New pyrazole/3-cyanopyridin-2-one conjugates 4a-f and 5a-h were designed and synthesized; their anti-inflammatory activities were evaluated in vitro and in vivo. In the LPS-induced RAW 264.7 cell line, nitric oxide (NO) inhibitory activity revealed that 4b, 4e, and 5c were the most powerful NO inhibitors, with
BACKGROUND:Fibrosis may coexist with emphysema in COPD, but computed tomography (CT) quantification is challenging. Persistent homology (PH), a topological data analysis technique, provides interpretable structural features in greyscale images. By using PH, this CT study aimed to quantify fibrotic lesions in nonemphysematous and emphysematous lungs and to investigate clinical implications of PH-based fibrosis quantification in patients with COPD. METHODS:The study included subjects from the Lung Cancer Screening (LCS) cohort (n=346) and two prospective COPD cohorts (Kyoto University n=234; Kyoto-Himeji n=166). Based on CT value patterns and spatial topology, PH assigned each voxel as fibrotic or nonfibrotic and calculated the percentage of fibrotic lung volume (PH-fibrosis%) in association with visually identified interstitial lung abnormality and COPD outcomes. RESULTS:Higher PH-fibrosis% was associated with interstitial lung abnormalities in the LCS and Kyoto University cohorts. The two COPD cohorts consistently showed significant associations between higher baseline PH-fibrosis% and future exacerbation risk independent of emphysema and airway wall thickness (hazard ratio (HR) 1.39 and 3.35 for Kyoto University and Kyoto-Himeji, respectively). In the Kyoto University cohort, higher PH-fibrosis% was significantly associated with increased mortality (HR 1.94), with a similar trend in the Kyoto-Himeji cohort (HR 1.86). Longitudinal increases in PH-fibrosis% over median 4.98 years were associated with higher exacerbation frequency and patients experiencing greater increase in PH-fibrosis% subsequently exhibited higher mortality in the Kyoto University cohort. CONCLUSIONS:PH can be used to quantify fibrotic lesions on CT and PH-fibrosis% could be a prognostic imaging marker in patients with COPD.
Introduction:Recently, methods for in vitro organogenesis have been widely developed due to their strong potential for medical applications. Cardiac organoids with functional ion channel activity are necessary for non-clinical applications. Methods:In the present study, we optimized the culturing method of human heart organoids (hHOs) from human embryonic stem cells (hESCs) in the presence of the highly concentrated laminin-entactin and fibroblast growth factor 4 by the supplementation of BMP4, BMP10 and ROCK inhibitor (Y27632). Results:The resulting hHOs showed distinctive cardiac morphology with atrium- and ventricle-like chambers composed of cardiac cells, smooth muscle and endothelial cells as well as expressed the integral proteins of gap junctions like Connexin 40 (Cx40), Cx43 and Cx45, and ion channel proteins including Kir2.1(KCNJ2), hERG (KCNH2), Nav1.5 (SCN5A), and Cav1.2 (CACNA1C). In addition to the contractile ability in hHOs, isolated cardiomyocytes from these hHOs exhibited Na and Ca currents by patch clamp analysis. Conclusions:These results indicate that hHOs generated in this study retain physiological cardiac functions, as they recapitulate in vivo cardiac ion currents and cardiac muscle contraction, although their abilities remain limited. The present method for hHOs will contribute to understanding the fundamental mechanism of cardiogenesis and provide an alternative tool for cardiac safety assessment of newly developed drugs as an in vitro human ESC-derived test system.
BACKGROUND:Leptospirosis is well-known to cause neurological involvement. However, data on the frequency of neuroleptospirosis as a cause of primary central nervous system (CNS) infections is sparse. METHODOLOGY/PRINCIPAL FINDINGS:An observational study was conducted in three regions in Sri Lanka between October 2021-March 2024. Patients with a primary diagnosis of meningitis, meningoencephalitis or encephalitis were recruited. Blood and cerebrospinal fluid (CSF) were analysed for pathogenic Leptospira DNA by real-time PCR, and serology by microscopic agglutination test (MAT) on admission and after 10-14 days. A confirmed case was a patient with evidence of CNS infection with positive CSF or blood PCR and/or 4-fold rise/single titre ≥1:320 in MAT. A total of 100 patients were studied with a median age of 55 (IQR 39.7 - 69.7) years and 52 (52%) males. Suspected clinical diagnoses were meningitis (n = 66,66%), meningoencephalitis (n = 22,22%) and encephalitis (n = 12,12%). Eleven (11%) patients were laboratory-confirmed as neuroleptospirosis; meningitis (n = 3), meningoencephalitis (n = 3), encephalitis (n = 5). Three patients had positive blood Leptospira PCR, one had positive blood and CSF Leptospira PCR, three had high initial MAT and four had a 4-fold rise in MAT. Neurological manifestations included headache (n = 8), seizures (n = 2), confusion (n = 7), photophobia (n = 4), neck stiffness (n = 6) and limb weakness (n = 5). Majority of patients with positive blood or CSF PCR for Leptospira (n = 3, 75%) did not have a CSF cellular reaction. The neuroleptospirosis group had a lower requirement for intensive care compared to other CNS infections (9% vs 13.5%) and recovered without residual neurological disability. There were no deaths in the neuroleptospirosis group compared to 11 (12.4%) deaths in other CNS infections. CONCLUSIONS:Leptospirosis is an important cause of primary CNS infections, and may lead to more favourable outcomes. It is important to consider leptospirosis as an aetiological agent in the laboratory workup of primary CNS infections in leptospirosis-prevalent settings.
Aleksandar Perić,1 Cveta Milutin Špadijer Mirković,2 Tijana Vidoje Vukadinović,3 Biserka Vukomanović Đurđević,4 Danilo Vojvodić51Department of Otorhinolaryngology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia; 2Department of Otorhinolaryngology, University of Priština Faculty of Medicine, Kosovska Mitrovica, Serbia; 3Department of Otorhinolaryngology, University of Montenegro Faculty of Medicine, Podgorica, Montenegro; 4Institute of Pathology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia; 5Institute of Medical Research, Division of Clinical & Experimental Immunology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, SerbiaCorrespondence: Aleksandar Perić, Department of Otorhinolaryngology, Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, 11040, Serbia, Email aleksandarperic1971@gmail.comAbstract: Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) in their non-polypous (CRS without nasal polyps - CRSsNP) and polypous (CRS with nasal polyps - CRSwNP) main phenotypes are chronic inflammatory diseases of the nasal mucosa and/or paranasal sinuses with a whole series of unknowns regarding etiology, pathogenesis, clinical manifestations, and therapeutic modalities. Although intranasal and oral antihistamines and intranasal corticosteroids are the main drugs in AR therapy, emerging evidence on the effects of herbal and biological drugs may add a new dimension to the treatment of these patients. CRS is a far more heterogeneous disease with numerous clinical phenotypes that require completely different approaches. In addition to endoscopic sinus surgery (ESS), which remains the mainstay of treatment, intranasal and systemic corticosteroids, macrolide antibiotics, and tetracyclines, as well as nasal irrigation with saline solutions, are the main modalities, especially in the period after surgical treatment. Recently, there has been increasing evidence for the beneficial effects of herbal medicines and biological therapy. However, to assess how well conservative treatment of AR and CRS keeps chronic inflammation under control, numerical parameters derived from cytological findings, biochemical analysis of nasal secretions by enzyme-linked immunoassay (ELISA), flow cytometry, and pathohistological and immunohistochemical analyses of tissue samples are necessary. This narrative review of the literature was done through a critical approach, which included our long-term experience in researching the effects of various drugs, as well as the results of other authors. The results of numerous studies have shown that the application of these drugs can significantly change the profile of inflammatory mediators (cytokines, chemokines, enzymes, growth factors) and thus direct the course of inflammation to a less intense form. Nevertheless, in spite of everything, the control of AR and CRS is still not at a satisfactory level, which directs us towards finding new modalities of conservative therapy, especially in the field of application of biological drugs and plant extracts.Keywords: cytokines, enzymes, inflammation, nasal polyps, rhinitis, allergic, sinusitis
