Suppression of heterochromatic gene variegation can be used to distinguish and characterize E(var) genes potentially important for chromosome structure in Drosophila melanogaster.

Hundreds of genic modifiers of position effect variegation (PEV) have been isolated in Drosophila melanogaster with a view to identifying genes important for chromosome structure. Here we propose a supplementary genetic screen to pinpoint candidate genes that are most likely to function in chromosome organization, within the enhancer of variegation [E(var)] class of modifiers. Our strategy takes advantage of the fact that variegating euchromatic and heterochromatic genes respond oppositely to changes in the dosage of heterochromatin proteins. Consequently, only when enhancement of euchromatic gene variegation results from increased formation of heterochromatin should suppression of heterochromatic gene variegation be observed. Mutations in four E(var) genes were tested for the ability to suppress variegation of multiple alleles of the heterochromatic light ( lt) gene in a variety of tissues and at several developmental stages. Mutations in E(var)3-4, E(var)3-5 and modifier of mdg4 [ mod(mdg4)] suppressed lt variegation. In contrast, a mutation in the Trithorax-like ( Trl) gene, which encodes GAGA factor, enhanced or had no effect on lt variegation, consistent with its known role in promoting transcription. These data show that suppression of lt variegation can be used as an assay to distinguish between members of the E(var) class of modifiers.

Chromosome rearrangements induce both variegated and reduced, uniform expression of heterochromatic genes in a development-specific manner.

In Drosophila melanogaster, chromosome rearrangements that juxtapose euchromatin and heterochromatin can result in position effect variegation (PEV), the variable expression of heterochromatic and euchromatic genes in the vicinity of the novel breakpoint. We examined PEV of the heterochromatic light (lt) and concertina (cta) genes in order to investigate potential tissue or developmental differences in chromosome structure that might be informative for comparing the mechanisms of PEV of heterochromatic and euchromatic genes. We employed tissue pigmentation and in situ hybridization to RNA to assess expression of lt in individual cells of multiple tissues during development. Variegation of lt was induced in the adult eye, larval salivary glands and larval Malpighian tubules for each of three different chromosome rearrangements. The relative severity of the effect in these tissues was not tissue-specific but rather was characteristic of each rearrangement. Surprisingly, larval imaginal discs did not exhibit variegated lt expression. Instead, a uniform reduction of the lt transcript was observed, which correlated in magnitude with the degree of variegation. The same results were obtained for cta expression. These two distinct effects of rearrangements on heterochromatic gene expression correlated with the developmental stage of the tissue. These results have implications for models of heterochromatin formation and the nuclear organization of chromosomes during development and differentiation.

Special care units for people with Alzheimer's disease. Only for the privileged few?

The number of Special Care Units (SCUs) for people with Alzheimer's disease (AD) in nursing homes have increased dramatically in the past 10 years. Despite the rapid increase in number of SCUs and the concern that most SCUs report higher costs than traditional nursing home units where residents with AD are integrated with cognitively intact residents, the evaluation of costs has been largely unsystematic and noncomparative. Studies are urgently needed to assess comparative costs so that administrators and policy makers can make informed decisions. This article reviews studies that examine the costs of care in SCUs and presents cost-related data comparing the outcomes of care for residents with AD on a SCU and on traditional units in one long-term care setting.

Quality of life more than 20 years after repair of esophageal atresia.

PURPOSE: To examine the quality of life after repair of esophageal atresia, follow-up studies were performed in 58 of 71 surviving patients (81.7%). METHODS: Fifty patients with primary anastomosis and all eight surviving patients with colon interposition were seen. The mean age was 25.3 years (range, 20 to 31). Symptoms were evaluated by a standardized interview. Quality of life assessment was performed using a visual analogue scale (0 to 100 points), the Spitzer Index (5 dimensions, 10 points), and the Gastrointestinal Quality of Life Index (GIQLI, 5 dimensions, 128 points). RESULTS: After primary anastomosis the estimated meal capacity was unrestricted in 46 patients (92%), but numerous symptoms such as recidivating cough (60%), hold up (48%), and short breath (30%) were reported. All symptoms except cough were seen more frequently in patients with colon interposition, and all of these patients suffered from periods of short breath. Quality of life scores were higher in patients with primary anastomosis compared with colon interposition. The difference in the visual analogue scale score did not reach statistical significance, but the mean Spitzer Index was 9.7 compared with 8.8 after colon interposition (P < .05). The GIQLI after primary anastomosis was similar to that in healthy controls and was significantly lower in patients with colon interposition. This was because of specific symptoms, which scored 49.3 after colon interposition compared with 61.7 after primary anastomosis (P < .05) and to 54.8 (SD 5) in healthy controls (P < .05). Physical and social functions, emotions, and inconvenience of a medical treatment scored similar in patients with primary anastomosis, colon interposition, and healthy volunteers. CONCLUSIONS: The long-term quality of life after primary anastomosis was excellent. Patients with colon interposition suffer more frequently from various gastrointestinal and respiratory symptoms, but they lead an otherwise normal life.

2'-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides.

Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)-guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.

Iowa nurses' knowledge of living wills and perceptions of patient autonomy.

The principle of patient autonomy is well recognized in the nursing profession. This study extends the exploration of patient autonomy by examining nurses' knowledge about living wills. The questions addressed in this study included the following: (1) Were Iowa nurses aware of the living will statute? (2) What sources of information did nurses use to learn about this legislation? (3) What were nurses' perceptions of patients' rights? (4) What were nurses' perceptions of nurses' role involving living wills? (5) Were living wills followed? (6) If not followed, which factors contributed to the failure to honor a living will? and (7) Which communication mechanisms were used to alert nurses to a living will? A questionnaire was mailed to 10,000 actively licensed nurses in Iowa. Approximately 3,000 Iowa nurses responded to the questionnaire regarding Iowa living wills. Seventy per cent of the nurses knew that Iowa had living will legislation. No single educational source was a predominate choice for targeted information about the living will statute. Nurses were reluctant to suggest to patients that they should consider writing a living will. Nurses were also more willing to assume a passive role of suggesting that patients talk with relatives about the need for a living will but were less likely to be suggest that a patient write a living will for future health care treatment decisions. The majority of the nurses favored the patient having some control in health care treatment decisions. Three major factors were pertinent to the failure to follow a living will: family request, treating physician's refusal, and lack of information that the living will existed. The medical record was the primary means of communication regarding a living will. To enhance patient efforts at self-determination, nurses must recognize the advance directive legislation is available in their state and the potential impact that their nursing care may have on the implementation of the document.

Mutations affecting donor preference during mating type interconversion in Saccharomyces cerevisiae.

Homothallic strains of Saccharomyces cerevisiae can convert mating type from a to alpha or alpha to a as often as every generation, by replacing genetic information specifying one mating type at the expressor locus, MAT, with information specifying the opposite mating type. The cryptic mating type information that is copied and inserted at MAT is contained in either of two loci, HML or HMR. The particular locus selected as donor during mating type interconversion is regulated by the allele expressed at MAT. MATa cells usually select HML, and MAT alpha cells usually select HMR, a process referred to as donor preference. To identify factors required for donor preference, we isolated and characterized a number of mutants that frequently selected the nonpreferred donor locus during mating type interconversion. Many of these mutants were found to harbor chromosome rearrangements or mutations at MAT or HML that interfered with the switching process. However, one mutant carried a recessive allele of CHL1, a gene previously shown to be required for efficient chromosome segregation during mitosis. Homothallic strains of yeast containing a null allele of CHL1 exhibited almost random selection of the donor locus in a MATa background but were normal in their ability to select HMR in a MAT alpha background. Our results indicate that Chl1p participates in the process of donor selection and are consistent with a model in which Chl1p helps establish an intrinsic bias in donor preference.

Heterochromatin and gene expression in Drosophila.

Heterochromatin is both necessary for the expression of heterochromatic genes and inhibitory for the expression of euchromatic genes. These two properties of heterochromatin have been elucidated from the study of chromosome rearrangements that induce position effect variegation (PEV) in Drosophila melanogaster. Novel euchromatin-heterochromatin junctions can affect the expression of euchromatic and heterochromatic genes located several megabases away, distinguishing higher order chromatin structure from most other regulatory mechanisms. Studies of PEV promise insights into the basis for heterochromatin formation and the role of higher order chromatin and chromosome structure in gene regulation. We evaluate the models and experimental data that address the mechanisms of PEV in different cell types, the potential functions of modifiers of PEV, and the relationship of PEV to other phenomena associated with variegated gene expression in Drosophila.

A dose-ranging study of the efficacy and safety of azelastine nasal spray in the treatment of seasonal allergic rhinitis with an acute model.

BACKGROUND: Oral azelastine, a nonsteroidal antiinflammatory respiratory investigational drug has demonstrated activity in the treatment of allergic rhinitis and asthma with a good safety profile. METHODS: Azelastine nasal spray was compared with sustained-release oral chlorpheniramine maleate and placebo for efficacy and safety in the treatment of seasonal allergic rhinitis in a double-dummy, two-center, 2-day, double-blind, randomized, dose-ranging, parallel-groups, onset and duration of action study. Two hundred sixty-four subjects reported to an outdoor park on Saturday morning during the height of the fall pollen season and remained there for 8 hours that day and the next to ensure maximal exposure to seasonal aeroallergens. Symptom diary cards were collected hourly Saturday from 8:00 AM to 10:00 AM (baseline period). Subjects who had sufficient symptoms were randomized into five groups and received medication at 10:00 AM and 10:00 PM on Saturday and at 10:00 AM on Sunday: azelastine 0.1% (1 spray [0.12 mg] per nostril every 12 hours, 2 sprays per nostril every every 12 hours, or 2 sprays per nostril once daily), Chlor-Trimeton Repetabs (12 mg twice daily), or placebo (twice daily). Diary cards were completed hourly (11:00 AM to 4:00 PM) and at 6:00, 8:00, and 10:00 PM on Saturday and again hourly on Sunday (from 8:00 AM to 4:00 PM) to evaluate rhinitis symptoms and adverse events. RESULTS: Two hundred fifty-nine subjects completed the study. The groups that received 2 sprays of azelastine per nostril once and twice daily and the chlorpheniramine group had statistically significantly more improvement in total rhinitis symptoms than the placebo group without serious adverse events. CONCLUSIONS: This study supports a once to twice daily dosing regimen for 2 sprays of 0.1% azelastine in the acute treatment of allergic rhinitis with onset of action within 2 to 3 hours.

Use of substitute decision makers by the mentally ill rural elderly: an issue of concern for mental health nurses.

In 1986, the Abbe Center for Community Mental Health implemented a nurse-led elderly outreach program (EOP) designed to identify and treat elderly rural residents in need of mental health care. Because some EOP clients evidenced a lack of or limited decision-making capacity, a record review was conducted to answer the following questions: Do any of the clients have a legal substitute decision maker? What are the forms of substitute decision making? Is there a familial relationship between the elderly client and the substitute decision maker? Is there evidence that any of the named legal substitute decision makers have abused the elder? Almost half the clients who had a substitute decision maker used a power of attorney. Adult children were the most frequent family members named as substitute decision makers. Four records indicated that an adult child had been given a power of attorney and that the child had potentially abused the parent. Implications for mental health nurses dealing with this vulnerable population are set forth.

Legal aspects of nursing documentation for the Alzheimer's patient.

1. Bergerson (1988) developed a set of charting rules called the FACT system (charting that is Factual, Accurate, Complete, and Timely). Nurses' notes are viewed as legal sources of documentation. 2. Nurse's notes made regarding the patient's cognitive status, ability to communicate and participate in treatment decisions, and safety needs may be carefully reviewed by the court system for a variety of reasons. 3. Nurses caring for patients with Alzheimer's disease must recognize that the primary function of any charting or documentation is optimal care for the individual patient. Nurses should not chart in anticipation of a legal review of the charting. However, nurses also must be aware that a legal challenge may prompt a review of the record and require the nurse to explain or clarify entries that have been made.