Clinical Impact of the Temporal Relationship between Depression and Type 2 Diabetes: The Fremantle Diabetes Study Phase II

Background

The clinical features of type 2 diabetes may differ depending on whether first depression episode precedes or follows the diagnosis of diabetes.

Methods

Type 2 patients from the observational community-based Fremantle Diabetes Study Phase II underwent assessment of lifetime depression using the Brief Lifetime Depression Scale (developed and validated for this study) supplemented by information on current depression symptoms (Patient Health Questionnaire, 9-item version) and use of antidepressants. Patients were categorized as never depressed (Group 1), having had depression before diabetes diagnosis (Group 2), diagnosed with depression and diabetes within 2 years of each other (Group 3) and having depression after diabetes diagnosis (Group 4).

Results

Of 1391 patients, 20.8% were assigned to Group 2, 6.0% to Group 3 and 14.5% to Group 4. In Group 2, depression occurred a median 15.6 years before diabetes onset at age 37.2±14.7 years. These patients had similar clinical characteristics to never depressed patients except for reduced self-care behaviours and having more symptomatic peripheral arterial disease. In Group 4, depression occurred a median 9.9 years after diabetes onset at age 59.8±13.0 years. These patients had long duration diabetes, poor glycaemic control, more intensive management and more diabetic complications. Group 4 patients had more current depression than Group 2 but were less likely to be receiving antidepressants.

Conclusions/Interpretation

The clinical features of depression and type 2 diabetes are heterogeneous depending on their temporal relationship. There may be corresponding differences in the pathogenesis of depression in diabetes that have implications for diagnosis and management.     

Intravital Video Microscopy Measurements of Retinal Blood Flow in Mice

Alterations in retinal blood flow can contribute to, or be a consequence of, ocular disease and visual dysfunction. Therefore, quantitation of altered perfusion can aid research into the mechanisms of retinal pathologies. Intravital video microscopy of fluorescent tracers can be used to measure vascular diameters and bloodstream velocities of the retinal vasculature, specifically the arterioles branching from the central retinal artery and of the venules leading into the central retinal vein. Blood flow rates can be calculated from the diameters and velocities, with the summation of arteriolar flow, and separately venular flow, providing values of total retinal blood flow. This paper and associated video describe the methods for applying this technique to mice, which includes 1) the preparation of the eye for intravital microscopy of the anesthetized animal, 2) the intravenous infusion of fluorescent microspheres to measure bloodstream velocity, 3) the intravenous infusion of a high molecular weight fluorescent dextran, to aid the microscopic visualization of the retinal microvasculature, 4) the use of a digital microscope camera to obtain videos of the perfused retina, and 5) the use of image processing software to analyze the video. The same techniques can be used for measuring retinal blood flow rates in rats.     

Two Antiproliferative Triterpene Saponins from Nematostylis anthophylla from the Highlands of Central Madagascar

Investigation of the endemic Madagascan plant Nematostylis anthophylla (Rubiaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the known triterpene saponin randianin ( 1 ), and the two new bioactive triterpene saponins 2″‐O‐acetylrandianin ( 2 ) and 6″‐O‐acetylrandianin ( 3 ). The structures of the two new compounds were elucidated based on analysis of their 1D‐ and 2D‐NMR spectra, and mass spectrometric data. The three isolated triterpene saponins displayed moderate but selective antiproliferative activities, with IC₅₀ values of 1.2, 1.7, and 2.2 μM , respectively, against the A2780 ovarian cancer, but only weak inhibitions of the proliferation of A2058 melanoma and the H522 lung cancer cell lines.     

Interferon-Inducible Mechanism of Dendritic Cell-Mediated HIV-1 Dissemination Is Dependent on Siglec-1/CD169

Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC – T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3 – CD169 interaction) for DC-dependent HIV dissemination.     

Fatal Asphyxiation in Bottlenose Dolphins (Tursiops truncatus) from the Indian River Lagoon

Multiple single case reports of asphyxiation in dolphins caused by fish lodged in the esophagus exist. However, the significance of this cause of mortality in a single population has not been documented. We performed a retrospective evaluation of pathology records from stranded bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon to evaluate the impact of this cause of death on this population. From 1997 to 2011, asphyxiation due to choking was identified as the cause of death in 14 of 350 cases (4%). Sampling of an unrelated but adjacent population over this same period yielded 186 necropsy cases of bottlenose dolphins with no cases of asphyxiation. Asphyxiated animals presented with a fish lodged in the cranial esophagus associated with a dislocated and obstructed or compressed larynx. There was no clear sex predilection. Affected animals included 12 adults and two juveniles. The fish species involved included sheepshead, black chin tilapia and striped mojarra. In five cases, recreational fishing gear was also present. Cetacean choking is related to selection of prey fish species with strong dorsal spines and may be secondarily associated with fish attached to fishing gear. Prey abundance and dolphin behavior may influence these selections. Environmental alterations leading to changes in prey availability or increased interactions with fishing gear may change the significance of fatal choking in dolphin populations.     

Etiology and Audiological Outcomes at 3 Years for 364 Children in Australia

Hearing loss is an etiologically heterogeneous trait with differences in the age of onset, severity and site of lesion. It is caused by a combination of genetic and/or environmental factors. A longitudinal study to examine the efficacy of early intervention for improving child outcomes is ongoing in Australia. To determine the cause of hearing loss in these children we undertook molecular testing of perinatal “Guthrie” blood spots of children whose hearing loss was either detected via newborn hearing screening or detected later in infancy. We analyzed the GJB2 and SLC26A4 genes for the presence of mutations, screened for the mitochondrial DNA (mtDNA) A1555G mutation, and screened for congenital CMV infection in DNA isolated from dried newborn blood spots. Results were obtained from 364 children. We established etiology for 60% of children. One or two known GJB2 mutations were present in 82 children. Twenty-four children had one or two known SLC26A4 mutations. GJB2 or SLC26A4 changes with unknown consequences on hearing were found in 32 children. The A1555G mutation was found in one child, and CMV infection was detected in 28 children. Auditory neuropathy spectrum disorder was confirmed in 26 children whose DNA evaluations were negative. A secondary objective was to investigate the relationship between etiology and audiological outcomes over the first 3 years of life. Regression analysis was used to investigate the relationship between hearing levels and etiology. Data analysis does not support the existence of differential effects of etiology on degree of hearing loss or on progressiveness of hearing loss.     

Evaluation of a Commercial Enzyme Linked Immunosorbent Assay (ELISA) for the Determination of the Neurotoxin BMAA in Surface Waters

The neurotoxin β-N-methylamino-L-alanine (BMAA) is suspected to play a role in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Because BMAA seems to be produced by cyanobacteria, surface waters are screened for BMAA. However, reliable analysis of BMAA requires specialized and expensive equipment. In 2012, a commercial enzyme-linked immunosorbent assay (ELISA) for determination of BMAA in surface waters was released. This kit could enable fast and relatively cheap screening of surface waters for BMAA. The objective of this study was to determine whether the BMAA ELISA kit was suitable for the determination of BMAA concentrations in surface waters. We hypothesised that the recovery of spiked samples was close to 100% and that the results of unspiked sample analysis were comparable between ELISA and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. However, we found that recovery was higher than 100% in most spiked samples, highest determined recovery was over 400%. Furthermore, the ELISA gave a positive signal for nearly each tested sample while no BMAA could be detected by LC-MS/MS. We therefore conclude that in its current state, the kit is not suitable for screening surface waters for BMAA.     

Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano- and micron-sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid

Background

Superparamagnetic iron-oxide nanoparticles are useful as contrast agents for anatomical, functional and cellular MRI, drug delivery agents, and diagnostic biosensors. Nanoparticles are generally cleared by the reticuloendothelial system (RES), in particular taken up by Kupffer cells in the liver, limiting particle bioavailability and in-vivo applications. Strategies that decrease the RES clearance and prolong the circulation residence time of particles can improve the in-vivo targeting efficiency.

Methods

Intralipid 20.0%, an FDA approved nutritional supplement, was intravenously administered in rats at the clinical dose (2 g/kg) 1 h before intravenous injection of ultra-small superparamagnetic iron-oxide (USPIO) or micron-sized paramagnetic iron-oxide (MPIO) particles. Blood half-life, monocyte labeling efficiency, and particle biodistribution were assessed by magnetic resonance relaxometry, flow cytometry, inductively-coupled plasma MS, and histology.

Results

Pre-treatment with Intralipid resulted in a 3.1-fold increase in USPIO blood half-life and a 2-fold increase in USPIO-labeled monocytes. A 2.5-fold increase in MPIO blood half-life and a 5-fold increase in MPIO-labeled monocytes were observed following Intralipid pre-treatment, with a 3.2-fold increase in mean iron content up to 2.60 pg Fe/monocyte. With Intralipid, there was a 49.2% and 45.1% reduction in liver uptake vs. untreated controls at 48 h for USPIO and MPIO, respectively.

Conclusions

Intralipid pre-treatment significantly decreases initial RES uptake and increases in-vivo circulation and blood monocyte labeling efficiency for nano- and micron-sized superparamagnetic iron-oxide particles.

General significance

Our findings can have broad applications for imaging and drug delivery applications, increasing the bioavailability of nano- and micron-sized particles for target sites other than the liver.