Analysis of region-specific changes in gene expression upon treatment with citalopram and desipramine reveals temporal dynamics in response to antidepressant drugs at the transcriptome level

RATIONALE: The notion that the onset of action of antidepressant drugs (ADs) takes weeks is widely accepted; however, the sequence of events necessary for therapeutic effects still remains obscure. OBJECTIVE: We aimed to evaluate a time-course of ADs-induced alterations in the expression of 95 selected genes in 4 regions of the rat brain: the prefrontal and cingulate cortices, the dentate gyrus of the hippocampus, and the amygdala. METHODS: We employed RT-PCR array to evaluate changes during a time-course (1, 3, 7, 14, and 21 days) of treatments with desipramine (DMI) and citalopram (CIT). In addition to repeated treatment, we also conducted acute treatment (a single dose of drug followed by the same time intervals as the repeated doses). RESULTS: Time-dependent and structure-specific changes in gene expression patterns allowed us to identify spatiotemporal differences in the molecular action of two ADs. Singular value decomposition analysis revealed differences in the global gene expression profiles between treatment types. The numbers of characteristic modes were generally smaller after CIT treatment than after DMI treatment. Analysis of the dynamics of gene expression revealed that the most significant changes concerned immediate early genes, whose expression was also visualized by in situ hybridization. Transcription factor binding site analysis revealed an over-representation of serum response factor binding sites in the promoters of genes that changed upon treatment with both ADs. CONCLUSIONS: The observed gene expression patterns were highly dynamic, with oscillations and peaks at various time points of treatment. Our study also revealed novel potential targets of antidepressant action, i.e., Dbp and Id1 genes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-012-2714-0) contains supplementary material, which is available to authorized users

Chronic mild stress alters the somatostatin receptors in the rat brain

RATIONALE: The involvement of somatostatin (SST) and its receptors in the pathophysiology of depression and stress has been evidenced by numerous studies. OBJECTIVES: The purpose of the present study was to find whether chronic mild stress (CMS), an animal model of depression, affects the SST receptors in the rat brain and pituitary, as well as the level of SST in plasma. METHODS: In CMS model, rats were subjected to 2 weeks of stress and behaviorally characterized using the sucrose consumption test into differently reacting groups based on their response to stress, i.e., stress-reactive (anhedonic), stress-non-reactive (resilient), and invert-reactive rats (characterized by excessive sucrose intake). We measured specific binding of [(125)I]Tyr(3)-Octreotide, expression of mRNA encoding sst2R receptors in the rat brains, expression of SST and its receptors in rat pituitary, and the level of SST in the plasma. RESULTS: The obtained results show decreases in binding of [(125)I]Tyr(3)-Octreotide in most of rat brain regions upon CMS and no significant differences between three stressed groups of animals, except for significant up-regulation of sst2 receptor in medial habenula (MHb) in the stress-reactive group. In the same group of animals, significant increase in plasma SST level was observed. CONCLUSIONS: There are two particularly sensitive sites distinguishing the response to stress in CMS model. In the brain, it is MHb, while on the periphery this predictor is SST level in plasma. These changes may broaden an understanding of the mechanisms involved in the stress response and point to the intriguing role of MHb

Laurentide ice-sheet instability during the last deglaciation

Changes in the amount of summer incoming solar radiation (insolation) reaching the Northern Hemisphere are the underlying pacemaker of glacial cycles. However, not all rises in boreal summer insolation over the past 800,000 years resulted in deglaciation to present-day ice volumes, suggesting that there may be a climatic threshold for the disappearance of land-based ice. Here we assess the surface mass balance stability of the Laurentide ice sheet—the largest glacial ice mass in the Northern Hemisphere—during the last deglaciation (24,000 to 9,000 years ago). We run a surface energy balance model with climate data from simulations with a fully coupled atmosphere–ocean general circulation model for key time slices during the last deglaciation. We find that the surface mass balance of the Laurentide ice sheet was positive throughout much of the deglaciation, and suggest that dynamic discharge was mainly responsible for mass loss during this time. Total surface mass balance became negative only in the early Holocene, indicating the transition to a new state where ice loss occurred primarily by surface ablation. We conclude that the Laurentide ice sheet remained a viable ice sheet before the Holocene and began to fully deglaciate only once summer temperatures and radiative forcing over the ice sheet increased by 6–7 °C and 16–20 W m⁻², respectively, relative to full glacial conditions

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p>0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5 ng/ml compared to 13.7±1.6 ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8 ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis

Earliest Holocene south Greenland ice sheet retreat within its late Holocene extent

Early Holocene summer warmth drove dramatic Greenland ice sheet (GIS) retreat. Subsequent insolation-driven cooling caused GIS margin readvance to late Holocene maxima, from which ice margins are now retreating. We use ¹⁰Be surface exposure ages from four locations between 69.4°N and 61.2°N to date when in the early Holocene south to west GIS margins retreated to within these late Holocene maximum extents. We find that this occurred at 11.1 ± 0.2 ka to 10.6 ± 0.5 ka in south Greenland, significantly earlier than previous estimates, and 6.8 ± 0.1 ka to 7.9 ± 0.1 ka in southwest to west Greenland, consistent with existing ¹⁰Be ages. At least in south Greenland, these ¹⁰Be ages likely provide a minimum constraint for when on a multicentury timescale summer temperatures after the last deglaciation warmed above late Holocene temperatures in the early Holocene. Current south Greenland ice margin retreat suggests that south Greenland may have now warmed to or above earliest Holocene summer temperatures.Keywords: Early Holocene climate, Greenland ice sheet, Cosmogenic datin

Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated In Vitro in cell cultures.

Purpose CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15. Methods Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2–10. Results This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a ‘classical’ tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton. Conclusion Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening

Individual participant data network meta-analysis of neoadjuvant chemotherapy or chemoradiotherapy in esophageal or gastroesophageal junction carcinoma

PURPOSEThe optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups.PATIENTS AND METHODSAll, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158).RESULTSIPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively).CONCLUSIONNeoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.Cellular mechanisms in basic and clinical gastroenterology and hepatolog