Low systemic vascular resistance after cardiopulmonary bypass: are we any closer to understanding the enigma?
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Cardiopulmonary Bypass↗
Biomedical subjects
M R Johnson
Publications and source records attributed to M R Johnson.
Postpartum bone mineral density following antenatal dexamethasone therapy.
The aim of this study was to determine whether the changes in bone metabolism, which we have demonstrated previously with antenatal dexamethasone therapy, are associated with a lower bone mineral density. We assessed bone mineral density in the proximal femur and lumbar spine using dual photon X-ray absorptiometry after delivery in 15 women who received dexamethasone therapy for fetal lung maturation, and in 30 women who did not have dexamethasone therapy in pregnancy. The absolute bone mineral density, T scores and Z scores at the proximal femur and lumbar spine were similar, and the median values of T and Z scores were positive in both groups. We conclude that antenatal dexamethasone therapy has no long term effect on bone mineral density.
Absorptiometry, Photon↗
Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil.
In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism. Cancer patients with decreased DPD activity are at increased risk for severe toxicity including diarrhea, stomatitis, mucositis, myelosuppression, neurotoxicity, and, in some cases, death. We now report the first known cancer patient who developed life-threatening complications after treatment with topical 5-FU and was shown subsequently to have profound DPD deficiency. RT-PCR and genomic PCR methodologies were used to identify a G to A mutation in the GT 5' splicing recognition sequence of intron 14, resulting in a 165-bp deletion (corresponding to exon 14) in this patient's DPD mRNA. Immunoprecipitation and Western blot analysis were then used to demonstrate that the aberrant DPD mRNA is translated into a nonfunctional DPD protein that is ubiquitinated. We conclude that the presence of this metabolic defect combined with topical 5-FU (a drug demonstrating a narrow therapeutic index) results in the unusual presentation of life-threatening toxicity after treatment with a topical drug. These data further suggest that degradation by the ubiquitin-proteosome-mediated system plays a role in the elimination of the DPD protein.
Aged↗
Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance.
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Antimetabolites, Antineoplastic↗
Sleep Deprivation in social phobia and generalized anxiety disorder.
BACKGROUND: Sleep deprivation has been shown to improve depressive symptoms in some patients with major depressive disorder, but it has not been tested in patients with generalized anxiety disorder (GAD) or social phobia (SP). METHODS: To determine if sleep deprivation altered anxiety or depressive symptoms in patients with GAD (n = 7) or SP (n = 8), we sleep deprived patients and normal controls (n = 18) for one night. RESULTS: On one measure of anxiety, GAD patients improved compared with controls, but there were otherwise no significant change differences between controls and SP or GAD patients. CONCLUSIONS: The lack of benefit is consistent with previous findings that sleep deprivation provides no benefit to patients with other anxiety disorders. Sleep deprivation may be a biological intervention that distinguishes anxiety from affective disorders.
Adolescent↗
The relationship of fetal serum markers of bone metabolism to gestational age.
The aim of this study is to determine the pattern of fetal bone metabolism by measuring umbilical cord levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP). PICP and ICTP directly monitors the rate of bone formation and resorption, respectively. Samples were obtained at the time of delivery from 20 healthy women with pregnancies at different gestations. There is a significant inverse correlation between fetal levels of PICP and ICTP, and gestation (PICP r=-0.504, p=0.023; ICTP r=-0.713, p < 0.001), and between ICTP and birth weight (r=-0.466, p=0.038), but the birth weight effect is a function of gestational age. Therefore, both bone formation and resorption decrease with gestational age. Although contrary to the suggestion that fetal ossification increases at the end of pregnancy, such changes may be due to the shift from growth to maintenance.
Adult↗
Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia.
BACKGROUND: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). METHODS: The density (Bmax) and dissociation constant (Kd) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). RESULTS: The GSP group was found to have a significantly lower PBR Bmax than the NC group (GSP = 2764 +/- 1242 vs. NC = 4327 +/- 1850 fmol/mg protein, df = 1,100, F = 22.7, p = .00001). CONCLUSIONS: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.
Adult↗
Comorbidity of major depression and panic disorder.
Panic disorder and major depression frequently coexist in the clinical setting. Patients with overlapping symptoms of depression and panic disorder may have more severe symptoms, may require earlier treatment, earlier and more frequent hospitalization, and may have worse outcomes. In addition, such patients are at greater risk for suicide than those having either disorder alone. In light of the importance of these clinical consequences, the authors will review the available literature on the prevalence and prognosis of comorbid depression and panic disorder and will highlight the major clinical characteristics of panic disorder in depressed patients and the treatment strategies most often used.
Comorbidity↗
Maternal and fetal plasma levels of markers of bone metabolism in gestational diabetic pregnancies.
The aim of this study is to determine whether gestational diabetes has any effect on maternal and fetal bone metabolism. We collected maternal and umbilical cord blood samples from 19 women with gestational diabetes and 19 controls at the time of delivery. The plasma levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were used to monitor the rate of bone formation and degradation respectively. There is a significant correlation between the 1 hour postprandial blood glucose and the maternal levels of ICTP (r = 0.560, P = 0.004), but there was no significant difference in maternal or fetal levels of PICP and ICTP between the study and control groups (P = 0.411 maternal PICP, P = 0.241 maternal ICTP, P = 0.365 fetal PICP and P = 0.781 fetal ICTP). In the gestational diabetes group, there was a significant correlation between maternal and fetal ICTP (r = 0.694, P = 0.001), but there was no correlation between maternal and fetal levels of PICP (r = 0.334, P = 0.175). Although the maternal levels of ICTP is related to the 1 hour postprandial blood glucose level, gestational diabetes does not affect the maternal or umbilical cord levels of the serum markers of bone metabolism.
Biomarkers↗
Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry.
T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.
Adult↗
FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells.
Normal breast tissue as well as most breast tumors are dependent on estrogen for growth. Breast tumors often progress to a hormone-independent state which is associated with poor prognosis. It has been proposed that activation of growth factor signaling pathways in the tumor cells may free them from hormonal control. Certain growth factors can mimic estrogen responses by activating the estrogen receptor via its phosphorylation by mitogen-activated protein (MAP) kinase. In this report, however, we show that fibroblast growth factor (FGF), despite activating MAP kinase, is growth-inhibitory for estrogen-dependent MCF-7 breast cancer cells. MCF-7 cells treated with FGFs exhibit slower growth than controls in both the presence and absence of estrogen, with a concomitant increase in the number of cells in G0/G1. Expression of a constitutively activated FGF receptor in these cells further decreases their growth rate, which is no longer influenced by FGF treatment. Activation of the FGF signaling pathway also reduces the induction of an estrogen-responsive CAT reporter plasmid by estrogen, an effect which appears to be independent of serine 118 in the estrogen receptor, a MAP kinase target site. The inhibitory effects of FGF are probably mediated through the sustained induction of the cyclin kinase inhibitor p21/WAF1/CIP1, which is upregulated at the mRNA and protein level by FGF. FGF treatment also results in the phosphorylation of STAT1. This upregulation of p21 and phosphorylation of STAT1 is not detectable in T47D breast cancer cells upon which FGF has no inhibitory effect.
Breast Neoplasms↗
What is the value of hospitalisation in antepartum haemorrhage of uncertain origin?
This retrospective analysis was designed to determine the need for hospitalisation in cases of antepartum haemorrhage of uncertain origin (AUO). All the cases of AUO that presented at the Chelsea and Westminster Hospital from February 1993 to December 1995 were analysed. AUO accounted for 72% of cases of antepartum, haemorrhage Hospitalisation of the cases of AUO conferred no benefit in terms of gestation at delivery, birth weight centile, 5 minutes Apgar score and recurrent haemorrhage. Also, the duration of stay in hospital was not significantly related to the gestation at delivery ( r = 0.084, P > 0.05), the birth weight centile ( r = 0.032, P > 0.05) or the Apgar score at 5 minutes ( r = 0.062, P > 0.05). We conclude that it is not necessary to hospitalise women with AUO in the absence of heavy or repeated bleeding, evidence of fetal or maternal compromise on any suggestion of the onset of labour.
Journal Article↗
Antenatal dexamethasone therapy does not affect circulating concentrations of insulin-like growth factor binding protein-1.
In animals, dexamethasone administration during pregnancy leads to fetal growth restriction due to enhanced expression of insulin-like growth factor binding protein-1 (IGFBP-1). In humans, there is also a significant inverse correlation between maternal and fetal concentrations of IGFBP-1 and birth weight. During pregnancy, maternal IGFBP-1 is derived from the decidualized endometrium. We have studied the effect of dexamethasone on circulating concentrations of IGFBP-1 in 12 pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before dexamethasone administration, at 24 h and 48 h after the course of dexamethasone, and within 24 h of delivery, for the measurement of IGFBP-1. There was no significant change in plasma IGFBP-1 concentrations at 24 and 48 h following dexamethasone therapy, and at delivery (P = 0.666, 0.307 and 0.398, respectively). Therefore, antenatal dexamethasone therapy does not influence decidual synthesis of IGFBP-1.
Adult↗
Treatment of generalized anxiety disorder with venlafaxine: a series of 11 cases.
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Adult↗
Nomenclature for human DPYD alleles.
To standardize DPYD allele nomenclature and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that each distinct allele be designed by DPYD followed by an asterisk and an Arabic numeral. The number specifies the key mutation and, where appropriate, a letter following the number indicates an additional mutation on the mutant allele. Criteria for classification as a distinct allele are also presented.
Alleles↗
Antenatal corticosteroid therapy and risk of osteoporosis.
OBJECTIVE: To assess the risk of maternal osteoporosis associated with antenatal corticosteroid administration for neonatal respiratory distress syndrome prophylaxis. DESIGN: Prospective longitudinal study. SETTING: Maternity unit of Chelsea and Westminster Hospital, London. POPULATION: Fourteen pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of delivery before 34 completed weeks of gestation. METHODS: Blood samples were collected before dexamethasone administration, 24 hours and 48 hours after the course of dexamethasone, and within 24 hours of delivery. Serum levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) were measured to monitor the rate of bone formation, and serum levels of cross-linked carboxy terminal telopeptide (ICTP) were measured as a marker of bone resorption. MAIN OUTCOME MEASURES: Changes in the markers of bone turnover following dexamethasone administration. RESULTS: Serum PICP levels dropped 24 hours after dexamethasone therapy (P = 0.001), but partially recovered by 48 hours (P = 0.014) to reach higher than pre-therapy levels at delivery (P = 0.044). Although there were no corresponding changes in the serum levels of ICTP after 24 and 48 hours of therapy, levels increased from pretherapy to delivery (P = 0.006). CONCLUSION: Antenatal corticosteroid therapy leads to a transient suppression of, followed by an increase in, bone formation without any significant alteration in the pattern of bone resorption expected during pregnancy.
Biomarkers↗
A survey of hantavirus antibody in small-mammal populations in selected United States National Parks.
Hantavirus activity in 39 National Parks in the eastern and central United States was surveyed by testing 1,815 small mammals of 38 species for antibody reactive to Sin Nombre virus. Antibody-positive rodents were found throughout the area sampled, and in most biotic communities. Antibody was detected in 7% of 647 deer mice (Peromyscus maniculatus), 2% of 590 white-footed mice (P. leucopus), 17% of 12 rice rats (Oryzomys palustris), 3% of 31 cotton rats (Sigmodon hispidus), and 33% of 18 western harvest mice (Reithrodontomys megalotis). Antibody was also found in three of six species of voles, and in one of 33 chipmunks (Tamias minimus). Prevalence among Peromyscus was highest in the northeast. Although few cases of hantavirus pulmonary syndrome have been identified from the eastern and central regions, widespread infection in reservoir populations indicates that potential exists for human infection throughout much of the United States.
Animals↗
Discordant epicardial and microvascular endothelial responses in heart transplant recipients early after transplantation.
BACKGROUND: Cardiac allograft vasculopathy represents the leading cause of death in heart transplant recipients who survive more than 1 year. Functional endothelial abnormalities are sensitive measures of the early development of cardiac allograft vasculopathy, but the relative importance of large and small coronary vessel abnormalities has not been evaluated. The purpose of the study was to distinguish between large and small coronary endothelial dysfunction in patients early after heart transplantation and to test the hypothesis that microvascular endothelial responses can be preserved in the presence of epicardial endothelial dysfunction. METHODS: Changes in epicardial lumen area and coronary artery blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously by use of an intravascular ultrasound catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed distinction between large and small coronary vascular responses. In 19 patients studied early after transplantation, adenosine (16 and 32 microg), acetylcholine (5.4 and 54 microg), and nitroglycerin (200 microg) were infused, with continuous intravascular ultrasound imaging and Doppler velocity measurements. RESULTS: Acetylcholine induced paradoxical epicardial vasoconstriction in 12 of 19 patients (73% +/- 6% of baseline); vasodilation occurred in 7 (108% +/- 3%). In spite of this constriction, coronary artery flow increased in all 19 patients, to the same extent in patients with constriction and those with dilation (239 +/- 26 vs 193 +/- 20, p = 0.38). Adenosine and nitroglycerin increased area (107% +/- 1% and 112% +/- 3%) and flow (258% +/- 17% and 197% +/- 11%) in all patients. None of the area or flow responses correlated with the degree of intimal thickening. CONCLUSIONS: Acetylcholine increased coronary artery flow early after transplantation, indicating preserved microvascular responses in spite of epicardial vasoconstriction. Simultaneous measurement of area and velocity responses, by permitting evaluation of the relative contribution of epicardial and microvascular vessels, may offer unique insights into coronary endothelial function.
Acetylcholine↗