Impact of right-handedness on anaesthetic sensitivity, intra-operative awareness and postoperative mortality.

Anatomical, neurological and behavioural research has suggested differences between the brains of right- and non-right-handed individuals, including differences in brain structure, electroencephalogram patterns, explicit memory and sleep architecture. Some studies have also found decreased longevity in left-handed individuals. We therefore aimed to determine whether handedness independently affects the relationship between volatile anaesthetic concentration and the bispectral index, the incidence of definite or possible intra-operative awareness with explicit recall, or postoperative mortality. We studied 5585 patients in this secondary analysis of data collected in a multicentre clinical trial. There were 4992 (89.4%) right-handed and 593 (10.6%) non-right-handed patients. Handedness was not associated with (a) an alteration in anaesthetic sensitivity in terms of the relationship between the bispectral index and volatile anaesthetic concentration (estimated effect on the regression relationship -0.52 parallel shift; 95% CI -1.27 to 0.23, p = 0.17); (b) the incidence of intra-operative awareness with 26/4992 (0.52%) right-handed vs 1/593 (0.17%) non-right-handed (difference = 0.35%; 95% CI -0.45 to 0.63%; p = 0.35); or (c) postoperative mortality rates (90-day relative risk for non-right-handedness 1.19, 95% CI 0.76-1.86; p = 0.45). Thus, no change in anaesthetic management is indicated for non-right-handed patients.

The effects of the presence of stored product pests on the microfauna of a flour community.

AIMS: To determine the effect that the presence of some beetles have on the species of bacteria found in their flour. METHODS AND RESULTS: Bacteria were isolated from flour that either did not contain beetles, contained Tribolium beetles in different environments, or contained either Stegobium paniceum or Lasioderma serricorne. These bacteria were tentatively identified by both the gas chromatography-fatty acid methyl esters (GC-FAME) method and partial sequencing of the 16S rRNA gene. All samples contained Bacillus species including the controls, but the non-Tribolium beetles and a Tribolium beetle line known to have low benzoquinones also contained Enterococcus and Enterobacter species. Additionally an unidentified bacteria isolate in the Enterobacteriaceae was also found in the L. serricorne sample. Our results also suggest incongruent identifications when using the GC-FAME method vs sequencing. CONCLUSIONS: Certain species of bacteria can be introduced by the presence of insect pests, but the diversity of species is far less in stocks of Tribolium beetles. SIGNIFICANCE AND IMPACT OF THE STUDY: Stored product pests can alter the bacterial community. Isolated species from this study show a strong genetic relationship to each other, suggesting an isolated evolving system. A unique bacteria was also isolated. GC and sequencing methods of identification are compared.

Program revision: a dynamic outcome of evaluation.

This critical review of program revision processes is guided by the program management model and considers issues germane to community-oriented health care programs, illustrated by examples from the literature. Options for program revision lie on a continuum from discontinuing a program, to various degrees of adjustments, to no change. Sustainability is the ultimate issue that must be addressed, and community and staff participation is critical for successful program revision.

Structural roles of acetylcholinesterase variants in biology and pathology.

Apart from its catalytic function in hydrolyzing acetylcholine, acetylcholinesterase (AChE) affects cell proliferation, differentiation and responses to various insults, including stress. These responses are at least in part specific to the three C-terminal variants of AChE which are produced by alternative splicing of the single ACHE gene. 'Synaptic' AChE-S constitutes the principal multimeric enzyme in brain and muscle; soluble, monomeric 'readthrough' AChE-R appears in embryonic and tumor cells and is induced under psychological, chemical and physical stress; and glypiated dimers of erythrocytic AChE-E associate with red blood cell membranes. We postulate that the homology of AChE to the cell adhesion proteins, gliotactin, glutactin and the neurexins, which have more established functions in nervous system development, is the basis of its morphogenic functions. Competition between AChE variants and their homologs on interactions with the corresponding protein partners would inevitably modify cellular signaling. This can explain why AChE-S exerts process extension from cultured amphibian, avian and mammalian glia and neurons in a manner that is C-terminus-dependent, refractory to several active site inhibitors and, in certain cases, redundant to the function of AChE-like proteins. Structural functions of AChE variants can explain their proliferative and developmental roles in blood, bone, retinal and neuronal cells. Moreover, the association of AChE excess with amyloid plaques in the degenerating human brain and with progressive cognitive and neuromotor deficiencies observed in AChE-transgenic animal models most likely reflects the combined contributions of catalytic and structural roles.

Advanced practice community health nursing in community nursing centers: a holistic approach to the community as client.

Community nursing centers are unique arenas for advanced practice community health nursing. These innovative nurse-managed delivery models are grounded in a holistic approach to the community-as-client. They provide the public with direct access to a range of advanced practice professional nursing services that are not otherwise available. Community Nursing Centers are collaborative with other health professions and organizations. They aim to meet the assessed needs of underserved populations using extant resources to achieve optimal health for all members of the community. This article discusses the underlying conceptual basis for development of community nursing centers and provides a case study example.

Neurobiology.

The IBRO World Congress of Neuroscience covered the full spectrum of neuroscience, from molecular and developmental neurobiology to behavioral pharmacology and neurodegeneration.

Efficacious topical treatment for murine cutaneous leishmaniasis with ethanolic formulations of amphotericin B.

The goal of the present study was to evaluate the antileishmanial effects of topically applied lipid-based formulations containing amphotericin B (AmB) in CBA mice as a model for human cutaneous leishmaniasis. Such treatment, if efficacious, is expected to be superior to systemic treatments since, by acting in a localized manner, it will require lower, and therefore less toxic, drug dosages. Three preparations of AmB complexed to polar lipids were tested: Fungizone (mixed micelles composed of AmB and deoxycholate), Amphocil (AmB and cholesteryl sulfate complex), and ABPLC (AmB and phospholipid complex). All these formulations killed parasites in vitro with similar efficacies but were ineffective when they were applied topically. However, Amphocil and ABPLC, but not Fungizone, when dispersed in an aqueous solution containing 5 to 25% ethanol, induced a statistically significant improvement in lesion size from week 2 or 3 onward (a total of 15 mg of AmB per kg of body weight was applied over 3 weeks). AmB biodistribution measurements following topical application of Amphocil, determined by high-pressure liquid chromatography, showed that AmB was detectable in the skin but not in the internal organs. Application of at least 10 times more drug was necessary to obtain detectable levels of AmB in the internal organs. After application of therapeutic doses of ABPLC, very low levels of AmB were detected in the internal organs. These experiments show for the first time that AmB administered topically as a complex either with cholesteryl sulfate or with phospholipids and in the presence of ethanol can penetrate the skin and kill sensitive organisms in a localized manner by using very low total drug concentrations.

Foot care: an innovative nursing service in a community nursing center.

In this article we describe how providing regular foot care for the residents of public housing at an on-site nursing clinic has become a vital part of the clinic's services for the elderly and disabled residents. Good foot care contributes significantly to the health and well-being of elderly and at-risk groups of clients. With relatively little extra education for the nursing staff and for minimal cost, foot care can become an integral part of nursing services provided in many different types of community health settings. A framework for initiating and implementing a foot care program is highlighted.

In vitro phosphorylation of acetylcholinesterase at non-consensus protein kinase A sites enhances the rate of acetylcholine hydrolysis.

Here, we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) but not casein kinase II or protein kinase C phosphorylates recombinant human acetylcholinesterase (AChE) in vitro. This enhances acetylthiocholine hydrolysis up to 10-fold as compared to untreated AChE, while leaving unaffected the enzyme's affinity for this substrate and for various active and peripheral site inhibitors. Alkaline phosphatase treatment enhanced the electrophoretic migration, under denaturing conditions, of part of the AChE proteins isolated from various mammalian sources and raised the isoelectric point of some of the treated AChE molecules, indicating that part of the AChE molecules are also phosphorylated in vivo. Enhancement of acetylthiocholine hydrolysis also occurred with Torpedo AChE, which has no consensus motif for PKA phosphorylation. Further, mutating the single PKA site in human AChE (threonine-249) did not prevent this enhancement, suggesting that in both cases it was due to phosphorylation at non-consensus sites. In vivo suppression of the acetylcholine hydrolyzing activity of AChE and consequent impairment in cholinergic neurotransmission occur under exposure to both natural and pharmacological compounds, including organophosphate and carbamate insecticides and chemical warfare agents. Phosphorylation of AChE may possibly offer a rapid feedback mechanism that can compensate for impairments in cholinergic neurotransmission, modulating the hydrolytic activity of this enzyme and enabling acetylcholine hydrolysis to proceed under such challenges.

Overlapping drug interaction sites of human butyrylcholinesterase dissected by site-directed mutagenesis.

Butyrylcholinesterase [BuChE (acylcholine acyl hydrolase); EC 3.1.1.8] limits the access of drugs, including tacrine, to other proteins. The "atypical" BuChE variant, in which Asp70 at the rim of the active site gorge is substituted by glycine, displayed a more drastically weakened interaction with tacrine than with cocaine, dibucaine, succinylcholine, BW284c51 [1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide], or alpha-solanine. To delineate the protein domains that are responsible for this phenomenon, we mutated residues within the rim of the active site gorge, the region parallel to the peripheral site in the homologous enzyme acetylcholinesterase [AChE (acetylcholine acetyl hydrolase); EC 3.1.1.7], the oxyanion hole, and the choline-binding site. When expressed in microinjected Xenopus laevis oocytes, all mutant DNAs yielded comparable amounts of immunoreactive protein products. Most mutants retained catalytic activity close to that of wild-type BuChE and were capable of binding ligands. However, certain modifications in and around the oxyanion hole caused a dramatic loss in activity. The affinities for tacrine were reduced more dramatically than for all other ligands, including cocaine, in both oxyanion hole and choline-binding site mutants. Modified ligand affinities further demonstrated a peripheral site in residues homologous with those of AChE. BuChE mutations that prevented tacrine interactions also hampered its ability to bind other drugs and inhibitors, which suggests a partial overlap of the binding sites. This predicts that in addition to their genetic predisposition to adverse responses to tacrine, homozygous carriers of "atypical" BuChE will be overly sensitive to additional anticholinesterases and especially so when exposed to several anticholinesterases in combination.

IgG immunoglobulins induce activation of the sphingomyelin cycle in HL-60 cells.

In HL-60 cells signal transduction via sphingomyelin hydrolysis (sphingomyelin cycle) is induced by binding of tumor necrosis factor alpha (TNFalpha) to cell surface TNFalpha receptor. We found that IgG immunoglobulins activate sphingomyelin hydrolysis in plasma membrane of HL-60 cells, with kinetics similar to that of activation by TNFalpha. Activation was induced by different IgG isotypes (most of which are irrelevant to known inducers of the sphingomyelin cycle) and also by Fcgamma fragments of IgG. The facts that inhibiting the binding of the antibodies to the cell surface by protein A prevents activation of sphingomyelin hydrolysis and that soluble TNF receptor of 55-kDa subtype (TBP55) inhibits activation, suggest that the mechanism of IgG-induced sphingomyelin hydrolysis involves binding of IgGs through their Fcgamma domain to Fcgamma surface receptors which mediate autocrine secretion of TNFalpha. The latter is responsible for inducing sphingomyelin hydrolysis. This study suggests that TBP55 may be an effective inhibitor of the sphingomyelin cycle.

The relationship between resource constraints and physician problem solving. Implications for improving the process of care.

OBJECTIVES: Research suggests that physicians will engage in more vigilant problem-solving under conditions of resource constraints than under conditions of resource slack. Increased vigilance related to physicians' clinical strategies enhances care by disposing physicians toward more optimal care choices. The authors examine whether pressures for clinical resource constraints encourage increased and sustained vigilance in problem-solving among cardiologists treating acute myocardial infarction. METHODS: The physician problem-solving process is reconstructed from the medical records of all eligible cases of acute myocardial infarction treated by the physician sample set over a 6-year period. The sample period encompasses phases of both resource slack and resource constraints. The Herfindahl index is used to measure the relative amount of vigilant problem-solving activity exhibited in each of five major tactical areas of the physician care strategies in each year of the study. RESULTS: The results support the hypothesis that resource constraints initially promote a shift to increased vigilance in physician problem-solving. Only one of the five major tactical areas, however, is characterized by sustained vigilance over time. The other areas are, instead, associated with a substantial reduction in vigilant activity after the initial peak period. CONCLUSIONS: The results suggest that resource constraints do set the stage for improved clinical decision-making. Sustained vigilance, however, appears to apply only to those portions of the care strategy for which the physician can draw a clear link between optimizing clinical activity and reducing resource consumption. For those portions of the care strategy for which the physician cannot establish a clear link, ongoing pressures to conserve resources results in reduced vigilance and a potential reduction in quality of clinical decision-making.

Doctoral education in community health nursing: a national survey.

The purpose of this study was to identify content areas specific to community health nursing in doctoral programs throughout the United States. The research foci related to community health nursing were compared with previously identified research priorities in the field. Surveys were sent to 52 doctoral program directors; 23 questionnaires were completed. Telephone interviews were conducted with 16 program directors to clarify responses. Newer programs tended to be more generally focussed and without doctoral specialty courses of any kind. The four programs that identified community health nursing as a specialty within their curriculum were some of the oldest and largest programs in the country.

Community development theory. Planning a community nursing center.

The authors describe the use of community development theory to assess the need for a community-based, nurse-managed primary care clinic. A community development model provided the framework for citizen participation in identifying collective health needs of public housing residents. The model facilitated the following: 1) planning for delivery of culturally appropriate primary care services that respond to health needs perceived by community residents; 2) ensuring acceptability and use of services; and 3) empowering residents to take responsibility for their own health. This article focuses on the assessment phase of the model and meeting the perceived needs of community residents.

Genetic predisposition to adverse consequences of anti-cholinesterases in 'atypical' BCHE carriers.

Normal butyrylcholinesterase (BuChE), but not several of its common genetic variants, serves as a scavenger for certain anti-cholinesterases (anti-ChEs). Consideration of this phenomenon becomes urgent in view of the large-scale prophylactic use of the anti-ChE, pyridostigmine, during the 1991 Persian Gulf War, in anticipation of nerve gas attack and of the anti-ChE, tacrine, for improving residual cholinergic neurotransmission in Alzheimer's disease patients. Adverse symptoms were reported for subjects in both groups, but have not been attributed to specific causes. Here, we report on an Israeli soldier, homozygous for 'atypical' BuChE, who suffered severe symptoms following pyridostigmine prophylaxis during the Persian Gulf War. His serum BuChE and recombinant 'atypical' BuChE were far less sensitive than normal BuChE to inhibition by pyridostigmine and several other carbamate anti-ChEs. Moreover, atypical BuChE demonstrated 1/200th the affinity for tacrine of normal BuChE or the related enzyme acetylcholinesterase (AChE). Genetic differences among BuChE variants may thus explain at least some of the adverse responses to anti-ChE therapies.

Successive organophosphate inhibition and oxime reactivation reveals distinct responses of recombinant human cholinesterase variants.

To explore the molecular basis of the biochemical differences among acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and their alternative splicing and allelic variants, we investigated the acylation phase of cholinesterase catalysis, using phosphorylation as an analogous reaction. Rate constants for organophosphate (DFP) inactivation, as well as for oxime (PAM)-promoted reactivation, were calculated for antibody-immobilized human cholinesterases produced in Xenopus oocytes from natural and site-directed variants of the corresponding DNA constructs. BuChE displayed inactivation and reactivation rates 200- and 25-fold higher than either product of 3'-variable AChE DNAs, consistent with a putative in vivo function for BuChE as a detoxifier that protects AChE from inactivation. Chimeric substitution of active site gorge-lining residues in BuChE with the more anionic and aromatic residues of AChE, reduced inactivation 60-fold but reactivation only 4-fold, and the rate-limiting step of its catalysis appeared to be deacylation. In contrast, a positive charge at the acyl-binding site of BuChE decreased inactivation 8-fold and reactivation 30-fold. Finally, substitution of Asp70 by glycine, as in the natural 'atypical' BuChE variant, did not change the inactivation rate yet reduced reactivation 4-fold. Thus, a combination of electrostatic active site charges with aromatic residue differences at the gorge lining can explain the biochemical distinction between AChE and BuChE. Also, gorge-lining residues, including Asp70, appear to affect the deacylation step of catalysis by BuChE. Individuals carrying the 'atypical' BuChE allele may hence be unresponsive to oxime reactivation therapy following organophosphate poisoning.

Engineering of human cholinesterases explains and predicts diverse consequences of administration of various drugs and poisons.

The acetylcholine hydrolyzing enzyme, acetylcholinesterase, primarily functions in nerve conduction, yet it appears in several guises, due to tissue-specific expression, alternative mRNA splicing and variable aggregation modes. The closely related enzyme, butyrylcholinesterase, most likely serves as a scavenger of toxins to protect acetylcholine binding proteins. One or both of the cholinesterases probably also plays a non-catalytic role(s) as a surface element on cells to direct intercellular interactions. The two enzymes are subject to inhibition by a wide variety of synthetic (e.g., organophosphorus and carbamate insecticides) and natural (e.g., glycoalkaloids) anticholinesterases that can compromise these functions. Butyrylcholinesterase may function, as well, to degrade several drugs of interest, notably aspirin, cocaine and cocaine-like local anesthetics. The widespread occurrence of butyrylcholinesterase mutants with modified activity further complicates this picture, in ways that are only now being dissected through the use of site-directed mutagenesis and heterologous expression of recombinant cholinesterases.