ALBERT

Notes: 1 The effects of the immunosuppressants, tacrolimus (FK506) and cyclosporin A (CsA), on catecholamine (CA) release were examined in cultured bovine adrenal chromaffin cells. 2 In intact cells, FK506 (1–30 μm) inhibited CA release stimulated by acetylcholine (ACh; 100 μm), 1,1-dimethyl-4-phenyl-piperazinium (DMPP, 10 μm) or high K+ (40 mm). CsA (1–30 μm) had a little inhibitory effect on the ACh- or DMPP-stimulated CA release, whereas it enhanced the high K+-stimulated CA release. 3 In β-escin-permeabilized cells, FK506 inhibited CA release stimulated by Ca2+ (1 and 10 μm) in the presence and absence of MgATP (2 mm). CsA induced CA release under Ca2+-free condition and enhanced the Ca2+-stimulated CA release in the presence and absence of MgATP. 4 It is known that the Ca2+-dependent exocytosis involves at least two distinct steps, ATP-requiring priming stage and ATP-independent fusion step in adrenal chromaffin cells. Therefore, it is suggested that FK506 inhibits the Ca2+-dependent exocytosis probably at the fusion step whereas CsA induces CA release from bovine adrenal chromaffin cells.

Notes: 1 Prolonged bed rest or exposure to microgravity may cause several alterations in autonomic nervous system response (ANSR). 2 Hindlimb unloading (HU) rats were used as an animal model of simulated microgravity to investigate ANSR changes. The experiments were carried out to investigate the effects of simulated microgravity on the autonomic nervous response of the perfused mesenteric vascular bed (MVB), vas deferens and the colon and duodenum from 2-week HU rats. 3 In MVB preparations of HU rats, the frequency-dependent increases in perfusion pressure with perivascular nerve stimulation (PNS; 8–40 Hz) were inhibited, whereas the noradrenaline (NA) concentration-dependent (1–100 μm) perfusion pressure increases were potentiated. The latter most probably reflected up-regulation of α-adrenergic receptor function. Relaxant responses of NA-precontracted MVB to PNS (4–30 Hz) or isoprenaline were not different between control and HU preparations, while vasodilation induced by the endothelial agonist ACh was reduced. 4 Transmural stimulation (2–40 Hz) induced frequency-dependent twitches of the vas deferens which were reduced in vas deferens of HU rats, while the sensitivity to NA-induced contraction was significantly increased. 5 In the gastroenteric system of HU rat, direct contractile responses to carbachol or tachykinin as well as relaxant or contractile responses to nervous stimulation appeared unchanged both in the proximal colon rings and in duodenal longitudinal strips. 6 In conclusion, HU treatment affects peripheral tissues in which the main contractile mediators are the adrenergic ones such as resistance vessels and vas deferens, probably by reducing the release of neuromediator. This study validates NA signalling impairment as a widespread process in microgravity, which may most dramatically result in the clinical phenotype of orthostatic intolerance.

Notes: 1 This double-blind, cross-over, placebo-controlled study on six healthy male volunteers was designed to evaluate the effects of α2-adrenoceptor antagonism on cardiac parasympathetic regulation. 2 The subjects received atipamezole intravenously as a three-step infusion, which aimed at steady-state serum concentrations of 10, 30 and 90 ng ml−1 at 50-min intervals. 3 Drug effects were assessed with repeated recordings of blood pressure and electrocardiogram, in which the high-frequency (0.15–0.40 Hz) R-R interval variation is supposed to reflect cardiac parasympathetic efferent neuronal activity. 4 At the end of the three steps of the infusion, the mean (±SD) concentrations of atipamezole were 10.5 (3.9), 26.8 (5.6) and 81.3 (21.1) ng ml−1. 5 Within this concentration range, atipamezole appeared to reduce slightly the high-frequency R-R interval fluctuations, indicating a minor vagolytic effect in the heart. 6 Atipamezole increased systolic and diastolic arterial pressure, on average by 20 and 14 mmHg (maxima at the second step of the infusion), which evidently reflects an overall sympathetic augmentation.

Notes: 1 We have compared vasoconstriction responses in isolated mesenteric small arteries from mice and rats as elicited by KCl, noradrenaline and the lysosphingolipids sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). 2 Contractile responses to KCl and noradrenaline, but not those of S1P or SPC, were significantly related to vessel diameter in both species. 3 When comparing vessels of similar diameter, contractile responses for KCl and the three agonists were much smaller in mice than in rats, e.g. 8.3 ± 0.4 vs. 14.7 ± 0.7 mn for noradrenaline. 4 Based upon the antagonist rank order of potency of prazosin (pKB 8.80) 〉 B8805-033 (pKB 7.89) 〉 yohimbine (pKB 6.18) ≈ BMY 7378 (pA2 6.03), noradrenaline responses in mice were mediated solely via α1A-adrenoceptors, similar to what repeatedly has been shown in rats. 5 The S1P3 receptor antagonist suramin (100 μm) significantly inhibited responses to S1P and SPC in rats but not in mice, and did not affect noradrenaline responses in either species. 6 We conclude that for any given diameter, mouse mesenteric arteries develop less contraction in response to various stimuli. Noradrenaline acts via α1A-adrenoceptors in both species. Responses to S1P and SPC differ between both species with regard to suramin-sensitivity indicating involvement of different receptor subtypes for lysosphingolipids in both species.

Notes: 1 A fructose (Fru)-enriched diet induces a mild increase in blood pressure associated with hyperglycaemia, hypertriglyceridaemia, and insulin resistance, resembling the human ‘syndrome X’, being an useful model to study hypertension and type 2 diabetes. 2 A sustained elevation of blood pressure is associated with cardiovascular structural modifications such as left ventricular hypertrophy and increased wall thickness:lumen diameter ratio in blood vessels. 3 Prostanoids (PR), metabolites of arachidonic acid through the cyclooxygenase pathway, include vasoactive substances synthesized and released by the vessel walls. 4 The aim of the present study was to analyse, in Fru-treated rats: (i) the morphology of mesenteric vessels and; (ii) the PR production in aorta and mesenteric vessels, in order to assess whether these parameters are related with the haemodynamic alterations observed in this experimental model. 5 Blood pressure, glycaemia and triglyceridaemia, were significantly elevated in both (4 and 22 weeks) Fru-treated groups. Meanwhile body and heart weight as well as insulinaemia were similar between experimental animals and controls. 6 The mesenteric vessels of Fru-treated rats (22 weeks) showed an increased thickness and area of the media when compared with the controls; meanwhile, the lumen diameter was similar in both groups. 7 The Fru treatment for 4 weeks did not modify PR production in aorta, whereas in the mesenteric bed it diminished prostaglandin (PG) E2 release significantly compared with the controls. However, in the group treated for 22 weeks, Fru reduced PGI2 production in the aorta, as assessed by 6-keto-PGF1α measurements. Meanwhile, in the mesenteric bed, the chronic Fru treatment decreased PGE2 release but, rather surprisingly, increased the output of PGI2 when compared with its corresponding controls. 8 In conclusion, the present study shows the existence of an alteration in the morphology of mesenteric vessels in Fru-treated rats, which could be related to an increase in peripheral resistance and the consequent mild hypertension observed in this model. However, a diminished release of vasodilator PRs, such as PGE2 in mesenteric vessels at 4 and 22 weeks and PGI2 in aorta at 22 weeks could further impair the vessel response. The increase in PGI2 observed in the chronic group in mesenteric vessels could be attributed to a compensatory mechanism.

Notes: 1 Electrical field stimulation (EFS) (0.5 ms in train of 2–32 Hz for 300 ms) in smooth muscle of pigeon oesophagus, in the presence of atropine (1 μm) and guanethidine (1 μm), elicited an inhibitory response consisting of a transient hyperpolarization (inhibitory junction potential, IJP) associated with muscle relaxation. 2 Sodium nitroprusside (SNP, 100 μm) induced hyperpolarization correlated to mechanical relaxation. 3 The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine (from 0.1 to 100 μm) caused a concentration-dependent reduction of electromechanical response to EFS indicating a role for NO in this response. 4 Apamin (1 μm) reduced both IJP and relaxation to EFS but was without effect on the response to SNP indicating a role for purines, which are also blocked by apamin. 5 Adenosine, AMP, ADP and ATP (all from 1 μm to 1 mm) application caused transient hyperpolarization and muscular relaxation with the following order of potency: adenosine 〉 AMP 〉 ADP 〉 ATP. 6 Inhibitory responses evoked by purines are TTX (1 μm) insensitive but they were inhibited by apamin. This indicates that a purine component for the non-adrenergic non-cholinergic (NANC) response exists but the purine receptor site is not located on the neurone. 7 Overall these results suggest that NANC inhibitory response elicited by EFS presents two different components apamin-sensitive, probably purines-mediated and apamin-insensitive probably NO-mediated as apamin only partially block the response to EFS.

Notes: 1 Sibenadet (Viozan®), a dual dopamine D2/β2-adrenoceptor agonist, suppresses histamine-induced tachypnoea in the dog by activating dopamine D2 receptors. We here compare the effects of sibenadet and formoterol, a selective β2-adrenoceptor agonist, on histamine-induced tachypnoea in the rhesus monkey. 2 Anaesthetized, spontaneously breathing, rhesus monkeys were set up for measuring airways resistance, respiratory rate, blood pressure and heart rate. 3 Both sibenadet and formoterol administered by aerosol, induced inhibition of the bronchoconstrictor response to aerosolized methacholine accompanied by tachycardia. Sibenadet, but not formoterol, also reduced blood pressure. 4 Administration of histamine by inhalation induced tachypnoea which was accompanied by bronchoconstriction. Tachypnoea to histamine was suppressed by both sibenadet and formoterol at doses which manifest anti-bronchoconstrictor activity. These effects and the accompanying tachycardia but not the hypotension induced by sibenadet were abolished by pretreatment with propranolol. 5 The dopamine D2 receptor agonist, quinagolide, did not suppress tachypnoea to histamine despite inducing a fall in blood pressure indicating activation of dopamine D2 receptors. 6 Thus, both sibenadet and formoterol suppress histamine-evoked tachypnoea in the rhesus monkey. The effect arises exclusively through activation of β2-adrenoceptors and probably reflects the anti-bronchoconstrictor effects of these agents. The results reveal a fundamental difference in the role of dopamine receptors in the airways of dog and rhesus monkey.

Notes: 1 We have investigated the actions of the calcium entry blockers nifedipine, R-verapamil and S-verapamil in rat aorta, colon and vas deferens. 2 In aorta and colon, these agents produced concentration-dependent relaxations of KCl (80 mm)-induced contractions. In both tissues, the order of potency was nifedipine 〉 S-verapamil 〉 R-verapamil. However, nifedipine showed selectivity for aorta (potency ratio, colon/aorta: 4.36), S-verapamil showed no selectivity (0.62), but R-verapamil showed selectivity for colon (0.19). 3 In prostatic portions of rat vas deferens, nifedipine (10 μm) abolished the contraction to a single electrical stimulus, but R- and S-verapamil were without effect. In epididymal portions of rat vas deferens, R- and S-verapamil inhibited α1-adrenoceptor-mediated contractions to a single electrical stimulus at concentrations of 10 μm and above. 4 In conclusion, R-verapamil may prove useful as an intestinal selective calcium entry blocker in the treatment of intestinal disease with a hypermotility component, e.g. irritable bowel syndrome.

Notes: 1 The present study was carried out to pharmacologically identify the β-adrenoceptor subtype that mediates isoprenaline-elicited relaxation in the isolated guinea-pig tracheal smooth muscle, to answer the question whether it is β1- or β2-subtype? 2 Isoprenaline as well as salbutamol, a well-known β2-selective adrenoceptor agonist, produced a concentration-dependent relaxation with a pD2 value of 8.12 vs. 7.54 for salbutamol. 3 Isoprenaline-elicited relaxation was not affected by β1-selective antagonists, atenolol and CGP-20,712A, within the concentration ranges supposed to antagonize β1-subtype: atenolol, ≤10−6 m; CGP-20,712A, ≤10−8 m. 4 By contrast, the concentration–response curves for isoprenaline as well as salbutamol were shifted rightwards in a competitive fashion by atenolol at the concentrations ≥3 × 10−6 m. However, pA2 values of atenolol against isoprenaline (5.86) and salbutamol (5.71) were consistent with the value corresponding to β2- but not to β1-subtype (around 7.00), and these values were not significantly different from each other. 5 Competitive antagonism of the relaxations to isoprenaline and salbutamol were also obtained with β2-selective antagonists, butoxamine and ICI-118,551. Against isoprenaline and salbutamol, the pA2 values of butoxamine (6.51 vs. 6.81) and ICI-118,551 (8.83 vs. 8.90) were substantially identical. Thus the primary mediation of β2-receptor in the relaxations was strongly supported. 6 The present findings provide evidence that the β-adrenoceptor which mediates isoprenaline-elicited relaxation of guinea-pig tracheal smooth muscle is essentially β2- but not β1-subtype. The present study also indicates the importance of using multiple receptor antagonists with different pA2 values to pharmacologically identify the responsible receptor subtype in smooth muscle mechanical responses.

Notes: 1 The role of histamine in heat-induced cardiovascular changes is uncertain. The purpose of this study was to examine effects of histamine H-1- and H-2-antagonism on heart rate, mean arterial blood pressure (MAP), localized body temperature changes, survival times, and lethal body temperatures that occur during the exposure of anaesthetized rats to 35 GHz radio frequency radiation (RFR). 2 Forty-eight ketamine-anaesthetized Sprague–Dawley rats were exposed, in several different treatment groups (n = 8 in each), to 35 GHz RFR at a level that resulted in significant body heating and subsequent death. During irradiation, a continuous increase in heart rate and a biphasic response in blood pressure (initial increase followed by a decrease) were observed in all groups of animals. 3 An H-1-antagonist, diphenhydramine (1 mg kg−1 body wt) and an H-2-antagonist, cimetidine (5 mg kg−1), administered after sustained RFR exposure, failed to reverse the RFR-induced hypotension. High doses of the drugs (5 and 10 mg kg−1, respectively) also did not alter the response. Post-RFR survival time was significantly decreased in the high-dose drug-treated group, compared with vehicle-treated (0.9% NaCl, 50% ethanol and 50% D5W) controls. 4 In experiments in which the two drugs were administered prior to RFR exposure, MAP in animals receiving high-dose antihistamines was significantly depressed compared with that of vehicle-treated animals during the first 35 min of RFR exposure. Antihistamine pretreatment, however, did not alter the total RFR exposure time required for death to occur. 5 In summary, pharmacological blockade of H-1 and H-2 receptors is not beneficial in anaesthetized rats made hypotensive by RFR exposure. This indicates that activation of H-1 and H-2 receptors by histamine does not occur to any significant extent and does not mediate the hypotensive response developed in this model of hyperthermia.

Notes: 1 The great taxonomic and prey base diversity of colubrids (non-front-fanged snakes) suggests that their venoms may represent a ‘literal gold mine’ for scientists eager to find novel pharmacological probes (Mackessy, 2002). 2 While pharmacological characterization is lacking for most of these venoms, this is even more so with regard to activity of colubrid venoms on the mammalian autonomic nervous system. This study characterizes the activity of venom from the colubrid, Boiga dendrophila using in vitro smooth muscle preparations and the anaesthetized rat. 3 In the prostatic segment of the rat vas deferens, cumulative additions of venom (1–150 μg ml−1) induced concentration-dependent inhibition of electrically evoked (0.2 Hz, 0.3 ms, 70–100 V) twitches. The inhibitory effect of venom (100 μg ml−1) was attenuated by 8-phenyltheophylline (8-PT) (20 μm) and 8-cyclopentyl-1, 3-dipropylxanthine (20 μm) but not idazoxan (1 μm), or a combination of ranitidine (0.2 μm) and thioperamide (10 μm). The inhibitory effect of venom (100 μg ml−1) was augmented by dipyridamole (10 μm) but abolished by pretreatment with adenosine deaminase (7.5 units/100 μl) suggesting that it contains components with adenosine A1 receptor activity, most likely adenosine. 4 In isolated segments of guinea-pig ileum, venom (10–100 μg ml−1) caused concentration-dependent contractions which were inhibited by the muscarinic receptor antagonist atropine (0.1 μm) but not by the histamine receptor antagonist mepyramine (0.5 μm). 5 In the anaesthetized rat, venom (5–7.5 mg kg−1, i.v.) caused a hypotensive effect. 6 Our data suggest that the venom contains components with purinergic and muscarinic receptor activity.

Notes: 1 β-Adrenoceptor (AR) ligands have been the mainstay of cardiovascular therapy for decades, with β-AR antagonist being used for hypertension, angina and myocardial infarction and adrenaline in use for cardiopulmonary resuscitation for nearly 100 years. 2 Ischaemia of the heart through coronary artery occlusion causes cell injury and death through necrosis and apoptosis. Reperfusion of the ischaemic myocardium results in cardiac dysfunction and infarction. 3 Stimulation of α- and β-ARs in the ischaemic heart have variable and inconsistent effects depending on when the agonist is applied. This review describes the different effects of stimulation of the three established β-AR subtypes (β1-, β2- and β3-ARs) either before ischaemia (preconditioning) or during ischaemia and reperfusion of the heart (postconditioning). 4 Brief periods of ischaemia preceding a major ischaemic episode can have a protective effect against post-ischaemia–reperfusion damage, known as ischaemic preconditioning. This review considers the role of endogenous catecholamines released during preconditioning and the nature of the adrenoceptor subtypes that mediate these effects. The clinical significance of this to the use of β-AR antagonists is considered. 5 The transduction pathways and effects on apoptosis of the cardioprotective and deleterious effects of AR activation are considered. 6 This commentary reviews the literature and attempts to bring together a unified synopsis of the effects of adrenoceptor stimulation in myocardial ischaemia and the potential clinical relevance.

Notes: 1 Cupric ions (Cu2+), at concentrations above 0.03 mm, induced a progressive increase in the tonic contraction of guinea-pig ileal longitudinal muscle. Maximal contraction of 0.1 mm Cu2+ attained a level above that of the 60-mm K+-induced tonic response, within 20 min of application. The tension induced by Cu2+ persisted for more than several hours. Tetrodotoxin (3 × 10−6 m) had no effect on the contraction induced by 0.1 mm Cu2+. 2 After incubation in a Ca2+-free medium, the ileal response to 0.1 mm Cu2+ was lost. Nifedipine, a L-type Ca2+ channel blocker, dose-dependently inhibited contractions induced by Cu2+. 3 As the duration of the first application of 0.1 mm Cu2+ increased above 30 min, after washing with normal medium, the contractile response to a second application of 0.1 mm Cu2+ decreased gradually. After 150 min of the first application of 0.1 mm Cu2+, a second application of Cu2+ could not evoke any contraction. 4 After the application of 0.1 mm Cu2+ for 150 min, when muscles were washed with a medium containing 1 mm EDTA, the response to 0.1 mm Cu2+ returned to a greater extent in the normal Ca2+ medium. 5 In conclusion, Cu2+ (0.1 mm) induced a maximal ileal tension above that of the K-induced tonic response within 20 min. The ileal contraction to Cu2+ persisted for more than several hours and depended on extracellular Ca2+ concentrations. It is possible that a part of Cu2+, bound to a EDTA-inaccessible site, also has a tension inhibitory effect.

Notes: 1 Anthraquinone stimulant cathartics, such as emodin, are believed to increase the rate of contraction of ileum tissue in vitro via multiple mechanisms. The aim of this study was to probe the effects of emodin on acetylcholine (ACh)-induced contraction of the rat isolated ileum preparation. 2 Ileal sections were incubated in Tyrode's solution and responses to methacholine, ACh and emodin obtained in the absence and presence of the muscarinic antagonist atropine and the choline uptake inhibitor hemicholinium (HC-3). Depletion of endogenous ACh in the presence of HC-3 was achieved by construction of an ACh dose–response curve, using exogenous ACh, prior to re-testing the effects of emodin in the presence of HC-3. 3 Emodin caused dose-dependent tissue contraction that was abolished by inclusion of atropine (1 μm) in the buffer. Atropine (1 μm) antagonized the response caused by methacholine. 4 Incubation of tissues with HC-3 (1 and 10 μm) reduced the maximum response caused by emodin by 45% and 71% respectively, but had no effect on ACh-induced tissue contraction. 5 These data suggest that, emodin causes contraction of the ileum by triggering the release of endogenous ACh which acts on muscarinic receptors to cause contraction of the rat isolated ileum preparation.

Notes: During brain development, neurons migrate great distances from proliferative zones to generate the cortical gray matter. A series of studies has identified genes that are critical for migration and targeting of neurons to specific brain regions. These genes encode three basic groups of proteins and produce three distinct phenotypes. The first group encodes cytoskeletal molecules and produces graded and dosage-dependent effects, with a significant amount of functional redundancy. This group also appears to play important roles during the initiation and ongoing progression of neuronal movement. The second group encodes signaling molecules for which homozygous mutations lead to an inverted cortex. In addition, this group is responsible for movement of neurons through anatomic boundaries to specific cortical layers. The third group encodes enzymatic regulators of glycosylation and appears to delineate where neuronal migration will arrest. There is significant cross-talk among these different groups of molecules, suggesting possible points of pathway convergence.

Notes: The principles underlying regeneration in planarians have been explored for over 100 years through surgical manipulations and cellular observations. Planarian regeneration involves the generation of new tissue at the wound site via cell proliferation (blastema formation), and the remodeling of pre-existing tissues to restore symmetry and proportion (morphallaxis). Because blastemas do not replace all tissues following most types of injuries, both blastema formation and morphallaxis are needed for complete regeneration. Here we discuss a proliferative cell population, the neoblasts, that is central to the regenerative capacities of planarians. Neoblasts may be a totipotent stem-cell population capable of generating essentially every cell type in the adult animal, including themselves. The population properties of the neoblasts and their descendants still await careful elucidation. We identify the types of structures produced by blastemas on a variety of wound surfaces, the principles guiding the reorganization of pre-existing tissues, and the manner in which scale and cell number proportions between body regions are restored during regeneration.

Notes: Plant membrane trafficking shares many features with other eukaryotic organisms, including the machinery for vesicle formation and fusion. However, the plant endomembrane system lacks an ER-Golgi intermediate compartment, has numerous Golgi stacks and several types of vacuoles, and forms a transient compartment during cell division. ER-Golgi trafficking involves bulk flow and efficient recycling of H/KDEL-bearing proteins. Sorting in the Golgi stacks separates bulk flow to the plasma membrane from receptor-mediated trafficking to the lytic vacuole. Cargo for the protein storage vacuole is delivered from the endoplasmic reticulum (ER), cis-Golgi, and trans-Golgi. Endocytosis includes recycling of plasma membrane proteins from early endosomes. Late endosomes appear identical with the multivesiculate prevacuolar compartment that lies on the Golgi-vacuole trafficking pathway. In dividing cells, homotypic fusion of Golgi-derived vesicles forms the cell plate, which expands laterally by targeted vesicle fusion at its margin, eventually fusing with the plasma membrane.

Notes: We review the current status of research in dorsal-ventral (D-V) patterning in vertebrates. Emphasis is placed on recent work on Xenopus, which provides a paradigm for vertebrate development based on a rich heritage of experimental embryology. D-V patterning starts much earlier than previously thought, under the influence of a dorsal nuclear -Catenin signal. At mid-blastula two signaling centers are present on the dorsal side: The prospective neuroectoderm expresses bone morphogenetic protein (BMP) antagonists, and the future dorsal endoderm secretes Nodal-related mesoderm-inducing factors. When dorsal mesoderm is formed at gastrula, a cocktail of growth factor antagonists is secreted by the Spemann organizer and further patterns the embryo. A ventral gastrula signaling center opposes the actions of the dorsal organizer, and another set of secreted antagonists is produced ventrally under the control of BMP4. The early dorsal -Catenin signal inhibits BMP expression at the transcriptional level and promotes expression of secreted BMP antagonists in the prospective central nervous system (CNS). In the absence of mesoderm, expression of Chordin and Noggin in ectoderm is required for anterior CNS formation. FGF (fibroblast growth factor) and IGF (insulin-like growth factor) signals are also potent neural inducers. Neural induction by anti-BMPs such as Chordin requires mitogen-activated protein kinase (MAPK) activation mediated by FGF and IGF. These multiple signals can be integrated at the level of Smad1. Phosphorylation by BMP receptor stimulates Smad1 transcriptional activity, whereas phosphorylation by MAPK has the opposite effect. Neural tissue is formed only at very low levels of activity of BMP-transducing Smads, which require the combination of both low BMP levels and high MAPK signals. Many of the molecular players that regulate D-V patterning via regulation of BMP signaling have been conserved between Drosophila and the vertebrates.

Notes: Macrophages are essential modulators of lipid metabolism and the innate immune system. Lipid and inflammatory pathways induced in activated macrophages are central to the pathogenesis of human diseases including atherosclerosis. Recent work has shown that expression of genes involved in lipid uptake and cholesterol efflux in macrophages is controlled by peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs). Other studies have implicated these same receptors in the modulation of macrophage inflammatory gene expression. Together, these observations position PPARs and LXRs at the crossroads of lipid metabolism and inflammation and suggest that these receptors may serve to integrate these pathways in the control of macrophage gene expression. In this review, we summarize recent work that has advanced our understanding of the roles of PPARs and LXRs in macrophage biology and discuss the implication of these results for cardiovascular physiology and disease.

Notes: The endoplasmic reticulum (ER) and the Golgi comprise the first two steps in protein secretion. Vesicular carriers mediate a continuous flux of proteins and lipids between these compartments, reflecting the transport of newly synthesized proteins out of the ER and the retrieval of escaped ER residents and vesicle machinery. Anterograde and retrograde transport is mediated by distinct sets of cytosolic coat proteins, the COPII and COPI coats, respectively, which act on the membrane to capture cargo proteins into nascent vesicles. We review the mechanisms that govern coat recruitment to the membrane, cargo capture into a transport vesicle, and accurate delivery to the target organelle.

Notes: The one-cell Caenorhabditis elegans embryo divides asymmetrically into a larger and smaller blastomere, each with a different fate. How does such asymmetry arise? The sperm-supplied centrosome establishes an axis of polarity in the embryo that is transduced into the establishment of anterior and posterior cortical domains. These cortical domains define the polarity of the embryo, acting upstream of the PAR proteins. The PAR proteins, in turn, determine the subsequent segregation of fate determinants and the plane of cell division. We address how cortical asymmetry could be established, relying on data from C. elegans and other polarized cells, as well as from applicable models. We discuss how cortical polarity influences spindle position to accomplish an asymmetric division, presenting the current models of spindle orientation and anaphase spindle displacement. We focus on asymmetric cell division as a function of the actin and microtubule cytoskeletons, emphasizing the cell biology of polarity.

Notes: The study of the epithelium of the adult mammalian intestine touches upon many modern aspects of biology. The epithelium is in a constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. The Wnt, TGF-beta, BMP, Notch, and Par polarity pathways are the major players in homeostatic control of the adult epithelium. Several hereditary cancer syndromes deregulate these same signaling cascades through mutational (in)activation. Moreover, these mutations often also occur in sporadic tumors. Thus symmetry exists between the roles that these signaling pathways play in physiology and in cancer of the intestine. This is particularly evident for the Wnt/APC pathway, for which the mammalian intestine has become one of the most-studied paradigms. Here, we integrate recent knowledge of the molecular inner workings of the prototype signaling cascades with their specific roles in intestinal epithelial homeostasis and in neoplastic transformation of the epithelium.

Notes: Plasmodium sporozoites display complex phenotypes including gliding motility and invasion of and transmigration through cells in the mosquito vector and the vertebrate host. Sporozoite studies have been difficult to perform because of technical concerns. Nevertheless, they have already provided insights into several aspects of sporozoite biology, shared in part with other apicomplexan invasive stages. Structure/function analysis of the thrombospondin-related anonymous protein paved the way to the understanding of the molecular mechanisms of apicomplexan gliding motility and host cell invasion. Functional studies of circumsporozoite protein revealed its role in Plasmodium sporozoite morphogenesis in addition to its well-known function in host cell invasion. Transcriptional surveys, which facilitate the investigation of gene expression programs that control sporozoite phenotypes, have revealed a high degree of previously unappreciated complexity and novel proteins that mediate sporozoite host cell infection.

Notes: Nucleation of microtubules by eukaryotic microtubule organizing centers (MTOCs) is required for a variety of functions, including chromosome segregation during mitosis and meiosis, cytokinesis, fertilization, cellular morphogenesis, cell motility, and intracellular trafficking. Analysis of MTOCs from different organisms shows that the structure of these organelles is widely varied even though they all share the function of microtubule nucleation. Despite their morphological diversity, many components and regulators of MTOCs, as well as principles in their assembly, seem to be conserved. This review focuses on one of the best-characterized MTOCs, the budding yeast spindle pole body (SPB). We review what is known about its structure, protein composition, duplication, regulation, and functions. In addition, we discuss how studies of the yeast SPB have aided investigation of other MTOCs, most notably the centrosome of animal cells.

Notes: knox genes encode homeodomain-containing transcription factors that are required for meristem maintenance and proper patterning of organ initiation. In plants with simple leaves, knox genes are expressed exclusively in the meristem and stem, but in dissected leaves, they are also expressed in leaf primordia, suggesting that they may play a role in the diversity of leaf form. This hypothesis is supported by the intriguing phenotypes found in gain-of-function mutations where knox gene misexpression affects leaf and petal shape. Similar phenotypes are also found in recessive mutations of genes that function to negatively regulate knox genes. KNOX proteins function as heterodimers with other homeodomains in the TALE superclass. The gibberellin and lignin biosynthetic pathways are known to be negatively regulated by KNOX proteins, which results in indeterminate cell fates.

Notes: The nervous system of higher organisms exhibits extraordinary cellular diversity owing to complex spatial and temporal patterning mechanisms. The role of spatial patterning in generating neuronal diversity is well known; here we discuss how neural progenitors change over time to contribute to cell diversity within the central nervous system (CNS). We focus on five model systems: the vertebrate retina, cortex, hindbrain, spinal cord, and Drosophila neuroblasts. For each, we address the following questions: Do multipotent progenitors generate different neuronal cell types in an invariant order? Do changes in progenitor-intrinsic factors or progenitor-extrinsic signals regulate temporal identity (i.e., the sequence of neuronal cell types produced)? What is the mechanism that regulates temporal identity transitions; i.e., what triggers the switch from one temporal identity to the next? By applying the same criteria to analyze each model system, we try to highlight common themes, point out unique attributes of each system, and identify directions for future research.

Notes: The Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers, and the APC protein has emerged as a multifunctional protein that is not only involved in the Wnt-regulated degradation of -catenin, but also regulates cytoskeletal proteins and thus plays a role in cell migration, cell adhesion, and mitosis. The gut epithelium is uniquely dependent on an intricate balance between a number of fundamental cellular processes including migration, differentiation, adhesion, apoptosis, and mitosis. In this review, I discuss the molecular mechanisms that govern the various functions of APC and their relationship to the role of APC in colon cancer.

Notes: Microtubules are dynamic polymers required for many aspects of eukaryotic cell function. The interphase microtubule network is essential for intracellular transport, organization, and cell polarization, whereas the mitotic spindle is required for chromosome segregation and cell division. Studies in different areas such as cell migration, mitosis, and asymmetric cell division have shown that Ran, Rho, and heterotrimeric G proteins regulate many aspects of microtubule functions. This review surveys how G protein-signaling coordinates microtubule polymerization and organization with specific cellular activities.

Notes: The problem of organelle size control can be addressed most simply by considering cellular structures that are linear, so that their size can be defined by a single parameter: length. We compare existing studies on several linear biological structures including prokaryotic flagella and flagellar hooks, eukaryotic flagella, sarcomere thin filaments, and microvilli. In some cases, existing evidence strongly supports the idea that length control involves a molecular ruler, in which the size of the overall structure is compared with the size of an individual molecule. In other cases, length control is likely to involve a steady-state balance of assembly and disassembly, in which one or the other rate is inherently length dependent. The lessons learned from size control in linear structures should be applicable to organelles with more complex three-dimensional structures.

Notes: The mitochondrion has developed an elaborate translocation system for the import of nuclear-coded proteins and the export of proteins coded on the mitochondrial genome. Precursor proteins contain targeting and sorting information to reach the mitochondrion, whereas the translocons recognize the information and direct the precursor to the correct compartment. The outer membrane contains the TOM (translocase of the outer membrane) complex for translocation and the SAM (sorting and assembly machinery) complex for assembly of outer membrane proteins with complex topologies. At the inner membrane, the TIM23 (translocase of the inner membrane) mediates the import of mitochondrial proteins with a typical N-terminal targeting sequence, and the TIM22 complex mediates the import of polytopic inner membrane proteins. Based on its prokaryotic origin, the inner membrane also contains several components that mediate the export and assembly of proteins from within the matrix. Together the translocation and assembly complexes coordinate assembly of the mitochondrion.

Notes: The synaptonemal complex (SC) is a protein lattice that resembles railroad tracks and connects paired homologous chromosomes in most meiotic systems. The two side rails of the SC, known as lateral elements (LEs), are connected by proteins known as transverse filaments. The LEs are derived from the axial elements of the chromosomes and play important roles in chromosome condensation, pairing, transverse filament assembly, and prohibiting double-strand breaks (DSBs) from entering into recombination pathways that involve sister chromatids. The proteins that make up the transverse filaments of the SC also play a much earlier role in committing a subset of DSBs into a recombination pathway, which results in the production of reciprocal meiotic crossovers. Sites of crossover commitment can be observed as locations where the SC initiates and as immunostaining foci for a set of proteins required for the processing of DSBs to mature crossovers. In most (but not all) organisms it is the establishment of sites marking such crossover-committed DSBs that facilitates completion of synapsis (full-length extension of the SC). The function of the mature full-length SC may involve both the completion of meiotic recombination at the DNA level and the exchange of the axial elements of the two chromatids involved in the crossover. However, the demonstration that the sites of crossover formation are designated prior to SC formation, and the finding that these sites display interference, argues against a role of the mature SC in mediating the process of interference. Finally, in at least some organisms, modifications of the SC alone are sufficient to ensure meiotic chromosome segregation in the complete absence of meiotic recombination.

Notes: Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells through the diffusion of ions, metabolites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication mediated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been linked to a variety of human diseases, including cardiovascular anomalies, peripheral neuropathy, deafness, skin disorders, and cataracts. In addition to their coupling function, recent studies suggest that connexin proteins may also mediate signaling. This could involve interactions with other protein partners that may play a role not only in connexin assembly, trafficking, gating and turnover, but also in the coordinate regulation of cell-cell communication with cell adhesion and cell motility. The integration of these cell functions is likely to be important in the role of gap junctions in development and disease.

Notes: Clathrin-coated vesicles (CCVs) are responsible for the transport of proteins between various compartments of the secretory and endocytic systems. Clathrin forms a scaffold around these vesicles that is linked to membranes by clathrin adaptors. The adaptors simultaneously bind to clathrin and to transmembrane proteins and/or phospholipids and can also interact with each other and with other components of the CCV formation machinery. The result is a collection of proteins that can make multiple, moderate strength (M Kd) interactions and thereby establish the dynamic regulatable networks to drive vesicle genesis at the correct time and place in the cell. This review focuses on the structure of clathrin adaptors and how these structures provide functional information on the mechanism of CCV formation.

Notes: Cell polarity, as reflected by polarized growth and organelle segregation during cell division in yeast, appears to follow a simple hierarchy. On the basis of physical cues from previous cell cycles or stochastic processes, yeast cells select a site for bud emergence that also defines the axis of cell division. Once polarity is established, rho protein-based signal pathways set up a polarized cytoskeleton by activating localized formins to nucleate and assemble polarized actin cables. These serve as tracks for the transport of secretory vesicles, the segregation of the trans Golgi network, the vacuole, peroxisomes, endoplasmic reticulum, mRNAs for cell fate determination, and microtubules that orient the nucleus in preparation for mitosis, all by myosin-Vs encoded by the MYO2 and MYO4 genes. Most of the proteins participating in these processes in yeast are conserved throughout the kingdoms of life, so the emerging models are likely to be generally applicable. Indeed, several parallels to cellular organization in animals are evident.

Notes: Programmed cell death involves the removal of cell corpses by other cells in a process termed engulfment. Genetic studies of the nematode Caenorhabditis elegans have led to a framework not only for the killing step of programmed cell death but also for the process of cell-corpse engulfment. This work has defined two signal transduction pathways that act redundantly to control engulfment. Signals expressed by dying cells probably regulate these C. elegans pathways. Components of the cell-corpse recognition system of one of the C. elegans pathways include the CED-7 ABC transporter, which likely presents a death ligand on the surface of the dying cell; the CED-1 transmembrane receptor, which recognizes this signal; and the CED-6 adaptor protein, which may transduce a signal from CED-1. The second C. elegans pathway acts in parallel and involves a novel Rac GTPase signaling pathway, with the components CED-2 CrkII, CED-5 DOCK180, CED-12 ELMO, and CED-10 Rac. The cell-corpse recognition system that activates this pathway remains to be characterized. In C. elegans, and possibly in mammals, the process of cell-corpse engulfment promotes the death process itself. The known mechanisms for cell-corpse engulfment leave much to be discovered concerning this fundamental aspect of metazoan biology.

Notes: To determine the taste components of Cheddar cheese, we fractionated one mild Cheddar cheese and one aged Cheddar cheese by water extraction, freeze-drying and gel filtration. Salty, sour and umami were the three predominant tastes present in the fractions. Neither trigeminal sensations nor astringency was perceived. We used response surface methodology to reconstruct a mild Cheddar cheese taste and an aged Cheddar cheese taste in water. Less salt and less acid were needed to simulate the taste of mild Cheddar cheese, compared with aged Cheddar cheese. Our optimized water solutions (containing sodium chloride, lactic acid and monosodium glutamate) were as similar to the real cheese samples as were the water extracts of the standard cheeses. However, neither our optimized solutions nor the water extracts matched the taste of the actual cheeses.

Notes: Judges were required to rate the total intensity of NaCl solutions using a variety of unstructured category and line scales under a ‘rank-rating’ protocol and a traditional protocol that did not allow retasting or the reviewing of scores. The various scales and protocols induced two types of scaling errors. The first type was named a different-stimulus error. This involved a judge rating a stronger stimulus as equal to or less than a weaker stimulus. The second type was named a same-stimulus error. This involved a judge giving different ratings to two stimuli of equal concentration. For all scales, judges made a higher proportion of same-stimulus errors than different-stimulus errors. ‘Rank-rating’ only reduced the proportion of different-stimulus errors. It was hypothesized that a category scale with fewer categories would induce a higher level of different-stimulus errors but lower level of same-stimulus errors. These trends were noted but not always significantly. For line scales, the equivalent hypotheses regarding line length were either weak or not supported. It would appear that increasing the length of a line scale is not always equivalent to increasing the number of categories in a category scale.

Notes: The assessor performance is a key point in a sensory evaluation. In particular, at the end of a session, a decrease of the performance can be feared. We propose to analyze this performance with various criteria: usual ones as the main product effect or the error variance; a new one measuring the perceived products variability. The performance can then be studied all along the session from two points of view: in taking into account the only products tested at a given instant (named instantaneous); in taking into account all the products tested up to a given instant (named cumulative). In the presented example, in spite of the large number of products successively tested by each assessor, the instantaneous performance of the panel shows no significant deterioration. Furthermore, when the number of products tested by each assessor increases, more significant product effects can be obtained thanks to the accumulation of the amount of data. This shows that the number of products that can be reasonably studied by one assessor during one session is generally underestimated.

Notes: Two experimental procedures recommended for the evaluation of the psychophysical characteristics of odorous compounds, olfactory matching with the 1-butanol scale and cross-modality matching with the finger span are compared. The intensity of ethyl butyrate and guaiacol solutions presented at four different concentration levels was evaluated by a panel of sixteen subjects over five repetitions using the two methods. Each stimulus was delivered to the subject from a Teflon bag through a nose-shaped glass sniffing port.The discrimination ability, repeatability, panel homogeneity and within-subject variability of the methods were assessed. Results indicate that with both methods, subjects were able to highly discriminate the presented concentration levels of the odorants. There were no great difference in repeatability and the same individual variability was observed between both methods. However, the smaller within-subject variability highlighted for the 1-butanol scale method suggested that this method is potentially more powerful than finger-span method.

Notes: People can eat a food without having a strong preference for it, and people can prefer a food without eating it. Given this seeming disconnect between attitude and behavior, which type of measure or segment can best be used to profile or identify loyal consumer segments of a food, such as soy? This research compares a usage-based method (heavy-light-nonusers) with a new attitude-based method (seeker-neutral-avoider), and finds that the attitude-based method differentiates purchase-related intentions better than the usage-based method. Implications for profiling consumer taste patterns and consumer segments are provided.

Notes: Astringent and bitter sensations are characteristic sensory qualities of black tea. Three different classes of potential astringent reference standards (two concentrations each of alum and tannic acid and three fruit juices) were evaluated in this study. The perceived astringency, bitterness and sourness of each were profiled using computerized time-intensity and compared with the astringent intensity of a standardized brew of black tea. The differences in temporal profiles of potential reference standards across taste attributes were evident and intensity ratings were found to be dependent upon the stimulus and its concentration. Both concentrations of tannic acid were evaluated as the highest in perceived bitterness. For the juices, a strong sour taste was perceived in addition to astringency. It was concluded that the best reference standard for the astringency of black tea is a solution of 0.7 g/L alum as it is low in perceived bitterness and sourness.

Notes: We developed an alternative method for the determination of 6-n propylthiouracil (PROP) taster status that is based on the comparison of intensity ratings of PROP solutions with intensity ratings of visual, tactile, and kinesthetic (physical) stimuli. We then compared the classification obtained with this method to those derived from traditional approaches. One hundred and forty-two subjects rated the perceived intensity of 0.000032, 0.00018, 0.00032, 0.0018, and 0.0032 M PROP, and 0.01, 0.032, 0.1, 0.32, and 1.0 M NaCl, as well as five levels each of perceived roughness of sandpaper, grayness of shades, and thickness of honey and water mixtures on the Labeled Magnitude Scale (LMS). Ratings for 0.00032 M PROP and 0.1 M NaCl were also compared in a one solution test. Subjects were classified as PROP nontasters, tasters or supertasters by all three procedures. Seventy-six percent of panelists were classified in a similar way by the physical stimuli and NaCl procedures, while 70% percent of panelists were classified similarly by the physical stimuli procedure and the one solution test, as well as by the NaCl procedure and the one solution test. Only 65% of panelists were classified similarly by all three procedures. Further, in replicate ratings of PROP solutions, supertasters’ evaluations of PROP at all concentration levels decreased significantly (P 〈 0.01) from the first to the second rating. It is evident from these findings that the method used to determine PROP taster status can greatly influence the outcome of any investigation of PROP taster status on other phenotypes.

Notes: The objective of this study was to verify key aroma-active compounds responsible for reconstituted fresh skim milk powder (SMP) aroma using threshold analysis, odor activity values, and model systems. Twelve odor-active compounds of SMP and one odor-active compound from fluid milk were selected based on flavor dilution factors from gas chromatography-olfactometry. Thresholds for the 13 odor-active compounds were identified using five-set ascending forced choice threshold analysis in odor-free water and fluid skim milk. Model systems were prepared using rehydrated milk retentate (RMR). The aroma of each model was evaluated by descriptive sensory analysis and by difference-from-control testing using a trained panel. The aroma of reconstituted fresh SMP and liquid skim milk were used as controls. Models containing a mixture of twelve of the thirteen chemicals had the most similar odor characteristics to rehydrated SMP aroma (9.0/10) indicating that these compounds constitute the character impact odorants of rehydrated fresh SMP.

Notes: The sensory characteristic “beany” is a limiting factor in introducing soy products to many consumers in western cultures. This research described sensory properties of beany flavor and described sensory odor characteristics of 19 chemicals that have been associated with beany aroma and flavor in previous literature. Seven concentrations varying from 1 to 100,000 ppm of each chemical (if soluble in propylene glycol) were examined by a five member trained descriptive panel. The panel described beany as having multiple attributes. Musty/earthy, musty/dusty, sour aromatics, and characterizing attributes such as green/pea pod, nutty, or brown collectively imparted beany aroma and flavor of most beans. Starchy flavor and powdery texture also were intrinsically associated with beany in bean product samples. Some chemicals tested were not beany at any level tested. Three alcohols, two ketones, one aldehyde, and one pyrazine exhibited beany characteristics (green/peapod or brown) only at low concentrations, generally 1-10 ppm.

Notes: This paper deals with the analysis of drivers for self-defined craveability assessed in an Internet-based, conjoint analysis task. The stimuli comprised 36 descriptions of restaurant hamburgers, including product features, benefits, restaurant names, and emotional reactions that might ensue after eating the hamburger. Elements were combined into concepts by experimental design, and the resulting concepts evaluated by 145 respondents, on the attribute of craveability. Models relating the presence/absence of concept elements to ratings revealed that statements about the hamburger itself were the most powerful, but that no single element was highest across all the respondents. Segmentation of the 145 individuals by the pattern of their individual utilities revealed four key segments. These are Elaborates who may be sensory-oriented and respond strongly to product descriptions; Classics who like the notion of a grilled hamburger; Imaginers who respond to restaurant name and advertising copy; and Emotionals who respond to statements about food to descriptions how the eater feels after consumption.

Notes: Judges were required to rate the total intensity of NaCl solutions and the sweetness of orange flavored beverages using a variety of unstructured category and line scales. Discrimination errors were noted for each type of scale. No strong differences were observed in discrimination between category and line scales although a 20-point category scale incurred fewer discrimination errors than 9-point category and line scales. Allowing judges to retaste stimuli and review and modify their scores reduced discrimination errors.

Notes: The objectives of this study were to compare oral and nonoral sensory evaluation for discrimination of texture of acid skim milk gels and to establish whether nonoral attributes could be correlated to the oral perception of texture. Trained panelists (n = 13) identified 11 nonoral (visual and in-hand) and 4 oral attributes during a preliminary profiling session that could be used to discriminate textures (P 〈 0.001) in a range of acid gels prepared with different solid contents and heat treatment of the milks. Both methods of sensory appraisal were found to discriminate between gels. Correlation analysis showed high interrelationship between individual oral and nonoral attributes (P 〈 0.01). Principal component analysis revealed that all 4 oral attributes could be combined into one single attribute (PC1), with equal relative importance of the individual attributes in explaining the variance in the oral sensory data set. Canonical correlation analysis revealed good correlation between the oral and nonoral set of attributes (R2 〉 87.5%).

Notes: Over the last decade, managed-care companies have been consolidating on both a regional and national scale. More recently, nonprofit health plans have been converting to for-profit status, and this conversion has frequently occurred as a step to facilitate merger or acquisition with a for-profit company. Some industry observers attribute these managed-care marketplace trends to an industry shakeout resulting from increased competition in the sector. At the same time, these perceived competitive pressures have led to questions about the long-run viability of nonprofit health plans. Furthermore, some industry and government leaders believe that some nonprofits are already conducting themselves like for-profit health plans and question the state premium tax exemption ordinarily accorded to such plans. This paper examines related health policy issues through the lens of a case study of the proposed conversion of the CareFirst Blue Cross Blue Shield company to a for-profit public-stock company and its merger with the Wellpoint Corporation. Company executives and board members argued that CareFirst lacked access to sufficient capital and faced serious threats to its viability as a financially healthy nonprofit health care company. They also argued that CareFirst and its beneficiaries would benefit from merger through enhanced economies of scale and product-line extensions. Critics of the proposed conversion and merger raised concerns about the adverse impacts on access to care, coverage availability, quality of care, safety-net providers, and the cost of health insurance. Analyses demonstrate that CareFirst wields substantial market power in its local market, that it is unlikely to realize cost savings through expanded economies of scale, and that access to capital concerns are largely driven by the perceived need for further expansion through merger and acquisition. Although it is impossible to predict future changes in quality of care for CareFirst, analyses suggest that quality appears to be somewhat lower in for-profit national managed-care companies. Additional research is needed to assess the viability of true nonprofits, the potential effects of nonprofits and for-profit national managed-care plans on the evolution of local insurance andprovider markets, and methods for effective oversight of nonprofit healthplans.

Notes: This paper describes three prototypical systems of therapeutic reference pricing (RP) for pharmaceuticals--Germany, the Netherlands, and New Zealand--and examines their effects on the availability of new drugs, reimbursement levels, manufacturer prices, and out-of-pocket surcharges to patients. RPfor pharmaceuticals is not simply analogous to a defined contribution approach to subsidizing insurance coverage. Although a major purpose of RPis to stimulate competition, theory suggests that the achievement of this goal is unlikely, and this is confirmed by the empirical evidence. Other effects of RPdiffer across countries in predictable ways, reflecting each country's system design and other cost-control policies. New Zealand's RPsystem has reduced reimbursement and limited the availability of new drugs, particularly more expensive drugs. Compared to these three countries, if RP were applied in the United States, it would likely have a more negative effect on prices of on-patent products because of the more competitive U.S. generic market, and on research and development (R&D) and the future supply of new drugs, because of the much larger U.S. share of global pharmaceutical sales.

Notes: This paper investigates a possible predictor of adverse selection problems in unsubsidized stand-alone prescription drug insurance: the persistence of an individual's high spending over multiple years. Using Medstat claims data and data from the Medicare Survey of Current Beneficiaries, we find that persistence is much higher for outpatient drug expenses than for other categories of medical expenses. We then use these estimates to develop a simple and intuitive model of adverse selection in competitive insurance markets and show that this high relative persistence makes it unlikely that unsubsidized drug insurance can be offered for sale, even with premiums partially risk adjusted, without a probable adverse selection death spiral. We show that this outcome can be avoided if drug coverage is bundled with other coverage, and we briefly discuss the need either for comprehensive coverage or generous subsidies if adverse selection is to be avoided in private and Medicare insurance markets.

Notes: The traditional focus of disability research has been on the elderly, with good reason. Chronic disability is much more prevalent among the elderly, and it has a more direct impact on the demand for medical care. It is also important to understand trends in disability among the young, however, particularly if these trends diverge from those among the elderly. These trends could have serious implications for future health care spending because more disability at younger ages almost certainlytranslates into more disability among tomorrow's elderly, and disability is a key predictor of health care spending.Using data from the Medicare Current Beneficiary Survey (MCBS) and the National Health Interview Study (NHIS), we forecast that per-capita Medicare costs will decline for the next fifteen to twenty years, in accordance with recent projections of declining disability among the elderly. By 2020, however, the trend reverses. Per-capita costs begin to rise due to growth in disability among the younger elderly. Total costs may well remain relatively flat until 2010 and then begin to rise because per-capita costs will cease to decline rapidly enough to offset the influx of new elderly people. Overall, cost forecasts for the elderly that incorporate information about disability among today's younger generations yield more pessimistic scenarios than those based solely on elderly data sets, and this information should be incorporated into official Medicare forecasts.

Notes: The ratio of controller-to-reliever medication use has been proposed as a measure of treatment quality for asthma patients. In this study we examine the effects of plan-level mean out-of-pocket asthma medication patient copayments and other features of benefit plan design on the use of controller medications alone, controller and reliever medications (combination therapy), and reliever medications alone. The 1995-2000 MarketScanTM claims data were used to construct plan-level out-of-pocket copayment and physician/practice prescriber preference variables for asthma medications. Separate multinomial logit models were estimated for patients in fee-for-service (FFS) and non-FFS plans relating benefit plan design features, physician/practice prescribing preferences, patient demographics, patient comorbidities, and county-level income variables to patient-level asthma treatment patterns. We find that the controller-to-reliever ratio rose steadily over 1995-2000, along with out-of-pocket payments for asthma medications, which rose more for controllers than for relievers. After controlling for other variables, however, plan-level mean out-of-pocket copayments were not found to have a statistically significant influence on patient-level asthma treatment patterns. On the other hand, physician/practice prescribing patterns strongly influenced patient-level treatment patterns. There is no strong statistical evidence that higher levels of out-of-pocket copayments for prescription drugs influence asthma treatment patterns. However, physician/practice prescribing preferences influence patient treatment.

Notes: Phagocytosis and phagolysosome biogenesis represent fundamental biological processes essential for proper tissue homeostasis, development, elimination of invading microorganisms, and antigen processing and presentation. Phagosome formation triggers a preprogramed pathway of maturation into the phagolysosome, a process controlled by Ca2+ and the regulators of organellar trafficking centered around the small GTP-binding proteins Rabs and their downstream effectors, including lipid kinases, organellar tethering molecules, and membrane fusion apparatus. Mycobacterium tuberculosis is a potent human pathogen parasitizing macrophages. It interferes with the Rab-controlled membrane trafficking and arrests the maturing phagosome at a stage where no harm can be done to the pathogen while the delivery of nutrients and membrane to the vacuole harboring the microorganism continues. This process, referred to as the M. tuberculosis phagosome maturation arrest or inhibition of phagosome-lysosome fusion, is critical for M. tuberculosis persistence in human populations. It also provides a general model system for dissecting the phagolysosome biogenesis pathways. Here we review the fundamental trafficking processes targeted by M. tuberculosis and the mycobacterial products that interfere with phagosomal maturation.

Notes: Dictyostelium is an accessible organism for studies of signaling via chemoattractant receptors. Chemoattractant-mediated signaling events and components are reviewed and presented as a series of connected modules, including excitation, inhibition, G protein-independent responses, early gene expression, inositol lipids, PH domain-containing proteins, cyclic AMP signaling, polarization acquisition, actin polymerization, and cortical myosin. The network incorporates information from biochemical, genetic, and cell biological experiments carried out on living cells. The modules and connections represent current understanding, and future information is expected to modify and build upon this structure.

Notes: Considerable evidence shows that lateral inhomogeneities in lipid composition and physical properties exist in biological membranes. These membrane lipid domains are proposed to play important roles in processes such as signal transduction and membrane traffic. However, there is not at present an adequate description of the nature of these lipid domains in terms of their size, abundance, composition, or dynamics. We discuss the current analyses of the properties and function of membrane domains in cells and compare their properties with chemically simpler model membrane systems that can be understood in greater detail.

Notes: Dynactin is a multisubunit protein complex that is required for most, if not all, types of cytoplasmic dynein activity in eukaryotes. Dynactin binds dynein directly and allows the motor to traverse the microtubule lattice over long distances. A single dynactin subunit, p150Glued, is sufficient for both activities, yet dynactin contains several other subunits that are organized into an elaborate structure. It is currently believed that the bulk of the dynactin structure participates in interactions with a wide range of cellular structures, many of which are cargoes of the dynein motor. Genetic studies verify the importance of all elements of dynactin structure to its function. Although dynein can bind some membranous cargoes independently of dynactin, establishment of a fully functional dynein-cargo link appears to depend on dynactin. In this review, I summarize what is presently known about dynactin structure, the cellular structures with which it associates, and the intermolecular interactions that underlie and regulate binding. Although the molecular details of dynactin's interactions with membranous organelles and other molecules are complex, the framework provided here is intended to distill what is presently known and to be of use to dynactin specialists and beginners alike.

Notes: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

Notes: The cell body has classically been considered the exclusive source of axonal proteins. However, significant evidence has accumulated recently to support the view that protein synthesis can occur in axons themselves, remote from the cell body. Indeed, local translation in axons may be integral to aspects of synaptogenesis, long-term facilitation, and memory storage in invertebrate axons, and for growth cone navigation in response to environmental stimuli in developing vertebrate axons. Here we review the evidence supporting mRNA translation in axons and discuss the potential roles that local protein synthesis may play during development and subsequent neuronal function. We advance the view that local translation provides a rapid supply of nascent proteins in restricted axonal compartments that can potentially underlie long-term responses to transient stimuli.

Notes: Myostatin is a secreted protein that acts as a negative regulator of skeletal muscle mass. During embryogenesis, myostatin is expressed by cells in the myotome and in developing skeletal muscle and acts to regulate the final number of muscle fibers that are formed. During adult life, myostatin protein is produced by skeletal muscle, circulates in the blood, and acts to limit muscle fiber growth. The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled. Skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism, and myostatin appears to be the first example of the long-sought chalone.

Notes: Significant advances have been made in the application of genetics to probe the functions of basement membrane laminins. These studies have shown that different laminin subunits profoundly affect tissue morphogenesis, starting around the time of embryonic implantation and extending through organogenesis and into the postnatal period. Collectively they have revealed common functions that include the induction and maintenance of cell polarity, the establishment of barriers between tissue compartments, the organization of cells into tissues, and the protection of adherent cells from detachment-induced cell death, anoikis. Interpreted in light of what is known about laminin structure and self-assembly and binding activities, these advances have begun to provide insights into mechanisms of action. In this review we focus on the contributions of the laminins in invertebrate and vertebrate tissue morphogenesis.

Notes: Human immunodeficiency virus (HIV) and other retroviruses acquire their envelopes and spread infection by budding through the limiting membranes of producer cells. To facilitate budding, retroviruses usurp a cellular pathway that is normally used to create vesicles that bud into late endosomal compartments called multivesicular bodies (MVB). Research on yeast and human MVB biogenesis has led to the identification of 25 human proteins that are required for vesicle formation and for HIV-1 budding, and has produced a working model for sequential recruitment of these proteins during MVB vesicle formation. Retroviruses can redirect this machinery to the plasma membrane and leave the cell in a single step or, alternatively, can bud directly into MVB compartments and then exit cells via the exosome pathway. Remarkably, virus release from both the plasma membrane and MVB compartments can occur directionally into specialized sites of cell-to-cell contact called virological synapses. Thus retroviruses have evolved elaborate mechanisms for escaping the cell and maximizing their chances of infecting a new host.

Notes: Myosin motor proteins use the energy derived from ATP hydrolysis to move cargo along actin tracks. Myosin VI, unlike almost all other myosins, moves toward the minus end of actin filaments and functions in a variety of intracellular processes such as vesicular membrane traffic, cell migration, and mitosis. These diverse roles of myosin VI are mediated by interaction with a number of different binding partners present in multi-protein complexes. Myosin VI can work in vitro as a processive dimeric motor and as a nonprocessive monomeric motor, each with a large working stroke. The possibility that both monomeric and dimeric forms of myosin VI operate in the cell may represent an important regulatory mechanism for controlling the multiple steps in transport pathways where nonprocessive and processive motors are required.

Notes: The flavor of eight samples of commercial strawberry yogurt was studied by Free-Choice Profile analysis (FCP). Generalized Procrustes Analysis (GPA) applied to FCP allowed differentiation between samples and highlighted flavor attributes responsible for the observed differences. The relation between sensory and physicochemical datasets was studied by means of GPA. Those samples with higher carbohydrate content were perceived as sweeter, having stronger strawberry flavor, and with more dairy and yogurt flavors. Samples with higher titratable acidity, ash and protein content were perceived as more acidic and higher in intensity of “faulty” or “defective” flavors. Higher moisture content was associated with lower intensity of “dairy” flavors (creamy, dairy, and yogurt) and greater intensity of rancid flavor. It is concluded that, though not often used to this end, GPA is a suitable method to study the relationship of sensory and instrumental measurements.

Notes: In a recent paper, we described the development and application of a labeled affective magnitude (LAM) scale for assessing liking/disliking (Schutz and Cardello 2001). Here we present the exact numerical scale-point locations corresponding to the verbal labels of the scale, so that investigators can easily construct the LAM scale for use with either paper or computer-based ballots.

Notes: This article describes an exploration of the concept of ‘oral freshness’ for as far as it is important in oral care. It intends to consider the most important mouth sensations and cognitive connotations, including (but not restricted to) the well-known effect of menthol in toothpaste.Two aspects were given attention:(1) The attributes that together form the concept of oral freshness were investigated using a ‘personal construct approach’(Kelly 1955). This method consists of unbiased, structured interviews with subjects, and ultimately yields attribute dimensions that the subjects have in common.(2) The intensity of the freshness sensation over time was investigated using the Time-Intensity method. Subjects gave repeated freshness judgments every few seconds after the intake of a freshness-related stimulus, and continued to do so after the stimulus had left their mouth. In addition we asked for ‘overall’ freshness judgments directly after the TI-measurements and after 2 months.The results confirm that ‘oral freshness’ is a complex concept. We identified 6 attributes, some of which were perceptual/physiological and some cognitive in nature: ‘water’-ness, cool/cold-ness, taste (menthol-ness), clean-ness, smell, energy (texture and touch, e.g., bubbles). Different persons will generally give different importance weights to each of these 6 attributes.Time-intensity measurements show that temperature, menthol-content and, to some extent, the presence of bubbles (energy) influence the momentous sensation of freshness. It appears, however, that in the way freshness is remembered after a few months, mainly cleanness and taste (menthol-ness) are important. Apparently, people tend to value (temporary) sensory input during the actual freshness experience, but tend to remember the freshness result in the longer run.

Notes: Time-intensity (TI) methodology and a trained panel were used to characterize the perceived bitterness of Yerba mate (YM) Ilex paraguariensis infusions. Two sampling procedures (sip and spit; sip and swallow) and two conditions for residence time in mouth (free or fixed duration of 5 s until spit or swallow) were evaluated.At a fixed duration the maximum bitterness as well as the time to reach it showed a significant YM concentration dependence. No change on bitterness was observed by swallowing or spitting YM infusions except a larger rate of decay of the response (vr) at spit condition. Dynamic bitterness at free sampling time showed that the decision period to spit or swallow the YM infusion approximately duplicated the fixed one of 5 s.

Notes: The effect of fat and fat replacers (FR) on the flavor release from cherry ice cream was investigated. Protein based FR, Simplesse (“S”) and carbohydrate based FR, Litesse (“L”) either partially or completely substituted milk fat in ice cream. Overall and temporal flavor profiles of ice cream during eating were obtained using chemical and sensory analyses. The performance of FR depended on the level of fat it was substituting and the amount of fat present in the ice cream. In the reduced fat ice cream group, both FRs failed to mimic the characteristics of 6% fat ice cream, mainly because of the low retention of cherry flavor. In the full fat ice cream group, the sensory properties of ice cream containing “L” were closer to the full-fat (12%) ice cream than those with “S”. The critical flavor volatile compounds that strongly impact the sensory flavor attributes were identified.

Notes: Response surface methodology was used to optimize formulations of chocolate peanut spread. Thirty-six formulations with varying levels of peanut (25-90%), chocolate (5-70%) and sugar (5-55%) were processed using a three-component constrained simplex lattice design. The processing variable, roast (light, medium, dark) was also included in the design. Response variables, measured with consumers (n = 60) participating in the test, were spreadability, overall acceptability, appearance, color, flavor, sweetness and texture/mouthfeel, using a 9-point hedonic scale. Regression analysis was performed and models were built for each significant (p 〈 0.01) response variable. Contour plots for each attribute, at each level of roast, were generated and superimposed to determine areas of overlap. Optimum formulations (consumer acceptance rating of ≥ 6.0 for all attributes) for chocolate peanut spread were all combinations of 29-65% peanut, 9-41% chocolate, and 17-36% sugar, adding up to 100%, at a medium roast. Verification of two formulations indicated no difference between predicted and observed values.

Notes: This paper presents the results from a study of consumer reactions to different attributes of red and white wine, with stimuli presented in the form of small, experimentally designed, test concepts (conjoint measurement). The results show that possibly four consumer mind-sets exist, with each mind-set comprising a different set of communication drivers for concept acceptance. Most subjects fit into one of three key categories; “Classics” (who want their wines to be traditional), “Imaginers” (who want to get into the drinking experience through knowing details about their wines) or “Elaborates” (who want their wines to produce many sensations and flavors). A fourth group (No Frills), were interested in simple and safe wines without any detail of flavor or origin. This segment was found in the red wine study, but not in the white wine study.

Notes: This paper describes a method that can be used to investigate consumers’ reported reasons for using a particular product. This method is applied to ratings of degree of agreement with statements about reasons for product use. The method is illustrated using data on self-reported reasons for smoking among adolescents. The approach used is based on a probabilistic model of similarity (Ennis et al. 1988) and provides a display of the density of respondents’ individual motivations concurrent with their perceptions of the statements. Factor analysis and its derived factor scores provide complementary information which is used to understand the interdependence of smoking motivations with the age of respondents and their degree of smoking. The probabilistic similarity model has many applications in studying consumer motivations such as those involved in the consumption of particular food and personal care products.

Notes: The addition of hazelnut paste to dark chocolate formulations altered the sensory profile. The flavors chocolate, burnt, rancid, hazelnut, green and metallic, and the texture attributes hardness, graininess, consistency of melt, viscosity and onset of melt determined by descriptive analysis were significantly (P 〈 0.05) influenced by the addition of up to 10% hazelnut paste. The shelf-life of dark chocolates containing hazelnut exceeded 10 months. The textural attributes of hardness, consistency of melt and onset of melt were highly correlated to instrumental measurements.

Notes: Sensory analysis was applied to the study of thermal perception, in order to determine and characterize end-users’ preferences concerning five indoor thermal environments generated by different heating systems. In this review, we developed a sensory profile method to describe and quantify the sensory characteristics of the thermal environments. A consumer test was also performed in order to investigate the hedonic judgment of 119 end users. The results show that trained assessors are able to describe and quantify sensory differences between the environments with high reliability. Consumers’ preferences are influenced by both their thermal sensations in the environments, as expressed by the sensory panel, and their personal opinions of the corresponding heating systems.

Notes: Survival analysis methodology was used to estimate the shelf life of alfajor (a chocolate-coated individually wrapped cake) at 20 and 35C by using results obtained from consumers when asked if they would accept or reject samples with different storage times. Sensory acceptability (measured by consumers), off-flavor (measured by a trained panel) and moisture content were linearly related to time. These correlations were used to estimate values at the shelf-life times calculated for 25 and 50% rejection probability. Survival analysis provided the following shelf-life estimation: 74 days at 20C and 33 days at 35C for a 25% of rejection, 87 days at 20C and 39 days at 35C for a 50% of rejection. An alfajor stored at 20C having an acceptability value below 4.9 (1–9 hedonic scale) and off-flavor intensity above 5.3 (0–10 scale) would be rejected by 25% of the consumers. Chemical data were not good shelf-life predictors.

Notes: Consumers rated a set of toothbrushes and a set of potato chips on 9-point and 21-point hedonic scales under two experimental protocols: a traditional approach and rank-rating. The hedonic data were analyzed in the usual way by using anova and multiple comparisons and also by ranking the data and using an R-index analysis. The hypothesis that the latter analysis would elicit fewer significant differences was not confirmed.

Notes: The profile of nine samples of Chardonnay wines was used to compare the performance of an expert panel and a trained descriptive panel using a common sensory terminology. Each panel (expert and trained) consisted of eight members, and the descriptors used by both groups were generated by the trained assessors. Thirteen out of 17 attributes evaluated turned out significant for wine discrimination among experts, and seven out of 17 for trained subjects. The trained panel reached a higher level of consensus, while the experts were more discriminative among attributes. The principal components analysis (PCA) corresponding to the expert group explained 88.68% of the total variance among the samples of the first two components. A third component was needed for the group of trained assessors (87.66% variance). The PCA showed the same wine grouping for both panels, indicating that differences were perceived in a similar way, despite that the sensory dimensions of these differences was not the same in all the cases.

Notes: Hispanics and non-Hispanics Americans participated in four sets of studies dealing with health-oriented foods, with the goal to identify how they respond to food categories relevant in any cuisine. Each study comprised a conjoint analysis using 36 elements followed by a self-profiling questionnaire to learn more about Hispanic and non-Hispanic food responses to concepts for four different product categories (morning bread, bottled water, healthful salad dressing and popcorn as a snack). The study identified patterns of preference of marketing statements in the areas of health information, sensory characteristics, emotional benefits and endorsements. Conjoint utility values generated by both Hispanics and non-Hispanic respondents correlated highly, suggesting that their food attitudes are quite similar for“non-signature”products despite the differences in their original cuisines.

Notes: In a descriptive sensory analysis, a principal component analysis (PCA) is usually applied to analyze products with attributes. To visualize the variability of a mean point (i.e., the center of gravity of the product), we introduced confidence ellipses. In this particular application, resampling methods are performed. Twenty products composed of five varieties of cider were studied. We would like to know if these five varieties are different. Confidence ellipses reveal differences between varieties foreshadowed in PCA.

Notes: The amount of training necessary to adequately “train” a descriptive panel is a matter of contention. The objectives of this research were to compare the performance of descriptive panelists after short-term (4 h), moderate (60 h) and extensive training (120 h). Seven screened panelists were chosen to evaluate three commercial tomato pasta sauces after each training period. Panelist performance improved with increased training. Sample differences were observed in all texture attributes and some flavor attributes, even after the shortest training time (4 h). However, more differences were found with at least 60 h of product training. After 120 h of training, product differences for all texture attributes and most of the flavor attributes studied could be ascertained by the trained panelists. These results suggested that only limited training may be necessary to find differences among products for many texture attributes and some flavor attributes. However, extensive training may be required to reduce variation among panelists and increase the discriminant abilities of panelists.

Notes: This study tests the possibility that sensory attributes are affected by the method by which a food is transferred to the mouth. For example, hot liquids appear to be considerably hotter when taken through a straw than when taken using a cup. Pre-weighed samples of two vanilla flavoured dairy custards were presented, in random order, to 16 trained panellists using a spoon, an 11-mm diameter straw or a modified straw that had a 4-mm diameter constriction within it. Panellists rated products using a subset of attributes generated by a quantitative descriptive analysis panel. The amount ingested was measured by re-weighing each sample after assessment. Each experiment was repeated three times. There were significant differences in the amount ingested for the two products. The delivery method had no effect on the sensory attributes of the products other than for thickness and melting, where products taken with the spoon were rated as less viscous than when taken through a straw. The constriction in the straw had no effect on either the amount ingested or on any of the sensory attributes. This study demonstrates that resistance to sucking does not affect perception of thickness.

Notes: Roasted peanuts were stored at 20 treatment combinations of water activities (0.33, 0.44, 0.54, 0.67, 0.75) and temperatures (23, 30, 35, 40C), and evaluated after storing for 0, 20, 40, 60, 80, 100, and 110% of estimated shelf life, ranging from 0 to 91 days. Regression models indicated that increasing storage time and storage water activity resulted in decreasing crispness, crunchiness, hardness, roasted peanutty, sweet aromatic, salty, bitter and sweet attributes and increasing fracturability, chewiness, tooth packing and cardboard flavor. Storage temperature did not contribute to regression models of textural properties of roasted peanuts. Increasing storage temperature resulted in a faster rate of decrease for roasted peanutty and faster rate of increase of cardboard flavor. Roasted peanuts stored between 0.33 and 0.41 a w at 23C are predicted to have the least change in sensory properties after 68 and 91 days respectively.

Notes: We investigated whether the perception of the crispness and staleness of potato chips can be affected by modifying the sounds produced during the biting action. Participants in our study bit into potato chips with their front teeth while rating either their crispness or freshness using a computer-based visual analog scale. The results demonstrate that the perception of both the crispness and staleness was systematically altered by varying the loudness and/or frequency composition of the auditory feedback elicited during the biting action. The potato chips were perceived as being both crisper and fresher when either the overall sound level was increased, or when just the high frequency sounds (in the range of 2 kHz−20 kHz) were selectively amplified. These results highlight the significant role that auditory cues can play in modulating the perception and evaluation of foodstuffs (despite the fact that consumers are often unaware of the influence of such auditory cues). The paradigm reported here also provides a novel empiric methodology for assessing such multisensory contributions to food perception.

Notes: The effect of three pleasant fine women's fragrances on the mood of women was assessed. The three fragrances had similar hedonic values but different sensory characteristics. The fragrances elicited nonspecific effects on mood. All three fragrances’ impact on mood was influenced by initial mood and lasted up to three hours, i.e., as long as the scent was still noticeable. Trends revealed that all three fragrances decreased negative affect and increased vigor. Also, independent of their hedonic value, the three fragrances elicited specific mood patterns. With the “woody citrus coniferous” scent, respondents experienced higher hostility and tension. The “floral chypre citrus” fragrance decreased anger and confusion. The “floral woody” scent had the lowest Total Mood Disturbance score and lowered depression, tension and confusion.

Notes: Amarone is a red wine produced with a technique already known to the ancient Romans, based on withered grapes and a slow fermentation. Amarone is now considered to be one of the great Italian wines and it is exported all over the world. Sensory and compositional analyses were carried out to describe the profile of the Amarone over four vintages (1998–2001) at different stages of aging. All wines were analyzed for titratable and volatile acidity, pH, alcohol content, residual sugars, t-resveratrol, antioxidant power, color, tonality, total polyphenols and anthocyans. Twelve trained people evaluated aroma and flavor attributes of all the wines in triplicate in a sensory session. Principal component analysis (PCA) of chemical, physical and sensory data for Amarone wine allowed us to highlight the differences between the wines. In general, the 1998 and 1999 vintages had higher aroma and flavor of Wood and Alcohol than the 2000 vintage, which, on the other hand, had higher aroma and flavor of Liquor and Cherry in alcohol. In contrast, the younger wine (2001 vintage) was the more Astringent and had many polyphenols and anthocyans, distinctive features for a red wine that has been in the cask for a short time.

Notes: This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids. We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses. Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCRalpha chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restricted T cells (NKT cells) to have unique effector functions without counterpart among MHC-restricted T cells. This review describes the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and in regulating the balance between tolerance and autoimmunity.

Notes: After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models-together with compelling data from human patients-indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting-elimination, equilibrium, and escape.

Notes: Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alphaCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alphaCD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

Notes: Understanding the molecular basis of lymphocyte homing to lymphoid organs was originally a problem of concern only to immunologists. With the discovery of l-selectin and its ligands, interested scientists have expanded to include glycobiologists, immunopathologists, cancer biologists, and developmental biologists. Going beyond its first discovered role in homing to lymph nodes, the l-selectin system is implicated in such diverse processes as inflammatory leukocyte trafficking in both acute and chronic settings, hematogenous metastasis of carcinoma cells, effector mechanisms for inflammatory demyelination of axons, and implantation of the early mammalian embryo. This review focuses on the ligands for l-selectin that are found on vascular endothelium, leukocytes, carcinoma cells, and at various extravascular sites. The discovery of selectins and their ligands has validated the long-predicted hypothesis that carbohydrate-directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given to the carbohydrate and sulfation modifications of the ligands, which enable recognition by l-selectin. The rapid "homing" of labeled cells into the lymph nodes presumably had its basis in the special affinity of small lymphocytes for the endothelium of the postcapillary venules. Gowans & Knight (1)

Notes: The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -e, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.

Notes: Because of the evolutionary conservation of innate mechanisms of host defense, Drosophila has emerged as an ideal animal in which to study the genetic control of immune recognition and responses. The discovery that the Toll pathway is required for defense against fungal infection in Drosophila was pivotal in studies of both mammalian and Drosophila immunity. Subsequent genetic screens in Drosophila to isolate additional mutants unable to induce humoral responses to infection have identified and ordered the function of components of two signaling cascades, the Toll and Imd pathways, that activate responses to infection. Drosophila blood cells also contribute to host defense through phagocytosis and signaling, and may carry out a form of self-nonself recognition that is independent of microbial pattern recognition. Recent work suggests that Drosophila will be a useful model for dissecting virulence mechanisms of several medically important pathogens.

Notes: Immune cell-mediated destruction of pathogens may result in excessive collateral damage to normal tissues, and the failure to control activated immune cells may cause immunopathologies. The search for physiological mechanisms that downregulate activated immune cells has revealed a critical role for extracellular adenosine and for immunosuppressive A2A adenosine receptors in protecting tissue from inflammatory damage. Tissue damage-associated deep hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with adenosine A2A receptors triggering "OFF" signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as "reporters," while A2A adenosine receptors serve as "sensors" of excessive tissue damage. The A2A receptor-triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative feedback manner to prevent additional tissue damage. Targeting A2A adenosine receptors may have important clinical applications.

Notes: The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.