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.     

Familial reciprocal translocation t(9;13)(p11;p12) investigated by silver staining and in situ hybridisation

Summary A maternal de novo reciprocal translocation between the short arms of chromosomes 9 and 13 is reported. Using C-, Q- or G-banding, it was not possible to determine the precise breakpoint on 13, but a combination of silver staining and in situ hybridisation was used to do so on the two chromosomes, and it was demonstrated that the break on chromosome 13 had occurred within the NOR.     

The effectiveness of flower strips and hedgerows on pest control,pollination services and crop yield: a quantitative synthesis

Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control (18 studies) and pollination services (17 studies) in adjacent crops in North America, Europe and New Zealand. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimise floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future.     

One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic—Lasalocid acid

Seven Mannich base derivatives of polyether antibiotic Lasalocid acid (2a–2g) were synthesized and screened for their antiproliferative activity against various human cancer cell lines. A novel chemoselective one-pot synthesis of these Mannich bases was developed. Compounds 2a–2c and 2g with sterically smaller dialkylamine substituent, displayed potent antiproliferative activity (IC₅₀: 3.2–7.3 μM), and demonstrated higher than twofold selectivity for specific type of cancer. The nature of Mannich base substituent on C-2 atom at the aromatic ring may be critical in the search for selectivity towards a particular cancer cell.     

13C-NMR study of 4-azasteroids in solution and solid state

A group of biologically active 4-azasteroids was studied by 13C-NMR spectroscopy in solution and in the solid phase. A full assignment of signals in the spectra of samples in chloroform was performed for thirteen 4-azasteroids using two-dimensional techniques. Substituent and steric effects of a nitrogen atom, and their influence on chemical shifts of the neighboring carbon atoms are discussed. CP MAS spectra were obtained for five 4-azasteroids including finasteride. The spectra confirmed polymorphism of the latter compound. In addition to the polymorphic forms that are already known, a new molecular complex of finasteride with dioxane is reported.     

Patterns of meiotic recombination in human fetal oocytes

Abnormal patterns of meiotic recombination (i.e., crossing-over) are believed to increase the risk of chromosome nondisjunction in human oocytes. To date, information on recombination has been obtained using indirect, genetic methods. Here we use an immunocytological approach, based on detection of foci of a DNA mismatch-repair protein, MLH1, on synaptonemal complexes at prophase I of meiosis, to provide the first direct estimate of the frequency of meiotic recombination in human oocytes. At pachytene, the stage of maximum homologous chromosome pairing, we found a mean of 70.3 foci (i.e., crossovers) per oocyte, with considerable intercell variability (range 48-102 foci). This mean equates to a genetic-map length of 3,515 cM. The numbers and positions of foci were determined for chromosomes 21, 18, 13, and X. These chromosomes yielded means of 1.23 foci (61.5 cM), 2.36 foci (118 cM), 2.5 foci (125 cM), and 3.22 foci (161 cM), respectively. The foci were almost invariably located interstitially and were only occasionally located close to chromosome ends. These data confirm the large difference, in recombination frequency, between human oocytes and spermatocytes and demonstrate a clear intersex variation in distribution of crossovers. In a few cells, chromosomes 21 and 18 did not have any foci (i.e., were presumptively noncrossover); however, configurations that lacked foci were not observed for chromosomes 13 and X. For the latter two chromosome pairs, the only instances of absence of foci were observed in abnormal cells that showed chromosome-pairing errors affecting these chromosomes. We speculate that these abnormal fetal oocytes may be the source of the nonrecombinant chromosomes 13 and X suggested, by genetic studies, to be associated with maternally derived chromosome nondisjunction.     

The effect of inorganic phosphate on the activity of bacterial ribokinase

Ribokinase and adenosine kinase are both members of the PfkB family of carbohydrate kinases. The activity of mammalian adenosine kinase was previously shown to be affected by pentavalent ions (PVI). We now present evidence that the catalytic activity of E. coli ribokinase is also affected by PVI, increasing both the velocity and affinity of the enzyme for d-ribose. The K_m for ribose decreased from 0.61 mM to 0.21, 0.25, and 0.33 mM in the presence of 20 mM phosphate, arsenate, and vanadate, respectively. The activity of ribokinase was stimulated in a hyperbolic fashion, with the maximum velocity increasing 23-fold, 13-fold, and 11-fold under the same conditions, respectively. Activity was also affected upon the addition of phosphoenolpyruvate, suggesting that phosphorylated metabolites could be involved in enzymatic control. The similar effect of PVI on distantly related enzymes suggests that a common mechanism for activity is shared among PfkB family members.     

Inhibitory action of microwave radiation on gamma-glutamyl transpeptidase activity in liver of rats treated with hydrocortisone

The influence of microwave irradiation on the activity of gamma-glutamyl transpeptidase (GGT) induced by hydrocortisone (HC) in the liver of rats was investigated. Animals were subjected to microwave irradiation (frequency 53.57 GHz, power density 10 mW/cm2 and 1 mW/cm2) during and after hydrocortisone (HC) treatment (20 mg/kg for 60 days). The results indicate that microwave radiation may block an inducible effect of HC on GGT activity in the liver of rats. This effect depends on the power density of millimetre microwaves.