Understanding American health-care and health-care reform.
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Career Choice↗
Biomedical subjects
D Johnson
Publications and source records attributed to D Johnson.
Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial.
PURPOSE: This prospective, randomized trial was designed to determine if three cycles of cisplatin plus etoposide (PVP16) can produce therapeutic results comparable to three cycles of cisplatin, etoposide, and bleomycin (PVP16B) in patients with disseminated germ cell tumors. PATIENTS AND METHODS: One hundred seventy-eight patients with minimal- or moderate-stage disease (Indiana staging system) were randomized to receive cisplatin (20 mg/m2 on days 1 to 5) plus etoposide (100 mg/m2 on days 1 to 5) with or without weekly bleomycin (30 IU/wk for 9 consecutive weeks). Following three cycles of chemotherapy over 9 weeks, patients with residual radiographic disease underwent surgical resection. If persistent carcinoma was noted, two additional 3-week courses of chemotherapy were administered. RESULTS: One hundred seventy-one patients were fully assessable for response and survival. The two treatment groups were similar with respect to patient characteristics. The toxicities were comparable between the two arms. No clinically significant incidence of pulmonary toxicity occurred with PVP16B. Overall, 81 of 86 patients (94%) who received PVP16B and 75 of 85 patients (88%) who received PVP16 achieved a disease-free status with chemotherapy and/or surgery. However, greater numbers of treatment failures, including persistent carcinoma in postchemotherapy resected residual disease and relapses from complete remission, occurred on the arm without bleomycin (overall adverse outcome, P = .004). The failure-free (86% v 69%; P = .01) and overall survival (95% v 86%; P = .01) rates were inferior on the PVP16 arm. CONCLUSION: Bleomycin is an essential component of PVP16B therapy in patients who receive three cycles of treatment for minimal- or moderate-stage disseminated germ cell tumors.
Adolescent↗
Depletion of neutrophils by filter during aortocoronary bypass surgery transiently improves postoperative cardiorespiratory status.
STUDY OBJECTIVE: To determine whether inclusion of a leukocyte specific filter into the extracorporeal circuit during aortocoronary bypass surgery alters postoperative cardiopulmonary function. DESIGN: Randomized, double-blinded control trial. SETTING: Tertiary care hospital. PATIENTS: Convenience sampling of patients undergoing elective aortocoronary bypass between October 1992 and June 1993. INTERVENTIONS: A total of 32 patients were randomized to a leukocyte specific filter (n = 16) or to a standard blood filter (n = 16) during the surgical procedure. MEASUREMENTS AND RESULTS: White blood cell count in the standard filter group (12.2 +/- 3.6 10(9)/L) was higher (p = 0.047) than in the leukocyte filter group (9.9 +/- 2.6 10(9)/L) at 4 h postoperatively but counts were similar (p = 0.063) at 24 h (10.8 +/- 2.7 vs 8.9 +/- 2.6 10(9)/L, respectively). Leukocyte activation assessed by chemiluminescence was similar between groups at all measurement periods. We noted transient improvements (p < 0.05) in intrapulmonary shunt (19 +/- 50% vs 24 +/- 9%) and mean blood pressure (85 +/- 8 vs 76 +/- 9 mm Hg, respectively) in the leukocyte filter group compared with the standard filter group, respectively. Otherwise there were no differences noted between groups. CONCLUSIONS: Inclusion of a leukocyte filter during cardiopulmonary bypass caused transient cardiorespiratory improvement that was lost within 24 h and did not offer any significant clinical benefits.
Aged↗
Sexual dimorphism and growth hormone induction of murine pheromone-binding proteins.
A number of structurally very similar pheromone-binding proteins (major urinary proteins; MUPs) are synthesized in mouse liver and rapidly excreted in the urine. Male and female inbred mice display different characteristic patterns of MUP expression. Here we present a detailed study of the RNA and protein products corresponding to specific MUP genes previously isolated from genomic DNA of the Balb/c strain. By in vitro transcription of equivalent cDNA clones, translation of the resulting RNA in the reticulocyte lysate system and isoelectric focusing, the protein products of genes BL1, BS1 and BS6 were shown to be MUP 2a, MUP 2b and MUP 4 respectively. MUPs 2a and 2b were shown to be abundant both in Balb/c male urine and among the translation products of total Balb/c male liver mRNA. Two oligodeoxynucleotide probes, oBL1A and oBS1, selective for BL1 and BS1 mRNA respectively, were chemically synthesized. mRNA that hybridized with these probes (oBL1A mRNA and oBS1 mRNA) was present at different characteristic levels in the Balb/c and C57BL/6 inbred strains. In both strains the level of expression was much higher in males than females and the male/female expression ratio of oBS1 RNA was higher than that of oBL1A RNA. Comparison of these mRNA levels with the amounts of different MUP proteins present in urine and the translation products of liver mRNA indicated that proteins other than MUP 2a and MUP 2b are coded for by the C57BL/6 oBL1A and oBS1 mRNAs. C57BL/6 mice homozygous for the lit mutation are GH deficient and transcribe MUP genes at a level much lower than that obtaining in normal mice of either sex, indicating that transcription is induced by GH in both males and females. When lit/lit mice were treated with GH under two different regimes, MUP gene transcription was partially induced to different degrees and the level of oBL1A mRNA was induced more highly than that of oBS1 mRNA. Thus there exists a correlation between the inducibility of these mRNAs and their level of expression in females relative to males; oBL1A mRNA is both more highly expressed in females and more readily induced by GH than oBS1 mRNA. This suggests that the male and female expression patterns are due to differential inducibility of different MUP genes together with a stronger inducing stimulus in males. GH administered continuously by infusion repressed MUP gene expression.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Localization of the response elements of a gene induced by intermittent growth hormone stimulation.
Three regions required for the expression of a mouse major urinary protein (MUP) transgene were identified by a deletion analysis. One of these was located upstream of the cap site between -2139 and -1800, another was the proximal promoter region downstream of -324 and the third lay within the 338 nucleotide intron 1. Both the proximal promoter and intron 1 are involved in sexually dimorphic expression of the transgene (male/female ratio 20), which is dictated by the different temporal profiles of circulating GH in the two sexes. The data also indicated that the region between exons 3 and 7 may contribute to full expression in males and that a region between -718 and -324 may contribute towards the low expression level that obtains in females, but compared with the three principal regions the effects of these regions are relatively minor. We propose (1) that full expression of the transgene requires the co-operation of transcription factors bindings to the three principal regions and (2) that the difference in expression between the sexes relates to interactions between transcription factors bound to the proximal promoter and to sites in intron 1. Our results complement earlier in vitro footprinting and gel-retardation studies of the homologous rat apha 2u-globulin genes. These identified a number of response elements, including putative C/EBP and AP1 sites in the proximal promoter and intron 1 respectively and three putative psi NF-1 sites, two in the proximal promoter and one in intron 1, but proof of the functionality of these sites in regulating transcription was lacking. The proximal promoter also contained a 34 nucleotide sequence that has 70% identity with the SPI GH response element.
Alpha-Globulins↗
Key trends in cost containment. Roundtable discussion.
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Cost Control↗
Protein binding of acetylsalicylic acid and salicylic acid in porcine and human serum.
As part of a pilot project establishing a porcine model for aspirin overdose, the percentage protein binding of acetylsalicylate (ASA) and salicylate (SA) in porcine and human sera was evaluated in vitro over a range of concentrations. Serum from 2 pigs and 4 humans were spiked with ASA concentrations of 0.5-100 mg/dL and SA concentrations of 1-120 mg/dL. Protein binding for each concentration of ASA and SA was determined using radiolabeled drug and ultrafiltration with the Centrifree micropartition system. The percentage protein binding for ASA in pig and human sera were similarly low (< 50%) for all concentrations evaluated. Percentage protein binding for SA for pig and human sera were high (approximately 90% and 80%) at low therapeutic concentrations, but then declined to approximately 30% at higher toxic concentrations (120 mg/dL). The protein binding of ASA and SA over a range of concentrations was similar for porcine and human sera.
Animals↗
Nurse's role in achieving patient outcomes.
Nephrology nursing's influence on patient outcomes has as many facets as there are practice roles in nephrology nursing. These speakers discussed the impact on patient outcomes from a variety of practice perspectives. The roles of administrator, educator, staff nurse, government nurse, research nurse, and corporate nurse are each described.
Humans↗
Building consensus for nephrology nursing practice.
Building consensus for nephrology nursing practice was the theme for the American Nephrology Nurses' Association's (ANNA's) 1994 Clinical Concerns Meetings in Chicago and LaJolla, California respectively. This article emphasizes the importance of consensus building, traditional approaches to consensus conferences, and the inherent risks in conducting such a conference. Additionally, the consensus conference design and steps leading to a final working document are presented by members of the Clinical Concerns Planning Committee.
Consensus Statements as Topic↗
Sexuality and the psyche.
A lack of knowledge of human sexuality, on completing medical school, was the prompt to explore this area more fully. However, as more experience is gained in an area, more questions are raised, emphasising that the black and white approach taken in medical school is often inappropriate in human health.
Adult↗
Autografting for multiple myeloma: a 5-year experience at a single institution.
Over a 5-year period, we have performed 33 autologous bone marrow or PBPC transplantations for multiple myeloma. Nine patients were in complete remission and 24 in partial remission at time of transplantation. Conditioning regimens were BEM (BCNU, etoposide and melphalan) in 29, busulphan and cyclophosphamide in three and melphalan alone in one. Two patients (6%), died within 3 months of transplant-related mortality, seven (21.3%), died of disease progression at a median follow-up of 11 months (range 4-24). Twenty-four patients (72.7%) are alive at a median follow-up of 15 months (range 4-61). Of nine patients transplanted in CR, four have relapsed and are alive and five remain in CR. Of 24 patients transplanted in PR, nine have died, six remain in PR, eight achieved CR and one has progressive disease. The overall median progression-free survival (PFS) is 31 months (95% CI = 20-42). For patients transplanted in PR the median PFS is 24 months (95% CI = 22-26), the median PFS for patients transplanted in CR has not yet been reached. The median PFS for patients achieving CR pre- or post-transplantation was better than for patients neither achieving CR pre- nor post-transplantation (P = 0.05). The median PFS was also significantly improved for patients requiring only primary therapy, compared to patients needing second-line therapy to achieve CR or stable PR prior to transplantation (31 vs 11 months, P = 0.02).
Adult↗
Clustering of six human 11p15 gene homologs within a 500-kb interval of proximal mouse chromosome 7.
Homologs of genes mapping to human chromosome 11p15 are located in three distinct, widely separated regions of mouse chromosome 7 (Mmu7). To date, six genes have been localized to the most proximal HSA11p15/Mmu7 homology region, including Ldh3 (encoding lactate dehydrogenase C), Ldh1 (lactate dehydrogenase A), Myod1 (myogenic differentiation factor-1), Tph (tryptophan hydroxylase), Saa1 (serum amyloid-A-1), and Kcnc1 (encoding a Shaw-type voltage-gated potassium channel). To define the overall size and organization of this region of Mmu7, we have established a long-range physical map including the murine Ldh1, Ldh3, Saa, Tph, Kcnc1, and Myod1 genes. Our results demonstrate that these six genes are physically clustered and are distributed throughout a 500-kb interval located just proximal of the pink-eyed dilution (p) locus. These data, together with recent mapping studies within the related region of HSA11p15, demonstrate that gene content and organization within this proximal homology segment have been highly conserved throughout evolution.
Animals↗
Management perspectives. There are three phases that novice, first line managers go through.
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Humans↗
Characterization of four human YAC libraries for clone size, chimerism and X chromosome sequence representation.
Four collections of human X-specific YACs, derived from human cells containing supernumerary X chromosomes or from somatic cell hybrids containing only X human DNA were characterized. In each collection, 80-85% of YAC strains contained a single X YAC. Five thousand YACs from the various libraries were sized, and cocloning was assessed in subsets by the fraction of YAC insert-ends with non-X sequences. Cocloning was substantial, ranging up to 50% for different collections; and in agreement with previous indications, in all libraries the larger the YACs, the higher the level of cocloning. In libraries made from human-hamster hybrid cells, expected numbers of clones were recovered by STS-based screening; but unexpectedly, the two collections from cells with 4 or 5 X chromosomes yielded numbers of YACs corresponding to an apparent content of only about two X equivalents. Thus it is possible that the DNA of inactive X chromosomes is poorly cloned into YACs, speculatively perhaps because of its specialized chromatin structure.
Animals↗
The gene encoding topoisomerase II from Plasmodium falciparum.
The gene for topoisomerase II has been isolated from genomic libraries of strain K1 of the human malarial parasite, Plasmodium falciparum. The sequence reveals an open reading frame of 4194 nucleotides which predicts a polypeptide of 1398 amino acids. There are apparently no introns. The sequence is present as a single copy which has an identity of 47.4% and a similarity of 65.4% with its human homologue. Sequences conserved in topoisomerase II from other species are present in Pftopoisomerase II but in addition it has two adjacent asparagine-rich insertions which are unique to it. We have also detected asparagine-rich regions in the gene for PfDNA polymerase alpha. The gene for Pftopoisomerase II has been localised to chromosome 14 and northern analysis reveals a transcript of 5.8 kb. Two independent antisera raised in mice against glutathione-S-transferase fusion proteins containing the amino terminal portion of the malarial protein detect a weak band on western blots at about 160kDa, the expected size of the protein. Use of the same antisera for immunofluorescence analysis suggests that the protein is present at all stages of intraerythrocytic growth of the parasite.
Amino Acid Sequence↗
Glycine inhibition of glutamate evoked-release of norepinephrine in the hypothalamus is strychnine-insensitive.
The effects of glycine (GLY), D-serine (D-SER), kynurenic acid (KYN), and 7-Cl kynurenic acid (7-Cl KYN), on the evoked release of endogenous norepinephrine (NE) by L-glutamate (L-GLU) in rat hypothalamic slices was investigated. KYN (500 and 100 microM) and 7-Cl KYN (10 microM) blocked evoked release of NE by L-GLU (1 mM). The inhibitory effects of 100 microM KYN on evoked release of NE by L-GLU were reversed by 10 microM and 100 microM D-SER and, but not 10 or 100 microM GLY. When KYN was not present in the superfusate, superfusion with either 10 or 100 microM GLY alone simultaneously with 1 mM L-GLU blocked the evoked release of NE produced by L-GLU. The addition of strychnine (3 or 100 microM) to the superfusate did not block the inhibitory effects of 10 microM GLY on L-GLU-evoked NE release. These findings suggest that a novel strychnine-resistant GLY receptor is present in the rat hypothalamus.
Animals↗
A nuclear mutation in maize blocks the processing and translation of several chloroplast mRNAs and provides evidence for the differential translation of alternative mRNA forms.
A mutant designated crp1 (chloroplast RNA processing 1) was identified in a screen for transposon-induced maize mutants with defects in chloroplast gene expression. crp1 is a recessive, nuclear mutation that causes the loss of the cytochrome f/b6 complex and a reduction in photosystem I. The molecular basis for these protein losses is unique relative to previously described mutants with defects in organelle gene expression; it involves defects in the metabolism of two organellar mRNAs and in the translation of two organellar proteins. Mutants lack the monocistronic forms of the petB and petD mRNAs (encoding cytochrome f/b6 subunits), but contain normal levels of their polycistronic precursors. Pulse-labeling experiments revealed normal synthesis of the petB gene product, but a large decrease in synthesis of the petD gene product. These results suggest that petD sequences are more efficiently translated in a monocistronic than in a polycistronic context, thereby providing evidence that the elaborate RNA processing typical of chloroplast transcripts can play a role in controlling gene expression. Structural predictions suggest that the petD start codon lies in a stable hairpin in the polycistronic RNA, but remains unpaired in the monocistronic transcript. Thus, processing to a monocistronic form may increase translational efficiency by releasing the translation initiation region from inhibitory interactions with upstream RNA sequences. Synthesis of a third cytochrome f/b6 subunit, encoded by the petA gene, was undetectable in crp1, although its mRNA appeared unaltered. Two mechanisms are consistent with the simultaneous loss of both petA and petD protein synthesis: the translation of the petA and petD mRNAs might be coupled via a mechanism independent of crp1, or the crp1 gene may function to coordinate the expression of the two genes, which encode subunits of the same complex.
Alternative Splicing↗
Phase II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer.
PURPOSE: To evaluate the efficacy and toxicity of the addition of etanidazole (ETA) to external beam radiation. METHODS AND MATERIALS: Fifty eight previously untreated patients with locally advanced adenocarcinoma of the prostate were entered on a Phase II trial of etanidazole (ETA) combined with standard external beam radiation therapy. ETA was given concurrently with irradiation. Four patients received less than 25% of the intended dose of ETA and were ineligible for further analysis. The stage of the remaining patients were T2c-11, T3-39, T4-1, bulky local recurrence after prostatectomy-1, and T3, N1-2. RESULTS: Forty-five of 54 patients (83.3%) achieved a clinical complete response (CCR) in the prostate and seminal vesicles as judged by digital rectal exam (DRE). Responses were rapid with a median time to CCR of 3.4 months, range 0-22.8 months. Local control was maintained in 82% of the patients who achieved a CCR. Fifteen of 32 eligible patients with a normal DRE underwent prostate biopsies from 12-20 months after treatment, seven had negative biopsies (46.6%). Distant metastases occurred in 18 patients (33.3%). Pretreatment prostatic specific antigen (PSA), Gleason score, and stage were not associated with treatment outcome in a univariate analysis. CONCLUSION: While ETA plus radiation was associated with a rapid CCR, the overall treatment outcome of these patients appeared to be similar to published reports of patients receiving RT alone. The rapid response rate may imply biologic activity of the ETA. In future trials, it may be reasonable to focus on patients at lower risk for the subsequent development of distant disease.
Adenocarcinoma↗