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.     

Is predation on waterfowl nests density dependent? – Tests at three spatial scales

We tested whether predation on duck nests ( Anas spp.) was density dependent at three spatial scales using artificial and natural nests in the Suisun Marsh, California, USA. At the largest spatial scale, we used 5 years (1998–2002) of data to examine the natural variation in duck nest success and nest densities among 8–16 fields per year, each 5–33 ha in size (n=62 fields). At an intermediate spatial scale, we deployed artificial nests (2000, n=280) within 1-ha plots at three experimental densities (5, 10, and 20 nests ha⁻¹) in a complete randomized block design and examined differences in nest predation. At the smallest spatial scale, we examined nest success in relation to nearest-neighbor fates and distances for artificial (2000, n=280) and natural nests (2000, n=507). We detected no relationship between nest success and the density of natural nests among fields in any year, nor when we pooled data for all years after controlling for year effects. The proportion of artificial nests that survived also did not depend on experimental nest densities within 1-ha plots. Overall, 15.0±12.4%, 15.0±11.0%, and 6.2±4.3% of artificial nests survived the 32-day exposure period in the low, intermediate, and high nest densities, respectively. Additionally, we detected no consistent effect of nearest-neighbor fate or distance on the success of artificial or natural nests. Thus, our results provide no evidence of density-dependent predation on duck nests at any scale of analysis, in contrast to a number of previous studies. Variation among geographical locations in the degree to which predation is density-dependent may reflect the composition of the predator community and the availability of alternate prey.     

Selection of cold‐tolerant plants for growth in soils contaminated with organics

A mixture of organic chemicals (MOC) containing equal molar amounts of benzoic acid, hexadecane, 2,2‐dimethyl 4,n‐propyl‐benzene, phenanthrene, pyrene, and either cycloheptane or cis‐decahydronaphthalene (cis‐decalin) was applied to soil at rates of 0 to 8000 mg/kg. In a plant‐screening experiment, growth responses of four legume and five nonlegume species were determined at 10 and 25°C. The MOC applied at 2000 mg/kg reduced the growth of several species without resulting in significant seedling death. At 10°C, the growth of alpine bluegrass (Poa alpina L.) in the 1000 and 2000 mg/kg treatments of soil increased by more than 185%. In a plant growth response experiment, alpine bluegrass and alfalfa (Medicago sativa L.) were grown in soil that had been contaminated at rates of 0 and 2000 mg/kg. At 14 weeks, the shoot and root dry weights of alfalfa were 97% lower in the contaminated soil, while the shoot dry weight, root dry weight, and root length of alpine bluegrass were 135,235 and 268% higher, respectively. Except for pyrene, <23% of the compounds comprising the MOC remained in the soil after 4 weeks and <5% after 14 weeks. The disappearance of the MOC was not significantly influenced by the presence of alfalfa or alpine bluegrass.     

Production of superoxide dismutases from Proteus mirabilis and Proteus vulgaris

Proteus mirabilis and Proteus vulgaris expressed a combination of superoxide dismutase (Sod) activities, which was assigned to FeSod1, FeSod2 and MnSod for P. mirabilis, and FeSod, MnSod and CuZnSod for P. vulgaris. Production of the Sod proteins was dependent on the availability of iron, whether cells were grown under anaerobiosis or aerobiosis and growth phase. Nalidixic acid and chloramphenicol inhibited cell growth and the iron- and dioxygen-dependent production of Sod. These results support the involvement of metal ions and redox status in the production of Proteus Sods.     

Preparation of Insect Chromosomes for Immunolabeling

We describe a method for isolating chromosomes from testes of the desert locust, Schistocerca gregaria, and their subsequent incubation with antibodies directed against chromosomal proteins. The procedure involves hypotonic pretreatment of the germ cells, centrifugation onto coverslips in a cytocentrifuge and immunolabeling, while still unfixed, using a chromatin-stabilizing buffer. In the present case, an antibody specific for the acetylated isoforms of his tone H4 was tested. After the antibody treatment, the preparations are fixed using formaldehyde, stained with a DNA-specific fluorescent dye and mounted. Analysis of the preparations revealed good preservation of chromosome structure in prophase spermatogonia and late prophase I spermatocytes. Fully condensed chromosomes were not observed and are probably lost during preparation. The bright fluorescence of the autosomes indicates that the reaction between the antibody against acetylated histone H4 and its chromosomal antigen is not impeded. In contrast, the X univalent remained unstained with the exception of a small terminal band. Thus, cytospin preparations of locust germ cells allow high resolution immunolabeling with antibodies against chromosome-associated proteins.     

Noncancer Risk Assessment: A Probabilistic Alternative to Current Practice

Based on imperfect data and theory, agencies such as the United States Environmental Protection Agency (USEPA) currently derive “reference doses” (RfDs) to guide risk managers charged with ensuring that human exposures to chemicals are below population thresholds. The RfD for a chemical is typically reported as a single number, even though it is widely acknowledged that there are significant uncertainties inherent in the derivation of this number.

In this article, the authors propose a probabilistic alternative to the EPA's method that expresses the human population threshold as a probability distribution of values (rather than a single RfD value), taking into account the major sources of scientific uncertainty in such estimates. The approach is illustrated using much of the same data that USEPA uses to justify their current RfD procedure.

Like the EPA's approach, our approach recognizes the four key extrapolations that are necessary to define the human population threshold based on animal data: animal to human, human heterogeneity, LOAEL to NOAEL, and subchronic to chronic. Rather than using available data to define point estimates of “uncertainty factors” for these extrapolations, the proposed approach uses available data to define a probability distribution of adjustment factors. These initial characterizations of uncertainty can then be refined when more robust or specific data become available for a particular chemical or class of chemicals.

Quantitative characterization of uncertainty in noncancer risk assessment will be useful to risk managers who face complex trade-offs between control costs and protection of public health. The new approach can help decision-makers understand how much extra control cost must be expended to achieve a specified increase in confidence that the human population threshold is not being exceeded.     

Qualitative mathematical discussion of different evolutionary states in water transport systems of plants

We shall present several qualitative mathematical models to describe the early evolution of water transport systems in plants. To perform this in a systematic way we apply methods which have been developed in phenomenological synergetics. These methods rest on the fact that it becomes possible to describe the macroscopic behavior of a complex system by a set of control and order parameters when they are suitably identified. Our presentation is addressed to community with interdisciplinary interests.     

Interleukin-12 gene expression after viral infection in the mouse.

Interleukin-12 is a lymphokine that triggers gamma interferon secretion by various cells and differentiation of T-helper lymphocytes towards the Th1 subtype. Since viruses are potent inducers of gamma interferon production and elicit immune responses most probably mediated by Th1 cells, like B-cell immunoglobulin G2a secretion, we analyzed interleukin-12 message expression after infection of mice with lactate dehydrogenase-elevating virus, mouse hepatitis virus, and mouse adenovirus. Our results indicated that the message for the p40 component of interleukin-12 was transiently increased shortly after infection. Interleukin-12 was expressed mainly by macrophages. Therefore, production of interleukin-12 might constitute the initial event that would determine the subsequent characteristics of the immune response elicited by viral infections.