The Cd/Zn Axis: Emerging Concepts in Cellular Fate and Cytotoxicity.

Cadmium (Cd) is a toxic and carcinogenic substance that is present in the natural environment. The underlying biomolecular mechanisms of Cd toxicity are not completely understood, and it continues to be a significant research target due to its impact on public health. The primary routes of exposure are through ingestion of contaminated food and water and inhalation. Cd's long biological half-life of 10-30 years allows it to accumulate in the body, leading to organ dysfunction notably in the kidney, liver, bone, and lungs. Cd has similar biochemical characteristics to Zinc (Zn). It shares the import transporters, ZIP8 and ZIP14, to enter the cells. This competitive behavior can be observed in multiple instances throughout the progression of Cd toxicity. Future studies on the biochemical interactions of Cd and Zn will elucidate the potential protective effects of Zn supplementation in reducing the effects of Cd toxicity. In addition, research can be focused on discovering key proteins and effective pathways for Cd elimination that confer fewer adverse effects than current antioxidant therapies.

Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

Guanylate Binding Protein 1 (GBP1): A Key Protein in Inflammatory Pyroptosis.

Scientists recently made a significant breakthrough in the recognition of pathogens via guanylate binding protein 1 (GBP1). Wandel et al. [1] in Nature Immunology described their findings where GBP1 acts as a pattern recognition receptor that directly connects to lipopolysaccharide (LPS). GBP1 identifies gram-negative bacteria such as the enteric pathogen, Salmonella enterica serovar Typhimurium, that enter the cytoplasm of the host cell. GBP1 then quickly connects to LPS and stimulates the assembly of more GBPs in the order of GBP2, GBP3, and GBP4. Subsequently, inflammatory caspase-4 arrives at the GBP1-4 activation platform. Next, the activated caspase-4 drives the cleavage of Gasdermin D, triggering the release of the pro-inflammatory cytokine, interleukin-18 (IL-18) leading to inflammatory pyroptosis and cell death. Not only do these remarkable results expand our current understanding of GBP1, but they also carry the potential to develop therapeutic targets for inflammasome-mediated human disorders.

A Case of Central Diabetes Insipidus Secondary to Neurosarcoidosis.

We present a case of central diabetes insipidus (DI) secondary to neurosarcoidosis. The path to final diagnosis was challenging. Along with reporting the case, we review the available medical literature relating to neurosarcoidosis and central diabetes insipidus in this case report. Patient is a 56-year-old female with notable history of rheumatoid arthritis, anxiety, asthma, hypertension, spinal stenosis, and seizures of unknown etiology who presented to the emergency department for worsening headache for one week. She also endorsed decreased vision, photophobia, nausea, vomiting, gait abnormality, polyuria, and polydipsia over the past three months. Physical exam and neurological exam were unremarkable. Labs on presentation were notable for hypernatremia, increased serum osmolality and urine output of 5 L/day. Given her persistent headache and history of seizure, she underwent a CT head without contrast which showed a posterior suprasellar soft tissue fullness measuring 6 mm in the hypothalamic region. She then had additional imaging studies of the brain including MRI brain w/wo contrast and MRI pituitary w/wo contrast. MRI of the brain showed enlarged optic chiasm with increased T2 signal involving the proximal optic nerves and bilateral optic tracts, no brain parenchymal lesions to suggest multiple sclerosis. MRI of the pituitary w/wo contrast showed suprasellar mass arising from either the hypothalamus or less likely the chiasm which was concerning for high-grade glioma initially. Lumbar puncture was done that showed lymphocytic pleocytosis. Patient underwent right supraorbital craniotomy for biopsy of the suprasellar lesion. Surgical pathology showed noncaseating granulomatous inflammation most consistent with neuro-sarcoidosis. The diagnosis of neurosarcoidosis was made and patient was started on high dose steroids. Although central DI can be seen as a post-op complication, in our case, based on the clinical presentation, labs and imaging, there was concern of central DI on initial presentation. Patient was started on desmopressin 50 mg twice a day which resulted in marked improvement in urine output, serum sodium, and osmolality. Although it is rare to have nervous system involvement of sarcoidosis, symptoms of central diabetes insipidus could represent the first clinical manifestations of neurosarcoidosis. Proper treatment should be initiated in a timely fashion to avoid complications such as hydrocephalus.

Minimal food effect for eicosapentaenoic acid and docosahexaenoic acid bioavailability from omega-3-acid ethyl esters with an Advanced Lipid TechnologiesTM (ALT®)-based formulation.

BACKGROUND: The absorption of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) omega-3-acid ethyl esters (EEs) is influenced by food. There is a need for a formulation of EE that is less impacted by food effect. SC401 is a novel Advanced Lipid Technologies-based formulation of EPA-EE and DHA-EE. In the presence of an aqueous medium, Advanced Lipid Technologies forms stable micelles in situ independent of bile salt secretion. This effect is hypothesized to improve EPA-EE and DHA-EE bioavailability while it helps mitigate the food effect associated with their consumption. OBJECTIVE: The aim of the article was to assess the effect of food on the bioavailability of DHA and EPA after a single oral dose of 1530 mg omega-3 fatty acids EE (SC401) in 24 healthy subjects under fasted and low-fat (9% of total calories from fat) and high-fat (50% of total calories from fat) meal conditions. METHODS: This was a randomized, open-label, single-dose, 3-period, 3-way crossover study. Blood samples for pharmacokinetic analyses were taken at predose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12 and 24 hours postdose. To assess the safety of the intervention, active monitoring of adverse events, physical examinations, vital signs, clinical laboratory assessments (chemistry, hematology, and urinalysis), and 12-lead electrocardiograms were conducted. RESULTS: SC401 showed high bioavailability of both EPA and DHA in fasted, low-fat meal, and high-fat meal conditions. No differences were found in SC401 DHA AUC0-t (t = 24 hours) among the 3 conditions (91.69% high-fat/fasted, 97.12% low-fat/fasted, and 105.92% low-fat/high-fat; P > .05 in all cases). In contrast, SC401 EPA AUC0-t was affected by food intake (179.06% high-fat/fasted, P < .0001; 150.05% low-fat/fasted, P < .0001) and the amount of fat taken with SC401 (83.80% low-fat/high-fat; P = .0009). SC401 was safe and well tolerated. CONCLUSIONS: A single dose of SC401 resulted in high levels of EPA and DHA total lipids in plasma in fasting and fed conditions. SC401 overcame the food effect for DHA and partially ameliorated it for EPA. SC401 represents a convenient option for treatment of severe hypertriglyceridemia, especially for patients under a restricted intake of dietary fat.

A Novel ω-3 Acid Ethyl Ester Formulation Incorporating Advanced Lipid TechnologiesTM (ALT®) Improves Docosahexaenoic Acid and Eicosapentaenoic Acid Bioavailability Compared with Lovaza®.

PURPOSE: The US Food and Drug Administration has approved several highly purified ω-3 fatty acid prescription drugs for the treatment of severe hypertriglyceridemia. These differ in the amounts and forms of docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). This study compared the bioavailability of SC401 (1530 mg EPA-ethyl esters [EEs] and DHA-EEs plus Advanced Lipid Technologies⁎ [ALT†], a proprietary lipid-delivery platform to improve absorption), with. Lovaza‡ (3600 mg ω-3, primarily EPA-EEs and DHA-EEs) under low-fat feeding conditions. METHODS: This was a Phase I, randomized, open-label, single-dose, 2-way crossover study in healthy participants housed from day -3 to day 2 in each treatment period. Blood samples for pharmacokinetic measurements were collected before and after dosing, and safety profile and tolerability were assessed. FINDINGS: In unadjusted analyses, SC401 had 5% lower Cmax and approximately the same AUC0-last of EPA + DHA total lipids compared with Lovaza. When adjusted for baseline, SC401 had ~6% higher Cmax and 18% higher AUC0-last for EPA + DHA total lipids, and dose- and baseline-adjusted analyses found that SC401 had ~149% higher Cmax and 178% higher AUC0-last than Lovaza for EPA + DHA total lipids. The Tmax was also substantially longer with Lovaza (~10 hours) than with SC401 (~6 hours). IMPLICATIONS: These results indicate that SC401, an ω-3 acid EE formulation containing ALT† achieved high bioavailability of EPA and DHA, at a lower dose (1530 mg) than Lovaza (3600 mg), under low-fat feeding conditions.

Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance.

The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters), used to treat severe hypertriglyceridemia, recommends the conduct of 2 studies: one with participants in the fasting state and one with participants in the fed state. For the fasting study, the primary measures of BE are baseline-adjusted EPA and DHA levels in total plasma lipids. For the fed study, the primary measures of BE are EPA and DHA ethyl esters in plasma. This guidance differs from that established for icosapent ethyl (EPA ethyl esters) in which the primary measure of BE is baseline-adjusted total EPA in plasma lipids for both the fasting and fed states. The FDA guidance for ω-3 acid ethyl esters is not supported by their physiologic characteristics and triglyceride-lowering mechanisms because EPA and DHA ethyl esters are best characterized as pro-drugs. This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions. This change would harmonize the approaches for demonstration of BE for ω-3 acid ethyl esters and icosapent ethyl (EPA ethyl esters) products for future development programs and is the most physiologically rational approach to BE testing.

The handwriting on the wall: program transformations utilizing effective change management strategies.

Historically, there have been indications that we need to change the way we work and think about our health care processes. Yet, with the urgency to keep abreast of the changing needs of our patients, have we seen these signs? Moreover, how do we respond to the inevitable change processes that must occur? In 2010, St. Michael's entered into a five-year partnership with Baxter Canada. The overall goal is to improve the quality of care and life for people living with chronic kidney disease. This initiative was undertaken in response to concerns identified internally related to existing health care delivery processes within the renal program. As in any work environment, the depth and breadth of inevitable changes evoke a variety of responses that are based on the individual's attitudes regarding change. As we embarked on this journey, the nursing leadership team and staff within the program were encouraged to review their usual responses toward change utilizing the book, Who Moved My Cheese? (Johnson, 1998). It is imperative to identify the attitudes of those people involved in change processes. This awareness facilitates the use of specific strategies to enhance the effectiveness of their engagement in the process and the outcome of the initiative. Reading the writing on the wall prepares people to participate in and embrace changes that promise to benefit those for whom we provide professional care.