Conditioned inhibition of fear and reward in male and female rats.

Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue.

Adherence in Atopic Dermatitis.

Atopic dermatitis is a chronic dermatologic condition requiring extended treatment times with topical application of medications. While atopic dermatitis treatments can be highly effective when used as directed, oftentimes patients do not respond as expected, raising concern for nonadherence versus nonresponse. This chapter aims to describe what is currently known about adherence in atopic dermatitis and to discuss strategies to improve adherence in order to improve treatment outcomes. Whether intentional or unintentional, nonadherence to treatment can limit patient outcomes of this disease for a variety of reasons. These include frustration with medication efficacy, inconvenience, and fear of side effects. Other factors include forgetfulness, financial burden of treatment, lack of trust in the physician, dislike of prescribed medication, or lack of understanding of disease or treatment. Several interventions have been studied with the aim of improving adherence in atopic dermatitis-such as educational workshops for patients and caregivers, earlier follow-up visits, and text messages reminders-however, these are often limited by sample size and power. Further research is needed to study both specific patterns of nonadherence in atopic dermatitis, as well as methods to improve them.

The Future of Atopic Dermatitis Treatment.

This chapter thoroughly examines recent breakthroughs in atopic dermatitis (AD) treatment, with a primary focus on the medications in the development pipeline. Biologics agents targeting new interleukin receptors like interleukin-31, interleukin-22, and interleukin-2 are discussed along with the novel pathway looking at the OX40-OX40L interaction. Oral agents and small molecule therapies like Janus kinase inhibitors, sphingosine-1-phosphate modulators, and Bruton's tyrosine kinase inhibitors are also discussed along with the various new topical medications. Newly approved topicals like phosphodiesterase-4 and JAK inhibitors are highlighted while also discussing the potential of tapinarof and emerging microbiome-targeted therapies. Beyond conventional approaches, the chapter touches upon unconventional therapies currently being studied. The goal of this chapter is to discuss new advances in AD treatment from medications in the initial stages of development to those nearing FDA approval.

Assessing the Efficacy of Imiquimod Use in Patients With Persistent Locally Advanced Melanoma In Situ

BACKGROUND: The standard of care when treating melanoma in situ (MMIS) is an excision with at least 5 mm surgical margins.1 Some studies have suggested up to 9 mm margins to maximize local recurrence-free survival.2 This retrospective review aims to assess the efficacy of imiquimod as a topical treatment for persistently positive MMIS at the margins of prior excisions or where surgery is not an option. METHODS: Retrospective study conducted at Moffitt Cancer Center between 2019 and 2021 with patients aged > 18 years with MMIS at the margins of excision of an invasive melanoma or MMIS. Included patients were not ideal candidates for primary or additional surgical resection due to non-feasibility of surgery because of comorbidity or cosmetically sensitive location and/or the need for repeated skin grafting, or due to patient's refusal. Patients received imiquimod on protocol for 16 weeks and were monitored for treatment response and side effects. Following completion of the treatment, scouting biopsies were performed to assess histological response, and dermoscopy was used to determine the clinical disease status. RESULTS: Ten patients completed 16 weeks of imiquimod. Seven (75%) had a median of 2 surgical resections, and 3 refused surgery despite discussion that surgery was standard of care. Seven were deemed free of disease on post-imiquimod treatment scouting biopsies, while 2 were found to be clinically free of disease following confocal microscopy, indicating a tumor clearance rate of 90% with imiquimod treatment. One patient was found to have persistent residual disease following 2 rounds of imiquimod and was taken for an additional surgical excision after which they were deemed free of disease. Median follow-up duration from the onset of imiquimod therapy to the last clinic visit was 18 months, without any recurrences to date. CONCLUSION: Imiquimod appears to demonstrate an encouraging tumor clearance among patients with persistent MMIS after surgery where further surgical resection may not be feasible. Although long-term durability has not been demonstrated in this study, a 90% tumor clearance rate is promising. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.6987.

Spectrum of pneumothorax/pneumomediastinum in patients with coronavirus disease 2019.

BACKGROUND: Spontaneous pneumothorax/pneumomediastinum is an uncommon complication of coronavirus disease 2019 (COVID-19). Herein, we describe the clinical spectrum and outcomes of COVID-19-associated pneumothorax/pneumomediastinum in critical care settings. MATERIALS AND METHODS: We hereby present a case series of 12 patients who tested positive for COVID-19 and developed air leak injuries in critical care settings in a tertiary care center in Northern India. Infection with severe acute respiratory syndrome coronavirus-2 was confirmed by nasal/oropharyngeal swab testing using real-time reverse-transcription polymerase chain reaction test. The clinical spectrum and outcomes of these patients were assessed. Each case has been presented as a brief synopsis. RESULTS: The onset of pneumothorax/pneumomediastinum varied from 11 to 28 days after the occurrence of initial symptoms and caused worsening of respiratory parameters in most patients. Of the 12 patients, eight were males who developed air leak injuries. One patient was a current smoker, and three patients had underlying lung disorders. Two patients with spontaneous breathing were managed conservatively. All intubated patients who developed air leak injuries died (100% mortality rate). CONCLUSION: Pneumothorax/pneumomediastinum is a rare and life-threatening complication in mechanically ventilated patients with COVID-19. Further research is needed to understand the pathophysiology behind the development of air leak injuries in patients with COVID-19.

Early Congenital Syphilis: Recognising Symptoms of an Increasingly Prevalent Disease.

BACKGROUND: Congenital syphilis (CS) is an infectious disease resulting from transplacental transmission of Treponema pallidum spirochetes from an infected mother to fetus during pregnancy. While uncommon, CS has shown an increased incidence in Canada and the United States since 2001 and 2012, respectively. CASE REPORT: We present the case of a 5-week-old female infant with blistering rash on the palms and soles. The infant displayed decreased movement of the left upper extremity, clinically consistent with Parrot pseudoparalysis. Cutaneous involvement was limited to few tan crusted papules on the palms and soles. Mother reported a "false-positive" result of rapid plasma reagin (RPR) testing at 31 weeks. Cerebrospinal fluid studies of the infant resulted with positive Venereal Disease Research Laboratory (VRDL) test and positive microhemagglutination assay (MHA-TP). Histopathology of a crusted papule revealed a lichenoid infiltrate composed of lymphocytes, histiocytes, and plasma cells. Immunohistochemical staining for T pallidum was negative. The patient completed treatment with a 10-day course of intravenous penicillin. DISCUSSION: While CS is largely considered a historic entity, it has been increasing in incidence in the United States since 2012 and in Canada since the early 2000s. Diagnosis of CS can be difficult as infants may be asymptomatic or present with nonspecific signs. This case highlights the presentation of minimal cutaneous involvement as well as skeletal involvement after birth. RPR testing may result in false negatives or indeterminate results, further complicating diagnosis. Given these difficulties in screening and the increasing incidence of CS, clinicians may need to refamiliarise themselves with its clinical findings.

Comparison of Single-Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) and Conventional Planar Lymphoscintigraphy for Sentinel Node Localization in Patients with Cutaneous Malignancies.

BACKGROUND: Accurate preoperative lymphoscintigraphy is vital to performing sentinel lymph node biopsy (SLNB) for cutaneous malignancies. Potential advantages of single-photon emission computed tomography with integrated computed tomography (SPECT/CT) include the ability to readily identify aberrant drainage patterns as well as provide the surgeon with three-dimensional anatomic landmarks not seen on conventional planar lymphoscintigraphy (PLS). METHODS: Patients with cutaneous malignancies who underwent SLNB with preoperative imaging using both SPECT/CT and PLS from 2011 to 2014 were identified. RESULTS: Both SPECT/CT and PLS were obtained in 351 patients (median age, 69 years; range, 5-94 years) with cutaneous malignancies (melanoma = 300, Merkel cell carcinoma = 33, squamous cell carcinoma = 8, other = 10) after intradermal injection of 99mtechnetium sulfur colloid (median dose 300 µCi). A mean of 4.3 hot spots were identified on SPECT/CT compared to 3.0 on PLS (p < 0.001). One hundred fifty-three patients (43.6 %) had identical findings between SPECT/CT and PLS, while 172 (49 %) had additional hot spots identified on SPECT/CT compared to only 24 (6.8 %) additional on PLS. SPECT/CT demonstrated additional nodal basins in 103 patients (29.4 %), compared to only 11 patients (3.1 %) with additional basins on PLS. CONCLUSIONS: SPECT/CT is a useful adjunct that can help with sentinel node localization in challenging cases. It identified additional hot spots not seen on PLS in almost 50 % of patients. Because PLS identified hot spots not seen on SPECT/CT in 6.8 % of patients, we recommend using both modalities jointly. Long-term follow-up will be required to validate the clinical significance of the additional hot spots identified by SPECT/CT.

Adherence in Atopic Dermatitis.

Atopic dermatitis is a chronic dermatologic condition requiring extended treatment times with topical application of medications. While atopic dermatitis treatments can be highly effective when used as directed, oftentimes patients do not respond as expected, raising concern for non-adherence versus non-response. This chapter aims to describe what is currently known about adherence in atopic dermatitis and to discuss strategies to improve adherence in order to improve treatment outcomes. Whether intentional or unintentional, non-adherence to treatment can limit patient outcomes of this disease for a variety of reasons. These include frustration with medication efficacy, inconvenience, and fear of side effects. Other factors include forgetfulness, financial burden of treatment, lack of trust in the physician, dislike of prescribed medication, or lack of understanding of disease or treatment. Several interventions have been studied with the aim of improving adherence in atopic dermatitis-such as educational workshops for patients and caregivers, earlier follow-up visits, and text messages reminders-however these are often limited by sample size and power. Further research is needed to study both specific patterns of nonadherence in atopic dermatitis, as well as methods to improve them.

The Future of Atopic Dermatitis Treatment.

In recent years, there has been a growing movement towards the use of targeted therapies in treating of atopic dermatitis (AD), parallel to that which has occurred in psoriasis. Among the systemic medications being studied are subcutaneous or intravenously administered biologic drugs targeting specific molecules such as IL4, IL13, IL17, and IgE. Non-biologic oral therapies are also being developed for AD and include small molecule drugs targeting phosphodiesterase type IV (PDE4) inhibition or Janus Kinase (JAK) inhibition. Numerous topical formulations are also being studied, with some formulations that are novel therapies that act as topical biologic or small molecule agents with mechanisms of action similar to systemic treatments. Others are being developed as skin barrier repair therapies for reduction of AD symptoms. This chapter will discuss new advances in AD treatment from medications in the initial stages of development to those nearing FDA approval.

Bilateral transversus abdominis plane block as a sole anesthetic technique in emergency surgery for perforative peritonitis in a high risk patient.

Although transversus abdominis plane (TAP) block is an effective way of providing analgesia in post-operative abdominal surgery patients; however, it can be considered as an anesthetic technique in high-risk cases for surgery. We report a case of a geriatric female with chronic obstructive pulmonary disease in the respiratory failure, hypotension, posted in an emergency with old perforation leading to peritonitis. The surgery was successfully conducted under bilateral TAP block, which was used as a sole anesthetic technique. TAP block can be considered as an anesthetic technique for abdominal surgery in moribund patients.

Clinical significance of Notch receptors in triple negative breast cancer.

BACKGROUND: The Notch signaling pathway is an evolutionary conserved cell signaling pathway that plays an indispensable role in essential developmental processes. Aberrant activation of Notch pathway is known to initiate wide array of diseases and cancers. OBJECTIVE: To evaluate the clinical significance of Notch receptors in Triple Negative Breast Cancer. METHODS: We evaluated the association between Notch receptors and clinicopathological parameters including disease-free survival and overall survival of one hundred TNBC patients by immunohistochemistry. RESULTS: Positive expression of nuclear Notch1 receptor (18%) was found be significantly correlated with positive lymph node (p = 0.009), high BR score (p = 0.02) and necrosis (p = 0.004) while cytoplasmic expression of Notch2 receptor (26%) was significantly correlated with metastasis (p = 0.05), worse DFS (p = 0.05) and poor OS (p = 0.02) in TNBC patients. Membrane (18%) and cytonuclear (3%) Notch3 expression were significantly associated with poorly differentiated tumors (p = 0.007), high BR score (p = 0.002) and necrosis (p = 0.03) respectively. However, cytoplasmic Notch3 and Notch4 expression were negatively correlated with poor prognostic factors. CONCLUSIONS: Our data indicated that Notch receptors play a key role in promoting TNBC and mainly, Notch2 may contribute to poor prognosis of the disease. Hence, it is implicated that Notch2 may serve as a potential biomarker and therapeutic target for TNBC.

Evaluating diaphragmatic dysfunction and predicting non-invasive ventilation failure in acute exacerbation of chronic obstructive pulmonary disease in India.

BACKGROUND: Baseline diaphragmatic dysfunction (DD) at the initiation of non-invasive ventilation (NIV) correlates positively with subsequent intubation. We investigated the utility of DD detected 2 hours after NIV initiation in estimating NIV failure in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients. METHODS: In a prospective-cohort design, we enrolled 60 consecutive patients with AECOPD initiated on NIV at intensive care unit admission, and NIV failure events were noted. The DD was assessed at baseline (T1 timepoint) and 2 hours after initiating NIV (T2 timepoint). We defined DD as ultrasound-assessed change in diaphragmatic thickness (ΔTDI) <20% (predefined criteria [PC]) or its cut-off that predicts NIV failure (calculated criteria [CC]) at both timepoints. A predictive-regression analysis was reported. RESULTS: In total, 32 patients developed NIV failure, nine within 2 hours of NIV and remaining in next 6 days. The ∆TDI cut-off that predicted NIV failure (DD-CC) at T1 was ≤19.04% (area under the curve [AUC], 0.73; sensitivity, 50%; specificity, 85.71%; accuracy; 66.67%), while that at T2 was ≤35.3% (AUC, 0.75; sensitivity, 95.65%; specificity, 57.14%; accuracy, 74.51%; hazard ratio, 19.55). The NIV failure rate was 35.1% in those with normal diaphragmatic function by PC (T2) versus 5.9% by CC (T2). The odds ratio for NIV failure with DD criteria ≤35.3 and <20 at T2 was 29.33 and 4.61, while that for ≤19.04 and <20 at T1 was 6, respectively. CONCLUSIONS: The DD criterion of ≤35.3 (T2) had a better diagnostic profile compared to baseline and PC in prediction of NIV failure.

Investigating the resistance mechanism of 5-fluorouracil in colorectal cancer based on surface markers of cancer stemness and cytokine level: A pre-clinical study.

BACKGROUND: Colorectal cancer (CRC) is the deadliest malignancy in the world. The first-line chemotherapy used for CRC is 5-fluorouracil (5-FU). 5-FU completely eradicates rapidly proliferating and terminally differentiated tumor cells but fails to target cancer stem cells (CSCs). As a result, the tumor may shrink temporarily, but remnant CSC multiplies and forms a tumor again more aggressively. The recurrence and resistance lead to metastasis. METHODOLOGY: CRC was induced in 12 Sprague-Dawley (RPCP/IAEC/2019-20/R2) rats by 1,2 dimethyl hydrazine. Later, animals were treated with 5-FU for 7 weeks at a 10 mg/kg dose by the subcutaneous route. At the end of treatment, half population was sacrificed (6), whereas the remaining half (6) was left without treatment of 5-FU for 5 weeks and then sacrificed. Parameters such as body weight, complete blood count (CBC), immune cell subset (CD4, CD8, and NK cells), colon length to weight index, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level, occult blood in stool, tumor multiplicity, and liver metastasis were estimated. In addition, the dissected colon was fixed in formalin and sent to the histology lab for hematoxylin-eosin staining and immunohistochemistry at both intervals. RESULTS: All blood and tissue-based markers have shown significant differences (p < 0.05) between the animals sacrificed at the end of the 27th week and the end of the 32nd week for 5-FU treatment. CONCLUSION: It can be concluded that 5-FU up-regulates inflammatory cytokines and cell surface markers of CSC that promote CRC stemness via the Wnt/ß-catenin pathway. Also, involvement of Nf-κB, fibronectin, MMP-9, and RANKL leads to tumorigenesis, disease aggressiveness, metastasis, and resistance.

Complete heart block in COVID-19 without prior cardiac disease.

Cardiac involvement in COVID-19 is not rare but underdiagnosed. We report a 78-year-old man with COVID-19 and complete heart block, timely managed by teamwork involving internist, cardiologist, and intensivist. This case highlights the importance of involvement of the conducting system of the heart in COVID-19 that needs immediate life-saving intervention, especially in community.