Photodynamic therapy provides local control of cholangiocarcinoma in patients awaiting liver transplantation.

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.

Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes.

Mismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication stalling [3] [4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, carboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose a model whereby MMR proteins - in addition to their role in DNA-damage recognition - decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression.

Irradiation in the setting of collagen vascular disease: acute and late complications.

PURPOSE: Based on reports of greater toxicity from radiation therapy, collagen vascular diseases (CVDs) have been considered a contraindication to irradiation. We assessed the complications of radiation therapy in patients with CVD. PATIENTS AND METHODS: A total of 209 patients with documented CVD were irradiated between 1960 and 1995. One hundred thirty-one had rheumatoid arthritis (RA), 25 had systemic lupus erythematosus (SLE); 17 had polymyositis or dermatomyositis; 16 had scleroderma; eight had ankylosing spondylitis; five had juvenile RA; three had discoid lupus erythematosus; and four had 4 mixed connective tissue disorders (MCTD). The mean follow-up duration of curative cases was more than 6 years. Doses ranged from 10 to 87.6 Gy, with a median of 45 Gy. RESULTS: Overall, 263 sites were assessable in 209 patients. Significant (> or = grade 3) acute toxicity was seen in 10% of irradiated sites. Severe late effects were associated with significant acute reactions and with non-RA CVDs (6% v 21% at 5 years). No difference was seen in late effects according to timing of CVD onset, presence of concurrent vascular insults, radiation dose, or other technical factors, or by measures of disease activity. CONCLUSION: RA does not appear to have an elevated rate of late toxicity. While non-RA CVD is significantly associated with increased radiation late effects at standard doses, radiation-related mortality remains exceedingly rare. The choice of therapeutic modality in this radiosensitive group of patients should be made on a case-by-case basis.

Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model.

64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown promise as a radioisotope for targeted radiotherapy. It has been demonstrated previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC, where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid) significantly inhibited the growth of somatostatin receptor-positive CA20948 rat pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944-1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new 64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3-TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu-TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3-TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean survival times compared with rats given a single dose; however, no complete regressions occurred. Complete regression of tumors was observed for all rats treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10 days; moreover, the mean survival time of these rats was nearly twice that of controls. Toxicity was determined by physical appearance and hematological and enzyme analysis, which revealed no overt toxicity and only transient changes in blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ to be the kidneys. The radiotherapy results, along with absorbed dose estimates to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues warrant continued consideration as agents for targeted radiotherapy.

Internal mammary node coverage: an investigation of presently accepted techniques.

PURPOSE: Recent publications have generated a renewed interest in regional nodal treatment to include the ipsilateral supraclavicular and internal mammary nodes (IMN). The purpose of this study is to evaluate three presently accepted treatment techniques for coverage of the intact breast and ipsilateral lymph node regions and to construct recommendations regarding the utilization of these techniques. METHODS AND MATERIALS: Anatomic data were obtained from five randomly selected patients with computerized tomography (CT) in treatment position. Three patients presented with cancer of the left breast and two with cancer of the right. Using the Pinnacle 3-D planning system, normal tissue volumes of breast, ipsilateral lung, heart, sternum, and the IMN target were delineated for each patient. Three accepted techniques used to treat ipsilateral breast, internal mammary and supraclavicular nodes (extended tangents, 5-field, partly wide tangents) were configured and compared to a supraclavicular field matched to standard tangential fields. A dosage of 50 Gy in 25 fractions was prescribed to the target volume. Dose-volume histograms (DVH) were generated and analyzed with regard to target volume coverage and lung/heart volumes treated. RESULTS: All of the treatment techniques covering IMN include at least 10% more lung and heart volume than that covered by standard tangential fields. The relative lung and heart volumes treated with each technique were consistent from patient to patient. The 5-field technique clearly treats the largest volume of normal tissue; however, most of this volume receives less than 50% of the dose prescribed. The percent of heart and ipsilateral lung treated to 20 Gy, 30 Gy, and 40 Gy have been calculated and compared. Due to the increase in chest wall thickness and depth of IMN superiorly, complete coverage was not achieved with any technique if the IMN target extended superiorly into the medial supraclavicular field where dose fall-off resulted in a significant underdosing at depth. For the same anatomic reasons, the 5-field technique underdosed 10-15% of the IMN target volume in 4 of the 5 cases. This technique also yielded a greater dose heterogeneity, which was not seen with the other techniques evaluated and correlated with the change of anterior chest wall thickness. CONCLUSIONS: Anatomic variation in chest wall thickness and IMN depth strongly suggests the routine use of multislice CT planning to ensure complete coverage of the target volume and optimal sparing of normal tissue. All of the techniques can be constructed to look acceptable at central axis. To cover the superior most aspect of the IMN chain either high tangential fields, a supraclavicular field photon beam of energy >6 MV, or an AP/PA supraclavicular setup should be considered. The 5-field technique has the most difficulty in compensating for the increased depth of the IMN in the superior aspect of the tangent fields with up to +/-40% variation of the dose noted in isolated areas within the target volume. Based on our evaluation, the partly wide tangent technique offers many advantages. It provides optimal coverage of the target volume, reduces coverage of normal tissue volumes to an acceptable level, and is easily reproducible with a high degree of dose homogeneity throughout the target.

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS: The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS: The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS: The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer.

PURPOSE: We performed a retrospective analysis to assess the durability of benefit derived from irradiation after prostatectomy for pT3N0 disease, and the possibility of cure. METHODS AND MATERIALS: We studied 88 patients who were irradiated after prostatectomy and had available prostate specific antigen (PSA) data, no known nodal or metastatic disease, no hormonal treatment, and follow-up of at least 12 months from surgery. Forty patients received adjuvant therapy for a high risk of local failure with undetectable PSA. Forty-eight patients received salvage therapy for elevated PSA levels. Mean follow up was 44 months from date of surgery and 31 months from irradiation. Biochemical failure was strictly defined as a confirmed rise in PSA of >10%, or as the ability to detect a previously undetectable PSA value. RESULTS: After salvage irradiation, 69% of patients attained an undetectable PSA. Eighty-eight percent of adjuvant patients were biochemically and clinically free of disease (bNED) at 3 years from prostatectomy. Sixty-eight percent of those receiving salvage irradiation were bNED 3 years after surgery. On univariate analysis, treatment group (adjuvant or salvage), pre-operative PSA, and the status of seminal vesicles were significant prognostic factors. The extent of PSA elevation in the salvage group was also significant. We did not demonstrate a significant difference between those salvage patients referred for persistently elevated PSA as compared to those with a late rise in PSA. On multivariate analysis, the only significant predictor of outcome was treatment group, with adjuvant irradiation having better outcome than salvage. CONCLUSION: More than two-thirds of this group of patients remain biochemically disease free at 3 years following irradiation, attesting to a number of potential cures. For patients with stage pT3N0 prostate cancer following radical prostatectomy, our data support the use of either routine postoperative adjuvant irradiation or close PSA follow-up with early salvage treatment.

Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection.

Cytokines are important mediators in the pathogenesis of central nervous system (CNS) inflammatory diseases including multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), viral encephalitis and virus induced demyelinating diseases. We have used immunohistochemical techniques to characterize the mononuclear cell infiltrate and cytokine profiles in the CNS following infection of mice with the demyelinating A7(74) strain of Semliki Forest virus (SFV), an important viral model of MS. Mononuclear cell infiltrates in the CNS, first observed at 3 days and maximal during clearance of infectious virus, were comprised predominantly of CD8+ lymphocytes. F4/80+ macrophage/microglia and CD45/B220+ B lymphocytes were most numerous during the subsequent phase of demyelination. CD4+ T-lymphocytes were observed at low levels throughout infection. By immunostaining MHC class I, IL-1beta , IL-3 and TGF beta1 were constitutively expressed in normal mice and were upregulated following infection. MHC class II, IL-1alpha, IL-2, IL-2R, TNF-alpha and IL-6 were strongly upregulated in the CNS of SFV-infected mice and mice with chronic relapsing EAE. The spatial and temporal distribution of these cytokines during the course of disease was analysed. Whereas IL-1alpha, IL-1beta, IL-10, and TGF beta1 were observed on day 3 following infection GMCSF, IL-2 and TNF alpha were first apparent at day 7 when the cellular infiltration in the CNS was most intense. In contrast IFN gamma and IL-6 were first observed on day 10 prior to the demyelination phase of disease. Cytokines in the lesions of demyelination suggest a role in the pathogeneisis of myelin damage. Based on cytokine profiles no clear bias of either a Th1 or Th2 response was observed in the CNS during infection.

Optic neuritis in chronic relapsing experimental allergic encephalomyelitis in Biozzi ABH mice: demyelination and fast axonal transport changes in disease.

The encephalitogenicity of optic nerve tissue was demonstrated in Biozzi ABH (H-2(dq1)) mice. Acute experimental allergic encephalomyelitis (EAE) occurred in 11/14 animals and 4/5 exhibited relapse. The involvement of the optic nerve in spinal cord homogenate induced chronic relapsing EAE (CREAE) was demonstrated by mononuclear cell infiltration and myelin degradation in the optic nerve prior to and during clinical disease. During the relapse phase gross pathological assessment revealed swollen and translucent plaques on the optic nerves. Advanced lesions showed widespread demyelination, astrocytic gliosis and fibrotic changes of the blood vessels. Physiologically, the fast axonal transport of proteins from the retina to the optic nerve and superior colliculus was significantly decreased during relapse. The association of inflammation and demyelination with physiological deficit in the optic nerve highlights the usefulness of this model in the study of multiple sclerosis in which acute monosymptomatic unilateral optic neuritis is a common manifestation. Furthermore, the novel induction of CREAE with optic nerve homogenate suggests that optic neuritis is a common significant role in the pathophysiology and progression of neurological disease in CREAE which may be relevant to studies of optic neuritis in multiple sclerosis.

A preview of implantable cardioverter defibrillator systems in the next millennium: an integrative cardiac rhythm management approach.

The implantable cardioverter defibrillator (ICD), a primary therapeutic option for preventing sudden cardiac death, has rapidly evolved since being introduced clinically in 1980. Technologic advances in several key areas have enabled ICDs to provide more sophisticated rhythm management. Recent emphasis has been placed on dual-chamber ICDs possessing adaptive-rate pacing capabilities. Adoption of dual-chamber ICD systems has been rapid. The capabilities of future ICD systems will be governed by an integrative strategy that brings together sets of features specifically targeted at multifaceted rhythm disorders. The addition of atrial therapy will require more sophisticated rhythm discrimination algorithms. ICD technology will improve on several fronts including leads, integrated circuits, batteries, and capacitors. Additionally, state-of-the-art pacemaker technology will continue to be incorporated into ICDs. As these new ICD systems become increasingly sophisticated from an engineering viewpoint, tremendous emphasis will be placed on decreasing the complexity of programming, device interrogation, and patient monitoring during routine patient follow-up. Vast improvements in ICD programming systems may ultimately permit the 1-minute follow-up.

Relationship-specific and global perceptions of social support: associations with well-being and attachment.

Is one's global sense of social support largely a summation of the support perceived to exist within current social relationships, or is it a trait-like construct independent of current support levels? To address this issue, 183 college students completed measures of global support, support from four different social domains, attachment style, and several measures of well-being. Hierarchical regression analyses revealed that for two well-being measures (global and social loneliness), both global and domain support displayed significant unique associations; for emotional loneliness, only domain support had a significant unique influence. For the well-being measure reflecting generalized negative affect, only global support displayed such a unique association. Thus, global and domain support appear to be, to a considerable degree, independent constructs, each with its own sphere of influence in affecting well-being.

A sialoglycoprotein (LEA.135) associated with favourable prognosis of patients with lymph node-negative primary breast carcinoma.

A cell-surface sialoglycoprotein (LEA.135) was identified using a monoclonal antibody that was generated by immunization of Balb/c mice with extracts of normal breast tissue following prior immune-tolerization with mammary carcinoma cell lines. LEA.135 is distinct from other known epithelial cell-associated antigens, including the family of mucins or keratins and epidermal growth factor receptor. Using immunohistochemical staining methods, LEA.135 expression was detected predominantly on the apical plasma membrane of normal and neoplastic mammary and extramammary epithelial cells in freshly frozen or formalin-fixed paraffin-embedded tissue sections. A retrospective study of 111 cases of lymph node-negative patients (TanyN0M0) with primary infiltrating ductal breast carcinoma, with a median follow-up of 7.9 years, was conducted. A comparison of overall survival (O.S.) was made of patients whose tumor cells exhibited reactivity with anti-LEA.135 antibody (O.S. 92.9 +/- 3.3% at 8 years), compared with those whose specimens showed the absence of LEA.135 expression (O.S. 68.3 +/- 10.8% at 8 years). A statistically significant univariant association between LEA.135 expression and O.S. was observed (logrank p < 0.001). In addition, in a subgroup of patients with histologically moderately differentiated tumors (N = 71), LEA.135-positive cases showed an improved O.S. (90.8 +/- 4.6% at 8 years; p < 0.001) compared with those who were LEA.135-negative (O.S. 55.6 +/- 13.6% at 8 years). The association remained statistically significant in a multivariable analysis after adjusting for histological grade, tumor size and age (p < 0.02). Thus, in this series of patients with lymph node-negative primary breast carcinoma, LEA.135 expression was associated with a significant decrease in the rate of recurrence and with an increase in overall survival, independent of tumor size, histologic grade, and patient's age. In contrast to the majority of other prognostic markers which predicts a worse biology, LEA.135 is a unique class of antigen whose expression indicates a lower aggressiveness of the tumor cells.

Advances in radiotherapy for carcinoma of the head and neck.

Increasingly, progress in the radiotherapy of carcinomas of the head and neck is being driven by principles of radiobiology. This article discusses some of the major advances in head and neck radiotherapy, including altered fractionation, concomitant chemotherapy, and intensity-modulated radiotherapy, in the context of radiobiologic rationale, potential impact on tumor control, and normal tissue complications.

Mutagens from the cooking of food. II. Survey by Ames/Salmonella test of mutagen formation in the major protein-rich foods of the American diet.

The formation of mutagens in the major cooked protein-rich foods in the US diet was studied in the Ames Salmonella typhimurium test. The nine protein-rich foods most commonly eaten in the USA--ground beef, beef steak, eggs, pork chops, fried chicken, pot-roasted beef, ham, roast beef and bacon--were examined for their mutagenicity towards S. typhimurium TA1538 after normal 'household' cooking (deep frying, griddle/pan frying, baking/roasting, broiling, stewing, braising or boiling of 100-475 degrees C). Well-done fried ground beef, beef steak, ham pork chops and bacon showed significant mutagen formation. For chicken and beef steak high-temperature broiling produced the most mutagenicity, followed by baking/roasting and frying. Stewing, braising and deep frying produced little mutagen. Eggs and egg products produced mutagens only after cooking at high temperatures (the yolk to a greater extent than the white). Commercially cooked hamburgers showed a wide range of mutagenic activity. We conclude that mutagen formation following cooking of protein-containing foods is a complex function of food type, cooking time and cooking temperature. It seems clear that all the major protein-rich foods if cooked to a well-done state on the griddle (eggs only at temperatures above 225 degrees C) or by broiling will contain mutagens detectable by the Ames/Salmonella assay. This survey is a step towards determining whether any human health hazard results from cooking protein-rich foods. Further testing in both short- and long-term genotoxicity bioassays and carcinogenesis assays are needed before any human risk extrapolations can be made.

Mutagens from the cooking of food. III. Survey by Ames/Salmonella test of mutagen formation in secondary sources of cooked dietary protein.

A survey of mutagen formation during the cooking of a variety of protein-rich foods that are minor sources of protein intake in the American diet is reported (see Bjeldanes, Morris, Felton et al. (1982) for survey of major protein foods). Milk, cheese, tofu and organ meats showed negligible mutagen formation except following high-temperature cooking for long periods of time. Even under the most extreme conditions, tofu, cheese and milk exhibited fewer than 500 Ames/Salmonella typhimurium revertants/100 g equivalents (wet weight of uncooked food), and organ meats only double that amount. Beans showed low mutagen formation after boiling and boiling followed by frying (with and without oil). Only boiling of beans followed by baking for 1 hr gave appreciable mutagenicity (3650 revertants/100g equivalents). Seafood samples gave a variety of results: red snapper, salmon, trout, halibut and rock cod all gave more than 1000 revertants/100 g wet weight equivalents when pan-fried or griddle-fried for about 6 min/side. Baked or poached rock and deep-fried shrimp showed no significant mutagen formation. Broiled lamb chops showed mutagen formation similar to that in red meats tested in the preceding paper: 16,000 revertants/100 g equivalents. These findings show that as measured by bioassay in S. typhimurium, most of the foods that are minor sources of protein in the American diet are also minor sources of cooking-induced mutagens.

Protective effects of fluticasone on allergen-induced airway responses and sputum inflammatory markers.

BACKGROUND: A direct comparison of the protective effects of single and regular doses of inhaled glucocorticoid on allergen-induced asthmatic responses and inflammation has not been made. OBJECTIVE: To compare the effects of pretreatment with fluticasone 250 microg 30 min before allergen inhalation and two weeks of 250 microg twice daily (last dose 24 h before challenge) with single and regular (twice daily) placebo doses on early and late asthmatic responses, induced sputum cell counts and measures of eosinophil activation at 7 h and 24 h, and methacholine airway responsiveness at 24 h. PATIENTS AND METHODS: Ten mild asthmatic patients were studied in a randomized, double-blind, placebo controlled crossover study. RESULTS: Regular fluticasone increased the baseline mean provocative concentration of methacholine to cause a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1) from 2.6 to 6.4 mg/mL (P<0.05) and lowered the eosinophil count from 3.1% to 0.4% (P<0.05) compared with regular placebo. Neither single nor regular fluticasone had any effect on the early asthmatic response. Single fluticasone attenuated the late asthmatic response, the mean +/- SEM maximum percentage fall in FEV1 (10.8+/-3.6 compared with single placebo 18. 8+/-3.5, P=0.03), the allergen-induced increase of airway responsiveness (P<0.05), and the eosinophilia (P<0.005) and activated eosinophils at 7 h (P<0.01) but not at 24 h. Regular fluticasone also attenuated the late asthmatic response (11.1+/-2.5) compared with regular placebo (19.6+/-4.5), but this was not statistically significant and did not protect against the induced increase in airway responsiveness or the sputum eosinophilia. CONCLUSION: Two weeks of regular inhaled fluticasone discontinued 24 h before allergen challenge does not offer any additional protection against the early or late asthmatic responses, increased airway responsiveness or sputum eosinophilia compared with a single dose of 250 microg immediately before allergen challenge, despite increasing baseline PC20 and decreasing sputum eosinophilia prechallenge. The significance of the protective effect of a single dose of inhaled steroid before an allergen inhalation and the duration of the protective effect need further investigation.

Nursing educators: perceptions of the curricular role of human genetics/bioethics.

In recent years medical geneticists have made tremendous advances in understanding hereditary diseases. Applying this new knowledge raises serious ethical questions which have relevance to nursing practice. Nursing educators must ask themselves: (1) what effects do these advances have on nursing practice; (2) have the subjects of human genetics and bioethics been sufficiently integrated into nursing educational programs; and (3) are professional nurses prepared to help patients become scientifically literate relative to principles of human genetics? A 35-item questionnaire was prepared, and 616 copies were mailed to the chief administrators of 31 Indiana state-approved nursing programs listed by the Indiana State Board of Nurses' Registration and Nursing Education. Data obtained from the 250 questionnaire respondents led to the conclusion that Indiana nursing educators are aware of the relevance of human genetics to their work, but they need direct access to helpful information to incorporate genetics instruction as a part of nursing education programs in Indiana. To accomplish this task, the respondents favor continuing education programs in human genetics. Although the data are based on responses of Indiana nursing educators, we believe that our findings can be generalized, at least, to nursing programs throughout the midwest. On the basis of our study, we recommend that continuing education programs in human genetics be implemented with the goal of providing all practicing nurses with a better understanding of the genetic basis of disease, thereby enabling them to counsel wisely those patients entrusted to their care.

For those left behind. An educational inpatient rehabilitation program.

1. An interdisciplinary program model was developed for the treatment of mentally ill individuals remaining in long-term state mental institutions that focused on self-maintenance, social functioning, and community living skills. 2. Patients were categorized according to their levels of functioning and diagnoses, and were assigned to programs that were developed to meet the needs of a specific group of patients. 3. The goals of the program were to enhance the quality of life for the patients; promote self-direction and capacity for self-care by increasing the patient's opportunities to make life decisions; and prepare the patients to live in a less restrictive environment.