Psychotherapies for depression: a network meta‐analysis covering efficacy,acceptability and long‐term outcomes of all main treatment types

The effects of psychotherapies for depression have been examined in several hundreds of randomized trials, but no recent network meta‐analysis (NMA) has integrated the results of these studies. We conducted an NMA of trials comparing cognitive behavioural, interpersonal, psychodynamic, problem‐solving, behavioural activation, life‐review and “third wave” therapies and non‐directive supportive counseling with each other and with care‐as‐usual, waiting list and pill placebo control conditions. Response (50% reduction in symptoms) was the primary outcome, but we also assessed remission, standardized mean difference, and acceptability (all‐cause dropout rate). Random‐effects pairwise and network meta‐analyses were conducted on 331 randomized trials with 34,285 patients. All therapies were more efficacious than care‐as‐usual and waiting list control conditions, and all therapies – except non‐directive supportive counseling and psychodynamic therapy – were more efficacious than pill placebo. Standardized mean differences compared with care‐as‐usual ranged from –0.81 for life‐review therapy to –0.32 for non‐directive supportive counseling. Individual psychotherapies did not differ significantly from each other, with the only exception of non‐directive supportive counseling, which was less efficacious than all other therapies. The results were similar when only studies with low risk of bias were included. Most therapies still had significant effects at 12‐month follow‐up compared to care‐as‐usual, and problem‐solving therapy was found to have a somewhat higher long‐term efficacy than some other therapies. No consistent differences in acceptability were found. Our conclusion is that the most important types of psychotherapy are efficacious and acceptable in the acute treatment of adult depression, with few significant differences between them. Patient preference and availability of each treatment type may play a larger role in the choice between types of psychotherapy, although it is possible that a more detailed characterization of patients with a diagnosis of depression may lead to a more precise matching between individual patients and individual psychotherapies.     

A teratocarcinoma glycoprotein carrying a developmentally regulated carbohydrate marker is a member of the immunoglobulin gene superfamily

Using the lambda gt11 expression library of murine teratocarcinoma cells, we isolated cDNA clones encoding a core protein carrying a developmentally regulated carbohydrate marker, namely the binding site for Dolichos biflorus agglutinin. The deduced amino acid sequence of the polypeptide (molecular weight, 37,102) revealed a leader sequence, nine potential asparagine glycosylation sites, and a transmembrane region. Sequence homology to variable domain of immunoglobulin kappa chain has been detected in a domain; homologous amino acids near cysteine residues are those conserved in many members of the immunoglobulin gene superfamily. In contrast to other members of the superfamily, the core protein gene was significantly expressed in embryonal carcinoma cells, which are similar to undifferentiated cells of early embryos.     

Gefitinib-sensitive EGFR lacking residues 746-750 exhibits hypophosphorylation at tyrosine residue 1045, hypoubiquitination, and impaired endocytosis

Gefitinib-sensitive nonsmall cell lung cancers (NSCLC) are characterized by somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR). The mutant EGFR forms are reported to mediate characteristic signal transduction pathways that are different from those mediated by the wild-type EGFR and are involved in transformation in vivo. We have examined signal transduction pathways initiated from a frequently identified gefitinib-sensitizing mutant EGFR lacking residues 746-750 by employing a mouse fibroblast cell line that is free of endogenous EGFR and transiently transfected COS-7 cells. Upon EGF stimulation, the deletion-mutant EGFR mediated prolonged downstream signals. The analysis of the phosphotyrosine patterns of the receptor revealed that the deletion-mutant EGFR lacked phosphorylation at tyrosine residue 1045, which is the major binding site of Cbl. The EGF-induced endocytosis of the deletion-mutant EGFR was impaired. The ubiquitination and downregulation of the deletion-mutant EGFR were also reduced. On the other hand, another mutant, EGFR, possessing a L858R substitution, exhibited phosphorylation at 1045 and its downstream signalings were not prolonged. These data suggest that the signal transduction pathways initiated from these mutant forms are different, and that impaired endocytosis might be responsible for the prolonged signals mediated by the deletion-mutant EGFR.     

<Emphasis Type="Italic">Chlamydia pneumoniae</Emphasis> aggravates vein graft intimal hyperplasia in a rat model

Background  

Along with angioplasty, autologus vein grafts are commonly used for artery bypass grafting in patients with advanced arterial stenosis and drug-resistant angina pectoris. Although initially a successful procedure, long-term functionality is limited due to proliferation and migration of smooth muscle cells. Like in atherosclerosis, common chronic infections caused by viruses and bacteria may contribute to this process of vein graft failure. Here we investigated the possible role of Chlamydia pneumoniae (Cpn) in the pathogenesis of venous graft failure in an experimental animal model. In 2 groups (n = 10 rats/group), an epigastric vein-to-common femoral artery interposition graft was placed. Immediately thereafter, rats were infected with Cpn (5*10⁸ IFU) or injected with control solutions. Rats were sacrificed three weeks after surgery and the grafts were harvested for morphometrical and immunohistochemical analysis.     

Amelioration of type II diabetes in db/db mice by continuous low-dose-rate gamma irradiation

Low-dose-rate radiation modulates various biological responses including carcinogenesis, immunological responses and diabetes. We found that continuous irradiation with low-dose-rate gamma rays ameliorated type II diabetes in db/db mice, diabetic mice that lack leptin receptors. Whole-body exposure of db/db mice to low dose-rate gamma radiation improved glucose clearance without affecting the response to insulin. Histological studies suggested that degeneration of pancreatic islets was significantly suppressed by the radiation. Insulin secretion in response to glucose loading was increased significantly in the irradiated mice. These results suggest that low-dose-rate gamma radiation ameliorates type II diabetes by maintaining insulin secretion, which gradually decreases during the progression of diabetes due to degeneration of pancreatic islets. We also inferred that protection from oxidative damage is involved in the anti-diabetic effect of low-dose-rate gamma rays because expression and activity of pancreatic superoxide dismutase were significantly elevated by low-dose-rate gamma radiation.     

Cell surface colony-stimulating factor 1 can be cleaved by TNF-alpha converting enzyme or endocytosed in a clathrin-dependent manner

CSF-1 is a hemopoietic growth factor, which plays an essential role in macrophage and osteoclast development. Alternative splice variants of CSF-1 are synthesized as soluble or membrane-anchored molecules, although membrane CSF-1 (mCSF-1) can be cleaved from the cell membrane to become soluble CSF-1. The activities involved in this proteolytic processing, also referred to as ectodomain shedding, remain poorly characterized. In the present study, we examined the properties of the mCSF-1 sheddase in cell-based assays. Shedding of mCSF-1 was up-regulated by phorbol ester treatment and was inhibited by the metalloprotease inhibitors GM6001 and tissue inhibitor of metalloproteases 3. Moreover, the stimulated shedding of mCSF-1 was abrogated in fibroblasts lacking the TNF-alpha converting enzyme (TACE, also known as a disintegrin and metalloprotease 17) and was rescued by expression of wild-type TACE in these cells, strongly suggesting that the stimulated shedding is TACE dependent. Additionally, we observed that mCSF-1 is predominantly localized to intracellular membrane compartments and is efficiently internalized in a clathrin-dependent manner. These results indicate that the local availability of mCSF-1 is actively regulated by ectodomain shedding and endocytosis. This mechanism may have important implications for the development and survival of monocyte lineage cells.     

Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons

Rapid modulation of hippocampal synaptic plasticity by estrogen has long been a hot topic, but analysis of molecular mechanisms via synaptic estrogen receptors has been seriously difficult. Here, two types of independent synaptic plasticity, long-term depression (LTD) and spinogenesis, were investigated, in response to 17beta-estradiol and agonists of estrogen receptors using hippocampal slices from adult male rats. Multi-electrode investigations demonstrated that estradiol rapidly enhanced LTD not only in CA1 but also in CA3 and dentate gyrus. Dendritic spine morphology analysis demonstrated that the density of thin type spines was selectively increased in CA1 pyramidal neurons within 2 h after application of 1 nm estradiol. This enhancement of spinogenesis was completely suppressed by mitogen-activated protein (MAP) kinase inhibitor. Only the estrogen receptor (ER) alpha agonist, (propyl-pyrazole-trinyl)tris-phenol (PPT), induced the same enhancing effect as estradiol on both LTD and spinogenesis in the CA1. The ERbeta agonist, (4-hydroxyphenyl)-propionitrile (DPN), suppressed LTD and did not affect spinogenesis. Because the mode of synaptic modulations by estradiol was mostly the same as that by the ERalpha agonist, a search was made for synaptic ERalpha using purified RC-19 antibody qualified using ERalpha knockout (KO) mice. Localization of ERalpha in spines of principal glutamatergic neurons was demonstrated using immunogold electron microscopy and immunohistochemistry. ERalpha was also located in nuclei, cytoplasm and presynapses.     

Expression and sub-cellular localization of human ABH family molecules

AlkB is an Escherichia coli protein that catalyses the oxidative demethylation of 1-methyladenine and 3-methylcytosine in DNA and RNA. The enzyme activity of AlkB is dependent on a 2-oxoglutarate- and Fe(II)-dependent (2OG-Fe[II]) oxygenase domain. Human AlkB homologues (hABH), hABH1, hABH2 and hABH3, which also possess the 2OG-Fe(II) oxygenase domain, have previously been identified. Recent bioinformatics analysis suggests the existence of an additional five ABH genes in humans. In this study, we identified the hABH4-hABH7 mRNAs and determined their expression in human tissues. Moreover, an hABH2 splice variant lacking the 2OG-Fe(II) oxygenase domain and a new gene, hABH8, were cloned from testis cDNA. hABH8 possesses not only the 2OG-Fe(II) oxygenase domain but both an RNA-binding motif and a methyl-transferase domain. mRNA of the eight hABH molecules was detected in the 16 normal human tissues examined. The sub-cellular localization of EmGFP-hABH8 was restricted to the cytoplasm. EmGFP-hABH1, 3, 4, 6 and 7 were localized in both the cytoplasm and nuclei. Interestingly, the EmGFP-hABH2 splice variant localized in nucleoplasm with a dot-like pattern. In some HeLa cells transfected with EmGFP-hABH5, dot-like fluorescence was also detected in the cytoplasm. These observations provide important information for the future annotation of the hABH family of molecules.