Management development: preparing nurse managers for the future. Part 2, program evaluation.

In Part 1 of this two-part series (JONA, June 1994), the authors described the factors that influenced the need for a nurse manager development program and the conceptual model used to plan and implement that program at The Johns Hopkins Hospital. In Part, 2 they describe the program evaluation and implications for future work.

Management development: preparing nurse managers for the future. Part 1, Program model.

Nurse executives need to develop programs to help nurse managers meet rapidly changing role expectations and prepare for new healthcare challenges. This two-part series reports on one such program for nurse managers at The Johns Hopkins Hospital. Part 1 describes the program model, its conceptual framework, and its various components. Part 2 will present an in-depth evaluation of the program and recommendations for future development.

Proton NMR study of the interaction of benzo(a)pyrene with rat liver microsomal cytochrome P-450.

1H nuclear magnetic resonance longitudinal relaxation time (T1) measurements were used to study the interaction of 1,3,6-H-benzo(a)pyrene (1,3,6-H-BaP) with microsomal cytochrome P-450 from livers of phenobarbital- and beta-naphthoflavone-treated rats. Upon addition of various amounts of cytochrome P-450 to solutions of BaP, the T1 values for the three BaP protons decreased. When the hemeprotein was converted to its carbon monoxyferrous derivative in the presence of BaP, the T1 values of the BaP protons increased. The paramagnetic contributions to the observed T1 values were calculated and resulted in distance estimates of greater than 6 A for the three BaP protons in both cases.

Evidence against a laminin receptor role for calsequestrin.

Calsequestrin, a muscle calcium binding protein, has been shown to bind the extracellular matrix protein laminin and evidence has been presented that CAL (initially called aspartactin) is on the cell surface, consistent with a role as a laminin receptor (1). In this report, we present evidence that does not support a laminin receptor function for CAL. We found that CAL immunoreactivity could not be detected on live cultured chick myotubes unless they were permeabilized with detergent. Furthermore, polyclonal anti-CAL antibodies did not perturb myotube adhesion to laminin or the rate of myoblast fusion on laminin. Expression of the CAL cDNA in a melanoma cell line that was poorly adherent to laminin did not increase adhesion to laminin. In these cells, CAL could not be detected on the cell surface, and the majority of CAL was found to be secreted into the media.

Efficient transfection and expression of heterologous genes in PC12 cells.

The PC12 pheochromocytoma cell line has been a favorite model system for cell and neurobiologists, but has proven relatively refractory to standard DNA transfection methods. We have found that the cationic lipid "lipofectin" provides a simple, gentle, and nontoxic procedure that vastly improves transfection efficiencies in PC12 cells. Transient expression of chloramphenicol acetyl transferase (CAT) driven by a Rous sarcoma virus long terminal repeat (LTR) is much more efficient using lipofectin when compared with calcium phosphate as a transfection procedure. Additionally, transient transfection of nerve growth factor (NGF)-differentiated PC12 cells proceeds with equal efficiency relative to naive, uninduced cells. Using the lipofectin procedure, the frequency of stable transfection is 100-fold higher than that reported with standard calcium phosphate precipitation protocols. To examine the effectiveness of different promoters for efficient expression of heterologous DNA in PC12 cells, three different promoter-bearing constructs were utilized. Each construct contains a different promoter sequence upstream from a chicken calsequestrin cDNA. A human cytomegalovirus (CMV) immediate early promoter construct produced the highest level of expression, followed by a human beta-actin promoter construct. Expression from a mouse Moloney sarcoma virus LTR construct could not be detected. These results overcome the previous transfection problems of low efficiency and low viability that have plagued many PC12 cell investigations.

The diagnosis and treatment of psychogenic glossodynia.

The symptoms of patients with psychogenic glossodynia are presented and discussed in the context of psychosomatic manifestations of psychiatric illnesses. The majority of patients with psychogenic glossodynia can be treated effectively by focusing on diagnosis and then initiating antidepressant medication or anxiolytics and other psychological treatments as needed.

Adenoid cystic carcinoma of the breast. Data from the Connecticut Tumor Registry and a review of the literature.

The case records of the Connecticut Tumor Registry were reviewed from 1952-1982. There were 37 cases of adenoid cystic carcinoma of the breast (ACC) from a total of 40,350 invasive breast tumors. Patient survival, complications, and pathologic sections were reviewed. Only 14 of 27 surgical pathology slides available for review could be confirmed histologically as ACC. All patients were white females with a mean age of 64 years. The tumor remained localized to the breast in all cases. Nine patients had either radical or modified radical mastectomy, four patients had either simple mastectomy or lumpectomy, and one patient refused treatment. There was no evidence of axillary node involvement, metastases, or local recurrence after excision. At the time of follow-up, nine patients were alive and disease free and four died of disease unrelated to their breast cancer. The one patient who died of breast cancer had a radical mastectomy and survived 11.7 years after diagnosis. It is concluded that ACC has a favorable biologic behavior characterized by a prolonged clinical course and good prognosis. Simple mastectomy is all that is required as initial treatment, and a chest x-ray and thorough physical examination looking for local recurrence is all that is needed for follow-up.

In vitro inhibition of the metabolism and mutagenicity of benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol by naphthazarin and other naphthol derivatives.

Among naphthol derivatives tested in the Ames assay, 5,8-dihydroxy-1,4-naphthoquinone or naphthazarin was found to be the most effective inhibitor of benzo(a)pyrene mutagenicity. The inhibitory activity is due in part to the redox cycling of naphthazarin with the concommitant transfer of reducing equivalents from NADPH to molecular oxygen, thus diverting electrons from cytochrome P-450 enzymes. Metabolite separations showed a decrease in microsomal metabolism of benzo(a)pyrene and of benzo(a)pyrene-7,8-dihydrodoil upon addition of naphthazarin. Since both NADP and dicoumarol inhibited the naphthazarin-stimulated non-stoichiometric consumption of NADPH and oxygen then naphthazarin redox cycling probably involves both DT-diaphorase and NADPH cytochrome P-450 reductase.

Inhibition of the mutagenicity and metabolism of 6-methyl-benzo[a]pyrene and 6-hydroxymethyl-benzo[a]pyrene.

Previously reported inhibitors of benzo[a]pyrene (BaP) mutagenicity in Salmonella typhimurium strain TA98 were tested for their effectiveness against the mutagenicity of 6-methyl-benzo[a]pyrene (6-CH3-BaP), 6-hydroxymethyl-benzo[a]pyrene (6-CH2OH-BaP) and 6-acetoxymethyl-benzo[a]pyrene (6-CH3COOCH2-BaP). Dose-response curves obtained for phenothiazine (PTH), 2-chlorophenothiazine (2Cl-PTH), phenylisothiocyanate (PHN), phenethylisothiocyanate (PNE), trans-retinol (TR) and disulfiram (TETD) showed a variety of degrees of inhibition of mutagenicity. Additionally, glutathione (GSH) was found to inhibit the mutagenicity of 6-CH3COOCH2-BaP, and the mutagenicity of 6-CH2OH-BaP was enhanced by the addition of supplemental ATP, Na2SO4 and EDTA. Only 2Cl-PTH was equally as good an inhibitor of 6-CH3-BaP and BaP, reducing revertant colonies to less than 50% of control at 10 X BaP concentration. To probe the mechanism of inhibition, the effect of 2Cl-PTH on the binding of BaP and the 6-substituted benzo[a]pyrenes to cytochrome P-450 was investigated by difference spectroscopy. Also, the effect of 2Cl-PTH on the subsequent metabolism of 6-CH3-BaP and 6-CH2OH-BaP was investigated by rapid scan difference spectroscopy and high-performance liquid chromatographic separation of products. The results are consistent with a major mechanism of inhibition for 2Cl-PTH involving a competition for the cytochrome P-450 binding site.

Resorufin inhibits the in vitro metabolism and mutagenesis of benzo(a)pyrene.

7-Hydroxyphenoxazin-3-one, commonly known as resorufin, strongly inhibits benzo(a)pyrene-induced mutation in the Ames bacterial reversion assay. The antimutagenic mechanism is due in part to redox cycling of resorufin with the concommitant transfer of reducing equivalents from NADPH to molecular oxygen. The diversion of electrons from cytochrome P-450 enzymes results in a large decrease in the percent of benzo(a)pyrene metabolized by rat liver microsomes as measured by HPLC. Resorufin stimulated a non-stoichiometric consumption of NADPH and was reduced in S-9 or microsomal solutions. These processes were sensitive to dicumarol and NADP inhibition to different degrees in each liver fraction. This suggests two pathways are involved in resorufin redox cycling, one involving DT-diaphorase and the other with NADPH cytochrome P-450 reductase. Oxygen was shown to be an electron acceptor for S-9 mediated resorufin redox cycling, but was not consumed by a microsomal solution in the presence of resorufin and NADPH.

Free radicals of benzo(a)pyrene and derivatives.

The evidence for biological involvement, the spectroscopic properties (especially EPR), and the reactions, of free radicals derived from benzo(a)pyrene and its methylated, hydroxylated, and fluorinated derivatives are reviewed.

Chemical and enzymatic oxidation of alkylated benzo[a]pyrenes.

The chemical and enzymatic oxidations of 6-, 7- and 10-methylbenzo[a]-pyrenes, 6,10- and 7,10-dimethylbenzo[a]pyrenes and benzo[a]pyrene (BP) itself have been investigated to study the effects of alkyl substitution on the pathways of oxidation. The chemical oxidizing systems employed were Fenton's reagent (FeSO4/H2O2); trifluoroacetic acid-hydrogen peroxide (TFA/H2O2); thallium tristrifluoracetate in trifluoroacetic acid (TTFA/TFA) and H2SO4. The enzymatic systems were horseradish peroxidase (HRP/H2O2) and rat liver microsomes. The oxidations were investigated by electron paramagnetic resonance (EPR) spectroscopy to detect radical intermediates and by high performance liquid chromatography (HPLC) to separate the products. All the compounds studied produced radicals, identified as cationic species, in both H2SO4 and TTFA/TFA. In addition the 7-methyl-, 10-methyl- and 7,10-dimethyl-BP's produced 6-oxy radicals in some or all of the remaining oxidizing systems. Both chemically and enzymatically these same three compounds were observed to produce quinones as stable products. Microsomal oxidations gave the broadest range of products exhibiting HPLC peaks in the diol, quinone and phenol regions of the chromatograms, however, there were considerable differences between products from the individual derivatives and those from the parent molecule. 6-Methyl and 6,10-dimethyl-BP's showed no evidence of oxy radical intermediates or quinones under any set of conditions, the 6-substituent effectively blocking this oxidation pathway. The observations are consistent with the expected effects of alkyl substituents at particular positions and indicate that studies such as this one are potentially useful in better understanding oxidation and possible activation pathways of polycyclic aromatic hydrocarbons.

Adenocarcinoma of the small bowel. Clinical features, similarity to regional enteritis, and analysis of 338 documented cases.

A case of ileal adenocarcinoma is presented and the clinical features of adenocarcinoma of the small bowel are discussed. Special attention is paid to the differentiation of this tumor from Crohn's disease. Analysis of Connecticut Tumor Registry data on 338 cases of small intestinal adenocarcinoma occurring between 1935 and 1978 reveals a predilection for the elderly but no sex predominance (male/female = 0.965). Two hundred fifty-four patients were followed for at least 5 yr, and the overall (1935-1978) 5-yr survival rate was 17.3%. No improvement in survival has taken place in Connecticut over the past 40 yr.

Screening of antioxidants and other compounds for antimutagenic properties towards benzo[a]pyrene-induced mutagenicity in strain TA98 of Salmonella typhimurium.

Antioxidants and several other compounds, some of which are known to inhibit carcinogenicity, have been screened for their effectiveness as inhibitors of benzo[a]pyrene (BP) mutagenicity towards Salmonella typhimurium strain TA98 in the Ames test. A total of 32 compounds were tested. In the assay, metabolic activation of BP (8.2 nmoles/plate) was mediated by the S9 fraction from beta-naphthoflavone-induced rat livers. Among compounds which are known to inhibit carcinogenicity, retinol, phenothiazine, disulfiram, phenethylisothiocyanate and phenylisothiocyanate were the most effective inhibitors of BP mutagenicity, being effective at equimolar concentrations. Several other compounds showed inhibition at higher concentrations of antioxidant and the remainder showed little or no inhibition. Dose-response curves have been obtained for the 17 most active compounds. No general pattern of inhibition is obvious from our studies, inhibitors are not drawn ;from any single class of compounds, nor does a particular compound necessarily appear to inhibit more than one mutagen.

The effect of substituted phenothiazines on the mutagenicity of benzo[a]pyrene.

The effect of phenothiazine and 11 of its derivatives on the mutagenicity of benzo[a]pyrene, as measured by the Ames test was investigated. Significant anti-mutagenic activity was detected for 10 phenothiazine derivatives, with the 2-chloro derivative being the most effective inhibitor tested and promazine the only phenothiazine drug tested which has no demonstrable inhibitory activity. It is considered that the anti-mutagenic activity and therefore potentially anticarcinogenic activity of these derivatives should be of interest to epidemiologists.