[Paraneoplastic subacute cutaneous lupus erythematosus]. / Paraneoplastischer subakut kutaner Lupus erythematodes.

The genesis of subacute cutaneous lupus erythematosus (SCLE) is multifactorial and includes idiopathic, drug-related and paraneoplastic etiologies. This article reports the case of a 70-year-old female patient with paraneoplastic SCLE in whom a lung adenocarcinoma was detected during the extended examination. A paraneoplastic SCLE should be considered when a patient with SCLE presents with lesions in regions of the skin not exposed to sunlight and beginning B symptoms.

K2P2.1 is a regulator of inflammatory cell responses in idiopathic inflammatory myopathies.

K2P2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K2P2.1 in the autoimmune response of IIMs. We detected K2P2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K2P2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K2P2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K2P2.1 and improved the disease course of a myositis mouse model. In humans, K2P2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K2P2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K2P2.1 could serve as novel therapeutic target.

Perspective: Council for Responsible Nutrition Science in Session. Optimizing Health with Nutrition-Opportunities, Gaps, and the Future.

Achieving optimal health is an aspirational goal for the population, yet the definition of health remains unclear. The role of nutrition in health has evolved beyond correcting malnutrition and specific deficiencies and has begun to focus more on achieving and maintaining 'optimal' health through nutrition. As such, the Council for Responsible Nutrition held its October 2022 Science in Session conference to advance this concept. Here, we summarize and discuss the findings of their Optimizing Health through Nutrition - Opportunities and Challenges workshop, including several gaps that need to be addressed to advance progress in the field. Defining and evaluating various indices of optimal health will require overcoming these key gaps. For example, there is a strong need to develop better biomarkers of nutrient status, including more accurate markers of food intake, as well as biomarkers of optimal health that account for maintaining resilience-the ability to recover from or respond to stressors without loss to physical and cognitive performance. In addition, there is a need to identify factors that drive individualized responses to nutrition, including genotype, metabotypes, and the gut microbiome, and to realize the opportunity of precision nutrition for optimal health. This review outlines hallmarks of resilience, provides current examples of nutritional factors to optimize cognitive and performance resilience, and gives an overview of various genetic, metabolic, and microbiome determinants of individualized responses.

Multivitamin/Multimineral Supplementation Prevents or Reverses Decline in Vitamin Biomarkers and Cellular Energy Metabolism in Healthy Older Men: A Randomized, Double-Blind, Placebo-Controlled Study.

Despite the reported prevalence of micronutrient deficiencies in older adults, it is not yet established whether multivitamin/multimineral (MV/MM) supplements improve blood micronutrient status in individuals over the age of 65. Therefore, a cohort of 35 healthy men (>67 years) was recruited for an MV/MM supplementation trial. The primary endpoint was, as an indicator of micronutrient status, changes in blood micronutrient biomarkers from baseline to at least six months of supplementation with MV/MM or placebo. The secondary endpoint was basal O2 consumption in monocytes as an indicator of cellular metabolism. MV/MM supplementation improved blood concentrations of pyridoxal phosphate, calcifediol, α-tocopherol, and ß-carotene concentrations throughout the cohort. By contrast, those in the placebo group generally showed declines in blood vitamin concentrations and an increased prevalence of suboptimal vitamin status during the study period. On the other hand, MV/MM supplementation did not significantly affect blood mineral concentrations, i.e., calcium, copper, iron, magnesium, and zinc. Interestingly, MV/MM supplementation prevented the decline in monocyte O2 consumption rate. Overall, MV/MM use improves or prevents declines in vitamin, but not mineral, status and limits declines in cellular O2 consumption, which may have important implications for metabolism and immune health in healthy older men.

Daily changes in spatial accessibility to ICU beds and their relationship with the case-fatality ratio of COVID-19 in the state of Texas, USA.

During the COVID-19 pandemic, many patients could not receive timely healthcare services due to limited availability and access to healthcare resources and services. Previous studies found that access to intensive care unit (ICU) beds saves lives, but they overlooked the temporal dynamics in the availability of healthcare resources and COVID-19 cases. To fill this gap, our study investigated daily changes in ICU bed accessibility with an enhanced two-step floating catchment area (E2SFCA) method in the state of Texas. Along with the increased temporal granularity of measurements, we uncovered two phenomena: 1) aggravated spatial inequality of access during the pandemic, and 2) the retrospective relationship between insufficient ICU bed accessibility and the high case-fatality ratio of COVID-19 in rural areas. Our findings suggest that those locations should be supplemented with additional healthcare resources to save lives in future pandemic scenarios.

Spatial accessibility to HIV testing, treatment, and prevention services in Illinois and Chicago, USA.

Accomplishing the goals outlined in "Ending the HIV (Human Immunodeficiency Virus) Epidemic: A Plan for America Initiative" will require properly estimating and increasing access to HIV testing, treatment, and prevention services. In this research, a computational spatial method for estimating access was applied to measure distance to services from all points of a city or state while considering the size of the population in need for services as well as both driving and public transportation. Specifically, this study employed the enhanced two-step floating catchment area (E2SFCA) method to measure spatial accessibility to HIV testing, treatment (i.e., Ryan White HIV/AIDS program), and prevention (i.e., Pre-Exposure Prophylaxis [PrEP]) services. The method considered the spatial location of MSM (Men Who have Sex with Men), PLWH (People Living with HIV), and the general adult population 15-64 depending on what HIV services the U.S. Centers for Disease Control (CDC) recommends for each group. The study delineated service- and population-specific accessibility maps, demonstrating the method's utility by analyzing data corresponding to the city of Chicago and the state of Illinois. Findings indicated health disparities in the south and the northwest of Chicago and particular areas in Illinois, as well as unique health disparities for public transportation compared to driving. The methodology details and computer code are shared for use in research and public policy.

Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms.

Chimeric antigen receptor (CAR) T cells are a cancer immunotherapy of extremes. Unprecedentedly effective, but complex and costly to manufacture, they are not yet a therapeutic option for all who would benefit. This disparity has motivated worldwide efforts to simplify treatment. Among the proposed solutions, the generation of CAR T cells directly in the patient, i.e., in vivo, is arguably simultaneously the most technically challenging and clinically useful approach to convert CAR therapy from a cell-based autologous medicinal product into a universally applicable off-the-shelf treatment. Here, we review the current state of the art of in vivo CAR therapy, focusing especially on the vector technologies used. These cover lentiviral vectors and adenovirus-associated vectors as well as synthetic polymer nanocarriers and lipid nanoparticles. Proof of concept, i.e., the generation of CAR cells directly in mouse models, has been demonstrated for all vector platforms. Receptor targeting of vector particles is crucial, as it can prevent CAR gene delivery into off-target cells, thus reducing toxicities. We discuss the properties of the vector platforms, such as their immunogenicity, potency, and modes of CAR delivery (permanent versus transient). Finally, we outline the work required to advance in vivo CAR therapy from proof of concept to a robust, scalable technology for clinical testing.

Lentiviral and adeno-associated vectors efficiently transduce mouse T lymphocytes when targeted to murine CD8.

Preclinical studies on gene delivery into mouse lymphocytes are often hampered by insufficient activity of lentiviral (LV) and adeno-associated vectors (AAVs) as well as missing tools for cell type selectivity when considering in vivo gene therapy. Here, we selected designed ankyrin repeat proteins (DARPins) binding to murine CD8. The top-performing DARPin was displayed as targeting ligand on both vector systems. When used on engineered measles virus (MV) glycoproteins, the resulting mCD8-LV transduced CD8+ mouse lymphocytes with near-absolute (>99%) selectivity. Despite its lower functional titer, mCD8-LV achieved 4-fold higher gene delivery to CD8+ cells than conventional VSV-LV when added to whole mouse blood. Addition of mCD8-LV encoding a chimeric antigen receptor (CAR) specific for mouse CD19 to splenocytes resulted in elimination of B lymphocytes and lymphoma cells. For display on AAV, the DARPin was inserted into the GH2-GH3 loop of the AAV2 capsid protein VP1, resulting in a DARPin-targeted AAV we termed DART-AAV. Stocks of mCD8-AAV contained similar genome copies as AAV2 but were >20-fold more active in gene delivery in mouse splenocytes, while exhibiting >99% specificity for CD8+ cells. These results suggest that receptor targeting can overcome blocks in transduction of mouse splenocytes.

Quantitative assays reveal cell fusion at minimal levels of SARS-CoV-2 spike protein and fusion from without.

Cell entry of the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its spike protein S. As a main antigenic determinant, S protein is in focus of various therapeutic strategies. Besides particle-cell fusion, S mediates fusion between infected and uninfected cells resulting in syncytia formation. Here, we present sensitive assay systems with a high dynamic range and high signal-to-noise ratios covering not only particle-cell and cell-cell fusion but also fusion from without (FFWO). In FFWO, S-containing viral particles induce syncytia independently of de novo synthesis of S. Neutralizing antibodies, as well as sera from convalescent patients, inhibited particle-cell fusion with high efficiency. Cell-cell fusion, in contrast, was only moderately inhibited despite requiring levels of S protein below the detection limit of flow cytometry and Western blot. The data indicate that syncytia formation as pathological consequence during coronavirus disease 2019 (COVID-19) can proceed at low levels of S protein and may not be effectively prevented by antibodies.

[Chimeric antigen receptors in oncology: clinical applications and new developments]. / Chimäre Antigenrezeptoren (CARs) in der Onkologie: eine Übersicht zu klinischer Anwendung und neuen Entwicklungen.

In 2018, two novel cancer therapies based on chimeric antigen receptors (CARs) were granted marketing authorization in the European Union. Authorized for use against advanced lymphoma and/or leukemia, the products were at the center of international attention, not only due to their novel mode of action and their encouraging efficacy but also because of their sometimes severe side effects and the economic and logistic challenges posed by their manufacture. Now, almost two years later, hundreds of active clinical trials emphasize the global drive to harness the full potential of CAR technology.In this article, we describe the mode of action of CAR T and CAR NK cells and review the clinical testing situation as well as early real-world data. In recent years, preclinical studies using advanced animal models have provided first insights into the mechanisms underlying the severe side effects of CAR T therapy. We summarize their results and describe the available models. Additionally, we discuss potential solutions to the hurdles currently limiting CAR technology. So far used as last-line treatment for patients with aggressive disease, CAR technology has the potential to become a new, broadly effective standard for tumor therapy.

Rapidly measuring spatial accessibility of COVID-19 healthcare resources: a case study of Illinois, USA.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, has infected millions of people and caused hundreds of thousands of deaths. While COVID-19 has overwhelmed healthcare resources (e.g., healthcare personnel, testing resources, hospital beds, and ventilators) in a number of countries, limited research has been conducted to understand spatial accessibility of such resources. This study fills this gap by rapidly measuring the spatial accessibility of COVID-19 healthcare resources with a particular focus on Illinois, USA. METHOD: The rapid measurement is achieved by resolving computational intensity of an enhanced two-step floating catchment area (E2SFCA) method through a parallel computing strategy based on cyberGIS (cyber geographic information science and systems). The E2SFCA has two major steps. First, it calculates a bed-to-population ratio for each hospital location. Second, it sums these ratios for residential locations where hospital locations overlap. RESULTS: The comparison of the spatial accessibility measures for COVID-19 patients to those of population at risk identifies which geographic areas need additional healthcare resources to improve access. The results also help delineate the areas that may face a COVID-19-induced shortage of healthcare resources. The Chicagoland, particularly the southern Chicago, shows an additional need for resources. This study also identified vulnerable population residing in the areas with low spatial accessibility in Chicago. CONCLUSION: Rapidly measuring spatial accessibility of healthcare resources provides an improved understanding of how well the healthcare infrastructure is equipped to save people's lives during the COVID-19 pandemic. The findings are relevant for policymakers and public health practitioners to allocate existing healthcare resources or distribute new resources for maximum access to health services.

The Effect of a Multivitamin and Mineral Supplement on Immune Function in Healthy Older Adults: A Double-Blind, Randomized, Controlled Trial.

Older adults are at increased risk for vitamin and mineral deficiencies that contribute to age-related immune system decline. Several lines of evidence suggest that taking a multi-vitamin and mineral supplement (MVM) could improve immune function in individuals 55 and older. To test this hypothesis, we provided healthy older adults with either an MVM supplement formulated to improve immune function (Redoxon® VI, Singapore) or an identical, inactive placebo control to take daily for 12 weeks. Prior to and after treatment, we measured (1) their blood mineral and vitamin status (i.e., vitamin C, zinc and vitamin D); (2) immune function (i.e., whole blood bacterial killing activity, neutrophil phagocytic activity, and reactive oxygen species production); (3) immune status (salivary IgA and plasma cytokine/chemokine levels); and (4) self-reported health status. MVM supplementation improved vitamin C and zinc status in blood and self-reported health-status without altering measures of immune function or status or vitamin D levels, suggesting that healthy older adults may benefit from MVM supplementation. Further development of functional assays and larger study populations should improve detection of specific changes in immune function after supplementation in healthy older adults. Clinical Trials Registration: ClinicalTrials.gov #NCT02876315.

A Randomized Controlled Trial of Long-Term (R)-α-Lipoic Acid Supplementation Promotes Weight Loss in Overweight or Obese Adults without Altering Baseline Elevated Plasma Triglyceride Concentrations.

BACKGROUND: α-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking. OBJECTIVES: The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation. METHODS: Overweight adults [n = 81; 57% women; 21-60 y old; BMI (in kg/m2) ≥ 25] with elevated plasma triglycerides ≥100 mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-α-lipoic acid (R-LA; 600 mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints. RESULTS: R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (-0.8; P = 0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P = 0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI ≥ 35) showed greater weight loss (-5.0% and -4.8%, respectively; both P < 0.001) and loss of body fat (-9.4% and -8.6%, respectively; both P < 0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1] : +22%; P = 0.02) than in placebo. Less urinary F2-isoprostanes (-25%; P = 0.005), blood leukocytes (-10.1%; P = 0.01), blood thrombocytes (-5.1%; P = 0.03), and ICAM-1 (-7.4%; P = 0.04) at 24 wk were also observed in the R-LA group than in placebo. CONCLUSIONS: Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.This trial was registered at clinicaltrials.gov as NCT00765310.

Isolation of Primary Murine Skeletal Muscle Microvascular Endothelial Cells.

The endothelial cells of skeletal muscle capillaries (muscle microvascular endothelial cells, MMEC) build up the barrier between blood stream and skeletal muscles regulating the exchange of fluids and nutrients as well as the immune response against infectious agents by controlling immune cell migration. For these functions, MMEC form a functional "myovascular unit" (MVU), with further cell types, such as fibroblasts, pericytes and skeletal muscle cells. Consequently, a dysfunction of MMEC and therefore the MVU contributes to a vast variety of myopathies. However, regulatory mechanisms of MMEC in health and disease remain insufficiently understood and their elucidation precedes more specific treatments for myopathies. The isolation and in-depth investigation of primary MMEC functions in the context of the MVU might facilitate a better understanding of these processes. This article provides a protocol to isolate primary murine MMEC of the skeletal muscle by mechanical and enzymatic dissociation including purification and culture maintenance steps.

Daily Consumption of Oregon Hazelnuts Affects α-Tocopherol Status in Healthy Older Adults: A Pre-Post Intervention Study.

Background: Inadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases. Objective: This study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes. Methods: Participants (n = 32 including 22 women; mean ± SD age: 63 ± 6 y) consumed hazelnuts (∼57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of α-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C-reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma α-tocopherol, 2) urinary α-carboxyethyl hydroxychromanol (α-CEHC; an α-tocopherol metabolite), and 3) serum magnesium. Results: Hazelnut consumption increased concentrations of the urinary α-tocopherol metabolite α-CEHC (mean ± SD: 0.84 ± 0.45 to 1.14 ± 0.50 µmol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (-3.4%, P = 0.03) and LDL cholesterol (-6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (-4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, high-sensitivity C-reactive protein, triglyceride, α-tocopherol, or HDL cholesterol. Conclusions: Consuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015-2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT03485989.

Myths, artifacts, and fatal flaws: identifying limitations and opportunities in vitamin C research.

Research progress to understand the role of vitamin C (ascorbic acid) in human health has been slow in coming. This is predominantly the result of several flawed approaches to study design, often lacking a full appreciation of the redox chemistry and biology of ascorbic acid. In this review, we summarize our knowledge surrounding the limitations of common approaches used in vitamin C research. In human cell culture, the primary issues are the high oxygen environment, presence of redox-active transition metal ions in culture media, and the use of immortalized cell lines grown in the absence of supplemental ascorbic acid. Studies in animal models are also limited due to the presence of endogenous ascorbic acid synthesis. Despite the use of genetically altered rodent strains lacking synthesis capacity, there are additional concerns that these models do not adequately recapitulate the effects of vitamin C deprivation and supplementation observed in humans. Lastly, several flaws in study design endemic to randomized controlled trials and other human studies greatly limit their conclusions and impact. There also is anecdotal evidence of positive and negative health effects of vitamin C that are widely accepted but have not been substantiated. Only with careful attention to study design and experimental detail can we further our understanding of the possible roles of vitamin C in promoting human health and preventing or treating disease.

Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function.

New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk.