Atovaquone alone or with fluconazole as oral therapy for Indian kala-azar.
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Biomedical subjects
Publications and source records attributed to M Rogers.
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OBJECTIVE: Craniotomy and brain mapping performed with the patient under local anesthesia and monitored sedation is an important technique to allow optimal resection of brain tumors or other lesions in close apposition to eloquent cortex. The subjective experience of patients undergoing this procedure has not been addressed in the literature. METHODS: This study formally, intensively, and prospectively assessed the subjective experience of 21 consecutive patients undergoing this procedure. Assessment involved structured interviews at 2 to 3 days postoperatively by a member of the surgical team and at 1 month postoperatively by a psychiatrist, supplemented by pre- and postoperative assessments of the patients' moods using the brief Profile of Mood States questionnaire. RESULTS: At the 1-month interview, all patients were entirely comfortable with the experience and there were no indications of adverse psychological sequelae of the event. In the early postoperative interview, approximately one-half of the patients reported that the experience was entirely satisfactory, without any intraoperative discomfort or pain. One-third of the patients recalled minor difficulties at some stage of the experience, and one-fifth recalled moderate difficulties. An operating room score was devised to quantify the data. Minor technical changes are suggested to improve the patients' subjective experience. CONCLUSIONS: This series confirmed that this technique is a very useful and safe technique for resection of lesions involving eloquent cortex that might otherwise be considered inoperable. This procedure involves a level of stress that remains within the tolerance level of the average adult.
A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.
The first reported human case of possible disseminated infection with the insect pathogen Metarrhizium anisopliae var. anisopliae, a fungus which has been used commercially for biocontrol of insects, is described. The patient, a 9-year-old boy, had a 5-year history of pre-B-cell acute lymphoblastic leukemia and had been on chemotherapy throughout this period. After 10 days of profound neutropenia, lesions consistent with ecthyma gangrenosum appeared on his arms and legs. M. anisopliae was grown from specimens from three separate sites, collected at different times over a period of 1 month: a skin biopsy, a swab from the base of a lesion, and the core of another skin lesion which spontaneously discharged. The initial skin biopsy also showed histological evidence of epidermal necrosis and dermal invasion with fungal hyphae. A computed-tomography (CT) scan of the chest demonstrated a lesion in the superior segment of the lower lobe of the left lung. A CT scan of the brain revealed a lesion in the left temporoparietal region of the brain, consistent with an abscess. Despite antifungal treatment including liposomal amphotericin and 5-flucytosine, the patient eventually died. The initial portal of entry is unknown, but hematogenous dissemination to the skin appears likely because of the multiple ecthymic lesions, and the appearances of the brain lesion on the CT scan are consistent with a hematogenous fungal abscess.
PURPOSE: We sought to determine the tolerance of estramustine phosphate (EMP) combined with a 3-hour paclitaxel infusion in women with solid paclitaxel-pretreated solid tumors. Paclitaxel pharmacology was to be studied at the recommended phase II dose. PATIENTS AND METHODS: Paclitaxel was administered to cohorts of at least three assessable patients at doses of 150, 180, 210, and 225 mg/m2, while EMP was given at 900 and 1,200 mg/m2/d in divided doses orally for 2 days preceding and on the day of paclitaxel. The pharmacologic study was performed at 225 mg/m2 paclitaxel given in the absence and 3 weeks later in the presence of EMP 900 mg/m2/d. RESULTS: Thirty-eight patients received a total of 178 courses. Grade 3 nausea, vomiting, and diarrhea were common at EMP 1,200 mg/m2 and paclitaxel 225 mg/ m2; this was considered the maximum-tolerated dose. Since these toxicities appeared related to EMP, the pharmacologic study used a dose of 900 mg/m2 of this agent with 225 mg/m2 paclitaxel. Antitumor activity was documented against breast and ovarian cancers at all levels. Paclitaxel pharmacokinetics without and with EMP did not differ. CONCLUSION: EMP 900 mg/m2 for 3 days and 225 mg/m2 paclitaxel by 3-hour infusion are well tolerated; antitumor activity was seen in women with paclitaxel-pretreated solid tumors. This apparent enhancement of antitumor effects is unlikely to be mediated by P-glycoprotein.
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We have observed that phospholipase A2 (PLA2) activation and arachidonate (AA) release are essential for monocyte/macrophage adherence and spreading. In this study, we addressed the relationship between AA release and cell adherence/spreading in murine resident peritoneal macrophages, and the roles of specific PLA2S in these processes. The PLA2-specific inhibitors, (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL, specific for the Ca(2+)-independent PLA2 (iPLA2)) and methyl arachidonoyl fluorophosphonate (MAFP, specific for the Ca(2+)-dependent phospholipase (cPLA2)) inhibited AA release and cell spreading in a correlated fashion but only modestly decreased cell adherence. Cell spreading was normalized by the addition of AA to PLA2-inhibited cells. AA release during spreading was also inhibited by Ca2+ depletion or protein kinase C (PKC) inhibition, and was accompanied by increased (but transient) phosphorylation of cPLA2-Inhibition of macrophage spreading, however, only partially inhibited AA release. Moreover, constitutive AA release was seen in fully spread macrophages which was inhibited by BEL, but not MAFP or Ca2+ depletion. BEL also reversed the phenotype of fully spread cells. These data suggest that macrophage spreading requires the release of AA by the iPLA2 (which appears to be constitutively active) and cPLA2 (which appears to be stimulated by adherence/spreading). Maintenance of macrophage spreading, in contrast, appears to be principally dependent on the iPLA2.
The prion protein gene (PrP) encodes a cellular protein of unknown function. A conformational isoform of this protein is involved in the neurodegenerative prion diseases. To facilitate the identification of structurally and antigenically important regions within the PrP molecule, the rabbit PrP open reading frame (ORF) was cloned and characterised. There is 82-87% identity at the nucleotide sequence level and 88-93% identity at the amino acid (aa) sequence level, between the rabbit gene and PrP sequences of other mammals. The rabbit gene shares structural and organisational features common to all known PrP genes signifying that it is the rabbit PrP gene. Comparison of the rabbit PrP aa sequence with PrP aa sequences from different species revealed several potential epitopes. Two anti-ovine PrP peptide Ab raised in rabbits, 168-92 and 98-92, confirmed that two separate cross-reacting epitopes segregate with single aa differences between rabbit and sheep PrP at positions 43 and 99 of the rabbit PrP polypeptide. The presence of these epitopes correlates with the species recognition patterns of previously published Ab. The usefulness of the rabbit PrP gene sequence in predicting antigenic regions within the PrP proteins of various species is illustrated. The structure of the rabbit PrP protein in relation to rabbits apparent resistance to infection by prions is discussed.
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OBJECTIVE: Our purpose was to review the outcome of pregnancies after external cephalic version at term, in particular the incidence and indications of intrapartum cesarean section after successful external cephalic version. STUDY DESIGN: A prospective study was performed of 241 term pregnancies that had a total of 243 external cephalic versions. Each case with successful external cephalic version was matched to two control cases with cephalic presentation to compare pregnancy outcome. RESULTS: External cephalic version was successful in 169 attempts (69.5%), of which 7 (4.1%) reverted to breech presentation. There was one case of abruptio placentae and eight cases (3.3%) of transient fetal bradycardia after the procedure. Among those who had a successful external cephalic version, the incidence of intrapartum cesarean section was 16.9%, which was 2.25 times higher than that of the control group (p < 0.005). This large number of abdominal deliveries was due to a significantly higher incidence of fetal distress and dystocic labor. The incidence of augmentation of labor was also significantly higher in the study group (37.7% vs 27.6%, p < 0.05). CONCLUSION: Pregnancies after a successful external cephalic version at term are not the same as those with cephalic presentation. They are at higher risk of both dystocic labor and fetal distress and therefore require close intrapartum monitoring.
OBJECTIVE: To demonstrate the use of generalized additive logistic regression in the development of a risk-scoring system to predict cesarean delivery. METHODS: Women who delivered in the Prince of Wales Hospital, Hong Kong, from 1994 to 1995 were the subjects of our study. Cases included were term singleton pregnancies with cephalic presentation, excluding those requiring cesarean delivery before labor. The cases were divided randomly into two sets. The prediction models were developed from set A and tested on set B, and vice versa. Maternal demographic and obstetric variables were used as potential predictors. Two models were formed, one before and one after the onset of labor. The generalized additive logistic regression was used to achieve optimal dichotomization of continuous measurements, and the predictive models were then developed. The validating results were pooled, represented, and compared as areas under receiver operating characteristic (ROC) curves. RESULTS: The first prediction model used maternal age, height, and weight at delivery as well as nulliparity, history of cesarean delivery, and the need for induction of labor. The second model had in addition the need for labor augmentation. The areas under the ROC curve for the models were 0.81 and 0.82, respectively, a statistically significant difference (z = 5.75, P < .001). CONCLUSION: The use of generalized additive logistic regression optimizes dichotomization of continuous measurements and facilitates the development of precise and reproducible prediction models. Generalized additive logistic regression appears to be a useful tool, and its use is commended.
Erythema multiforme and Stevens-Johnson syndrome are both characterized by areas of epithelial necrosis. An important clinical feature that distinguishes the two is the extensive mucosal necrosis in Stevens-Johnson syndrome but not in erythema multiforme. Because significant and serious complications may develop with Stevens-Johnson syndrome and not with erythema multiforme, it is important to differentiate between the conditions. We describe three boys with herpes simplex virus-associated erythema multiforme who had severe necrosis of the lips develop and were initially diagnosed with Stevens-Johnson syndrome. The lip lesions were large target lesions of erythema multiforme rather than the extensive necrosis seen in Stevens-Johnson syndrome and all three had a benign course.
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The pattern of scrapie prion protein (PrP(Sc)) accumulation in the brain is different for each prion strain. We tested whether the PrP(Sc) deposition pattern is influenced by the Asn-linked oligosaccharides of PrP(C) in transgenic mice. Deletion of the first oligosaccharide altered PrP(C) trafficking and prevented infection with two prion strains. Deletion of the second did not alter PrP(C) trafficking, permitted infection with one prion strain, and had a profound effect on the PrP(Sc) deposition pattern. Our data raise the possibility that glycosylation can modify the conformation of PrP(C). Glycosylation could affect the affinity of PrP(C) for a particular conformer of PrP(Sc), thereby determining the rate of nascent PrP(Sc) formation and the specific patterns of PrP(Sc) deposition.
To examine the efficacy of atovaquone as salvage therapy in patients with AIDS-related toxoplasmic encephalitis, 93 patients with AIDS and toxoplasmic encephalitis who were intolerant of standard therapy (pyrimethamine plus sulfadiazine or clindamycin) or for whom such therapy was failing were treated with atovaquone tablets (750 mg four times daily) for 18 weeks. Plasma levels of atovaquone were measured with high-pressure liquid chromatography, and the clinical and radiological responses and survival were compared according to median plasma concentration groups. During the acute-therapy phase (the first 6 weeks), the conditions of 52% and 37% of the patients, respectively, were clinically or radiologically improved; the conditions of 26% and 15% remained clinically or radiologically improved by week 18. Median survival for all patients was 189 days (Kaplan-Meier estimate). A post-hoc analysis revealed a positive relationship between clinical and radiological responses and median atovaquone plasma concentrations. Survival time among patients with high or medium median steady-state plasma concentrations (319 and 289 days) was significantly better than that among those with low plasma concentrations (114 days; P = .003 and P = .006, respectively).