (Atelerix albiventris).

Histiocytic sarcoma (HS) is a haematopoietic tumour of histiocyte origin that has been sporadically reported in four-toed hedgehogs (Atelerix albiventris). The present study aimed to investigate clinical, gross, histopathological and immunohistochemical features of HS in eight hedgehogs. Histological and immunohistochemical features of normal histiocytes and Langerhans cells (LCs) of hedgehogs were also investigated. HLA-DR-, Iba-1- and E-cadherin-positive LCs were observed in the epidermis, while Iba-1- and CD204-positive histiocytes were detected in the lymph nodes and spleen of normal hedgehogs. Localized HS (six cases) developed in the skin and spleen, while disseminated HS (two cases) occurred in the intestine. Tumour cells of disseminated HS were also distributed within the mesenteric lymph nodes, liver, kidney, spleen, lung and adrenal glands. Tumour cells of both localized and disseminated HS were composed of histiocytic cells, spindle to pleomorphic cells, multinucleated giant cells and erythrophagocytic cells. Most tumour cells were immunopositive for Iba-1, CD204 and lysozyme. A small number of tumour cells were positive for E-cadherin and CD208, and the tumour cells in one case were positive for HLA-DR. These results suggest that the tumour cells have variable features of histiocyte origin, including dendritic cells, LCs and macrophages. The behaviour of HS in the hedgehog was very aggressive, and 50% of cases died within 90 days of resection. The present study also highlighted the tendency for local tumour recurrence in localized cutaneous HS cases, suggesting a requirement for a long-term follow-up after excision.

Ultrafast Creation of Overlapping Rydberg Electrons in an Atomic BEC and Mott-Insulator Lattice.

We study an array of ultracold atoms in an optical lattice (Mott insulator) excited with a coherent ultrashort laser pulse to a state where single-electron wave functions spatially overlap. Beyond a threshold principal quantum number where Rydberg orbitals of neighboring lattice sites overlap with each other, the atoms efficiently undergo spontaneous Penning ionization resulting in a drastic change of ion-counting statistics, sharp increase of avalanche ionization, and the formation of an ultracold plasma. These observations signal the actual creation of electronic states with overlapping wave functions, which is further confirmed by a significant difference in ionization dynamics between a Bose-Einstein condensate and a Mott insulator. This system is a promising platform for simulating electronic many-body phenomena dominated by Coulomb interactions in the condensed phase.

Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling.

Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.

Lachrymal Gland Basal Cell Adenocarcinoma in a Ferret (Mustela putorius furo).

A 1 cm diameter mass was detected in the caudal superotemporal area of the left eye of a 6-year-old neutered male ferret (Mustela putorius furo). The mass and the left eye were removed surgically. Microscopical examination revealed a tumour of the adnexal gland of the eye that had invaded the surrounding ocular muscle. The tumour was composed of basal-type epithelial cells arranged in a solid, or occasionally tubular, pattern. Immunohistochemically, the tumour cells expressed cytokeratin and p63, but not smooth muscle actin. Based on these findings, the tumour was diagnosed as a basal cell adenocarcinoma of the lachrymal gland. In addition to the tumour, the retina of the left eye was detached and folded at the centre of the globe. This is the first report of a non-human case of basal cell adenocarcinoma of the lachrymal gland.

Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories.

BACKGROUND: Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear. METHOD: We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects. RESULTS: A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant. CONCLUSIONS: A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.

Differential impacts of duration of untreated psychosis (DUP) on cognitive function in first-episode schizophrenia according to mode of onset.

BACKGROUND: The mode of onset and the course of schizophrenia illness exhibit substantial individual variations. Previous studies have pointed out that the mode of onset affects the duration of untreated psychosis (DUP) and clinical outcomes, such as cognitive and social functioning. This study attempted to clarify the association between the DUP and clinical features, taking the different modes of onset into consideration, in a prospective longitudinal study examining patients with first-episode schizophrenia. METHODS: This study was conducted in six areas of Japan. Patients with first-episode schizophrenia were followed for over 18 months. Cognitive function, psychopathology, and social functioning were assessed at baseline and at 6, 12, and 18-month follow-up points. RESULTS: We identified 168 patients and sufficient information was available to determine the DUP and the mode of onset for 156 patients (92.9%): 79 had an acute onset, and 77 had an insidious onset. The DUP was significantly associated with quality of life (QOL), social functioning, and cognitive function at most of the follow-up points in the insidious-onset group. The DUP and negative symptoms at baseline were significant predictors of cognitive function at the 18-month follow-up in the insidious-onset group. CONCLUSIONS: The present results further support the hypothesis that the DUP affects QOL, social functioning, and cognitive function over the course of illness, especially in patients with an insidious onset. Effective strategies for detecting and caring for individuals with insidious onset early during the course of schizophrenia will be essential for achieving a full patient recovery.

Salivary Gland Epithelial-Myoepithelial Carcinoma with High-Grade Transformation in a Dog.

An 8-year-old male neutered standard dachshund was presented with a slowly growing mass in the left submandibular salivary gland. Histopathological examination revealed a tumour that was composed of bilayered duct-like structures with an inner layer of ductal cells and an outer layer of clear cells. Both inner and outer cells in the greater part of the tumour exhibited low to moderate atypia and low mitotic activity. However, a focal area towards the periphery showed enhanced cellular atypia and mitotic activity in tumour cells. Immunohistochemically, the outer layer of clear cells expressed myoepithelial markers, while the inner layer cells were positive for a luminal epithelial marker. No local recurrence or lymph node or distant metastasis was observed 18 months following surgery. Based on the morphology and immunohistochemical findings, a final diagnosis of epithelial-myoepithelial carcinoma with high-grade transformation was made.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Increased ratio of FoxP3+ regulatory T cells/CD3+ T cells in skin lesions in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug rash with eosinophilia with systemic symptoms (DIHS/DRESS) is a severe drug eruption accompanied by multiorgan disorders. Several unique aspects of DIHS/DRESS, including herpesvirus reactivation, liver dysfunction and hypogammaglobulinaemia, have similarities to graft-versus-host disease (GVHD). AIM: In this study, we focused on the dynamics of regulatory T cells (Tregs) infiltrating into the skin lesions of DIHS/DRESS and GVHD. METHODS: Skin biopsies were taken from patients with DIHS/DRESS, GVHD, or maculopapular drug eruption. Tregs were detected using immunostaining with anti-FoxP3. RESULTS: The ratio of FoxP3+ T cells to CD3+ T cells was significantly higher in the skin lesions of patients with DIHS/DRESS than in those of patients with GVHD, and was positively correlated with the number of days from disease onset in the acute phase. CONCLUSIONS: The dynamics of Tregs in skin lesions are different between DIHS/DRESS and GVHD, despite there being many similarities between these conditions.

Differences in indicators of malignancy between luminal epithelial cell type and myoepithelial cell type of simple solid carcinoma in the canine mammary gland.

Routinely diagnosed simple solid carcinoma (SSC) of the canine mammary gland comprises a heterogeneous group of tumors. Seventy-two cases that had been diagnosed as SSC based on hematoxylin and eosin-stained tissue sections were reclassified immunohistochemically on the basis of myoepithelial markers p63 and α-smooth muscle actin, as well as a luminal epithelial marker cytokeratin 8. Only 23 cases (32%) were true SSC, composed only of luminal epithelial cells, whereas 11 cases (15%) were malignant myoepithelioma (MM), composed predominantly of myoepithelial cells, and 38 cases (53%) were biphasic carcinoma (BC), characterized by biphasic proliferation of luminal epithelial and basal/myoepithelial components. As the pathological parameters were compared between the reclassified tumor types, infiltrative potential, vascular/lymphatic invasion, lymph node metastasis, and Ki-67 labeling index were higher in true SSC compared with MM and BC, suggesting that the former may exhibit a poorer prognosis compared with the latter two.

Condyloma acuminata induces focal intense FDG uptake mimicking vaginal stump recurrence from uterine cervical cancer: a case report.

The 2-deoxy-2-[18F] fluoro-D-glucose position emission tomography/computed tomography (FDG PET/CT) findings of condyloma acuminata in a patient with FIGO Stage IB1 cervical cancer who had previously been treated with radical hysterectomy, pelvic chemoradiotherapy, and consolidation chemotherapy is described in this article. This case highlights the importance of considering condyloma acuminata during the differential diagnosis of abnormal vaginal FDG uptake in patients who have been treated for gynecological cancer.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics.

Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting 6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months; treatment failure; hospitalization; and dropout owing to any cause, non-adherence and intolerability. Pooled relative risk (RR) (±95% confidence intervals (CIs)) was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4504, mean duration=61.9±22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidone's superiority at 3 and 6 months when requiring ≥3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0 versus 37.5%, RR=0.80, CI: 0.70-0.91, P=0.0007, I(2)=37%; NNT=17, CI: 10-50, P=0.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (P=0.04, P<0.0001, P=0.0001), treatment failure (P=0.003) and hospitalization (P=0.004). SGAs showed trend-level superiority for dropout owing to intolerability (P=0.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several key outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.

Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome.

The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABA(A) receptor agonist, bretazenil, or a GABA(A) α2/α3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of Comt to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both Comt overexpression and Comt inhibition caused an abnormal responsiveness to Bretazenil, a GABA(A) receptor agonist in control mice. Comt overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as Gabrb2 (GABA(A)receptor ß2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a Comt expression level in PFC. Our data suggest that Comt-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice.

The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers.

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response.

Peptidoglycan and lipopolysaccharide synergistically enhance bone resorption and osteoclastogenesis.

BACKGROUND AND OBJECTIVE: Peptidoglycan (PGN) and lipopolysaccharide (LPS) are bacterial cell wall constituents that are able to induce bone resorption by stimulating Toll-like receptor (TLR) 2 and TLR4, respectively. The fragments of PGN also stimulate inflammatory responses via nucleotide-binding oligomerization domain (NOD) 1 and NOD2, although there are differences in the NOD-stimulatory activities between gram-positive and gram-negative PGNs. The TLR and NOD signaling pathways are known to engage in cross-talk to enhance the production of inflammatory cytokines. In the present study, we investigated the effects of gram-negative and gram-positive PGNs on bone resorption and osteoclastogenesis in the presence or absence of LPS. MATERIAL AND METHODS: We injected Escherichia coli PGN or Staphylococcus aureus PGN with or without LPS into mouse gingiva, and histopathologically assessed alveolar bone resorption by tartrate-resistant acid phosphatase staining. We also stimulated osteoclast precursors from mouse bone marrow macrophages with these PGNs in vitro and assessed osteoclastogenesis. The cells were also stimulated with synthetic ligands for NOD1; γ-D-glutamyl-meso-DAP NOD2; muramyl dipeptide or TLR2; Pam(3) CSK(4) with or without LPS to analyse the signaling cross-talk. RESULTS: S. aureus PGN, but not E. coli PGN, induced alveolar bone resorption, as did LPS. However, PGN from both sources significantly enhanced the bone resorption in the mice co-injected with LPS. Both types of PGNs induced osteoclastogenesis and accelerated osteoclastogenesis when the cells were co-stimulated with LPS in vitro. All synthetic ligands synergistically induced osteoclastogenesis by co-stimulation with LPS. CONCLUSION: Gram-positive or gram-negative PGN worked synergistically with LPS to induce bone resorption and osteoclastogenesis, possibly by co-ordinating the effects of TLR2, NOD1, NOD2 and TLR4 signaling.

Narrow-linewidth light source for a coherent Raman transfer of ultracold molecules.

We describe a tunable two-color CW light source sufficient for realizing a coherent Raman transfer between two molecular states that are more than 0.5 eV (120 THz) apart. The simultaneous frequency stabilization of 901 nm and 655 nm light was achieved by locking diode lasers to a single ultralow expansion cavity with dual wavelengths coating. By utilizing offset-locking and optical phase-locked loop (OPLL), we ensured a large mode-hop free tuning range (> 2 GHz). The obtained short term linewidth (<10 Hz) and the linear drift of frequency (65 mHz/s) were both sufficient to eliminate the influence of laser linewidths on the efficiency of coherent Raman transition.