Showing papers by "Tufts University published in 2000"

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

Reactive oxygen species in cell signaling

Abstract: Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of “oxidative stress” is thought to contribute to the pathogenesis of a number of human diseases including those of the lung. Recent studies have also implicated ROS that are generated by specialized plasma membrane oxidases in normal physiological signaling by growth factors and cytokines. In this review, we examine the evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated. Emerging concepts on the mechanisms of signal transduction by ROS that involve alterations in cellular redox state and oxidative modifications of proteins are also discussed.

Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.

Abstract: Animal studies and preliminary results in humans suggest that lower extremity and myocardial ischemia can be attenuated by treatment with angiogenic cytokines. The resident population of endothelial cells that is competent to respond to an available level of angiogenic growth factors, however, may potentially limit the extent to which cytokine supplementation enhances tissue neovascularization. Accordingly, we transplanted human endothelial progenitor cells (hEPCs) to athymic nude mice with hindlimb ischemia. Blood flow recovery and capillary density in the ischemic hindlimb were markedly improved, and the rate of limb loss was significantly reduced. Ex vivo expanded hEPCs may thus have utility as a “supply-side” strategy for therapeutic neovascularization.

The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.

Abstract: Recent studies suggest that statins can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. We show here that statins rapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits. Therefore, activation of Akt represents a mechanism that can account for some of the beneficial side effects of statins, including the promotion of new blood vessel growth.

Cross-reactive chemical sensor arrays.

Abstract: Conventional approaches to chemical sensors have traditionally made use of a “lock-and-key” design, wherein a specific receptor is synthesized in order to strongly and highly selectively bind the analyte of interest.1-6 A related approach involves exploiting a general physicochemical effect selectively toward a single analyte, such as the use of the ionic effect in the construction of a pH electrode. In the first approach, selectivity is achieved through recognition of the analyte at the receptor site, and in the second, selectivity is achieved through the transduction process in which the method of detection dictates which species are sensed. Such approaches are appropriate when a specific target compound is to be identified in the presence of controlled backgrounds and interferences. However, this type of approach requires the synthesis of a separate, highly selective sensor for each analyte to be detected. In addition, this type of approach is not particularly useful for analyzing, classifying, or assigning human value judgments to the composition of complex vapor mixtures such as perfumes, beers, foods, mixtures of solvents, etc.

Null hypothesis significance testing : A review of an old and continuing controversy

Abstract: Null hypothesis significance testing (NHST) is arguably the most widely used approach to hypothesis evaluation among behavioral and social scientists. It is also very controversial. A major concern expressed by critics is that such testing is misunderstood by many of those who use it. Several other objections to its use have also been raised. In this article the author reviews and comments on the claimed misunderstandings as well as on other criticisms of the approach, and he notes arguments that have been advanced in support of NHST. Alternatives and supplements to NHST are considered, as are several related recommendations regarding the interpretation of experimental data. The concluding opinion is that NHST is easily misunderstood and misused but that when applied with good judgment it can be an effective aid to the interpretation of experimental data.

Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

Abstract: Background—IGF-1 has been shown to protect myocardium against death in animal models of infarct and ischemia-reperfusion injury. In the present study, we investigated the role of the IGF-1–regulated protein kinase Akt in cardiac myocyte survival in vitro and in vivo. Methods and Results—IGF-1 promoted survival of cultured cardiomyocytes under conditions of serum deprivation in a dose-dependent manner but had no effect on cardiac fibroblast survival. The cytoprotective effect of IGF-1 on cardiomyocytes was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin. Wortmannin had no effect on cardiomyocyte viability in the absence of IGF-1. IGF-1–mediated cytoprotection correlated with the wortmannin-sensitive induction of Akt protein kinase activity. To examine the functional consequences of Akt activation in cardiomyocyte survival, replication-defective adenoviral constructs expressing wild-type, dominant-negative, and constitutively active Akt genes were constructed. Transduction ...

Low-temperature water-gas shift reaction over Cu- and Ni-loaded cerium oxide catalysts

Abstract: In this paper we report on the activity of Cu- and Ni-containing cerium oxide catalysts for low-temperature water-gas shift (WGS). Bulk catalysts were prepared in nanocrystalline form by the urea co-precipitation–gelation method. Lanthanum dopant (10 at.%) was used as a structural stabilizer of ceria, while the content of Cu or Ni was in the range of 5–15 at.% (2–8 wt.%). At low metal loadings, Cu or Ni were present in the form of highly dispersed oxide clusters, while at high loadings, clusters as well as particles of CuO or NiO (>10 nm in size) were present on ceria. Both Cu and Ni increased the reducibility of ceria, as evidenced by H2-TPR experiments. The WGS reaction activity of Ce(La)Ox was increased significantly by addition of a small amount (2 wt.%) of Cu or Ni. The catalysts were not activated prior to testing. Steady-state WGS kinetics were measured over the temperature range of 175–300 and 250–300°C, respectively, for Cu- and Ni–Ce(La)Ox. The activation energy of the reaction over Ce(La)Ox was 58.5 kJ/mol, while it was 38.2 and 30.4 kJ/mol, respectively, over the 5 at.% Ni–Ce(La)Ox and 5 at.% Cu–Ce(La)Ox catalysts in CO-rich conditions. A co-operative redox reaction mechanism, involving oxidation of CO adsorbed on the metal cluster by oxygen supplied to the metal interface by ceria, followed by H2O capping the oxygen vacancy on ceria, was used to fit the kinetics. Parametric studies were mainly performed with the 5 at.% Cu–(La)Ox catalyst. Notably, this material requires no activation and retains high WGS activity and stability at temperatures up to 600°C.

Naming-Speed Processes, Timing, and Reading A Conceptual Review

Abstract: This article integrates the findings in the special issue with a comprehensive review of the evidence for seven central questions about the role of naming-speed deficits in developmental reading disabilities. Cross-sectional, longitudinal, and cross-linguistic research on naming-speed processes, timing processes, and reading is presented. An evolving model of visual naming illustrates areas of difference and areas of overlap between naming speed and phonology in their underlying requirements. Work in the cognitive neurosciences is used to explore two nonexclusive hypotheses about the putative links between naming speed and reading processes and about the sources of disruption that may cause subtypes of reading disabilities predicted by the double-deficit hypothesis. Finally, the implications of the work in this special issue for diagnosis and intervention are elaborated.

Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor.

Abstract: Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5′-methoxyhydnocarpin (5′-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5′-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5′-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5′-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5′-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.

Association of Muscle Power With Functional Status in Community-Dwelling Elderly Women

Abstract: Background. Identification of the physiologic factors most relevant to functional independence in the elderly population is critical for the design of effective interventions. It has been suggested that muscle power may be more directly related to impaired physical performance than muscle strength in elderly persons. We tested the hypothesis that peak muscle power is closely associated with self-reported functional status in sedentary elderly community-dwelling women. Methods. We used baseline data that were collected as part of a 1-year randomized controlled clinical trial of a combined program of strength, power, and endurance training in 80 elderly women (mean age 74.8 6 5.0 years) with 3.2 6 1.9 chronic diseases, selected for baseline functional impairment and/or falls. Results. Functional status at baseline was related in univariate analyses to physiologic capacity, habitual physical activity level, neuropsychological status, and medical diagnoses. Leg power had the strongest univariate correlation to self-reported functional status ( r 5 2 .47, p , .0001) of any of the physiologic factors we tested. In a forward stepwise regression model, leg press power and habitual physical activity level were the only two factors that contributed independently to functional status ( r 5 .64, p , .0001), accounting for 40% of the variance in functional status.

Sarcopenia Current Concepts

Abstract: Sarcopenia, the loss of muscle mass and strength with age, is becoming recognized as a major cause of disability and morbidity in the elderly population. Sarcopenia is part of normal aging and does not require a disease to occur, although muscle wasting is accelerated by chronic diseases. Sarcopenia is thought to have multiple causes, although the relative importance of each is not clear. Neurological, metabolic, hormonal, nutritional, and physical-activity-related changes with age are likely to contribute to the loss of muscle mass. In this review, we discuss current concepts of the pathogenesis, treatment, and prevention of sarcopenia.

Vascular Endothelial Growth Factor165 Gene Transfer Augments Circulating Endothelial Progenitor Cells in Human Subjects

Abstract: Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.

Detection of preinvasive cancer cells

Abstract: Early-warning changes in precancerous epithelial cells can now be spotted in situ. More than 85% of all cancers originate in the epithelium that lines the internal surfaces of organs throughout the body. Although these are readily treatable provided they are diagnosed in one of the preinvasive stages1, early lesions are often almost impossible to detect. Here we present a new optical-probe technique based on light-scattering spectroscopy that is able to detect precancerous and early cancerous changes in cell-rich epithelia.

Role for Matrix Metalloproteinase 9 after Focal Cerebral Ischemia: Effects of Gene Knockout and Enzyme Inhibition with BB-94:

Abstract: It has been shown recently that matrix metalloproteinases (MMPs) are elevated after cerebral ischemia. In the current study, we investigated the pathophysiologic role for MMP-9 (gelatinase B, EC.3.4.24.35) in a mouse model of permanent focal cerebral ischemia, using a combination of genetic and pharmacologic approaches. Zymography and Western blot analysis demonstrated that MMP-9 protein levels were rapidly up-regulated in brain after ischemic onset. Reverse transcription polymerase chain reaction showed increased transcription of MMP-9. There were no differences in systemic hemodynamic parameters and gross cerebrovascular anatomy between wild type mice and mutant mice with a targeted knockout of the MMP-9 gene. After induction of focal ischemia, similar reductions in cerebral blood flow were obtained. In the MMP-9 knockout mice, ischemic lesion volumes were significantly reduced compared with wild type littermates in male and female mice. In normal wild type mice, the broad spectrum MMP inhibitor BB-94 (batimastat) also significantly reduced ischemic lesion size. However, BB-94 had no detectable protective effect when administered to MMP-9 knockout mice subjected to focal cerebral ischemia. These data demonstrate that MMP-9 plays a deleterious role in the development of brain injury after focal ischemia.

From Chance to Choice: Genetics and Justice

Abstract: This book, written by four internationally renowned bioethicists and first published in 2000, was the first systematic treatment of the fundamental ethical issues underlying the application of genetic technologies to human beings. Probing the implications of the remarkable advances in genetics, the authors ask how should these affect our understanding of distributive justice, equality of opportunity, the rights and obligations as parents, the meaning of disability, and the role of the concept of human nature in ethical theory and practice. The book offers a historical context to contemporary debate over the use of these technologies by examining the eugenics movement of the late nineteenth and early twentieth centuries. The questions raised in this book will be of interest to any reflective reader concerned about science and society and the rapid development of biotechnology, as well as to professionals in such areas as philosophy, bioethics, medical ethics, health management, law, and political science.

Estimating future hepatitis C morbidity, mortality, and costs in the United States.

Abstract: OBJECTIVES: This study estimated future morbidity, mortality, and costs resulting from hepatitis C virus (HCV). METHODS: We used a computer cohort simulation of the natural history of HCV in the US population. RESULTS: From the year 2010 through 2019, our model projected 165,900 deaths from chronic liver disease, 27,200 deaths from hepatocellular carcinoma, and $10.7 billion in direct medical expenditures for HCV. During this period, HCV may lead to 720,700 years of decompensated cirrhosis and hepatocellular carcinoma and to the loss of 1.83 million years of life in those younger than 65 at a societal cost of $21.3 and $54.2 billion, respectively. In sensitivity analysis, these estimates depended on (1) whether patients with HCV and normal transaminase levels develop progressive liver disease, (2) the extent of alcohol ingestion, and (3) the likelihood of dying from other causes related to the route of HCV acquisition. CONCLUSIONS: Our results confirm prior Centers for Disease Control and Prevention projections and suggest that HCV may lead to a substantial health and economic burden over the next 10 to 20 years.

Programmed Death in Bacteria

Abstract: Programmed cell death (PCD) in bacteria plays an important role in developmental processes, such as lysis of the mother cell during sporulation of Bacillus subtilis and lysis of vegetative cells in fruiting body formation of Myxococcus xanthus. The signal transduction pathway leading to autolysis of the mother cell includes the terminal sporulation sigma factor EςK, which induces the synthesis of autolysins CwlC and CwlH. An activator of autolysin in this and other PCD processes is yet to be identified. Autolysis plays a role in genetic exchange in Streptococcus pneumoniae, and the gene for the major autolysin, lytA, is located in the same operon with recA. DNA from lysed cells is picked up by their neighbors and recombined into the chromosome by RecA. LytA requires an unknown activator controlled by a sensory kinase, VncS. Deletion of vncS inhibits autolysis and also decreases killing by unrelated antibiotics. This observation suggests that PCD in bacteria serves to eliminate damaged cells, similar to apoptosis of defective cells in metazoa. The presence of genes affecting survival without changing growth sensitivity to antibiotics (vncS, lytA, hipAB, sulA, and mar) indicates that bacteria are able to control their fate. Elimination of defective cells could limit the spread of a viral infection and donate nutrients to healthy kin cells. An altruistic suicide would be challenged by the appearance of asocial mutants without PCD and by the possibility of maladaptive total suicide in response to a uniformly present lethal factor or nutrient depletion. It is proposed that a low rate of mutation serves to decrease the probability that asocial mutants without PCD will take over the population. It is suggested that PCD is disabled in persistors, rare cells that are resistant to killing, to ensure population survival. It is suggested that lack of nutrients leads to the stringent response that suppresses PCD, producing a state of tolerance to antibiotics, allowing cells to discriminate between nutrient deprivation and unrepairable damage. High levels of persistors are apparently responsible for the extraordinary survival properties of bacterial biofilms, and genes affecting persistence appear to be promising targets for development of drugs aimed at eradicating recalcitrant infections. PCD in unicellular eukaryotes is also considered, including aging in Saccharomyces cerevisiae. Apoptosis-like elimination of defective cells in S. cerevisiae and protozoa suggests that all unicellular life forms evolved altruistic programmed death that serves a variety of useful functions.

Evaluation of eye gaze interaction

Abstract: Eye gaze interaction can provide a convenient and natural addition to user-computer dialogues. We have previously reported on our interaction techniques using eye gaze [10]. While our techniques seemed useful in demonstration, we now investigate their strengths and weaknesses in a controlled setting. In this paper, we present two experiments that compare an interaction technique we developed for object selection based on a where a person is looking with the most commonly used selection method using a mouse. We find that our eye gaze interaction technique is faster than selection with a mouse. The results show that our algorithm, which makes use of knowledge about how the eyes behave, preserves the natural quickness of the eye. Eye gaze interaction is a reasonable addition to computer interaction and is convenient in situations where it is important to use the hands for other tasks. It is particularly beneficial for the larger screen workspaces and virtual environments of the future, and it will become increasingly practical as eye tracker technology matures.

Antioxidant Phytochemicals in Fruits and Vegetables: Diet and Health Implications

Abstract: Received for publication 26 May 1999. Accepted for publication 10 Aug. 1999. Mention of a trade name, proprietary product ,or specific equipment does not constitute a guarantee by the U.S. Dept. of Agriculture and does not imply its approval to the exclusion of other products that may be suitable.The cost of publishing this paper was defrayed in part by the payment of page charges. Under postal regulations, this paper therefore must be hereby marked advertisement solely to indicate this fact. To whom reprint requests should be addressed (phone: (617) 556-3311; fax: (617) 556-3299; e-mail: prior@hnrc.tufts.edu). Increased consumption of fruits and vegetables has been associated with protection against various age-related diseases (Ames et al., 1993; Steinberg, 1991). What dietary constituents are responsible for this association is not known, but well-characterized antioxidants, including vitamins C and E, or β-carotene, are often assumed to contribute to the observed protection (Ames et al., 1993; Buring and Hennekens, 1997; Gey et al., 1991; Stahelin et al., 1991; Steinberg, 1991; Willett, 1994). However, the results from intervention trials have not been conclusive regarding the protection following supplementation with such antioxidants (Hennekens et al., 1996; Omenn et al., 1996; Prieme et al., 1997; Van Poppel et al., 1995). Recent epidemiological evidence indicates that the putative beneficial effects of a high intake of fruits and vegetables on the risk of diseases of aging may not be exclusively due to these antioxidants (Hertog et al., 1992; Knekt et al., 1997), but other antioxidant phytochemicals contained in fruits and vegetables may be equally important. To critically evaluate the potential roles of these phytochemicals in prevention of agerelated diseases, we will discuss the free radical or oxidative stress theory of aging and present data on the antioxidant capacities of fruits, vegetables, and their phytochemical components, mainly flavonoids. Reports on the absorption of these flavonoids and the effects of fruit and vegetable intake on the antioxidant status in humans will be reviewed.

A large-scale North American study of fungal isolates from nails: The frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns

Abstract: Background: Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. Objective: A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. Methods: A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. Results: The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. Conclusion: Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America. (J Am Acad Dermatol 2000;43:641-8.).

Three-dimensional mapping of cortical thickness using Laplace's equation.

Abstract: We present a novel, computerized method of examining cerebral cortical thickness. The normal cortex varies in thickness from 2 to 4 mm, reflecting the morphology of neuronal sublayers. Cortical pathologies often manifest abnormal variations in thickness, with examples of Alzheimer's disease and cortical dysplasia as thin and thick cortex, respectively. Radiologically, images are 2-D slices through a highly convoluted 3-D object. Depending on the relative orientation of the slices with respect to the object, it is impossible to deduce abnormal cortical thickness without additional information from neighboring slices. We approach the problem by applying Laplace's Equation (∇2ψ = 0) from mathematical physics. The volume of the cortex is represented as the domain for the solution of the differential equation, with separate boundary conditions at the gray-white junction and the gray-CSF junction. Normalized gradients of ψ form a vector field, representing tangent vectors along field lines connecting both boundaries. We define the cortical thickness at any point in the cortex to be the pathlength along such lines. Key advantages of this method are that it is fully three-dimensional, and the thickness is uniquely defined for any point in the cortex. We present graphical results that map cortical thickness everywhere in a normal brain. Results show global variations in cortical thickness consistent with known neuroanatomy. The application of this technique to visualization of cortical thickness in brains with known pathology has broad clinical implications. Hum. Brain Mapping 11:12–32, 2000. © 2000 Wiley-Liss, Inc.

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance.

Abstract: This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro—in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drugmetabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of ≥200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP 1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.

The Development of Close Relationships in Japan and the United States: Paths of Symbiotic Harmony and Generative Tension

Abstract: Findings from research on parent-child and adult mate relationships suggest that there are different paths of development in Japan and the United States. In Japan, the path is one of symbiotic harmony, as seen in the emphasis on union in infancy, others' expectations in childhood, the stability of relationships with parents and peers in adolescence, and assurance about the mate relationship in adulthood. In the United States, the path is one of generative tension, as seen in the tug between separation and reunion in infancy, the emphasis on personal preferences in childhood, the transfer of closeness from parents to peers in adolescence, and the emphasis on trust-a faith and hope in new relationships-in adulthood. The notion that there are different paths of development challenges Western investigators' presumption that certain processes-separation-individuation, use of the relational partner as a secure base for exploration, and conflict between partners-are central in all relationships. The notion of different paths also challenges the assumption of many cross-cultural investigators that relationships in the United States are less valued or weaker than those in Japan; this article highlights cultural differences in the meaning and dynamics, as opposed to the importance and strength, of relationships. The model suggests a need to investigate the processes underlying, and the adaptive consequences of, these two alternative paths.