Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK ...inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.
Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated STING-associated vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.
Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range IQR, 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.
Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.
ClinicalTrials.gov NCT01724580 and NCT02974595.
This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.
Background Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been ...reported. Objective We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. Methods We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. Results A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. Limitations The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. Conclusion A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.
Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker ...and consistent evidence shows a significant proportion (20–30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study.
We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-β-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index.
In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (β = −1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (β = −0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients.
These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation.
•Males with MDD show decreased levels of testosterone and TSI.•Females with MDD and healthy controls have similar sex hormone levels.•Males with MDD with high-CRP have decreased levels of testosterone.•Females with MDD and high-CRP have decreased levels of SHBG.•In MDD, CRP levels are predicted by testosterone in males and by SHBG in females.
•Electroactive molecularly imprinted polymer nanoparticles (nanoMIPs) are robust actuators due to their polymeric nature.•Graphene-assisted nanoMIPs-based sensors are easily integrated and compatible ...with the mass production of sensor devices.•Sensors were evaluated on spiked human plasma and street samples,also validated successfully using UPLC-MS.•NanoMIP-based sensors can be applied in clinical and forensic analysis.
Screening drugs on the street and biological samples pose a challenge to law enforcement agencies due to existing detection methods and instrument limitations. Herein we present a graphene-assisted molecularly imprinted polymer nanoparticle-based sensor for amphetamine. These nanoparticles are electroactive by incorporating ferrocene in their structure. These particles act as specific actuators in electrochemical sensors, and the presence of a ferrocene redox probe embedded in the structure allows the detection of non-electroactive amphetamine. In a control approach, nanoparticles were covalently immobilised onto electrochemical sensors by drop-casting using silanes. Alternatively, nanoparticles were immobilised employing 3D printing and a graphene ink composite. The electrochemical performance of both approaches was evaluated. As a result, 3D printed nanoMIPs/graphene sensors displayed the highest selectivity in spiked human plasma, with sensitivity at 73 nA nM−1, LOD of 68 nM (RSD 2.4%) when compared to the silane drop cast electrodes. The main advantage of the optimised 3D printing technology is that it allows quantitative determination of amphetamine, a non-electroactive drug, challenging to detect with conventional electrochemical sensors. In addition, the cost-efficient 3D printing method makes these sensors easy to manufacture, leading to robust, highly selective and sensitive sensors. As proof of concept, sensors were evaluated on the street specimens and clinically relevant samples and successfully validated using UPLC-MS.
Treatment options for Duchenne muscular dystrophy remain limited, although consensus treatment guidelines recommend corticosteroid use.
This retrospective analysis assessed corticosteroid use in ...ambulatory and nonambulatory US males with Duchenne, age 35 and under, or Becker muscular dystrophy, who enrolled in The Duchenne Registry from 2007 to 2016 (formerly DuchenneConnect).
The mean (SD) age of corticosteroid use initiation was 5.9 (2.5) years, and deflazacort use (54%) was slightly more common than prednisone/prednisolone (46%). Among all responses from those with Duchenne, 63% were currently on corticosteroids, 12% were no longer on corticosteroids, and 25% had never been on corticosteroids. Among those who were nonambulatory, 49% were currently on corticosteroids, 28% had discontinued corticosteroids, and 23% had never used corticosteroids. Primary reasons for never initiating therapy were that corticosteroids were not prescribed or recommended and concerns about side effects. Corticosteroid use was maximal at age 8 (84% on corticosteroids) and gradually declined from age 10 to 19. The primary reasons for corticosteroid discontinuation were problems with side effects (65%) or not enough benefit (28%). Average doses of corticosteroids were below recommended doses. In the 159 responses with Becker muscular dystrophy, 20% were currently using corticosteroids.
Recognizing the self-selected nature of participation, it appears that a considerable proportion of US participants registered with The Duchenne Registry were either not on corticosteroids or not on recommended doses despite consensus recommendations. Side effects were a consideration in initiating and discontinuing treatment. These data reinforce the need for additional treatment options for those affected by Duchenne.
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the ...interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
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•Cefquinome electrochemical fingerprint allows its identification in the nanomolar range.•Conductive imprinted polymers are obtained by electropolymerization of 4-amino benzoic ...acid.•The synergistic contribution of MWCNTs and MIP is crucial to achieve higher sensitivity.•Under optimum conditions, the lower detectable CFQ concentration on the sensor is 50 nM.
A biomimetic sensor for cefquinome (CFQ) was designed at multi-walled carbon nanotubes modified graphite screen-printed electrodes (MWCNTs-G-SPEs) as a proof-of-concept for the creation of a sensors array for β-lactam antibiotics detection in milk. The sensitive and selective detection of antibiotic residues in food and environment is a fundamental step in the elaboration of prevention strategies to fight the insurgence of antimicrobial resistance (AMR) as recommended by authorities around the world (EU, WHO, FDA). The detection strategy is based on the characteristic electrochemical fingerprint of the target antibiotic cefquinome. A conductive electropolymerized molecularly imprinted polymer (MIP) coupled with MWCNTs was found to be the optimal electrode modifier, able to provide an increased selectivity and sensitivity for CFQ detection. The design of CFQ-MIP was facilitated by the rational selection of the monomer, 4-aminobenzoic acid (4-ABA). The electropolymerization process of 4-ABA have not been fully elucidated yet; for this reason a thorough study and optimization of electropolymerization conditions was performed to obtain a conductive and stable poly(4-ABA) film. The modified electrodes were characterized by electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM) and cyclic voltammetry (CV). CFQ-MIP were synthesized at MWCNT-G-SPEs by electropolymerization in pH≈1 (0.1 M sulphuric acid) with a monomer:template ratio of 5:1. Two different analytical protocols were tested (single and double step detection) to minimize unspecific adsorptions and improve the sensitivity. Under optimal conditions, the lowest CFQ concentration detectable by square wave voltammetry (SWV) at the modified sensor was 50 nM in 0.1 M phosphate buffer pH 2.
An enduring focus in the science of emotion is the question of which psychological states are signaled in expressive behavior. Based on empirical findings from previous studies, we created ...photographs of facial-bodily expressions of 18 states and presented these to participants in nine cultures. In a well-validated recognition paradigm, participants matched stories of causal antecedents to one of four expressions of the same valence. All 18 facial-bodily expressions were recognized at well above chance levels. We conclude by discussing the methodological shortcomings of our study and the conceptual implications of its findings.
We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and ...fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/μL; median, 14.5 cells/μL), B lymphocytopenia (mean, 9.4 cells/μL; median, 4 cells/μL), and NK lymphocytopenia (mean, 16 cells/μL; median, 5.5 cells/μL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus+ leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti–granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
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