Showing papers by "University of Colorado Denver published in 1995"
TL;DR: In this paper, customer switching behavior damages market share and profitability of service firms yet has remained virtually unexplored in the marketing literature, and the author reports results of a critical incid...
Abstract: Customer switching behavior damages market share and profitability of service firms yet has remained virtually unexplored in the marketing literature. The author reports results of a critical incid...
2,756 citations
TL;DR: CD95 ligand expression in the testis probably acts by inducing apoptotic cell death of CD95-expressing, recipient T cells activated in response to graft antigens, and indicates that CD 95 ligand could be used to create immune-privileged tissue for a variety of transplant uses.
Abstract: Testis is a remarkable immune-privileged site, long known for its ability to support allogeneic and xenogeneic tissue transplants. Here we have investigated the molecular basis for testis immune privilege. Testis grafts derived from mice that can express functional CD95 (Fas or Apo-1) ligand survived indefinitely when transplanted under the kidney capsule of allogeneic animals, whereas testis grafts derived from mutant gld mice, which express non-functional ligand, were rejected. Further analysis of testis showed that CD95 ligand messenger RNA is constitutively expressed by testicular Sertoli cells, and that Sertoli cells from normal mice, but not gld mice, were accepted when transplanted into allogeneic recipients. CD95 ligand expression in the testis probably acts by inducing apoptotic cell death of CD95-expressing, recipient T cells activated in response to graft antigens. These findings indicate that CD95 ligand could be used to create immune-privileged tissue for a variety of transplant uses.
1,203 citations
TL;DR: It is concluded that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
Abstract: GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-β superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons1 and is expressed in the developing striatum2,3. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin l–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substan-tia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
1,117 citations
1,094 citations
TL;DR: The evidence to date shows that 5 of 6 criteria for identifying mediators of tissue damage in human autoimmune diseases are satisfied and the last criterion, prevention of clinical progression in patients with RA, is currently being evaluated.
Abstract: This review has summarized information published over the last 5 years on the presence and pathophysiologic role of IL-1 and TNF alpha in RA. The evidence to date shows that 5 of 6 criteria for identifying mediators of tissue damage in human autoimmune diseases are satisfied (Table 1). The last criterion, prevention of clinical progression in patients with RA, is currently being evaluated. Many new therapeutic approaches are currently being developed, including the use of soluble receptors to IL-1 or TNF, monoclonal antibodies to TNF alpha, a specific IL-1 receptor antagonist, and gene therapy with the latter molecule. It should be emphasized that both IL-1 and TNF alpha play important roles in normal host defense; the possible complications of blocking their production or effects need to be carefully evaluated in long-term studies. A recent review has emphasized that although IL-1 and TNF alpha have many overlapping biologic properties, each may exhibit distinct effects in joint disease (99). Anti-TNF treatment may be primarily antiinflammatory but blocking IL-1 may be more effective in preventing cartilage destruction (100). The possibility exists that simultaneous inhibition of TNF alpha and IL-1 may be more therapeutically efficacious than blockade of either agent alone, as was recently demonstrated with IL-1ra and soluble TNF receptors in bacterial cell wall-induced arthritis in rats (101). The next level of clinical studies in rheumatoid arthritis should include the use of two biologic response modifiers together, or one agent combined with a more traditional form of therapy.
946 citations
TL;DR: There was no decrease in mortality between placebo and TNF-α MAb in all infused patients, and in septic shock patients who received T NF- α MAb, a significant reduction in mortality was present 3 days after infusion; however, although a trend toward reduced mortality continued at 28 days following treatment with TTFMAb, the difference in mortality among shock patients treated with placebo or TFB was not significant.
Abstract: Objective. —To evaluate the efficacy and safety of anti—tumor necrosis factor α monoclonal antibody (TNF-α MAb) in the treatment of patients with sepsis syndrome. Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting. —A total of 31 hospitals in the United States and Canada. Patients. —There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug. Intervention. —Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-α MAb, 7.5 mg/kg of TNF-α MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period. Outcome Measure. —Twenty-eight-day all-cause mortality. Results. —The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-α MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-α MAb. In septic patients with shock (n=478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-α MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-α MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P =.01; 7.5 mg/kg: 48.7% reduction vs placebo, P =.004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-α MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P =.20 for 7.5 mg/kg and P =.15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-α MAb were reported. Serum sickness—like reactions were seen in 2.5% of patients receiving TNF-α MAb. Conclusions. —There was no decrease in mortality between placebo and TNF-α MAb in all infused patients. In septic shock patients who received TNF-α MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-α MAb, the difference in mortality among shock patients treated with placebo or TNF-α MAb was not significant. ( JAMA . 1995;273:934-941)
757 citations
Journal Article•
TL;DR: This review of literature and research into the effectiveness of distance education systems deals with a number of factors which affect their success or failure.
Abstract: This review of literature and research into the effectiveness of distance education systems deals with a number of factors which affect their success or failure. These include the influence of distance learning theory upon instructional design and delivery, redefining the roles of partners in distance education teams, media selection, technology adoption, change implementation, methods and strategies to increase interactivity, inquiry, and active learning, learner characteristics and modes of learning, teacher mediation and learner support, operational issues, policy and management issues, and cost/ benefit tradeoffs. It is intended as a companion piece to Sherry and Morse’s (1994) training needs assessment.
700 citations
TL;DR: An algebraic multigrid algorithm for symmetric, positive definite linear systems is developed based on the concept of prolongation by smoothed aggregation based on a set of requirements motivated heuristically by a convergence theory.
Abstract: An algebraic multigrid algorithm is developed based on prolongations by smoothed aggregation. Coarse levels are generated automatically. Guidelines for the selection of method components are presented based on energy considerations. Efficiency of the resulting algorithm is demonstrated by computational results.
648 citations
TL;DR: In low-risk subjects, the normal distribution and lower abnormal cutoff point values of the ABI differed by type of test, sex, ankle vessel, and leg and an abnormal dorsalis pedis and posterior tibial ABI in the same leg at rest should be used for the diagnosis of PAD in epidemiological studies.
Abstract: Background The ankle/brachial systolic blood pressure index (ABI), a noninvasive measure of peripheral arterial disease (PAD), is widely used in epidemiological studies. However, the normal ranges of the ABI in healthy populations and ABI criteria for the diagnosis of PAD in large population studies have not been critically evaluated. Methods and Results The San Luis Valley Diabetes Study (SLVDS) was designed to evaluate the prevalence and complications of non–insulin-dependent diabetes mellitus (NIDDM) in a biethnic population. The present study was conducted as part of the SLVDS to assess the prevalence of vascular disease in 1280 nondiabetic control subjects and 430 patients with NIDDM. The ABI criteria for PAD were developed in 403 healthy individuals with a low risk for cardiovascular disease. In these low-risk subjects, the average resting ABI value was 0.07 lower in women than in men. In both sexes, the dorsalis pedis ABI was 0.04 lower than in the posterior tibial artery, and the left leg ABI was ...
537 citations
TL;DR: The finding of αTTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.
Abstract: Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease which maps to chromosome 8q13. AVED patients have an impaired ability to incorporate alpha-tocopherol into lipoproteins secreted by the liver, a function putatively attributable to the alpha-tocopherol transfer protein (alpha-TTP). Here we report the identification of three frame-shift mutations in the alpha TTP gene. A 744delA mutation accounts for 68% of the mutant alleles in the 17 families analysed and appears to have spread in North Africa and Italy. This mutation correlates with a severe phenotype but alters only the C-terminal tenth of the protein. Two other mutations were found in single families. The finding of alpha TTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.
523 citations
TL;DR: In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.
Abstract: Background The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. Methods Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. Results Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respec...
TL;DR: The use of moderated multiple regression (MMR) has become pervasive in numerous management specialties such as organizational behavior, human resources management, and strategy, to name a few as mentioned in this paper.
TL;DR: In this article, the authors report that people at every organizational level must be creative and flexible problem solvers (Lynton, 1989), which requires the ability to apply experience and a definition knowledge to address novel problems.
Abstract: In today's complex world, simply knowing how to use tools and knowledge in a single domain is not sufficient to remain competitive as either individuals or companies. People must also learn to apply tools and knowledge in new domains and different situations. Industry specialists report that people at every organizational level must be creative and flexible problem solvers (Lynton, 1989). This requires the ability to apply experience and a definition knowledge to address novel problems. Consequently, learning to think critically, to analyse and synthesize information to solve technical, social, economic, political, and scientific problems, and to work productively in groups are crucial skills for successful and fulfilling participation in our modern, competitive society. DOI: 10.1080/0968776950030202
TL;DR: The integration of G12 and G13 with the regulation of the actin cytoskeleton is defined, indicating that α12 and α13, but not other G protein α subunits or βγ complexes, regulate Rho-dependent responses.
TL;DR: Investigation of the effect of two forms of intensive speech treatment on the speech and voice deficits associated with idiopathic Parkinson disease suggests intensive voice and respiration treatment is more effective than respiration (R) treatment alone for improving vocal intensity and decreasing the impact of Parkinson disease on communication.
Abstract: This study investigated the effect of two forms of intensive speech treatment, (a) respiration (R) and (b) voice and respiration (Lee Silverman Voice Treatment [LSVT]), on the speech and voice deficits associated with idiopathic Parkinson disease. Forty-five subjects with Idiopathic Parkinson disease completed extensive pretreatment neurological, otolaryngological, neuropsychological, and speech assessments. All subjects completed 16 sessions of intensive speech treatment, 4 times a week for 1 month. Pre- and post-treatment measures included intensity and maximum duration during sustained vowel phonation. Intensity, habitual fundamental frequency, fundamental frequency variability, and utterance and pause duration were measured during reading of the "Rainbow Passage" and conversational monologue as well. Family and subject self-ratings were completed pre- and post-treatment for the perceptual variables loudness, monotonicity, hoarseness, overall intelligibility, and initiation of conversation. Significant pre- to post-treatment improvements were observed for more variables and were of greater magnitude for the subjects who received the voice and respiration treatment (LSVT). Only subjects who received the LSVT rated a significant decrease post-treatment on the impact of Parkinson disease on their communication. Correlations between descriptive prognostic variables (i.e., stage of disease, speech/voice severity rating, depression, and time since diagnosis) and magnitude of treatment-related change indicated these factors did not significantly predict treatment effectiveness. These findings suggest that intensive voice and respiration (LSVT) treatment, focusing on increased vocal fold adduction and respiration, is more effective than respiration (R) treatment alone for improving vocal intensity and decreasing the impact of Parkinson disease on communication.
TL;DR: The use of moderated multiple regression (MMR) has become pervasive in numerous management specialties such as organizational behavior, human resources management, and strategy, to name a few as mentioned in this paper.
TL;DR: The frequency of otitis media is one of a number of factors causing physicians to seek out the most cost-effective clinical strategies for managing the condition.
Abstract: The frequency of otitis media is one of a number of factors causing physicians to seek out the most cost-effective clinical strategies for managing the condition. It is estimated that, by the time they reach two years of age, all the children in the United States currently under that age will have had a total of 9.3 million episodes of acute otitis media,1 and that approximately 17 percent of children have three or more episodes during a six-month period.2 Frequent episodes of otitis disrupt child-care arrangements and work schedules and generate parental anxiety and stress. The annual cost of the . . .
TL;DR: The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.
Abstract: Glial cell-lined derived neurotrophic factor (GDNF) has been shown to promote survival of developing mesencephalic dopaminergic neurons in vitro. In order to determine if there is a positive effect of GDNF on injured adult midbrain dopaminergic neurons in situ, we have carried out experiments in which a single dose of GDNF was injected into the substantia nigra following a unilateral lesion of the nigrostriatal system. Rats were unilaterally lesioned by a single stereotaxic injection of 6-hydroxydopamine (6-OHDA; 9 micrograms/4 microliters normal saline with 0.02% ascorbate) into the medial forebrain bundle and tested weekly for apomorphine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested > 300 turns/hour received a nigral injection of 100 micrograms GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA lesion. Rotation behavior was quantified weekly for 5 weeks after GDNF. Rats were subsequently anesthetized, transcardially perfused, and processed for tyrosine hydroxylase immunohistochemistry. It was found that 100 micrograms GDNF decreased apomorphine-induced rotational behavior by more than 85%. Immunohistochemical studies revealed that tyrosine hydroxylase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contrast, large increments in tyrosine hydroxylase immunoreactivity were observed in the substantia nigra of animals treated with 100 micrograms of GDNF, with a significant increase in numbers of tyrosine hydroxylase-immunoreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.
TL;DR: The clinical presentation may mimic that of bacterial or other viral CNS infections, a circumstance making laboratory diagnosis of paramount importance for reducing unnecessary hospitalization and therapy.
Abstract: Infections of the CNS with the nonpolio enteroviruses are common and important causes of morbidity in both children and adults. Studies have recently defined the short-term and long-term outcomes of aseptic meningitis due to the enteroviruses. Focal encephalitis is increasingly recognized as a complication of enterovirus infection. Patients at greatest risk for sequelae of CNS enteroviral disease include neonates and those who are immunocompromised. The clinical presentation may mimic that of bacterial or other viral CNS infections, a circumstance making laboratory diagnosis of paramount importance for reducing unnecessary hospitalization and therapy. Recent advances in PCR technology, including its adaptation to a colorimetric microwell plate format, promise to greatly facilitate diagnosis of enteroviral infections. Promising antiviral drugs for CNS disease and other serious manifestations of enteroviral infections are under development.
TL;DR: Peripheral arterial disease (PAD) affects a large proportion of the general population, with an age-adjusted prevalence of approximately 12% and a prevalence of intermittent claudication of 3% to 7%.
Abstract: Peripheral arterial disease (PAD) affects a large proportion of the general population, with an age-adjusted prevalence of approximately 12% and a prevalence of intermittent claudication of 3% to 7%.1 2 In symptomatic persons, the limited lower extremity arterial supply cannot meet the dynamic metabolic demand of the muscles during ambulatory activities, resulting in the symptom of claudication. Claudication is associated with a severe limitation in walking ability,3 which may adversely affect social, leisure, and occupational activities in many patients.4
The treatment of all patients with PAD is initially directed at cardiovascular risk factor modification, since these individuals have a high future risk of cardiovascular mortality.5 Severely affected patients who have ischemic rest pain or tissue loss are candidates for interventional therapy (bypass surgery or angioplasty) to maintain limb viability.6 7 However, since the majority of patients with claudication are not at short-term risk of limb loss, the primary therapeutic goal is to improve exercise performance and community-based functional status.
The past decade has witnessed a marked increase in the evaluation and utilization of therapies to treat patients with claudication.8 Percutaneous transluminal angioplasty is considered an appropriate intervention for patients with “earlier stages of symptomatic disability” due to claudication,9 and the American Heart Association has recently recommended that invasive interventions are appropriate for patients with incapacitating claudication.6 In addition, there is increased interest in medical therapies for claudication. Exercise training elicits well-established and clinically important changes in treadmill exercise performance and community-based walking ability.3 10 11 Recent pharmacological advances have led to a greater use of drugs to treat claudication, with new agents in clinical development. Examples include drugs that alter blood rheology12 and drugs that improve ischemic skeletal muscle metabolism.13
A clinical classification to evaluate therapies for PAD has …
TL;DR: In this article, the authors tested the hypothesis that T cells in acute guttate psoriasis skin lesions may be activated by streptococcal superantigens and found that the expansion of V beta 2+ T cells occurred in both the CD4+ and the CD8+ T cell subsets.
Abstract: Recent studies have suggested that T cells play a critical role in the pathogenesis of psoriasis. Guttate psoriasis is a well-defined form of psoriasis frequently associated with streptococcal throat infection. This study tested the hypothesis that T cells in acute guttate psoriasis skin lesions may be activated by streptococcal superantigens. Peripheral blood as well as lesional and perilesional skin biopsies were analyzed for T cell receptor V beta repertoire using monoclonal antibodies against 10 different V beta families. Skin biopsies from all patients with acute guttate psoriasis, but not skin biopsies from patients with acute atopic dermatitis or inflammatory skin lesions induced in normal subjects with sodium lauryl sulfate, demonstrated selective accumulation of V beta 2+ T cells (P < 0.05). The expansion of V beta 2+ T cells occurred in both the CD4+ and the CD8+ T cell subsets. Sequence analysis of T cell receptor beta chain genes of V beta 2-expressing T cells from skin biopsies of patients with guttate psoriasis showed extensive junctional region diversity that is more compatible with a superantigen rather than a conventional (nominal) antigen-driven T cell response. All streptococcal isolates from patients with guttate psoriasis secreted streptococcal pyrogenic exotoxin C, a superantigen known to stimulate marked V beta 2+ T cell expansion. These data support the concept that acute guttate psoriasis is associated with superantigenic stimulation of T cells triggered by streptococcal superantigen(s).
TL;DR: The service process/service package matrix is introduced to meet the need to foster strategic thinking in services and to gain strategic insights by aligning the type of service package offered with thetype of process used to create the service and to have a better understanding of their service operations strategy.
TL;DR: The unique interactions of ethanol with GABAA receptors are shown and protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol are suggested.
Abstract: Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.
TL;DR: A role for PTP1C in regulating the tyrosine phosphorylation state of the resting BCR complex components is suggested, supported by the observation that PTP 1C specifically induces dephosphorylation of a 35-kD BCR-associated protein likely representing Ig-alpha.
Abstract: Recent data implicating loss of PTP1C tyrosine phosphatase activity in the genesis of the multiple hemopoietic cell defects found in systemic autoimmune/immunodeficient motheaten (me) and viable motheaten (mev) mice suggest that PTP1C plays an important role in modulating intracellular signaling events regulating cell activation and differentiation. To begin elucidating the role for this cytosolic phosphatase in lymphoid cell signal transduction, we have examined early signaling events and mitogenic responses induced by B cell antigen receptor (BCR) ligation in me and mev splenic B cells and in CD5+ CH12 lymphoma cells, which represent the lymphoid population amplified in motheaten mice. Despite their lack of functional PTP1C, me and mev B cells proliferated normally in response to LPS. However, compared with wild-type B cells, cells from the mutant mice were hyperresponsive to normally submitogenic concentrations of F(ab')2 anti-Ig antibody, and they exhibited reduced susceptibility to the inhibitory effects of Fc gamma IIRB cross-linking on BCR-induced proliferation. Additional studies of unstimulated CH12 and wild-type splenic B cells revealed the constitutive association of PTP1C with the resting BCR complex, as evidenced by coprecipitation of PTP1C protein and phosphatase activity with BCR components and the depletion of BCR-associated tyrosine phosphatase activity by anti-PTP1C antibodies. These results suggest a role for PTP1C in regulating the tyrosine phosphorylation state of the resting BCR complex components, a hypothesis supported by the observation that PTP1C specifically induces dephosphorylation of a 35-kD BCR-associated protein likely representing Ig-alpha. In contrast, whereas membrane Ig cross-linking was associated with an increase in the tyrosine phosphorylation of PTP1C and an approximately 140-kD coprecipitated protein, PTP1C was no longer detected in the BCR complex after receptor engagement, suggesting that PTP1C dissociates from the activated receptor complex. Together these results suggest a critical role for PTP1C in modulating BCR signaling capacity, and they indicate that the PTP1C influence on B cell signaling is likely to be realized in both resting and activated cells.
TL;DR: Whether HIV-1 resistance to zidovudine predicted clinical progression during antiretroviral therapy when other prognostic factors were controlled for was determined, by evaluating baseline HIV- 1 isolates from patients who participated in the AIDS Clinical Trials Group (ACTG) protocol 116B/117.
Abstract: Objective To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. Design Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. Setting Participating ACTG virology laboratories. Patients 187 patients with baseline HIV-1 isolates. Measurements Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. Results Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. Conclusions High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.
TL;DR: Intracellular generation of hydroperoxides by mitochondria appears to be an early event in hydrophobic bile acid-induced hepatocyte toxicity and may be of benefit in cholestasis.
TL;DR: The central finding was that the degree or level of contact can be measured at the episode level by averaging the normalized values of communication time, the information richness, and the level of intimacy.
Abstract: This research provides an empirically derived measurement model for customer contact, a widely used construct in service management. The model was created by applying two psychometric scaling techniques, Multidimensional Scaling MDS and the method of paired comparisons, and Content Analysis, to the ratings and responses of service research experts. MDS showed that the construct of Customer Contact is multidimensional and complex. An interval scale was developed using the paired comparison methodology, and a measurement model was developed using this contact scale. The central finding was that the degree or level of contact can be measured at the episode level by averaging the normalized values of communication time, the information richness, and the level of intimacy. The uses of the measurement model include refining current research, and reevaluating past research, developing contingency models for service quality and design, and providing practitioners with a richer understanding of customer contact to facilitate service system design.
Journal Article•
TL;DR: The results of the continued mutational analysis to map the critical structural elements of the HCV IRES has led to the identification of a pseudoknot structure upstream of the initiator AUG, which represents a highly conserved feature of all HCV subtypes and members of the pestivirus family.
Abstract: Translation of the human hepatitis C virus (HCV) RNA genome occurs by a mechanism known as "internal ribosome entry." This unusual strategy of translation is employed by naturally uncapped picornaviral genomic RNAs and several cellular mRNAs. A common feature of these RNAs is a relatively long 5' noncoding region (NCR) that folds into a complex secondary structure harboring an internal ribosome entry site (IRES). Evidence derived from the use of dicistronic expression systems, combined with an extensive mutational analysis, demonstrated the presence of an IRES within the HCV 5'NCR. The results of our continued mutational analysis to map the critical structural elements of the HCV IRES has led to the identification of a pseudoknot structure upstream of the initiator AUG. The evidence presented in this study is based upon the mutational analysis of the putative pseudoknot structure. This is further substantiated by biochemical and enzymatic probing of the wild-type and mutant 5'NCR. Further, the thermodynamic calculations, based upon a modified RNAKNOT program, are consistent with the presence of a pseudoknot structure located upstream of the initiator AUG. Maintenance of this structural element is critical for internal initiation of translation. The pseudoknot structure in the 5'NCR represents a highly conserved feature of all HCV subtypes and members of the pestivirus family, including hog cholera virus and bovine viral diarrhea virus.
TL;DR: The cytostatic activity of GSNO may best correlate with antiproliferative or antimicrobial effects of NO, which are unassociated with overt cell injury and may provide a specific pathway for GSNO-mediated signaling in biological systems.
Abstract: Paradoxically, nitric oxide (NO) has been found to exhibit cytotoxic, antiproliferative, or cytoprotective activity under different conditions. We have utilized Salmonella mutants deficient in antioxidant defenses or peptide transport to gain insights into NO actions. Comparison of three NO donor compounds reveals distinct and independent cellular responses associated with specific redox forms of NO. The peroxynitrite (OONO-) generator 3-morpholinosydnonimine hydrochloride mediates oxygen-dependent Salmonella killing, whereas S-nitrosoglutathione (GSNO) causes oxygen-independent cytostasis, and the NO. donor diethylenetriamine-nitric oxide adduct has no antibacterial activity. GSNO has the greatest activity for stationary cells, a characteristic relevant to latent or intracellular pathogens. Moreover, the cytostatic activity of GSNO may best correlate with antiproliferative or antimicrobial effects of NO, which are unassociated with overt cell injury. dpp mutants defective in active dipeptide transport are resistant to GSNO, implicating heterolytic NO+ transfer rather than homolytic NO. release in the mechanism of cytostasis. This transport system may provide a specific pathway for GSNO-mediated signaling in biological systems. The redox state and associated carrier molecules are critical determinants of NO activity.
TL;DR: Data suggest that this glial cell line-derived factor has a potent influence on adult rat dopamine neurons and may have a potentially important role as a trophic factor for these neurons.