Search Results (714)

Background: Patients in Intensive Care Units (ICUs) often develop non-thyroidal illness syndrome. Potentially, thyroid hormones may be removed during continuous veno-venous hemodiafiltration (CVVHDF), as their molecular size is smaller than the filter pores’ cutoff. The study’s main aim was to assess whether the serum concentration of thyroid hormones changes over time during CVVHDF. Methods: This was a prospective observational trial that included 30 patients treated in an ICU. All patients developed acute kidney injury (AKI) and had clinical indications for implementation of CVVHDF. Blood samples were collected before initiation of CVVHDF and at 1, 2, 3, 6, 9 and 12 days after. The last sample was collected three days after CVVHDF withdrawal. Thyroid function was evaluated by determining the serum concentration of TSH, thyrotropin-releasing hormone (TRH), free triiodothyronine (fT₃), free thyroxine (fT₄), total triiodothyronine (tT₃), total thyroxine (tT₄) and reverse triiodothyronine (rT₃). We additionally calculated the total activity of peripheral deiodinases (G_D) using a mathematical model. Results: TRH and TSH levels remained mostly within normal ranges. fT4 and tT4 were in normal range or slightly below. In contrast, fT3 and tT3 were undetectably low in most patients throughout. Reverse T3 levels remained within normal limits. There were no statistically significant changes in any thyroid hormone levels over the CVVHDF treatment period. The calculated peripheral G_D activity was lower than normal, but importantly, it did not change significantly over time. Conclusions: Thyroid hormones are not lost due to hemodiafiltration. Decreased deiodinases activity is responsible for alterations in serum concentrations of thyroid hormones in patients during CVVHDF. Full article

Objectives: Saccharomyces boulardii CNCM I-745, a probiotic yeast, is effectively used for the treatment of acute diarrhea as well as for the prevention and treatment of traveller‘s diarrhea and diarrhea under tube feeding. The underlying mechanisms are not fully elucidated. Both antitoxic and regulatory effects on the intestinal barrier, mediated either by the yeast or yeast-derived substrates, have been discussed. Methods: To examine the effects of Saccharomyces boulardii released substrates (S.b.S) on gastrointestinal (GI) barrier function, a murine small intestinal organoid cell model under stress was used. Stress was induced by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GF_Red). Stressed organoids were treated with S.b.S (200 µg/mL), and markers of GI barrier and inflammatory response were assessed. Results: GF_Red-induced stress was characterized by disturbances in selected tight junction (TJ) (p < 0.05), adherent junction (AJ) (p < 0.001), and mucin (Muc) formation (p < 0.01), measured by gene expressions, whereby additional S.b.S treatment was found to reverse these effects by increasing Muc2 (from 0.22 to 0.97-fold change, p < 0.05), Occludin (Ocln) (from 0.37 to 3.5-fold change, p < 0.0001), and Claudin (Cldn)7 expression (from 0.13 ± 0.066-fold change, p < 0.05) and by decreasing Muc1, Cldn2, Cldn5, and junctional adhesion molecule A (JAM-A) expression (all p < 0.01). Further, S.b.S normalized expression of nucleotide binding oligomerization domain (Nod)2- (from 44.5 to 0.51, p < 0.0001) and matrix metalloproteinase (Mmp)7-dependent activation (from 28.3 to 0.02875 ± 0.0044 ** p < 0.01) of antimicrobial peptide defense and reduced the expression of several inflammatory markers, such as myeloid differentiation primary response 88 (Myd88) (p < 0.01), tumor necrosis factor α (Tnfα) (p < 0.01), interleukin (IL)-6 (p < 0.01), and IL-1β (p < 0.001). Conclusions: Our data provide new insights into the molecular mechanisms by which Saccharomyces boulardii CNCM I-745-derived secretome attenuates inflammatory responses and restores GI barrier function in small intestinal organoids. Full article

Antibiotic residues in poultry pose health and resistance risks, necessitating breed-specific WDTs. In this study, the residue elimination patterns of seven antibiotics in Taihang chicken tissues under free-range conditions were studied and the appropriate WDT was formulated. A total of 240 healthy Taihang chickens aged 100 days were randomly divided into 8 groups, each comprising 30 chickens. Chickens in groups 1 to 7 were administered oxytetracycline, chlortetracycline, erythromycin, tylosin, tylvalosin, lincomycin, and tiamulin, respectively. Regarding the administration method, we adopted the highest dose and maximum course of treatment recommended by the Veterinary Pharmacopoeia of the People’s Republic of China. Group 8 served as the control group. Muscle, sebum, liver, and kidney samples were collected at 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 13 d, and 16 d after drug withdrawal. Our results demonstrated that the drug residues after drug withdrawal gradually decreased with the increase in drug withdrawal days, and the elimination rate in the early stage of drug withdrawal was significantly faster than that in the later stage. At 4 h after drug withdrawal, the drug residues in various tissues reached their highest values. In most cases, the drug concentrations in the kidney and liver were higher than those in the muscles and sebum; however, some drugs also exhibited concentration peaks in the sebum. On the first day of drug withdrawal, the amount of residues in various tissues decreased rapidly. In general, the elimination rate of various drugs in the muscles, liver, and kidneys is faster but slower in the sebum. Based on the WDT calculation software WT1.4, the recommended WDTs for oxytetracycline, chlortetracycline, erythromycin, tylosin, tylvalosin, lincomycin, and tiamulin chickens are 4 d, 5 d, 11 d, 8 d, 13 d, 13 d, and 7 d, respectively. These findings support food safety and industry development. Full article

Acne vulgaris is a multifactorial inflammatory skin disorder that significantly impairs quality of life and may signal underlying systemic dysfunction, particularly in adult women with treatment-resistant or atypical presentations. This case series presents three clinically and etiologically distinct examples of persistent acne in female patients, each associated with different contributing factors: long-term topical corticosteroid misuse, polycystic ovary syndrome (PCOS), and metabolic syndrome with autoimmune thyroiditis. All cases underwent comprehensive dermatologic evaluation, endocrine/metabolic assessments, and personalized therapeutic interventions, ranging from corticosteroid withdrawal and barrier repair to hormonal modulation and insulin-sensitizing therapy. Clinical progression was monitored for up to six months, revealing favorable responses in all cases, with substantial lesion clearance and improved skin quality. These real-world cases highlight the importance of an integrative, interdisciplinary diagnostic approach in refractory acne and support the need for individualized, long-term management strategies tailored to underlying systemic contributors. Full article

Tobacco use disorder remains a leading cause of preventable mortality, with nicotine playing a central role in the development and maintenance of dependence, mainly through its action on α4β2 nicotinic acetylcholine receptors (nAChRs). Smoking cessation treatments must address both physiological withdrawal and the affective disturbances (such as anxiety, irritability, and mood lability) which often facilitate relapses. This review compares two pharmacotherapies used in smoking cessation, varenicline and cytisinicline (cytisine), with particular focus on their impact on emotional regulation, psychological symptoms, and neuropsychiatric safety. Varenicline, a high-affinity partial agonist at α4β2 nAChRs, has demonstrated superior efficacy in maintaining abstinence and is well-supported by robust clinical data, including in psychiatric populations. However, its use may be limited by adverse effects such as nausea and sleep disorders. Cytisinicline, a structurally similar but less potent partial agonist, has recently gained renewed interest due to its lower cost, favorable tolerability profile, and comparable effectiveness in the general population. Although less extensively studied in patients with serious mental illness, preliminary data suggest cytisinicline may offer a better side effect profile, particularly regarding sleep disturbances and emotional reactivity. Both agents appear to ameliorate withdrawal-related affective symptoms without significantly increasing psychiatric risk. Ultimately, pharmacotherapy choice should be guided by individual clinical features, mental health status, treatment tolerability, and resource availability. Further research is needed to establish cytisinicline’s efficacy and safety across diverse clinical contexts, particularly among individuals with severe psychiatric comorbidities. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

Background: Belantamab mafodotin (belamaf) is a BCMA-targeting antibody–drug conjugate used in triple-class refractory multiple myeloma. Despite its efficacy, keratopathy remains a significant dose-limiting toxicity. Following its withdrawal from the U.S. market in 2022, its use in Austria is limited to clinical trials or compassionate use. Methods: In this real-world, retrospective study, we analyzed 36 relapsed/refractory, BCMA-naïve multiple myeloma patients treated at the University Hospital of Vienna (January 2020–June 2024); 42% received a reduced dose (1.9 mg/kg) throughout all treatment cycles. The primary objective was to assess adverse events, particularly keratopathy, and the impact of dose modifications on toxicity and efficacy. Results: The overall response rate was 64%, with responders having significantly fewer prior therapy lines (median 3 vs. 4.5, p = 0.015). Median PFS was 7.3 months, significantly longer in responders (11.1 vs. 1.6 months, p < 0.0001); median OS was 20.1 months, also longer in responders (not reached vs. 18 months, p = 0.031). Keratopathy occurred in 75% of patients; 33% experienced grade 3–4 events. Dose reduction significantly decreased grade 3–4 keratopathy (7% vs. 52%, p = 0.004) and thrombocytopenia (33% vs. 67%, p = 0.048) without compromising efficacy. Conclusions: Belamaf dose reductions improved tolerability without loss of efficacy, supporting reduced dosing in practice. Full article

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid homeostasis, neuroactive steroid deficiency (notably allopregnanolone, ALLO), and gut–brain axis alterations. Objective: This study aimed to investigate the effects of finasteride withdrawal (FW) in a rat model and evaluate the potential protective effects of ALLO on gut and hypothalamic inflammation. Methods: Adult male Sprague Dawley rats were treated with finasteride for 20 days, followed by one month of drug withdrawal. A subgroup received ALLO treatment during the withdrawal. Histological, molecular, and biochemical analyses were performed on the colon and hypothalamus. Gut microbiota-derived metabolites and markers of neuroinflammation and blood–brain barrier (BBB) integrity were also assessed. Results: At FW, rats exhibited significant colonic inflammation, including a 4.3-fold increase in Mφ1 levels (p < 0.001), a 2.31-fold decrease in butyrate concentration (p < 0.01), and elevated hypothalamic GFAP and Iba-1 protein expression (+360%, p < 0.01 and +100%, p < 0.01, respectively). ALLO treatment rescued these parameters in both the colon and hypothalamus but only partially restored mucosal and BBB structural integrity, as well as the NF-κB/PPARγ pathway. Conclusions: This preclinical study shows that FW causes inflammation in both the gut and hypothalamus in rats. ALLO treatment helped reduce several of these effects. These results suggest ALLO could have a protective role and have potential as a treatment for PFS patients. Full article

Background: Alcohol withdrawal syndrome is a common clinical challenge that may lead to significant complications if not properly managed. Symptom-triggered therapy (STT) represents a promising alternative to fixed-dose regimens (FDRs) providing benzodiazepine prescriptions based on objectively quantified withdrawal symptoms. This study aimed to evaluate the effectiveness and safety of STT using the Hamburg Alcohol Withdrawal Scale (HAES) compared to FDRs in the management of inpatient alcohol detoxification. Methods: In a retrospective case–control study, alcohol detoxification treatment in STT was compared with FDRs. During a twelve-month observation period, a total of 123 patients in the STT group were recruited and compared with 123 controls in the FDR group (matched according to sex, age, and current amount of alcohol consumption) treated in the same hospital before the implementation of STT. The study outcomes included the total benzodiazepine dosage, duration of acute detoxification phase, length of inpatient stay, and occurrence of complications such as epileptic seizures and delirium tremens. Results: STT showed a significantly lower total benzodiazepine dosage (22.50 mg vs. 115.00 mg, p < 0.001), a shorter duration of the detoxification phase (48.00 h vs. 201.75 h, p < 0.001), and a reduced length of inpatient stay (23.00 days vs. 28.00 days, p = 0.003) compared to FDRs. There were no significant differences in the rates of complications between the two settings. Linear mixed model analysis revealed that the differences remained highly significant even after adjusting for various explanatory variables (i.e., age, sex, standard units of alcohol, psychiatric comorbidities, treatment discontinuation, and occurrence of any complication). Conclusions: STT appears to be as effective and safe as traditional fixed-dose regimens of benzodiazepines for the management of inpatient alcohol detoxification. This approach may thereby minimize unnecessary pharmacological exposure, facilitate the earlier integration of patients into psychoeducational and psychosocial interventions, and reduce healthcare costs. Full article

Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids. Full article

Background: Thymus numidicus Poiret. (Lamiaceae) is an endemic plant with well-known antibacterial properties. It has been largely used in traditional Algerian medicine. This study aimed to compare the chemical composition of essential oils (EOs) extracted from leaves and flowers using the gas chromatography–mass spectrometry method, as well as to investigate its analgesic and anti-inflammatory activities. Results: The EOs were rich in monoterpenes and classified as a thymol chemotype. In vivo experiments revealed that acute treatment with T. numidicus EO (20 and 80 mg/kg) significantly increased the thermal threshold on the hot-plate at all tested hours compared to the control animals (p < 0.001, respectively), while only the higher dose had a similar effect to the metamizole group at 2 and 3 h. In the mechanical stimulus test, both doses of the EO led to a late analgesic effect presented with increased paw withdrawal threshold only during the third hour compared to the control group (p < 0.05, respectively). In the plethysmometer test both doses of the EO dose-dependently reduced paw volume with nearly 10% and 15% compared to the control animals at all tested hours (p < 0.001, respectively), with a more pronounced volume reduction in the higher dose. In a neuropathic pain model, the EO (20 mg/kg and 80 mg/kg) dose-dependently increased the withdrawal latency time towards thermal stimuli and enhanced the paw withdrawal threshold in response to mechanical pressure at all tested hours compared to the CCI-group (p < 0.001, respectively). These findings demonstrate the potent analgesic and anti-inflammatory effects of T. numidicus EO in models of acute and neuropathic pain. Full article

Pediatric delirium (PD) is an acute neuropsychiatric syndrome marked by fluctuating disturbances in attention and cognition, frequently observed in pediatric intensive care units (PICUs) and associated with increased morbidity, mortality, and long-term cognitive impairment. Despite its clinical significance, PD remains underdiagnosed due to challenges inherent in assessing consciousness and cognition in children at varying developmental stages. Several bedside tools have been developed and validated in recent years, including the Cornell Assessment of Pediatric Delirium (CAPD), PreSchool Confusion Assessment Method for the Intensive Care Unit (psCAM-ICU); Pediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU), and Sophia Observation Withdrawal Symptoms—Pediatric Delirium Scale (SOS-PD), enhancing early recognition and management of PD in critically ill children. This narrative review explores the historical background, epidemiology, risk factors, pathophysiology, clinical subtypes, diagnostic tools, and current prevention and treatment strategies for PD from newborns to 21 years old. The screening tools available and the integration of non-pharmacological interventions, such as environmental modifications and family-centered care, as well as cautious and selective pharmacological management, are emphasized in this review. Early identification and targeted interventions are essential to mitigate the adverse outcomes associated with PD. Full article

Introduction: Chronic alcohol use is a complex condition influenced by psychological, behavioral, and socio-demographic factors. This study aimed to develop a comprehensive psychosocial profile of individuals with alcohol use disorder (AUD) by examining associations between psychometric variables and relapse risk including repeated psychiatric hospitalizations. Methodology: A cross-sectional observational analytical study was conducted on a sample of 104 patients admitted for alcohol withdrawal management at the “Prof. Dr. Al. Obregia” Psychiatric Clinical Hospital in Bucharest between March 2023 and September 2024. Participants completed a set of validated psychometric tools: the Drinker Inventory of Consequences—Lifetime Version (DrInC), Readiness to Change Questionnaire—Treatment Version (RTCQ), Drinking Expectancy Questionnaire (DEQ), and Drinking Refusal Self-Efficacy Questionnaire (DRSEQ). Additional data were collected on the socio-demographic (education level, socio-professional category), genetic (family history of alcohol use), and behavioral factors (length of abstinence, tobacco use, co-occurring substance use disorders). Results: Higher alcohol-related consequence scores (DrInC) were significantly associated with lower education (p < 0.001, η² = 0.483), disadvantaged socio-professional status (p < 0.001, η² = 0.514), and family history of alcohol use (p < 0.001, η² = 0.226). Self-efficacy (DRSEQ) was significantly lower among individuals with co-occurring substance use (p < 0.001) and nicotine dependence (p < 0.001). Logistic regression showed that the DrInC scores significantly predicted readmission within three months (OR = 1.09, p = 0.001). Conclusions: Psychometric tools are effective in identifying individuals at high risk. Personalized, evidence-based interventions tailored to both psychological and socio-professional profiles, combined with structured post-discharge support, are essential for improving long-term recovery and reducing the readmission rates. Full article

Pancreatic cancer is one of the most lethal malignancies, in part due to its profound metabolic adaptability, which underlies drug resistance and therapeutic failure. This study explores the metabolic rewiring associated with resistance to treatment using a systems metabolomics approach. Exposure to the redox-disrupting agent erastin revealed key metabolic vulnerabilities but failed to produce lasting growth suppression. Combinatorial treatments with methotrexate or alpelisib significantly impaired proliferation and triggered marked metabolic shifts. Systems-level analyses identified serine metabolism as a central adaptive pathway in resilient cells. Metabolic tracing and gene expression profiling showed increased de novo serine biosynthesis and uptake, supporting redox homeostasis, biosynthetic activity, and epigenetic regulation. Notably, cells that resumed growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways, along with elevated expression of genes linked to survival, proliferation, and migration. These findings establish serine metabolism as a functional biomarker of metabolic plasticity and adaptive resilience in pancreatic cancer, suggesting that targeting this adaptive axis may enhance therapeutic efficacy. Full article

Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [³⁵S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED₅₀ value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article