Phase II trial of PCNU in children with recurrent brain tumors and Hodgkin's disease.
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Biomedical subjects
Publications and source records attributed to J Allen.
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Brainstem gliomas of children are variably malignant tumors that rarely have been reported to produce subarachnoid dissemination. Nevertheless, during a two-year period, 5 of 15 such patients treated by us developed symptoms of leptomeningeal metastases. The diagnosis of an anaplastic astrocytoma with meningeal gliomatosis was confirmed postmortem in all 5. In 3 children, meningeal symptoms preceded other signs of posterior fossa recurrence. Symptoms of meningeal gliomatosis included local or radiating back pain (5 patients), segmental weakness (3), paresthesia (2), and incontinence (2). Myelography, performed in 4 patients, was the most useful diagnostic technique, disclosing multiple intradural filling defects or a high degree of block in 3 patients. Although the cerebrospinal fluid was abnormal in all 4 examined patients, in only 1 were malignant cells detected. Prolonged survival, which appears to predispose to dissemination of adult malignant gliomas, was not an apparent factor in our patients.
Osteosarcoma patients free of CNS metastases are at risk for acquiring leukoencephalopathy after receiving multiple courses of high dose intravenous methotrexate followed by oral leucovorin rescue (MTX-LV). A prospective study of the adequacy of CNS rescue of MTX biochemical toxicity by oral leucovorin was undertaken in newly diagnosed neurologically normal osteosarcoma patients. Prior to surgical resection of the primary tumor, ten patients received 4 weekly courses of MTX-LV. During the fourth weekly MTX-LV treatment, 0 and 72 hr serum and CSF determinations of MTX, 5-methyl-tetrahydrofolate (5-MTHF) and LV were made. No CSF MTX was detectable at 0 hr in any patient, but a significant elevation in CSF MTX occurred in 9/9 patients at 72 hr (mean 47.2 +/- 31.8 ng/ml or 1.04 +/- 0.7 X 10(-7) M). There was no significant change in mean CSF 5-MTHF over 72 hr despite a rise in serum 5-MTHF. MTX exceeded 5-MTHF in 6/9 patients in CSF, whereas only 3/8 patients had higher MTX in the serum at 72 hr. No acute systemic or neurotoxicity was seen. The failure of oral leucovorin to consistently elevate CSF 5-MTHF levels at 72 hr in the context of significant levels of CSF MTX may result in intermittent CNS folate deficiency. The clinical and pathological syndrome of leukoencephalopathy may be related to this phenomenon and may evolve after repeated MTX-LV treatments.
An industrially manufactured ready-to-use PGE2 gel for cervical ripening was clinically evaluated. The study included 42 primiparous and eight multiparous women with an unfavourable cervix (Bishop score less than or equal to 5) admitted to hospital for induction of labour on medical grounds. PGE2, 0.5 mg, in 2 ml triacetin gel was instilled into the cervical canal. In nine patients (18%) the gel induced labour and subsequent delivery. In the remaining women the mean Bishop score increased from 3.0 to 7.7 during a 24-h period and labour was induced by either i.v. oxytocin or PGF2 alpha. None of the 50 patients experienced gastrointestinal side effects during pretreatment with PGE2. In 50% of the patients slight uterine contractility was noticed. All patients went into labour. The incidence of Cesarean section was 10%. Except for two patients treated because of intrauterine fetal death there was no perinatal mortality. The 5-min Apgar score was 8 or more in all newborn but 1. The main advantage of the new gel is that it is ready to use without any mixing procedure. Moreover, the stability of PGE2 is sufficient to allow routine clinical use.
In the cell-mediated approach, intact cells metabolically activate the chemical and the genetic end points are measured in cocultivated or coincubated target cells. Cell-mediated systems have been used to study fundamental problems in carcinogenesis, such as organ and species specificity of carcinogen activation, and in screening for carcinogenic chemicals. In the studies discussed here, cells from various rat, hamster, or bovine tissues are used to metabolically activate the chemical, and mutation and/or SCE induction in V79 cells and mutation of S. typhimurium are measured as genetic end points. The detection of genetic activity of a chemical depends both on the cell (organ, species, type, etc.) used for metabolic activation and on the genetic end point measured. Hydrocarbons and nitrosamines are two classes of environmentally significant chemicals that are sensitively detected with cell-mediated systems. The cell-mediated approach provides a valuable metabolic activation component for short-term in vitro systems, and further studies are needed to utilize and evaluate its full potential.
This paper examines the effects on fundamental frequency (F0) patterns of modality operators, such as sentential adverbs, modals, negatives, and quantifiers. These words form inherently contrastive classes which have varying tendencies to produce emphasis deviations in F0 contours. Three speakers read a set of 186 sentences and three paragraphs to provide data for F0 analysis. The important words in each sentence were marked intonationally with rises or sharp falls in F0, compared to gradually falling F0 in unemphasized words. These emphasis deviations were measured in terms of F0 variations from the norm; they were larger toward the beginning of sentences, in longer sentences, on syllables surrounded by unemphasized syllables, and in contrastive contexts. Other results showed that embedded clauses tended to have lower F0, and negative contractions were emphasized on their first syllables. Individual speakers differed in overall F0 levels, while using roughly similar emphasis strategies. F0 levels changed in paragraphs, with emphasis going to contextually new information.
In 100 pregnant women at term, labor was induced for medical reasons by i.v. infusion of a low dose of prostaglandin F2 alpha (PGF2 alpha). With a dose not exceeding 6 micrograms PGF2 alpha/min, all patients were induced into labor. The mean induction-delivery time was 6.6 hours and the overall proportion of instrumental deliveries was 19%, including 6% cesarean sections. Very few side effects were observed. It is concluded that i.v. infusion of prostaglandin F2 alpha in a low dose regimen might be considered as an alternative to existing methods for the induction of labor at term.
The in vitro effects of therapeutic amounts of polyanionic heparin on human polymorphonuclear leukocytes (PMN) aggregation and on the release of cationic lactoferrin from PMN-specific granules were investigated. Incubation of 1 X 10(7) human PMNs with 0.3 unit/ml of heparin followed by stimulation with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 2 X 10(-7) M significantly increased PMN aggregation, compared with controls. Cytochalasin B potentiated aggregation, which was further increased by incubation of the PMNs with heparin. Similarly, heparin also increased PMN degranulation and lactoferrin release following stimulation with FMLP with or without cytochalasin B, compared with controls. In addition, human lactoferrin complexed with heparin on a sucrose density gradient and caused a significant shift in the migration of 3H-heparin. Finally, rabbits pretreated with intravenous heparin resulting in prolongation of their activated partial thromboplastin time (APTT) to 1.5 to 2.5 times baseline had more profound reduction in PMN counts following a challenge with the secretagogue phorbol myristate acetate (PMA). These studies demonstrate that heparin can interact synergistically with chemotactic stimuli known to evoke lactoferrin release, which in turn leads to enhancement of PMN aggregation. Our data further suggest that heparin may be contraindicated in the treatment of syndromes with increased PMN aggregation such as endotoxin-induced Schwartzman-type reactions.
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The effects of the climacteric and sequential mestranol and norethisterone on the epithelium of the cervix and genital tract were determined in 12 postmenopausal women. Before treatment the squamocolumnar junction was visible in only six of the 12 women, but after treatment with sequential mestranol and norethisterone the squamocolumnar junction became visible due to a minor degree of eversion. Mucus, which was always absent before therapy, was always seen afterwards and any atrophic effects were reversed by therapy within 3 months. The effects of oestrogen and progestogen deficiency were more easily seen by scanning electron microscopy (SEM) than with conventional histology. Before treatment six of the nine women studied by SEM had a cervix covered by mature squamous epithelium, but after therapy all the women had mature squamous epithelium. The pretreatment lateral vaginal wall and urinary sediment smears showed mainly immature squamous cells; this correlated poorly with the histology and SEM of the cervix. There was a good correlation between urinary sediment and lateral vaginal wall smears both before and after treatment.
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Four guests at a ski resort in Vermont reported contracting a characteristic papular, pustular, or vesicular rash after using the resort's whirlpool. Pseudomonas aeruginosa serotype 1, bacteriophage type 86, was isolated from a pustule on one patient, water within the whirlpool, and the whirlpool diatomaceous earth filter. This appears to be the first outbreak of dermatitis associated with P. aeruginosa serotype 1. Previous reports of whirlpool-associated dermatitis outbreaks have identified serotype 9 and 11 isolates of P aeruginosa as the causative agents.
Blood sera components from Arkansas regressor line (R-line) and progressor line (Pr-line) chickens are compared for the first time for Rous sarcoma virus neutralizing activity. Sera was fractionated by Sephadex G-100 filtration into a high molecular weight fraction I (HMW-I) and a low molecular weight fraction II (LMW-II) component (HMW-I greater than 14,000 daltons, LMW-II less than 5,000 daltons). Both fractions from each line of chickens exhibit activity against Rous sarcoma virus (RSV) judged by a wing web assay. Both HMW-I (principally antibodies) and LMW-II neutralized RSV when obtained from hyperimmune R-chickens and Pr-chickens with large progressing tumors. However, HMW-I and LMW-II obtained from R- or Pr-chickens before challenge contain so RSV neutralizing activity. The novel low molecular weight fraction II disappeared from the sera of R-line chickens 2 weeks after tumor regression, whereas the HMW-I persisted after tumor regression.
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The reaction of FMLP with granulocytes causes aggregation and degranulation and enhances adherence to endothelium. To evaluate whether prevention of granule extrusion could impair these granulocyte activities, granulocytes were treated with either dexamethasone or hydrocortisone prior to treatment with FMLP. Dexamethasone was added to suspensions of cytochalasin B-treated granulocytes; it markedly impaired the aggregation response of the granulocytes of FMLP. When cytochalasin-B was not used, granulocyte aggregation in response to FMLP or PMA was inhibited by dexamethasone. Although dexamethasone prevented aggregation of cells following stimulation with FMLP or PMA, it failed to prevent the aggregation of granulocytes induced by rabbit lactoferrin. Adherence of granulocytes to human endothelial monolayers was enhanced by FMLP; dexamethasone inhibited the enhancement. However, with the addition of human lactoferrin to the granulocytes exposed to dexamethasone, the cells were able to adhere as well to endothelium as the cells exposed to FMLP but free of dexamethasone. When cytochalasin-B-treated granulocytes were incubated with dexamethasone or hydrocortisone prior to the addition of FMLP, the subsequent release of lactoferrin was substantially blocked, whereas the release of the primary granule products, lysozyme and beta-glucuronidase, was attenuated but not completely blocked. Thus, corticosteroids might block chemotactic-factor-induced granulocyte aggregation by selectively preventing release of specific granule products that contribute to and sustain aggregation.