A 26-year-old woman with a rash on her extremities.
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Exanthema↗
Biomedical subjects
Margaret Lee
Publications and source records attributed to Margaret Lee.
Synergistic attenuation of vesicular stomatitis virus by combination of specific G gene truncations and N gene translocations.
A variety of rational approaches to attenuate growth and virulence of vesicular stomatitis virus (VSV) have been described previously. These include gene shuffling, truncation of the cytoplasmic tail of the G protein, and generation of noncytopathic M gene mutants. When separately introduced into recombinant VSV (rVSV), these mutations gave rise to viruses distinguished from their "wild-type" progenitor by diminished reproductive capacity in cell culture and/or reduced cytopathology and decreased pathogenicity in vivo. However, histopathology data from an exploratory nonhuman primate neurovirulence study indicated that some of these attenuated viruses could still cause significant levels of neurological injury. In this study, additional attenuated rVSV variants were generated by combination of the above-named three distinct classes of mutation. The resulting combination mutants were characterized by plaque size and growth kinetics in cell culture, and virulence was assessed by determination of the intracranial (IC) 50% lethal dose (LD(50)) in mice. Compared to virus having only one type of attenuating mutation, all of the mutation combinations examined gave rise to virus with smaller plaque phenotypes, delayed growth kinetics, and 10- to 500-fold-lower peak titers in cell culture. A similar pattern of attenuation was also observed following IC inoculation of mice, where differences in LD(50) of many orders of magnitude between viruses containing one and two types of attenuating mutation were sometimes seen. The results show synergistic rather than cumulative increases in attenuation and demonstrate a new approach to the attenuation of VSV and possibly other viruses.
Animals↗
Neurovirulence properties of recombinant vesicular stomatitis virus vectors in non-human primates.
Although vesicular stomatitis virus (VSV) neurovirulence and pathogenicity in rodents have been well studied, little is known about VSV pathogenicity in non-human primates. To address this question, we measured VSV viremia, shedding, and neurovirulence in macaques. Following intranasal inoculation, macaques shed minimal recombinant VSV (rVSV) in nasal washes for 1 day post-inoculation; viremia was not detected. Following intranasal inoculation of macaques, wild type (wt) VSV, rVSV, and two rVSV-HIV vectors showed no evidence of spread to CNS tissues. However, macaques inoculated intrathalamically with wt VSV developed severe neurological disease. One of four macaques receiving rVSV developed clinical and histological signs similar to the wt group, while the remaining three macaques in this group and all of the macaques in the rVSV-HIV vector groups showed no clinical signs of disease and reduced severity of histopathology compared to the wt group. The implications of these findings for rVSV vaccine development are discussed.
AIDS Vaccines↗
Dynamic pulmonary perfusion and flow quantification with MR imaging, 3.0T vs. 1.5T: initial results.
PURPOSE: To prospectively evaluate the technical feasibility and relative performance of pulmonary time-resolved MR angiography (MRA) and pulmonary artery (PA) flow quantification at 3.0T vs. 1.5T. MATERIALS AND METHODS: Time-resolved contrast-enhanced (CE) MRA of the pulmonary circulation, and flow quantification of the main PA (MPA) were performed in 14 consecutive adult healthy volunteers at both 1.5 and 3.0 Tesla with nearly identical sequence parameters. Image quality, signal-to-noise ratio (SNR), and quantitative indices of pulmonary perfusion, flow, and velocity were evaluated and compared at both field strengths. RESULTS: Time-resolved pulmonary MRA, perfusion, and flow quantification were successfully performed at both magnetic fields. The results of pulmonary perfusion and flow indices were comparable at both magnetic fields, with no statistically significant difference. The SNR values for vascular structures were higher at 3.0T vs. 1.5T (P = 0.001). The SNR values and the definition scores for parenchymal enhancement were significantly lower (P = 0.008 and 0.001, respectively) at 3.0T. CONCLUSION: Time-resolved pulmonary MRA, perfusion, and flow quantification at 3.0T was feasible, with comparable results to 1.5T. The lower parenchymal enhancement at 3.0T is believed to reflect increased susceptibility effects at higher magnetic fields. Further work is needed to fully exploit the potential of pulmonary perfusion imaging at 3.0T and to address the current limitations.
Adult↗
Inhibition of macrophage apoptosis by Neisseria meningitidis requires nitric oxide detoxification mechanisms.
Host-driven macrophage apoptosis contributes to innate immunity during bacterial infection. Neisseria meningitidis inhibits apoptosis in a variety of cells, but its impact on macrophage apoptosis is unknown. We demonstrate that N. meningitidis prevents macrophage apoptosis via genes encoding nitric oxide detoxification and a porin, PorB.
Apoptosis↗
Recombinant vesicular stomatitis virus vectors expressing herpes simplex virus type 2 gD elicit robust CD4+ Th1 immune responses and are protective in mouse and guinea pig models of vaginal challenge.
Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4+ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.
Animals↗
High-spatial-resolution contrast-enhanced MR angiography of abdominal arteries with parallel acquisition at 3.0 T: initial experience in 32 patients.
OBJECTIVE: The objective of our study was to evaluate an isotropic high-spatial-resolution 3D contrast-enhanced MR angiography (CE-MRA) protocol with high acceleration parallel acquisition at 3.0 T for the display of the abdominal vasculature. SUBJECTS AND METHODS: Thirty-two consecutive patients (13 men, 19 women; age range, 28-88 years) with suspected abdominal arterial disease underwent abdominal 3D CE-MRA on a 3.0-T MR system, using a high-spatial-resolution (0.7 x 0.82 x 0.8 mm3) 3D gradient-refocused echo (GRE) sequence, integrated with a generalized autocalibrating partially parallel acquisitions (GRAPPA) technique with an acceleration factor of 3. Two vascular radiologists evaluated image quality and the presence and degree of arterial stenoses. Interobserver variability was calculated, using the kappa coefficient. The sensitivity and specificity of the technique were calculated and comparative analysis was performed with those of conventional catheter angiography (in eight patients) as the standard of reference. RESULTS: The abdominal arterial vasculature was visualized with diagnostic image quality in all subjects. Arterial stenoses were detected in 148 and 142 arterial segments by observer 1 and observer 2, respectively, with good interobserver agreement (kappa = 0.75; 95% confidence interval [CI]: 0.69-0.81). The sensitivity and specificity values for CE-MRA for the detection of significant (> 50%) arterial stenoses were 100% and 96% for observer 1 and 100% and 92% for observer 2, respectively. There was a significant correlation between CE-MRA and conventional angiography (R = 0.96 and 0.93 for observers 1 and 2, respectively) for the assessment of the degree of stenosis. CONCLUSION: The outlined MR angiography protocol at 3.0 T combined with parallel acquisition technique renders highly reliable and isotropic high-spatial-resolution imaging of the abdominal vasculature.
Abdomen↗
Cyclooxygenase inhibitor modulation of dopamine-related behaviours.
The sequential action of phospholipase A(2) and cyclooxygenase leads to the production of prostaglandins in the brain, an event hypothesised to cause dopaminergic stimulation. To investigate this further, we examined the effect of the nonselective cyclooxygenase inhibitors indomethacin and piroxicam on several indices of dopaminergic function in adult male rats. Both drugs inhibited catalepsy induced by the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), the dopamine D2-like receptor antagonist raclopride and by haloperidol, findings in agreement with a dopaminergic effect of cyclooxygenase inhibitors. However, neither cyclooxygenase inhibitor had an effect upon disruption of prepulse inhibition of the auditory startle reflex by amphetamine or on the rate of amphetamine self-administration. Both drugs reduced amphetamine-stimulated locomotor activity. Our data indicate that the mechanism by which cyclooxygenase inhibitors alter motor behaviour is unlikely to be due to a simple direct action at the dopaminergic synapse. Their apparent ability to antagonise hypoactivity without generalised dopaminergic stimulation suggests that other, possibly multiple, neurotransmitter systems may be involved.
Amphetamine↗
Predicting the decrease of conjugated bilirubin with extracorporeal albumin dialysis MARS using the predialysis molar ratio of conjugated bilirubin to albumin.
Extracorporeal albumin dialysis with the molecular adsorbent recirculating system (MARS) machine is a new supportive intervention for patients with liver failure. It removes bilirubin and other albumin-bound toxins from the patient and has been shown by preliminary studies of liver failure patients to be beneficial. Our study examines the ability of predialysis molar ratio of bilirubin to albumin to predict the decrease of bilirubin by MARS. We had 5 patients and results from 29 treatments. The results showed a significant correlation between the predialysis molar ratio of bilirubin (total and conjugated) to albumin to the reduction in bilirubin (total and conjugated): R(2) = 0.27 and 0.62 respectively, P <.005 for both. There was no significant correlation with the predialysis molar ratio of unconjugated bilirubin to albumin to the reduction in unconjugated bilirubin. The ratio of change in total bilirubin (micromol/L) to the predialysis molar ratio of total bilirubin to albumin and the ratio of change in conjugated bilirubin (micromol/L) to the predialysis molar ratio of conjugated bilirubin to albumin were 6.2 (+/- 4.2) and 10.8 (+/- 4.3), respectively (mean (+/- SD)). The results enable us to predict the likely reduction in bilirubin (especially conjugated) after each MARS treatment and also suggest to us that albumin infusion before MARS treatment may reduce the efficacy of bilirubin removal. Whether this ratio applies to other albumin-bound toxins remains open for investigation.
Bilirubin↗
Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period.
Anew case of cobalamin C disease associated with hemolytic-uremic syndrome (HUS) in the neonatal period is described. A 28-day-old boy presented with failure to thrive, hypotonia, pancytopenia, and features of HUS (microangiopathic hemolytic anemia, thrombocytopenia, and renal failure). The possibility of the diagnosis of an underlying vitamin B12 disorder was prompted by evidence of megaloblastic changes on the peripheral smear and by finding in the literature a suggested association of neonatal HUS with this cobalamin-related metabolic disorder. Amino acid analysis showed elevated homocysteine levels in the plasma and increased levels of both homocysteine and methyl malonic acid in the urine. Diagnosis of cobalamin C disease was confirmed by complementation studies using skin fibroblasts. Therapy included parenteral hydroxocobalamin, carnitine, and leucovorin calcium (folinic acid). Cobalamin C disease should be considered in the diagnosis of patients presenting with HUS in infancy who have unexplained megaloblastosis, pancytopenia, neurologic impairment, and failure to thrive. Early diagnosis and institution of therapy may be effective in improving survival and quality of life.
Diagnosis, Differential↗
Kasabach-merritt phenomenon: a retrospective study of treatment with vincristine.
PURPOSE: Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, a consumptive coagulopathy, and an enlarging vascular lesion. The syndrome develops in infancy and is associated with a high morbidity and mortality rate. The purpose of this study was to assess the effectiveness of vincristine in the treatment of KMP. METHODS: We retrospectively reviewed the clinical and laboratory data of 15 patients with KMP treated with vincristine at 9 institutions across the United States, South America, and Europe. RESULTS: All 15 patients had profound thrombocytopenia and consumption of fibrinogen at presentation. Ten patients had biopsies of their lesions, and results included five (33.3%) kaposiform hemangioendotheliomas, three (20%) tufted angiomas, one lesion (6.7%) with features of both kaposiform hemangioendothelioma and tufted angioma, and one (6.7%) unclassified vascular tumor. All 15 patients had an increase in platelet count of at least 20,000 with an average response time of 4.0 weeks after initiation of vincristine therapy. Thirteen patients had an increase in fibrinogen level of 50 mg/dL with an average response time of 3.4 weeks. In 13 patients there was a significant decrease in the size of the vascular lesion. The average duration of treatment was 21.5 (+/-12.6) weeks. Four patients (26%) relapsed. All four were successfully treated with a second course of vincristine. Complications included one patient with abdominal pain, one patient with transient loss of deep tendon reflexes, and one patient with irritability. CONCLUSION: Vincristine presents a safe and sometimes effective treatment option in the management of KMP.
Antineoplastic Agents, Phytogenic↗