Calcium calmodulin kinase IV deficiency in podocytes prevents the development of lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread organ involvement including the kidney. Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to conrol immune cell nad podocyte function. To address the effect of genetic podocyte-specific CaMK4 deficiency on systemic autoimmunity and kidney pathology in lupus-prone mice we generated B6.

Injury pattern of feet and lower limbs in a feet-first fall from height.

In fatalities caused by falls from height, the analysis of the injury pattern, alongside with circumstantial data, is crucial for understanding the dynamics of the incident. In rare cases, even a differentiation between accidental and intentional events might be possible. The injury pattern of the lower limbs is particularly significant in this context.

CD38 in SLE CD4 T cells promotes Ca flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane.

CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4 T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca flux through the PLCγ1-IP3 pathway.

The PP2A regulatory subunit PPP2R2A controls NAD biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.

The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells.

CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (T) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the T-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα).

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile.

Estimation of Late Postmortem Interval: Where Do We Stand? A Literature Review.

Estimating time since death can be challenging for forensic experts, and is one of the most challenging activities concerning the forensic world. Various methods have been assessed to calculate the postmortem interval on dead bodies in different stages of decomposition and are currently widely used. Nowadays, the only well-recognized dating technique is carbon-14 radioisotope measurement, whereas other methods have been tested throughout the years involving different disciplines with different and sometimes not univocal results.

Multiorgan immunohistochemical endothelial expression of E-selectin in a forensic case of sepsis.

Sepsis is one of the major threats for the survival and prognosis of patients in intensive care units. In cases where detailed clinical data and monitoring is available, the diagnosis of sepsis is reliable. But when clinical data are incomplete or missing and sepsis is only suspected based on the autopsy results, the picture is often equivocal.

IL-27 attenuates IL-23 mediated inflammatory arthritis.

Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b GR1 and CD3CD11bCD11cGR1 cells.

A Fatal Case Report Resulting from the Abuse of the Designer Benzodiazepines Clonazolam and Flualprazolam in Conjunction with Dried Opium Poppy Pods‡.

Toxicologists are often confronted with the abuse of multiple drugs and are obliged to decide which compound may have been the cause of death. We report on a 21-year-old man (182 cm, 84 kg), who was found unconscious in his bed. Beside him, the police found several controlled substances, among them were dried opium poppy pods containing thebaine, codeine and morphine, a clear liquid with the designer benzodiazepines flualprazolam and clonazolam and a white powder with the imprint SGT-25, instead of SGT-78 (CUMYL-4CN-BINACA).

Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6. lupus-prone mice and expands T cells.

Fatal injuries due to direct helicopter propeller strike.

During a helicopter exercise, due to the scarce visibility caused by the presence of snow, a collision between a landing helicopter and one already on the ground occurred. The 40-year-old pilot of the already landed aircraft was killed as a result of a direct propeller impact in the right side of the pilot's cockpit, while the co-pilot remained uninjured. At autopsy, the macroscopic characteristic findings in the form of cut injuries and amputations along the axis of the rotor blade impact as well as a 3D reconstruction through CT-Scan were analyzed and discussed for a thorough reconstruction of the injuries and the dynamics.

PPP2R2D Suppresses Effector T Cell Exhaustion and Regulatory T Cell Expansion and Inhibits Tumor Growth in Melanoma.

We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (LckR2D) compared with wild type (R2D) mice. The numbers of intratumoral T cells in LckR2D mice were reduced compared with R2D mice, and they expressed a PD-1CD3CD44 exhaustion phenotype.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

Objective: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA.

Methods: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded.

Lymphocytes in the neighborhood: good or bad for the kidney?

Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). In this issue of the JCI, Abraham, Durkee, et al. presented a large-scale immune cell landscape of kidney biopsies from patients with LN by combining multiplexed confocal microscopy imaging with customized computer vision and quantification.

CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.

Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD, is up-regulated in CD8 T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8 T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control.

Production and Secretion of Gelsolin by Both Human Macrophage- and Fibroblast-like Synoviocytes and GSN Modulation in the Synovial Fluid of Patients with Various Forms of Arthritis.

Gelsolin (GSN) is an actin-binding protein involved in cell formation, metabolism and wound closure processes. Since this protein is known to play a role in arthritis, here we investigate how the synovial membrane with its specific synoviocytes contributes to the expression of GSN and how the amount of GSN expressed is modulated by different types of arthritis. Synovial membranes from adult healthy subjects and patients with rheumatoid arthritis (RA) and osteoarthritis (OA) are analyzed by immunofluorescence, Western blot and ELISA.

Intertwined pathways of complement activation command the pathogenesis of lupus nephritis.

The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus.

Epidemiologic, Postmortem Computed Tomography-Morphologic and Biomechanical Analysis of the Effects of Non-Invasive External Pelvic Stabilizers in Genuine Unstable Pelvic Injuries.

Unstable pelvic injuries are rare (3-8% of all fractures) but are associated with a mortality of up to 30%. An effective way to treat venous and cancellous sources of bleeding prehospital is to reduce intrapelvic volume with external noninvasive pelvic stabilizers. Scientifically reliable data regarding pelvic volume reduction and applicable pressure are lacking.

Prevalence and concentrations of new designer stimulants, synthetic opioids, benzodiazepines, and hallucinogens in postmortem hair samples: A 13-year retrospective study.

Hair samples are frequently analyzed in order to characterize consumption patterns of drugs. However, the interpretation of new psychoactive substance (NPS) findings in hair remains difficult because of lacking data for comparison. In this study, selected postmortem hair samples (n = 1203) from 2008 to 2020 were reanalyzed for synthetic cathinones, piperazines, phenethylamines, hallucinogens, benzodiazepines and opioids to evaluate prevalence data and concentration ranges.

Discrepancies between clinical diagnosis and hospital autopsy: A comparative retrospective analysis of 1,112 cases.

Aims: The aim of this study was to compare discrepancies between diagnosed and autopsied causes of death in 1,112 hospital autopsies and to determine the factors causing this discrepancies.

Methods: 1,112 hospital autopsies between 2010 and 2013 were retrospectively studied. Ante-mortem diagnoses were compared to causes of death as determined by autopsy.

Complement activation and increased expression of Syk, mucin-1 and CaMK4 in kidneys of patients with COVID-19.

Acute and chronic kidney failure is common in hospitalized patients with COVID-19, yet the mechanism of injury and predisposing factors remain poorly understood. We investigated the role of complement activation by determining the levels of deposited complement components (C1q, C3, FH, C5b-9) and immunoglobulin along with the expression levels of the injury-associated molecules spleen tyrosine kinase (Syk), mucin-1 (MUC1) and calcium/calmodulin-dependent protein kinase IV (CaMK4) in the kidney tissues of people who succumbed to COVID-19. We report increased deposition of C1q, C3, C5b-9, total immunoglobulin, and high expression levels of Syk, MUC1 and CaMK4 in the kidneys of COVID-19 patients.