The metabolic response of human trophoblasts derived from term placentas to metformin.

AIMS/HYPOTHESIS: Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS: A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS: Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION: In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.

Immunoglobulin G4-Related Disease-Associated Dermatitis with Pruritus: A Positive Response to Dupilumab.

Immunoglobulin G4-related disease (IgG4-RD) is a rare fibro-inflammatory condition characterized by IgG4-expressing plasma cell infiltration of the skin and other organs, leading to profound itchiness. Oral corticosteroids are the first-line therapy for IgG4-RD but relapses and potential side effects are common. In this case, we discuss a patient with a hyperpigmented, scaling dermatitis on his arms, back, and chest with lichen amyloidosis (LA) that incompletely responded to corticosteroids. He had reduced quality of life secondary to chronic pruritus. Dupilumab, an IL-4 and IL-13 inhibitor, was initiated. He experienced a transient worsening, followed by complete resolution of his itch with remission of his rash. While the pathogenesis of IgG4-RD is not entirely understood, a T-helper 2 (Th2) immune response has been implicated, with interleukins (IL) 4, 5, 10, and 13 playing a role in IgG4 class switch, resulting in eosinophilia and elevated IgE. The strong response of dupilumab in this case may provide evidence in favor of the involvement of IL-4 and IL-13 in the pathogenesis of cutaneous IgG4-RD. Future clinical studies involving larger patient populations may be warranted.

A Retrospective Review of Tofacitinib in the Treatment of Refractory Dermatomyositis.

Dermatomyositis (DM) is an autoimmune myopathy with characteristic dermatologic features.1 Tofacitinib is an immunomodulator with proven efficacy against numerous immune-mediated disorders, including rheumatoid arthritis (RA) and psoriasis.2 Several reports have demonstrated oral tofacitinib’s ability to treat the cutaneous and extracutaneous manifestations of refractory dermatomyositis (DM).1,4,5 However, evidence for sustained improvement remains limited.2,3 The goal of this study is to investigate the long-term response of recalcitrant DM to oral and topical tofacitinib at varied dosing regimens.

Impact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress.

Metformin is increasingly prescribed in pregnancy, with beneficial maternal effects. However, it is not known how metformin-treatment impacts metabolism and energy production in the developing feto-placental unit. We assessed the human placental response to metformin using both in vivo and in vitro treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated in vitro with metformin (0.01 mM, 0.1 mM or vehicle). Metformin-concentrations were measured using liquid-chromatography mass-spectrometry. Oxygen consumption in cultured-trophoblasts was measured using a Seahorse-XF Mito Stress Test. Markers of oxidative-stress were assayed using qRT-PCR. Metformin-transporter mRNA and protein-levels were determined by quantitative RT-PCR and Western-blotting respectively. Metformin concentrations were also measured in sample trios (maternal plasma/fetal plasma/placental tissue) from pregnancies exposed to metformin on clinical-grounds. Maternal and fetal metformin concentrations in vivo were highly correlated over a range of concentrations (R2 = 0.76, p < 0.001; average fetal:maternal ratio 1.5; range 0.8-2.1). Basal respiration in trophoblasts was reduced by metformin treatment (0.01 mM metformin; p < 0.05, 0.1 mM metformin; p < 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (p < 0.001). Oxidative stress markers were significantly reduced in primary-trophoblast-cultures following treatment with metformin. There is a close linear relationship between placental, fetal, and maternal metformin concentrations. Primary-trophoblast cultures exposed to clinically-relevant metformin concentrations have reduced mitochondrial-respiration, mitochondrial-dependent ATP-production, and reduced markers of oxidative-stress. Given the crucial role of placental energy-production in supporting fetal growth and well-being during pregnancy, the implications of these findings are concerning for intrauterine fetal growth and longer-term metabolic programming in metformin-exposed pregnancies.

The Impact of Racial Differences on Treatment Strategies in Hidradenitis Suppurativa: A Retrospective Review.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic disease that causes inflammatory lesions typically found in the axillary, inguinal, and perineal regions that can result in permanent scarring, fibrosis, and sinus tract formation. Although HS is more prevalent in patients with skin of color, research in HS has historically been performed in European and White populations. We aimed to explore management differences in skin of color HS patients compared to White patients. METHODS: We performed a cross-sectional retrospective review of HS-associated outpatient encounters in the Medical University of South Carolina’s Research Data Warehouse from 1/2017–12/2020. We performed descriptive statistics and chi-square analyses. RESULTS: We found that Black HS patients were more likely to receive metformin and nonsteroidal anti-inflammatory drugs (NSAIDs) during HS-associated visits. We also found that Black patients were less likely to see dermatology and primary care and more likely to see surgery for their HS-associated visits. Lastly, skin of color HS patients were more likely to have a complex excision (P<0.001). DISCUSSION: We found differences in the medical and procedural care provided to Black HS patients compared to White patients. A limitation of our study is the lack of information concerning efficacy of treatment interventions and clinical outcomes. Future studies should include a representative population of HS patients with a higher proportion of skin of color HS patients and include race as a variable when investigating medical and surgical outcomes to understand mechanisms that could explain differences in disease profiles across racial groups. J Drugs Dermatol. 2022;21(3):270-275. doi:10.36849/JDD.6446.

Feasibility of Specimen Self-collection in Young Children Undergoing SARS-CoV-2 Surveillance for In-Person Learning.

Importance: There is an urgent need to assess the feasibility of COVID-19 surveillance measures in educational settings. Objective: To assess whether young children can feasibly self-collect SARS-CoV-2 samples for surveillance testing over the course of an academic year. Design, Setting, and Participants: This prospective pilot cohort study was conducted from September 10, 2020, to June 10, 2021, at a K-8 school in San Mateo County, California. The research consisted of quantitative data collection efforts: (1) demographic data collected, (2) student sample self-collection error rates, and (3) student sample self-collection time durations. Students were enrolled in a hybrid learning model, a teaching model in which students were taught in person and online, with students having the option to attend virtually as needed. Data were collected under waiver of consent from students participating in weekly SARS-CoV-2 testing. Main Outcomes and Measures: Errors over time for self-collection of nasal swabs such as contaminated swabs and inadequate or shallow swabbing; time taken for sample collection. Results: Of 296 participants, 148 (50.0%) were boys and 148 (50.0%) were girls. A total of 87 participants (29.2%) identified as Asian; 2 (0.6%), Black or African American; 13 (4.4%), Hispanic/Latinx; 103 (34.6%), non-Hispanic White; 87 (29.2%), multiracial; and 6 (2.0%), other. The median school grade was fourth grade. From September 2020 to March 2021, a total of 4203 samples were obtained from 221 students on a weekly basis, while data on error rates were collected. Errors occurred in 2.7% (n = 107; 95% CI, 2.2%-3.2%) of student encounters, with the highest rate occurring on the first day of testing (20 [10.2%]). There was an overall decrease in error rates over time. From April to June 2021, a total of 2021 samples were obtained from 296 students on a weekly basis while data on encounter lengths were collected. Between April and June 2021, 193 encounters were timed. The mean duration of each encounter was 70 seconds (95% CI, 66.4-73.7 seconds). Conclusions and Relevance: Mastery of self-collected lower nasal swabs is possible for children 5 years and older. Testing duration can be condensed once students gain proficiency in testing procedures. Scalability for larger schools is possible if consideration is given to the resource-intensive nature of the testing and the setting's weather patterns.

Eosinophils and melanoma: Implications for immunotherapy.

New therapies such as immune checkpoint blockers (ICB) have offered extended survival to patients affected by advanced melanoma. However, ICBs have demonstrated debilitating side effects on the joints, liver, lungs, skin, and gut. Several biomarkers have been identified for their role in predicting which patients better tolerate ICBs. Still, these biomarkers are limited by immunologic and genetic heterogeneity and the complexity of translation into clinical practice. Recent observational studies have suggested eosinophil counts, and serum levels of eosinophil cationic protein are significantly associated with prolonged survival in advanced-stage melanoma. It is likely that eosinophils thereby modulate treatment response through mechanisms yet to be explored. Here, we review the functionality of eosinophils, their oncogenic role in melanoma and discuss how these mechanisms may influence patient response to ICBs and their implications in clinical practice.

Psoriasiform dermatitis following intravenous immunoglobulin therapy: A case series.

Intravenous immunoglobulin (IVIg) is a frequently used treatment modality in the pediatric inpatient population for acute diseases such as Kawasaki disease and Stevens-Johnson syndrome. There are few reported cutaneous adverse events after IVIg in the pediatric population. Here, we present two patients with psoriasiform dermatitis appearing after IVIg treatment for two different disease processes, Kawasaki disease and mycoplasma-associated mucositis, suggesting an association with the treatment instead of the disease process.