The potential health effects associated with electronic-cigarette.

A good old gateway theory that electronic-cigarettes (e-cigarettes) are widely recognized as safer tobacco substitutes. In actuality, demographics also show that vaping cannibalizes smoking, the best explanation of the data is the "common liability". However, the utilization of e-cigarette products remains a controversial topic at present. Currently, there has been a widespread and substantial growth in e-cigarette use worldwide owing to their endless new flavors and customizable characteristics. Furthermore, e-cigarette has grown widespread among smokers as well as non-smokers, including adolescents and young adults. And some studies have shown that e-cigarette users are at greater risk to start using combustible cigarettes while e-cigarettes use was also observed the potential benefits to people who want to quit smoking or not. Although it is true that e-cigarettes generally contain fewer toxic substances than combustible cigarettes, this does not mean that the chemical composition in e-cigarettes aerosols poses absolutely no risks. While concerns about toxic substances in e-cigarettes and their widespread use in the population are reasonable, it is also crucial to consider that e-cigarettes have been associated with the potential for promoting smoking cessation and the clinically relevant improvements in users with smoking-related pathologies. Meanwhile, there is still short of understanding of the health impacts associated with e-cigarette use. Therefore, in this review, we discussed the health impacts of e-cigarette exposure on oral, nasal, pulmonary, cardiovascular systems and brain. We aspire for this review to change people's previous perceptions of e-cigarettes and provide them with a more balanced perspective. Additionally, we suggest appropriate adjustments on regulation and policy for e-cigarette to gain greater public health benefits.

Study effect of MAPA-VIP on control of allergic asthma pathophysiology.

Introduction: Asthma is a pulmonary disease and its pathogenesis is involved with immune cells and related signalling pathways. Alpha-alumina is material for therapy applications and mucus adhesion promoting protein is cell-surface protein. Vasoactive intestinal peptide (VIP) exerts immunomodulation. Therefore, the drug delivery system and target binding molecule could be applicable for treatment of asthma. Material and methods: VIP-MapA-α-alumina was administered to asthmatic mice. Then, eosinophil percentage, IgE, IL-4, IL-5, and IL-13 levels, GATA3, and MUC5AC gene expression, ROS and lung histopathology were studied. Results: Eosinophil percentage, IgE, IL-4, IL-5, IL-13, and ROS levels, expression of GATA3 and MUC5AC genes, goblet cell hyperplasia, mucus hyper-production, perivascular and peribronchial inflammation were decreased in VIP and VIP-MapA treated groups and treatment with VIP-MapA has a stronger effect than VIP alone. Conclusions: The delivery system of VIP carrying to the lung with the use of MapA as an adhesion molecule, could easily carry VIP and led to penetration of this component to the mucus and reach bronchial cells and present an effective, strong, and long-acting effect on therapy of asthma.

Chronic low-level JUUL aerosol exposure causes pulmonary immunologic, transcriptomic, and proteomic changes.

E-cigarettes currently divide public opinion, with some considering them a useful tool for smoking cessation and while others are concerned with potentially adverse health consequences. However, it may take decades to fully understand the effects of e-cigarette use in humans given their relative newness on the market. This highlights the need for comprehensive preclinical studies investigating the effects of e-cigarette exposure on health outcomes. Here, we investigated the impact of chronic, low-level JUUL aerosol exposure on multiple lung outcomes. JUUL is a brand of e-cigarettes popular with youth and young adults. To replicate human exposures, 8- to 12-week-old male and female C57BL/6J mice were exposed to commercially available JUUL products (containing 59 mg/ml nicotine). Mice were exposed to room air, PG/VG, or JUUL daily for 4 weeks. After the exposure period, inflammatory markers were assessed via qRT-PCR, multiplex cytokine assays, and differential cell count. Proteomic and transcriptomic analyses were also performed on samples isolated from the lavage of the lungs; this included unbiased analysis of proteins contained within extracellular vesicles (EVs). Mice exposed to JUUL aerosols for 4 weeks had significantly increased neutrophil and lymphocyte populations in the BAL and some changes in cytokine mRNA expression. However, BAL cytokines did not change. Proteomic and transcriptomic analysis revealed significant changes in numerous biological pathways including neutrophil degranulation, PPAR signaling, and xenobiotic metabolism. Thus, e-cigarettes are not inert and can cause significant cellular and molecular changes in the lungs.

Proposed cardio-pulmonary model to investigate the effects of COVID-19 on the cardiovascular system.

In this paper, we propose a new mathematical model of cardiovascular system coupled with a respiratory system to study the effects of COVID-19 on global blood circulation parameters using the lumped parameters model. We use the fourth-order Runge-Kutta method for solving the sets of equations of motion. We validate our model by showing that the simulated flows in pulmonary and aortic valves corroborate, respectively, the results established by Smith et al. [IFAC Proceedings Volumes, 39 (2006) 453-458]. Then we examine the effects of the new coronavirus (covid-19) on the cardiopulmonary system through the impact of the high respiratory frequency and the variation of the alveoli volume. To achieve this aim, we propose a new exponential law for the time varying of the pulmonary resistance. It appears that when the respiratory frequency grows, the delay between the systemic artery flow and the flow in the pulmonary artery diminishes. Therefore, the efficiency of the cardiac pump is reduced. Moreover, our results also show that variations of the alveoli volume cause the increment of the pleural pressure in the vascular cavities that induces an exponential growth of the pulmonary resistance. Furthermore, this growth of the pulmonary resistance provokes the augmentation of pressure in some organs and its reduction in others. We found that patient with covid-19 having a prior history of cardiovascular diseases is exposed to a severe case of inflammation/damage of certain organs than those with no history of cardiovascular disease.

Biomedical and biophysical limits to mathematical modeling of pulmonary system mechanics: a scoping review on aerosol and drug delivery.

Undoubtedly, the construction of the biomechanical geometry systems with the help of computer tomography (CT) and magnetic resonance imaging (MRI) has made a significant advancement in studying in vitro numerical models as accurately as possible. However, some simplifying assumptions in the computational studies of the respiratory system have caused errors and deviations from the in vivo actual state. The most important of these hypotheses is how to generate volume from the point cloud exported from CT or MRI images, not paying attention to the wall thickness and its effect in computational fluid dynamic method, statistical logic of aerosol trap in software; and most importantly, the viscoelastic effect of respiratory tract wall in living tissue pointed in the fluid-structure interaction method. So that applying the viscoelastic dynamic mesh effect in the form of the moving deforming mesh can be very effective in achieving more appropriate response quality. Also, changing the volume fraction of the pulmonary extracellular matrix constituents leads to changes in elastic modulus (storage modulus) and the viscous modulus (loss modulus) of lung tissue. Therefore, in the biomedical computational methods where the model wall is considered flexible, the viscoelastic properties of the texture must be considered correctly.

Fabrication, characterization and optimization of nanostructured lipid carrier formulations using Beclomethasone dipropionate for pulmonary drug delivery via medical nebulizers.

Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 - F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ~241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1-3) and higher (circa 82 and 85%) in the lateral stages (4-8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ~42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations.

Behçet's Disease: Different Systemic Manifestations at Different Ages.

Behçet's disease, an inflammatory condition, can involve various systems. The disease usually manifests with dermatologic and ocular signs but can also cause serious symptoms due to pulmonary or neurologic involvement. Although the onset may occur at any age, it typically emerges in the second to fourth decades of life. As in the case presented here, Behçet's disease can manifest with the central nervous system involvement early in life and pulmonary involvement in adulthood.

SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19.

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.

Wearable positive end-expiratory pressure valve improves exercise performance.

We tested a PEEP (4.2 cmH2O) mouthpiece (PMP) on maximal cycling performance in healthy adults. Experiment-1, PMP vs. non-PMP mouthpiece (CON) [n  = 9 (5♂), Age = 30 ±â€¯2 yr]; Experiment-2, PMP vs. no mouthpiece (NMP) [n = 10 (7♂), Age = 27 ±â€¯1 yr]. At timepoint 1 in both experiments (mouthpiece condition randomized) subjects performed graded cycling testing (GXT) (Corival® cycle ergometer) to determine V ˙ O2peak (ml∗kg∗min -1), O2pulse (mlO2∗bt -1), GXT endurance time (GXT-T(s)), and V ˙ O2(ml∗kg∗min -1)-at-ventilatory-threshold ( V ˙ O2 @VT). At timepoint 2 72 h later, subjects completed a ventilatory-threshold-endurance-ride [VTER(s)] timed to exhaustion at V ˙ O2 @VT power (W). One week later at timepoints 3 and 4 (time-of-day controlled), subjects repeated testing protocols under the alternate mouthpiece condition. Selected results (paired T-test, p<0.05): Experiment 1 PMP vs. CON, respectively: V ˙ O2peak â€‹= â€‹45.2 â€‹± â€‹2.4 vs. 42.4 â€‹± â€‹2.3 p<0.05; V ˙ O2@VT â€‹= â€‹33.7 â€‹± â€‹2.0 vs. 32.3 â€‹± â€‹1.6; GXT-TTE â€‹= â€‹521.7 â€‹± â€‹73.4 vs. 495.3 â€‹± â€‹72.8 (p<0.05); VTER â€‹= â€‹846.2 â€‹± â€‹166.0 vs. 743.1 â€‹± â€‹124.7; O2pulse â€‹= â€‹24.5 â€‹± â€‹1.4 vs. 23.1 â€‹± â€‹1.3 (p<0.05). Experiment 2 PMP vs. NMP, respectively: V ˙ O2peak â€‹= â€‹43.3 â€‹± â€‹1.6 vs. 41.7 â€‹± â€‹1.6 (p<0.05); V ˙ O2@VT â€‹= â€‹31.1 â€‹± â€‹1.2 vs. 29.1 â€‹± â€‹1.3 (p<0.05); GXT-TTE â€‹= â€‹511.7 â€‹± â€‹49.6 vs. 486.4 â€‹± â€‹49.6 (p<0.05); VTER 872.4 â€‹± â€‹134.0 vs. 792.9 â€‹± â€‹122.4; O2pulse â€‹= â€‹24.1 â€‹± â€‹0.9 vs. 23.4 â€‹± â€‹0.9 (p<0.05). Results demonstrate that the PMP conferred a significant performance benefit to cyclists completing high intensity cycling exercise.

Diallyl disulfide inhibits ethanol-induced pulmonary cell vitamin D and antimicrobial peptide cathelicidin depletion.

Ethanol has been found to affect pulmonary cells by interfering with vitamin D metabolism and pulmonary defense mechanisms. The objective of this study was to understand the mechanisms of ethanol's disruptive influence on the vitamin D pathway and inhibition of anti-microbial peptide cathelicidin (LL-37). Bronchial epithelial cells (BEAS-2Bs), primary human bronchial epithelial cells (HBECs), primary human alveolar epithelial cells (HPAEpiCs), and human monocyte cells (THP-1s) were used in this study. These cells were cultured and exposed to different treatment groups: medium-only control, ethanol (70 mM) only, diallyl disulfide (DADS) (10 µM) -only, and a co-exposure of ethanol (70 mM) and DADS (10 µM) for 10 or 24 h. Calcidiol (50 ng/mL) and calcitriol (0.05 ng/mL) dose-response studies were conducted for 48 h. After incubation, cells were trypsinized, lysed, and centrifuged, and the cellular lysate was prepared for assay. Protein was quantified, and levels of inactive vitamin D [25(OH)D3], active vitamin D [1, 25(OH)2 D3], and anti-microbial peptides (cathelicidin/LL-37) in the samples were assayed using commercially available ELISA kits. In the ethanol-exposed group, cellular lysate concentrations of 25(OH)D3 and LL-37 were significantly reduced by 30%, and 40% in BEAS-2B cells, and 35% and 80% in HPAEpi cells respectively. Overall 1, 25(OH)2D3 cellular lysate levels were lower but followed a similar trend as the 25(OH)D3 response. LL-37 levels in primary bronchial, alveolar cells, and ThP-1 cells were statistically reduced in ethanol-exposed groups (60%, 80%, and 65%, respectively) when compared with control. Following the addition of DADS, levels of LL-37 were recovered to within control levels for all three cell types. This study establishes two clinically relevant observations: that the exposure of pulmonary epithelial and monocyte cells to physiologically relevant levels of excessive ethanol selectively disrupts the activation of pulmonary vitamin D and inhibits the presence of anti-microbial peptide (LL-37) in vitro, and the co-exposure of DADS significantly attenuates ethanol-induced intracellular LL-37 depletion.

The Applications of 3D Printing in Pulmonary Drug Delivery and Treatment of Respiratory Disorders.

BACKGROUND: Pulmonary diseases are the third leading cause of morbidity worldwide, however treatment and diagnosis of these diseases continue to be challenging due to the complex anatomical structure as well as physiological processes in the lungs. METHODS: 3D printing is progressively finding new avenues in the medical field and this technology is constantly being used for diseases where diagnosis and treatment heavily rely on the thorough understanding of complex structural-physiology relationships. The structural and functional complexity of the pulmonary system makes it well suited to 3D printing technology. RESULTS: 3D printing can be used to deconstruct the complex anatomy of the lungs and improve our understanding of its physiological mechanisms, cell interactions and pathophysiology of pulmonary diseases. Thus, this technology can be quite helpful in the discovery of novel therapeutic targets, new drugs and devices for the treatment of lung diseases. CONCLUSION: The intention of this review is to detail our current understanding of the applications of 3D printing in the design and evaluation of inhalable medicines and to provide an overview on its application in the diagnosis and treatment of pulmonary diseases. This review also discusses other technical and regulatory challenges associated with the progression of 3D printing into clinical practice.

Immune-regulating effects of exercise on cigarette smoke-induced inflammation.

Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus-capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic antioxidative capacity and several compensatory mechanisms in tissues such as an increased anabolic signaling in muscle or an increased compliance of the vascular system. Accordingly, regular exercise training seems to protect long-term smokers against some important negative local and systemic consequences of smoking. Data suggest that it seems to be important to start exercise training as early as possible.

Regulation of vascular signalling by nuclear Sprouty2 in fetal lung epithelial cells: Implications for co-ordinated airway and vascular branching in lung development.

Sprouty2 (Spry2) acts as a central regulator of tubular growth and branch patterning in the developing mammalian lung by controlling both magnitude and duration of growth factor signalling. To determine if this protein coordinates airway and vascular growth factor signalling, we tested the hypothesis that Spry2 links the primary cue for airway outgrowth, fibroblast growth factor-10 (FGF-10), to genomic events underpinning the expression and release of vascular endothelial growth factor-A (VEGF-A). Using primary fetal distal lung epithelial cells (FDLE) from rat, and immortalised human bronchial epithelial cells (16HBE14o-), we identified a nuclear sub-population of Spry2 which interacted with regions of the rat and human VEGF-A promoter spanning the hypoxia response element (HRE) and adjacent 3' sites. In FDLE cultured at the PO2 of the fetal lung, FGF-10 relieved the Spry2 interaction at the HRE region by promoting clearance of a 39 kDa form and this was accompanied by histone-3 S10K14 phosphoacetylation, promoter de-methylation, hypoxia inducible factor-1α activation and VEGF-A expression. This repressive characteristic of nuclear Spry2 was relieved in 16HBE14o- by shRNA knockdown, and stable expression of mutants (C218A; C221A) that do not interact with the VEGF-A promoter HRE region. We conclude that nuclear Spry2 acts as a molecular link which co-ordinates airway and vascular growth of the cardiopulmonary system. This identifies Spry2 as a contributing determinant of design optimality in the mammalian lung.

Age is the main factor related to expiratory flow limitation during constant load exercise

OBJECTIVE: The objective of this study was to investigate the interaction among the determinants of expiratory flow limitation (EFL), peak oxygen uptake (VO2peak), dysanapsis ratio (DR) and age during cycling at different intensities in young and middle-aged men. METHODS: Twenty-two (11 young and 11 middle-aged) men were assessed. Pulmonary function tests (DR), cardiopulmonary exercise tests (VO2peak) and two constant load tests (CLTs) at 75% (moderate intensity) and 125% (high intensity) of the gas exchange threshold were performed to assess EFL. EFL was classified using the percentage of EFL determined from both CLTs (mild: 5%-30%, moderate: 30%-50%, severe: >50%). RESULTS: Only the middle-aged group displayed EFL at both exercise intensities (p<0.05). However, the number of participants with EFL and the percentage of EFL were only associated with age during high-intensity exercise. CONCLUSIONS: There was no interaction between the determinants. However, age was the only factor that was related to the presence of EFL during exercise in the age groups studied.

Interaction of levofloxacin with lung surfactant at the air-water interface.

The molecular-level interaction of levofloxacin with lung surfactant was investigated using Langmuir monolayers and atomistic molecular dynamics (MD) simulations. In the simulation, the DPPC/POPC mixed monolayer was used as a lung surfactant model and the molecules of levofloxacin were placed at the air-lipid interface to mimic the adsorption process on the lung surfactant model. The simulation results indicate that amphoteric levofloxacin expands the lung surfactant, also stabilizing the film for levofloxacin fractions until 10% w/w at least. The Langmuir monolayers made with the lung surfactant Curosurf had expanded isotherms upon incorporation of levofloxacin, without changes in monolayer elasticity. In fact, levofloxacin induced film stability with increased collapse pressures in the Curosurf isotherms and delayed the phase transition, according to Brewster angle microscopy (BAM) imaging. Using polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS), we found that levofloxacin is preferentially located in the head group region, inducing an increased organization of the Curosurf film. This location of levofloxacin was confirmed with MD simulations. The stability inferred demonstrates that the lung surfactant can be used as a drug delivery system for the administration via inhalation or intratracheal instillation of levofloxacin to treat lung diseases such as pneumonia and respiratory distress syndrome.

Quantifying the shape of maximal expiratory flow-volume curves in healthy humans and asthmatic patients.

Differences in the absolute flow and volume of maximal expiratory flow-volume (MEFV) curves have been studied extensively in health and disease. However, the shapes of MEFV curves have received less attention. We questioned if the MEFV curve shape was associated with (i) expiratory flow limitation (EFL) in health and (ii) changes in bronchial caliber in asthmatics. Using the slope-ratio (SR) index, we quantified MEFV curve shape in 84 healthy subjects and 8 matched asthmatics. Healthy subjects performed a maximal exercise test to assess EFL. Those with EFL during had a greater SR (1.15 ± 0.20 vs. 0.85 ± 0.20, p<0.05) yet, there was no association between maximal oxygen consumption and SR (r=0.14, p>0.05). Asthmatics average SR was greater than the healthy subjects (1.35 ± 0.03 vs. 0.90 ± 0.11, p<0.05), but there were no differences when bronchial caliber was manipulated. In conclusion, a greater SR is related to EFL and this metric could aid in discriminating between groups known to differ in the absolute size of MEFV curves.

Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links.

The cardiovascular response to xenobiotic particle exposure has been increasingly studied over the last two decades, producing an extraordinary scope and depth of research findings. With the flourishing of nanotechnology, the term "xenobiotic particles" has expanded to encompass not only air pollution particulate matter (PM) but also anthropogenic particles, such as engineered nanomaterials (ENMs). Historically, the majority of research in these fields has focused on pulmonary exposure and the adverse physiological effects associated with a host inflammatory response or direct particle-tissue interactions. Because these hypotheses can neither account entirely for the deleterious cardiovascular effects of xenobiotic particle exposure nor their time course, the case for substantial neurological involvement is apparent. Indeed, considerable evidence suggests that not only is neural involvement a significant contributor but also a reality that needs to be investigated more thoroughly when assessing xenobiotic particle toxicities. Therefore, the scope of this review is several-fold. First, we provide a brief overview of the major anatomical components of the central and peripheral nervous systems, giving consideration to the potential biologic targets affected by inhaled particles. Second, the autonomic arcs and mechanisms that may be involved are reviewed. Third, the cardiovascular outcomes following neurological responses are discussed. Lastly, unique problems, future risks, and hurdles associated with xenobiotic particle exposure are discussed. A better understanding of these neural issues may facilitate research that in conjunction with existing research, will ultimately prevent the untoward cardiovascular outcomes associated with PM exposures and/or identify safe ENMs for the advancement of human health.

Drug-targeting methodologies with applications: A review.

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system.

mTOR signalling, embryogenesis and the control of lung development.

The existence of a nutrient sensitive "autocatakinetic" regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford-Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development.

Examination of the Ability of N-acetylcysteine Administration during Anesthesia to Prevent Perioperative Deterioration of Pulmonary Function in Patients Undergoing Nephrectomy.

BACKGROUND: Postoperative pulmonary complications are associated with significant morbidity and mortality in patients undergoing major surgeries. Acetylcysteine is a known antioxidant and is also used as a mucolytic agent to reduce hypersecretion and the viscosity of mucus secretions by the lung. Several studies have revealed that high doses of N-acetylcysteine can significantly prevent pulmonary complications. However, it has not yet been established whether low doses of N-acetylcysteine are also of clinical benefit. Here, we investigated the efficacy of a low dose of N-acetylcysteine, which was administered intravenously to patients under general anesthesia, in preventing perioperative deterioration of pulmonary function. METHODS: A total of 52 patients who were scheduled for nephrectomy were randomly assigned to receive either 600 mg of intravenous N-acetylcysteine or the same volume of normal saline. Patient hemodynamic and pulmonary parameters and the incidence of pulmonary complications were recorded and compared between the groups. RESULTS: No significant pulmonary complications occurred in either group. Moreover, no significant differences were observed regarding either patient characteristics or hemodynamic parameters between the two groups. Contrary to our expectations, the pulmonary parameters were also not significantly different between the two groups. CONCLUSION: A low dose of N-acetylcysteine appears to have only limited value in preventing perioperative pulmonary complications.