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This paper provides an analysis and translation of a previously edited, but otherwise unstudied work by Miskawayh (d. 1030) entitled On Pleasures and Pains (Fī al-Laḏḏāt wa-al-ālām). After a brief orientation regarding the Aristotelian account of pleasure in the Nicomachean Ethics, which is Miskawayh's main source, the theory of pleasure set out in On Pleasures and Pains is compared to the discussion of pleasure in Miskawayh's better known Refinement of Character (Tahḏīb al-aḫlāq). Despite considerable harmony between the two texts, their treatments of pleasure differ in that the Refinement accepts, whereas On Pleasures and Pains rejects, the “restoration” theory of pleasure of Plato's Timaeus.

Purpose To investigate the potential of lipoprotein-associated phospholipase A 2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). Design Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. Participants Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). Methods Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. Main Outcome Measures Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. Results Five patients in the study received intravitreal anti–vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3–5.8) and of 57 μm in central subfield thickness (95% CI, −84 to −30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, −1.0 to 4.4) and a decrease in center subfield thickness of 34 μm (95% CI, −75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. Conclusions Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A 2 inhibitory mechanism for the treatment of DME.

Elevated tumor necrosis factor (TNF) α levels are associated with chronic autoimmune diseases in which effects of TNFα on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNFα and a significant population of CD4 + TNFα + cells in the periphery and the eye at peak disease (TNFα hi ). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNFα lo model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNFα hi disease, whereas glucocorticoid treatment is successful. TNFα has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNFα blockade suppressed severe ocular disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNFα blockade with SIRT1 activation, a synergistic suppression of severe disease compared with TNFα blockade alone occurred. Our data suggest a new role for TNFα in exacerbating the severity of autoimmune disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNFα inhibitors.

This article offers an analysis, translation, and edition of a brief, recently uncovered Arabic text by the tenth-century CE Christian Aristotelian thinker Yaḥyā ibn ʿAdī. Ibn ʿAdī here takes issue with an argument for the existence of God, widely used in kalām (Islamic theology). According to this argument, bodies cannot exist without being either in motion or at rest; motion and rest must begin; therefore all bodies and hence the universe as a whole must have begun. Ibn ʿAdī diagnoses various flaws in this reasoning, including a supposed part–whole fallacy. The analysis of the text shows how it fits into Ibn ʿAdī’s intellectual profile and the project of the Baghdad Aristotelian school.

Mutations in rhodopsin, the light-sensitive protein of rod cells, are the most common cause of dominant retinitis pigmentosa (RP), a type of inherited blindness caused by the dysfunction and death of photoreceptor cells. The P23H mutation, the most frequent single cause of RP in the USA, causes rhodopsin misfolding and induction of the unfolded protein response (UPR), an adaptive ER stress response and signalling network that aims to enhance the folding and degradation of misfolded proteins to restore proteostasis. Prolonged UPR activation, and in particular the PERK branch, can reduce protein synthesis and initiate cell death through induction of pro-apoptotic pathways. Here, we investigated the effect of pharmacological PERK inhibition on retinal disease process in the P23H-1 transgenic rat model of retinal degeneration. PERK inhibition with GSK2606414A led to an inhibition of eIF2α phosphorylation, which correlated with reduced ERG function and decreased photoreceptor survival at both high and low doses of PERK inhibitor. Additionally, PERK inhibition increased the incidence of inclusion formation in cultured cells overexpressing P23H rod opsin, and increased rhodopsin aggregation in the P23H-1 rat retina, suggesting enhanced P23H misfolding and aggregation. In contrast, treatment of P23H-1 rats with an inhibitor of eIF2α phosphatase, salubrinal, led to improved photoreceptor survival. Collectively, these data suggest the activation of PERK is part of a protective response to mutant rhodopsin that ultimately limits photoreceptor cell death.

The Tonle Sap Lake of Cambodia is the largest freshwater body of Southeast Asia, forming an important part of the Mekong River system. The lake has an extremely productive ecosystem and operates as a natural floodwater reservoir for the lower Mekong Basin, offering flood protection and assuring the dry season flow to the Mekong Delta. In light of the accelerating pace of water resources development within the Mekong Basin and the anticipation of potentially significant hydrological impacts, it is critical to understand the overall hydrologic regime of Tonle Sap Lake. We present here a detailed water balance model based on observed data of discharges from the lake's tributaries, discharge between Mekong and the lake through the Tonle Sap River, precipitation, and evaporation. The overland flow between the Mekong and lake was modelled with the EIA 3D hydrodynamic model. We found that majority (53.5%) of the water originates from the Mekong mainstream but the lake's tributaries also play an important role contributing 34% of the annual flow, while 12.5% is derived from precipitation. The water level in the lake is mainly controlled by the water level in the Mekong mainstream. The Tonle Sap system is hence very vulnerable, from a water quantity point of view, to possible changes in the Mekong mainstream and thus, development activities in the whole Mekong basin. From a biogeochemical point of view, the possible changes in the lake's own catchment are equally important, together with the changes in the whole Mekong Basin. Based on our findings we recommend of continuing the monitoring programmes in lake's tributaries and urgently starting of groundwater measurement campaign within the floodplain, and including the groundwater modelling to be part of the hydrodynamic models applied for the lake. Copyright © 2013 John Wiley & Sons, Ltd.

This chapter offers an overview and analysis of an important ethical work by the early thinker Abū Bakr Muḥammad ibn Zakariyyāʾ al-Rāzī (251/865–313/925). In keeping with his main occupation as a medical doctor, this work approaches ethics as “spiritual medicine,” echoing the ancient idea of ethical improvement as a kind of regime the soul. The chapter shows how al-Rāzī drew on Galen in developing this idea, and explores the central idea of the treatise (taken ultimately from Plato, by way of Galen), which is that reason must rule the lower parts of the soul. Consideration is also given to whether the teaching of The Spiritual Medicine can be reconciled with another work of al-Rāzī’s, The Philosophical Life, and with his infamous cosmological theory.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

PURPOSE Choroidal neovascularization (CNV) is a major cause of visual loss with age-related macular degeneration (AMD). We evaluated whether blockade of phosphatidyl-inositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR), by impairing VEGF-A and other growth factor receptors like platelet-derived growth factor (PDGF), would reduce laser-induced CNV in mice. METHODS Choroidal neovascularization lesions were induced in C57BL/6 mice. Two groups of mice received oral GSK2126458 (3 mg/kg) or vehicle for 14 days following laser, whereas three groups were treated with GSK2126458 (6 μg/eye), aflibercept (2 μL/eye), or vehicle intravitreally on days 0 and 7 after laser. Vascular leakage was measured by fluorescein angiography (FA) on day 14. Choroidal neovascularization membranes were evaluated on choroidal flat mounts following FITC-dextran perfusion, as well as ED1 and isolectin B4 (IB4) immunohistochemistry. RESULTS Oral and intravitreal (IVT) GSK2126458 reduced leakage and area of CNV lesions. Greater probability of leaking lesions (∼60%; P < 0.05) was observed in both vehicle groups. Fluorescein isothiocyanate-dextran-labeled total CNV burden area (total lesion area/eye) was reduced ∼67% (P < 0.05) and 35% (P = 0.0528) after oral and IVT GSK2126458 administration. GSK2126458 treatment reduced lesion size by ∼80% (P < 0.05) and 50% (P < 0.05) for oral and IVT control groups. Aflibercept did not alter lesion size (∼27% reduction). CONCLUSIONS Phosphatidyl-inositol-3-kinase/mTOR is involved in laser-induced CNV angiogenic processes. GSK2126458 effectively reduces CNV size and leakage. Choroidal neovascularization size following IVT GSK2126458 was smaller than after oral administration. Therefore, inhibition of PI3K/mTOR pathways may be more effective due to blockade of action of multiple growth factors.

Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1–dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4+ lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1–induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1–induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.

First paragraph: A recent survey volume on medieval philosophy has called Dimitri Gutas, Professor of Arabic and Graeco-Arabic at Yale University, “the leading living historian of Islamic thought.” Such judgments are to some extent a matter of taste, of course, but few scholars have as good a claim to the title as Gutas. His publications include pioneer-ing work on the tradition of Greek-Arabic gnomologia, one of the most significant monographs ever published on Avicenna, and a penetrating and influential study of the Graeco-Arabic translation movement. In collaboration with Gerhard Endress he has also led the GALex project to document this same translation movement. In short, this is a man who deserves a good Festschrift., First paragraph:A recent survey volume on medieval philosophy has called Dimitri Gutas, Professor of Arabic and Graeco-Arabic at Yale University, “the leading living historian of Islamic thought.” Such judgments are to some extent a matter of taste, of course, but few scholars have as good a claim to the title as Gutas. His publications include pioneer-ing work on the tradition of Greek-Arabic gnomologia, one of the most significant monographs ever published on Avicenna, and a penetrating and influential study of the Graeco-Arabic translation movement. In collaboration with Gerhard Endress he has also led the GALex project to document this same translation movement. In short, this is a man who deserves a good Festschrift.

As a gatekeeper of leukocyte trafficking the vasculature fulfills an essential immune function. We have recently shown that paracellular transendothelial lymphocyte migration is controlled by intercellular adhesion molecule 1 (ICAM-1)-mediated vascular endothelial cadherin (VEC) phosphorylation [Turowski et al., J. Cell Sci. 121, 29–37 (2008)]. Here we show that endothelial nitric oxide synthase (eNOS) is a critical regulator of this pathway. ICAM-1 stimulated eNOS by a mechanism that was clearly distinct from that utilized by insulin. In particular, phosphorylation of eNOS on S1177 in response to ICAM-1 activation was regulated by src family protein kinase, rho GTPase, Ca2+, CaMKK, and AMPK, but not Akt/PI3K. Functional neutralization of any component of this pathway or its downstream effector guanylyl cyclase significantly reduced lymphocyte diapedesis across the endothelial monolayer. In turn, activation of NO signaling promoted lymphocyte transmigration. The eNOS signaling pathway was required for T-cell transmigration across primary rat and human microvascular endothelial cells and also when shear flow was applied, suggesting that this pathway is ubiquitously used. These data reveal a novel and essential role of eNOS in basic immune function and provide a key link in the molecular network governing endothelial cell compliance to diapedesis.

This chapter explores philosophy in the Islamic world. It begins with an overview of ancient Greek philosophy, focusing on how the ideas of Aristotle and Plotinus relate to the teachings of Islam. It then considers the philosophical theology of al-Kindī, the first philosopher of the Islamic world, and his rejection of the Aristotelian conception of God as an intellect who gives rise to an eternal motion by thinking about Himself. It also discusses the philosophical views of thinkers who were known as thefalāsifa(practitioners offalsafa) in the relevant period, including al-Fārābī and Avicenna. The chapter treats Avicenna as the culmination of ‘philosophy’, since thinkers after him by and large respond to him rather than to Aristotle and other authors of the Greek tradition.

Purpose To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO). Methods Wild-type mice and rats were treated with ASO by intravitreal (IVT) injection and rhodopsin mRNA and protein expression were measured. Transgenic rats expressing the murine P23H rhodopsin gene (P23H transgenic rat Line 1) were administered either a mouse-specific P23H ASO or a control ASO. The contralateral eye was injected with PBS and used as a comparator control. Electroretinography (ERG) measurements and analyses of the retinal outer nuclear layer were conducted and correlated with rhodopsin mRNA levels. Results Rhodopsin mRNA and protein expression was reduced after a single ASO injection in wild-type mice with a rhodopsin-specific ASO. Transgenic rat eyes that express a murine P23H rhodopsin gene injected with a murine P23H ASO had a 181 ± 39% better maximum amplitude response (scotopic a-wave) as compared with contralateral PBS-injected eyes; the response in control ASO eyes was not significantly different from comparator contralateral eyes. Morphometric analysis of the outer nuclear layer showed a significantly thicker nuclear layer in eyes injected with murine P23H ASO (18%) versus contralateral PBS-injected eyes. Conclusions Allele-specific ASO-mediated knockdown of mutant P23H rhodopsin expression slowed the rate of photoreceptor degeneration and preserved the function of photoreceptor cells in eyes of the P23H rhodopsin transgenic rat. Our data indicate that ASO treatment is a potentially effective therapy for the treatment of retinitis pigmentosa.