Thyrotropin internalization is directed by a highly conserved motif in the seventh transmembrane region of its receptor

The thyrotropin (TSH) receptor is a member of G protein-coupled seven-transmembrane-segment receptors. It is characterized by a large extracellular domain linked to the seven transmembrane segments and ending with a cytoplasmic tail. Sequence alignment shows that a highly conserved motif, NPXXY where X is any amino acid, exists at the boundary between the seventh transmembrane domain and proximal part of the cytoplasmic tail of virtually all G protein-coupled receptors. This motif has been implicated as an internalization signal for several cell surface receptors, such as the low density lipoprotein (LDL), insulin and insulin-like growth factor-1 (IGF-1) receptors. The potential effects of this motif on the TSH receptor signal transduction and receptor-mediated TSH internalization was analysed by replacement of the tyrosine⁶⁷⁸ residue with an alanine residue. This mutation does not impair high affinity TSH binding, but completely abolishes the ability of cAMP response upon TSH stimulation. It also significantly reduces TSH internalization. The role of the cytoplasmic tail of the TSH receptor in receptor-mediated internalization was also assessed. Deletion of up to 56 amino acids from the C-terminus of the cytoplasmic tail enhances TSH internalization as compared to the wild-type receptor. We conclude that tyrosine⁶⁷⁸ in the NPXXY motif is required for efficient receptor-mediated TSH internalization and G protein coupling. The cytoplasmic tail of the TSH receptor may contain sequence domains which could modulate the effects of the NPXXY internalization signal.     

Formation and emission of large furans and oxygenated hydrocarbons from flames

Many oxygenated hydrocarbon species formed during combustion, such as furans, are highly toxic and detrimental to human health and the environment. These species may also increase the hygroscopicity of soot and strongly influence the effects of soot on regional and global climate. However, large furans and associated oxygenated species have not previously been observed in flames, and their formation mechanism and interplay with polycyclic aromatic hydrocarbons (PAHs) are poorly understood. We report on a synergistic computational and experimental effort that elucidates the formation of oxygen-embedded compounds, such as furans and other oxygenated hydrocarbons, during the combustion of hydrocarbon fuels. We used ab initio and probabilistic computational techniques to identify low-barrier reaction mechanisms for the formation of large furans and other oxygenated hydrocarbons. We used vacuum-UV photoionization aerosol mass spectrometry and X-ray photoelectron spectroscopy to confirm these predictions. We show that furans are produced in the high-temperature regions of hydrocarbon flames, where they remarkably survive and become the main functional group of oxygenates that incorporate into incipient soot. In controlled flame studies, we discovered ∼100 oxygenated species previously unaccounted for. We found that large alcohols and enols act as precursors to furans, leading to incorporation of oxygen into the carbon skeletons of PAHs. Our results depart dramatically from the crude chemistry of carbon- and oxygen-containing molecules previously considered in hydrocarbon formation and oxidation models and spearhead the emerging understanding of the oxidation chemistry that is critical, for example, to control emissions of toxic and carcinogenic combustion by-products, which also greatly affect global warming.Oxygenated hydrocarbons produced during combustion can have a wide range of detrimental effects on human health, air quality, and regional and global climate. Furans, for example, are compounds that contain five-membered rings with four carbon atoms and one oxygen atom. They are frequently observed in the exhaust plumes and nearby environment of combustion sources. Many studies have shown that they are toxic, whether ingested or inhaled, and thus pose a considerable threat to human health (1–4). The simplest of these compounds (i.e., unsubstituted furan, C₄H₄O) is a cyclic, dienic ether with a low molecular weight, high volatility, and high lipophilicity. Studies on rats and mice have shown a dose-dependent increase in hepatocellular adenomas and carcinomas, indicating that furan is carcinogenic (4), and furan is marked as a high-priority substance and a carcinogenic risk by the World Health Organization (5).Combustion sources of furans include biomass burning (6–9), cigarette and pipe smoke (10, 11), waste incineration (12), electronic waste recycling (13, 14), and volcanic activity (15). The polychlorinated dibenzofurans (PCDFs) are among the most notorious environmental pollutants, and the main source of PCDFs is biomass burning (6–9, 16). Nonchlorinated furans and PCDFs have been shown to be kinetically linked (17, 18). Furans released during combustion are often partitioned into particles and are found in ash from peat (9) and wood (6) burning, in primary organic aerosols from meat cooking (19), and in secondary organic aerosols from hydrocarbon oxidation (20, 21). Wood burning for heating and cooking constitute a major human exposure to airborne particulate PCDFs in some parts of the world (22, 23).Previous work has suggested that oxygenated species can be attached to surfaces of soot particles of varying maturity emitted from flames and diesel engines, even before atmospheric processing (24–32). Functional groups that have been identified include alcohols/enols, carbonyls, peroxies, and ethers. Oxygen atoms bound to organic species on the particle surface have been shown to greatly affect soot hygroscopicity (28) and the ability of soot particles to adsorb atmospheric water vapor and act as cloud-condensation or ice nuclei. Soot particles emitted from combustors, such as diesel engines, are generally hydrophobic, and enhancements in hygroscopic particle emissions could have substantial indirect climate effects via their influence on cloud formation (33). The effect of soot emissions on cloud-nucleation properties is a major uncertainty in climate predictions (34–36).Despite the impact of large oxygenated hydrocarbons on combustion chemistry, the environment, and human health, very little is known about their formation mechanisms and emissions. In this paper we present evidence of the formation of oxygenated compounds, including furans, during the combustion of hydrocarbon fuels. Via a synergistic approach that includes ab initio methods and a stochastic model in conjunction with experimental measurements, we identify reaction pathways leading to formation of oxygenated compounds during the combustion of ethylene. We recorded aerosol mass spectra sampled from premixed and diffusion flames, using synchrotron-generated vacuum-UV (VUV) radiation for ionization, for comparison with masses of the predicted chemical compositions. The mass spectra show masses of oxygenated species that agree with the atomic compositions predicted by the simulations. Both experiments and simulations demonstrate that ∼50% of the mass peaks observed at some flame heights in the mass range 140–350 u (unified atomic mass units) contain signal from oxygenated species. We also recorded X-ray photoelectron spectroscopy (XPS) spectra of soot samples extracted from these flames for further validation of these mechanisms by comparison with functional groups of the predicted oxygenated species incorporated into particles. The XPS measurements confirm formation of furan precursors, hydroxyl groups, early in the soot-formation process and evolution of furan signatures, ether groups, as the combustion and particles evolve.The present study represents an important step toward the development of predictive models for the oxidation of hydrocarbons, which will require that the presence and reactivity of these oxygenated compounds are taken into account. Understanding the chemistry related to high-temperature hydrocarbon oxidation may provide a key to controlling emissions of harmful combustion byproducts, such as soot, nonchlorinated furans, and PCDFs, leading to multiple environmental and health benefits.     

Evaluation of fluticasone (flixonase) nasal spray versus beclomethasone (beconase) nasal spray in the treatment of allergic rhinitis

Although response to intranasal steroid therapy has been reported in patients with allergic rhinitis, efficacy of some nasal steroids is noteworthy.This study was undertaken to evaluate the efficacy of a two-week course of Fluticasone (Flixonase) nasal spray vs. Beclomethasone (beconase) nasal spray in patients with symptoms of allergic rhinitis referred to our clinic. This study reviewed sixty randomized studies with symptoms of allergic rhinitis which supported common aeroallergens with skin prick test. Patients received a total daily dose of nasal spray of Fluticasone (Flixonase) 100 mcg bid (N=30) compared with patients with allergic rhinitis who received a total daily dose of Beclomethasone (Beconase) 50mcg 2 puffs bid (N=30). Patients were visited before and after therapy, and efficacy of Flixonase and Beconase was evaluated by the change in nasal symptoms including: nasal discharge, nasal obstruction, nasal itching, and sneezing. After two weeks of treatment nasal symptoms of blockage, discharge, sneezing and itching were significantly better in the group treated with Fluticasone nasal spray (65%, 82%, 67%, 79% respectively (p<0.001) but after treatment with beconase nasal spray lower benefits in the nasal symptoms includes: 50%, 71%, 51%, 57% respectively. After two weeks of treatment no deleterious changes consequent to therapy were observed in nasal symptoms. 100 mcg bid Flixonase (Fluticasone) intranasal spray is more effective than 50 mcg 2 puffs bid Beconase (Beclomethasone) intranasal spray. Like asthma, allergic rhinitis is an inflammatory disease and should be managed with anti-inflammatory medication.     

Successful aztreonam treatment of acute typhoid fever after chloramphenicol failure

Aztreonam treatment was successful in 4 cases of typhoid fever. The patients were seriously ill with growth of Salmonella typhi in blood cultures despite treatment with chloramphenicol. Aztreonam appears to be a useful alternative to standard therapy of typhoid fever.     

Microbiological infections in HIV positive Bahraini patients with low CD4+ T-lymphocyte count

The correlation of CD4+ T-lymphocyte count and the distribution of pathogenic or opportunistic microbial infection most commonly found in HIV positive individuals differ from one area to the other. The present study reports such findings in 67 HIV positive Bahraini patients in the period May 1997 to Nov. 1998. CD4+ T-lymphocyte count was measured using flow cytometry. Bacterial and fungal cultures were performed. Serological diagnosis was performed when indicated. Viral study was done serologically. The distribution of CD4+ T-lymphocyte count in the studied group was: 21 patients (31.3%) less than 100 cells/microl, 5 patients (7.5%) 100-200 cells/microl, 25 patients (37.3%) 201-500 cells/microl and 16 patients (23.9%) with count more than 500 cells/microl. Among patients with low CD4 count (less than 100 cells/microl) (n=21), microbial infections varied from fungal infections 66%, bacterial infections 57% and viral infections 4.8%. Bacterial infections included Salmonellosis (14.3%), Staphylococcus epidermidis (14.3%), Pseudomonas aeruginosa (9.5%), H. influenzae (9.5%), Legionellosis (4.8%) and E. coli (4.8%). Fungal infection included Candida albicans (52.4%), Pneumocystis carinii (9.5%), Cryptococcus neoformans (4.8%). Viral infection included H. simplex to (4.8%). Fungal infections were the highest common infection in thus study. The most common microbial infection was Candida albicans. P. carinii and Cryptococcus neoformans were less common than found in other studies world wide.     

Evaluation of the Incidence of Chronic Thromboembolic Pulmonary Hypertension 1 Year After First Episode of Acute Pulmonary Embolism: A Cohort Study

Purpose

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important complication after acute pulmonary embolism (PE) with considerable morbidity and mortality. The aim of this study was to estimate the CTEPH incidence in a cohort after the first occurrence of PE.

Methods

We conducted a 1-year follow-up cohort study between 2015 and 2018 to assess the incidence of CTEPH in 474 patients with their first acute episode of PE. For the diagnosis of CTEPH, patients with unexplained persistent dyspnea during follow-up underwent transthoracic echocardiography, right heart catheterization, ventilation-perfusion lung scanning, and CT pulmonary angiography.

Results

Overall, 317 patients were included in the study. The mean age of the patients was 56.5 ± 16 years. One hundred and three patients (32%) had exertional dyspnea at the 1-year follow-up. Patients with evidence of pulmonary hypertension (PH) on echocardiography underwent right heart catheterization. Eleven patients (18%) had no PH (mPAP < 25 mmHg); 47 patients (81%) had mPAP > 25 mmHg. Fifteen patients had PAWP > 15 mmHg, including those with underlying left heart problems or valvular diseases. There were 32 patients with PAH (mPAP > 25 mmHg and PVR > 3 WU) undergoing CTEPH studies; 22 patients (6.9%) had multiple segmental defects suggesting CTEPH on a perfusion scan.

Conclusion

The incidence of CTEPH observed in this study 1 year after the first episode of acute PE was approximately 6.9%. This incidence seems to be high in our population, and diagnostic and therapeutic strategies for the early identification of CTEPH are needed.

     

Genetic polymorphisms of HbE/beta thalassemia related to clinical presentation: implications for clinical diversity

Annals of Hematology - HbE/Beta thalassemia (HbE/β-thalassemia) is one of the common genetic disorders in South East Asia. It is heterogeneous in its clinical presentation and molecular...