Frontal haemodynamic responses in depression and the effect of electroconvulsive therapy

BACKGROUND: Reduced frontal cortex metabolism and blood flow in depression may be associated with low mood and cognitive impairment. Further reduction has been reported during a course of electroconvulsive therapy but it is not known if this relates to mood and cognitive changes caused by electroconvulsive therapy. // AIMS: The purpose of this study was to investigate frontal function while undertaking cognitive tasks in depressed patients compared with healthy controls, and following electroconvulsive therapy in patients. // METHODS: We measured frontal haemodynamic responses to a category verbal fluency task and a working memory N-back task using portable functional near infra-red spectroscopy (fNIRS) in 51 healthy controls and 18 severely depressed patients, 12 of whom were retested after the fourth treatment of a course of electroconvulsive therapy. Mood was assessed using the Montgomery Åsberg Depression Rating Scale and cognitive function using category Verbal Fluency from the Controlled Oral Word Association Test and Digit Span backwards. // RESULTS: Compared to healthy controls, depressed patients had bilaterally lower frontal oxyhaemoglobin responses to the cognitive tasks, although this was only significant for the N-Back task where performance correlated inversely with depression severity in patients. After four electroconvulsive therapy treatments oxyhaemoglobin responses were further reduced during the Verbal Fluency task but the changes did not correlate with mood or cognitive changes. // DISCUSSION: Our results confirmed a now extensive literature showing impaired frontal fNIRS oxyhaemoglobin responses to cognitive tasks in depression, and showed for the first time that these are further reduced during a course of electroconvulsive therapy. Further research is needed to investigate the biology and clinical utility of frontal fNIRS in psychiatric patients

Identifying the nature of episodic memory deficits in Major Depressive Disorder using a Real-World What-Where-When task

Deficits in episodic memory have been reported in various psychiatric conditions, including Major Depressive Disorder (MDD). Many widely used episodic memory tests do not have the ability to distinguish between impaired memory of separate components of a real-life event (e.g. what happened, where it happened and when), and impaired binding of such real-life features. To address this issue, a naturalistic, real-world What-Where-When memory task was employed to assess the nature of episodic memory impairments in MDD. A validation study established that the task is sensitive to age-related episodic memory changes, and that intentional encoding does not invalidate the task. The main study then compared the performance of patients with depression and control participants on the intentionally encoded WWW task. Patients with MDD presented an overall episodic memory impairment arising from deficits in object memory and the ability to bind objects to temporal context. Taken together, our study confirms the episodic memory impairment in MDD, by providing evidence of deficient object memory and reduced ability to bind temporal context to objects in patients. Our naturalistic WWW task presents a promising approach for thorough identification of the nature of episodic memory impairments, under a real-world environment, in various conditions, including MDD

D-brane potentials in the warped resolved conifold and natural inflation

In this paper we obtain a model of Natural Inflation from string theory with a Planckian decay constant. We investigate D-brane dynamics in the background of the warped resolved conifold (WRC) throat approximation of Type IIB string compactifications on Calabi-Yau manifolds. When we glue the throat to a compact bulk Calabi-Yau, we generate a D-brane potential which is a solution to the Laplace equation on the resolved conifold. We can exactly solve this equation, including dependence on the angular coordinates. The solutions are valid down to the tip of the resolved conifold, which is not the case for the more commonly used deformed conifold. This allows us to exploit the effect of the warping, which is strongest at the tip. We inflate near the tip using an angular coordinate of a D5-brane in the WRC which has a discrete shift symmetry, and feels a cosine potential, giving us a model of Natural Inflation, from which it is possible to get a Planckian decay constant whilst maintaining control over the backreaction. This is because the decay constant for a wrapped brane contains powers of the warp factor, and so can be made large, while the wrapping parameter can be kept small enough so that backreaction is under control.Comment: 41 pages, 3 appendices, 1 figure, PDFLaTex; various clarifications added along with a new appendix on b-axions and wrapped D5 branes;version matches the one published in JHE

A Terminal Velocity on the Landscape: Particle Production near Extra Species Loci in Higher Dimensions

We investigate particle production near extra species loci (ESL) in a higher dimensional field space and derive a speed limit in moduli space at weak coupling. This terminal velocity is set by the characteristic ESL-separation and the coupling of the extra degrees of freedom to the moduli, but it is independent of the moduli's potential if the dimensionality of the field space is considerably larger than the dimensionality of the loci, D >> d. Once the terminal velocity is approached, particles are produced at a plethora of nearby ESLs, preventing a further increase in speed via their backreaction. It is possible to drive inflation at the terminal velocity, providing a generalization of trapped inflation with attractive features: we find that more than sixty e-folds of inflation for sub-Planckian excursions in field space are possible if ESLs are ubiquitous, without fine tuning of initial conditions and less tuned potentials. We construct a simple, observationally viable model with a slightly red scalar power-spectrum and suppressed gravitational waves; we comment on the presence of additional observational signatures originating from IR-cascading and individual massive particles. We also show that moduli-trapping at an ESL is suppressed for D >> d, hindering dynamical selection of high-symmetry vacua on the landscape based on this mechanism.Comment: 46 pages, 6 figures. V3: typos corrected compared to JHEP version, conclusions unchange

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

Purpose The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. Methods 3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. Results Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. Conclusions 3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery. KEY WORDS transdermal drug delivery. microneedles. intradermal. hollow microstructures. MT

MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer

Cell–cell adhesions constitute the structural “glue” that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell–cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell–cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER−/PR− breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell–cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease-specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER−/PR− breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype

Estrogen aggravates inflammation in Pseudomonas aeruginosa pneumonia in cystic fibrosis mice

<p>Abstract</p> <p>Background</p> <p>Among patients with cystic fibrosis (CF), females have worse pulmonary function and survival than males, primarily due to chronic lung inflammation and infection with <it>Pseudomonas aeruginosa </it>(<it>P. aeruginosa</it>). A role for gender hormones in the causation of the CF "gender gap" has been proposed. The female gender hormone 17β-estradiol (E2) plays a complex immunomodulatory role in humans and in animal models of disease, suppressing inflammation in some situations while enhancing it in others. Helper T-cells were long thought to belong exclusively to either T helper type 1 (Th1) or type 2 (Th2) lineages. However, a distinct lineage named Th17 is now recognized that is induced by interleukin (IL)-23 to produce IL-17 and other pro-inflammatory Th17 effector molecules. Recent evidence suggests a central role for the IL-23/IL-17 pathway in the pathogenesis of CF lung inflammation. We used a mouse model to test the hypothesis that E2 aggravates the CF lung inflammation that occurs in response to airway infection with <it>P. aeruginosa </it>by a Th17-mediated mechanism.</p> <p>Results</p> <p>Exogenous E2 caused adult male CF mice with pneumonia due to a mucoid CF clinical isolate, the <it>P. aeruginosa </it>strain PA508 (PA508), to develop more severe manifestations of inflammation in both lung tissue and in bronchial alveolar lavage (BAL) fluid, with increased total white blood cell counts and differential and absolute cell counts of polymorphonuclear leukocytes (neutrophils). Inflammatory infiltrates and mucin production were increased on histology. Increased lung tissue mRNA levels for IL-23 and IL-17 were accompanied by elevated protein levels of Th17-associated pro-inflammatory mediators in BAL fluid. The burden of PA508 bacteria was increased in lung tissue homogenate and in BAL fluid, and there was a virtual elimination in lung tissue of mRNA for lactoferrin, an antimicrobial peptide active against <it>P. aeruginosa </it>in vitro.</p> <p>Conclusions</p> <p>Our data show that E2 increases the severity of PA508 pneumonia in adult CF male mice, and suggest two potential mechanisms: enhancement of Th17-regulated inflammation and suppression of innate antibacterial defences. Although this animal model does not recapitulate all aspects of human CF lung disease, our present findings argue for further investigation of the effects of E2 on inflammation and infection with <it>P. aeruginosa </it>in the CF lung.</p