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Leptin receptor downregulation in the carotid body treats obesity-induced hypertension
No full textObesity and comorbid sleep disordered breathing (SDB) lead to high cardiovascular morbidity and mortality via multiple mechanisms including hypertension. Obesity also leads to high levels of leptin, which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (Lepr), and diet-induced obesity (DIO) increases Lepr expression levels, but the mechanisms and consequences of leptin action in CB are poorly understood. We hypothesize that leptin signaling in CB in obesity leads to hypertension, which can be treated by Lepr knockdown specifically in CB. DIO male and female mice and lean male C57BL/6J mice were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring. The adenoviral vectors carrying antisense RNA, Ad-LepR shRNA or Ad-scrambled control shRNA, were administered locally to the CB region. Blood pressure measurements were performed at baseline and 9-11 days after CB infection with the adenoviral vector. DIO male mice showed increased blood pressure compared with lean males and DIO females. Ad-LepR shRNA induced a twofold decrease in Lepr mRNA level in CB and abolished obesity-induced hypertension. Lepr knockdown was particularly effective during the light phase, when animals were predominantly asleep, decreasing mean arterial pressure by 8.5 mmHg. Control shRNA had no effect on DIO-induced hypertension. We conclude that inhibition of Lepr in the carotid bodies abolished obesity-induced hypertension. Obesity and comorbid sleep apnea are key predisposing factors to hypertension. Obesity increases circulating leptin levels and hyperleptinemia may contribute to hypertension but mechanisms are not clear. Here, we have shown that knockdown of the leptin receptor LepR in the carotid body decreased blood pressure and treated hypertension in diet-induced obese mice. Thus, we identified a novel mechanism of obesity hypertension and a novel drug target, LepR in the carotid body
Genetic variants of accessory proteins and G proteins in human genetic disease
No full textWe present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss G protein-coupled receptor (GPCR) gene variants and human genetic disease and in the third article, we survey G protein-coupled receptor pharmacogenomics . In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes
Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy
No full textCholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA
Cholera in Africa: A Climate Change Crisis
No full textBACKGROUND: Cholera, an acute diarrheal infection caused by Vibrio cholerae, remains a significant public health concern globally, with 1.4-4.0 million cases and 21,000-143,000 deaths annually. While the disease is endemic in 47 less-developed countries across Africa and Asia, the African continent has been particularly affected, with 19 of 29 countries reporting cases in 2023 being from Africa. AIM: To explore the trend of cholera outbreaks in Africa and analyze how climate change has contributed to the spread of the disease in the continent. METHODS: A review of current cholera outbreaks in Africa, with particular focus on Sudan and Ethiopia as case studies, examining the relationship between climatic factors and cholera transmission. RESULTS: Recent outbreaks in Sudan (declared September 26, 2023) resulted in 5,414 suspected cases and 170 deaths (case fatality rate 3.1%) across nine states as of December 5, 2023. In Ethiopia\u27s Somali region, 772 confirmed cases and 23 deaths were reported within two weeks, with approximately 80% of cases affecting children. Climate factors significantly influence cholera transmission: a 1 °C temperature rise doubled cholera cases in Zanzibar. Both drought conditions, which increase Vibrio cholerae concentration in groundwater, and heavy rainfall periods, which lead to flooding and breakdown of sanitary conditions, contribute to outbreak risks. CONCLUSIONS: Climate change impacts cholera transmission through rainfall patterns, temperature variations, and extreme weather events. Management recommendations include implementing accurate weather surveillance systems, strategic vaccination programs, flood-proof water supply infrastructure, and community engagement protocols. These interventions should be integrated while considering the growing influence of climate change on disease patterns. CLINICAL TRIAL NUMBER: Not applicable
CTA-Derived Plaque Characteristics and Risk of Acute Coronary Syndrome in Patients With Coronary Artery Calcium Score of Zero: Insights From the ICONIC Trial
No full textCoronary artery calcium (CAC) scoring is used to stratify acute coronary syndrome (ACS) risk. Nonetheless, patients with CAC score of zero (CAC) remain at risk from noncalcified plaque components. To explore CTA-derived coronary artery plaque characteristics in symptomatic patients with CAC who experience subsequent ACS through comparisons with patients with CAC score greater than zero (CAC) who experience subsequent ACS, and with patients with CAC but without subsequent ACS. This study entailed secondary retrospective analysis of prior prospective registry data. The international multicenter CONFIRM registry collected longitudinal observational data on symptomatic patients who underwent clinically indicated coronary CTA from January, 2004 to May, 2010. ICONIC was a nested cohort study conducted within CONFIRM that identified patients without known coronary artery disease (CAD) at time of CTA who did and did not experience subsequent ACS (i.e., ACS and control groups), propensity matched in a 1:1 ratio based on CAD risk factors and CAD severity on CTA. The present ICONIC substudy selected matched patients in the ACS and control groups who both had documented CAC scores. CTA examinations were analyzed using artificial intelligence software for automated quantitative plaque assessment. In the ACS group, invasive angiography findings were used to identify culprit lesions. The present study included 216 patients (mean age, 55.6 years; 91 female, 125 male), with 108 patients in each of the ACS and control groups. In the ACS group, 23% (n=25) of patients had CAC. In the ACS group, culprit lesions in CAC and CAC subsets showed no significant differences in fibrous, fibrofatty, or necrotic-core plaque volumes (p\u3e.05). In the CAC subset, patients with ACS, compared with control patients, had greater mean fibrous plaque volume (29.4±42.0 vs 5.5±15.2 mm3, p\u3c.001), fibrofatty plaque volume (27.3±52.2 vs 1.3±3.7 mm3, p\u3c.001), and necrotic-core plaque volume (2.8±6.4 vs 1.3±3.7 mm3, p\u3c.001). After propensity-score matching, 23% of patients with ACS had CAC. Patients with CAC in the ACS and control groups showed significant differences in volumes of noncalcified plaque components. Methods that identify and quantify noncalcified plaque forms may help characterize ACS risk in symptomatic patients with CAC
Risk and management of cardiac disease in kidney and liver transplant recipients
No full textOrgan transplantation is the treatment of choice for individuals with kidney failure requiring kidney replacement therapy, as well as for those with end-stage liver disease. Despite the significant reduction in long-term morbidity and mortality with transplantation, kidney and liver allograft recipients remain at high risk for cardiovascular disease (CVD) and premature death from cardiovascular causes. This heightened risk is represented across all phenotypes of CVD, including coronary heart disease, heart failure, arrhythmias, valvulopathies and pulmonary hypertension. Pre-existing vascular risk factors for CVD, coupled with superimposed cardiovascular-kidney-metabolic derangements after transplantation, driven at least in part by post-transplant weight gain, immunosuppressive therapies and de novo risk factors such as dyslipidaemia and diabetes, coalesce to increase total CVD risk. In this review, we summarise pathophysiological considerations for both the short- and long-term increase in CVD risk following kidney/liver transplantation. We review the different phenotypes of CVD, with unique considerations for post-transplant care in this patient population. Finally, we highlight the need for awareness about long-term CVD risk and a multidisciplinary approach to managing organ-specific CVD risk in kidney and liver transplant patients
Linguistic equity: Anatomy educators and inclusive language
No full textIncorporating inclusive language in healthcare education allows learners to develop holistic communication skills. Adhering to principles of linguistic equity in healthcare, specific to sex- and gender-inclusive language (SGIL), creates a safe environment for all participants. Anatomy education introduces students to a standard, consistent language used in healthcare. This report presents data from the 2022 Experimental Biology conference roundtable discussion regarding the use of SGIL in anatomy education. Most of the respondents had defined sex (i.e. male/female; 83%) and gender (i.e. man/woman; 66.7%) for their learners since 2018 (67.4%). Most often, sex- and gender-diverse (SGD) topics are discussed during the pelvis, perineum, and reproduction content (50%). While teaching teams and departments have made attempts, most believe the current use of SGIL is inconsistent (66.7%). Although there is no consensus on best practice, a few recommendations emerged, including (1) early integration of linguistic equity, (2) patient-centered educational interventions, and (3) multi-level discussions. These data and recommendations should be treated as a pilot for future research. Future studies should investigate anatomy educators\u27 use of SGIL, including modality, context, bias, time, duration, and integration of SGD topics, students\u27 response, perspective, and implementation in clinical practice
A case of cutaneous leishmaniasis by a needlestick injury: an occupational infection or experimental infection ?
No full textLeishmaniasis is a Neglected Tropical Disease caused by unicellular parasitic kinetoplastids of the genus Leishmania spp., with 20 species associated with human infections. This case report describes an accidental inoculation of Leishmania major suffered by a graduate student in a research and education institution laboratory. Eight months after the occupational accident, the student developed an erythematous, painless papule at the needlestick injury site. Within a week, the lesion worsened, showing ulceration and an increase in size. The diagnosis of cutaneous leishmaniasis was based on clinical observations and confirmed by histopathological analysis, immunohistochemistry, and parasite culture. Following diagnosis, the patient was referred for treatment with a dosage of 81 mg SbV/kg of Glucantime, administered slowly via intravenous infusion diluted in 100 ml of 5 % glucose saline solution, every 24 h for 20 consecutive days. Furthermore, this case report emphasises the critical need for periodic training for research professionals to ensure their knowledge of protocols guiding prevention and response to occupational infections
North American Contact Dermatitis Group Patch Test Results: 2021-2022
No full textPatch testing is an important diagnostic tool for the assessment of allergic contact dermatitis (ACD). This study documents the North American Contact Dermatitis Group (NACDG) patch testing results from 2021 to 2022. At 12 centers in North America, patients were tested in a standardized manner with a screening series of 80 allergens. Overall, 3056 patients were tested; 2200 (72.0%) had at least 1 positive/allergic patch test reaction and 1412 patients (46.6%) had a primary diagnosis of ACD. The most commonly positive allergens were nickel sulfate hexahydrate 5% and 2.5% petrolatum (24.9% and 22.1%, respectively), methylisothiazolinone (MI) (11.5%), hydroperoxides of linalool (10.1%), cobalt chloride hexahydrate (9.2%), and methylchloroisothiazolinone/methylisothiazolinone (9.0%). Compared with 2019-2020, prevalence of the top 20 allergens statistically increased for nickel (P \u3c 0.001), cobalt (P \u3c 0.01), gold (P \u3c 0.001), hydroperoxides of limonene (P \u3c 0.001), oleamidopropyl dimethylamine (P \u3c 0.01), dimethylaminopropylamine (P \u3c 0.01), and ammonium persulfate (P \u3c 0.001). MI positivity continued to decrease from its peak in 2017-2018. More than one-fifth of patients (n = 640, 21.1%) had at least one clinically relevant reaction to an allergen/substance not present in the NACDG screening series. The epidemic of MI contact allergy in North America appears to continue its descent. Fragrance allergy is still very common, but the composition of fragrance allergy markers appears to be changing. Patch testing using a robust screening series, and supplemental allergens as indicated, is necessary for the comprehensive evaluation of ACD