Eliciting Exploratory Patient Preference Data: A Case Study in a Rare Disease.

Introduction: Qualitative and quantitative methods provide different and complementary insights into patients' preferences for treatment.

Objective: The aim of this study was to use a novel, mixed-methods approach employing qualitative and quantitative approaches to generate preliminary insights into patient preferences for the treatment of a rare disease-generalized myasthenia gravis (gMG).

Methods: We conducted a mixed-methods study to collect exploratory qualitative and quantitative patient preference information and generate informative results within a condensed timeline (about 4 months).

Efficacy and safety of PICOPREP tailored dosing compared with PICOPREP day-before dosing for colon cleansing: a multi-centric randomised study.

 The success of any colonoscopy procedure depends upon the quality of bowel preparation. We evaluated the efficacy and safety of a new tailored dosing (TD) regimen compared with the approved PICOPREP day-before dosing regimen (DBD) in the European Union.  Patients (≥ 18 years) undergoing colonoscopy were randomised (2:1) to TD (Dose 1, 10 - 18 hours; Dose 2, 4 - 6 hours before colonoscopy) or DBD (Dose 1 before 8:00AM on the day before colonoscopy; Dose 2, 6 - 8 hours after Dose 1).

Metallic gold slows disease progression, reduces cell death and induces astrogliosis while simultaneously increasing stem cell responses in an EAE rat model of multiple sclerosis.

Multiple sclerosis (MS) is the most common neurodegenerative disease in the Western world affecting younger, otherwise healthy individuals. Today no curative treatment exists. Patients suffer from recurring attacks caused by demyelination and underlying neuroinflammation, ultimately leading to loss of neurons.

Apical localization of zinc transporter ZnT4 in human airway epithelial cells and its loss in a murine model of allergic airway inflammation.

The apical cytoplasm of airway epithelium (AE) contains abundant labile zinc (Zn) ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG)-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm.

Uptake of silver from metallic silver surfaces induces cell death and a pro-inflammatory response in cultured J774 macrophages.

In clinical medicine metallic silver is used as anti-bacterial coating on various catheters, bandages and prostheses. By means of dissolucytosis, i.e.

Metallic silver fragments cause massive tissue loss in the mouse brain.

Silver is a metal with well-known antibacterial effects. This makes silver an attractive coating material for medical devices for use inside the body, e.g.

Chemical blocking of zinc ions in CNS increases neuronal damage following traumatic brain injury (TBI) in mice.

Background: Traumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate.

Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AbetaPP/PS1 transgenic mouse.

The presence of senile plaques containing abundant amyloid-beta (Abeta) peptide is one of the major pathological hallmarks of Alzheimer's disease (AD). Recent studies support the notion that overexpression of zinc transporters (ZnT) is involved in zinc metabolic disturbances and Abeta aggregation in AD brains. Here we present data showing an elevated expression of zinc transporter 3 (ZnT3) protein, revealed by immunoblotting assay, in the cerebellum of the amyloid-beta protein precursor (AbetaPP)/presenilin 1 (PS1) transgenic mouse.

Biodistribution of gold nanoparticles in mouse lung following intratracheal instillation.

Background: The fate of gold nanoparticles, 2, 40 and 100 nm, administered intratracheally to adult female mice was examined. The nanoparticles were traced by autometallography (AMG) at both ultrastructural and light microscopic levels. Also, the gold content was quantified by inductively coupled plasma mass spectrometry (ICP-MS) and neutron activation analysis (NAA).

Bio-released gold ions modulate expression of neuroprotective and hematopoietic factors after brain injury.

The discovery of neural stem cells (NSCs) provides new therapeutic strategies for brain injury by means of endogenous cell renewal. In the injured mouse brain, bio-liberated gold ions from gold implants mediate anti-inflammatory and antiapoptotic effects and activation of NSCs. This paper investigates the neuroprotective effects of gold following brain injury in mice.

SLC30A3 responds to glucose- and zinc variations in beta-cells and is critical for insulin production and in vivo glucose-metabolism during beta-cell stress.

Background: Ion transporters of the Slc30A- (ZnT-) family regulate zinc fluxes into sub-cellular compartments. beta-cells depend on zinc for both insulin crystallization and regulation of cell mass.

Methodology/principal Findings: This study examined: the effect of glucose and zinc chelation on ZnT gene and protein levels and apoptosis in beta-cells and pancreatic islets, the effects of ZnT-3 knock-down on insulin secretion in a beta-cell line and ZnT-3 knock-out on glucose metabolism in mice during streptozotocin-induced beta-cell stress.

The role of metallothionein in oncogenesis and cancer prognosis.

The antiapoptotic, antioxidant, proliferative, and angiogenic effects of metallothionein (MT)-I+II has resulted in increased focus on their role in oncogenesis, tumor progression, therapy response, and patient prognosis. Studies have reported increased expression of MT-I+II mRNA and protein in various human cancers; such as breast, kidney, lung, nasopharynx, ovary, prostate, salivary gland, testes, urinary bladder, cervical, endometrial, skin carcinoma, melanoma, acute lymphoblastic leukemia (ALL), and pancreatic cancers, where MT-I+II expression is sometimes correlated to higher tumor grade/stage, chemotherapy/radiation resistance, and poor prognosis. However, MT-I+II are downregulated in other types of tumors (e.

Cell death in the injured brain: roles of metallothioneins.

In traumatic brain injury (TBI), the primary, irreversible damage associated with the moment of impact consists of cells dying from necrosis. This contributes to fuelling a chronic central nervous system (CNS) inflammation with increased formation of proinflammatory cytokines, enzymes and reactive oxygen species (ROS). ROS promote oxidative stress, which leads to neurodegeneration and ultimately results in programmed cell death (secondary injury).

Metallic gold reduces TNFalpha expression, oxidative DNA damage and pro-apoptotic signals after experimental brain injury.

Brain injury represents a major health problem and may result in chronic inflammation and neurodegeneration. Due to antiinflammatory effects of gold, we have investigated the cerebral effects of metallic gold particles following a focal brain injury (freeze-lesion) in mice. Gold particles 20-45 microm in size or the vehicle (placebo) were implanted in the cortical tissue followed by a cortical freeze-lesioning.

Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury.

Unlabelled: Traumatic brain injury represents a leading cause of morbidity in young individuals and there is an imperative need for neuroprotective treatments limiting the neurologic impairment following such injury. It has recently been demonstrated that bio-liberated gold ions liberated from small metallic gold implants reduce inflammation and neuronal apoptosis, while generating an increased neuronal stem cell response following focal brain damage. In this study mice were subjected to a unilateral traumatic cryo-lesion with concomitant injection of 25-45 microm gold particles near the lesion.

Hydroxyapatite coatings did not increase TGF-beta and BMP-2 secretion in murine J774A.1 macrophages, but induced a pro-inflammatory cytokine response.

Hydroxyapatite (Ca(10)(PO(2))(6)(OH)(2), HA) coatings are widely used in un-cemented total hip arthroplasties because it increases implant fixation and bone in-growth. HA adsorbs high levels of proteins (e.g.

Protracted elimination of gold nanoparticles from mouse liver.

The present study aims at revealing the fate of 40-nm gold nanoparticles after intravenous injections. The gold nanoparticles were traced histochemically with light and transmission electron microscopy using autometallographic (AMG) staining, and the gold content in the liver was determined with inductively coupled plasma mass spectrometry (ICP-MS). Gold nanoparticles were identified in almost all Kupffer cells one day after the injection, but the fraction of gold-loaded cells gradually decreased to about one fifth after 6 months.

Cultured macrophages cause dissolucytosis of metallic silver.

The present study proves that cultured macrophages can liberate silver ions from metallic silver surfaces by a process called dissolucytosis. Macrophages (J774) were grown on a silver plate for different periods of time and after fixation in glutaraldehyde, they were subjected to autometallograhy in order to amplify possible cellular silver-sulphur nanocrystals. Light and electron microscopic analysis of the cells revealed that silver ions released from the plate had been taken up by the macrophages and accumulated in lysosome-like structures.

Lack of plasma protein hemopexin dampens mercury-induced autoimmune response in mice.

Several factors affect the autoimmune response, including iron-dependent modulation of T cells. Hemopexin is the plasma protein with the highest binding affinity to heme. It mediates heme-iron recovery in the liver, thus controlling heme-iron availability in peripheral cells.

Abundant expression of zinc transporters in the amyloid plaques of Alzheimer's disease brain.

The pathological key features of Alzheimer's disease (AD) are beta-amyloid peptide (Abeta)-containing senile plaques (SP) and neurofibrillary tangles. Previous studies have suggested that an extracellular elevation of the zinc concentration can initiate the deposition of Abeta and lead to the formation of SP. In the present study, we present data showing a correlation between zinc ions, zinc transporters (ZNTs) and AD, using immersion autometallography (AMG) and double immunofluorescence for the ZNTs and Abeta.

Gold ions bio-released from metallic gold particles reduce inflammation and apoptosis and increase the regenerative responses in focal brain injury.

Traumatic brain injury results in loss of neurons caused as much by the resulting neuroinflammation as by the injury. Gold salts are known to be immunosuppressive, but their use are limited by nephrotoxicity. However, as we have proven that implants of pure metallic gold release gold ions which do not spread in the body, but are taken up by cells near the implant, we hypothesize that metallic gold could reduce local neuroinflammation in a safe way.

Zinc transporter 3 immunohistochemical tracing of sprouting mossy fibres.

Zinc transporter 3 (ZNT3) has been shown to transport zinc ions from the cytosol into presynaptic vesicles in the mammalian brain. Several studies have stated that the zinc ion containing synaptic vesicles of zinc-enriched neurons (ZEN) are loaded with ZNT3 proteins in their membranes. This fact makes it possible to trace sprouting mossy fibres in the temporal lobe epileptic hippocampus.

Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain.

Pathological accumulation of beta-amyloid peptide (Abeta) is an early and common feature of Alzheimer's disease (AD). An increased zinc concentration can initiate the deposition of Abeta. The present study aimed to study the expression and distribution patterns of six members of the zinc transporter (ZnT) family, ZnT1, ZnT3, ZnT4, ZnT5, ZnT6, and ZnT7, in the APPswe/PS1dE9 transgenic mouse brain.

Cobalt-chromium-molybdenum alloy causes metal accumulation and metallothionein up-regulation in rat liver and kidney.

Cobalt-chromium-molybdenum (CoCrMo) metal-on-metal hip prosthesis has had a revival due to their excellent wear properties. However, particulate wear debris and metal ions liberated from the CoCrMo alloys might cause carcinogenicity, hypersensitivity, local and general tissue toxicity, genotoxicity and inflammation-generating qualities. Nine months after implanting small pieces of CoCrMo alloy intramuscularly and intraperitoneally in rats, we analysed the accumulation of metals with a multi-element analysis, and the levels of metallothionein I/II with real-time reverse transcriptase-polymerase chain reaction in liver and kidney.