Housing and public health Shaw, Mary
Annual review of public health,
01/2004, Letnik:
25, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This review considers the broad area of housing and public health, one of the traditional and core areas of public health research and intervention. The review takes into account the range of ...factors, acting at different levels, directly and indirectly, through which housing affects health. In public health terms, housing affects health in a myriad of relatively minor ways, in total forming one of the key social determinants of health. The paper closes by considering how the improvement of housing and neighborhoods has been a core activity of public health and a central component in tackling poverty. Investment in housing can be more than an investment in bricks and mortar: It can also form a foundation for the future health and well-being of the population. Addressing poor-quality housing and detrimental neighborhoods, in the broadest sense, is thus a task that should be grasped with vigor and determination by all those involved in public health.
Background and Purpose
Macropinocytosis is involved in many pathologies, including cardiovascular disorders, cancer, allergic diseases, viral and bacterial infections. Unfortunately, the currently ...available pharmacological inhibitors of macropinocytosis interrupt other endocytic processes and have non‐specific endocytosis‐independent effects. Here we have sought to identify new, clinically relevant inhibitors of macropinocytosis, using an FDA‐approved drug library.
Experimental Approach
In the present study, 640 FDA‐approved compounds were tested for their ability to inhibit macropinocytosis. A series of secondary assays were performed to confirm inhibitory activity, determine IC50 values and investigate cell toxicity. The ability of identified hits to inhibit phagocytosis and clathrin‐mediated and caveolin‐mediated endocytosis was also investigated. Scanning electron microscopy and molecular biology techniques were utilized to examine the mechanisms by which selected compounds inhibit macropinocytosis.
Key Results
The primary screen identified 14 compounds that at ~10 μM concentration inhibit >95% of macropinocytotic solute internalization. Three compounds ‐ imipramine, phenoxybenzamine and vinblastine ‐ potently inhibited (IC50 ≤ 131 nM) macropinocytosis without exerting cytotoxic effects or inhibiting other endocytic pathways. Scanning electron microscopy imaging indicated that imipramine inhibits membrane ruffle formation, a critical early step leading to initiation of macropinocytosis. Finally, imipramine has been shown to inhibit macropinocytosis in several cell types, including cancer cells, dendritic cells and macrophages.
Conclusions and Implications
Our results identify imipramine as a new pharmacological tool to study macropinocytosis in cellular and biological systems. This study also suggests that imipramine could be a good candidate for repurposing as a therapeutic agent in pathological processes involving macropinocytosis.
Acute lung injury (ALI) is an acute inflammatory process arises from a wide range of lung insults. A major cause of ALI is dysfunction of the pulmonary vascular endothelial barrier but the mechanisms ...involved are incompletely understood. The therapeutic potential of histone deacetylase (HDAC) inhibitors for the treatment of cardiovascular and inflammatory diseases is increasingly apparent, but the mechanisms by which HDACs regulate pulmonary vascular barrier function remain to be resolved. We found that specific Class IIa HDACs inhibitor, TMP269, significantly attenuated the lipopolysaccharide (LPS)‐induced human lung microvascular endothelial cells (HLMVEC) barrier compromise in vitro and improved vascular barrier integrity and lung function in murine model of ALI in vivo. TMP269 decreased LPS‐induced myosin light chain phosphorylation suggesting the role for Class IIa HDACs in LPS‐induced cytoskeleton reorganization. TMP269 did not affect microtubule structure and tubulin acetylation in contrast to the HDAC6‐specific inhibitor, Tubastatin A suggesting that Class IIa HDACs and HDAC6 (Class IIb) regulate endothelial cytoskeleton and permeability via different mechanisms. Furthermore, LPS increased the expression of ArgBP2 which has recently been attributed to HDAC‐mediated activation of Rho. Depletion of ArgBP2 abolished the ability of LPS to disrupt barrier function in HLMVEC and both TMP269 and Tubastatin A decreased the level of ArgBP2 expression after LPS stimulation suggesting that both Class IIa and IIb HDACs regulate endothelial permeability via ArgBP2‐dependent mechanism. Collectively, our data strongly suggest that Class IIa HDACs are involved in LPS‐induced ALI in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization.
Class IIa histone deacetylases are involved in lipopolysaccharide‐induced acute lung injury in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization.
Most programs today are written not by professional software developers, but by people with expertise in other domains working towards goals for which they need computational support. For example, a ...teacher might write a grading spreadsheet to save time grading, or an interaction designer might use an interface builder to test some user interface design ideas. Although these end-user programmers may not have the same goals as professional developers, they do face many of the same software engineering challenges, including understanding their requirements, as well as making decisions about design, reuse, integration, testing, and debugging. This article summarizes and classifies research on these activities, defining the area of End-User Software Engineering (EUSE) and related terminology. The article then discusses empirical research about end-user software engineering activities and the technologies designed to support them. The article also addresses several crosscutting issues in the design of EUSE tools, including the roles of risk, reward, and domain complexity, and self-efficacy in the design of EUSE tools and the potential of educating users about software engineering principles.
We have previously shown that Gs‐coupled adenosine receptors (A2a) are primarily involved in adenosine‐induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the ...downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study, we tested the overall hypothesis that adenosine‐induced Rac1 activation and EC barrier enhancement is mediated by Gs‐dependent stimulation of cAMP‐dependent Epac1‐mediated signaling cascades. Adenoviral transduction of HPAEC with constitutively‐active (C/A) Rac1 (V12Rac1) significantly increases transendothelial electrical resistance (TER) reflecting an enhancement of the EC barrier. Conversely, expression of an inactive Rac1 mutant (N17Rac1) decreases TER reflecting a compromised EC barrier. The adenosine‐induced increase in TER was accompanied by activation of Rac1, decrease in contractility (MLC dephosphorylation), but not Rho inhibition. Conversely, inhibition of Rac1 activity attenuates adenosine‐induced increase in TER. We next examined the role of cAMP‐activated Epac1 and its putative downstream targets Rac1, Vav2, Rap1, and Tiam1. Depletion of Epac1 attenuated the adenosine‐induced Rac1 activation and the increase in TER. Furthermore, silencing of Rac1 specific guanine nucleotide exchange factors (GEFs), Vav2 and Rap1a expression significantly attenuated adenosine‐induced increases in TER and activation of Rac1. Depletion of Rap1b only modestly impacted adenosine‐induced increases in TER and Tiam1 depletion had no effect on adenosine‐induced Rac1 activation and TER. Together these data strongly suggest that Rac1 activity is required for adenosine‐induced EC barrier enhancement and that the activation of Rac1 and ability to strengthen the EC barrier depends, at least in part, on cAMP‐dependent Epac1/Vav2/Rap1‐mediated signaling.
Rac1 activity is required for adenosine‐induced EC barrier enhancement and the activation of Rac1 and ability to strengthen the EC barrier depends, at least in part, on cAMP‐dependent Epac1/Vav2/Rap1‐mediated signaling.
Maintenance of the endothelial cell (EC) barrier is critical to vascular homeostasis and a loss of barrier integrity results in increased vascular permeability. While the mechanisms that govern ...increased EC permeability have been under intense investigation over the past several decades, the processes regulating the preservation/restoration of the EC barrier remain poorly understood. Herein we show that the extracellular purines, adenosine (Ado) and adenosine 5′‐γ‐thio‐triphosphate (ATPγS) can strengthen the barrier function of human lung microvascular EC (HLMVEC). This ability involves protein kinase A (PKA) activation and decreases in myosin light chain 20 (MLC20) phosphorylation secondary to the involvement of MLC phosphatase (MLCP). In contrast to Ado, ATPγS‐induced PKA activation is accompanied by a modest, but significant decrease in cyclic adenosine monophosphate (cAMP) levels supporting the existence of an unconventional cAMP‐independent pathway of PKA activation. Furthermore, ATPγS‐induced EC barrier strengthening does not involve the Rap guanine nucleotide exchange factor 3 (EPAC1) which is directly activated by cAMP but is instead dependent upon PKA‐anchor protein 2 (AKAP2) expression. We also found that AKAP2 can directly interact with the myosin phosphatase‐targeting protein MYPT1 and that depletion of AKAP2 abolished ATPγS‐induced increases in transendothelial electrical resistance. Ado‐induced strengthening of the HLMVEC barrier required the coordinated activation of PKA and EPAC1 in a cAMP‐dependent manner. In summary, ATPγS‐induced enhancement of the EC barrier is EPAC1‐independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP‐independent mechanism, to activate MLCP which dephosphorylates MLC20 resulting in reduced EC contraction and preservation.
In the present study we define and compare the molecular mechanisms linking adenosine‐ and ATPγ‐induced purinergic receptor activation and barrier strengthening in HLMVECs. We found that ATPγS‐induced EC barrier enhancement is EPAC1‐independent and is instead mediated by activation of PKA which is then guided by AKAP2, in a cAMP‐independent mechanism, to activate MLCP and dephosphorylate MLC20 resulting in reduced EC contraction.
The Dahl Salt‐Sensitive (SS) rat is a well‐established translational model of human salt sensitive hypertension. When challenged with a high salt (4.0% NaCl) diet, Dahl SS develop an increase in mean ...arterial pressure (MAP) and renal damage, as assessed by an increase in albumin excretion and infiltration of immune cells in the kidneys. Our colony of Dahl SS recently moved to a new animal facility, and we observed that the SS rats challenged on a high salt diet showed an attenuation of the high salt‐induced increase in MAP and albumin excretion. Upon further investigation, differences in the animal bedding were noted between the locations. In the present study, the salt‐sensitive disease phenotype was examined in age‐matched, genetically‐identical male Dahl SS rats fed the same diets (AIN‐76A with 0.4% or 4.0% NaCl) maintained on either an aspen‐based wood bedding or a corn‐cob based bedding. Based upon the known protective effects of a plant‐based diet and observations that the rats were eating the corn‐cob bedding, we hypothesized that the change in bedding from wood to corn was providing a protective phenotype to the SS rats. We tested this hypothesis by comparing the disease phenotypes in Dahl SS maintained on the corn‐cob or wood bedding from birth until the end of the study. SS rats were instrumented at 7 weeks of age with radiotelemeters for continuous blood pressure monitoring and were allowed about a week to recover. While the rats were maintained on a low salt (0.4% NaCl) diet, there were no significant differences in MAP (123.2±1.1 vs 126.8±0.8 mmHg, n=13, 16) or albumin excretion rate (7.5±1.8 vs 18.8±3.5 mg/day, n=10, 17) in Dahl SS maintained on the corn‐cob vs the wood bedding, respectively. While MAP and albumin excretion significantly increased in all Dahl SS following a 21‐day high salt challenge, there was significantly reduced albumin excretion in the corn‐cob bedding rats (128±27 mg/day, n=10) when compared to the wood bedding rats (332±50 mg/day, n=17, p˂0.005). The SS rats maintained on the corn‐cob bedding also had significantly attenuated MAP at the end of the 21 day challenge when compared to the rats on the wood bedding (corn‐cob bedding: 141.1±4.2 mmHg vs wood bedding: 159.5±3.6 mmHg, p˂0.0001, n=12, 16 respectively). This was further characterized with a significant reduction in CD45+ leukocytes infiltrating in the SS rat kidneys on corn‐cob bedding by ~48% (p<0.003). That occurred by a significant reduction observed in the CD11b/c+ macrophages/monocytes by ~49% (p<0.003) and in CD45R+ B‐cells by ~64% (p<0.004). There was no difference between the body weights of the rats between the different beddings (corn‐cob bedding: 336±6 g vs wood bedding: 339±5 g, n=13, 17) respectively but kidney weight was a significantly reduced by ~17% (p<0.0001) in corn‐cob bedding compared to the SS rats on the wood bedding. This attenuated phenotype was also mirrored in female Dahl SS rats when maintained on the corn‐cob bedding compared to age‐matched females on the wood bedding. These data suggest that the change in bedding from wood to corn had a significant protective effect in the Dahl SS rat. Further work will need to be performed to determine the exact cause in the reduction of the salt‐sensitive phenotype when on a corn‐cob bedding. These data highlight the importance of controlling all environmental parameters in experimental work, and to consider environmental effects that may influence other disease phenotypes.
Previous work has implicated the immune system in potentiating salt‐sensitive (SS) hypertension. The innate immunity protein Cluster of Differentiation 14 (CD14), a co‐receptor with Toll‐like ...Receptor 4 in the inflammasome pathway of macrophages, has been associated with cardiovascular disease in humans. Interestingly, genetic deletion of CD14 in the Dahl SS rat (SSCD14‐/‐) confers a significant exacerbation of salt‐induced hypertension and associated renal disease that is specific to females. We speculated that CD14 may modulate the production of reaction oxygen species (ROS), since our previous findings implicate NADPH oxidase 2 (NOX2) derived ROS in immune cells in the pathogenesis of salt‐sensitive hypertension. In initial in vitro studies (n>4), peritoneal macrophages from Dahl SS, SSCD14‐/‐, and SSp67phox‐/‐ (a strain lacking the critical p67phox subunit of NOX2) rats were stimulated with phorbol 12‐myristate 13‐acetate, and the production of superoxide was assessed by chemiluminescence via luminol derivative L‐012. Specificity was determined using superoxide dismutase which diminished all detected signal. Superoxide release was 2.4x greater from peritoneal macrophages from female SSCD14‐/‐ when compared to SS macrophages. The SSp67phox‐/‐, lacking NOX2 activity, served as a negative control. The present study tests the hypothesis that the amplification of salt‐sensitive hypertension and renal damage in Dahl SS females lacking CD14 is mediated by NOX2. A double knockout Dahl SS rat was bred to lack both CD14 and functional NOX2 (SSCD14‐/‐p67phox‐/‐ (DKO)) to investigate a potential link between CD14 and oxidative stress. The hypertensive and kidney injury phenotype in response to a 3 week high salt challenge (HS, 4.0% NaCl, AIN‐76A) was examined in DKO females compared to SSCD14‐/‐ and SSp67phox‐/‐ females. After 3 weeks of HS, DKOrats had a significantly blunted change in mean arterial pressure (MAP) from baseline (0.4%) to HS day 21 compared to SSCD14‐/‐ rats (15 mmHg, n=3 versus 38 mmHg, n=7, p=0.01). Importantly, HS MAP in the DKO was not different than that of the SSp67phox‐/‐ (121 ± 4 mmHg versus 120 ± 2 mmHg, n=3, p>0.05), indicating that ROS production from NOX2 is likely mediating the amplified elevation of MAP following CD14 deletion. As an index of renal damage, albuminuria was significantly reduced in the DKO (11.8 ± 1.7 mg/day, n=9, p=0.004) compared to the SSCD14‐/‐ (101.8 ± 17.5 mg/day, n=12) at HS day 21. There was no difference in albuminuria between the DKO and SSp67phox‐/‐(11.7 ± 2.9 mg/day, n=7, p>0.05). Flow cytometric analysis of immune cells isolated from the kidneys of these rats indicated a reduction in renal inflammation in the DKO compared to the SSCD14‐/‐. There were fewer CD45+ total leukocytes (46% reduction), CD3+ T cells (45%), CD45R+ B cells (60%), and CD11b/c+ monocytes/macrophages (46%) in DKO (n=7) versus SSCD14‐/‐ kidneys (n=7). Together, these data suggest a role of CD14 in reducing the pathogenesis of salt‐sensitive hypertension and renal damage in a process dependent upon NOX2‐mediated oxidative stress. Here we highlight a novel renoprotective role of CD14.
Terbinafine is a commonly used antifungal medication. Its side effects, while widely known, are rarely described and can be missed by the medical community. We present a 55-year-old woman who visited ...her primary care physician with onychomycosis. She started treatment with terbinafine, and 1 week later developed a rash in the left flank that extended to the chest, back, and upper part of lower extremities. Laboratory results showed elevated liver enzymes. A treatment with steroids did not improve the rash and she was admitted to our institution. She was started with intravenous dexamethasone, topical hydrocortisone and triamcinolone. Seven days later the liver enzymes normalised, and the rash resolved on the chest and back. Our patient had concurrent acute generalised exanthematous pustulosis and hepatitis that together has been very rarely associated with terbinafine.
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