Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.

Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.

Type I IFN drives unconventional IL-1ß secretion in lupus monocytes.

Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1ß (mIL-1ß) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1ß (IL-1ß) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1ß secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1ß into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1ß and expanded in SLE patients with active disease.

Non-criteria antiphospholipid antibodies and calprotectin as potential biomarkers in pediatric antiphospholipid syndrome.

Our study aimed to evaluate the presence, clinical associations, and potential mechanistic roles of non-criteria antiphospholipid antibodies (aPL) and circulating calprotectin, a highly stable marker of neutrophil extracellular trap release (NETosis), in pediatric APS patients. We found that 79% of pediatric APS patients had at least one non-criteria aPL at moderate-to-high titer. Univariate logistic regression demonstrated that positive anti-beta-2 glycoprotein I domain 1 (anti-D1) IgG (p = 0.008), anti-phosphatidylserine/prothrombin (aPS/PT) IgG (p < 0.001), and aPS/PT IgM (p < 0.001) were significantly associated with venous thrombosis. Positive anti-D1 IgG (p < 0.001), aPS/PT IgG (p < 0.001), and aPS/PT IgM (p = 0.001) were also associated with non-thrombotic manifestations of APS, such as thrombocytopenia. Increased levels of calprotectin were detected in children with APS. Calprotectin correlated positively with absolute neutrophil count (r = 0.63, p = 0.008) and negatively with platelet count (r = -0.59, p = 0.015). Mechanistically, plasma from pediatric APS patients with high calprotectin levels impaired platelet viability in a dose-dependent manner.

Operative Versus Nonoperative Treatment After Acute Patellar Dislocation: Which Is More Effective at Reducing Recurrence in Adolescents?

Clinical Scenario: Acute patellar dislocations during adolescence often lead to future patellar instability. Two common treatment options include nonoperative treatment or operative repair of injured structures. Focused Clinical Question: In adolescents with acute patellar dislocation, how does operative stabilization compare with nonoperative treatment for reducing dislocation recurrence? Summary of Key Findings: Three studies were included: 2 randomized controlled trials and 1 nonrandomized study. All studies compared operative and nonoperative treatment outcomes in adolescents who experienced an acute patellar dislocation. Each study included nonoperative treatment such as patellar bracing and quadriceps strengthening. The operative treatments utilized in each study included lateral retinacular release and medial retinacular repair. All 3 of the studies included a follow-up of at least 6 years. Two of the studies concluded there to be no significant difference between treatment groups regarding redislocation rate, pain, and function. The third study reported a lower redislocation rate following operative treatment. Clinical Bottom Line: Reviewed evidence suggests that outcomes are similar when comparing operative and nonoperative treatment approaches with little agreement as to which is the optimal plan of action. Strength of Recommendation: One level II randomized controlled trial and a level III nonrandomized study suggest that patellar dislocation recurrence rates are similar among operative and nonoperative treatment approaches, while another level II randomized controlled trial suggests that an operative approach is superior.

Effects of gestational and lactational exposure to heptachlor epoxide on age at puberty and reproductive function in men and women.

BACKGROUND: For 15 months in 1981-1982, the commercial milk supply on the Hawaiian island of Oahu was contaminated with heptachlor epoxide, a metabolite of the insecticide heptachlor, resulting in gestational and/or lactational exposure to offspring of women who drank cow milk during that period. OBJECTIVE: To determine whether gestational and lactational exposure to heptachlor epoxide alters reproductive function and age at puberty in men or women. METHODS: 457 participants were recruited from a prior high school enrollment sampling frame of 20,000 adults born during 1981-1982 who lived on Oahu since at least first grade. Number of glasses of cow milk consumed weekly by the mother during the participant's gestation was used as a surrogate measure of heptachlor epoxide exposure. Reproductive function measures included semen analyses; reproductive hormones or their metabolites in daily urine specimens for one menstrual cycle; serum reproductive hormone levels in both sexes; and reported ages of onset for pubertal milestones. RESULTS: We observed no strong associations of heptachlor epoxide exposure during gestation and lactation with reproductive endpoints. In females, heptachlor epoxide exposure was associated with longer luteal phase length and slower drop in the ratio of estradiol to progesterone metabolites after ovulation. In males, heptachlor epoxide exposure was weakly associated with higher serum follicle stimulating hormone and luteinizing hormone concentrations, but no dose-response relationship was apparent. CONCLUSIONS: The results provide limited evidence that gestational and lactational exposure to heptachlor epoxide, due to milk contamination on Oahu in 1981-1982, resulted in clinically significant disturbances of reproductive function in men or women.

Enteral nutrition tolerance in patients receiving neuromuscular blockade.

BACKGROUND: Nutrition support is an essential part of critical care medicine. It is commonly accepted that for the critically ill patient, enteral nutrition (EN) is favored. For the patient who receives neuromuscular blockades, EN may be held, or initiation delayed, because of concerns for EN intolerance. We hypothesized there would be no difference in EN tolerance between groups receiving cisatracurium while receiving EN compared with those not receiving cisatracurium. METHODS: This was a retrospective study that included 459 patients from a combined medical and surgical intensive care unit. There were 44 patients who received cisatracurium with EN and 415 who received EN alone. Data collected included gastric residual volume (GRV) and emesis occurrences, new-onset abdominal pain, new or worsening abdominal distention, and bowel ischemia. RESULTS: There were more patients with new or worsening abdominal distention in the group receiving cisatracurium (31.82% vs 14.94%; P < 0.01) as well as occurrences of GRV > 300 ml (P < 0.01). There was no statistically significant difference between the groups regarding emesis, new-onset abdominal pain, or bowel ischemia. CONCLUSION: Our findings suggest that it is acceptable to provide patients with EN who are receiving cisatracurium.

Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

An unconventional mechanism of IL-1ß secretion that requires Type I IFN in lupus monocytes.

Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1ß (IL-1ß) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1ß production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1ß release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

Safety and Tolerance of Enteral Nutrition in the Medical and Surgical Intensive Care Unit Patient Receiving Vasopressors.

BACKGROUND: Multiple societal guidelines recommend enteral nutrition (EN) be initiated within 24 to 48 hours of admission to the intensive care unit (ICU) once a patient is hemodynamically stable. Gastrointestinal intolerance and occurrence of bowel ischemia have been a concern for patients receiving vasopressors while concurrently receiving luminal nutrients. The study objective was to determine whether patients receiving vasopressors while concomitantly receiving enteral nutrients had more incidences of bowel ischemia and intolerance than those receiving EN without vasopressor agents. METHODS: This retrospective study included 319 medical and surgical ICU patients from a level 1 trauma center. The patients were either receiving vasopressors simultaneously with EN (n = 178) or EN alone (n = 141). Data regarding gastric residual volume (GRV), new abdominal pain, emesis, and bowel ischemia were collected. RESULTS: There were more patients who had elevated GRV in the group that received vasopressors than patients who did not (20% vs 7%; P-value < .01). There were no differences between rates of bowel ischemia, emesis, or new abdominal pain between the 2 groups. CONCLUSION: Based on our findings, EN is generally well tolerated and safe for those patients simultaneously receiving vasopressors.

A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate.

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

Orbital Granulomatosis With Polyangiitis Mimicking IgG4-Related Disease in a 12-Year-Old Male.

Granulomatosis with polyangiitis is rare in children. We report a case of a 12-year-old male who presented with new symptoms of left eyelid swelling and ptosis. Magnetic resonance imaging showed an enhancing orbital mass suspicious for a neoplasm. Excisional biopsy was performed. Microscopic examination revealed fibrovascular tissue with dense collagenous fibrosis and mixed inflammatory infiltrate that included many plasma cells. Many small and medium-sized blood vessels showed granulomatous and necrotizing vasculitis with disruption of the vessel walls and fibrinoid necrosis. Immunostain for IgG highlighted the numerous plasma cells, approximately 50% of which were positive for IgG4 immunostain. A diagnosis of granulomatosis with polyangiitis was suggested, with recommendation of serologic testing for anti-neutrophil cytoplasmic antibodies. Serum anti-neutrophil cytoplasmic antibodies were borderline high with a cytoplasmic staining pattern. The patient improved with steroid and methotrexate therapy. Granulomatosis with polyangiitis can present as an orbital mass in up to 30% of children. It may be misdiagnosed as IgG4-related disease since the inflammatory background in both conditions may be rich in plasma cells with a high proportion of IgG4+ plasma cells, and accompanied by fibrosis and obliterated blood vessels. The differential diagnosis in this location should also include inflammatory pseudotumor and inflammatory myofibroblastic tumor. Knowledge of this unusual manifestation of granulomatosis with polyangiitis and its diagnostic pitfalls can facilitate early diagnosis and treatment.

Morin Stain Detects Aluminum-Containing Macrophages in Macrophagic Myofasciitis and Vaccination Granuloma With High Sensitivity and Specificity.

Macrophagic myofasciitis (MMF) is an inflammatory condition associated with the intramuscular (i.m.) injection of aluminum adjuvant-containing vaccines. It is clinically characterized by myalgia, weakness, and chronic fatigue and histologically by aggregates of cohesive macrophages with abundant basophilic, periodic acid-Schiff (PAS)-positive, diastase-resistant granules that percolate through the peri- and endomysium without eliciting substantial myofiber damage. The definitive diagnosis of MMF requires demonstration of aluminum within these macrophages. We evaluated the Morin stain, a simple, 2-step histochemical stain for aluminum, as a confirmatory diagnostic tool for MMF. Among 2270 muscle biopsies processed at UTSW between 2010 and 2015, a total of 12 MMF cases and 1 subcutaneous vaccination granuloma case were identified (11 pediatric, 2 adults). With the Morin stain, all 13 cases showed strong granular reactivity within the cytoplasm of macrophages but not in myofibers or connective tissue. Three cases of inflammatory myopathy with abundant macrophages (IMAM), 8 cases of granulomatous inflammation and 23 other deltoid muscle biopsies used as controls were all negative. Morin stain could be used in both formalin-fixed paraffin-embedded and cryostat sections. Thus, Morin stain detects aluminum with high sensitivity and specificity in human muscle and soft tissue and may improve the diagnostic yield of MMF and vaccination granuloma.

Differential response to exercise in claudin-low breast cancer.

Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.

Surveillance for febrile respiratory infections during Cobra Gold 2003.

The Naval Health Research Center conducted laboratory-based surveillance for febrile respiratory infections at the 2003 Cobra Gold Exercise in Thailand. Seventeen individuals met the case definition for febrile respiratory illness, and diagnostic specimens were obtained from 16. Laboratory testing identified influenza A for 44%; sequence analysis demonstrated that these were Fujian-like influenza strains, which represented the predominant strain found globally in 2003/2004. Other pathogens identified included coronavirus OC43, respiratory syncytial virus, and rhinovirus. Logistical challenges were overcome as laboratory-supported febrile respiratory illness surveillance was conducted during a military training exercise. With heightened concern over the potential for another global influenza pandemic, such surveillance could prove critical for the detection of emerging influenza and respiratory pathogen strains with potential for importation to the United States.

A lengthy look at the daily grind: time series analysis of events, mood, stress, and satisfaction.

The present study investigated processes by which job stress and satisfaction unfold over time by examining the relations between daily stressful events, mood, and these variables. Using a Web-based daily survey of stressor events, perceived strain, mood, and job satisfaction completed by 14 university workers, 1,060 occasions of data were collected. Transfer function analysis, a multivariate version of time series analysis, was used to examine the data for relationships among the measured variables after factoring out the contaminating influences of serial dependency. Results revealed a contrast effect in which a stressful event associated positively with higher strain on the same day and associated negatively with strain on the following day. Perceived strain increased over the course of a semester for a majority of participants, suggesting that effects of stress build over time. Finally, the data were consistent with the notion that job satisfaction is a distal outcome that is mediated by perceived strain.

A randomised placebo-controlled trial of oral hydrocortisone for treating tobacco withdrawal symptoms.

RATIONALE: Many smokers experience a decline in cortisol to sub-normal levels during the first days of smoking cessation. A greater decline in cortisol is associated with more intense cigarette withdrawal symptoms, urge to smoke and relapse to smoking. Findings from an uncontrolled study suggest that glucocorticoids could ameliorate cigarette withdrawal. OBJECTIVES: We investigated whether taking oral hydrocortisone would reduce withdrawal symptoms and the desire to smoke on the first day of temporary smoking abstinence compared with placebo. METHODS: Using a double-blind within-subject randomised crossover design, 48 smokers took a single dose of 40 mg hydrocortisone, 20 mg hydrocortisone or placebo following overnight smoking abstinence. Abstinence was maintained through the afternoon, and withdrawal symptoms and the desire to smoke were rated across the morning. Salivary cortisol was assessed in the afternoon prior to abstinence (baseline) and while abstinent after each treatment. RESULTS: There was a significant dose-response relation between dose of hydrocortisone and reduction in depression and anxiety ratings while abstinent, but there were no other statistically significant associations with dose. Overall, the decline in cortisol following smoking cessation (placebo only) was not significant. Cortisol level on the afternoon of smoking abstinence was not significantly associated with symptom ratings. CONCLUSIONS: Supplements of hydrocortisone do not reduce the desire to smoke but may ameliorate withdrawal-related depression and anxiety, although the clinical benefit is slight.

A new heterobinuclear FeIIICuII complex with a single terminal FeIII-O(phenolate) bond. Relevance to purple acid phosphatases and nucleases.

A novel heterobinuclear mixed valence complex [Fe(III)Cu(II)(BPBPMP)(OAc)(2)]ClO(4), 1, with the unsymmetrical N(5)O(2) donor ligand 2-bis[{(2-pyridylmethyl)aminomethyl}-6-{(2-hydroxybenzyl)(2-pyridylmethyl)}aminomethyl]-4-methylphenol (H(2)BPBPMP) has been synthesized and characterized. A combination of data from mass spectrometry, potentiometric titrations, X-ray absorption and electron paramagnetic resonance spectroscopy, as well as kinetics measurements indicates that in ethanol/water solutions an [Fe(III)-(mu)OH-Cu(II)OH(2)](+) species is generated which is the likely catalyst for 2,4-bis(dinitrophenyl)phosphate and DNA hydrolysis. Insofar as the data are consistent with the presence of an Fe(III)-bound hydroxide acting as a nucleophile during catalysis, 1 presents a suitable mimic for the hydrolytic enzyme purple acid phosphatase. Notably, 1 is significantly more reactive than its isostructural homologues with different metal composition (Fe(III)M(II), where M(II) is Zn(II), Mn(II), Ni(II), or Fe(II)). Of particular interest is the observation that cleavage of double-stranded plasmid DNA occurs even at very low concentrations of 1 (2.5 microM), under physiological conditions (optimum pH of 7.0), with a rate enhancement of 2.7 x 10(7) over the uncatalyzed reaction. Thus, 1 is one of the most effective model complexes to date, mimicking the function of nucleases.

Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion.

Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P =.00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.