Nodular regenerative hyperplasia of the liver associated with a Factor V Leiden mutation.
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Aged↗
Biomedical subjects
P Nguyen
Publications and source records attributed to P Nguyen.
Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.
OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.
Adult↗
Monitoring the effect of heparin bolus during percutaneous coronary angioplasty (PTCA): assessment of three bedside coagulation monitors.
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Angioplasty, Balloon, Coronary↗
Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.
OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.
Adult↗
Skeletal muscle oxygenation and oxygen uptake kinetics following constant work rate exercise in chronic congestive heart failure.
The aim of the present study was to determine the kinetics of recovery of muscle oxygenation (MO) from comparable levels of exercise in patients with chronic congestive heart failure (CHF) and in normal subjects, and to relate MO kinetics to the level of exercise intolerance. Ten patients with stable CHF secondary to ischemic cardiomyopathy (ejection fraction 34 +/- 6%) (mean age 47 +/- 10 years) and 8 healthy matched control subjects underwent an upright incremental cycle ergometer exercise test with gas exchange analysis and a 6-minute constant work rate protocol at 60% of peak oxygen consumption (VO2). Oxygenation of the vastus lateralis muscle was continuously monitored during exercise and recovery using near infrared spectroscopy. Recovery VO2 and MO mean response times for the constant work rate exercise test were longer in patients with CHF than in control subjects (p <0.05). Both VO2 and MO mean response times were inversely related to peak VO2 (r = -0.73 and -0.52, respectively; p <0.05 for both). Thus recovery of muscle and total body oxygenation from submaximal exercise is more delayed the greater the cardiac dysfunction, as assessed by peak VO2. This suggests that regeneration of phosphocreatine and/or resaturation of venous oxyhemoglobin take place more slowly the worse the cardiac function.
Adult↗
Regulation of cyclin D1 by calpain protease.
Cyclin D1, a critical positive regulator of G1 progression, has been implicated in the pathogenesis of certain cancers. Regulation of cyclin D1 occurs at the transcriptional and posttranscriptional level. Here we present evidence that cyclin D1 levels are regulated at the posttranscriptional level by the Ca2+-activated protease calpain. Serum starvation of NIH 3T3 cells resulted in rapid loss of cyclin D1 protein that was completely reversible by calpain inhibitors. Actinomycin D and lovastatin induced rapid loss of cyclin D1 in prostate and breast cancer cells that was reversible by calpain inhibitors and not by phenylmethylsulfonyl fluoride, caspase inhibitors, or lactacystin, a specific inhibitor of the 26 S proteasome. Treatment of intact NIH 3T3, prostate, and breast cancer cells with a calpain inhibitor dramatically increased the half-life of cyclin D1 protein. Addition of purified calpain to PC-3-M lysates resulted in Ca2+-dependent cyclin D1 degradation. Transient expression of the calpain inhibitor calpastatin increased cyclin D1 protein in serum-starved NIH 3T3 cells. Cyclins A, E, and B1 have been reported to be regulated by proteasome-associated proteolysis. The data presented here implicate calpain in cyclin D1 posttranslational regulation.
3T3 Cells↗
Factor V Leiden: detection in whole blood by ASA PCR using an additional mismatch in antepenultimate position.
Factor V Leiden mutation was initially detected in thrombophilic patients and relatives by PCR RFLP (Restriction Fragment Length Polymorphism) according to Bertina (1). This technique presents some drawbacks and the current trend is to simplify the diagnosis. We describe a technique of Allele Specific Amplification (ASA) which is optimized in terms of reliability: an additional mismatch in antepenultimate position enables to obtain the same specificity as PCR RFLP. Furthermore, coamplification of internal control warrants an optimal sensitivity. All the PCR have been simplified: the DNA extraction improvement allows to analyse the genotype with only a few microliters of whole blood whatever the anticoagulant and the procedure of preservation (freezing, dried blood spots, storage at +4 degrees C for several days). This technique saves time. Moreover, full automation of the ASA technique may be shortened thanks to the lack of extraction and the positive/negative reading of the PCR signal.
Alleles↗
Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen?
The murine gamma-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62L(lo)) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2(b)) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vbeta4+ phenotype. Interestingly, the Vbeta4 dominance was also seen, to varying extents, in H-2(k), H-2(d), H-2(u), and H-2(q) strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vbeta4 bias of the T cells, the Vbeta4+CD8+ expansion was absent in H-2IA(b)-deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody-depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vbeta4+CD8+ T cells.
Animals↗
The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma.
BACKGROUND: Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) of pancreatic lesions is being increasingly used. Our aim was to determine the safety, accuracy, and clinical utility of EUS-guided FNA in both the diagnosis and staging of pancreatic cancer. METHODS: Forty-four patients (24 men/20 women) had EUS-guided FNA of pancreatic lesions (39 head/neck, 5 body, 3 tail) and/or associated lymph nodes. The mean age was 61 (range, 28 to 88 years). The indication for EUS-guided FNA was a pancreatic lesion seen initially on CT (39%), ERCP (43%), or EUS (18%). Follow-up data were collected on all patients for mean of 14.5 months (range 1 to 33 months). RESULTS: CT detected only 15 of 61 (25%) focal lesions seen by EUS, Adequate specimens were obtained by EUS-guided FNA in 44 of 47 (94%) pancreatic lesions and 14 of 14 (100%) associated lymph nodes (overall adequacy was 95%). Of the 46 lesions in which specimens were adequate and a final diagnosis was available (32 malignant, 14 benign), EUS-guided FNA had a sensitivity of 92%, specificity of 100%, and diagnostic accuracy of 95% for pancreatic lesions and 83%, 100%, and 88% for lymph nodes, respectively. Six percent of pancreatic cases had inadequate specimens and, if included, lowered the sensitivity to 83%, specificity to 80%, and diagnostic accuracy to 88% for pancreatic lesions. In 3 patients with enlarged celiac nodes on EUS, EUS-guided FNA was able to make a tissue diagnosis of metastasis, which changed the preoperative staging and precluded surgery. EUS in combination with EUS-guided FNA precluded surgery in 12 of 44 (27%) and may have precluded surgery in an additional 6 of 44 (14%). EUS-guided FNA avoided the need for further diagnostic tests, thus expediting therapy in a total of 25 (57%) patients and influenced clinical decisions in 30 of 44 (68%) patients. The estimated cost savings based on surgeries avoided was approximately $3300 per patient. There was only one complication (2%), a post-FNA fever. CONCLUSION: EUS-guided FNA of the pancreas appears to be a safe and effective method that increases both the diagnostic and staging capability of EUS in pancreatic cancer. The clinical impact of EUS-guided FNA includes avoiding surgery and additional imaging studies with a substantial cost savings.
Adult↗
Cellular immune correlates of clinical severity in oral lichen planus: preliminary association with mood states.
OBJECTIVES: We investigated cellular immune and psycho-immune dysfunctions in patients with erosive and non-erosive oral lichen planus (OLP) lesions. METHODS: Patients with erosive or non-erosive OLP were screened at the UCLA Dental Clinic. The profile of mood states (POMS) was administered. T lymphocyte subpopulations were monitored by dual fluorescence. T lymphocytes were stimulated with phytohemagglutinin (PHA) for assessment of markers of activation by flow cytometry and of interleukin (IL)-2 production by ELISA. Plasma cortisol and neopterin levels were assessed by radioimmunoassay. RESULTS: Circulating T cells that express the cluster of differentiation no. 4 (CD4+) but devoid of the CD45RA marker, and POMS score were significantly associated (r = 0.83, P < 0.05) in the patients we studied. We found a significantly higher (P < 0.05) per cent and absolute lymphocyte numbers of circulating CD4+CD45RA- cells in the OLP patients with erosive lesions, compared to OLP patients with non-erosive lesions. The ratio of CD4+ CD45RA+ over CD4+CD45RA- cells was significantly (P < 0.05) biased toward the CD4+CD45RA- subpopulation in OLP patients with erosive lesions (ratio = 0.19 +/- 0.09) compared to patients with non-erosive OLP lesions (ratio = 0.47 +/- 0.15). The expression of CD54, but not that of CD69, was significantly blunted (P < 0.05) in OLP patients following CD3+ cell stimulation. IL-2 production and plasma neopterin were normal in these patients. There was no correlation between plasma cortisol and T cell populations. CONCLUSIONS: We find fine differences in psycho-immune interactions between patients afflicted with non-erosive OLP lesions compared to those with erosive OLP lesions.
Adult↗
Clinical application of the Ottawa ankle rules for the use of radiography in acute ankle injuries: an independent site assessment.
OBJECTIVE: Previous studies show that the clinical criteria known as the Ottawa ankle rules (OAR), used for determining the need for radiographs of the ankle when a fracture is suspected, have a sensitivity of 100%, a specificity of 50%, and an overall reduction in radiographs of the ankle of 28%. The purpose of this study was to further assess the clinical usefulness of the OAR when implemented in an emergency department of a level 1 trauma center. SUBJECTS AND METHODS: Over a 1-year period, all patients who were between 18 and 55 years old and who presented to the emergency department with blunt ankle trauma were examined by emergency department clinicians who used the OAR to determine the need for ordering ankle radiographs. RESULTS: Of 926 patients with blunt ankle trauma, 759 met OAR criteria for ordering radiographs of the ankle. Of these patients, 152 were found to have a fracture. Another 167 of the patients were determined not to need ankle radiographs. Through either telephone contact or medical records review. 152 (91%) of these 167 patients were successfully followed up for the purpose of detecting any missed fractures. Two missed fractures were discovered, but only one required plaster immobilization. Based on these numbers, overall sensitivity using the OAR was 99% (confidence interval, 95-100%), and specificity was 22%. We found an overall 16% reduction in the number of ankle films ordered. CONCLUSION: When implemented at a level 1 trauma center, the OAR can adequately screen for ankle fractures.
Acute Disease↗
ROC curves to evaluate the performance of 'clotting' methods for factor V Leiden.
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Blood Coagulation↗
Detection of factor V Leiden using ASO (allele specific oligonucleotide)
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Alleles↗
A major role for the Fas pathway in acute graft-versus-host disease.
Recent studies have suggested a role for the Fas pathway in the wasting syndrome associated with lpr-->wild-type bone marrow transplants. To directly examine whether Fas ligand has a major role in the development of acute graft-vs-host disease (GVHD), Fas ligand-deficient (gld) mice were used as donors and C3H/HeJ x C57BL/6F1 as recipients in the parent-into-F1 model of acute GVHD. Transplantation of C3H/gld spleen cells induced significantly less host lymphoid depletion and was associated with less antihost cytotoxic activity in vitro when compared with wild-type C3H donor cells. The reduced depletion of host lymphocytes was explained by both impaired antihost T cell cytolytic activity and by reduced expansion of gld donor T cells in F1 recipients. These findings not only indicate that the Fas ligand is an important effector molecule in acute GVHD, but also provide in vivo evidence supporting a role for Fas/Fas ligand interactions in T cell expansion and maturation.
Acute Disease↗
Lethal synergism between influenza infection and staphylococcal enterotoxin B in mice.
Superantigen hyperactivation of the immune system has variable, sometimes lethal consequences for the host. Here we show that concurrent influenza infection enhanced the effects of the bacterial superantigen staphylococcal enterotoxin B (SEB) in mice. The effect was T cell-dependent, and maximal synergism was observed when SEB was administered 7 days after the virus, a timepoint during infection associated with high viral titers, a vigorous cytotoxic T cell response, and extensive lung pathology. The influenza infection enhanced the SEB-induced cytokine response in terms of higher absolute levels of cytokine, sustained secretion, and localization to the respiratory tract. In particular, TNF and IFN-gamma were implicated in the mechanism of death because their neutralization protected the mice from death, and recombinant IFN-gamma and TNFalpha mimicked the lethal effect of SEB in influenza-infected mice. This lethal synergism between concurrent influenza infection and superantigen exposure points to the danger of secondary bacterial involvement in viral pneumonia, and suggests mechanisms that may contribute to sudden and unexpected death from influenza infection. In addition, these data demonstrate that the in vivo effects of superantigen exposure can be strongly influenced by the immune activation status of the host.
Animals↗
Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD.
The role of costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), respectively. The soluble fusion protein, murine CTLA4Ig, which blocks engagement of CD28 by its natural ligand B7-1 and B7-2, was administered either early, at the time of GVHD induction, or delayed, after the establishment of Th1 or Th2 effector responses (day 7). Early administration of CTLA4Ig prevented the development of both acute and chronic GVHD by preventing the activation of donor T cells, i.e., by blocking characteristic Th1 or Th2 cytokine production and blocking memory marker up-regulation on donor T cells. Delayed CTLA4Ig administration was unable to alter acute GVHD but did reverse chronic GVHD as evidenced by normalization of serum autoantibody levels, normal host B cell numbers and MHC class II expression, reduced donor T cell expression of CD40 ligand, and reduced numbers of donor CD4+ memory T cells. The percentage of donor memory cells was not altered by delayed CTLA4Ig. We conclude that in this model, alloantigen-driven Th1 or Th2 responses are equally susceptible to costimulatory blockade at the onset of disease; however, once effector mechanisms become established, only Th2-driven responses have a requirement for further costimulation for the continued expansion of CD4+ T cells. These data suggest that humoral, lupus-like autoimmunity requires continuous T cell help for B cells, and agents that interrupt this process may be beneficial.
Abatacept↗
Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway.
c-Raf-1 (Raf-1) is a central component of signal transduction pathways stimulated by various growth factors, protein kinase C, and other protein kinases. Raf-1 activation is thought to be initiated at the plasma membrane after its recruitment by Ras. Raf-1 activation is associated primarily with proliferation and cell survival, but it has also been implicated in apoptosis. Raf-1 has also been shown to form complexes with both R-Ras and Bcl-2, raising the possibility that this component of cellular Raf-1 plays a role in apoptosis. Recently, taxol was reported to induce Bcl-2 phosphorylation and inactivation. We have previously demonstrated Raf-1 activation following taxol in MCF7 cells. We now present evidence that taxol fails to stimulate either apoptosis or phosphorylation of Bel-2 in the absence of Raf-1. Moreover, Raf-1 activation by taxol coincided with Bel-2 phosphorylation, showing similar dose and time dependence. Thus, our data support a role for a distinct subcellular component of Raf-1, which is taxol but not phorbol myristate acetate sensitive, in mediating an apoptotic pathway involving Bc1-2.
Antineoplastic Agents, Phytogenic↗
p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2.
Treatment of SKBr3 cells with benzoquinone ansamycins, such as geldanamycin (GA), depletes p185erbB2, the receptor tyrosine kinase encoded by the erbB2 gene. In the same cells, a biologically active benzoquinone photoaffinity label specifically binds a protein of about 100 kDa, and the ability of various GA derivatives to reduce the intracellular level of p185erbB2 correlates with their ability to compete with the photoaffinity label for binding to this protein. In this report, we present evidence that the approximately 100-kDa ansamycin-binding protein is GRP94. Membrane-associated p185erbB2 exists in a stable complex with GRP94. GA binding to GRP94 disrupts this complex, leading to degradation of pre-existing p185erbB2 protein, and resulting in an altered subcellular distribution of newly synthesized p185erbB2.
Benzoquinones↗