Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.     

Dissociation, hemispheric asymmetry, and dysfunction of hemispheric interaction: a transcranial magnetic stimulation approach

The authors investigated the hypothesis that dissociation may represent a functional dysconnectivity syndrome using a transcranial magnetic stimulation (TMS) approach. Transcranial magnetic stimulation investigations that included motor thresholds and the transcallosal conduction time (TCT) reflecting the interhemispheric transfer were performed in 74 right-handed students. All subjects completed the Dissociative Experience Scale. The high dissociators had a significantly lower left hemispheric excitability than right hemispheric excitability. They also had a significantly shorter TCT from the left to the right hemisphere than did the low dissociators. These results suggest that the neural basis of dissociation may involve a cortical asymmetry with a left hemispheric superiority or, alternatively, a lack of right hemispheric integration.     

Menstrual Suppression for Adolescents with Developmental Disabilities

The approach to menstrual suppression for adolescents with developmental disabilities has evolved considerably over the years due to changing philosophies and evolving treatment options. We review the medical management options available for menstrual suppression with a focus on the needs and treatment of adolescents with developmental disabilities.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Topical anesthesia for gynecologic procedures

Topical benzocaine 20% gel was evaluated for its ability to reduce pain associated with several common gynecologic procedures. In the first phase of the investigation, designed to determine the efficacy of the gel, 40 women received it before one or more of five procedures (cervical biopsy, intrauterine device insertion, endocervical curettage, paracervical block, and tenaculum placement). These women reported significantly less pain than 42 control subjects (P less than .05 to P less than .0005). In the second phase of the study, a placebo gel was compared in a blind fashion with 20% benzocaine gel in 63 study subjects and 64 control women undergoing procedures similar to those in the first part of the study. The modal pain rating by both physician and patient was "none" in the study group for all procedures except endocervical curettage, for which the rating was "mild"; ratings were "mild" or "moderate" in the control group. Compliance with respect to keeping follow-up visits was significantly greater in the study group. These data indicate that benzocaine 20% significantly reduces the pain experienced by patients after many gynecologic procedures performed vaginally.     

Detection of conditions related to human papillomavirus. Comparison of cytology, colposcopy, histology and hybridization

The diagnosis of lesions associated with human papillomavirus infection can be difficult because the results of the tests used can be contradictory. Our goal was to compare some of these tests and to evaluate their comparative strengths and weaknesses as clinically useful tools in confirming the diagnosis, especially in borderline cases. Twenty-one consecutive patients from our colposcopy clinic were screened with cytology and colposcopy. Biopsies were taken from representative areas on the cervix and vulva and divided. One-half was evaluated with Southern blot hybridization and the other half with histology and with RNA and DNA in situ hybridization. Cytology and histology were interpreted as either "positive" (showing definite evidence of human papillomavirus infection or cervical intraepithelial neoplasia [CIN]), "negative" (showing no evidence of human papillomavirus infection or CIN) or "equivocal" (atypical [class II] Papanicolaou smears or histology suggestive but not diagnostic of condyloma). In order to determine the clinical significance of equivocal results the sensitivity and specificity of these tests were calculated, with the equivocal results reclassified as either positive or negative. Colposcopy was the most sensitive technique but was not very specific. Cytology was a very sensitive screening tool when the atypical (class II) smears were considered positive but not when they were considered negative. The specificity of the histologic diagnosis was doubled with the equivocal results considered negative when compared to the specificity of the histologic diagnosis with the equivocal results considered positive, with no loss of sensitivity. Each technique has drawbacks, and therefore no one should be used to diagnose and treat these lesions to the exclusion of all others.     

Genetic screening with exfoliated cervicovaginal cells collected by a noninvasive lavage technique performed during routine gynecologic cancer screening

We have investigated and established the feasibility of the use of exfoliated cervicovaginal cells as an abundant source of genetic material. We routinely use this material for the detection by molecular hybridization of human papillomavirus infection of the cervix. We have analyzed deoxyribonucleic acid isolated from cervicovaginal cells by Southern blot hybridization to detect a common restriction fragment length polymorphism on chromosome 13. We suggest that in the near future most, if not all, major human genetic disease loci will be cloned and their mutations will be identified. With this knowledge and innovative methods, such as the polymerase chain reaction, it will be possible to distinguish normal individuals who harbor a variety of recessive genetic mutations that may place them at risk to produce offspring with serious genetic diseases. We propose that both genetic and cancer screening can be performed during the same office visit. Such testing offers the advantage of identification of women at risk for genetic disease with a noninvasive procedure before or concurrent with childbearing. Easily accessible genetic material extracted from exfoliated cervicovaginal cells can also be used for population genetic studies.     

Mechanical ventilation in preterm infants: neurosonographic and developmental studies.

Surviving preterm infants of less than 34 weeks' gestation who were selected on the basis of serial cranial ultrasonographic findings during their nursery course had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 46) or absence (n = 205) of spastic forms of cerebral palsy. Of the 205 infants without cerebral palsy, 22 scored abnormally low on standardized developmental testing during early childhood. The need for mechanical ventilation beginning on the first day of life (n = 92) was significantly related to gestational age, birth weight, Apgar scores, patent ductus arteriosus, grade III/IV intracranial hemorrhage, large periventricular cysts, and the development of cerebral palsy. In the 192 mechanically ventilated infants, vaginal bleeding during the third trimester, low Apgar scores, and maximally low PCO2 values during the first 3 days of life were significantly related to large periventricular cysts (n = 41) and cerebral palsy (n = 43), but not to developmental delay in the absence of cerebral palsy (n = 18). The severity of intracranial hemorrhage in mechanically ventilated infants was significantly associated with gestational age and maximally low measurements of PCO2 and pH, but not with Apgar scores or maximally low measurements of PO2. Logistic regression analyses controlling for possible confounding variables disclosed that PCO2 values of less than 17 mm Hg during the first 3 days of life in mechanically ventilated infants were associated with a significantly increased risk of moderate to severe periventricular echodensity, large periventricular cysts, grade III/IV intracranial hemorrhage, and cerebral palsy. Neurosonographic abnormalities were highly predictive of cerebral palsy independent of PCO2 measurements.(ABSTRACT TRUNCATED AT 250 WORDS)