Expression of a D2 dopamine receptor antisense RNA in brain inhibits D2-mediated behaviors

We reported that 3'-azidothymidine-3'-deoxythymidine (AZT) plus 5-fluorouracil or methotrexate produces additive cytotoxicity in HCT-8 cells: a reflection of increased AZT metabolism when de novo thymidylate (dTMP) synthesis was inhibited. We now report that AZT plus human recombinant interferon alpha-2a (rIFN-alpha 2a) produces synergistic growth inhibition in these cells. Evaluation of the effect of rIFN-alpha 2a on dTMP metabolism revealed that exposure to rIFN-alpha 2a (+/-AZT) did not affect dTMP synthase activity significantly but increased thymidine (dThd) kinase activity significantly. Consequently, AZT nucleotide production and incorporation into DNA were increased by coexposure to rIFN-alpha 2a. This alone, however, cannot explain the observed synergism. Therefore, the effect of these agents on DNA excision/repair processes was assessed. Isotope clearance studies demonstrated that rIFN-alpha 2a did not alter the rate of [3H]AZT excision from DNA. In contrast, filter-elution studies revealed that rIFN-alpha 2a (+/-AZT) produced more DNA damage and delayed repair compared with the effects produced by AZT alone. Since DNA polymerases alpha and beta are directly involved in gap-filling repair synthesis, experiments next assessed the effect of rIFN-alpha 2a and/or 3'- azido-3'-deoxythymidine-5'-triphosphate (AZTTP) on their activities. Polymerase alpha was inhibited slightly by AZTTP but not by rIFN-alpha 2a. Polymerase beta activity, however, was inhibited dramatically by rIFN-alpha 2a + AZTTP. Finally, western analysis revealed that a 24-hr exposure to 5000 IU/mL rIFN-alpha 2a (+/-20 microM AZT) significantly reduced wild-type p53 expression compared with AZT-exposed cells. We conclude that rIFN-alpha 2a enhances AZT-induced tumor cell growth inhibition by (i) increasing AZT metabolism, and (ii) inhibiting DNA repair and p53-mediated cell cycle control processes.     

Prospective evaluation of complications of dorsal penile nerve block for neonatal circumcision

OBJECTIVE: To evaluate the complications of the dorsal penile nerve block (DPNB) when used for routine neonatal circumcisions. METHODS: All male newborns born in a community hospital between November 1, 1989 and August 31, 1990, and circumcised after DPNB were evaluated. Questionnaires were completed at the time of hospital discharge and at a health supervision visit 2 weeks later. RESULTS: Questionnaires were returned for 491 (85%) eligible patients. The only complication of DPNB found was bruising at the site of injection in 54 patients (11%). All bruising had resolved by the 2-week visit, and none was thought to have any clinical significance. CONCLUSION: DPNB is a safe method of decreasing the pain and stress of neonatal circumcision.     

Changes in carotenoid intake in the United States: the 1987 and 1992 National Health Interview Surveys

OBJECTIVES: To assess the changes in carotenoid intake between 1987 and 1992 among US adults by sociodemographic characteristics and high-risk groups for chronic disease; and to identify the dietary sources of specific carotenoid intake. DESIGN: A food frequency questionnaire (FFQ) was collected from a representative sample of respondents to the 1987 and 1992 National Health Interview Surveys throughout two calendar quarters. Black and white adults, 18 to 69 years old, participated in 1987 (n = 8,161) and 1992 (n = 8,341). METHOD: FFQ data were matched and linked to the US Department of Agriculture-National Cancer Institute carotenoid food composition database for analysis. STATISTICAL ANALYSIS: Mean differences in carotenoid intake over time were compared by sociodemographic characteristics and region of the country, after adjustment for sampling weights in a multiple linear regression model. RESULTS: Mean intake of the carotenoid lutein declined among white women (18%), among adults aged 40 to 69 years (16%), among persons with 9 to 12 years of education (11%), among nondrinkers (18%), among drinkers of 1 to 6 alcoholic drinks/ week (7%), among smokers (former smokers by 11%, current smokers by 7%, and never smokers by 9%), among income groups (< $20,000 by 7%, > or = $20,000 by 9%), and residents in the south and northeast (by 13% each, respectively). Mean intake of the carotenoid lycopene increased among white men (9%), among adults aged 18 to 39 years and aged 40 to 69 years (by 5% and 6%, respectively), among those with 13 years of education or more (12.5%), among alcohol drinkers (by 10% and 7% for 1 to 6 vs 7 or more drinks/week, respectively), among former and current smokers (by 6% each), among those with incomes > or = $20,000 (8%), and among residents in the west (16%) and midwest (5%). All differences described were statistically significant (P < .01). APPLICATION: The decline in lutein intake (from dark green leafy vegetables), particularly in white women, may have public health implications as a result of the recognized inverse association between carotenoid intake and disease risk.     

Charting progress

Logbooks can be considered aggregate databases that registered nurses (RNs) have the primary responsibility of completing in most health care settings. However, RNs may be unaware of the many uses for the information contained in logbooks and the importance of these entries (Paine et al., 1988). Labor and delivery (L&D) logs provide an essential source of vital statistics birth data for the medical records staff. These data bits are used for reporting statistics, projecting trends, and planning future care for pregnant women.     

Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.     

Differential regulation of discrete apoptotic pathways by Ras

The products of the ras genes are known to regulate cell proliferation and differentiation; recently, they have been found to play a role in apoptosis. The expression of oncogenic p21(ras) in a number of cell types, including Jurkat (a human T lymphoblastoid cell line) and murine fibroblasts, makes the cells susceptible to apoptosis following suppression of protein kinase C (PKC) activity (PKC/Ras-mediated apoptosis). Engagement of Fas antigen, a potent effector of apoptosis, activates cellular p21(ras), which may be required for completion of the cell death program. To further investigate the role of p21(ras) in the regulation of apoptosis, the cellular mechanisms employed in these two apoptotic processes in which Ras activity is involved (PKC/Ras-related and Fas-triggered apoptosis), was explored. Increasing p21(ras) activity by expressing v-ras or by treatment with an antisense oligonucleotide to the GTPase-activating protein was found to accelerate the Fas-mediated apoptotic process in Jurkat and mouse LF cells. PKC/Ras-related apoptosis was associated with, and required, cell cycle progression, accompanied by the expression of the G1/S cyclins. In contrast, Fas engagement, although inducing a vigorous and PKC-independent activation of endogenous p21(ras), did not alter cell cycle progression, nor did it require such progression for apoptosis. Both the protein synthesis inhibitor cycloheximide and cyclin E antisense oligonucleotides partially abolished PKC/Ras-mediated apoptosis but had only a moderate effect on Fas-induced apoptosis. In contrast, the CED-3/interleukin-1beta-converting enzyme (ICE) protease inhibitor Z-VADfmk efficiently suppressed Fas-induced apoptosis and only marginally inhibited PKC/Ras-mediated apoptosis. Induction of both pathways resulted in activation of the Jun NH2-terminal kinase/JUN signaling system. These results suggest that different cell death programs, such as PKC/Ras-mediated and Fas-mediated apoptosis, may be interconnected via p21(ras) and perhaps Jun NH2-terminal kinase/JUN. In response to various death stimuli, p21(ras) may act as a common intermediate regulator in the transduction of apoptotic signals.     

Clinical interpretations of transient otoacoustic emissions

The object was to study retrospectively the perioperative complications and results of the Bologna procedure for the treatment of stress urinary incontinence associated with cystocele grade 2 or more. In the study, 80 patients underwent a repair of all defects of pelvic support plus the Bologna procedure. Mean duration of follow-up was 40.2 months (range 3-127). The incidence of operative complications was 2.5% for inadvertent cystostomy and for hemorrhage. Mean hospital stay was 7.2 days (range 2-17). At 2-year follow-up 85% of the patients were completely free of incontinence symptoms (95% CI: 75-92) and 76% at 3-year follow-up (95% CI: 66-86). None of the parameters tested in a univariate analysis was independently linked with surgical failure. Further studies are needed to establish the place of this technique in the surgical management of urinary incontinence associated with genital prolapse.