Search

Preliminary ab initio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored in vitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors. Potential mechanisms of actions are discussed therein. The compound 4-meth-yl-3-[2-(4-methylbiphenyl-4-yl)-2-oxoethyl] thiazolium bromide displayed high activity across all three assays, establishing it as a lead compound. The cytotoxicological properties of the compounds were evaluated using LDH and MTT assays. However, the lead compound exhibited cytotoxicity, indicating the need for additional investigations aimed at decreasing toxicity while maintaining activity. The targeted thiazolium salts were synthesized through an N-alkylation reaction between the corresponding thiazoles and phenacyl bromides., (© 2024 John Wiley & Sons Ltd.)

This article is devoted to the experimental validation of the possibility of early detection of precancerous lesions in the oral mucosa in vivo using diffuse reflectance spectroscopy in the wavelength range from 360 to 1000 nm. During the study, a sample of 119 patients with precancerous lesions has been collected and analyzed. As a result of the analysis, the most informative wavelength ranges were determined, in which the maximum differences in the backscattering spectra of lesions and intact tissues were observed, methods for automatic classification of backscattering spectra of the oral mucosa were studied, sensitivity and specificity values, achievable using diffuse reflectance spectroscopy for detecting hyperkeratosis on the tongue ventrolateral mucosa surface and buccal mucosa, were evaluated. As a result of preliminary experimental studies in vivo, the possibility of automatic detection of precancerous lesions of the oral mucosa surface using diffuse reflectance spectroscopy in the wavelength range from 500 to 900 nm with an accuracy of at least 75 percent has been shown.

For the first time, amides and ureas based on both 5-nitroisoquinoline and 5-nitrosoisoquinoline were obtained by direct nucleophilic substitution of hydrogen in the 5-nitroisoquinoline molecule. In the case of urea and monosubstituted ureas, only 5-nitrosoisoquinoline-6-amine is formed under anhydrous conditions.

A meso -functionalization strategy has successfully been applied to the synthesis of novel 1,3,7-triazapyrene derivatives of calixarenes. The key synthetic step in these transformations providing the direct C-C bond formation is nucleophilic substitution of hydrogen (S N H ) in 1,3,7-triazapyrene. General photophysical characteristics for these macrocyclic compounds, as well as features in emission properties upon addition of various metal cations have been elaborated. Studies using NMR spectroscopy have also shown a mutual effect of both calix[4]arene and 1,3,7-triazapyrene moieties on the coordination process. The complex stoichiometry and binding constants for Al 3+ and Fe 3+ guests have been explored with titration experiments., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: Acute lung injury (ALI) is one of the most common extra-pancreatic complications of acute pancreatitis. In this study, we examined the protective effect of protease inhibitor aprotinin and a matrix metalloproteinase inhibitor (MMPi) on pulmonary inflammation in rats with severe pancreatitis-associated ALI., Method: A rat model of acute pancreatitis (AP) was established by injecting sodium glycodeoxycholate (GDOC) into the pancreatic duct. Pharmacological interventions included pretreatment with a protease inhibitor aprotinin (10mg/kg) and a matrix metalloproteinase inhibitor (MMPi, 100g/kg). The extent of pancreatic and lung injury and systemic inflammation was assessed by examinations of blood, bronchoalveolar lavage (BAL), and lung tissue. Pancreatic or lung tissue edema was evaluated by tissue water content. Pulmonary arterial pressure and alveolar-capillary membrane permeability were evaluated post-injury via a catheter inserted into the pulmonary artery in an isolated, perfused lung model., Results: Pre-treatment with aprotinin or MMPi significantly decreased amylase and lactate dehydrogenase (LDH), and the wet/dry weight ratio of the lung and pancreas in AP rats. Compared to the GDOC alone group, administration of aprotinin or MMPi prevented pancreatitis-induced IL-6 increases in the lung. Similarly, treatment with aprotinin or MMPi significantly decreased the accumulation of white blood cells, oxygen radicals, nitrite/nitrates in both blood and BAL, and markedly reduced lung permeability., Conclusion: Pretreatment with either aprotinin or MMPi attenuated the systemic inflammation and reduced the severity of lung and pancreas injuries. In short, our study demonstrated that inhibition of protease may be therapeutic to pulmonary inflammation in this GDOC-induced AP model., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: For marginally operable stage IIIA non-small-cell lung cancer (NSCLC), surgery might not be done as planned after neoadjuvant concurrent chemoradiotherapy (CCRT) for reasons (unresectable or medically inoperable conditions, or patient refusal). This study aims to investigate the outcomes of a phased CCRT protocol established to maximize the operability of marginally operable stage IIIA NSCLC and to care for reassessed inoperable patients, in comparison with continuous-course definitive CCRT., Materials and Methods: Forty-seven patients with marginally operable stage IIIA NSCLC receiving CCRT were included. Twenty-eight patients were treated with our phased CCRT protocol, including neoadjuvant CCRT followed by surgery (group A, n = 16) or, for reassessed inoperable patients, maintenance chemotherapy and split-course CCRT boost (group B, n = 12). The other 19 were treated with continuous-course definitive CCRT (group C). Overall survival (OS) and progression-free survival (PFS) were analyzed., Results: Among all, median OS and PFS were 35.6 and 12.8 months, respectively (median follow-up, 22.3 months). The median OS of group A (not reached) was better than that of group B (34.4 months) and group C (15.2 months) (P = .009). On multivariate analysis, performance status 0 to 1 (hazard ratio [HR], 0.026; P < .001), adenocarcinoma (HR, 0.156; P = .003), and group A (HR, 0.199; P = .033) were independent prognostic factors. The OS of group B (HR, 0.450; 95% confidence interval, 0.118-1.717; P = .243) was not statistically different from that of group C., Conclusions: For marginally operable stage IIIA NSCLC, our phased CCRT strategy may optimize survival by maximizing operability and maintain an acceptable survival for reassessed inoperable patients by split-course CCRT boost following maintenance chemotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The association between spontaneous pneumothorax (SP) and stroke has not been reported, and this study aimed to explore this association. We used the National Health Insurance Research Database for conducting a nationwide, population-based, retrospective cohort study of patients newly hospitalized for SP from 2000 to 2010. A total of 2541 patients with newly diagnosed SP were included and compared with patients without SP. We observed that patients with SP were at higher risk for developing stroke, with an adjusted hazard ratio (HR) of 1.56. In addition, these patients had a significantly higher risk of hemorrhagic stroke (adjusted HR = 2.22) than of ischemic stroke (adjusted HR = 1.48). The risk of stroke was the highest in the initial 4 months after hospitalization for SP (adjusted HR = 3.41, 95% confidence interval = 1.98-5.87). In conclusion, our study revealed a correlation between stroke and a history of SP, and the risk of stroke after SP was time sensitive.

Human lymphotoxin-β receptor (LTβR), a member of the tumor necrosis factor receptor superfamily, plays an essential role in secondary lymphoid organ development, host defense, chemokine secretion, and apoptosis. In our study, LTβR activations by different stimulations were all found to induce RANTES secretion. Overexpression of LTβR or stimulation LTβR by ligands or agonistic antibody in human lung epithelial cells induced RANTES secretion However, the regulatory mechanism and the signaling cascade have not been fully elucidated. Therefore, the aim of this study was to elucidate the mechanism underlying LTβR-mediated RANTES production. Our study indicated that activation of JNK and ERK was important for the regulation of RANTES secretion. In addition, dominant negative mutants of ASK1, TAK1, and MEKK1 inhibited LTβR-induced RANTES expression. The dominant negative mutants of TRAF2, 3, and 5 also inhibited LTβR-mediated RANTES secretion. Chromatin immunoprecipitation analysis showed that LTβR activation induced the binding of c-Jun and NF-κB to the RANTES promoter. The results of this study show that LTβR activates ASK1, TAK1, and MEKK1 cascades via TRAF2, 3, and 5, resulting in the activation of JNK and ERK, which promotes the binding of c-Jun and NF-κB to the RANTES promoter, thereby increasing RANTES expression and secretion., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Eosinophilic pneumonia (EP) is a disease characterized by prominent infiltration of lung structures by eosinophils. The lung interstitium is infiltrated by eosinophils, and essentially the alveolar spaces are filled with eosinophils and a fibrinous exudate, with conservation of the global architecture of the lung. Diagnosis of EP relies on pathological demonstration of alveolar eosinophilia along with characteristic clinical manifestations of nonproductive cough, dyspnea, chest pain and/or unique imaging features. EP may be categorized according to the origin: EP of undetermined origin may overlap with well-individualized syndromes, while EP with a definite cause are mainly due to infections or drug abuse. Here, we report a case of an amphetamine abuser who developed acute EP and acute respiratory distress syndrome after amphetamine inhalation. Related studies on the pathogenesis of stimulant-related lung injury and treatment strategies are also discussed.

Purpose: Malawi is a sub-Saharan African nation with a severe HIV epidemic. The quality of life (QoL) has never been investigated among people living with HIV and AIDS (PLWHA) in Malawi. This study examines the QoL and associated factors including life needs among PLWHA at different stages of their illness in the northern region of Malawi., Methods: Survey analysis of consecutive outpatient participants receiving highly active antiretroviral therapy at the Rainbow Clinic and non-HIV patients receiving care at the affiliated Mzuzu Central Hospital during a one-month period was performed. Laboratory testing and clinical diagnosis were used to determine HIV status, determine CD4 count, and classify WHO clinical stage. A total of 267 HIV-infected patients and 598 non-HIV participants completed a needs assessment and a Short Form-36 (SF-36) questionnaire, which contained a QoL subscale. SF-36 subscales and needs assessment scores were analyzed using t-test, ANOVA test, and Generalized Linear Model-Tukey's test., Results: HIV-positive patients had significantly lower physical functioning (p=0.0365), mental health (p=0.001), social functioning (p<0.0001), and mental component summary (p=0.0069) scores than HIV-negative patients. Further, WHO Stage III HIV patients had significantly lower vitality (p=0.0439) and mental health (p=0.0022) scores than WHO Stages I and II patients; and WHO Stage IV patients had significantly lower vitality (p=0.0015), mental health (p=0.0006), and physical component summary (p=0.0443) scores than WHO Stages I and II patients. Finally, AIDS patients, as determined by CD4 count, had significantly lower bodily pain (p=0.0423) and physical component summary (p=0.0148) scores than non-AIDS, HIV-positive patients., Conclusion: HIV patients undergoing treatment in Malawi have a significantly lower QoL, both mentally and physically, than their non-HIV counterparts. Further, HIV patients at more advanced stages, both by the WHO definition and by CD4 count, have a significantly lower QoL than HIV patients at earlier stages of the disease.

Thymectomy is performed in infants during cardiothoracic surgery leaving many patients with reduced thympopoiesis. An association between immune disorders and regulatory T cells (Treg) after incidental thymectomy has not been investigated. Questionnaires soliciting symptoms of atopic or autoimmune disease and biomarkers were measured in children and adults with congenital heart disease and either reduced or preserved thymopoiesis. Tregs were examined. Atopic or autoimmune-like symptoms and elevated anti-dsDNA antibodies were common after surgery in individuals with low thymopoiesis. Total Treg number and function were maintained but with fewer naïve Treg. TCR spectratypes were similar to other memory T cells. These data suggest that thymectomy does not reduce total Treg number but homeostasis is affected with reduced naïve Treg. Prevalence of autoimmune or atopic symptoms after surgery is not associated with total number or proportion of Tregs but appears to be due to otherwise unknown factors that may include altered Treg homeostasis.

Objective: An explosive outbreak of HIV-1 circulating recombinant form (CRF) 07&#95;BC among injection drug users (IDUs) in Taiwan was first reported in 2004 and reach the peak in 2005. The objectives of this study were to investigate the molecular epidemiology of different HIV-1 subtypes and their associated risk factors among Taiwanese IDUs in 2004 and 2005., Methods: Questionnaires and blood specimens were collected from inmates from 4 detention centers and 2 prisons. HIV-1 subtypes were determined using nested polymerase chain reactions with multiplex primers and phylogenetic analyses. A case-control study was conducted to elucidate risk factors associated with CRF07&#95;BC infection., Results: A total of 93.8%, 4%, and 2.2% of 451 inmates with IDU history were infected with CRF07&#95;BC, subtype B, and CRF01&#95;AE, respectively. Besides CRF07&#95;BC, a new outbreak of CRF01&#95;AE infection was identified among IDUs from central region. Multivariate analysis showed that sharing dissolved heroine solution [odds ratio (OR) = 17.2], sharing syringes (OR = 34), number of persons sharing syringes (2 vs. 1, OR = 3.1), and lower educational level (OR = 2.3) were risk factors associated with CRF07&#95;BC infection., Conclusions: Sharing dissolved heroine solution is a neglected risk factor associated with HIV-1 infection and it should be emphasized in the AIDS education and harm reduction programs immediately.

It was found that microdialysis, i.e., passage of aqueous solutions of iron-N-methyl-D-glucamine dithiocarbamate complexes through dialysis fibers implanted into heart, kidney and liver tissues of narcotized rats, was accompanied by effective binding of the complexes to nitric oxide from interstitial fluid. The walls of dialysis fibers used in this study were permeable for compounds with molecular weight not exceeding 5 kDa. The dialyzate samples collected every 20 min and containing diamagnetic nitrosyl Fe3+-MGD adducts were reduced to the paramagnetic state with sodium dithionite; their concentration was measured by the EPR method. The basic level of the adducts, which represented mononitrosyl iron complexes with MGD (MNIC-MGD), in the dialyzate samples of all tested organs were similar (1 microM). Treatment of animals with the water-soluble nitroglycerine analog Isoket or a low-molecular dinitrosyl iron thiosulfate complex as a NO donor increased the concentration of MNIC-MGD with going out into a plateau. The novel approach allows determination of nitric oxide levels in tissue interstitial fluid from concentration of MNIC-MGD formed during microdialysis.

FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.

Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challenges compared to normoxia rats. We also detected a temporal association between the attenuation in HPV and increased NO production level with a negative pre-L-NAME correlation between HPV and NO (R = 0.52, P < 0.05). After L-NAME administration, a second hypoxic challenge restored the HPV response in the hyperoxic group. There were increased protein expression of eNOS (12.6 +/- 3.1-fold, n = 3) (X200) and iNOS (8.1 +/- 2.6-fold, n = 3) (X200) in the hyperoxia group. We conclude that hyperoxia increases the protein expression of eNOS and iNOS with a subsequent increased release of endogenous NO, which attenuates the HPV response.

Study Objectives: Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage., Design and Setting: A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ., Methods: In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed., Results: I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage., Conclusions: The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.

Goals of Work: The use of complementary and alternative medicine (CAM) amongst oncology patients is widespread. There is little data regarding the sources of clinical information on CAM that oncology practitioners utilise. The aim of this study was to investigate the sources of clinical information on CAM utilised by Australian oncology practitioners., Methods: A structured self-administered questionnaire was sent to Australian oncology practitioners, defined as oncologists, oncology pharmacists and pharmacists at drug information centres (DICs). Key information was sought on their level of satisfaction with the accessibility, reliability and usefulness of this information and the frequency of, and initiating factors for, seeking this information., Main Results: A substantial proportion of oncologists (57.1%) reported having never sought information on CAM, compared to 27.3% of oncology pharmacists, and 18.8% of DIC pharmacists. Oncologists most commonly reported seeking information on CAM one to three times per year compared to four to ten times per year for oncology pharmacists. Databases were the most common information source used by oncologists (48.1%) and oncology pharmacists (91.7%) and the second most common information source used by DICs (92.3%). There was wide variation in the source of clinical information on CAM used by the three different professional groups., Conclusion: . Oncology practitioners often seek information on CAM; however the frequency, nature and sources of information utilised varied widely. The usefulness and reliability of the sources utilised were inconsistent.