Showing papers by "University of Louisville published in 2000"
TL;DR: Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality, and suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.
Abstract: Background : Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables. Methods Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing. Results Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival. Conclusions Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.
1,028 citations
TL;DR: Relatively large-dose intraoperative remifentanil increased postoperative pain and morphine consumption is suggested to have caused acute opioid tolerance and hyperalgesia.
Abstract: BackgroundRapid development of acute opioid tolerance is well established in animals and is more likely to occur with large doses of short-acting drugs. The authors therefore tested the hypothesis that intraoperative remifentanil administration results in acute opioid tolerance that is manifested by
855 citations
TL;DR: The cardioprotective effects of late PC can be reproduced pharmacologically with clinically relevant agents (eg, NO donors, adenosine receptors agonists, endotoxin derivatives, or opioid receptor agonists), suggesting that this phenomenon might be exploited for therapeutic purposes.
Abstract: —Unlike the early phase of preconditioning (PC), which lasts 2 to 3 hours and protects against infarction but not against stunning, the late phase of PC lasts 3 to 4 days and protects against both infarction and stunning, suggesting that it may have greater clinical relevance. It is now clear that late PC is a polygenic phenomenon that requires the simultaneous activation of multiple stress-responsive genes. Chemical signals released by a sublethal ischemic stress (such as NO, reactive oxygen species, and adenosine) trigger a complex cascade of signaling events that includes the activation of protein kinase C, Src protein tyrosine kinases, and nuclear factor κB and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. An analogous sequence of events can be triggered by a variety of stimuli, such as heat stress, exercise, and cytokines. Thus, late PC appears to be a universal response of the heart to stress in general. Importantly, the cardioprotective effects of late PC can be reproduced pharmacologically with clinically relevant agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists), suggesting that this phenomenon might be exploited for therapeutic purposes. The purpose of this review is to summarize current information regarding the pathophysiology and mechanism of late PC.
780 citations
Journal Article•
TL;DR: Large-scale molecular epidemiological studies that investigate the role of NAT1 and NAT2 genotypes and/or phenotypes together with other genetic susceptibility gene polymorphisms and biomarkers of carcinogen exposure are necessary to expand the current understanding of the roles of NAT2 acetylation polymorphisms in cancer risk.
Abstract: The focus of this review is the molecular genetics, including consensus NAT1 and NAT2 nomenclature, and cancer epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Two N-acetyltransferase isozymes, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers. Associations between slow NAT2 acetylator genotypes and urinary bladder cancer and between rapid NAT2 acetylator genotypes and colorectal cancer are the most consistently reported. The individual risks associated with NAT1 and/or NAT2 acetylator genotypes are small, but they increase when considered in conjunction with other susceptibility genes and/or aromatic and heterocyclic amine carcinogen exposures. Because of the relatively high frequency of some NAT1 and NAT2 genotypes in the population, the attributable cancer risk may be high. The effect of NAT1 and NAT2 genotype on cancer risk varies with organ site, probably reflecting tissue-specific expression of NAT1 and NAT2. Ethnic differences exist in NAT1 and NAT2 genotype frequencies that may be a factor in cancer incidence. Large-scale molecular epidemiological studies that investigate the role of NAT1 and NAT2 genotypes and/or phenotypes together with other genetic susceptibility gene polymorphisms and biomarkers of carcinogen exposure are necessary to expand our current understanding of the role of NAT1 and NAT2 acetylation polymorphisms in cancer risk.
661 citations
TL;DR: In multi-institutional practice, sentinel lymph node biopsy using dual-agent injection provides optimal sensitivity for detection of nodal metastases and indicates that this procedure is a suitable alternative to routine axillary dissection across a wide spectrum of surgical practice and hospital environments.
Abstract: PURPOSE: Previous studies have demonstrated the feasibility of sentinel lymph node (SLN) biopsy for nodal staging of patients with breast cancer. However, unacceptably high false-negative rates have been reported in several studies, raising doubt about the applicability of this technique in widespread surgical practice. Controversy persists regarding the optimal technique for correctly identifying the SLN. Some investigators advocate SLN biopsy using injection of a vital blue dye, others recommend radioactive colloid, and still others recommend the use of both agents together. PATIENTS AND METHODS: A total of 806 patients were enrolled by 99 surgeons. SLN biopsy was performed by single-agent (blue dye alone or radioactive colloid alone) or dual-agent injection at the discretion of the operating surgeon. All patients underwent attempted SLN biopsy followed by completion level I/II axillary lymph node dissection to determine the false-negative rate. RESULTS: There was no significant difference (86% v 90%) i...
563 citations
TL;DR: It is reported that resveratrol binds ERb and ERa with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2), which indicates that those tissues that uniquely express ERb or that express higher levels of ERb than ERa may be more sensitive to resver atrol’s estrogen agonist activity.
Abstract: Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors a and b (ERa and ERb). Resveratrol, trans-3,5,49-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERa vs. ERb in this binding is unknown. Here we report that resveratrol binds ERb and ERa with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERb with higher affinity than ERa. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERa or ERb. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERb has higher transcriptional activity than E2-liganded ERb at a single palindromic ERE. This indicates that those tissues that uniquely express ERb or that express higher levels of ERb than ERa may be more sensitive to resveratrol’s estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERa with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERb. These data indicate that resveratrol differentially affects the transcriptional activity of ERa and ERb in an ERE sequence-dependent manner. (Endocrinology 141: 3657‐3667, 2000)
521 citations
TL;DR: In this paper, the authors consider the effect that national culture has on the propensity for small independent manufacturing enterprises to cooperate with other firms for technological innovation and use equity in their own manufacturing operations.
Abstract: We consider the effect that national culture has on the propensity for small, independent manufacturing enterprises to (1) cooperate with other firms for technological innovation and (2) use equity...
489 citations
488 citations
434 citations
American Society of Clinical Oncology1, Harvard University2, Memorial Sloan Kettering Cancer Center3, University of Pittsburgh4, University of South Florida5, University of Texas MD Anderson Cancer Center6, University of Alabama at Birmingham7, University of Washington8, University of Sydney9, University of Louisville10
TL;DR: The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria to better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities.
Abstract: The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.
418 citations
TL;DR: Results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC.
Abstract: We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E(2) and 6-keto-PGF(1alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGI(2) as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.
TL;DR: A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound.
Abstract: A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as `correct'. One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol−1 of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.
TL;DR: In this paper, auditory event-related potentials recorded at birth to speech and nonspeech syllables from six scalp electrodes discriminated between newborn infants who 8 years later would be characterized as dyslexic, poor, or normal readers.
TL;DR: In this paper, the authors developed a protocol for human hand transplantation based on positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite tissue transplantation.
Abstract: BACKGROUND On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite tissue transplantation, we developed a protocol for human hand transplantation. METHODS After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. RESULTS The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient had regained the ability to perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces. CONCLUSIONS Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs.
TL;DR: A Williams Syndrome Cognitive Profile (WSCP) is outlined that operationalizes the cognitive characteristics of the syndrome using measures of absolute and relative performance on subtests of the Differential Abilities Scales (Elliot, 1990a).
TL;DR: The treatment and outcome of liver injuries have changed dramatically in 25 years and the death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study.
Abstract: Objective To define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. Summary Background Data No study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. Methods A database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. Results A total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. Conclusions The treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome.
TL;DR: A significant shift in Bax localization from cytosol to cellular membranes in two human tumor cell lines exposed to staurosporine or etoposide is demonstrated and indicates that prevention of Bax translocation to the mitochondrial membrane represents a novel mechanism by which Bcl-2 inhibits drug-induced apoptosis.
Abstract: The pro-apoptotic protein, Bax, has been reported to translocate from cytosol to mitochondria following exposure of cells to apoptotic stresses including cytokine withdrawal and treatment with glucocorticoids and cytotoxic drugs. These observations, coupled with reports showing that Bax causes the release of mitochondrial cytochrome c, implicate Bax as a central mediator of the apoptotic process. In this report we demonstrate by subcellular fractionation a significant shift in Bax localization from cytosol to cellular membranes in two human tumor cell lines exposed to staurosporine or etoposide. Immunofluorescence studies confirmed that Bax specifically relocalized to the mitochondria. This redistribution of Bax occurred in concert with, or just prior to, proteolytic processing of procaspase-3, activation of DEVD-specific cleavage activity and degradation of poly(ADP-ribose) polymerase. However, Bax membrane translocation was independent of caspase activity as determined using the broad-range caspase inhibitor z-VAD-fmk. High level overexpression of the anti-apoptotic protein Bcl-2 prevented Bax redistribution to the mitochondria, caspase activation and apoptosis following exposure to staurosporine or etoposide. These data confirm the role of Bax in mitochondrial cytochrome c release, and indicate that prevention of Bax translocation to the mitochondrial membrane represents a novel mechanism by which Bcl-2 inhibits drug-induced apoptosis.
TL;DR: A protocol for human hand transplantation was developed after a comprehensive pretransplantation evaluation and informed-consent process, and the left hand of a 58-year-old cadaveric donor was transplanted to a 37- year-old man who had lost his dominant left hand 13 years earlier.
Abstract: Background On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite-tissue transplantation, we developed a protocol for human hand transplantation. Methods After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. Results The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus...
TL;DR: Results validate the hypothetical assumption that postoperative smoking cessation helps to reverse the impact of cigarette smoking on outcome after spinal fusion.
Abstract: Study Design. The effect of cigarette smoking and smoking cessation on spinal fusion was studied in a retrospective review of 357 patients who had undergone instrumented spinal fusion. Objective: To document the widely assumed but unreported benefit of cigarette smoking cessation on fusion rate and clinical outcome after spinal fusion surgery. Background Data. Cigarette smoking has been shown to inhibit lumbar spinal fusion and to adversely effect outcome in treatment of lumbar spinal disorders. Prior reports have compared smokers and nonsmokers, as opposed to comparing smokers and quitters. Methods. This study retrospectively identified 357 patients who underwent a posterior instrumented fusion at either L4-L5 or L4-S1 between 1992 and 1996. Analysis of the medical record and follow-up telephone surveys were conducted. Clinical outcome and fusion status was analyzed in relation to preoperative and postoperative smoking parameters. Results. In this study, the nonunion rate was 14.2% for nonsmokers and 26.5% for patients who continued to smoke after surgery (P< 0.05). Patients who quit smoking after surgery for longer than 6 months had a nonunion rate of 17.1%. The nonunion rate was not significantly affected by either the quantity that a patient smoked before surgery or the duration of preoperative smoking abatement. Return-to-work was achieved in 71% of nonsmokers, 53% of nonquitters, and 75% of patients who quit smoking for more than 6 months after surgery. Discussion. These results validate the hypothetical assumption that postoperative smoking, cessation helps to reverse the impact of cigarette smoking on outcome after spinal fusion.
TL;DR: The univariate distribution of PIBI scores was used to set threshold PIBI values for the assessment of ecological condition in Mid-Appalachian streams and Canonical correlation analysis revealed significant correlations between the 10 PIBI metrics and 4 significant environmental gradients related to general human disturbances.
Abstract: Periphyton assemblage data collected from 233 stream site-visits (49 in 1993, 56 in 1994, and 128 in 1995) throughout the Mid-Appalachian region were used to develop a periphyton index of biotic integrity (PIBI) based on 1) algal genera richness; 2) the relative abundances of diatoms, Cyanobacteria, dominant diatom genus, acidophilic diatoms, eutraphentic diatoms, and motile diatoms; 3) chlorophyll and biomass (ash-free dry mass) standing crops; and 4) alkaline phosphatase activity. Thirty-seven diatom genera and 38 non-diatom genera were collected. The relative richness and relative abundance (RA) of these genera were used to calculate the RA metrics of the PIBI. PIBI scores ranged from 48.0 to 85.1 among the 233 site-visits with an overall regional mean (±1 SE) of 66.1 ± 0.5. The 10 metrics and the PIBI were correlated with 27 chemical, 12 physical habitat, and 3 landscape variables. Overall, PIBI was inversely correlated with stream depth, stream water color, and Fe. Component metrics were sign...
TL;DR: Esrock et al. as mentioned in this paper reported on two sets of data that were collected to lay the groundwork for developing an empirically based typology of corporate World Wide Web sites and found that more than 85% of the sample had substantial content that addressed two or more publics.
TL;DR: A review of affinity membrane publications from 1989 to 1999 is presented to point out opportunities for more applied development of affinity membranes, including the design of appropriate modules to house them, as well as a selection of interesting applications that have appeared during the period.
TL;DR: On-line hemodiafiltration provides superior solute removal to high-flux hemodialysis over a wide molecular weight range, and the improved removal may not result in lower pretreatment plasma concentrations, however, possibly because of limitations in mass transfer rates within the body.
Abstract: Some of the morbidity associated with chronic hemodialysis is thought to result from retention of large molecular weight solutes that are poorly removed by diffusion in conventional hemodialysis. Hemodiafiltration combines convective and diffusive solute removal in a single therapy. The hypothesis that hemodiafiltration provides better solute removal than high-flux hemodialysis was tested in a prospective, randomized clinical trial. Patients were randomized to either on-line postdilution hemodiafiltration or high-flux hemodialysis. The groups did not differ in body size, treatment time, blood flow rate, or net fluid removal. The filtration volume in hemodiafiltration was 21 +/-1 L. Therapy prescriptions were unchanged for a 12-mo study period. Removal of both small (urea and creatinine) and large (ss(2)-microglobulin and complement factor D) solutes was significantly greater for hemodiafiltration than for high-flux hemodialysis. The increased urea and creatinine removal did not result in lower pretreatment serum concentrations in the hemodiafiltration group. Pretreatment plasma beta(2)-microglobulin concentrations decreased with time (P< 0.001); however, the decrease was similar for both therapies (P = 0.317). Pretreatment plasma complement factor D concentrations also decreased with time (P<0.001), and the decrease was significantly greater with hemodiafiltration than with high-flux hemodialysis (P = 0.010). The conclusion is that on-line hemodiafiltration provides superior solute removal to high-flux hemodialysis over a wide molecular weight range. The improved removal may not result in lower pretreatment plasma concentrations, however, possibly because of limitations in mass transfer rates within the body.
TL;DR: The data suggest that alpha-enolase plays an important role in regulation of c-myc promoter activity in the form of an alternative translation product MBP-1, which is distinct from its role as a glycolytic enzyme.
TL;DR: Results indicate IL-8 and GM-CSF act, in part, to delay neutrophil apoptosis by stimulating PI 3-kinase and ERK-dependent pathways.
Abstract: Activated neutrophils play an important role in the pathogenesis of sepsis, glomerulonephritis, acute renal failure, and other inflammatory processes. The resolution of neutrophil-induced inflammation relies, in large part, on removal of apoptotic neutrophils. Neutrophils are constitutively committed to apoptosis, but inflammatory mediators, such as GM-CSF, slow neutrophil apoptosis by incompletely understood mechanisms. We addressed the hypothesis that GM-CSF delays neutrophil apoptosis by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI 3-kinase) pathways. GM-CSF (20 ng/ml) significantly inhibited neutrophil apoptosis (GM-CSF, 32 vs 65% of cells p < 0. 0001). GM-CSF activated the PI 3-kinase/Akt pathway as determined by phosphorylation of Akt and BAD. GM-CSF-dependent Akt and BAD phosphorylation was blocked by the PI 3-kinase inhibitor LY294002. A role for the PI 3-kinase/Akt pathway in GM-CSF-stimulated delay of apoptosis was indicated by the ability of LY294002 to attenuate apoptosis delay. GM-CSF-dependent inhibition of apoptosis was significantly attenuated by PD98059, an ERK pathway inhibitor. LY294002 and PD98059 did not produce additive inhibition of apoptosis delay. To determine whether PI 3-kinase and ERK are used by other ligands that delay neutrophil apoptosis, we examined the role of these pathways in IL-8-induced apoptosis delay. LY294002 blocked IL-8-dependent Akt phosphorylation. PD98059 and LY294002 significantly attenuated IL-8 delay of apoptosis. These results indicate IL-8 and GM-CSF act, in part, to delay neutrophil apoptosis by stimulating PI 3-kinase and ERK-dependent pathways.
TL;DR: The adaptive behavior profile for Williams syndrome involves clear strength in socialization skills (especially interpersonal skills related to initiating social interaction), strength in communication, and clear weakness in daily living skills and motor skills, relative to overall level of adaptive behavior functioning.
Abstract: Williams syndrome is caused by a microdeletion of at least 16 genes on chromosome 7q11.23. The syndrome results in mild to moderate mental retardation or learning disability. The behavioral phenotype for Williams syndrome is characterized by a distinctive cognitive profile and an unusual personality profile. Relative to overall level of intellectual ability, individuals with Williams syndrome typically show a clear strength in auditory rote memory, a strength in language, and an extreme weakness in visuospatial construction. The personality of individuals with Williams syndrome involves high sociability, overfriendliness, and empathy, with an undercurrent of anxiety related to social situations. The adaptive behavior profile for Williams syndrome involves clear strength in socialization skills (especially interpersonal skills related to initiating social interaction), strength in communication, and clear weakness in daily living skills and motor skills, relative to overall level of adaptive behavior functioning. Literature relevant to each of the components of the Williams syndrome behavioral phenotype is reviewed, including operationalizations of the Williams syndrome cognitive profile and the Williams syndrome personality profile. The sensitivity and specificity of these profiles for Williams syndrome, relative to individuals with other syndromes or mental retardation or borderline normal intelligence of unknown etiology, is considered. The adaptive behavior profile is discussed in relation to the cognitive and personality profiles. The importance of operationalizations of crucial components of the behavioral phenotype for the study of genotype/phenotype correlations in Williams syndrome is stressed. MRDD Research Reviews 2000;6:148-158.
TL;DR: The results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.
Abstract: Rationale: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. Objective: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? Methods: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02–0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. Results: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. Conclusions: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.
TL;DR: The purpose of this review is to summarize the current understanding regarding the regulatory mechanisms of intestinal blood flow in fasted and fed conditions and during pathological stress.
TL;DR: The proposed approach would allow a design team to reconcile tradeoffs among the various performance characteristics representing customer satisfaction as well as the inherent fuzziness in the system.
TL;DR: It is concluded that aggressive intraoperative warming reduces blood loss during hip arthroplasty and may, be beneficial in patients undergoing hip ar Throplasty.
Abstract: We evaluated the effects of aggressive warming and maintenance of normothermia on surgical blood loss and allogeneic transfusion requirement. We randomly assigned 150 patients undergoing total hip arthroplasty with spinal anesthesia to aggressive warming (to maintain a tympanic membrane temperature