Artificial intelligence in detecting left atrial appendage thrombus by transthoracic echocardiography and clinical features: the Left Atrial Thrombus on Transoesophageal Echocardiography (LATTEE) registry.

AIMS: Transoesophageal echocardiography (TOE) is often performed before catheter ablation or cardioversion to rule out the presence of left atrial appendage thrombus (LAT) in patients on chronic oral anticoagulation (OAC), despite associated discomfort. A machine learning model [LAT-artificial intelligence (AI)] was developed to predict the presence of LAT based on clinical and transthoracic echocardiography (TTE) features. METHODS AND RESULTS: Data from a 13-site prospective registry of patients who underwent TOE before cardioversion or catheter ablation were used. LAT-AI was trained to predict LAT using data from 12 sites (n = 2827) and tested externally in patients on chronic OAC from two sites (n = 1284). Areas under the receiver operating characteristic curve (AUC) of LAT-AI were compared with that of left ventricular ejection fraction (LVEF) and CHA2DS2-VASc score. A decision threshold allowing for a 99% negative predictive value was defined in the development cohort. A protocol where TOE in patients on chronic OAC is performed depending on the LAT-AI score was validated in the external cohort. In the external testing cohort, LAT was found in 5.5% of patients. LAT-AI achieved an AUC of 0.85 [95% confidence interval (CI): 0.82-0.89], outperforming LVEF (0.81, 95% CI 0.76-0.86, P < .0001) and CHA2DS2-VASc score (0.69, 95% CI: 0.63-0.7, P < .0001) in the entire external cohort. Based on the proposed protocol, 40% of patients on chronic OAC from the external cohort would safely avoid TOE. CONCLUSION: LAT-AI allows accurate prediction of LAT. A LAT-AI-based protocol could be used to guide the decision to perform TOE despite chronic OAC.

Medicinal Anti-Inflammatory Patch Loaded with Lavender Essential Oil.

Transdermal drug delivery offers a promising alternative for administering medications like ibuprofen, known for its analgesic and anti-inflammatory properties, with reduced gastrointestinal side effects compared to oral administration. This study explored the potential synergistic effects of combining ibuprofen with lavender essential oil (LEO) in transdermal patches. The composition of LEO was analyzed, revealing predominant compounds such as linalyl acetate and linalool, which are known for their analgesic and anti-inflammatory properties. The physicochemical properties of the patches were investigated, indicating improved cohesion with the addition of LEO. Additionally, thermal stability assessments demonstrated enhanced stability with LEO incorporation with an increase in onset decomposition temperature from 49.0 to 67.9 °C. The antioxidant activity of patches containing LEO was significantly higher with a free radical scavenging ability of 79.13% RSA compared to 60% RSA in patches without LEO. Release and permeation studies showed that patches with LEO exhibited an increased permeation of ibuprofen through the skin with 74.40% of the drug released from LEO-containing patches compared to 36.29% from patches without LEO after 24 h. Moreover, the permeation rate was notably faster with LEO, indicating quicker therapeutic effects. The inclusion of LEO in transdermal patches containing ibuprofen holds promise for enhancing drug delivery efficiency and therapeutic effectiveness, offering a potential strategy for improved pain management with reduced side effects.

Investigating the Anti-Inflammatory Properties and Skin Penetration Ability of Cornelian Cherry (Cornus mas L.) Extracts.

Plant extracts can be a valuable source of biologically active compounds in many cosmetic preparations. Their effect depends on the phytochemicals they contain and their ability to penetrate the skin. Therefore, in this study, the possibility of skin penetration by phenolic acids contained in dogwood extracts of different fruit colors (yellow, red, and dark ruby red) prepared using different extractants was investigated. These analyses were performed using a Franz chamber and HPLC-UV chromatography. Moreover, the antioxidant properties of the tested extracts were compared and their impact on the intracellular level of free radicals in skin cells was assessed. The cytotoxicity of these extracts towards keratinocytes and fibroblasts was also analyzed and their anti-inflammatory properties were assessed using the enzyme-linked immunosorbent assay (ELISA). The analyses showed differences in the penetration of individual phenolic acids into the skin and different biological activities of the tested extracts. None of the extracts had cytotoxic effects on skin cells in vitro, and the strongest antioxidant and anti-inflammatory properties were found in dogwood extracts with dark ruby red fruits.

Kombucha as a Potential Active Ingredient in Cosmetics-An Ex Vivo Skin Permeation Study.

Kombucha is a non-alcoholic beverage, that is increasingly used in the cosmetic industry. The available literature reports the positive effects of kombucha on the skin, in particular its antioxidant action. However, there is a lack of information on skin permeation and the accumulation of active ingredients showing such effects. Skin aging is largely dependent on oxidative stress, therefore in our study we assessed the ex vivo permeation of two types of kombucha (green and black tea) through porcine skin. The antioxidant activity (DPPH, ABTS, FRAP methods) and total polyphenol content of these extracts were determined before and after permeation testing. Moreover, the content of selected phenolic acids as well as caffeine was assessed. Skin permeation was determined using a Franz diffusion cell. The antioxidant activity of both Kombuchas was found to be high. In addition, gallic acid, chlorogenic acid, protocatechuic acid, coumaric acid, m-hydroxybenzoic acid, and caffeine were identified. A 24-h ex vivo study showed the permeation of some phenolic acids and caffeine and their accumulation in the skin. Our results confirm the importance of studying the skin permeation of what are still little known ingredients in cosmetic preparations. Evaluation of the accumulation of these ingredients can guarantee the efficacy of such preparations.

Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study.

Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.

Inborn errors of purine and pyrimidine metabolism: A guide to diagnosis.

Inborn errors of purine and pyrimidine (P/P) metabolism are under-reported and rarely mentioned in the general literature or in clinical practice, as well as in reviews dedicated to other inborn errors of metabolism (IEMs). However, their diagnosis is important because genetic counseling can be provided and, in some cases, specific treatment exists that may slow or even reverse clinical signs. The purpose of this review is to provide a practical guideline on the suspicion and investigation of inborn errors of P/P metabolism. Failure of a physician to recognize the presence of these disorders may be devastating for affected infants and children because of its permanent effects in the patient, and for their parents because of implications for future offspring. Diagnosis is crucial because genetic counseling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. This review highlights the risk factors in the history, the important examination findings, and the appropriate biochemical investigation of the child. Herein we describe the approach to the diagnosis of P/P disorders and emphasize clinical situations in which physicians should consider these diseases as diagnostic possibilities.

Long-term effect of azelaic acid peel on sebum production in acne.

Seborrhea and the associated oily skin are undoubtedly the problem of women and men around the world. The pathogenesis of acne vulgaris involves excessive activity of sebaceous glands, as well as disturbances in the composition of sebum. The aim of the study was to assess the severity of seborrhea in a group of acne vulgaris patients and to determine the effect of a 20% azelaic acid solution on the activity of sebaceous glands. Twenty seven women, aged 19-25 years, underwent a series of six treatments with the application of a 20% solution of azelaic acid to the face. The mean values of sebum level showed a decreasing tendency. On the forehead, the results were as follows-195.5 before the treatment and 162.7 2 weeks after the last treatment. Measurements of the right cheek decreased from 175.3 to 141.3 The measurements taken 3 months after the study were 151.3 on the forehead and 138.9 on the cheek. Similarly, the values determining the total number of acne lesions and the severity of the disease according to the IGA scale also changed significantly. Chemical peel with 20% azelaic acid shows long-term sebostatic action, which inhibits the formation of new acne lesions.

The impact of systemic psoriasis treatments on human papillomavirus activation and propagation.

Psoriasis is one of the most prevalent diseases in the world and it affects up to 2% of the worldwide population. Its pathogenesis is complex and the lesions may be triggered by multiple factors. Human papillomavirus (HPV) is associated with anogenital cancers, cutaneous warts and is considered one of the most prevalent infections in the world. In this review, the available literature on the systemic treatment of patients with psoriasis and concomitant HPV infection was analysed.

Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients.

Eleven patients from Yakutia with a new lysosomal disease assumed then as mucopolysaccharidosis-plus syndrome (MPS-PS) were reported by Gurinova et al. in 2014. Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected. Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, and visceral obesity. Functional analyses revealed a slight presence of chondroitin sulphate (only) in urine glycosaminoglycan electrophoresis, presence of sialooligosaccharides in urine by thin-layer chromatography, and normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot. The comparison with other MPS-PS described cases was also provided. The presented description of the natural history of MPS-PS in our patient may broaden the spectrum of phenotypes in this disease.

Pharmacological chaperone therapy for the treatment of inborn errors of metabolism / Stosowanie farmakologicznych chaperonów w leczeniu wrodzonych chorób metabolicznych.

The article describes the mechanism of molecular and pharmacological chaperones in the treatment of inborn errors of metabolism. The literature review of the usage of ambroxol acting as a pharmacological chaperone for beta-glucocerebrosidase in Gaucher disease and Parkinson's disease associated with GBA variants has been reviewed.

Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Treatment trials in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood-brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

The Effect of Brewing Process Parameters on Antioxidant Activity and Caffeine Content in Infusions of Roasted and Unroasted Arabica Coffee Beans Originated from Different Countries.

Coffee is one of the most often consumed beverages almost all over the world. The multiplicity of beans, as well as the methods and parameters used to brew, encourages the optimization of the brewing process. The study aimed to analyze the effect of roasting beans, the brewing technique, and its parameters (time and water temperature) on antioxidant activity (determined using several in vitro methods), total polyphenols, flavonoids, and caffeine content. The infusions of unroasted and roasted Arabica beans from Brazil, Colombia, India, Peru, and Rwanda were analyzed. In general, infusions prepared from roasted beans had higher antioxidant activity and the content of above-mentioned compounds. The hot brew method was used to obtain infusions with a higher antioxidant activity, while the cold brew with higher caffeine content. The phenolic compound content in infusions prepared using both techniques depended on the roasting process. Moreover, the bean's origin, roasting process, and brewing technique had a significant effect on the tested properties, in contrary to brewing time and water temperature (below and above 90 °C), which had less impact. The results confirm the importance of coffee brewing optimization.

Disturbance of lipid homeostasis in lysosomal lipase deficiency ­ pathomechanism, diagnosis and treatment / Zaburzenie homeostazy lipidowej w deficycie lizosomalnej lipazy ­ patomechanizm, diagnostyka i leczenie.

Lysosomal acid lipase (LAL) plays a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes. LAL deficiency is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. In the case of LAL deficiency, cholesteryl esters and triglycerides accumulate within the lysosomes. The up-regulation of endogenous cholesterol production, increased synthesis of apolipoprotein B (ApoB) and increased production of very-low-density lipoprotein cholesterol (VLDL-C) is observed. The diagnosis is easy due to the currently available method of testing the enzyme activity in a dry blood spot. Molecular analysis is necessary to verify the clinical and biochemical diagnosis and to analyze the genotype-phenotype correlation. Sebelipase alfa is a recombinant human lysosomal lipase intended for use in enzyme replacement therapy in patients with LAL deficiency.

Controlled attenuation parameter and liver stiffness measurements using transient elastography by FibroScan in Gaucher disease.

BACKGROUND: Liver involvement in Gaucher disease (GD) is a result of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) infiltration of macrophages. The long-term liver-related complications of GD could include liver fibrosis and cirrhosis. The aim of the study was to evaluate clinical utility and relevance of TE by FibroScan in GD patients by assessing two parameters: controlled attenuation parameter (CAP) and liver stiffness (LS), in regard of GD-related variables, type of GD, age of patients, enzymatic replacement therapy (ERT), and metabolic features. METHODS: 59 Polish patients (55 adults, 4 children) with GD (43 patients with type 1 and 16 patients with type 3) aged 7-86 years, underwent TE by FibroScan; elevated CAP was defined as >250 dB/m and elevated LS as >7 kPa. All patients, except five patients with type 1 GD (patients' refusal), were treated by ERT. RESULTS: Elevated CAP was present in 23% of GD1 patients and 19% of GD3 patients. Elevated LS was present in 21% of GD1 patients and 13% of GD3 patients. CAP was fairly, positively (ρ = 0.356) correlated with BMI. LS was fairly, positively (ρ = 0.4) correlated with patient's age, as well as the age at start of ERT (ρ = 0.326). CAP was strongly, negatively (ρ = -0.52) correlated with the age at start of ERT. LS and CAP were correlated (strongly, positively) only in GD3. CONCLUSIONS: TE by FibroScan could be considered as an additional method for evaluating GD patients for non-invasive assessment of CAP and LS. The investigation of serial TE measurements in untreated as well as treated GD patients is needed to better determine whether this technology should be added to recommendations for monitoring GD patients. TE by FibroScan could be performed in GD patients with increased BMI and especially those with metabolic syndrome as they have other important risks for liver disease. After our analysis we think these risks factors are independent of GD but still very important for their overall health.

Visfatin as a predictor of obstructive sleep apnea in atrial fibrillation patients.

BACKGROUND: Obstructive sleep apnea (OSA) often coexists with atrial fibrillation (AF) and makes the course of AF worse. The negative impact of OSA on AF may be due to atrial stretch, hypoxia, hypertension, obesity, fibrosis, and inflammation. Several mediators are thought to be responsible for this correlation, among them adipokines such as visfatin. This study aimed to assess the association between visfatin concentrations and OSA in patients with AF. AIMS: This study aimed to assess the association between visfatin concentrations and OSA in AF patients. METHODS: In a tertiary Cardiology Department, hospitalized patients previously diagnosed with AF were enrolled in the study. Diagnosis of OSA was made based on a respiratory polygraphy and patients had blood samples taken for assessment of plasma visfatin concentration. RESULTS: A total of 266 patients with AF (65% men, age 57.6 ± 10.1) were enrolled, and 121 (45%) were diagnosed with OSA. Patients with OSA had higher visfatin concentrations than those without OSA (2.13 ± 0.17 vs. 1.70 ± 0.21 ng/mL; p = 0.04). Patients with mild OSA had visfatin levels equal to 1.77 ± 0.17 ng/mL, moderate OSA 2.38 ± 0.18 ng/mL, and severe OSA 3.55 ± 0.61 ng/mL (p for trend = 0.017). Multivariate regression analysis showed that increased visfatin concentrations were associated with the risk of OSA (odds ratio 1.92; 95% confidence interval 1.09-3.40). CONCLUSIONS: Patients with AF who were diagnosed with OSA had significantly higher plasma visfatin levels which increased according to the severity of OSA. Furthermore, multivariate regression analysis identified visfatin concentration over 1.25 ng/mL, male sex, age over 59.1 years, and permanent AF as the factors showing independent correlation with OSA.

Prevalence of obstructive sleep apnea in patients with peripheral arterial diseases.

BACKGROUND: The presence of obstructive sleep apnea (OSA), a novel cardiovascular risk factor, contributes to the development of peripheral arterial diseases (PAD). There is a lack of data showing how often these diseases coexist. AIMS: The aim of the study was to determine the prevalence of OSA in the population of patients with PAD. METHODS: Patients previously qualified for the first revascularization due to PAD were included in the study. All patients underwent an overnight sleep study to detect OSA. Diagnosis of OSA was made when the apnea-hypopnea index (AHI) was ≥5 per hour. RESULTS: From 141 patients (60% men, age 69.6 ± 9.5 years), OSA was diagnosed in 68 patients (48%). OSA occurred in mild form (5 ≤ AHI < 15/h) in 39 cases (28%), in moderate form (15 ≤ AHI < 30/h) in 21 cases (15%), and in severe form (AHI ≥ 30/h) in 8 cases (6%). Patients without OSA had significantly lower body mass index (BMI; 26.9 ± 5.5 vs. 27.7 ± 5.3 kg/m2, p = 0.01) and lower hip circumference (97.4 ± 11.7 vs. 98.7 ± 7.4, p = 0.04). There were no differences in the distribution of other investigated cardiovascular risk factors and diseases between these groups. There were no significant differences in OSA distribution or its severity between patients with lower extremity artery disease and carotid artery disease. CONCLUSIONS: The prevalence of OSA in patients with PAD is very high, affecting nearly half of the studied population.

Liver involvement in NGLY1 congenital disorder of deglycosylation.

N-glycanase 1 deficiency is a congenital disorder of deglycosylation, which has been diagnosed in 27 patients, including 2 of them from Poland. The most characteristic symptoms include global developmental disability, hyperkinetic movement disorder, hypo-/alacrimia, and elevated serum transaminases. We reported on a patient in whom the liver biopsy done at the age of 3 years revealed the presence of steatosis, fibrosis, and an amorphous periodic acid-Schiff staining positive diastases-digested material in the cytoplasm.

A Possible Role for Arylsulfatase G in Dermatan Sulfate Metabolism.

Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)-lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. Here, we explored the effects of silencing the ARSB gene on the growth of human pulmonary artery smooth muscle cells in the presence of different concentrations of dermatan sulfate (DS). The viability of pulmonary artery smooth muscle cells with a silenced ARSB gene was stimulated by the dermatan sulfate. In contrast, the growth of pulmonary artery endothelial cells was not affected. As shown by microarray analysis, the expression of the arylsulfatase G (ARSG) in pulmonary artery smooth muscle cells increased after silencing the arylsulfatase B gene, but the expression of genes encoding other enzymes involved in the degradation of dermatan sulfate did not. The active site of arylsulfatase G closely resembles that of arylsulfatase B, as shown by molecular modeling. Together, these results lead us to propose that arylsulfatase G can take part in DS degradation; therefore, it can affect the functioning of the cells with a silenced arylsulfatase B gene.