Biomedical subjects
Publications and source records attributed to G Lu.
In 1987, six Yale graduate students set out to study the concurrent review methods used in key hospitals across the US. They examined the advantages and disadvantages of concurrent review and the tie-in of medical record concurrent review coding with utilization review activities. The first part of their report is published this month, with the conclusion appearing next month.
In 1987, six Yale graduate students set out to study the concurrent review methods used in key hospitals across the US. They examined the advantages and disadvantages of concurrent review and the tie-in of medical record concurrent review coding with utilization review activities. The first part of their report appeared in the May issue of JAMRA. The second part appears below.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Fetal calf serum (FCS) is used as a component of the media for cells grown in culture. However, the high cost of FCS has stimulated a search for a possible alternative. Approximately 10% of human platelet concentrates prepared for clinical transfusions are outdated. Sera prepared from platelet concentrates were compared with FCS and calf serum (CS) as a media supplement. A similar number of fibroblast (NSF-791) colonies grew in media supplemented with the three different sera. However, colonies grown in the presence of human platelet serum (HPS) were larger than those grown in media containing CS and FCS. Hence, serum prepared from outdated human platelet concentrates may be substituted for fetal calf serum as a cell culture nutrient, for fibroblasts.
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Two cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), which are released by macrophages during the early inflammatory phase of nerve injury, are known to induce activation of mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK), which locate at different signal transduction pathways and are involved in cell cycle G0/G1 transition and cellular proliferation in human fibroblasts. Activation of these two protein kinases by the cytokines may stimulate fibroblast proliferation in damaged nerves and thereby play a role in the formation of a neuroma, a disorganized mass of tissue that interferes with neural regeneration and repair. To investigate the possibility that this mechanism is operative in neuroma formation, we used cultured, serum-starved fibroblasts from surgically removed human neuromas stimulated with TNF-alpha and/or IL-1 alpha and IL-1 beta, and measured the activation of MAPK and SAPK using myelin basic protein (MBP) and human c-Jun (1-169) glutathione S-agarose transferase (GST) fusion protein as substrates. For comparison, neuroma fibroblast cultures were also stimulated with phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor-AB (PDGF-AB), a potent activator for MAPK. TNF-alpha and both forms of IL-1 produced a rapid activation of MAPK, with a peak at 15 min for TNF-alpha stimulation, and a peak at 30 min for IL-1 stimulation. TNF-alpha combined with either IL-1 alpha or IL-1 beta produced a synergistic effect on the activation of MAPK. The increases in MAPK induced by TNF-alpha and IL-1 were similar to the increases induced by PMA and PDGF-AB. To confirm the presence of MAPK, immunoprecipitation and immunoblotting were carried out on experimental and control lysates. TNF-alpha and IL-1 also increased activation of SAPK, but to a lesser extent than MAPK. PMA and PDGF-AB were also much less effective in stimulating activation of SAPK. Our findings indicate that TNF-alpha and IL-1 activate parallel signal transduction pathways in human neuroma fibroblasts, and that they are relatively stronger activators of MAPK than of SAPK. Previous studies have convincingly demonstrated that MAPK and SAPK are involved in human fibroblast proliferation. The results of our study suggest that TNF-alpha and IL-1 may play a role in frustrating functional nerve regeneration after injury by stimulating these two kinases, which, in turn, leads to fibroblast proliferation and formation of neuromas.
Insulin resistance emerges as a central component of the risk factor cluster and is a likely contributor to vascular disease independently of traditional risk factors such as hypertension and diabetes mellitus. However, the intermediary mechanisms by which atherosclerosis is accelerated among patients with the insulin resistance syndrome remain inadequately defined. Most of the attention has centered on hyperinsulinemia and defects of insulin-mediated glucose disposal. However, we observed that obese hypertensive patients have elevated plasma concentrations of non-esterified fatty acids (NEFAs), including oleic acid, which are highly resistant to suppression by insulin. Resistance to insulin's fatty acid lowering action correlate with blood pressure in obese subjects independently of defects in glucose disposal. This observation raises the possibility that NEFAs have biologically significant effects on the cardiovascular system. In fact, oleic acid impairs nitric oxide synthase activity and endothelium-dependent vasorelaxation in vitro. Moreover, raising NEFAs in normal human volunteers to levels observed in obese hypertensive patients impairs lower extremity endothelium-dependent vasodilation and augments local and systemic vascular alpha1-adrenoceptor reactivity in normal volunteers. Thus, raising NEFAs replicates in healthy subjects important functional vascular changes implicated in the hypertension and atherosclerosis observed in patients with the risk factor cluster. At a molecular level, experiments in cultured vascular smooth muscle cells demonstrate that oleic acid activates a mitogenic signaling cascade which includes protein kinase C, reactive oxygen species and extracellular signal-regulated kinases. Each of these signaling events has been implicated in the structural and functional vascular changes which accompany the risk factor cluster. Collectively, these observations raise the possibility that fatty acids contribute to functional and structural vascular changes among insulin-resistant individuals. A better understanding of the signaling mechanisms by which NEFAs exert their vascular effects may facilitate novel and more effective therapeutic approaches to managing the cardiovascular risk factor cluster.
Tolerance to hypoxia in vivo and in vitro was significantly increased by acute and repetitive exposure of mice to autoprogressive hypoxia. The average tolerance times of the successive 2nd, 3rd, 4th and 5th runs of exposure were, respectively, 2, 4, 6 and 8 times as long as that of the first exposure. The survival times under hypobaric chamber and cyanide toxification in the 4th exposure were, respectively, 10 (and even as much as 86) and 4 times those in control mice without exposure to hypoxia. Mandibular respiration and spinal reflex in vitro in hypoxia-resistant animals lasted 5-6 times as long as in control animals not previously exposed to hypoxia. Animals that received brain homogenate from hypoxia-resistant mice remained alive in a hypobaric chamber 2 times as long as those that received homogenate from controls and those that received saline. These results indicate that a kind of quickly developing adaptation with increased tolerance is achieved by acute and repetitive exposure of mice to progressive autohypoxia and some plastic or adaptive changes occur in the brain of hypoxia-resistant animals, including the production of some kind of water-soluble antihypoxic factors.
Changes in the composition and contents of phospholipids and free fatty acids were observed and compared in three groups: (A) unpreconditoned normal controls, (B) exposure to 1 run of hypoxia and (C) exposure to 4 runs of hypoxia. In group B, the content of phosphatidyl ethanolamine (PE), phosphatidyl serine (PS) and free fatty acids (FFAs) increased significantly and the content of phosphatidyl choline (PC) and sphingomyelin (SM) decreased significantly. While in group C the content of PE, PS, PC and FFAs changed significantly when compared with that of group B, all phospholipid (except SM) and FFA contents tended to decrease to the level of group A. No new FFA was seen in the brain homogenates in any of the three groups. These results suggest that the changes in the content of mouse brain phospholipids and FFAs may be adaptive and involved in the animals' tolerance to hypoxia.
We examined the effects of the extrinsic ionotropic NMDA receptor agonist (aspartate) and antagonist (ketamine) on the hypoxic preconditioning of mice and the concentration changes of intrinsic excitatory amino acids (EAAs), aspartate and glutamate, in the whole brain and different brain regions during preconditioning by an HPLC method. Our results showed that aspartate and ketamine significantly prolonged and shortened the standard tolerance time of mice during preconditioning and survival time in hypobaric chambers, respectively. After the 1st exposure, EAA concentrations in the whole brain and brain regions were increased. After run 4, they were decreased or maintained. It is suggested that the activation and suppression of ionotropic NMDA receptors is harmful and beneficial to hypoxic preconditioning, respectively. Degradation and/or inactivation of EAAs might be beneficial to the tolerance of mice to hypoxia.
Intracellular recordings from the lumbosacral dorsal horn were made to identify the axonal projection and the afferent innervation of the lateral cervical nucleus (LCN) and solitary tract nucleus (STN) on the spinal neurons of chloralose-anesthetized cats. A total of 49 neurons from laminae III-V in the spinal dorsal horn responded to stimulation of both the LCN and STN. Of these, 28 and 21 neurons responded antidromically and orthodromically to stimulation of the LCN and STN, respectively. Seven of the 28 antidromically activated neurons were followed by one or more responses synaptically driven from the LCN and/or STN. The diameter of these ascending or descending fibers was in the range of A delta fibers. The results indicate that (1) some spinal neurons, namely spinocervical tract-spinosolitary tract (SCT-SST) neurons, issue branched axons of A delta-fibers and dually project to both LCN and STN; (2) some SCT-SST neurons receive innervation from both the LCN and STN; (3) some spinal neurons and interneurons are dually innervated by descending fibers originating from both the LCN and STN, and (4) the convergence and integration between somatic and visceral sensory inputs might occur in the SCT-SST neurons.
There has been an increasing interest in using expected value of information (EVI) theory in medical decision making, to identify the need for further research to reduce uncertainty in decision and as a tool for sensitivity analysis. Expected value of sample information (EVSI) has been proposed for determination of optimum sample size and allocation rates in randomized clinical trials. This article derives simple Monte Carlo, or nested Monte Carlo, methods that extend the use of EVSI calculations to medical decision applications with multiple sources of uncertainty, with particular attention to the form in which epidemiological data and research findings are structured. In particular, information on key decision parameters such as treatment efficacy are invariably available on measures of relative efficacy such as risk differences or odds ratios, but not on model parameters themselves. In addition, estimates of model parameters and of relative effect measures in the literature may be heterogeneous, reflecting additional sources of variation besides statistical sampling error. The authors describe Monte Carlo procedures for calculating EVSI for probability, rate, or continuous variable parameters in multi parameter decision models and approximate methods for relative measures such as risk differences, odds ratios, risk ratios, and hazard ratios. Where prior evidence is based on a random effects meta-analysis, the authors describe different ESVI calculations, one relevant for decisions concerning a specific patient group and the other for decisions concerning the entire population of patient groups. They also consider EVSI methods for new studies intended to update information on both baseline treatment efficacy and the relative efficacy of 2 treatments. Although there are restrictions regarding models with prior correlation between parameters, these methods can be applied to the majority of probabilistic decision models. Illustrative worked examples of EVSI calculations are given in an appendix.
This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors' analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.