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Cigarette smoke causes significant oxidant stress which is further enhanced by recruitment and activation of inflammatory cells to the lung. Polymorphisms in some detoxification enzymes are thought to increase the risk of developing chronic obstructive pulmonary disease (COPD), but the ultimate role of genetic variability in antioxidant and/or detoxification enzymes in COPD remains obscure. Some antioxidant enzymes are inducted, but the extent of induction is insufficient to protect the lung/alveolar epithelium against cigarette smoke. Exogenous antioxidants such as vitamins do not seem to protect against cigarette smoke related lung injury. Glutathione related synthetic drugs such as N-acetylcysteine have shown some benefits, but they may have pro-oxidant side effects. Synthetic compounds with superoxide dismutase and catalase activities have shown promising results in animal models against a variety of oxidant exposures including cigarette smoke in the lung. These results are in agreement with studies highlighting the importance of alveolar antioxidant protection mechanisms in oxidant stress and their inducibility. These new drugs need to be tested in cigarette smoking related lung injury/inflammation since inflammation/oxidant stress can continue after discontinuation of smoking.
- COPD, chronic obstructive pulmonary disease
- CuZnSOD, copper zinc SOD, ECSOD, extracellular SOD
- ELF, epithelial lining fluid
- GCL, glutamate cysteine ligase
- GPX, glutathione peroxidase
- GR, glutathione reductase
- GRX, glutaredoxin
- GSH, glutathione
- GST, glutathione-S-transferase
- γGT, γ-glutamyl transpeptidase
- HO-1, heme oxygenase-1
- MnSOD, manganese SOD
- MRP, multidrug resistance protein
- NAC, N-acetylcysteine
- NO, nitric oxide
- PRX, peroxiredoxin
- ROS, reactive oxygen species
- RNS, reactive nitrogen species
- SOD, superoxide dismutase
- TRX, thioredoxin
- chronic obstructive pulmonary disease
- antioxidant enzymes
- smoking
- smoker's lung
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- COPD, chronic obstructive pulmonary disease
- CuZnSOD, copper zinc SOD, ECSOD, extracellular SOD
- ELF, epithelial lining fluid
- GCL, glutamate cysteine ligase
- GPX, glutathione peroxidase
- GR, glutathione reductase
- GRX, glutaredoxin
- GSH, glutathione
- GST, glutathione-S-transferase
- γGT, γ-glutamyl transpeptidase
- HO-1, heme oxygenase-1
- MnSOD, manganese SOD
- MRP, multidrug resistance protein
- NAC, N-acetylcysteine
- NO, nitric oxide
- PRX, peroxiredoxin
- ROS, reactive oxygen species
- RNS, reactive nitrogen species
- SOD, superoxide dismutase
- TRX, thioredoxin
The most important non-malignant lung disease caused by cigarette smoke is chronic obstructive lung disease (COPD), a globally escalating problem that mirrors the extent of cigarette smoking in the community. In addition to COPD, cigarette smoking is associated with respiratory bronchiolitis interstitial pneumonia (RB-ILD)/desquamative interstitial pneumonia (DIP), a disease entity classified as a histopathological group of interstitial pneumonias.1 Both disease groups are underdiagnosed; this is a serious problem, especially for COPD because of its high prevalence, progressive nature, and cost to healthcare systems throughout the world. Smoking cessation is the only therapeutic intervention that has been shown to improve the prognosis of COPD with reduction of disease progression. This review will concentrate on the importance of the oxidant/antioxidant balance and the major antioxidant enzymes and detoxification mechanisms in smoker's lung and COPD, and the possibilities that new synthetic antioxidants will be able to prevent the progression of cigarette smoke mediated injury in the human lung.
The lung is a unique tissue compared with many other vital organs since it is directly exposed to high levels of oxygen. It therefore has to have efficient antioxidant mechanisms for the primary protection of the airways against ambient oxygen and exogenous oxidants. In cigarette smokers the oxidant burden is further increased for a number of reasons. Firstly, one puff of cigarette smoke contains millions of oxygen free radicals. Cigarette smoke contains high concentrations of nitric oxide (NO). Tar includes organic compounds such as quinones, which react with oxygen and increase the generation of superoxide radicals in intracellular redox cycling reactions. Free radicals activate inflammatory cells which, in turn, generate high levels of reactive oxygen (ROS) and nitrogen species (RNS) and other toxic metabolites. The most important of these mechanisms include myeloperoxidase, NADPH oxidase, and nitric oxide synthases (NOSs) (such as inducible NOS) and, in certain inflammatory conditions, eosinophil peroxidase. Typical features of smoker's lung are inflammation with the recruitment of neutrophils and macrophages into the airways, small airway obstruction/fibrosis, and destructive processes of the lung parenchyma.2,3 Some studies have suggested that oxidative stress/lipid peroxidation is associated with pulmonary airway narrowing in the general population.4,5 Many studies have also shown that there is a significant oxidant burden both in the lung and systemic circulation in COPD.6–11 The airways of patients with COPD, especially during disease exacerbations, contain high levels of activated neutrophils, activated macrophages, and also eosinophils, representing an even higher oxidant burden during the active phase of this disease.3,12 A number of studies have detected increased levels of oxidant markers in COPD lung tissue as well as in sputum, exhaled air, and exhaled breath condensate. These markers include increased levels of myeloperoxidase, the neutrophil markers lipocalin and lactoferrin, and markers of lipid peroxidation such as 4-hydroxy-2-nonenal (4-HNE) in the tissue and sputum, increased levels of hydrogen peroxide, and markers of lipid peroxidation products (thiobarbituric acid reactive substances) in the exhaled air/breath condensate in COPD. These studies have been extensively reviewed previously.9,13–16 Most studies have been conducted on chronic smokers. However, acute exposure to cigarette smoke has also been shown to lead to an immediate transient oxidant burden, although unchanged and even decreased levels of exhaled NO have also been reported (reviewed by van der Vaart8). Overall, there is a significant ROS/RNS production in COPD that apparently overwhelms lung antioxidant protection in this disease.
In contrast to the oxidant producing systems, relatively little is known about the primary antioxidant defence of human lung, and even less is known about this system in smokers. Furthermore, alterations in the primary antioxidant defence as well as the effects of exogenous antioxidants in COPD have been less extensively investigated. There are many questions that still remain unanswered, such as the importance of individual variability in the primary antioxidant defence and the risk for COPD, the significance of the induction of the primary antioxidant mechanisms in smoke related inflammation, the importance of specific lung cell types in lung protection, the effects of the ultrastructural localisation of these enzyme proteins and/or small molecular weight antioxidants in smoker's lung, and also whether antioxidant enzymes have any effects on the inflammatory process itself such as the survival of inflammatory cells or apoptosis. The balance between oxidants and antioxidants is complex and the interactions between these pathways have received little attention. However, the significance of the primary antioxidant defence mechanisms in the development of COPD as well as finding ways to improve lung antioxidant protection, especially in areas where the oxidant stress is highest, may be major questions in predicting COPD progression.
The lung has an efficient protection capacity against exogenous oxygen and ROS. Studies on animal models have shown that mucins, which are cysteine rich glycoproteins present in the epithelial lining fluid, provide significant protection against oxidants, and that the levels of these glycoproteins are increased by oxidants.17,18 Epithelial lining fluid contains a high glutathione (GSH) content,19 a molecule that also has been considered as one of the primary antioxidants in the human lung. In addition to these compounds, lung tissue contains several proteins capable of binding free iron and other metals (albumin, transferrin, ferritin, ceruloplasmin, lactoferrin, metallothionein). These proteins may have fundamental roles in protecting lung tissue against oxidant attack since metals are potent generators of free radicals in the Fenton and superoxide derived Haber-Weiss reactions.20 Human airways contain both lipid and water soluble vitamins, but their relative roles in the airways are poorly understood. One typical feature of the antioxidant enzymes and closely related thiol proteins of human lung is their highly cell specific arrangement and compartmentalisation, in that they are localised to different cell types, cell organelles (one example being mitochondria), and also different extracellular compartments.
Superoxide dismutases
Superoxide dismutases (SODs) are the only enzyme family with activity against superoxide radicals. These enzymes include manganese SOD (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD).21–23 All of them are widely expressed in human lung.24 CuZnSOD, which is mainly a cytosolic enzyme, is evenly distributed intracellularly but is also found in the nucleus and lysosomes.25 It is expressed in the bronchial epithelium of human lung,26 and in the alveolar epithelium, mesenchymal cells, fibroblasts and vascular endothelial cells in rat lung.27 MnSOD is localised to the mitochondria, a critical cell organelle both for cellular energy metabolism and cell survival. MnSOD is mainly expressed in alveolar type II epithelial cells and alveolar macrophages in the human lung.26,28 ECSOD is primarily localised to the extracellular matrix, especially in areas containing high amounts of type I collagen fibres and around pulmonary and systemic vessels.29 It has also been detected in the bronchial epithelium, alveolar epithelium, and alveolar macrophages. Overall, CuZnSOD and MnSOD are generally thought to act as bulk scavengers of superoxide radicals. However, the relatively high ECSOD level in the lung with its specific binding to the extracellular matrix components may represent a fundamental component of lung matrix protection. All SODs also have functional polymorphisms with potential consequences to the individual variability for the risk of lung diseases.30 SODs are also induced by cytokines. In this respect, MnSOD is unique since it is highly responsive to multiple extracellular stimuli including cytokines, oxidants and radiation, and this induction is thought to have physiological significance, especially in the protection of alveolar epithelium.24
Destruction of hydrogen peroxide
The major enzymes associated with hydrogen peroxide decomposition include catalase and enzymes associated with GSH metabolism. The latter group of enzymes includes glutathione peroxidases (GPXs), glutathione reductase, glutamate cysteine ligase (GCL)—that is, gammaglutamyl cysteine synthase (γGCS) and glutathione synthase. Catalase, a peroxisomal hydrogen peroxide consuming enzyme, is expressed intracellularly mainly in alveolar macrophages and neutrophils.31,32 Due to the high level of GSH (a tripeptide containing one cysteine amino acid—that is, a thiol group)19,33 in the epithelial lining fluid (ELF), enzymes associated with GSH synthesis are thought to have central roles in lung protection. In contrast to catalase, GPXs, a selenium containing family of enzymes, can break down not only hydrogen peroxide but also lipid peroxides. Five GPX gene products have been characterised: GPX1 is the classsic GPX; GPX2 is gastrointestinal; GPX3 is the plasma GPX that has also been detected in the epithelial lining fluid of human lung; GPX4 is the phospholipid hydroperoxide GPX; and GPX5 is a secreted protein synthesised by the caput epididymis. Of these, GPX3 has been most widely investigated in human lung.34 "Oxidised GSH" (that is, glutathione disulphide (GSSG)) is reduced back to GSH by glutathione reductase; the level of GSSG in normal tissues is very low (below 1%) due to the immediate reaction by glutathione reductase. Another important pathway for GSH replenishment in the lung is, however, its synthesis by GCL and glutathione synthase. The rate limiting enzyme in GSH synthesis, GCL, has been suggested to play a fundamental role in the regulation of lung GSH homeostasis. Mammalian GCL is a heterodimer that contains two subunits—the catalytically active heavy subunit (GCLh) and a light subunit (GCLl) that modulates the affinity of the heavy subunit for substrates and inhibitors. Both subunits are localised to the cytosol and expressed especially in human bronchial epithelium and occasionally in alveolar macrophages.35,36 The regulation of GCLh is still somewhat controversial but it does appear to be induced by oxidants and cytokines and downregulated by transforming growth factor β in vitro.37–39 GCL is cleaved during the apoptotic process of human cells,40–42 but it is not known whether this cleavage also occurs in human lung and lung diseases.
In addition, disposal of hydrogen peroxide is closely associated with several thiol-containing proteins—namely, thioredoxins (TRX1 and TRX2), thioredoxin reductases (TRR), peroxiredoxins (PRX) (which are thioredoxin perixidases), and glutaredoxins (GRX).43–46 All these enzymes are considered to be powerful redox modulators; they also have antioxidant properties, protect cells against high oxygen tension, and participate in cell proliferation and survival. Two TRXs and TRRs have been characterised in human cells, existing in both cytosol and mitochondria. In human lung, TRX and TRR are expressed in bronchial and alveolar epithelium and macrophages.47 Six different PRXs have been found in human cells, differing in their ultrastructural compartmentalisation. Experimental studies have revealed the importance of PRX VI in the protection of alveolar epithelium. Human lung expresses all PRXs in bronchial epithelium, alveolar epithelium, and macrophages.48 PRX V has recently been found to function as a peroxynitrite reductase,49 which means that it may function as a potential protective compound in the development of ROS/RNS mediated lung injury. GRXs (I–II) are also localised in both the cytosol and mitochondria.43 GRX1 has recently been found especially in human alveolar macrophages and, to a lesser degree, in bronchial epithelium. It is downregulated by growth factors and possibly induced transiently by oxidant stress in vitro.50 Thus, there are several redox modulatory thiol containing proteins in human lung that have recently been shown to participate not only in cell protection against oxidants but also in the regulation of cell growth and survival.
Other detoxification pathways
Glutathione-S-transferases (GSTs) and multidrug resistance proteins (MRPs) belong to a group of detoxification enzymes that require intracellular GSH for their catalytic activity. GSTs constitute a protein family with high genetic variability, having potential effects on the development of smoking related non-malignant and malignant diseases. Three mammalian GST families—namely cytosolic, mitochondrial and microsomal—have been characterised.51 The relative importance of GSTs and MRPs in human lung is still unknown. For example, there are nine related MRPs. MRP1, at least, is located in the epithelium at the intersection of many thiol-based protection mechanisms that modulate the extrusion of GSSG from the cells (reviewed by Kruh52). Both these families of detoxification enzymes are often considered to be important in malignant diseases and the resistance of cancer cells to oxidant generating drugs. However, they are also expressed in normal lung, mainly in the airways.53 They protect cells against numerous oxidant generating compounds and drugs, including pollutants, quinones, hydroperoxides, and other end products of oxidative metabolism. MRP substrates include structurally diverse GSH, glucuronate and sulphate conjugates, but the precise mechanism by which GSH participates in MRP mediated efflux of the natural toxic products is currently unknown.52 Gamma-glutamyltranspeptidase (γGT) is a plasma membrane enzyme which is also expressed in lung epithelial cells. The released GSH/GSSG is not freely diffusible and needs first to be decomposed to the amino acids where γGT decomposes the γ-glutamyl bond of GSH. Experimental studies have shown that γGT is induced by oxidant stress,54 and also that γGT deficiency results in increased oxidative stress in normoxia.55 Heme oxygenase-1 is a stress response protein with significant functions in cell protection and homeostasis; this is also an enzyme which can be induced by oxidants and cytokines.56 Thus, in addition to the classical antioxidant enzymes and thiol proteins, human lung contains stress inducible enzymes and detoxification systems which seem to confer primary protection for the human airways. The reactions of the major antioxidant and detoxification enzymes are summarised in fig 1. Overall, there are numerous enzyme systems that participate in the scavenging of ROS in human lung with tight interaction; these enzymes are localised to specific cell types and organelles, mostly in bronchial epithelium, alveolar epithelial type II cells and alveolar macrophages. Some of the enzymes are also bound to the extracellular matrix, providing potential protection to the lung interstitium (fig 2).
Polymorphisms of antioxidant and detoxification enzymes in COPD
Many antioxidant enzymes such as all three SODs exhibit functional polymorphisms which can impact on enzyme activity/localisation. No studies are available on the polymorphisms of MnSOD or CuZnSOD in the development/progresssion of COPD. Their polymorphisms appear to have no effect on asthma development.57 In ECSOD, a single nucleotide substitution resulting in an amino acid change from Arg to Gly at 213 (in the middle of the positive charged sequence of the heparin binding domain of ECSOD) leads to increased circulating ECSOD activity (10-fold) and decreased tissue binding of ECSOD.58 One preliminary report on this polymorphism suggests that ECSOD polymorphism might be an additional risk for the development of chronic lung disease.59 However, it is likely that polymorphism of ECSOD, which is very rare, cannot alone explain the early development of common lung diseases like COPD. Several studies have suggested that polymorphisms of the GSH associated detoxification enzymes may be associated with COPD. In one study, three GST polymorphisms (GST T1, GST P1 and GST M1) but not hemeoxygenase-1 showed a significant association with the rapid decline in lung function parameters in smokers.60 In some, but not all, studies there were also significant associations between GST M1 null genotypes, GST P1, microsomal epoxide hydrolase, and COPD.61–63 Overall, it appears that GST genotypes are risk factors for a rapid decline or low function in smokers with mild to moderate airflow obstruction.64
Regulation of antioxidant enzymes in smoker's lung, COPD, and smoking related desquamative interstitial pneumonia
A recent microarray study on the bronchial brushings assessed 44 antioxidant related genes in four categories (catalase, SOD/GSH metabolism/redox balance, and pentose phosphate cycle) in non-smokers and smokers (average smoking history 21 years, no lung disease).65 There was some variation in the gene expression levels within the same individual, but a remarkable interindividual variability. Altogether, 16 of the 44 antioxidant related genes were increased in the epithelium of smokers compared with non-smokers.65 Neither SODs nor catalase were altered in the epithelium of smokers, while 33% (7 of 21) of the genes encoding enzymes of the GSH pathway were upregulated, the most prominent being GPX2, although others with minor induction included GCL (both subunits), glutathione reductase, GPX3, GSTs and—among the redox balance regulating enzymes—TRR 1. Another recent study that used microarray technology characterised the gene expression profile of lung tissue samples from healthy subjects and advanced emphysema.66 A typical feature of severe emphysema, both in "usual emphysema"and alpha-1-antitrypsin deficiency, was a global decrease in gene expression but an increased expression of the transcipts encoding proteins involved in inflammation and proteolysis. The major finding among the classical antioxidant enzymes was a significant decline in GPX3. Overall, GSH associated enzymes represent a group of enzymes that can be induced by cigarette smoke in human lung but may probably also decline during the progression of COPD.
MnSOD is significantly induced by cigarette smoke in rat lungs,67 which is consistent with the high inducibility of MnSOD by cytokines and oxidant exposure in vivo.24 Many studies have, however, also observed that the induction is transient, and that antioxidant enzymes may also be downregulated during severe and/or chronic oxidant exposure.68 Superoxide dismutase and catalase activities have been reported to be increased in human alveolar macrophages in chronic smokers,69 whereas several antioxidant enzymes such as CuZnSOD, GST, and GPX seem to decline in elderly smokers with long smoking histories.70 A recent human study evaluated MnSOD in smokers and in subjects with mild/moderate COPD and found MnSOD to be increased especially in the alveolar pneumocyte II cells of smokers and patients with COPD.71 In conclusion, it seems that MnSOD can be induced in smoker's lung, especially in the alveolar epithelium, and that this is probably a consequence of cytokine/oxidant mediated induction. Furthermore, it can be viewed as one indicator of the oxidant burden, especially at the alveolar level of smokers.
Cigarette smoke causes depletion of intracellular GSH in cultured airway epithelial cells with a transient decrease of GPX and glucose-6-phosphatase activities,72 but also an increase in GPX 3 expression.73 Some in vitro studies also suggest that, after initial GSH depletion, there is an increase in the GSH levels apparently due to GCL induction (reviewed by Rahman and MacNee74). In general, the results obtained from various animal species and cell cultures are, however, variable, which emphasises the importance of not generalising results from in vitro or animal experiments to human disease states. In humans, these enzymes have been investigated both after acute exposure to smoke and in chronic smokers. Acute smoking, which evidently causes remarkable oxidant stress, does not increase GSH levels in ELF, but several studies have shown that GSH levels in the BAL fluid and ELF of chronic smokers are raised.74–76 On the other hand, GSH is not increased intracellularly—that is, in the BAL fluid cells (mainly alveolar macrophages) of smokers or patients with COPD; thus, extracellular GSH clearly does not reflect intracellular antioxidant enzymes in the lungs of smokers.76 The regulation of ELF GSH levels is still poorly understood; it may be related both to the epithelial injury and also to complex mechanisms of GSH transport and synthesis.
Several studies indicate that GPX 3 is increased during the oxidative stress of human airways and is increased both in the bronchial epithelium and ELF of smokers77 and in asthmatic airways.34 The results with GCL are variable, partly due to the many experimental designs used in animal models and cells.38 Two studies on smokers and/or patients with COPD have shown increased gene expression of GCL in the bronchial epithelium,65,78 while others have reported lowered GCL immunoreactive protein in the bronchial epithelium and alveolar macrophages of subjects with smoker's lung and COPD.79,76 On the other hand, the extent of GCL immunoreactivity was increased in the metaplastic/dysplastic bronchial lesions of COPD,79,80 as was also the case with some other protective enzymes such as TRX, pointing to the importance of oxidant stress in lung/bronchial epithelial cell carcinogensis.80 The variable results in GCL expression in smoker's lung and COPD may therefore be related to the cell type present in the epithelium (either normal or metaplastic), and to differences in the smoking history and disease severity or its activity. Induction of antioxidant/detoxification enzymes protects not only normal bronchial epithelium against oxidative insults, but possibly also against cell death/apoptosis, which then might maintain cell proliferation even though the cells contain oxidised DNA alterations.
In addition to the classical antioxidant enzymes, GSTs and heme oxygenase-1 have been investigated in the airways of smokers since it is known that both these enzymes can protect lung cells against oxidants. In one study on a relatively small number of patients, smoking had no effect on GST levels,81 while the transcripts of several GSTs were increased in the bronchial epithelium of smokers without COPD.65 Heme oxygenase-1, an enzyme that is highly inducible by oxidants, is increased in the alveolar macrophages of smokers but decreased in severe COPD.82,83 Moreover, heme oxygenase-1 can be induced, especially in the alveolar macrophages of acute asthmatics.84 There are remarkable differences in the individual variability of the detoxification enzymes (GSTs) and heme oxygenase-1 in human airways, but several studies suggest their induction during the oxidative stress caused by cigarette smoke. Recent results also suggest that, during the ongoing progression of COPD, there is some decline in the efficacy of protective mechanisms in human airways.
Cigarette smoking is also associated with airway/interstitial lung diseases, RB-ILD/DIP as smokers account for 90% of all cases. Several antioxidant enzymes and related mechanisms have been found to be increased in these diseases, probably due to oxidant stress and inflammation. Enzymes that have been found to be increased in these disorders include MnSOD, GCL, TRX, and heme oxygenase-1 (box 1).28,35,47,85
Box 1 Activity and/or expression of antioxidant enzymes, redox modulatory proteins, and detoxification enzymes in smoking related non-malignant lung diseases
Manganese superoxide dismutase (MnSOD)
Unchanged gene expression in the airway epithelium of smokers65
Increased activity and immunoreactivity in the alveolar epithelium of smokers71
Increased immunoreactivity in the inflammatory areas of interstitial lung disorders (DIP)28
CuZn superoxide dismutase (CuZnSOD)
Unchanged gene expression, protein and activity in the airway epithelium and lung homogenates of smokers65,71
Decreased activity in the alveolar macrophages of elderly smokers70
Extracellular superoxide dismutase (ECSOD)
Unchanged gene expression in the airway epithelium of smokers65
Unchanged immunoreactivity in the lung homogenates of smokers71
Unchanged gene expression in the airway epithelium of smokers65
Increased catalase activity in the alveolar macrophages of chronic smokers69
Enzymes associated with glutathione metabolism
Increased glutamate cysteine ligase (GCL) (gene expression) or decreased (immunoreactive protein) in airway epithelium of smokers65,78,79
Increased GCL immunoreactivity in metaplastic and dysplatic epithelium of smokers79,80
Increased GCL immunoreactivity in the inflammatory areas of DIP35
Increased GPX2, GPX3 and glutathione reductase gene expressions in the bronchial epithelium of smokers65
Increased GPX3 gene expression in the bronchial epithelium of smokers113
Decreased GPX3 gene expression in severe emphysema66
Increased GSTs (gene expressions) in airway epithelium of smokers65
Decreased GST and GPX activities in the alveolar macrophages of elderly smokers70
Thioredoxin and thioredoxin peroxidases (peroxiredoxins)
Unchanged (thioredoxin gene expression) in the airways of smokers65
Increased (thioredoxin reductase gene expression) in the airways of smokers65
Increased thioredoxin immunoreactive protein in the inflammatory areas of DIP47
Heme oxygenase-1
Increased immunoreactivity in the alveolar walls of smokers83
Decreased immunoreactivity in the lung of severe COPD82
Increased immunoreactivity in the inflammatory areas of DIP85
Antioxidants and antioxidant enzymes of inflammatory cells and lung inflammation
A typical feature of cigarette smoking related lung diseases such as COPD is the recruitment of macrophages and neutrophils to the lung which increases oxidant burden also in the lung interstitium. Exogenous antioxidants and new synthetic molecules with SOD-like activity decrease lung inflammation in several experimental models of lung injury including cigarette smoke (see next section). However, little is known about the effects of antioxidant enzymes of inflammatory cells themselves on the survival/apoptosis or persistence of inflammation in human lung. Antioxidant enzymes of the inflammatory cells can have a pivotal role in the inflammatory reaction of the lung by offering significant protection against oxidants both intracellularly and extracellularly. They can prolong the survival of inflammatory cells, decrease their apoptosis, but some of them are also released into the interstitium with consequent protection of the extracellular matrix (GSH and extracellular antioxidant enzymes such as ECSOD). Alveolar macrophages have a long life span (several months) and there are suggestions that the survival of macrophages is prolonged in the lungs of smokers and subjects with COPD.86 Macrophages express several antioxidant enzymes and related compounds including at least MnSOD, ECSOD, catalase, enzymes associated with the TRX-PRX system, and especially GRX and HO-1.26,32,47,48,50,87,88 MnSOD and HO-1 appear to be increased in the alveolar macrophages of subjects with smoker's lung, mild COPD, and acute asthmatic inflammation.83,84 In contrast to alveolar macrophages, the life span of neutrophils is very short. The physiological half life of neutrophils in circulation is only 6 hours, and there is evidence that neutrophil apoptosis is further enhanced by oxidants.89 Very few studies have investigated antioxidant mechanisms of human neutrophils. These studies have shown that typical features of the antioxidant profile of neutrophils are their high catalase content, low levels of GSH-dependent enzymes, and nearly non-detectable levels of TRX and HO-1 by immunohistochemistry.32,87,90 Antioxidant enzymes in the inflammatory cells have been shown to decrease during the progression of several systemic diseases (reviewed by Kinnula90), but whether this also occurs in smoking related human lung diseases or has clinical significance is unclear.
Several studies have investigated the systemic oxidant stress which occurs in COPD such as observations of a decline in lung and plasma levels of antioxidants, but variable results have been obtained by administering exogenous antioxidants (mainly vitamins such as vitamin E) to patients with COPD.91 The disappointing results can be explained, at least in part, by the complex cell specific antioxidant systems present in human lung and the fact that vitamins taken orally do not reach the critical areas of the lung where the oxidant stress is highest. Since GSH is considered as one of the most important antioxidants in human lung, numerous studies have tried to improve GSH homeostasis in oxidant mediated lung injury. However, GSH has a poor penetration capability. Neither inhalation nor oral ingestion of GSH have improved the GSH balance in oxidative stress; in fact, it has caused side effects such as bronchoconstriction.74 GSH is readily transported to the extracellular space by several mechanisms (including GSTs and MRPs), but is not directly transported from the extracellular milieu into the cells. N-acetylcysteine (NAC) is a widely used drug that might improve GSH homeostasis. In animal models NAC has attenuated elastase induced emphysema.92 It is relatively safe also in humans and has already been tested in a variety of conditions and treatment schedules, being used orally, by inhalation, and intravenously (reviewed by Rahman74). On the other hand, NAC may also have some pro-oxidant effects at the cellular level. In rats, NAC attenuated pulmonary inflammation caused by various antigens; it also decreased neutrophil recruitment and P-selectin upregulation.93 NAC also decreased H2O2 levels in the exhaled air in COPD and COPD exacerbations.94–97 On the other hand, it had relatively minor effects on lung GSH homeostasis.98–100 Both controlled studies and a systematic review with NAC in COPD have shown a small reduction in exacerbations.101,102 Other compounds with NAC-like activity have been tested in many laboratories including N-acystelyn, GSH esters and GSH precursors, but there are no studies on these compounds in human smokers with COPD. Antioxidants that improve GSH homeostasis have potential possibilities in protecting the lung during oxidative stress, but these need to be investigated in future studies in combination with other new drugs with antioxidant activity.
Another group of antioxidants that have had beneficial results in several animal models are SODs. In the initial experiments, exogenous CuZnSOD or recombinant MnSOD were administered by inhalation or instillation, often encapsulated to liposomes or in combination with other antioxidant enzymes such as catalase (reviewed by Kinnula and Crapo24). However, antioxidant enzymes have several drawbacks such as high immunogenity. In another approach, synthetic SOD mimetics have been developed to avoid the problems associated with endogenous antioxidant enzymes and to improve their penetration capability and efficacy. They have been shown to have at least four properties—namely, scavenging of superoxide, hydrogen peroxide, peroxynitrite, and lipid peroxides. These agents include salen compounds,103 macrocyclics,104 and metalloporphyrins.105 Salen compounds (such as EUKs) can attenuate oxidant injury in numerous organs including lung injury in ARDS.106 The macrocyclic agents (such as M40403) have been reported to decrease lung inflammation and pleurisy by inhibiting ROS/RNS formation, neutrophil infiltration, and release of pro-inflammatory cytokines.104 Metalloporphyrins such as manganese (III) meso-tetrakis (4-benzoic acid) porphyrin (MnTBAP) have been tested in a number of models of lung injury including paraquat and carrageenan-induced pleurisy, exposure to bleomycin, asbestos and radiation, in airway inflammation, and models of bronchopulmonary dysplasia and lung haemorrhage.107–111 In all these models, these synthetic compounds have had very positive results including a significant effect on lung protection. MnTBAP has also been found to reduce smoking related lung injury in rat lungs.112 In that study, one of the compounds, AEOL 10150, significantly decreased the BAL cell number within the first weeks of exposure. Importantly, squamous metaplasia following 8 weeks of tobacco smoke exposure was only 2% in animals treated with the drug compared with 12% in animals exposed to cigarette smoke without AEOL 10150. This study clearly showed that new synthetic SOD mimetics can significantly reduce the adverse effects of exposure to tobacco smoke and suggest that they may even have beneficial effects in preventing malignant conversion of epithelial cells. These new synthetic antioxidants may prove also to have significant importance in human lung inflammation caused by cigarette smoke.
The lung is exposed to high levels of oxidants, not only in normal conditions but especially in inflammatory states such as cigarette smoking related disorders. The lung has an efficient but complicated antioxidant defence system, where antioxidant enzymes and related detoxification enzymes have a cell specific expression and compartmentalisation and variable induction capacities. Cigarette smoke leads to an induction of some of these enzymes, especially in the bronchial and alveolar epithelium, possibly reflecting high oxidant burden in these locations. Although there is a systemic oxidant stress in COPD, one key determinator in preventing COPD and emphysema progression might be provision of treatment that is specifically directed to the target areas where the oxidant stress is high and the cells are especially vulnerable to injury.
Funded by Helsinki University Hospital, Sigrid Juselius Foundation, Finnish Antituberculosis Association Foundation, and the Cancer Society of Finland.


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Luka Doncic might be the favourite to win Rookie of the Year, but Trae Young showed on Sunday why he deserves to be in the conversation.
On a day where his shot wasn't falling, Young still managed to steal the show by recording his first career triple-double. The Atlanta Hawks rookie scored 23 points on 4-for-14 shooting from the field and 13-for-16 from the free throw line, dished out 11 assists and pulled down 10 rebounds in 28 minutes, all while turning the ball over only twice.
While Doncic leads all rookies this season with four triple-doubles, Young joined Markelle Fultz, Ben Simmons, Tim Hardaway and Jason Kidd as the only first-year players in Basketball Reference's database to finish with a triple-double in less than 30 minutes of action.
It still wasn't enough for the Hawks to beat the Nets — Vince Carter missed a 3-pointer in the closing seconds that would've won the game — but Atlanta outscored Brooklyn by a total of 13 points in Young's minutes on the court, giving him the second-highest +/- of the game.
Young has been incredible over the last month. Prior to Sunday's matchup with the Nets, he was averaging 28.5 points, 8.6 assists and 4.1 rebounds since the All-Star break on 45.3 percent shooting from the field and 43.5 percent from 3-point range.
He recently made history by joining Michael Jordan and LeBron James as the only rookies in the last 40 years to post 40-plus points and 10-plus assists in a single game when he exploded for 49 points and 16 assists in a quadruple overtime loss to the Chicago Bulls.
Doncic, meanwhile, has cooled off a little since a scorching first half of the season. Not individually, but only the Los Angeles Lakers have a worse net rating than the Dallas Mavericks over the last 15 games.
The Hawks rank 23rd in the league during that stretch, but they've been mostly competitive, posting a 6-9 record and losing by a margin of only 2.8 points per 100 possessions.
Sunday's loss was yet another example of how much better both Young and the Hawks have been playing following a slow start to the season.

subset: commoncrawl


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In the year 2020, perhaps our vision will finally be improved and augmented. Perhaps a population desperately needing to change will identify the path forward through mental lucidity. Shedding ourselves of the baggage of today's world will no doubt help with that clarity. And if we can finally, thankfully, breathe a little and focus on the exact things that are important while banishing what's not, maybe then, our minds will be free.
Some people worry about climate and/or socioeconomic change. Others get worked up over presidential tweets. Then there's genetically modified organisms, spy drones, terrorists, hacking, fracking, weapons of mass destruction, robotic bugs that spy on us, political agendas, student loan debt, or the moving line of words at the bottom of the television screen, endlessly reporting what's wrong in a world where tragic news drives ratings.
We need a reset. We need to focus. And we need to do it soon.
Cannabis provides one method for intro- and extrospection; psychedelics provide another. And just as cannabis is reaching into the far recesses of the Earth, healing its way back into modern medicine, conversations regarding the utility of psychedelics are mushrooming, literally. I spoke with Jackee Stang, who co-founded Delic Corp., a company focused on "destigmatizing psychedelics for a mainstream audience", with her husband, a seasoned veteran of High Times.
"Delic exists to define what psychedelics are and to better understand these hallucinogenic substances," Jackee explained. "Often, the conversational level becomes a gray area. When we're talking about psychedelics, we're referencing MDMA [3,4-methylenedioxymethamphetamine], psilocybin, ketamine, ibogaine, mescaline, LSD [lysergic acid diethylamide], san pedro, and other hallucinogenic substances you've not heard of yet."
"The mental health crisis can't be denied," she continued. "One of 5 people are affected by a mental health condition such as depression. Opioids are more prevalent and too easy to obtain. As the world is literally heating up from environmental and intrapersonal issues, the need for release of that stress is becoming greater. Psilocybin can have a greater impact on a person's life than cognitive therapy has been doing for the last 40 or 50 years."
Jackee has been around psychedelics for over 20 years. "Psychedelics offered me a way to move on from my childhood trauma," she explained. "I'm extremely grateful that they exist."
Like cannabis, psychedelics are nothing new. Albert Hoffman first synthesized LSD in 1938 from compounds found in a fungus that grew on rye. And while it's well-known that the US government experimented with using LSD during MK-Ultra, there were also studies conducted exploring the medicinal benefits of LSD, such as in psychotherapy and for treating alcoholism. Psychedelic-assisted psychotherapy is making a comeback. [1, 2]
Psilocybin is useful in treating depression [2] and cluster headaches. Ketamine was used in Vietnam as an anesthetic for wounded soldiers. The drug put the soldiers into a dissociative state. WebMD identifies ketamine as having major potential for treating severe depression. [3] "We're right in the middle of several significant studies," Jackee added. "A much higher efficacy rate is being seen through the use of psychedelics compared to traditional techniques for clinical therapy. In some cases, we're seeing up to an 80% effectiveness in treating depression."
"I'm not a scientist, however," she continued. "I am an advocate for human freedom. Access to psychedelics is a human right." Whole cities, like Denver and Oakland agree. Denver recently decriminalized personal possession. Oakland decriminalized entheogenic plants. Chicago passed a "lowest priority" law, making possession of psychedelics below a parking ticket. Oregon is weighing legalization.
This is just the beginning. In November of 2020, California will vote on the legalization of psilocybin possession, sales, and amnesty, perhaps, in part, due to the surging commonality of micro-dosing within the Silicon Valley community.
"The legal and medical conversations are very different," Jackee commented. "Much like with cannabis, it becomes a pattern of states' rights. The new psychedelic renaissance is happening much faster than cannabis."
Why might this be? "There's no doubt that the 30+ years of cannabis legalization efforts helped pave the road for psychedelics," Jackee replied. "But psychedelics have more research being done. The psychedelic community has taken the academic approach, via organizations like MAPS [Multidisciplinary Association for Psychedelic Studies] and a myriad of other academic organizations proving the medicinal aspects of psychedelics."
But Jackee says the psychedelic community is "reaping the benefits, but also the problems" associated with legalization. Anderson Cooper recently covered a story for 60 Minutes on psychedelics. Consumption of psychedelics is becoming much more mainstream in the US than you likely might think. One study back in 2013 reported 32 million psychedelic consumers within the US. [4] An odd number of current articles cites this archaic figure, so who knows what the 2019 tally looks like. Or better yet, the 2020 number.
To many people, though, this much usage of psychedelics will sound frightening. They may not be aware of micro-dosing. Rather, they likely associate psychedelic use with "free-love" hippies or the Manson Family. "The source and quality of the substance matters!" Jackee exclaimed. "This is where we went wrong in the 60s. LSD wasn't regulated. There was no effort to educate on dosage. It was a free-for-all that created erratic behavior, or at least behavior not understood in "normal" terms. It freaked some people out. Hysteria ensued. Which of course leads to really bad marketing."
Add to these stereotypes the usage of MDMA or ketamine in rave culture, where many people might be consuming just to consume or fit in, without having knowledge on what they're ingesting. While people might need psychedelics with increasing regularity, they absolutely require education.
And Delic Corp is ready to better educate the hordes of people now considering whether psychedelics can help facilitate their journey to a different way of life than what they've traditionally known or have been "taught". MeetDelic will be the first psychedelic wellness conference, held May 2nd, 2020, at Wisdome LA in Los Angeles. Jackee and company have been working on the full-legal framework for legalization with Decriminalize California to provide a "citizens' initiative" to be on the ballot in November 2020. They also specifically acquired the web platform Reality Sandwich to provide guides on psychedelic resources that have been vetted by researchers.
"Safety is key," Jackee advised. "There's a lot of misinformation. No one has ever died from psilocybin due to the psilocybin. It, in particular, is arguably one of the safest drugs known to man. But there are other psychedelic substances – mostly synthesized chemical compounds – that are not as cut and dry. We're working to make safety cool again."
She continued. "There hasn't been a lot of effort to educate or re-educate the public. How is 5-MeO-DMT [N,N-dimethyltryptamine] sourced, for example? When you take it from a Colorado River Toad, how does that affect the toad and its ecology? There's been a barrier to educating people on what these substances are."
"But the fact is that psychedelic wellness is for everyone, not just the elite. Psychedelics are safer than alcohol. They're safer than a lot of the air that we breathe. We're trying to encourage people to come out of the psychedelic closet. It's not illegal to talk about your experience."
This is a conversation that we're going to continue to have. Each dialogue on the science, or logic, or medicine, or compassion, or spiritual healing helps nail down the coffin lid on archaic, enshrouded ways of thinking. We Earthlings, Riders on the Pale Blue Dot, are a rare culture of beings, alone in the Milky Way, and for who knows how far out in the cosmos. This status comes before any race or creed. We need healing first as individuals, which should synchronously translate into greater harmony as a globe. The science has spoken, and the projections are what many have prophesied. Our minds and bodies can profoundly benefit from psychedelics.
[1] Nielson, E. et al. "The Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Change Phenomena through Qualitative Content Analysis of Clinical Sessions," Front. Pharmacol., volume 9, 2018, p. 132. [journal impact factor = 4.418; cited by 27]
[2] Carhart-Harris, R. et al. "Psilocybin with psychological support for treatment-resistant depression: six-month follow-up," Psychopharmacology, Volume 235, Issue 2, 2018, p. 399–408. [journal impact factor = 3.875; cited by 27]
[3] Singh, I. et al. "Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight," The Lancet Psychiatry, 2017 [journal impact factor = 18.329; cited by 27]
[4] Krebs, T. and Johansen, P. "Over 30 million psychedelic users in the United States," F1000 Research, volume 2, 2013, p. 98. [journal impact factor = 1.24; cited by 27]


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Brain-Body Breakthroughs – Cure Aging or Die Trying: An interview with Dr. William Andrews
Podcast: Play in new window | Download
As the Founder, President and CEO of Sierra Sciences, a bio-tech company in Reno, Nevada, he is in the process of doing just that. Seem unlikely? You wont feel that way after you hear what he has to say. Dr. Andrews views aging just as any other disease. He tells you why he feels that way and has data to back him up.
The Nobel Prize for Medicine or Physiology in 2009 was awarded for work done on telemore biology. This is the same field we will be discussing today. You'll soon see why it has the potential to turn back the hands of time as well as cure cancer and a host of other chronic diseases. You'll even hear how the ability to lengthen telomeres might enable AIDs patients to live normal lives.
Sound too good to be true? Only if you've never heard Bill Andrews explain how close he is to solving these difficult problems.
George Clooney just celebrated his big 5-0 and he said his current aspiration is to be AARP's Sexiest Man to Still be Alive! We all want to live long and healthy lives. Listen today to learn how to take the first step!


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As a result of this lesson, students will be able to:
· Identify aesthetic and functional qualities of the Modern Architecture of Brazil.
· Recognize cultural impact of government policy on public planning in Brazilian society circa 1950s/1960s.
· Identify the works and design aspects of Oscar Niemeyer's architecture.
· Create their own model city or building using Niemeyer's concepts of site specificity as seen in Brasilia.
Discussion Question(s)
· How does modern Brazilian architecture compare/contrast with pre-existing Portuguese influenced colonial architecture?
Materials Needed
· Foam core, cardstock, X-acto knives, foam cutter, hot glue gun, large flat surface.
· Site of the Museo de Arte Contemporaneo (Museum of Contemporary Art), Niteroi, Brazil, http://www.macniteroi.com.br/ (September 13, 2009)
Books such as:
Related material also on this website
Set Up and Introduction
View the Power Point presentation and use discussion questions such as these to stimulate dialogue. Students can use the first part of the activity sheet to take notes during the discussion.
· What are three characteristics of Oscar Niemeyer's work? (Slide 8 of Power Point: Expressive/curvilinear lines, white concrete, utilizing surrounding environment in the design, brises-soleil, azuielo)
· How does modern Brazilian architecture compare/contrast with pre-existing Portuguese influenced colonial architecture? (Slide 2 of PPT: Modern architecture rejected the highly decorative Baroque style for simplified forms with minimal flourishes. )
· What would an architect need to have in mind when developing a plan for an entire city versus planning for one specific building? (Slide 9-18 of PPT; If building one building, architects need to focus on the main purpose of their specific building, as well as considering how their building relates or stands out from its neighbors. When planning a whole city, architects have the chance to design a multitude of buildings that have different purposes. Architects also need to plan out the entire city, from the placement of buildings, man-made lakes, and traffic patterns.)
· How does modern Brazilian architecture utilize the existing surrounding environment into its designs? (Niemeyer used stilts to raise his buildings up so that one could see under/through to the surrounding environment, creating a sense that nature and environment could become part of architectural design. With the MAM in Caracas and the MAC in Niteroi, Niemeyer used the natural outcropping of rocks to highlight his designs, which mimic the natural landscape surrounding it. )
· How can environment and climate influence architectural design (compare and contrast local climate with Brazil's climate, etc.)? (Brises-soleil are permanent shades built onto the exterior of buildings to shade interiors from tropical sun. Azuielo, or tiled exterior components, are used for their durability as well as their ability to repel humidity and moisture much like tiles in a bathroom while adding color and decoration to the outside.)
1. Based on the previous discussion, have students generate a list of aesthetic qualities for Niemeyer's work. Decide as a group which they admire most.
2. Teams of students choose a building from their own city to study architecturally and recreate in the style of Niemeyer.
3. Divide into teams to recreate specific buildings in their town in Niemeyer's style using the second part of the activity sheet. (An alternative assignment would be to create an ideal building. The activity sheet would have to be modified.)
4. Review the concept of scale and how to use it in creating model buildings.
5. Demonstrate appropriate tool safety techniques.
6. Teams create a scale model of their buildings using mat board, cardstock, etc.
7. Assemble the buildings into a town.
8. Critique layout and construction in written and verbal formats. Be sure to consider the aesthetic qualities of Niemeyer's work.
Extending the lesson:
· Arrange a field trip to local public buildings to discuss the form and function in local architecture.
· Invite a local architect to show how to create models and discuss function of urban planning and how it relates to architecture.
· If students have access to CADD lab, they can create designs using that technology.
Assessment and Wrap Up
· Review the three characteristics of Niemeyer's work and the aesthetic principles discussed earlier.
· In writing, critique the town that was created; then, share the ideas in a group discussion.
Brazilian Modernist Architecture Worksheet
Background for Teachers
Define architecture: It is the art of designing buildings and large structures.
What makes a work of art or architecture "modernist"? The architect's or artist's rejection of previous styles of art or architecture for a more modern and streamlined aesthetic style.
What is "cultural anthropophagy"? It is the philosophy of the digestion and destruction of the existing Portuguese colonialism to create a new Brazilian culture.
The following words are aspects of Brazilian architecture's aesthetics. Define and explain their importance to the Brazilian Modernist style, using specific Niemeyer buildings as reference:
Concrete: Material used by Niemeyer to create more organic forms. Concrete was easily available in Brazil as a material and therefore allowed buildings to be made by local craftsmen. White concrete is evident in the curved pedestrian pathways leading to the MAC and the MAM.
Pilotis: Concrete stilts used to raise the bulk of the building up so that a sense of lightness is achieved. Pilotis allow for the eyeline to continue underneath the façade. Seen in Palacio Gustavo Capanema, MAC and the Oscar Niemeyer Museum.
Brises-soleil: Permanent fixtures to the outside of a building which deflect harsh tropical sunlight. They keep light and heat out. They are evident on the Palacio Gustavo Capanema and the 1939 World's Fair Pavilion.
Azuielo: Tiled accents added to the exteriors of buildings, seen on exterior of church of Sao Francisco at Pampuhla and Palacio Gustavo Capanema.
Curvilinear: A curved line or form. The MAC, the Basilica at Brasilia, and the Oscar Niemeyer Museum's eye shape and pedestrian walkway are examples of curvilinear lines.
Site specific architecture: A building designed with the surrounding environment in mind. The Modern Art Museum in Caracas and the MAC are examples of this concept.
How did Le Corbusier influence Oscar Niemeyer's work? Le Corbusier used concrete as well as bold geometric shapes and colors in his work, and used pilotis.
How did Brasilidade and Estado Novo influence the architecture of Brazil? These government programs created opportunities for regional architects to design and plan entire site-specific cities using local materials and labor.
Name _______________________ Date ____________________
Brazilian Modernist Architecture Worksheet
Define architecture
What makes a work of art or architecture "modernist"?
What is "cultural anthropophagy"?
The following words are aspects of Brazilian architecture's aesthetics. Define and explain their importance to the Brazilian Modernist style, using specific Niemeyer buildings as reference:
Site specific architecture:
How did Le Corbusier influence Oscar Niemeyer's work?
How did Brasilidade and Estado Novo influence the architecture of Brazil?
Name _______________________ Date ____________________
Redesigning in the style of Niemeyer:
1. Working in a pair or team, choose a local building to recreate in the style of Oscar Niemeyer.
2. Discuss what the building's purpose is, where it is currently located, and ways the present architecture of the building succeeds or fails aesthetically. Does it blend in with its surroundings? Is it a work of art? What could you do to make it more appealing or user friendly?
3. Consider the building information (from Step 2) and the key aspects of Niemeyer's work (curvilinear forms in white concrete, use of natural surroundings to determine form, pilotis, and the use of environmentally-aware architectural forms such as brises-soleil and exterior mosaics). Each team member makes several sketches using the aesthetics.
4. Each member presents his/her ideas to the team (just as Niemeyer did working with the international team of architects for the United Nations). The team chooses the strongest design to be made into model.
5. Using the materials provided, build a mock-up scale model of the building. Be sure to create the surrounding environment as well, including trees, water elements, etc.
6. Prepare a report of your building.
* Identify your building and its purpose.
* Explain the ways you utilized Oscar Niemeyer's aesthetics to redesign it.
* Compare and contrast the existing building with your design.
7. Present your building to the class as a team.


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Farmparts Ltd is the official Distributor For ATS England spare parts.
We have full range in stock please contact us for your requirements
ATS spare parts are premium quality spare parts for diesel engines & gensets, commercial vehicles and earthmoving equipment's.
We have full stock for Massey Ferguson, Fiat New Holland, Cummins, Duetz, Perkins Gensets, JCB, Cat……. to name a few.


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With a historic organic farm in Westport, Massachusetts as our home base, we are able to provide the freshest grown tomatoes and other vegetables for your catered event. Lyn and Cleo started the company "Three Tomatoes" in 2005 and provide 82 varieties of Heirloom and cherry tomatoes. You can find these delicious tomatoes at Lees Supermarket, Bayside Restaurant or you can visit Lyn and Cleo in the summer at Three Tomatoes farmer's market on Monday's from 3-6 at the farm. Email us for directions.
Click on any image to enlarge and to create a slideshow.
Click on any image to enlarge and to create a slideshow.
Catering backed by a Local Organic Vegetable & Produce Farm in MA
As a Local Organic Farm, we feature our own vegetables & fresh produce in the gourmet food catering services we provide here in the SouthCoast MA & FarmCoast RI area
Catering services feature real Farm to Table sourcing of local organic vegetables and produce from our own farm and via other SouthCoast MA & Farmcoast RI area growers and greenhouses


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Photos we are missing.
The Bohemian Waxwing has a very large breeding range of 12,800,000 square kilometers. This includes boreal forests in northern Scandinavia, Russia, Alaska, and northern and western Canada south to northern Washington state. During the winter, this species is a short distance migrant to wooded habitats with fruiting trees in the northern and western United States, Japan, Mongolia, Kazakhstan, northern China, and parts of eastern and northern Europe. The Bohemian Waxwing has an estimated breeding population of 4,000,000 individuals, and a conservation rating of Least Concern.
Bohemian Waxwing: Large waxwing with gray upperparts, pink-gray crest, black mask and chin, and gray underparts. The wings are black with a sharp yellow or white line and red spots on secondaries (visible when folded). Tail is dark and yellow-tipped with cinnamon-brown undertail coverts.
Bohemian Waxwing: Widespread throughout Europe, Asia, and North America from Alaska across northern Canada. Breeds in the northern regions of Alaska and Canada. Winters south of its breeding range across the southern territories and northern states. Preferred habitats include open and coniferous woodlands.
Bohemian Waxwing E1
Calls from a flock.
Bohemian Waxwing A1
High-pitched begging calls from nestlings.
"scree", "zirrrr"
Waxwings (Bombycillidae)
The waxwings are one of the one hundred eighteen families of birds in the order PASSERIFORMES (pronounced pas-ser-i-FOR-meez); a large taxonomic order that includes silky-flycatchers, bulbuls, and babblers.
There are three species of waxwings in one genus in the Bombycillidae (pronounced bom-bih-SILL-uh-dee) family, a group found in the temperate zone of the Northern Hemisphere.
North America has two species of waxwings in one genus. These two species are the Bohemian Waxwing and the Cedar Waxwing.
Both the Cedar and the Bohemian Waxwings are mostly known for the small red structures on their secondary feathers of the wings that resemble drops of wax.
Members of this family are small birds with soft plumage, rather short tails, long wings, and heads with wispy crests. They have thin bills with fairly wide gapes, and short legs adapted to perching in trees and bushes.
The waxwings are plumaged in warm browns, russet, and grays. They also have black coloration in the wings, on the tail, and markings on the face that give them a masked appearance. In addition to the red markings on their wings, they also have yellow on the belly, in the wings, and on the tail.
Outside of the tundra, waxwings can be found in most areas of the continent with the Cedar Waxwing being the most widespread species. Breeding in open woodlands in the northern half of the United States and in much of Canada, it wanders into open and thinly wooded areas of the southern United States during the winter. The Bohemian Waxwing also wanders in the winter but mostly to the northwestern United States from its breeding grounds in Alaska and northwestern Canada.
Depending upon availability of food sources, waxwings can migrate short or even long distances to Central America.
Waxwings are very social birds almost always found in flocks that wander in search of fruiting trees, especially those with berries. They eat fruit by gleaning it from the vegetation when perched or plucking it while hovering. They also eat insects, often catching them in flight. These arboreal birds do not come to the ground and are often heard giving their high pitched lisping calls as they fly overhead.
There are apparently plenty of fruiting trees available for waxwings, as neither species is threatened.
Waxwings are among the most frugivorous of North American birds. Instead of regurgitating seeds like most birds, they excrete them in their waste, thus helping with seed dispersal. In the fall, they can get also become intoxicated by eating too many fermented berries.
Michael Oberhofer
Belly, undertail coverts, chest, flanks, and foreneck.


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The Trillion-Dollar Bank Shakedown That Bodes Ill
The Clinton administration has turned the Community Reinvestment Act, a once-obscure and lightly enforced banking regulation law, into one of the most powerful mandates shaping American cities—and, as Senate Banking Committee chairman Phil Gramm memorably put it, a vast extortion scheme against the nation's banks. Under its provisions, U.S. banks have committed nearly $1 trillion for inner-city and low-income mortgages and real estate development projects, most of it funneled through a nationwide network of left-wing community groups, intent, in some cases, on teaching their low-income clients that the financial system is their enemy and, implicitly, that government, rather than their own striving, is the key to their well-being.
The CRA's premise sounds unassailable: helping the poor buy and keep homes will stabilize and rebuild city neighborhoods. As enforced today, though, the law portends just the opposite, threatening to undermine the efforts of the upwardly mobile poor by saddling them with neighbors more than usually likely to depress property values by not maintaining their homes adequately or by losing them to foreclosure. The CRA's logic also helps to ensure that inner-city neighborhoods stay poor by discouraging the kinds of investment that might make them better off.
~City Journal article in 2000 by Howard Husock


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4 Steps to THRIVE on a Therapeutic Diet
I'm writing this article for all the amazing people taking charge of their health who are committed to following a therapeutic diet to heal their bodies. If this is you, than please take a moment to acknowledge your awesomeness because it's not always easy and down right challenging sometimes. Choosing to be on a therapeutic diet to improve your health can completely change your life, elevate your possibilities and be an amazing opportunity if you allow it to be.
A therapeutic diet includes or eliminates different foods and/or nutrients with the specific intention of bringing your body back into balance and improving health in some way. They can be short or long term. Sometimes you progress to different healing phases as you improve however continuing may be required. You know a therapeutic diet is working for you when you have some measurable positive outcome or a reduction in symptoms.
It's fair to say there are other lifestyle factors involved too. We know scarfing down all the right foods with 3 seconds of chewing is enough to sabotage the most ideal meals but we're not talking about that here. This is about re-defining the deprivation and owning the motivation of a therapeutic diet so you can let go of the struggle and embrace your results.
Step One: Connect with the heart of your motivation and know what you are saying YES to.
Take a step back and explore WHY you are committing to this diet in the first place. Are you trying to manage inflammation, digestive symptoms, improved your mood or get more energy? If it's for a reduction in symptoms then that's great, especially if you're in the bathroom every hour or have joint pain. However, getting crystal clear on what you really want out of the experience beyond an absence of symptoms is a lot more powerful. In other words, define it's purpose and the part it's playing in the bigger picture of your life. Deprivation is one of the biggest struggles on a therapeutic diet. Once you've gotten clear on the purpose you will know what you are REALLY depriving yourself of if you don't follow through. Saying no to foods that won't serve you is a lot easier when you know what you are saying YES to.
Also consider that while healing CAN contribute to your overall happiness, it doesn't mean it will. Often the rock we need to look under is the one we keep avoiding. If you've been on a your diet for a period of time and your results have plateaued or your not sure it's serving you anymore than consider experimenting in a different direction. I'm not suggesting abandoning the diet but often there are other things that need our attention that aren't diet related in order for us to heal.
Step Two: Transform the stress into empowerment.
You're likely taking foods out of your diet that you are used to eating and enjoy. This can feel like you are in FOOD JAIL, which for some is scarier than a real jail sentence. You can feel totally defeated if you break the rules and scarf down one cookie, which turned into three or ten…oops.
Damned if you do, Damned if you don't!
There's nothing that makes you want something more than someone telling you that you can't have it. What you appreciate, appreciates. If you can't have chocolate or cheese than all of sudden there are NO OTHER FOODS except for chocolate and cheese you can possibly think of eating. Are there any other foods? The entire grocery store is chocolate and cheese.
How about when you are the one cooking and everyone wants you to make that "thing" that only you make. It's so delicious and you aren't supposed to have any. So unfair!
Or the social scenario of everyone having ice cream and you are dead in the middle of a healing protocol that restricts sugar and dairy. You decide to join in (a little won't hurt) because you hate to feel left out and your aunt is pressuring you to have "just one bite"! Then you feel guilty for cheating or maybe you didn't cheat but you truly felt left out and sad you couldn't join in.
Hmmmmm …..Got STRESS? Because I got stressed just writing that and those are all very real situations when following a diet with restrictions. Stress will sabotage the purest health efforts even more than three cookies.
Here's the thing: the reality of a therapeutic diet is that to get results there will likely be things you will not be able to eat however I invite you to look at it in a different way. What if you decided nothing was off limits regardless of your diet? Because it's not really. You can always eat whatever you want because the conscience choice is yours at every meal. You get to decide. If you really want chocolate and cheese then you can have it. The point here is that lightening is not going to strike you if you decide to eat something off your diet nor is your health practitioner going to slap your hand with a ruler if you reach for the wrong thing.
The responsibility is yours and it has to be owned by you for results.
This is a helpful way to look at it because just taking things away is simply disempowering and stressful. Expanding choice is one of the most important parts of successful, lasting change. Doesn't it feel better to know you can absolutely eat whatever you want, but you are choosing not too because it's for your highest good?
Step 3: Let it Go!
There's some mourning and letting go that happens when we have to say goodbye to certain foods for a period of time AND mourning the version of you that is in need of the healing. Ask yourself:
What might you have to let go of to follow through?
Answering this question takes a lot of courage but it is helpful to allow your self to explore it. See what comes up when you do, because on the days you are feeling like it's time for a bottle of champagne and pizza, you'll want to know what you are holding on to that's so dear that's preventing you from moving forward. (Hint: It's not the champagne and pizza). We're always letting go as we grow and heal so being aware of the experience you ARE wanting is so important(Step One).
It can be a huge loss to let go of certain foods especially if that food is part of the strategy of your day. Eating can bring pleasure, energy, stress relief, joy and pick me ups. The hope of feeling better or reducing nagging symptoms is enough for some people but most need to find new strategies to replace what they were getting from the foods, especially if there is a strong emotional eating pattern. This is tricky because whatever you are replacing the food with has to be AT LEAST as effective as what you got from the food or it's unlikely to stick. There's some deconstructing during this process and it's a perfect opportunity to examine our habits, patterns and to once again expand our choices so we aren't feel so restricted by what we can't have.
Consider that there can be more to let go of than just the food.…
The other piece that deserves mourning is the version of you with the health challenges or symptoms. Our health status and our body image can penetrate our identity so as we start to heal it can feel very uncomfortable especially if we haven't felt good in a while or ever. Sounds strange but for some, feeling good can actually feel bad or foreign. Ever notice that when things are going really well that seems to be the time the sabotage sets in or things start to go wrong in some way?
Step 4. Don't expect people to get it but deeply appreciate it when they do!
No one likes to feel left out. You still belong and are loved even if you aren't eating the same thing. It can be very confronting to other people around you who may not have the courage to own their health(yet). It may not be apparent at first but know you are inspiring the people around you. When you do meet people who get it, let them know how much you appreciate it!You've got this! You don't want to embark on a therapeutic diet without considering these 4 Steps. It will not only alleviate stress but more importantly it can help you get more from your health endeavors than you ever imagined!]]>


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Cloudwater was born of good fortune and much hard work. The constellation of events that conspired to give Kaua'i its first tea farm brought together an inspired young woman, twenty acres of tropical rain forest and brush, and the vision of producing premium tea in the middle of the Pacific Ocean.
The path that led Michelle Rose to a life of tea began in Shizuoka Prefecture, Japan. There, as a visiting college student, she began a home stay with a family in one of the world's premiere tea growing areas. The momentum of this initiation into the culture of tea carried her forward for two decades of study and practice of nutrition, cuisine, and hospitality. Ultimately she was guided to the edge of a remote nature preserve at the base of an extinct volcano. Ten years later Cloudwater was producing extraordinary tea.
The challenges of pioneering a novel agriculture on the island of Kaua'i are as many and as varied as are the rewards. Michelle credits good luck, resilience, and the wisdom of Eva Lee & Nigel Melican, her mentors, for the success she has enjoyed.
There is no single attribute that gives Cloudwater its distinctive terroir. The bountiful rains brought by the Trade Winds to this mountainside plateau are ideal for the original three Sinensis and one Assamica cultivar that are the original tea garden's foundation plantings. Abundant sun, cool breezes, the shade of bamboo hedges, and native trees contribute to create a remarkable climate. Local friends attribute much of the success to the mana, or spiritual energy that is the hallmark of this unusual location.
This is the beginning of Kaua'i, and Hawai'i, as recognized sources for world class tea. These are the early days of tea culture in the mid-Pacific.
"Drink your tea slowly and reverently, as if it is the axis on which the world earth revolves – slowly, evenly, without rushing toward the future." – Thich Nat Hahn


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When I started working on Pyrseas, I reviewed several other products. Robert Brewer's Post Facto was probably the one with the most unique design. Although it compared database schemas in order to generate SQL to synch them up, it did not store database object definitions in a standard VCS repository. Rather, it used a Postgres database as the repository analog.
While Post Facto's design certainly influenced Pyrseas, there is one aspect of the former that, unfortunately, I did not emulate.
The Dependables
As any developer knows, database objects have dependencies on each other: table A has a primary key PK1, table B is declared with a foreign key dependent on PK1, function C is dependent on type X, view D is based on table A and includes a call to function C.
Pyrseas currently deals with these dependencies in an object-specific manner. For example, it does at least two passes through pg_class objects (tables, views, sequences, etc.) in order to create, alter or drop these objects in the correct order. However, this ad hoc approach can result in incorrect sequencing of generated SQL statements in some cases, particularly those like view D above.
The missing feature from Post Facto that avoids this conundrum? If you answered topological sort you were obviously paying attention in your Algorithms class. If you didn't, may I suggest chapter 15, "Devising and engineering an algorithm: Topological Sort" of Bertrand Meyer's Touch of Class.
Daniele's Quest
Over two years ago, someone opened an issue about the need to create primary keys before creating views. Later, Daniele Varrazzo reported another issue with dependencies.
Many of you Postgres users will recognize Daniele as the maintainer of Psycopg, the popular Python PG adapter, which of course is used by Pyrseas. Daniele and I chatted online, I mentioned Post Facto's solution and he, fortuitously and generously, started implementing a topological sort on a deptrack branch of Pyrseas.
We then collaborated for about eight months. He did most of the initial coding and I ran tests and fixed some issues. Unfortunately, Daniele is very busy, with a full-time job, Psycopg and other interests, so the work came to a near standstill.
Where We Stand
The last time changes were submitted to the deptrack branch, about six months ago, only four tests failed (out of over 600) running on both Python 2.7 and 3.4 against Postgres 9.3. Regrettably, three of those tests are integration and functional tests, so correcting those is critical to adding this feature.
In addition, although most tests complete successfully, the run times have been impacted severely. This will require an effort at re-optimizing performance before releasing the changes. Last but not least, the implementation needs internal documentation so that it can be properly maintained.
Sadly, I have not had much time or incentives to address these shortcomings. Are there any Pyrseas, Postgres or Python enthusiasts looking for a challenge?


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France's strike culture conundrum
By Stephen Evans
BBC News, Berlin
- Published
Germans watch the scenes of militancy from France with amazement. It is true that German railway workers have been on strike this week but it is a very rare event.
And it is very focused on pay. Germans usually strike when long-running negotiations reach deadlock. The issue is specific and monetary.
Contrast this with the tumult in France, which is over a broad issue with political ramifications.
But a look at the figures reveals interesting comparisons.
It is clear that the French are much more militant than their neighbours to the east, and also those across the Channel to the west.
They certainly put on a spectacular - occasionally violent - show when they take to the streets but are they more active when it comes to bread and butter issues?
Striking hard
"Yes and no" is the true but, no doubt, unsatisfactory answer.
They do not join unions like their comrades in neighbouring countries. According to the Federation of European Employers, about 30% of workers are in unions in Italy and Britain with slightly fewer in Germany - but still far more than in France - at only 9%.
But they do manage to go on strike more.
In the last five years, France has consistently lost more than 100 days of work a year through strikes for every 1,000 employees.
For Germany, it is a fraction of that, at just under four days for 1,000 workers, on the last figures available.
Britain - 19 days lost for 1,000 workers in 2009 - comes above Germany but still nowhere near France.
It should be said, though, that France has some catching up to do.
The truly militant country in the Western world is Canada - nice, reasonable Canada.
According to the UN's International Labour Organization, Canada often far exceeds France in working days lost through strikes.
This was particularly true before the great crash.
In 2005, for example, Canada lost 303 days for every 1,000 workers compared with 151 in France (Germany: 0.5, UK: six).
Last year, Canada lost a total of 2.2 million working days through strikes. France, with nearly double the population, lost 1.4 million.
Canadian militancy
So why is Canada the true militant nation when it comes to strikes?
It is partly because some bits of the Canadian economy such as mining have boomed.
The sizzling growth has bumped up wages and made workers in weaker industries like car-making try to keep up.
As Canadian industrial relations expert Stuart Jamieson put it: "A by-product of Canada's rapid but unstable pattern of economic growth, and one particularly provocative of industrial conflict, has been the problem of wage disparities."
In other words, mining unions exert muscle to get a slice of the profits. Non-mining unions in manufacturing exert muscle to try to get what the miners have. But it is money, not broad politics, which drives the militancy.
In France, in contrast, many of the days lost are through grand general strikes, with no immediate gain in wages.
Some do involve public sector workers with pay at the centre but many, too, are over broader issues, like the current plans for the higher pension age.
It is very hard to compare countries exactly when you try to discover reasons for militancy.
In Britain, for example, the law bans all but direct strikes against the striker's own employer and over very specific issues.
A general strike leaves the unions open to legal challenges and attacks on their funds via the courts.
Marked by the 1930s
Germany clearly has a very different industrial relations set-up because the war broke old ways of thinking and doing.
The consequences of the economic collapse of the 1930s are so seared into the national psyche that confrontational industrial relations seem to be a last resort.
Negotiations are done through works councils, with the strike then used sparingly to break a deadlock and force a deal.
And often not needed at all. The German machine manufacturer Bosch has just brought forward a pay rise for 85,000 workers.
"In difficult times we benefited from the strong loyalty of our staff, which was not a given," the company said.
But in less benign, consensual industrial environments, there are a few further questions: When might strikers become rioters? When does an industrial dispute turn into a social protest? Is what is happening in France a strike, or is it a protest which turns to riot on occasion? It matters because the causes might be different.
In a strike, pay is often the great driver. In riots down the ages, it is a sense of injustice, justified or not, which prompts the explosion.
Labour historians note that in some of the 19th-Century riots in Britain, wheat would be destroyed rather than stolen for use.
In the riots in Trafalgar Square in 1990, the source was a tax, the poll tax, which hit the poor proportionally harder than the rich - the tax was the same no matter what the wealth of the bearer.
Riots are often gestures against perceived injustice. Strikes are often industrial action in furtherance of more money - lose money now to get more money soon.


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Molekule cleans the air with stunning industrial design
You've never seen an air purifier that looked this good.
Say hello to the world's first molecular air purifier and a stunning one at that. Using patented technology, the purifier cleans the air of pollutants using PECO (Photo Electrochemical Oxidation), the end result of 20 years of r&d takes a nanoparticle-coated filter to help eliminate allergens, bacteria, viruses, mold and VOCs. Available in 2017, the Molekule will be available for $499 at its pre-order price and $799 when it hits full retail. One year of filters will be included.


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i cant open the game on mac
Tales of Saleana
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great stuff :) Would love to see it continue!!
This also has been dropped?? Sad
it's easy to get my attention with the words 'vampire' and 'otome', but keeping my interest is not so easy. the art, story, and characterization however, have done that. my only suggestions at the moment would be to give the reader a bit more influence over the mc's personality/choices. we tend to be forced to be passive and sweet in these types of games, and i think that especially with being a vampire, it would be a real shame to not even have the option of being more confident.
It sure would be nice but given this game hasn't received a single update (not even an status update) since 2017, I'd say the chances of it being dead or abandoned are high. I also went and looked for it on Lemma Soft forums and it was the same - last post on 2017. Better look for other games to play instead.
so many promising games here are dead or dying... it brings me much sadness T.T
I really like it, the art and the story
is this going to be finished? it is amazing!! good luck with the team ^^
it is sad to see a game like this never be finished...
Great art, interesting demo. I just wasn't expecting Saleanna to freak out over the mud stain. The way you described her made me think she's a nice girl or at least used to being dirty since she hunts rabbits. I've no issues if Ash paled in comparison to Kalen, especially since he was muddied by the pigs, however. It's just that, other than her, her relatives', and her home's fancy appearances, there was no foreshadowing of her reaction. If you're keeping the scene, maybe add something like her thinking about the consequences of a dirty cloak--maybe humans paying less attention to her so she'll be less able to seduce them, or the dangers of not having a cloak ready in case she needs to escape outside (e.g. while it's in the laundry)--to make her reaction more understandable. But it's really up to you, we've only seen a short demo.
good game i like it than k u
more now get
I wanna play the new game. Where's the dude who made it? Why is he not responsive?
He could be a she.
Wait, that did not make any sense.
Point is...
Why isn't anybody making this game's full version??
I know, right.
Like, bruh. (Or sis.)
It looks fucking rad.
and again,nothing for months.
I love this game already, it's funny too.
Looking forward to the full game <3
Wooow ! how did you do such an amazing art and game <3 i really like it <3
here is my game :D:D come and see my collections
the facebook hasn't been updated since christmas, anyone know if this is still coming out?
I have a mac and it says the file cannot be opened after I extract it :(
any updates :) ?
i want to check it out as well but i need zip file
Fantastic demo :D When are You planning to go with full version?
I'm really want to play this, but in a future update could you consider making a zip folder of the game for those of us that can't download .rar files?
Hey, I liked your demo a lot) When there will be a full game?
there weren't any news from you for a long time. U okay? :)
I think this isn't ever going to be published right? :/
I love the demo!! The CGs are beautiful and the characters are great. This is going to be an amazing game and I can't wait.
I'd like to know about the release date too. Originally, it was planned for mid-august but it seems as if this didn't work out. Their facebook page also didn't update since July and on here there aren't any news either. I'll keep coming here to check about ToS though :)
The demo is really great! I already love Cassius <3 I just have a question: will the full game be free ?
I love the demo!! The CGs are beautiful and the characters are great. This is going to be an amazing game and I can't wait.
The pasteur's gentleness... his brother's clumsiness... the hunter's coldhearted-ness....
This demo is heaven of otome-ness xD
I am absolutely excited about this game
I can't believe summer is finally here, I hope the countdown to the release starts soon.
Good luck to all of you and thank you for your hardwork so far!
Hi!! I LOVED your demo and I can't wait for the full game!!
I did a playthrough of it here:
However, I did notice some grammar mistakes! I am offering to proofread any of the text you want for free! Just let me know (:
Hi Ceirahmoon!
Thank you so much for your interest and Youtube playthrough!
Your offer for translation is much appreciated! We are still working on the script at the moment, but we find it inconvenient just to send out short parts (and they might be change at any moment ;A;) . So we decide to ask for proofread when a considerable amount has been written and fixed on.
We hope you will continue to support us in the future!
Cant wait for the full game :D >w> Cass seems like a fun route XD
Hi Anira!
Thank you for your interest in our game! XD
Cass's route is indeed a funny one. Please stay tune to find out! ;)
Any idea when the release date will be? :x I'm really excited about this~
Hi Arisa~!
Unfortunately we are not set on a release day at the moment. We are aiming for mid-August, but circumstances may arise and change that, because at the moments our team could only afford to do this in our spare time. We will be sure to keep you update once we decide on a date. Thank you so much for your interest though!
Good luck!
I hope you can manage. c: If you need any help with proof reading, feel free to ask~ Excited! xD
Love, love, LOVE the demo!
The characters were engaging, and the art was gorgeous! The characters' proportions are often off in VNs, but in Saleana the proportions were perfect (did I mention that the characters were mesmerising?). Aside from the occasional grammar mistake and some word choices that seem out of context, the story (at least so far) seems promising.
Great work! Can't wait for the full game!
P.S. I'm using a mac, and while I couldn't open the file manually, I could open it through the itch.io app. Just thought that this bit of info might help!
Hi jordanyak!
Thank you so much for your helpful compliment!!! (°▽°)/
We are trying to improve our grammar and vocabulary during the writing as well, but it involves a lot of re-read and re-write, which takes longer than expect.
Thank you for the heads up about the Mac version as well. Since we don't own a Mac (nor any acquaintances do - which is weird, we know, but it happens) we were a bit perplexed as to how to answer inquiries related to it. Your information is very helpful and we will be sure to update it in our game info above.
We hope you will continue to support us!!! (´ ω `♡)
I am absolutely excited about this game
I can't believe summer is finally here, I hope the countdown to the release starts soon.
Good luck to all of you and thank you for your hardwork so far!
Hi theffingmonster!
Thank you so much for your lovely comment! (〃>_<;〃)
The game would be released during mid-August - still summer but a bit later than planned because exams and RL held us back a bit ;;-;;
We hope you will continue to support us!!!
I wish YOU GOOD LUCK ON YOUR EXAms and I hope all of your efforts will be rewarded!
I will always continue supporting you!!
So far so good! I'm smitten with the artwork! I also wrote in more detail about the demo in my blog: http://pajamagaming.blogspot.c...
Hi Bellannmae!
Thank you so much for your helpful review! We will make sure to take in your feedback in the final version.
The writer agrees that the theme is overdone too, but since it's our first game, approaching it from a familiar position seems safer for us haha. But we are trying our best to refresh this theme, so please look forward to it!
Thank you again and we hope you will continue to support us in the future!
I just played the demo and I'm looking forward the full version!! I love the music and the drawings and I'm looking forward the story's development! Good luck in finishing your first game!
Hi Choubadaba!
Thank you for your kind comment! We are happy to hear that you like the demo!
We will be sure to keep up with the good points and polish the game further. We hope that you will continue to support us in the future!
Wow, i really loved the demo, even though she was pretty short and the menu isn't at its final state yet, the whole game seems already so great. I've instantly fallen for the hunter, damn man.
The artwork is gorgeous and i'm already so excited for the full game to be released, since i'm pretty sure i'll buy it if it still meets my expectations.
But i got a little question, judging from the Main Menu Backgroundpicture, will this Visual Novel only contain Kalen's Route or are there other maincharacter-boys to choose from?
(EDIT: I already read the info about the game, but i didn't get a safe answer from that)
Greetings and keep up the great work,
komae :)
Hi Komae!
Apologize for the delay answer, we were busy with final exams and real life stuffs and couldn't check the comments sooner.
Thank you for your encouragement, we are glad that you like the game! We will be trying our best to improve the UI/UX design (and of course keep the artwork quality up!)
Yes there will be other characters to choose from (The hunter is one of them haha XD). Forgive us from saying anything else about the cast, we feel it's a bit of a spoil to say how many you can choose from. We still have a lot to learn from this experience so if this point proved to be a bother, next time we would make sure to state it clearly.
Thank you so much again for your support!
Hi, when will this be released? I've fallen in love with it!!
Hello Cswanxx,
Thank you so much for your compliment! If things go well, the full game should be released during Summer this year!
We hope you will continue to support us in the future!
Amazing! Not long before summer comes, :) I loved the demo
when is your summer lol
Hi Sandpixie,
That's a good question actually. Completing is always easier said than done, and we also have to balance other life activities as well.
It should be around mid-August at the latest. It really depends on how fast we can draw the CGs and write the rest of the script.
Thank you so much for asking that question though. It's like a whip to our laziness!>_<b
Hello, I cannot seem to play this game. I used Mac. I extracted the game file from the rar, and did what I alway do when I open a VN game but it simply won't open.
Hello PineFresh,
First of all, thank you for taking an interest in our demo and telling us about the issue.
Unfortunately at this moment, we really don't have any solutions for this issue, because we're having troubles finding someone with a Mac and experience with it to help us. We're very, very sorry for this inconvenience.
If we find a solution, we will be sure to let you know. Thank you for your patience!
Try downloading the itch.io software then download the game from there. What the software does is extract and install the game for you. All you have to do is run it from the software itself. See if that helps? Good luck~
Hi will this game also be available on steam?
Hello TheRosetteWolf!
We apologize for the late reply. The game won't be on Steam unfortunately.
Thank you so much for your interest in the game! We hope you will continue your support in the future!


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Bordeaux Babydoll
100% poly long sleeve with babydoll bodice. This top runs slightly small through the shoulders.
While all vendors are a little different....most sizing runs S (0-4), M (6-8), L (10-12). We have a free personal stylist available in our boutique to help you with sizing as well. We know how each style fits & we will be happy to assist you. Contact us by message via Facebook, Instagram, our website or call 423-765-3003.


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This is a very rare poker set from Gucci with their famous branded red and green stripes produced in the 1960s. The leather on each end of the cube has fared extremely well with no noticeable scratches (but maybe 1 or two marks that are hard to see). The striped cloth is not perfect but also has no significant fraying to be seen. The piece overall is a wonderful find and comes with over 140 chips along with two Milano playing card decks. Please see all images for full quality representation.Ranking - The item has aging but overall has retained a wonderful look for it's vintage production retaining near-full quality of red and green stripes along with quality wood and leather that have avoided scratches (although two wood corners have some scuffing). The sliding covers are fully functional and the set retains over 140 rectangular clips that fit snug in their respective spots. Please see all images for accuracy before purchasing. Authentic Gucci Vintage Collectible Leather Wood Poker Set Cube with Classic Green and Red Stripes. Box - Brown, Green, Red. Chips - Green, Blue, Red, Yellow, White. Cards - Red, Black, White with Blue or Red back covers. 2 Decks of Morreale Milano Playing Cards.
20 Small, 20 Medium, 10 Large Tile Chips of each white, red, blue, and green! 19 Small, 16 Medium, 9 large Tile Chips (of Yellow). This is a wood and leather vintage poker set from Gucci with leather sides and wooden borders in a cube shaped design. Famous company hallmark stripes can be seen on all sides with the top and bottom removable lids having the design featured in a circle. The item was definitely used, which fortunately proves it's practicality, while it's vintage nature and scarcity online proves it's collectible nature.
This is a simply amazing find for any collector of vintage Gucci as it was produced in the 1960s! It is an even more unique find for those looking for unique poker sets, especially as it keeps it's contents safe in a cubed storage fashion rather than rectangular lock box styles you see today. The chips come in 5 different colors in a unique rectangular shape and can be valued differently as they come in three different sizes each.Please let us know if you have any questions, need further info, or wish to discuss possible pricing options for single or grouped items. We have other Gucci vintage collectibles available at time of posting this that can be combined if needed. Review all images before purchasing. S : New or new without a tag. (Like New - little to no use).
A : Good condition, barely used with few to no imperfections. B : There is a sense of overall use, with some minor damages. C : Overall there is a damage, very noticeable scratches or dirt.
D : Junk condition in need of repair. Please note that vintage items are not new and therefore usually have minor wear.All imperfections for this item have been included in pictures but please let us know if you need greater detail. It is of utmost importance that our customers receive quality items with the authenticity they are expecting. Please be aware that the color of items may be slightly different because of the specs of certain PC monitors. We ONLY sell authentic merchandise. The item "Authentic Gucci Vintage Poker Cube Set Leather Wood Signature Green Red Stripes" is in sale since Monday, March 9, 2020. This item is in the category "Collectibles\Casino\Chips\Sets\Other Casino Chip Sets". The seller is "archive_kagiya78" and is located in Mishima, Shizuoka. This item can be shipped worldwide.