Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR-α agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR-γ agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-α/γ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-δ and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use

Safety of Aggressive Lipid Management

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4× higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity

First documented record of the leatherback turtle (Dermochelys coriacea) from Djibouti waters

AbstractA subadult leatherback turtle was documented in the Gulf of Goubet (Djibouti) during a research expedition. This sighting confirms for the first time previous anecdotal observations of the occurrence of the leatherback turtle, Dermochelys coriacea (Vandelli, 1761), in Djibouti waters. Coupled with observations from fishers, this finding underlines the urgent need to carry out research programs to evaluate the species habitat use within Djibouti waters, and to review the species distribution in the Gulf of Aden. Although marine turtles are protected in Djibouti, illegal harvest and entanglement in fishing gear pose a threat to their survival, and conservation measures should be implemented

Novel hydrogel system eliminates subculturing and improves retention of nonsenescent mesenchymal stem cell populations

Aim: To compare the physiological behavior of mesenchymal stem/stromal cells (MSCs) within an expandable tissue-mimetic 3D system relative to in vitro expansion in a traditional 2D system. Methods: Adipose-derived MSCs (ASCs) were continuously cultured for 6 weeks on either 2D culture plastic or in a 3D hydrogel system that eliminated subculturing. ASCs were assessed for senescence, ‘stem-like’ MSC markers, and ability for their secretome to augment a secondary cell population. Results: The 3D hydrogel system resulted in an enhanced retention of more regenerative, nonsenescent ASC populations that exhibited increased expression of ‘stem-like’ MSC surface markers. Conclusion: This study introduces a proof-of-concept design for a novel modular 3D system that can improve in vitro expansion of stem-like cell populations for future regenerative therapies

Tailoring the secretome composition of mesenchymal stem cells to augment specific functions of epidermal regeneration: an in vitro diabetic model

Introduction: Wound healing consists of a dynamic series of events that are highly dependent on paracrine factors for proper progression through the phases of wound healing. Inappropriate progression through the phases is associated with insufficient epidermal regeneration (i.e., re-epithelialization) of wounds and subsequent propagation of chronic wounds, such as diabetic ulcers, which are associated with increased patient morbidity. Recently, investigation into the dynamic secretome of Adipose-derived Mesenchymal Stem Cells (ASCs), have shown promise in augmenting the wound healing response of chronic diabetic wounds. However, currently utilized 2D culture techniques are known to drastically alter the regenerative phenotype of ASCs. In this study a novel tissue-mimetic 3D system was utilized as a means to culture ASCs. Methods: The capacity for the ASC secretome to augment epidermal regeneration activity was then evaluated after exposure of ASCs to “wound priming stimuli” in 2D and 3D. The priming stimuli consisted of coating the 2D and 3D systems with the wound matrix proteins, collagen type I, fibronectin, and fibrin. To understand the potential benefit of the ASC secretome in the context of diabetic wounds, keratinocytes (KCs) were exposed to super-physiological glucose levels to induce a diabetic-like phenotype (idKCs). Results: Relative to KCs, idKC exhibited a 52% and 23% decline in proliferation and migration, respectively. Subsequently, analyses of the ASC secretome were performed. ASC conditioned media (ASC-CM) from tissue-mimetic culture demonstrated a > 50% increase secretion of proteins and a 2-fold increase in secreted EVs, relative to 2D culture. Interestingly, the different priming stimuli did not alter the total amount of protein or EVs secreted within the tissue-mimetic system. However, evaluation of specific soluble proteins via ELISA revealed significant differences in key epidermal regeneration factors, such as EGF, IGF-1, FGF-2, MMP-1, TIMP-1, and TGFβ-1. Additionally, the relative effect of ASC-EVs from the 2D and 3D system on idKCs epidermal regeneration functionality varied significantly, with EVs from 3D-Collagen culture providing the most significant benefit on idKC activity. Discussion: Together, these data support the utilization of tissue-mimetic culture system to enhance the adaptability and secretory activity of MSC-like populations in order to generate tailored biologics, via priming stimuli, for specific wound healing applications

Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex.

Adaptor protein complex 5 (AP-5) and its partners, SPG11 and SPG15, are recruited onto late endosomes and lysosomes. Here we show that recruitment of AP-5/SPG11/SPG15 is enhanced in starved cells and occurs by coincidence detection, requiring both phosphatidylinositol 3-phosphate (PI3P) and Rag GTPases. PI3P binding is via the SPG15 FYVE domain, which, on its own, localizes to early endosomes. GDP-locked RagC promotes recruitment of AP-5/SPG11/SPG15, while GTP-locked RagA prevents its recruitment. Our results uncover an interplay between AP-5/SPG11/SPG15 and the mTORC1 pathway and help to explain the phenotype of AP-5/SPG11/SPG15 deficiency in patients, including the defect in autophagic lysosome reformation

Plant Macrofossils Associated with an Early Holocene Beaver Dam in Interior Alaska

Dynamic climate changes and expansion of new biomes characterize the late Pleistocene–early Holocene of eastern Beringia. Analysis of plant macrofossils from an early Holocene (ca. 9300 14C yrs BP) beaver dam in central Alaska provides insight into the local environment and vegetation. The plant macrofossil assemblage comprises remains of trees and shrubs, graminoids, and forbs, including Betula sp., Carex sp., Rubus sp., Eleocharis sp., Scirpus sp., Potamogeton sp., Najas flexilis and Typha latifolia, indicative of standing water of a beaver pond. Bryophytes from the beaver dam include Warnstorfia spp. and Drepanocladus aduncus, suggesting shallow, stagnant, or slow-moving water. The presence of Najas flexilis, Typha latifolia, and modern beaver (Castor canadensis) suggest that central Alaska had a warmer climate during the early Holocene.Changements climatiques dynamiques et expansion de nouveaux biomes caractérisent la période du Pléistocène supérieur et de l’Holocène inférieur de la Béringie de l’Est. L’analyse des macrofossiles de plantes provenant d’une digue de castor du centre de l’Alaska datant de l’Holocène inférieur (env. 9300 14C années BP) donne des indices sur l’environnement et la végétation de la région. L’assemblage de macrofossiles de plantes est composé d’arbres et d’arbustes, de graminoïdes et d’herbes non graminéennes, dont Betula sp., Carex sp., Rubus sp., Eleocharis sp., Scirpus sp., Potamogeton sp., Najas flexilis et Typha latifolia, ce qui signale la présence d’eau stagnante dans un étang de castor. Parmi les bryophytes de la digue de castor, notons Warnstorfia spp. et Drepanocladus aduncus, ce qui laisse supposer la présence d’eau peu profonde stagnante ou se déplaçant lentement. Par ailleurs, la présence de Najas flexilis, Typha latifolia et du castor contemporain (Castor canadensis) laissent croire que le climat du centre de l’Alaska était plus chaud pendant l’Holocène inférieur