Archives of clinical and biomedical research最新文献

Bilateral Inhalation of carfentanil (CRF) aerosol could rapidly induce death in humans and CRF aerosol exposure induces respiratory depression in animals; however, the dynamic progression of cardiorespiratory failure leading to sudden death induced by acute CRF aerosol exposure remains unclear. This study aimed to establish a rat model that allows dynamically characterizing the cardiorespiratory failure prior to death following acute exposure to a lethal concentration of CRF aerosol. Two groups of anesthetized and spontaneously breathing rats were exposed to aerosolized vehicle and CRF (4 mg/m³) for 10 minutes respectively. CRF exposure resulted in 100% mortality among the tested rats. The cardiorespiratory responses were characterized sequentially by: immediate ventilatory depression resulting from rapidly developed bradypnea, persistent ventilatory depression, and hypotension and significant irregularities in both breathing (ataxic breathing) and heart beat rhythms that ultimately caused ventilatory and cardiac arrest at 7.7 ± 0.6 and 9.0 ± 0.7 minutes, respectively, after the onset of CRF exposure. Our results establish a rat model of cardiorespiratory failure and sudden death resulted from acute exposure to CRF aerosol. This model may facilitate further investigation into the mechanisms underlying cardiorespiratory failure and the development of potential countermeasures.

The isolation of primary brain cells is essential for studying cellular behavior, signaling pathways, and disease mechanisms in the central nervous system. This paper explores the general and specific steps involved in extracting and culturing neurons, astrocytes, and microglia from brain tissue, highlighting how primary cells maintain their functionality and structural integrity without genetic modification like immortalized cell lines. Marker proteins such as MAP-2, GFAP, IBA-1, and TMEM119 help confirm cell identity and allow tracking of phenotypic changes, such as inflammation or maturation. We critically discussed some technological problems that researchers usually face during extraction and culturing procedures, emphasizing that each brain source and particular cell type require strict conditions to maximize cellular yield and viability. Environmental control of the cells in culture, such as pH, CO₂, substrate coating and correct medium formulation, are critical for maintaining healthy and viable brain cell cultures. Limited lifespan and sensitivity of primary neurons restrict long-term experiments and increase the risk of experimental variability. Batch-to-batch variation in tissue sources leads to inconsistency in phenotype and function, especially with primary cell isolations. Ethical and practical limitations in sourcing human brain tissue reduce the generalization of findings and force reliance on clinically relevant experimental animal models that represent human conditions.

Microglial cells constitute the largest number of non-neuronal cells in the brain. As part of their immune surveillance function, they are responsible for detecting the presence of both external and internal danger signals, stimulating a defense response through the release of pro-inflammatory cytokines. Once the damage is controlled, microglia stimulate a reparative response that allows tissue homeostasis to be maintained. When this balance is not physiologically achieved, the use of drugs or other non-pharmacological therapies is needed to promote tissue repair and prevent the appearance of complications secondary to the primary damage. In the particular case of traumatic brain injury (TBI), the application of low frequency electromagnetic field (EMF) has proven very helpful in reducing the levels of inflammatory mediators. In the present study we investigated the effect of EMF in an "in vitro" model of tumor necrosis factor alpha (TNF-α)-induced neuroinflammation. Human microglial cells (HMC3) were treated with TNF-α (50 ng/mL) and, after 20 minutes, were exposed to 2.5 or 5 Hz EMF for 3 min. The effect of both treatments on survival, migration capacity and transcriptional expression of M1/M2 phenotypic markers was evaluated at 6, 24 and 48 hours. The exposure to EMF increased the survival rate of cells incubated with high doses of TNF-α and significantly reduced the migration rate of TNF-α treated cells. The analysis of expression patterns in different time points showed that EMF promoted the expression of M1 and M2 phenotypic markers in a time-dependent manner, suggesting a stimulating effect on the phagocytic capacity of microglial cells. Further studies are necessary to fully characterize the effects of EMF on the function of primary microglial cells within a brain injury-like microenvironment.

This case report describes an unusual presentation of concurrent typhoid fever and pulmonary tuberculosis (TB) in an 82-year-old female. She was admitted with syncope and dehydration and initially suspected of having pneumonia and a urinary tract infection (UTI). Urine and blood cultures rapidly identified gram-negative rods, while CT imaging showed cavitary lesions in the bilateral upper lobes and left lower lobe. The gram-negative rods were identified as Salmonella enterica subspecies enterica Typhi, and sputum acid-fast bacilli (AFB) PCR and cultures confirmed the presence of Mycobacterium tuberculosis complex. The patient was treated for both typhoid fever and pulmonary tuberculosis. This rare case highlights the clinical challenge of distinguishing whether a single disease process is responsible for multiple symptoms (Occam's Razor) or if multiple diseases are concurrently affecting the patient (Hickam's dictum). Here, two distinct infections explained the complex presentation. Although typhoid fever was diagnosed first and could rarely be associated with pulmonary abscesses, cavitary lung lesions are more commonly seen in pulmonary tuberculosis. This case underscores the importance of considering multiple concurrent infections in complex clinical scenarios.

Antidepressants are widely prescribed for major depressive disorder and anxiety, yet their long-term use is associated with weight gain, affecting up to 55-65% of patients. This adverse effect contributes to treatment discontinuation, relapse, and worsened metabolic health outcomes, including increased risk for obesity and type 2 diabetes. This artic le presents a critical evaluation of the published reports on the mechanisms underlying antidepressant-induced weight gain, comparative effects across drug classes, and mitigation strategies. Weight gain varies significantly by antidepressant class. Tricyclic antidepressants, monoamine oxidase inhibitors, and a tetracyclic antidepressant, mirtazapine, are associated with the most substantial weight increases, while selective serotonin reuptake inhibitors typically induce weight gain after prolonged use. Mechanisms involve serotonergic and dopaminergic signaling, receptor desensitization, insulin resistance, and altered leptin and ghrelin levels. Genetic factors, including CYP2C19 metabolizer status, and lifestyle factors such as baseline body mass index and diet, further influence risk. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is the only commonly prescribed antidepressant consistently associated with weight loss or neutrality. Mitigation strategies include switching medications, adding agents like metformin or GLP-1 receptor agonists, and incorporating behavioral interventions. Antidepressant-induced weight gain is a multifactorial issue requiring individualized management. Understanding pharmacologic mechanisms and patient-specific risk factors is essential for optimizing treatment efficacy while minimizing metabolic burden.

RSPO3, as a member of the R-spondin gene family, is a secreted molecule that enhances one of the fundamental biological pathways, the canonical Wnt signaling pathway. Once secreted from endothelial cells or macrophages, it typically binds to specific receptors from the LGR family. Additionally, LGR-independent activation of the Wnt cascade, driven by RSPOs, has also been described, mediated by heparan sulfate proteoglycans (HSPGs). LGR4 (GPR48) belongs to the G-protein-coupled receptor superfamily, subfamily B. It is widely recognized as an RSPO3-binding receptor and, thereafter, a Wnt signaling potentiator. Expression patterns of both RSPO3 and LGR4 have been found across various tissues. RSPO3 regulates stem cell maintenance in the intestine, in addition to its function in liver endothelial cells in terms of liver zonation or osteoblast differentiation. LGR4 has shown expression in hypothalamic neurons, regulating reproductive hormone secretion and control of food intake. Various studies reported the contribution of both RSPO3 and LGR4 to inflammatory cascades. Specifically, the RSPO3-LGR4 ligand-receptor interaction was shown to activate the NLRP3 inflammasome and β-catenin-NF-kB signaling cascade. Endothelial-derived RSPO3 exerts regenerative potential via the RSPO3-LGR4-ILK-AKT pathway, as presented in vitro model of inflammatory vascular injury. As a reaction to H.pylori infection, NF-κB was produced in response to RSPO3-LGR4 interaction. In order to get better insight into the signaling cascade between RSPO3 as a ligand and LGR4 as a receptor, in the context of inflammation, in silico analysis was performed. Gene input list included core Wnt pathway proteins, their downstream molecules, and various inflammatory mediators and cytokines related to RSPO3 and LGR4, as described in the literature. Network analysis included protein-protein, transcription factor-gene, and microRNAs-gene interactions. Molecules revealed from the network analysis are potential therapeutic targets in the treatment of inflammatory conditions. Further investigations are needed to test the predicted molecular pathways in vitro or in vivo. From the translational point of view, providing a proper anti-inflammatory agent in the clinical setting will be the ultimate research goal.

Objectives: To balance the costs and effects comparing a strict lockdown versus a flexible social distancing strategy for societies affected by Coronavirus-19 Disease (COVID-19).

Design: Cost-effectiveness analysis.

Participants: We used societal data and COVID-19 mortality rates from the public domain.

Interventions: The intervention was a strict lockdown strategy that has been followed by Denmark. Reference strategy was flexible social distancing policy as was applied by Sweden. We derived mortality rates from COVID-19 national statistics, assumed the expected life years lost from each COVID-19 death to be 11 years and calculated lost life years until 31^st August 2020. Expected economic costs were derived from gross domestic productivity (GDP) statistics from each country's official statistics bureau and forecasted GDP. The incremental financial costs of the strict lockdown were calculated by comparing Sweden with Denmark using externally available market information. Calculations were projected per one million inhabitants. In sensitivity analyses we varied the total cost of the lockdown (range -50% to +100%).

Main outcome measure: Financial costs per life years saved.

Results: In Sweden, the number of people who died with COVID-19 was 577 per million inhabitants, resulting in an estimated 6,350 life years lost per million inhabitants. In Denmark, where a strict lockdown strategy was installed for months, the number of people dying with COVID-19 was on average 111 per million, resulting in an estimated 1,216 life years per million inhabitants lost. The incremental costs of strict lockdown to save one life year was US$ 137,285, and higher in most of the sensitivity analyses.

Conclusions: Comparisons of public health interventions for COVID-19 should take into account life years saved and not only lost lives. Strict lockdown costs more than US$ 130,000 per life year saved. As our all our assumptions were in favour of strict lockdown, a flexible social distancing policy in response to COVID19 is defendable.

Introduction: Younger generations are an important market for the tobacco products industry since most smokers try their first cigarette before the age of 18. Electronic cigarettes (e-cigarettes) are a common mode of smoking among teens, and the number of users is increasing exponentially.

Objective: This study aimed to estimate the current prevalence of e-cigarettes and vaping usage among adolescents between the ages of 15 and 19 in the city of Mecca, Saudi Arabia.

Methods: This study was conducted among 534 students at four high schools. They were asked to complete a 23-item questionnaire retrieved from the Global Youth Tobacco Survey. Descriptive statistics and regression analysis were conducted. The study was approved by the Ministry of Health Saudi Arabia Medical Research Center Institutional Review Board committee on October 10, 2018 (research number 18-506E).

Results: A total of 109 (20.6%) of the participants reported being smokers of e-cigarettes. Being a male (OR = 1.55; 95% CI: [1.01-2.37]), in the second year of high school (OR = 2.91; 95% CI: [1.61-5.24], ever experimenting with regular tobacco cigarettes, being a current shisha smoker, living with a smoker, and believing that e-cigarettes are less addictive than traditional cigarettes are all factors independently associated with e-cigarette use in this sample of adolescents.

Conclusion: Among adolescent smokers, even minimal experience with smoking is correlated with pro-smoking attitudes. E-cigarette use is common in adolescents and related to the use of other combustible tobacco products. Tobacco control efforts at all levels should eliminate factors fostering future tobacco use to minimize the burden of disease and disability in vulnerable populations.