Regulation and Role of the Presynaptic and Myocardial Na+/H+ Exchanger NHE1: Effects on the Sympathetic Nervous System in Heart Failure

In acute myocardial ischemia and in chronic heart failure, sympathetic activation with excessive norepinephrine (NE) release from and reduced NE reuptake into sympathetic nerve endings is a prominent cause of arrhythmias and cardiac dysfunction. The Na⁺/H⁺ exchanger NHE1 is the predominant isoform in the heart. It contributes to cellular acid–base balance, and electrolyte, and volume homeostasis, and is activated in response to intracellular acidosis and/or activation of guanine nucleotide binding (G) protein‐coupled receptors. NHE1 mediates its signaling via protein kinases A (PKA) or C (PKC). In cardiomyocytes, NHE1 is restricted to specialized membrane domains, where it regulates the activity of pH‐sensitive proteins and modulates the driving force of the Na⁺/Ca²⁺ exchanger. During acute ischemia/reperfusion and in heart failure the activity/amount of NHE1 is increased, leading to intracellular Ca²⁺ overload and promoting structural (apoptosis, hypertrophy) and functional (arrhythmias, hypercontraction) myocardial damage. In sympathetic nerve endings, increased NHE1 activity results in the accumulation of axoplasmic Na⁺ that diminishes the inward and/or favors the outward transport of NE via the neuronal norepinephrine transporter (NET). The increased NE levels within the nerve–muscle junction facilitate the sustained stimulation of myocardial α‐ and β‐adrenoceptors (ARs), which in turn aggravate the increases in myocardial NHE1 activity and the associated deleterious effects. Furthermore, the responsiveness of the β‐AR declines overtime, which results in further release of NE, initiating a vicious cycle. Accordingly, NHE1 is a potential candidate for targeted intervention to suppress this feedback loop.     

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.     

Event-related potential evidence for a dual-locus model of global/local processing

We investigated the perceptual time course of global/local processing using event-related potentials (ERPs). Participants discriminated the global or local level of hierarchical letters of different sizes and densities. Participants were faster to discriminate the local level of large/sparse letters and the global level of small/dense letters. This was mirrored in early ERP components: The N1/N2 had smaller peak amplitudes when participants made discriminations at the level that took precedence. Only global discriminations for large/sparse letters led to amplitude enhancement of the later P3 component, suggesting that additional attention-demanding processes are involved in discriminating the global level of these stimuli. Our findings suggest a dual-locus time course for global/local processing: (a) Level precedence occurs early in visual processing; (b) extra processing is required at a later stage, but only for global discriminations of large, sparse, stimuli, which may require additional attentional resources for active grouping.     

Human Rhinoviruses

Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs.     

The AAGP Scholars Program: Predictors of Pursuing Geriatric Psychiatry Fellowship Training

ObjectiveThe American Association for Geriatric Psychiatry (AAGP) Scholars Program was developed to recruit trainees into geriatric psychiatry fellowships and is considered a pipeline for fellowship recruitment. Nonetheless, the number of trainees entering geriatric psychiatry fellowship is declining, making it important to identify modifiable factors that may influence trainees’ decisions to pursue fellowship. We analyzed survey data from Scholars Program participants to identify demographic characteristics, attitudes toward program components, and behaviors after the program that were independently associated with the decision to pursue fellowship.MethodsWeb-based surveys were distributed to all 289 former Scholars participants (2010–2018), whether or not they had completed geriatric psychiatry fellowships. We conducted a hierarchical binary logistic regression analysis to examine demographics, program components, and behaviors after the program associated with deciding to pursue geriatric psychiatry fellowship.ResultsSixty-one percent of Scholars decided to pursue geriatric psychiatry fellowship. Attending more than one AAGP annual meeting (relative variance explained [RVE] = 34.2%), maintaining membership in the AAGP (RVE = 28.2%), and rating the Scholars Program as important for meeting potential collaborators (RVE = 26.6%) explained the vast majority of variance in the decision to pursue geriatric psychiatry fellowship.ConclusionNearly two-thirds of Scholars Program participants decided to pursue geriatric psychiatry fellowship, suggesting the existing program is an effective fellowship recruitment pipeline. Moreover, greater involvement in the AAGP longitudinally may positively influence Scholars to pursue fellowship. Creative approaches that encourage Scholars to develop collaborations, maintain AAGP membership, and regularly attend AAGP annual meetings may help attract more trainees into geriatric psychiatry.     

TNF-α and IL-1β sensitize human MSC for IFN-γ signaling and enhance neutrophil recruitment

During inflammatory processes, tissue environmental cues are influencing the immunoregulatory properties of tissue-resident mesenchymal stem/stromal cells (MSC). In this study, we elucidated one of the molecular and cellular responses of human MSC exposed to combinations of inflammatory cytokines. We showed that during multi-cytokine priming by TNF-α, IL-1β, and IFN-γ, IL-1β further augmented the well-established immunoregulatory activity induced by TNF-α/IFN-γ. On the molecular level, TNF-α and IL-1β enhanced the expression of IFN-γ receptor (IFN-γR) via NF 'kappa-light-chain-enhancer' of activated B-cells (NF-κΒ) signaling. In turn, enhanced responsiveness to IFN-γ stimulation activated STAT5 and p38-MAPK signaling. This molecular feedback resulted in an increased IL-8 release and augmented recruitment of polymorphonuclear granulocytes (PMN). Our study suggests the possibility that responses of MSC to multi-cytokine priming regimens may be exploited therapeutically to fine-tune inflammatory activity in tissues. This study elucidates molecular mechanisms underlying the immunological priming of mesenchymal stromal cells (MSC) and their interaction with neutrophils.     

Emergence of racial/ethnic and socioeconomic differences in objectively measured sleep–wake patterns in early infancy: results of the Rise & SHINE study

Study ObjectivesTo characterize objectively assessed sleep–wake patterns in infants at approximately 1 month and 6 months and examine the differences among infants with different racial/ethnic backgrounds and household socioeconomic status (SES).MethodsFull-term healthy singletons wore an ankle-placed actigraph at approximately 1 month and 6 months and parents completed sleep diaries. Associations of racial/ethnic and socioeconomic indices with sleep outcomes were examined using multivariable analyses. Covariates included sex, birth weight for gestational age z-score, age at assessment, maternal education, household income, bed-sharing, and breastfeeding.ResultsThe sample included 306 infants, of whom 51% were female, 42.5% non-Hispanic white, 32.7% Hispanic, 17.3% Asian, and 7.5% black. Between 1 month and 6 months, night sleep duration increased by 65.7 minutes (95% CI: 55.4, 76.0), night awakenings decreased by 2.2 episodes (2.0, 2.4), and daytime sleep duration decreased by 73.3 minutes (66.4, 80.2). Compared to change in night sleep duration over this development period for white infants (82.3 minutes [66.5, 98.0]), night sleep increased less for Hispanic (48.9 minutes [30.8, 66.9]) and black infants (31.6 minutes [−5.9, 69.1]). Night sleep duration also increased less for infants with lower maternal education and household income. Asian infants had more frequent night awakenings. Adjustment for maternal education and household income attenuated all observed day and night sleep duration differences other than in Asians, where persistently reduced nighttime sleep at 6 months was observed.ConclusionsRacial/ethnic differences in sleep emerge in early infancy. Night and 24-hour sleep durations increase less in Hispanic and black infants compared to white infants, with differences largely explained by SES.     

β3-integrin Leu33Pro gain of function variant does not modulate inflammatory activity in human derived macrophages in diabetes

Objective: We aimed to investigate the association between the Leu33Pro (rs5918) polymorphism in β3-integrin with diabetic complications and inflammatory function of macrophages depending on the genotype in subjects with diabetes mellitus.Material and methods: We determined the Leu33Pro polymorphism in 186 diabetic subjects and collected laboratory data. Monocytes from 24 patients were collected for macrophage differentiation to determine the inflammatory activity by treating with different stimulants.Results: We could demonstrate that human derived differentiated macrophages expressed β3‑integrin. Their secretory capacity upon inflammatory stimulation did not reveal any differences depending on the Leu33Pro variant. We found trends for an association of the polymorphism with the presence of diabetic nephropathy (p = 0.071), as well as with creatinine [1.32 mg/dL (1) vs. 0.98 mg/dL (0)] (p = 0.029 in recessive model) and glomerular filtration rate [75.6 ml/min ± 22 vs. 62.3 ml/min ± 25] (p = 0.076 in recessive model) as quantitative markers of kidney function.Conclusion: Despite the expression of β3‑integrin in human macrophages, the Leu33Pro polymorphism in β3‑integrin does not modify the inflammatory response upon stimulation but might play a role in the progression of diabetic nephropathy. Further studies are necessary to substantiate such a hypothesis.     

Staging more important than grading? Evaluation of malignancy grading,depth of invasion,and resection margins in oral squamous cell carcinoma

Clinical Oral Investigations - The present study evaluated the predictive value of staging and grading parameters concerning the presence of lymph-node metastases, overall survival (OS), and...