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Advanced Drug Delivery Reviews (v.61, #14)

Editorial board members (pp. ii).

Mitochondrial medicine and therapeutics, Part II by Sarah Hamm-Alvarez Theme Editors; Enrique Cadenas Theme Editors (pp. 1233-1233).

Mitochondrial kinases in cell signaling: Facts and perspectives by Valeria G. Antico Arciuch; Yael Alippe; María Cecilia Carreras; Juan José Poderoso (pp. 1234-1249).

Phylogenetic studies had shown that evolution of mitochondria occurred in parallel with the maturation of kinases implicated in growth and final size of modern organisms. In the last years, different reports confirmed that MAPKs, Akt, PKA and PKC are present in mitochondria, particularly in the intermembrane space and inner membrane where they meet mitochondrial constitutive upstream activators. Although a priori phosphorylation is the apparent aim of translocation, new perspectives indicate that kinase activation depends on redox status as determined by the mitochondrial production of oxygen species. We observed that the degree of mitochondrial oxidation of ERK Cys³⁸ and Cys²¹⁴ discriminates the kinase to be phosphorylated and determines translocation to the nuclear compartment and proliferation, or accumulation in mitochondria and arrest. Otherwise, transcriptional gene regulation by Akt depends on Cys⁶⁰ and Cys³¹⁰ oxidation to sulfenic and sulfonic acids. It is concluded that the interactions between kinases and mitochondria control cell signaling pathways and participate in the modulation of cell proliferation and arrest, tissue protection, tumorigenesis and cancer progression.

Keywords: Mitochondria; MAPK; ERK1/2; Akt; Hydrogen peroxide; Proliferation; Apoptosis; Cancer

Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism by Divya Pathania; Melissa Millard; Nouri Neamati (pp. 1250-1275).

Cancer cells are characterized by self-sufficiency in the absence of growth signals, their ability to evade apoptosis, resistance to anti-growth signals, sustained angiogenesis, uncontrolled proliferation, and invasion and metastasis. Alterations in cellular bioenergetics are an emerging hallmark of cancer. The mitochondrion is the major organelle implicated in the cellular bioenergetic and biosynthetic changes accompanying cancer. These bioenergetic modifications contribute to the invasive, metastatic and adaptive properties typical in most tumors. Moreover, mitochondrial DNA mutations complement the bioenergetic changes in cancer. Several cancer management therapies have been proposed that target tumor cell metabolism and mitochondria. Glycolytic inhibitors serve as a classical example of cancer metabolism targeting agents. Several TCA cycle and OXPHOS inhibitors are being tested for their anticancer potential. Moreover, agents targeting the PDC/PDK (pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase) interaction are being studied for reversal of Warburg effect. Targeting of the apoptotic regulatory machinery of mitochondria is another potential anticancer field in need of exploration. Additionally, oxidative phosphorylation uncouplers, potassium channel modulators, and mitochondrial redox are under investigation for their anticancer potential. To this end there is an increased demand for agents that specifically hit their target. Delocalized lipophilic cations have shown tremendous potential in delivering anticancer agents selectively to tumor cells. This review provides an overview of the potential anticancer agents that act by targeting cancer cell metabolism and mitochondria, and also brings us face to face with the emerging opportunities in cancer therapy.

Keywords: Abbreviations; AIF; apoptosis inducing factor; AVPI; alanine valine proline isoleucine; BAD; Bcl-2 antagonist of cell death; BAX; Bcl-2 associated protein X; BAK; Bcl-2 homologous antagonist/killer; BH; Bcl-2 homology domain; BIR; baculovirus IAP repeat; 1,3-BPG; 1,3-bisphosphoglycerate; AMF; autocrine motility factor; ANT; adenine nucleotide transporter; ARD1; arrest-defective 1 protein; BCNU; bis-chloronitrosourea; 3-BrP; 3-bromopyruvate; CAD; c-terminal activation domain; CARD; caspase recruitment domain; CBP; CREB binding protein; CCCP; carbonylcyanide-3-chlorophenylhydrazone; COX4/2; cyotochrome oxidase isoform2; CT; computed tomography; DCA; dichloroacetate; 2-DG; 2-deoxyglucose; DHAP; dihydroxy acetone phosphate; DIABLO; Direct Inhibitor of Apoptosis Binding protein with a Low pI; DLC; delocalized lipophilic cation; DNP; 2,4-dinitrophenol; EGFR; epidermal growth factor receptor; ERK; extracellular signal regulated kinase; ETC; electron transport chain; FAD; flavin adenine dinucleotide (oxidized); FADH; ₂; flavin adenine dinucleotide (reduced); ¹⁸; FBzTPP; 4-(; ¹⁸; F-benzyl) triphenylphosphonium; FCCP; p-trifluoromethoxyphenylhydrazone; FDA; Food and Drug Administration; ¹⁸; F-FDG; 18F-deoxygluxose; FH; fumarate hydratase; FIH; factor inhibiting HIF-1; FNQ; furanonapthoquinone; F-1,6-BP; fructose-1,6-bisphosphate; F-6-P; fructose-6-phosphate; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; GPI; glucose phosphate isomerase; Glut; glucose transporter; G-6-P; glucose-6-phosphate; Glyc-3-P; glyceraldehydes-3-phosphate; HBD; hydrogen bonding donor; HBA; hydrogen bonding acceptor; HDAC; histone deacetylase; HIF-1; hypoxia inducible factor-1; HK; hexokinase; HLRCC; hereditary leiomyomatosis/renal cell cancer; PGL; hereditary paraganglioma; Hsp90; heat shock protein 90; ³; H-TPP; 3H-tetraphenylphosphonium; IAP; inhibitor of apoptosis protein; IMM; inner mitochondrial membrane; JNK; c-Jun N-terminal kinase; LDH; lactate dehydrogenase; MAPK; mitogen activated protein kinase; MDR; multidrug resistance; MEK; MAPK-ERK kinase; M2-PK; pyruvate kinase M2; MMP; matrix metalloproteinase; MOM; mitochondrial outer membrane; MPP+; 1-methyl-4-phenylpyridinium cation; MPT; membrane permeability transition; MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ⁹⁹; m-Tc-MIBI; ⁹⁹; m-Tc-Sestamibi; MTD; maximum tolerated dose; mTOR; mammalian target of rapamycin; NAD; ⁺; nicotinamide adenine dinucleotide (oxidized); NADH; nicotinamide adenine dinucleotide (reduced); NADPH; nicotinamide adenine dinucleotide phosphate (reduced); NCI; National Cancer Institute; NFAT; nuclear factor of activated T cells; NO; nitric oxide; OXPHOS; oxidative phosphorylation; PCD; programmed cell death; PDC; pyruvate dehydrogenase complex; PDT; photodynamic therapy; PDK; pyruvate dehydrogenase kinase; PDP; pyruvate dehydrogenase phosphatase; PEP; phosphoenol pyruvate; PET; positron emission tomography; PHD; prolyl hydroxylase; PI3K; phosphoinositide 3-kinase; PFK; phosphofructokinase; PFKFB; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; 2-PG; 2-phosphoglycerate; 3-PG; 3-phosphoglcerate; PGK; phosphoglycerate kinase; PGM; phosphoglycerate mutase; Pgp; p-glycoprotein; PK; pyruvate kinase; PKCδ; protein kinase C delta; PS; photosensitizer; PSA; prostate specific antigen; PTP; permeability transition pore; pVHL; von Hippel–Lindau protein; ROS; reactive oxygen species; SAR; structure activity relationship; SCO2; synthesis of cytochrome; c; oxidase2; SDH; succinate dehydrogenase; Smac; Second mitochondria derived activator of caspases; SPECT; single photon emission computed tomography; TIGAR; tp53 induced glycolysis and apoptosis regulator; TCA cycle; tricarboxyclic acid cycle; TNFR; tumor necrosis factor receptor; TPA; triphenylarsonium; TPP; triphenylphosphonium cation; TRAF; TNF receptor associated family of proteins; TKTL1; transketolase like enzyme1; αTOS; α-tocopheryl succinate; TPI; triosephosphate isomerase; Trx/TrxR; thioredoxin/thioredoxin reductase; VDAC; voltage dependent anion channel; XIAP; X-linked inhibitor of apoptosis proteinWarburg effect; Aerobic glycolysis; Glycolytic inhibitors; Targeted drug delivery to cancer; Delocalized lipophilic cations; Inhibitors of mitochondrial electron transport chain; Biosynthetic alterations in cancer cells; Mitochondrial redox system; Mitochondrial apoptotic machinery; Triphenylphosphonium compounds

PI-3-K and AKT: Onto the mitochondria by Bangyan L. Stiles (pp. 1276-1282).

The role of PI-3-K in the regulation of mitochondrial functions is becoming a field that draws attentions from cancer as well as metabolic diseases. In this review, we focus on the action of the major downstream target of PI-3-K, the serine/threonine kinase AKT, a proto-oncoprotein. We reviewed the functions of AKT in the mitochondrial intrinsic apoptosis pathway. We analyzed how AKT regulates the different factors in the Bcl-2 family of anti- and pro-apoptotic factors either directly or indirectly. We further reviewed the role of AKT in regulating mitochondrial coupled glycolysis through hexokinase II and VDAC. This review is focused on the function of PI-3-K and AKT at the mitochondrial. These interactions between the mitogenic PI-3-K/AKT and the mitochondrial function may provide clues on how tumors overcome the ongoing need for nutrient supply. Such characterizations can provide new targets for drug discoveries targeted at blocking tumor progression.

Keywords: PI-3-K; AKT; Mitochondria; Bcl-2; Hexokinase; VDAC

The energy–redox axis in aging and age-related neurodegeneration by Li-Peng Yap; Jerome V. Garcia; Derick Han; Enrique Cadenas (pp. 1283-1298).

Decrease in mitochondrial energy-transducing capacity is a feature of the aging process that accompanies redox alterations, such as increased generation of mitochondrial oxidants, altered GSH status, and increased protein oxidation. The decrease in mitochondrial energy-transducing capacity and altered redox status should be viewed as a concerted process that embodies the mitochondrial energy–redox axis and is linked through various mechanisms including: (a) an inter-convertible reducing equivalents pool ( i.e., NAD(P)⁺/NAD(P)H) and (b) redox-mediated protein post-translational modifications involved in energy metabolism. The energy–redox axis provides the rationale for therapeutic approaches targeted to each or both component(s) of the axis that effectively preserves or improve mitochondrial function and that have implications for aging and age-related neurodegenerative disorders.

Keywords: Mitochondria; Energy–redox axis; Lipoic acid; Thiol/disulfide exchange; Alzheimer's disease; Aging

Mitochondria and reactive oxygen and nitrogen species in neurological disorders and stroke: Therapeutic implications by Bolanos Juan P. Bolaños; Maria A. Moro; Ignacio Lizasoain; Angeles Almeida (pp. 1299-1315).

Mitochondria represent both the main source and target of reactive oxygen and nitrogen species (RONS). In view of the large energy expenditure made by neurons during neurotransmission, an intact mitochondrial function is of paramount importance for the correct function of the brain. Accordingly, the search of therapeutic strategies against situations in which there is an abnormal brain function, such as neurological disorders and stroke, should be focused towards mitochondria. Here, we have reviewed the normal and abnormal mitochondrial bioenergetics and dynamics, highlighting the relevance that, for these processes in the brain RONS exert. Evidence suggests that disruption of mitochondrial bioenergetics and dynamics may have a critical role in the pathogenesis of these brain diseases. Drug therapies directed toward providing safer mitochondria are currently under both pre- and clinical investigations.

Keywords: Abbreviations; 6-OHDA; 6-hydroxydopamine; AD; Alzheimer's disease; AIF; apoptosis-inducing factor; Apaf-1; apoptotic protease-activating factor 1; APP; amyloid precursor protein; Aß; amyloid-ß peptide; Bak; Bcl-2 antagonist/killer-1; Bax; Bcl-2-associated X protein; Bcl-XL; Bcl-2-like 1; BH; Bcl-2 homology; Bid; BH3-interacting-domain death agonist; Bim; Bcl-2-interacting mediator of cell death; CDK1; cyclin-dependent kinase 1; CDK5; cyclin-dependent kinase 5; CoQ; ubiquinone or coenzyme Q; DRP1; dynamin-related protein 1; GDAP1; ganglioside-induced differentiation associated protein 1; GSK3β; glycogen synthase kinase 3ß; hFIS1; human fission protein 1; IMS; intermembrane space; Mcl-1; myeloid cell leukemia-1; METC; mitochondrial electron transport chain; MFN; mitofusin; mHtt; mutant huntingtin; MnSOD; manganese (mitochondrial) superoxide dismutase; MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine; NMDA; N-methyl-; d; -aspartate; OMM; outer mitochondrial membrane; OPA1; optic atrophy 1; PARP-1; poly(ADP-ribose) polymerase-1; PCD; programmed cell death; PGC-1α; peroxisome proliferators-activated receptor-γ coactivator 1α; PLA; ₂; phospholipase A; ₂; PS1; presenilin 1; PS2; presenilin 2; RONS; reactive oxygen and nitrogen species; SIN-1; morpholinosydnonimine; SIRTs; sirtuins; Smac; second mitochondria-derived activator of caspase; SUMO1; small ubiquitin-related modif55er 1; TPP; triphenylphosphonium; VDAC; voltage-dependent anion channelMitochondria; Oxidative stress; Nitric oxide; Neurodegeneration; Stroke; Therapeutics; Pharmacology

The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start? by Junghee Lee; Jung Hyun Boo; Hoon Ryu (pp. 1316-1323).

Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death. In this context, the regulation of mitochondrial function via therapeutic approaches may exert some salutary and neuroprotective mechanisms. Understanding the relationship of mitochondria-dependent pathogenesis may provide important pharmacological utility in the treatment of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease. Indeed, the modulation of mitochondrial pathways is rapidly emerging as a novel therapeutic target. This review focuses on how mitochondria are involved in neurodegeneration and what therapeutics are available to target mitochondrial pathways.

Keywords: Neuroprotection; Alzheimer's disease; Amyotrophic lateral sclerosis; Huntington's disease; Parkinson's disease; Therapeutics

Regulated production of free radicals by the mitochondrial electron transport chain: Cardiac ischemic preconditioning by Satoshi Matsuzaki; Pamela A. Szweda; Luke I. Szweda; Kenneth M. Humphries (pp. 1324-1331).

Excessive production of free radicals by mitochondria is associated with, and likely contributes to, the progression of numerous pathological conditions. Nevertheless, the production of free radicals by the mitochondria may have important biological functions under normal or stressed conditions by activating or modulating redox-sensitive cellular signaling pathways. This raises the intriguing possibility that regulated mitochondrial free radical production occurs via mechanisms that are distinct from pathologies associated with oxidative damage. Indeed, the capacity of mitochondria to produce free radicals in a limited manner may play a role in ischemic preconditioning, the phenomenon whereby short bouts of ischemia protect from subsequent prolonged ischemia and reperfusion. Ischemic preconditioning can thus serve as an important model system for defining regulatory mechanisms that allow for transient, signal-inducing, production of free radicals by mitochondria. Defining how these mechanism(s) occur will provide insight into therapeutic approaches that minimize oxidative damage without altering normal cellular redox biology. The aim of this review is to present and discuss evidence for the regulated production of superoxide by the electron transport chain within the ischemic preconditioning paradigm of redox regulation.

Keywords: Cardiac ischemia; Preconditioning; Mitochondria; Electron transport chain; Free radicals; Oxidation and reduction

Mitochondria in the elderly: Is acetylcarnitine a rejuvenator? by Mariana G. Rosca; Hélène Lemieux; Charles L. Hoppel (pp. 1332-1342).

Endogenous acetylcarnitine is an indicator of acetyl-CoA synthesized by multiple metabolic pathways involving carbohydrates, amino acids, fatty acids, sterols, and ketone bodies, and utilized mainly by the tricarboxylic acid cycle. Acetylcarnitine supplementation has beneficial effects in elderly animals and humans, including restoration of mitochondrial content and function. These effects appear to be dose-dependent and occur even after short-term therapy. In order to set the stage for understanding the mechanism of action of acetylcarnitine, we review the metabolism and role of this compound. We suggest that acetylation of mitochondrial proteins leads to a specific increase in mitochondrial gene expression and mitochondrial protein synthesis. In the aged rat heart, this effect is translated to increased cytochrome b content, restoration of complex III activity, and oxidative phosphorylation, resulting in amelioration of the age-related mitochondrial defect.

Keywords: Aging; Mitochondrial metabolism; Acetyl-CoA; Electron transport chain complexes; Mitochondrial proteins; Mitochondrial biogenesis; Complex III

Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients by Jiankang Liu; Weili Shen; Baolu Zhao; Ying Wang; Karin Wertz; Peter Weber; Peifang Zhang (pp. 1343-1352).

Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear and may involve pathological changes in multiple tissues. Mitochondrial dysfunction, including mitochondrial loss and over-production of oxidants, has been suggested to be involved in the development of insulin resistance. Increasing evidence suggests that targeting mitochondria to protect mitochondrial function as a unique measure, i.e. mitochondrial medicine, could prevent and ameliorate various diseases associated with mitochondrial dysfunction. In this review, we have summarized recent progress in pharmaceutical and nutritional studies of drugs and nutrients to targeting mitochondria by stimulating mitochondrial metabolism (biogenesis and degradation) to improve mitochondrial function and decrease oxidative stress for preventing and ameliorating insulin resistance. We have focused on nutrients from natural sources to stimulating mitochondrial biogenesis in cellular systems and in animal models. The in vitro and in vivo studies, especially our own work on the effects and mechanisms of mitochondrial targeting nutrients or their combinations, may help us to understand the importance and mechanisms of mitochondrial biogenesis in insulin resistance, and provide hope for developing mitochondria-targeting agents for preventing and treating insulin resistance in type 2 diabetes and obesity.

Keywords: Lipoic acid; Acetyl-; l; -carnitine; Hydroxytyrosol; (−)-Epigallocatechin gallate (EGCG); B vitamins; Mitochondrial nutrients; Reactive oxygen species

Carnitine, mitochondrial function and therapy by Victor A. Zammit; Rona R. Ramsay; Mario Bonomini; Arduino Arduini (pp. 1353-1362).

Carnitine is important for cell function and survival primarily because of its involvement in the multiple equilibria between acylcarnitine and acyl-CoA esters established through the enzymatic activities of the family of carnitine acyltransferases. These have different acyl chain-length specificities and intracellular compartment distributions, and act in synchrony to regulate multiple aspects of metabolism, ranging from fuel-selection and -sensing, to the modulation of the signal transduction mechanisms involved in many homeostatic systems. This review aims to rationalise the extensive range of experimental and clinical data that have been obtained through the pharmacological use of L-carnitine and its short-chain acylesters, over the past two decades, in terms of the basic biochemical mechanisms involved in the effects of carnitine on the various cellular acyl-CoA pools in health and disease.

Keywords: Carnitine; Mitochondria; Coenzyme A; Carnitine acyltransferases

Strategies for reducing oxidative damage in ageing skeletal muscle by Malcolm J. Jackson (pp. 1363-1368).

It is recognised that reactive oxygen species (ROS) are both key regulators of cellular signalling and initiators of oxidative damage to DNA, lipids and proteins under different circumstances. Thus in skeletal muscle from animals and humans, studies indicate that ROS can potentially contribute to the pathophysiology of the age-related loss of skeletal muscle mass and function, while additionally acting as a key signal for contraction-induced adaptations in the tissue. The specific nature and sources of generation of the ROS contributing to these actions remain unknown, but the combination of physiological and pathological roles of ROS imply that interventions based on a simple suppression of ROS activities through use on non-specific antioxidants are unlikely to retard or improve the age-related declines in muscle mass and function. This review will briefly describe the background to this area and describe alternative strategies aimed at correcting specific redox-related changes in ageing muscle, such as the decline in oxidative signalling pathways, that may indicate rational interventions to help maintain muscle mass and function in the elderly.

Keywords: Superoxide; Nitric oxide; Hydrogen peroxide; Cell signalling; Antioxidant; Redox signalling

Mitochondrial biogenesis in exercise and in ageing by Vina Jose Viña; Mari Carmen Gomez-Cabrera; Consuelo Borras; Teresa Froio; Fabian Sanchis-Gomar; Vladimir E. Martinez-Bello; Federico V. Pallardo (pp. 1369-1374).

Mitochondrial biogenesis is critical for the normal function of cells. It is well known that mitochondria are produced and eventually after normal functioning they are degraded. Thus, the actual level of mitochondria in cells is dependent both on the synthesis and the degradation. Ever since the proposal of the mitochondrial theory of ageing by Jaime Miquel in the 70's, it was appreciated that mitochondria, which are both a target and a source of radicals in cells, are most important organelles to understand ageing. Thus, a common feature between cell physiology of ageing and exercise is that in both situations mitochondria are critical for normal cell functioning.Mitochondrial synthesis is stimulated by the PGC-1α–NRF1–TFAM pathway. PGC-1α is the first stimulator of mitochondrial biogenesis. NRF1 is an intermediate transcription factor which stimulates the synthesis of TFAM which is a final effector activating the duplication of mitochondrial DNA molecules. This pathway is impaired in ageing. On the contrary, exercise, particularly aerobic exercise, activates mitochondriogenesis in the young animal but its effects on mitochondrial biogenesis in the old animal are doubtful. In this chapter we consider the interrelationship between mitochondrial biogenesis stimulated by exercise and the possible impairment of this pathway in ageing leading to mitochondrial deficiency and eventually muscle sarcopenia.

Keywords: PGC-1α; NRF1; TFAM; Sarcopenia; Skeletal and cardiac muscle

Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions by Valerian E. Kagan; Peter Wipf; Detcho Stoyanovsky; Joel S. Greenberger; Grigory Borisenko; Natalia A. Belikova; Naveena Yanamala; Alejandro K. Samhan Arias; Muhammad A. Tungekar; Jianfei Jiang; Yulia Y. Tyurina; Jing Ji; Judith Klein-Seetharaman; Bruce R. Pitt; Anna A. Shvedova; Hülya Bayır (pp. 1375-1385).

Effective regulation of highly compartmentalized production of reactive oxygen species and peroxidation reactions in mitochondria requires targeting of small molecule antioxidants and antioxidant enzymes into the organelles. This review describes recently developed approaches to mitochondrial targeting of small biologically active molecules based on: (i) preferential accumulation in mitochondria because of their hydrophobicity and positive charge (hydrophobic cations), (ii) binding with high affinity to an intra-mitochondrial constituent, and (iii) metabolic conversions by specific mitochondrial enzymes to reveal an active entity. In addition, targeted delivery of antioxidant enzymes via expression of leader sequences directing the proteins into mitochondria is considered. Examples of successful antioxidant and anti-apoptotic protection based on the ability of targeted cargoes to inhibit cytochrome c-catalyzed peroxidation of a mitochondria-specific phospholipid cardiolipin, in vitro and in vivo are presented. Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants.

Keywords: Cytochrome; c; Cardiolipin; Mitochondria; Apoptosis; Triphenylphosphonium; MnSOD; Peroxidation; Nitroxides; Gramicidin S-conjugates

Corrigendum to “Matrices and scaffolds for drug delivery in vascular tissue engineering” [Advanced Drug Delivery Reviews 59 (2007) 360–373] by Ge Zhang; Laura J. Suggs (pp. 1386-1386).

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Advanced Drug Delivery Reviews (v.61, #14)