Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.

INTRODUCTION: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses. METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma. RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle). CONCLUSION: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.

A Rare Organism Causing Cholecystitis With Bacteremia in a Breast Cancer Patient.

Pantoea, a gram-negative, rod-shaped, anaerobic bacterium, is a rare cause of human disease. Pantoea species have been known to mostly cause pulmonary disease in agricultural workers as they are native to select crops and wild animal furs. However, in very few documented cases, Pantoea has been discovered as the source of nosocomial infections, usually in the setting of an immunocompromised host. This case report details the clinical course of a 62-year-old immunocompromised female with stage 3 breast cancer presenting with acute cholecystitis and bacteremia and the unexpected discovery of Pantoea in peripheral and chemotherapy port blood cultures. After appropriate management and susceptibility testing, the patient fortunately recovered with initial cefepime and eventual levofloxacin to target the Pantoea species. To our knowledge, this is the third documented case worldwide of Pantoea isolated from cholecystitis with associated bacteremia and the first documented case in North America. Of special interest, a few months after her infection, the patient was found to be free of breast cancer. Pantoea species are known to contain levan, an exopolysaccharide, that has been seen to upregulate tumor suppressor genes. This should be considered in the future management and research of Pantoea infections.

Evidence-Based Approach of Biologic Therapy in Bronchial Asthma.

The emergence of biologic agents in the treatment of bronchial asthma has a wide impact on improving quality of life, reducing morbidity, and overall health care utilization. These therapies usually work by targeting specific inflammatory pathways involving type 2 inflammation and are particularly effective in severe eosinophilic asthma. Various randomized controlled trials have shown their effectiveness by reducing exacerbation rates and decreasing required glucocorticoid dosages. One of the relatively newer agents, tezepelumab, targets thymic stromal lymphoprotein and has proven its efficacy in patients independent of asthma phenotype and serum biomarker levels. This article reviews the pathophysiologic mechanism behind biologic therapy and offers an evidence-based discussion related to the indication, benefits, and adverse effects of such therapies.

Prefrontal cortical protease TACE/ADAM17 is involved in neuroinflammation and stress-related eating alterations.

Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme / a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACE/ADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACE/ADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell™ SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACE/ADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACE/ADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations.

The Interplay of COVID-19 and Hereditary Angioedema: Preventing an Acute Attack.

Hereditary angioedema (HAE) is a rare inherited disease that is caused by the inactivation of the C1 esterase inhibitor. In this case report, we present a 51-year-old female previously diagnosed with HAE who tested positive for SARS-Cov-2 (COVID-19). The patient was treated symptomatically. Dexamethasone was used to treat COVID-19 pneumonia. Broad-spectrum antibiotics (vancomycin and meropenem) were utilized to prevent future infection. Although the patient did not experience an acute angioedema attack during her hospital stay, the patient expired due to the exacerbation of COVID-19 pneumonia.

Lessons From Early COVID-19: Associations With Undergraduate Students' Academic Performance, Social Life, and Mental Health in the United States.

Objectives: This study aims to explore the influence of COVID-19 on undergraduate students' academic performance, social life, and mental health during the pandemic's early stage, and evaluate potential correlates of stress, anxiety, and depression in relation to COVID-19. Methods: Participant data was collected as part of a survey that consisted of demographic questions, a DASS-21 questionnaire, and an open-ended question. The final sample consisted of 1077 full-time students in the United States. Results: 19%, 20%, and 28% of participants met the cutoff for "severe" and "extremely severe" levels of stress, anxiety, and depression according to DASS-21. During COVID-19, a significant increase in hours of sleep, and decrease in hours spent on extracurriculars and studying were observed. While talking to family was significantly associated with stress, anxiety, and depression, engaging in hobbies was only associated with depression. Conclusion: With the continued spread of COVID-19, it is critical for universities to adapt to the mental health needs of their students. Future institutional advancements should create treatment programs to ensure better academic and social outcomes.

Remdesivir-Associated Sinus Arrest in COVID-19: A Potential Indication for Close Cardiac Monitoring.

Remdesivir is an antiviral, nucleoside analog used extensively during the coronavirus-disease 2019 (COVID-19) pandemic with proven efficacy against COVID-19-induced acute respiratory distress syndrome (ARDS). Our case report details the clinical course of a 50-year-old, COVID-19-positive patient who developed sinus arrest after being treated with remdesivir. Within 24 hours of discontinuing remdesivir therapy, the patient's sinus arrest resolved to a normal sinus rhythm. The findings from our case report add to a growing body of evidence on the cardiotoxic profile of remdesivir. Remdesivir's ability to cause bradyarrhythmias, and specifically sinus arrest, should be acknowledged when considering the use of this drug in at-risk patients.

Nipple Reconstruction: Risk Factors and Complications after 189 Procedures.

BACKGROUND: A multitude of different approaches have been proposed for achieving optimal aesthetic results after nipple reconstruction. In contrast, however, only a few studies focus on the morbidity associated with this procedure, particularly after implant-based breast reconstruction. METHODS: Using a cross-sectional study design all patients who underwent implant-based breast reconstruction with subsequent nipple reconstruction between 2000 and 2010 at Stanford University Medical Center were identified. The aim of the study was to analyze the impact of the following parameters on the occurrence of postoperative complications: age, final implant volume, time interval from placement of final implant to nipple reconstruction, and history of radiotherapy. RESULTS: A total of 139 patients with a mean age of 47.5 years (range, 29 to 75 years) underwent 189 nipple reconstructions. The overall complication rate was 13.2 percent (N = 25 nipple reconstructions). No association was observed between age (p = 0.43) or implant volume (p = 0.47) and the occurrence of complications. A trend towards higher complication rates in patients in whom the time interval between final implant placement and nipple reconstruction was greater than 8.5 months was seen (p = 0.07). Radiotherapy was the only parameter that was associated with a statistically significant increase in postoperative complication rate (51.7 percent vs. 6.25 percent; p < 0.00001). CONCLUSION: While nipple reconstruction is a safe procedure after implant-based breast reconstruction in patients without a history of radiotherapy, the presence of an irradiated field converts it to a high-risk one with a significant increase in postoperative complication rate. Patients with a history of radiotherapy should be informed about their risk profile and as a result may choose autologous reconstruction instead. LEVEL OF EVIDENCE: IV.

Nipple reconstruction after implant-based breast reconstruction: a "matched-pair" outcome analysis focusing on the effects of radiotherapy.

BACKGROUND: The major focus of research when addressing nipple reconstruction has been on developing new techniques to provide for long-lasting nipple projection. Rarely, has the outcome of nipple reconstruction as it relates to postoperative morbidity, particularly after implant-based breast reconstruction, been analyzed. METHODS: A "matched-pair" study was designed to specifically answer the question whether a history of radiotherapy predisposes to a higher complication rate after nipple reconstruction in patients after implant-based breast reconstruction. Only patients with a history of unilateral radiotherapy who underwent bilateral mastectomy and implant-based breast reconstruction followed by bilateral nipple reconstruction were included in the study. RESULTS: A total of 17 patients (i.e. 34 nipple reconstructions) were identified who met inclusion criteria. The mean age of the study population was 43.5 years (range, 23-69). Complications were seen after a total of 8 nipple reconstructions (23.5 percent). Of these, 7 complications were seen on the irradiated side (41.2 percent) (p = 0.03). CONCLUSION: While nipple reconstruction is a safe procedure after implant-based breast reconstruction in patients without a history of radiotherapy the presence of an irradiated field converts it to a procedure with a significant increase in postoperative complication rate.