The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf⁺/⁻ heterozygous null mice

Accumulating evidence suggests that biogenic amine-based antidepressants act, at least in part, via regulation of brain-derived neurotrophic factor (BDNF) signaling. Biogenic amine-based antidepressants increase BDNF synthesis and activate its signaling pathway through TrkB receptors. Moreover, the antidepressant-like effects of these molecules are abolished in BDNF deficient mice. Glutamate-based drugs, including the NMDA antagonist ketamine, and the AMPA receptor potentiator LY 451646, mimic the effects of antidepressants in preclinical tests with high predictive validity. In humans, a single intravenous dose of ketamine produces an antidepressant effect that is rapid, robust and persistent. In this study, we examined the role of BDNF in expression of the antidepressant-like effects of ketamine and an AMPA receptor potentiator (LY 451646) in the forced swim test (FST). Ketamine and LY 451646 produced antidepressant-like effects in the FST in mice at 45 min after a single injection, but no effects were observed one week after a single ketamine injection. As previously reported, the effects of imipramine in the forced swim test were blunted in heterozygous BDNF knockout (bdnf(+/-)) mice. However ketamine and LY 451646 produced similar antidepressant-like responses in wildtype and bdnf(+/-) mice. Neither ketamine nor LY 451646 significantly influenced the levels BDNF or TrkB phosphorylation in the hippocampus when assessed at 45 min or 7 days after the drug administration. These data demonstrate that under the conditions tested, neither ketamine nor the AMPA-potentiator LY 451656 activate BDNF signaling, but produce a characteristic antidepressant-like response in heterozygous bdnf(+/-) mice. These data indicate that unlike biogenic amine-based agents, BDNF signaling does not play a pivotal role in the antidepressant effects of glutamate-based compounds. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Potential of the gastric motility drug lorglumide in prostate cancer imaging

The use of tissue-specific receptor ligands is a promising approach for cancer diagnostics and therapy. Lorglumide, a highly effective competitive ligand for the cholecystokinine-A receptor (CCKRA) was conjugated to a fluorescent dye and a magnetic resonance imaging (MRI) contrast agent to obtain a bifunctional marker for tissue with high CCKRA expression. An intermediate conjugate containing only lorglumide and a fluorescent dye was also produced. By performing CCKRA mRNA expression analysis on carcinoma cell lines we found that CCKRA is highly expressed in PC3 prostate carcinoma cells compared to U373 glioma and U2OS osteosarcoma cells. Uptake, specificity and detection sensitivity of both lorglumide conjugates was evaluated by confocal laser scanning microscopy, fluorescence activated cell sorting (FACS) and magnetic resonance relaxometry. While the conjugate containing only lorglumide and rhodamine isothiocyanate as fluorescent dye showed clearly higher uptake than the bifunctional conjugate in FACS analysis, both conjugates clearly showed preferential staining of the PC3 prostate carcinoma cells. Magnetic resonance relaxometry experiments with the bifunctional conjugate containing the MRI contrast agent gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid confirmed the higher PC3-affinity of the lorglumide ligand. Confocal laser scanning microscopy images of PC3/U2OS mixed cell cultures incubated with the bifunctional conjugate also clearly showed PC3 preference and cytoplasmic dot-like staining concurring with uptake by receptor binding and subsequent receptor internalization. Considering these results, CCKRA ligands like lorglumide could play a role in the future design of prostate-cancer-specific markers.     

Magnetic resonance imaging findings in patients with systemic scleroderma and musculoskeletal symptoms

Objective

To explore the role of whole-body magnetic resonance imaging (MRI) in detecting musculoskeletal involvement in patients with systemic scleroderma and musculoskeletal symptoms.

Methods

Eighteen consecutive patients (8 men, 10 women) with systemic scleroderma (median age 46 years) presenting with musculoskeletal complaints underwent whole-body MRI at 1.5 T. Images were evaluated for abnormal signal intensity and/or thickening of subcutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity and articular or tendon sheath synovial abnormalities on STIR and post-gadolinium scans. Additionally, C-reactive protein, creatinine kinase and the modified Rodnan skin score were determined.

Results

MRI indicated evidence of fasciitis, articular synovial inflammation, and subcutaneous thickening in 16 (89 %) patients. MRI findings were compatible with myopathy or myositis in 14 (78 %) patients, tenosynovitis in 11 (61 %) patients and enthesitis in 10 (56 %) patients. Typically, these manifestations were distributed symmetrically and mostly generalised. We only found few correlations with modified Rodnan skin score, C-reactive protein and creatinine kinase.

Conclusion

In patients with systemic scleroderma experiencing musculoskeletal symptoms, whole-body MRI is able to detect involvement of muscles, fasciae, joints and entheses more confidently compared with clinical and laboratory parameters.

Key Points

? Whole-body MRI reliably detects musculoskeletal involvement in patients with systemic scleroderma. ? Abnormal MRI findings are frequently seen in patients with symptomatic systemic scleroderma. ? Musculoskeletal MRI findings correlate only in part with the clinical score and laboratory biomarkers. ? Early detection of musculoskeletal abnormalities by MRI may improve the staging.     

Diffuse alveolar hemorrhage in patients with hematological malignancies: HRCT patterns of pulmonary involvement and disease course

ObjectiveTo analyze high-resolution computed tomography (HRCT) patterns of lung involvement and disease course in patients with hematological malignancies experiencing diffuse alveolar hemorrhage (DAH) after chemotherapy ±allogeneic stem cell transplantation (allo-SCT).Materials and methodsSixteen patients experiencing DAH after chemotherapy±allo-SCT were enrolled. A total of 74 computed tomography (CT) scans obtained before, during, and after onset of DAH were evaluated retrospectively.ResultsCT features of DAH are each, by oneself, nonspecific. However, conjoint bilateral, diffuse, and dependent ground glass opacity±crazy paving, accompanied by airspace bronchograms, should suggest this complication. The HRCT course comprises a wide range of trends that are not predictive for patient's outcome, but progression of parenchymal consolidations at follow up was more often detrimental.     

In situ eosinophil activation in 26 primary cutaneous T-cell lymphomas with blood eosinophilia

Blood and tissue eosinophils can be associated with Hodgkin and non-Hodgkin lymphomas in that they have prognostic value. Tissue eosinophils in T-cell lymphoma patients with blood eosinophilia have not been systematically assessed. The objective of this research was to study the presence, density, and activation of tissue eosinophils in patients with primary cutaneous T-cell lymphomas (CTCLs) with blood eosinophilia and a possible relationship between features of the disease and prognosis. With skin biopsy specimens from 26 CTCL patients with blood eosinophilia, tissue eosinophils were studied with electron microscopy, extracellular eosinophil peroxidase deposits, and interleukin-5 expression. Tissue eosinophils, found in 22 of 26 cases, were constantly activated. Both density and activation of tissue eosinophils were significantly related to disease progression. The state of activation of tissue eosinophils in CTCL might reflect inflammatory flare-ups associated with aggressive lymphomas. Further studies are needed to confirm the value of eosinophil density as a simple and reliable marker of CTCL progression.     

The role of the pedicle omental flap in ruptured abdominal aortic aneurysm: a case report and literature review

A ruptured infrarenal abdominal aortic aneurysm (rAAA) is associated with an in-hospital mortality rate of 40% and an overall mortality rate of 60–80%. Open surgical repair for rAAA remains the principal method of treatment when endovascular repair is not available. Graft infection occurs in 1–4% of patients at 5 years, with a high incidence following emergency treatment. Other graft-related complications include pseudoaneurysm, graft occlusion and aorto-enteric fistula. This case report describes a 66-year-old male patient that was admitted to hospital complaining of intense abdominal pain, low blood pressure and tachycardia. He was diagnosed with a rAAA and treated using segmental resection of the abdominal aorta followed by reconstruction with a synthetic Dacron prosthesis. A pedicle omental flap was wrapped around the prosthetic graft and it was also used to fill the retroperitoneal cavity in order to reduce the risk of graft-related complications. Computed tomography angiography after 6 months showed good integration of the aortic prosthetic graft and the viability of the omental flap. In our opinion, vascular surgeons should consider the pedicle omental flap when they perform open surgical repair for rAAA in order to reduce the incidence of graft-related complications.     

Allergic contact dermatitis following exposure to essential oils

Allergic contact dermatitis from the topical use of essential oils is not widely recognized as an occupational hazard. Four cases of allergic contact dermatitis to essential oils occurring in three aromatherapists and one chemist with a particular interest in aromatherapy are described. All presented with predominantly hand dermatitis and demonstrated sensitization to multiple essential oils. One patient developed a recurrence of cutaneous symptoms following ingestion of lemongrass tea. Workers within this industry should be aware of the sensitization potential of these products and the risk of limiting their ability to continue employment.     

Evolution and genomic signatures of spontaneous somatic mutation in Drosophila intestinal stem cells

Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. Although large-scale sequencing projects have illuminated processes that influence somatic mutation and subsequent tumor evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. To explore mutational processes in the early stages of cancer evolution, we exploited neoplasia arising spontaneously in the Drosophila intestine. Analysing whole-genome sequencing data with a dedicated bioinformatic pipeline, we found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. The genome-wide mutational burden in neoplasia was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation, and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short timescale in the genetic model system, Drosophila melanogaster.

The accumulation of mutations in somatic tissues plays a major role in cancer and is proposed to contribute to aging (Al Zouabi and Bardin 2020). Although the majority of mutations acquired throughout life are harmless, some alter cellular fitness and become subject to the selective forces operative in cells and tissues. Mutations that confer a selective advantage can lead to the formation of a clonal population of mutant cells under positive selection. Such events, termed driver mutations, underscore cancer formation and, as such, have been the subject of extensive investigation (Bailey et al. 2018; Alexandrov et al. 2020; Rheinbay et al. 2020; The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium 2020). These initiating mutations are thought to arise in normal cells and can therefore provide key insights into the mutational processes at play in precancerous states. Large-scale sequencing projects have detailed the mutational burdens of human cancer genomes and have revealed the repertoire of somatic mutations driving cancer formation, illuminating the biological processes underlying somatic mutation. Cancer genomes, however, represent the end-point of a long evolutionary process that shapes the mutational landscape of tumors. Similarly, the mutations recently described to arise in aged normal cells and early-stage cancers represent the result of many years of selective pressure and mutational dynamics (Martincorena et al. 2015, 2018; Lee-Six et al. 2019; Moore et al. 2020; Yokoyama et al. 2019). Knowledge of mutational processes operative in the very earliest stages of cancer is therefore currently incomplete.Our previous work has established the Drosophila midgut as an excellent model system for understanding somatic mutation in an adult tissue-specific stem cell population (Siudeja et al. 2015). In this tissue, intestinal stem cells (ISCs) self-renew and divide to give rise to two differentiated cell types: absorptive enterocytes (ECs) and secretory enteroendocrine cells (EEs) (Micchelli and Perrimon 2006; Ohlstein and Spradling 2006). We have previously shown that during aging, 12% of wild-type male flies harbor spontaneous mutations that inactivate the X-linked tumor-suppressor gene Notch, driving hyperproliferation of ISCs and EEs and resulting in neoplasm formation (Siudeja et al. 2015).Here, we take advantage of the spontaneous formation of neoplasia in the intestine of the fruit fly to investigate the processes underlying early somatic mutation and evolution within a clonal cell population.