Treatment-resistant depression: definition,prevalence, detection,management, and investigational interventions

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.     

CYTOCHEMICAL STUDIES OF MITOCHONDRIA : I. THE SEPARATION AND IDENTIFICATION OF A MEMBRANE FRACTION FROM ISOLATED MITOCHONDRIA

Mitochondria isolated from rat liver and suspended in 0.44 M sucrose were disrupted by treatment with 0.3 per cent Na deoxycholate. The treated suspension was fractionated by differential centrifugation into a number of fractions and the respective pellets were examined in sections in the electron microscope. One of these fractions was found to consist of apparently membrane-bound (vesicular) elements. The difference between interfaces and membranes was discussed and the material of this fraction was found to meet stated requirements identifying it as membranous. A detailed study of the disruption process undergone by mitochondria in the presence of Na deoxycholate showed that the elements of this fraction were derived from structural elements assumed to be mitochondrial membranes. The findings thus demonstrate that mitochondria do possess membranes as defined and that these membranes can be isolated in a relatively pure form.     

MONOCLONAL ANTIBODIES AS MOLECULAR MARKERS FOR THE INTRACELLULAR AND CELL WALL DISTRIBUTION OF CARRAGEENAN EPITOPES IN KAPPAPHYCUS (RHODOPHYTA) DURING TISSUE DEVELOPMENT1

Carrageenan, the major cell wall carbohydrate of certain red algae, is variable in structure and gelling properties. Sequence types include gelling (kappa and iota) and nongelling (lambda) types in addition to precursors, often in hybrid molecules containing more than one precursor and/or sequence type. Molecular markers to subunits were needed to study carrageenan synthesis, cell wall organization, and the relationship between structure and function. Monoclonal antibodies were produced to carrageenan, and their specificities were determined by competitive enzyme immunoassay. Antibodies were identified with specificities related to kappa, iota, and lambda carrageenan. The patterns of immunofluorescence localization on Kappaphycus alvarezii = Eucheuma alvarezii var. tambalang (Doty) sections were distinctive for each antibody. The antibody to a kappa-related epitope labeled mature tissue strongly; antibodies to an iota-related epitope and a lambda-related epitope labeled weakly, consistent with the kappa-enriched carrageenan produced by this alga. Kappa-related epitopes were distributed throughout the wall and matrix, whereas iota-related epitopes were concentrated in the middle lamella. Lambda-related epitopes were localized primarily at the plant cuticle where kappa and iota antigens were lacking. An antibody appeared to be specific for a precursor of the gelling subunits because it showed maximal wall and intracellular labeling at the youngest developmental stage. All antibodies labeled intracellular inclusions in the transition zone between the epidermis and medulla during the development of medullary cells from the peripheral meristem in young branches. The results demonstrate the intracellular synthesis of epitopes related to all major carrageenan subunits and their differential extracellular distribution.     

Ultrastructure of the Flame Bulbs of Urastoma cyprinae (Platyhelminthes, ‘Prolecithophora’, Urastomidae)

The ultrastructure of the flame bulbs of the turbellarian Urastoma cyprinae from Mytilus galloprovincialis in the Mediterranean is described. The nucleus of the terminal cell is located some distance basal to the rootlets of the cilia forming the flame; the cytoplasm contains numerous tubules approximately 54–66 nm in diameter, and vesicles. Thick walled, densely packed rod-like structures coil around each other with a tendency towards longitudinal orientation close to the flame. The rod-like structures tightly surround the basal part of the flame and the distal cytoplasmic tube in the apical part of the flame. Some of them, including the inner predominantly longitudinally directed ones, are continuous with the cytoplasm of the terminal cell, others are continuous with the cytoplasm of the distal cytoplasmic tube. Internal leptotriches arise from the cytoplasm of the terminal cell and intrude between the basal parts of the cilia of the flame. The distal cytoplasmic tube possesses a septate junction. The flame bulb of Urastoma differs distinctly from those known from other Platyhelminthes; implications for the phylogeny of Platyhelminthes are discussed.     

Can the biotic nestedness matrix be used predictively?

The biotas of a suite of neighboring patches of remnant vegetation often form a series of nested sub-sets, in which the species present in species-poor patches are non-random sub-sets of those present in richer patches. There has been recent interest in ways in which this knowledge may be used to aid conservation. We focus here on whether nested patterns can be used predictively. If nestedness in a fragmented system increases over time through biotic relaxation, locations where particular species may become extinct or are likely to colonize might be predictable and this could be useful in threatened-species management. We used the Temperature Calculator of Atmar and Patterson (1995) to arrange a matrix of bird species' occurrences in a series of buloke Allocasuarina leuhmannii woodland remnants so that nestedness was maximized. Probability bands generated by the calculator were used to predict possible colonization and extinction events. We then re-surveyed the avifauna of the fragments after a seven-year interval to test these predictions. Although nestedness increased between the two survey periods, there was no linear relationship between the generated probability of extinctions or colonizations and the accuracy of the predictions. The predictions derived from the calculator were no more accurate than a second set of predictions generated by use of a simple non-nested model. Despite the increase in nestedness, the arrangement of sites in each of the two maximally packed matrices was substantially different. For the nestedness matrix to generate accurate predictions, an increase in nestedness must be due to a minimization of unexpected species presences and absences rather than an extensive redistribution of species among remnants, as we found. The potential utility of nested patterns in predicting systematic colonization and extinction events should be further evaluated in other, less dynamic, fragmented systems such as those undergoing biotic relaxation.     

The CD95 (Fas/APO-1) receptor is phosphorylatedin vitro andin vivo and constitutively associates with several cellular proteins

Different CD95 (Fas/APO-1) isoforms and phosphory lated CD95 species were identified in human T and B cell lines. We had shown previously that the CD95 intracellular domain (IC), expressed as a glutathione S-transferase (GST) fusion protein in murine L929 fibroblasts, was phosphorylatedin vivo. GST-CD95IC was phosphorylatedin vitro by a kinase present in extracts from the human lymphocytic cell lines Jurkat and MP-1 and from murine L929 cells. Phosphoamino acid analysis indicated that phosphorylation occurred at multiple threonine residues and also at tyrosine (Tyr232 and Tyr291) and serine. Amino acids 191 to 275 of CD95 were sufficient for phosphorylation at threonine, tyrosine and serine and also mediated interaction with a 35 kDa cellular protein. Immuno-precipitation of CD95 and chemical cross-linking revealed CD95-associated proteins of approximately 35, 45 and 75 kDa. GST-CD95IC affinity chromatography detected binding of the 35 and 75 kDa protein species. The 75 kDa species may correspond to the CD95-associated proteins RIP or FAF1 and the 35 kDa protein may represent a TRADD analogue. These data indicate that several cellular proteins interact with CD95, possibly in a multi-protein complex, and that a kinase activity is associated with CD95 not onlyin vitro but alsoin vivo. Therefore, receptor phosphorylation may play a role in CD95 signal transduction. This work was in part supported by a grant from the Health Research Council of New Zealand (to JW).     

Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.

OBJECTIVE--To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. DESIGN--Randomised controlled trial. SETTING--Specialist recurrent miscarriage clinic. SUBJECTS--106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. INTERVENTIONS--Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. MAIN OUTCOME MEASURES--Conception and live birth rates over six cycles. RESULTS--Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS--Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent.     

A Tobacco Ornithine Decarboxylase Partial cDNA Clone

A partial cDNA clone encoding ornithine decarboxylase (ODC) has been isolated and sequenced from Nicotiana tabaccum. This 961 by long cDNA contained an open reading frame in only one of the six possible frames. Sequence comparisons have shown it to be very similar with other ODCs, and most similar to that from Datura. The present sequence is a partial sequence containing only 3′ half of the cDNA.     

Phospholipases Involved in Activation of the Neutrophil NADPH Oxidase

Stimulation of neutrophils with a variety of stimuli can result in the activation of phospholipases A₂, C, or D with the resultant hydrolysis of plasma membrane phospholipids and the formation of important second messenger molecules. In the neutrophil, the activities of these phospholipases have been implicated in the processes of both stimulating and maintaining oxidase activation. In this review, some of the methods currently used to measure the products of phospholipase activation in the neutrophil are described, along with the possible role of their products in reactive oxidant production by the neutrophil NADPH oxidase.