Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH.

CO2, the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO2 is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO2-sensing mechanisms and downstream pathways involved. We found that elevated CO2 correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO2 reduces migration in vitro. Mechanistically, CO2 reduces autocrine inflammatory gene expression, thereby inhibiting macrophage activation in a manner dependent on decreased intracellular pH. Pharmacologic or genetic inhibition of carbonic anhydrases (CAs) uncouples a CO2-elicited intracellular pH response and attenuates CO2 sensitivity in immune cells. Conversely, CRISPR-driven upregulation of the isoenzyme CA2 confers CO2 sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO2 (hypercapnia) display a greater risk of developing anastomotic leakage following gastrointestinal surgery, indicating impaired wound healing. Furthermore, low intraoperative pH levels in these patients correlate with reduced intestinal macrophage infiltration. In conclusion, CO2 is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.

Prevalence, Predictors, and Treatment of Impostor Syndrome: a Systematic Review.

BACKGROUND: Impostor syndrome is increasingly presented in the media and lay literature as a key behavioral health condition impairing professional performance and contributing to burnout. However, there is no published review of the evidence to guide the diagnosis or treatment of patients presenting with impostor syndrome. PURPOSE: To evaluate the evidence on the prevalence, predictors, comorbidities, and treatment of impostor syndrome. DATA SOURCES: Medline, Embase, and PsycINFO (January 1966 to May 2018) and bibliographies of retrieved articles. STUDY SELECTION: English-language reports of evaluations of the prevalence, predictors, comorbidities, or treatment of impostor syndrome. DATA EXTRACTION: Two independent investigators extracted data on study variables (e.g., study methodology, treatments provided); participant variables (e.g., demographics, professional setting); diagnostic tools used, outcome variables (e.g., workplace performance, reductions in comorbid conditions); and pre-defined quality variables (e.g., human subjects approval, response rates reported). DATA SYNTHESIS: In total, 62 studies of 14,161 participants met the inclusion criteria (half were published in the past 6 years). Prevalence rates of impostor syndrome varied widely from 9 to 82% largely depending on the screening tool and cutoff used to assess symptoms and were particularly high among ethnic minority groups. Impostor syndrome was common among both men and women and across a range of age groups (adolescents to late-stage professionals). Impostor syndrome is often comorbid with depression and anxiety and is associated with impaired job performance, job satisfaction, and burnout among various employee populations including clinicians. No published studies evaluated treatments for this condition. LIMITATIONS: Studies were heterogeneous; publication bias may be present. CONCLUSIONS: Clinicians and employers should be mindful of the prevalence of impostor syndrome among professional populations and take steps to assess for impostor feelings and common comorbidities. Future research should include evaluations of treatments to mitigate impostor symptoms and its common comorbidities.

Constitutive regulation of the glutamate/aspartate transporter EAAT1 by Calcium-Calmodulin-Dependent Protein Kinase II.

Glutamate clearance by astrocytes is an essential part of normal excitatory neurotransmission. Failure to adapt or maintain low levels of glutamate in the central nervous system is associated with multiple acute and chronic neurodegenerative diseases. The primary excitatory amino acid transporters in human astrocytes are EAAT1 and EAAT2 (GLAST and GLT-1, respectively, in rodents). While the inhibition of calcium/calmodulin-dependent kinase (CaMKII), a ubiquitously expressed serine/threonine protein kinase, results in diminished glutamate uptake in cultured primary rodent astrocytes (Ashpole et al. 2013), the molecular mechanism underlying this regulation is unknown. Here, we use a heterologous expression model to explore CaMKII regulation of EAAT1 and EAAT2. In transiently transfected HEK293T cells, pharmacological inhibition of CaMKII (using KN-93 or tat-CN21) reduces [3 H]-glutamate uptake in EAAT1 without altering EAAT2-mediated glutamate uptake. While over-expressing the Thr287Asp mutant to enhance autonomous CaMKII activity had no effect on either EAAT1 or EAAT2-mediated glutamate uptake, over-expressing a dominant-negative version of CaMKII (Asp136Asn) diminished EAAT1 glutamate uptake. SPOTS peptide arrays and recombinant glutathione S-transferase-fusion proteins of the intracellular N- and C-termini of EAAT1 identified two potential phosphorylation sites at residues Thr26 and Thr37 in the N-terminus. Introducing an Ala (a non-phospho mimetic) at Thr37 diminished EAAT1-mediated glutamate uptake, suggesting that the phosphorylation state of this residue is important for constitutive EAAT1 function. Our study is the first to identify a glutamate transporter as a direct CaMKII substrate and suggests that CaMKII signaling is a critical driver of constitutive glutamate uptake by EAAT1.

Integrating behavioral health services at employer-sponsored health clinics: A descriptive analysis.

INTRODUCTION: Approximately, 20% of adults in the United States have a behavioral health concern, resulting in $732M in direct medical spending and over 5 million lost workdays annually. Employers bear a substantial share of these costs. The objective of this study was to describe the integration of behavioral health services at employer-sponsored health clinics. METHOD: Retrospective cohort analysis of patients seen for individual behavioral health services from 1/1/2018 to 12/31/2018 in employer-sponsored clinics. RESULTS: Among the 2,954 patients cared for by a behavioral health provider, 49% met criteria for moderate or severe depression and/or anxiety. The median duration between appointment scheduling and a behavioral health triage visit was 2 days (SD = 7.2 days), and median interval to an initial psychotherapy visit was 10 days (SD = 14 days). The mean number of visits with a behavioral health provider within the initial 3 months after presenting for care was 5.3 visits (SD = 2.8 visits). During the course of treatment, anxiety (Generalized Anxiety Disorder-7 [GAD-7] scores) decreased by 31% and depression (Patient Health Questionnaire-9 [PHQ-9] scores) decreased by 24%. Patient satisfaction with their behavioral health care was excellent. DISCUSSION: Integrating behavioral health services into employer-sponsored clinics can result in timely access to psychotherapy, improvements in clinical symptoms, and excellent patient satisfaction. Employers interested in providing greater access to behavioral health care should evaluate integrating such services into onsite or near-site health clinics. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

An EPR Study of 2,3-Bis(diphenylphosphino)maleic Anhydride (BMA) Complexes and the BMA Radical Anion.

EPR spectra are reported for four metal complexes of 2,3-bis(diphenylphosphino)maleic anhydride (BMA), [Co(2)(PhCCR)(CO)(4)(eta-BMA)](-), R = Ph, H, [Co(2)(PhCCPh)(CO)(4)(&mgr;-BMA)](-), and [PhCW(CO)(2)(BMA)Cl](-), as well as the radical anions, [BMA](-) and [BPCD](-), BPCD = 4,5-bis(diphenylphosphino)cyclopentene-1,3-dione. At room temperature, all spectra are 1:2:1 triplets due to hyperfine coupling to two equivalent (31)P nuclei with coupling to two equivalent (1)H nuclei for [BPCD](-) and unresolved coupling to one or two (59)Co nuclei for the Co complexes with chelating or bridging BMA, respectively. The (31)P couplings are temperature dependent, ca. -3 and -13 mG K(-)(1) for the metal complexes and ligand radical anions, respectively. At low temperature, the spectrum of [BMA](-) shows the presence of symmetric and asymmetric PPh(2) rotational conformers, related by the thermodynamic parameters DeltaH degrees = -0.8 +/- 0.2 kJ mol(-)(1) and DeltaS degrees = 4 +/- 1 J mol(-)(1) K(-)(1) and interconverted with activation parameters DeltaH() = 18.2 +/- 0.4 kJ mol(-)(1), DeltaS() = -30 +/- 2 J mol(-)(1) K(-)(1). The temperature dependence of the (31)P couplings is explained by a negative spin-polarization contribution to and a positive contribution due to P 3s character; the latter increases with the asymmetry of the PPh(2) conformations. The range of conformations accessible to the metal complexes is less than for the ligand radical anions, and accordingly the temperature dependence is significantly smaller.

Relationships between pediatric asthma and socioeconomic/urban variables in Baltimore, Maryland.

Spatial relationships between clinical data for pediatric asthmatics (hospital and emergency department utilization rates), and socioeconomic and urban characteristics in Baltimore City were analyzed with the aim of identifying factors that contribute to increased asthma rates. Socioeconomic variables and urban characteristics derived from satellite data explained 95% of the spatial variation in hospital rates. The proportion of families headed by a single female was the most important variable accounting for 89% of the spatial variation. Evidence suggests that the high rates of hospital admissions and emergency department (ED) visits may partially be due to the difficulty of single parents with limited resources managing their child's asthma condition properly. This knowledge can be used for education towards mitigating ED and hospital events in Baltimore City.