Neurotrophins are not required for normal embryonic development of olfactory neurons.

Neurons of the vertebrate olfactory epithelium (OE) regenerate continuously throughout life. The capacity of these neurons to regenerate and make new and precise synaptic connections in the olfactory bulb provides a useful model to study factors that may control or mediate neuronal regeneration. Expression and in vitro studies have suggested potential roles for the neurotrophins in the olfactory system. To directly examine whether neurotrophins are required for olfactory neuron development, we characterized in vivo the role of the neurotrophins in the primary olfactory system. For this, we generated mutant mice for TrkA, TrkB, TrkC, and also for BDNF and NT3 together with P2-IRES-tau-LacZ trangenic mice. Histochemical staining for beta-galactosidase at birth allowed in vivo analysis of the P2 subpopulation of olfactory neurons as well as their projections to the olfactory bulb. Our data indicate that Trk signaling is not required for normal embryonic development of the olfactory system.

Molecular cloning of neuropathy target esterase (NTE).

Covalent modification of NTE, a neuronal protein with serine esterase activity, by certain organophosphates (OP) initiates degeneration of long axons in the peripheral and central nervous system. Simple inhibition of NTE esterase activity does not initiate neuropathy; the latter requires aging of the OP bound to the catalytic serine residue so that a negatively-charged species is left attached to the active site. This may indicate that a non-esterase function of NTE is important for axonal maintenance. We have recently cloned NTE and shown that it is unrelated to any known serine hydrolases but contains a novel C-terminal domain which is conserved from bacteria to man. Furthermore, the catalytic serine is located within this domain at the centre of a helical hydrophobic segment of the polypeptide's secondary structure. The integrity of NTE would be severely compromised by the presence of a negatively-charged organophosphate moiety at this site. Implications for possible higher-order structures and functions for NTE are discussed.

Developing a nursing outcomes measurement tool.

In an era of rapidly shifting resources and changing models of care, healthcare providers must demonstrate quality and cost-effective patient care. Historically, quality of care has been described using administrative variables such as mortality, morbidity, length of stay, readmissions, and cost. Methods have not been readily available to define quality in terms of the effect of care delivery on the health of patients. Combined administrative and health-related databases are foundational to outcome infrastructures evolving with the electronic medical record. Nursing leaders in a large health maintenance organization sponsored the development of the Health Status Outcome Dimensions (HSOD) instrument. The HSOD instrument includes measures of functional status, knowledge, and engagement in healthcare and the patient and family psychosocial well-being. This article describes the processes used and the challenges faced in the development of the HSOD instrument. The current status of the HSOD instrument is described, as well as its planned future development.

Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man.

The N-terminal amino acid sequences of proteolytic fragments of neuropathy target esterase (NTE), covalently labelled on its active-site serine by a biotinylated organophosphorus ester, were determined and used to deduce the location of this serine residue and to initiate cloning of its cDNA. A putative NTE clone, isolated from a human foetal brain cDNA library, encoded a 1327 residue polypeptide with no homology to any known serine esterases or proteases. The active-site serine of NTE (Ser-966) lay in the centre of a predicted hydrophobic helix within a 200-amino-acid C-terminal domain with marked similarity to conceptual proteins in bacteria, yeast and nematodes; these proteins may comprise a novel family of potential serine hydrolases. The Swiss Cheese protein which, when mutated, leads to widespread cell death in Drosophila brain [Kretzschmar, Hasan, Sharma, Heisenberg and Benzer (1997) J. Neurosci. 17, 7425-7432], was strikingly homologous to NTE, suggesting that genetically altered NTE may be involved in human neurodegenerative disease.

Health status measurement in computer-based patient record systems.

As requests for information about quality of health care have increased, purchasers of computer-based patient record (CPR) systems are demanding information regarding the manner in which these systems can assist in measuring health care quality. The type of information requested by purchasers of health care, accrediting agencies, and consumer groups is shifting toward more complex measures of health status. Both provider and patient perceptions of health status are relevant in measuring the impact of health care interventions. Standardized coding and classification systems and standardized health status measurement instruments each offer utility in capturing and representing health status in CPR systems.

Nurses use of health status data to plan for patient care: implications for the development of a computer-based outcomes infrastructure.

The purpose of this study was to examine the relationships between the patient's health status at hospital admission and the initial care planned by the nurse. Functional status, engagement in care, and psychosocial well-being were measured by the Health Status Outcome Dimensions(HSOD) instrument. The HSOD is the foundation for developing a computer-based infrastructure for the analysis of health related outcomes. The consecutive, convenience sample of 308 subjects was drawn from five acute clinical populations: pulmonary; cerebrovascular, cardiac; gastrointestinal; and infection. Logistic and multiple regression analyses were used to test the relationships between control (patient and setting) variables, health status, and the dependent variables of type of problem identified, number of problems identified, and the time required to implement interventions ordered for the patient. In seven of ten models, control variables of facility, age, and/or severity of illness contributed to a model at p < .01. In six of ten models, at least one health status measure significantly explained variation beyond the control variables, at p < .01. Study results support using data gathered during the course of care, to evaluate the process of that care. Further work is needed to understand the effects of setting and provider variables on the use of health status data in care planning. Computer-based outcomes infrastructures are essential to support the collection and analysis of health status over time.

Developing a generic health status measure for use in a computer-based outcomes infrastructure.

This descriptive, correlational study was designed to determine the sensitivity of a generic health status instrument to patient population and to time. The study sample included adult patients undergoing total joint replacement (TJR), adult patients in acute congestive heart failure (CHF), and pediatric patients receiving chemotherapy (PediOnc). A 2 x 3 (population x time) ANOVA for TJR and CHF demonstrated a significant main effect of time (F = 8.0, p = .0006) and a significant interaction effect between time and population (F = 14.4, p < .0001) for functional status. In the PediOnc subsample (HSOD child version), the highest scores for all HSOD factors with the exception of functional status were at Time 3. There was also a significant main effect of time on health care involvement, on the caregiver factor, and the family factor. These results support the sensitivity of the HSOD to patient population and to time.

The imperative of outcomes analysis: an integration of traditional and nontraditional outcomes measures.

The health care industry is compelled to reduce costs while providing high-quality patient care. Outcomes analysis enables monitoring and maintenance of quality of care in our rapidly changing practice environment. Comprehensive outcomes research cannot occur, however, without a database incorporating practice-related data, interventions and components of care, and outcomes of care. The article reports the design and proposed implementation of an outcomes assessment infrastructure in a multifacility health maintenance organization in Northern California. The infrastructure integrates traditionally measured outcomes and cost data with nontraditional, nurse-influenced, health-related outcomes.

Developing an outcomes infrastructure for nursing. The Outcomes Taskforce.

An infrastructure to support the evaluation of patient care sensitive to the intervention of nursing personnel is being developed within a major health maintenance organization. In addition to traditional administrative measures of care, the database infrastructure will include measures of the patient's functional status, knowledge and engagement in care and psychosocial well-being. These measures are believed to be particularly sensitive to the independent intervention of the nurse. Reported here are the structures in place to monitor and support the reliability and validity of the administrative data elements; algorithm elements created to account for missing data; the model for the first generation of successful practice reports and the results of a study establishing the content validity of the clinical data elements.

Genetic linkage between von Hippel-Lindau disease and three microsatellite polymorphisms refines the localisation of the VHL locus.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and presymptomatic diagnosis using linked DNA markers is available. We have previously mapped the VHL disease gene to a 4 cM interval between D3S1250 and D3S18. To increase access to presymptomatic diagnosis and to accelerate progress towards isolating the VHL disease gene we attempted to identify microsatellite DNA markers linked to the disease gene by genetic linkage analysis in 29 families. We found significant linkage between the VHL disease gene and dinucleotide (CA) repeat polymorphisms at D3S1038 (Zmax = 22.24 at theta = 0.01, CI 0.0001-0.06), D3S1110 (Zmax = 11.32 at theta = 0.07, CI 0.03-0.14) and D3S651 (Zmax = 7.73 at theta = 0.04, CI 0.008-0.13). We localised D3S1038 between D3S1250 and D3S601, and mapped D3S1110 and D3S651 centromeric to D3S1250. Multipoint linkage analysis mapped the VHL disease locus between D3S1038 and D3S18 with the maximum likelihood at D3S601. There was no evidence of locus heterogeneity. This study has (i) identified three microsatellite DNA markers in chromosome 3p25 linked to the VHL disease gene and (ii) narrowed the target region for the isolation of the VHL disease gene by positional cloning techniques. These findings will improve the management of families with VHL disease by improving the accuracy and availability of presymptomatic diagnosis using linked DNA markers, and will accelerate progress towards isolating the VHL disease gene.

Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited familial cancer syndrome characterised by a predisposition to the development of retinal, cerebellar, and spinal haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. We report the detailed genetic mapping of the VHL disease locus in 38 families. Significant linkage was detected between VHL disease and D3S601 (Zmax = 18.86 at theta = 0.0, CI 0.0-0.025), D3S18 (Zmax = 11.42 at theta = 0.03, CI 0.005-0.08), RAF1 (Zmax = 11.02 at theta = 0.04, CI 0.007-0.01), and D3S1250 (Zmax = 4.73 at theta = 0.05, CI 0.005-0.15). Multipoint linkage analysis mapped the VHL disease locus between D3S1250 and D3S18 close to D3S601. There was no evidence of locus heterogeneity. This study has (1) confirmed the tight linkage between VHL disease and D3S601, (2) identified D3S1250 as the first marker telomeric to RAF1 which maps centromeric to the VHL disease gene, and (3) narrowed the target region for isolation of the VHL disease gene by positional cloning techniques to a 4 cM interval between D3S1250 and D3S18. These findings will improve the clinical management of families with VHL disease by improving the accuracy of presymptomatic diagnosis using linked DNA markers, and will enhance progress towards isolating the VHL disease gene.

Multiple self-healing squamous epitheliomata (ESS1) mapped to chromosome 9q22-q31 in families with common ancestry.

A gene (ESS1) predisposing to the development of multiple invasive but self-healing skin tumours (squamous cell epitheliomata) is tightly linked to the polymorphic DNA marker D9S53 (9q31) with a maximum lod score of 9.02 at a recombination fraction of 0.03. Multipoint linkage analysis demonstrates that the disease locus is most likely to lie between D9S58 (9q22.3-31) and ASSP3 (9q11-q22). Comparison of markers associated with ESS1 in independently ascertained families suggests a common origin of the disease and defines the location of ESS1. Haplotype studies indicate that the disease locus is most likely to lie between D9S29 (9q31) and D9S1 (9q22.1-q22.2).

Dose-response relationship between objective measures of histamine-induced weals and dose of terfenadine.

Terfenadine is a safe non-sedative H1-receptor antagonist. This study aimed to quantify the relative reduction in weal and flare area, thickness and erythema at 4, 8, 12 and 24 h following a single but variable oral dose of terfenadine compared with pre-treatment measurements, in order to compare the dose-effect relationship and time course of the different dosages. In a double-blind randomized cross-over study, 12 healthy volunteers were given 60, 120 or 240 mg of terfenadine or placebo. Twenty micrograms of histamine acid phosphate was then injected intradermally at 4, 8, 12 and 24 h. The weal and flare areas were measured by planimetry, the thickness of the weal by an A-scan pulsed ultrasound device and the redness of both the weal and flare by an erythema-meter. A definite dose-response relationship was demonstrated between the weal and flare areas and the three active treatments. For the weal area, there was a significant difference between 60 mg and 240 mg of terfenadine at 4 h (p less than 0.01), at 8 and 12 h (p less than 0.05). For the flare area there was a similar significant difference at 4 h (p less than 0.01) and at 8 h (p less than 0.05). A dose-response relationship was demonstrated between weal erythema and 120 mg or 240 mg and 60 mg of terfenadine (p less than 0.05). There was a correlation between the plasma levels of the major metabolite and the initial dose of terfenadine, demonstrating their expected proportionality. This metabolite was also demonstrated in tissue fluid.

Dyspnea in the ventilator-assisted patient.

Our purpose in this study was to investigate the factors coincident with the occurrence of dyspnea in ventilator-assisted patients. Five alert and oriented patients with pulmonary disease that was restrictive, obstructive, or both, who were receiving mechanical ventilation, participated in this descriptive study. At 4-hour intervals and at complaint of dyspnea, patients quantified the severity of their dyspnea using the visual analogue and modified Borg scales. At each measurement of dyspnea, nurses observed concomitant physiologic and environmental variables. A moderate correlation (r = 0.51, p less than 0.001) was found between the number of events and activities occurring in the intensive care unit environment and the occurrence and severity of dyspnea. The visual analogue scale and modified Borg scale measures of dyspnea were highly correlated (r = 0.92, p less than 0.001) and may be useful tools for assessing dyspnea in patients undergoing mechanical ventilation.