Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits.

BACKGROUND: Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. METHODS: RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5-7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi-Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5-7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5-7. RESULTS: Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. CONCLUSION: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice.

BACKGROUND: Isoflurane is widely used for anaesthesia in humans. Isoflurane exposure of rodents prior to post-natal day 7 (PND7) leads to widespread neurodegeneration in laboratory animals. Previous data from our laboratory suggest an attenuation of apoptosis with the p75 neurotrophin receptor (p75NTR) inhibitor TAT-Pep5. We hypothesized that isoflurane toxicity leads to behavioural and cognitive abnormalities and can be rescued with pre-anaesthesia administration of TAT-Pep5. METHODS: Neonatal mouse pups were pretreated with either TAT-Pep5 (25 µl, 10 µM i.p.) or a scrambled control peptide (TAT-ctrl; 25 µl, 10 µM i.p.) prior to isoflurane exposure (1.4%; 4 h) or control ( n = 15-26/group). Three to 5 months after exposure, behavioural testing and endpoint assays [brain volume (stereology) and immunoblotting] were performed. RESULTS: No significant difference was observed in open field, T-maze, balance beam or wire-hanging testing. The Barnes maze revealed a significant effect of isoflurane ( P = 0.019) in errors to find the escape tunnel during the day 5 probe trial, a finding indicative of impaired short-term spatial memory. No difference was found for brain volumes or protein expression. TAT-Pep5 treatment did not reverse the effects of isoflurane on neurocognitive behaviour. CONCLUSION: A single isoflurane exposure to early post-natal mice caused a hippocampal-dependent memory deficit that was not prevented by pre-administration of TAT-Pep5, although TAT-Pep5, an inhibitor of p75NTR, has been shown to reduce isoflurane-induced apoptosis. These findings suggest that neuronal apoptosis is not requisite for the development of cognitive deficits in the adults attendant with neonatal anaesthetic exposure.

Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae.

G-protein-coupled receptors (GPCRs) and post-GPCR signalling components are expressed at low overall abundance in plasma membranes, yet they evoke rapid, high-fidelity responses. Considerable evidence suggests that GPCR signalling components are organized together in membrane microdomains, in particular lipid rafts, enriched in cholesterol and sphingolipids, and caveolae, a subset of lipid rafts that also possess the protein caveolin, whose scaffolding domain may serve as an anchor for signalling components. Caveolae were originally identified based on their morphological appearance but their role in compartmentation of GPCR signalling has been primarily studied by biochemical techniques, such as subcellular fractionation and immunoprecipitation. Our recent studies obtained using both microscopic and biochemical methods with adult cardiac myocytes show expression of caveolin not only in surface sarcolemmal domains but also at, or close to, internal regions located at transverse tubules/sarcoplasmic reticulum. Other results show co-localization in lipid rafts/caveolae of AC (adenylyl cyclase), in particular AC6, certain GPCRs, G-proteins and eNOS (endothelial nitric oxide synthase; NOS3), which generates NO, a modulator of AC6. Existence of multiple caveolin-rich microdomains and their expression of multiple modulators of signalling strengthen the evidence that caveolins and lipid rafts/caveolae organize and regulate GPCR signal transduction in eukaryotic cells.

The effect of 7 days of creatine supplementation on 24-hour urinary creatine excretion.

Since the discovery that oral ingestion of creatine leads to an increase in intramuscular creatine, its supplementation has become widespread. However, the dosage necessary to maximize retention and create significant increases in intramuscular creatine is poorly understood. In this study, 24-hour urinary creatine and creatinine levels of 20 university men's football players and 20 university men's hockey players involved in a resistance-exercise program and supplementing with creatine were collected and analyzed. In a double-blind, randomized design, 10 football players and 10 hockey players were randomly assigned to either the supplement or placebo group. Subjects provided a 24-hour urine sample twice during the study: once prior to supplementation (baseline) and the second 7 days after daily supplementation and resistance exercise. Creatine dosage was 0.1 g x kg(-1) lean body mass. The quantity of creatine ingested was compared with the amount excreted in the urine of those subjects supplementing with creatine and with placebo. Creatinine levels were compared between the first and second urine collection and between groups. Creatine and creatinine concentrations were determined using high-performance liquid chromatography. In 24-hours, 46% of the ingested creatine was excreted. There was no change in creatine levels for placebo subjects. Creatinine levels remained the same within groups at the first and second collection times (p < 0.05). Our findings indicate that when supplementing with dosages of 0.1 g x kg(-1) lean body mass or between 6 and 8 g at a time, approximately half of the ingested creatine gets excreted. Because there was no change in urinary creatinine, it can be assumed that enhanced degradation of creatine did not occur.

The prognostication problem.

With increased focus on end-of-life care; prognosis may be finally receiving the attention it deserves. Hopefully, this will result in further research, the development of effective tools, and adequate education and training related to prognostication.

Hospice outcomes: meeting requirements and developing a national consensus.

This article describes the rationale for outcome measurement in hospice care and the requirements related to such measurement as stipulated by regulatory bodies, third party payers, and accreditation organizations. Also discussed are the end-result outcomes of hospice care and efforts by the National Hospice and Palliative Care Organization to develop consensus related to definition and measurement of these outcomes.

Treatment planning for success: wise choices for maxillary single-tooth implants.

The purpose of this article is to demonstrate to general practitioners who have no experience with dental implant treatment the esthetic limitations of such treatment. The criteria for wise case selection will be described so that esthetic excellence can be predictably achieved in general practice. A checklist of criteria will be provided as a treatment-planning tool to determine if a patient is likely to have an esthetically successful outcome.

Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity.

BACKGROUND: We tested the hypothesis that intracoronary injection of a recombinant adenovirus encoding adenylyl cyclase type VI (AC(VI)) would increase cardiac function in pigs. METHODS AND RESULTS: Left ventricular (LV) dP/dt and cardiac output in response to isoproterenol and NKH477 stimulation were assessed in normal pigs before and 12 days after intracoronary delivery of histamine followed by intracoronary delivery of an adenovirus encoding lacZ (control) or AC(VI) (1.4x10(12) vp). Animals that had received AC(VI) gene transfer showed increases in peak LV dP/dt (average increase of 1267+/-807 mm Hg/s; P=0.0002) and cardiac output (average increase of 39+/-20 mL. kg(-1). min(-1); P<0.0001); control animals showed no changes. Increased LV dP/dt was evident 6 days after gene transfer and persisted for at least 57 days. Basal heart rate, blood pressure, and LV dP/dt were unchanged, despite changes in cardiac responsiveness to catecholamine stimulation. Twenty-three hour ECG recordings showed no change in mean heart rate or ectopic beats and no arrhythmias. LV homogenates from animals receiving AC(VI) gene transfer showed increased AC(VI) protein content (P=0.0007) and stimulated cAMP production (P=0.0006), confirming transgene expression and function; basal LV AC activity was unchanged. Increased cAMP-generating capacity persisted for at least 18 weeks (P<0.0002). CONCLUSIONS: Intracoronary injection of a recombinant adenovirus encoding AC provides enduring increases in cardiac function.

Evaluation of dental erosion in patients with gastroesophageal reflux disease.

STATEMENT OF PROBLEM: The cause of dental erosion may be difficult to establish because of its many presentations. Determination of the cause is an important aspect of diagnosis before extensive prosthodontic rehabilitation. PURPOSE: This cross-sectional study evaluated the association between loss of tooth structure as a result of dental erosion and gastroesophageal reflux disease. MATERIAL AND METHODS: Twenty consecutive adult dentate subjects referred to the Division of Gastroenterology for investigation of gastroesophageal tract disease were also evaluated for signs of dental erosion. All subjects underwent a dental evaluation that included a patient history to determine potential etiologic factors responsible for dental erosion. Subjects were examined clinically to quantify loss of tooth structure using a Tooth Wear Index (TWI). Endoscopic examination and 24-hour pH manometry were carried out to determine which subjects met the criteria for gastroesophageal reflux disease (GERD). Scores for maxillary versus mandibular dentition and anterior versus posterior dentition were also compared. Data were analyzed with the Kruskal-Wallis test (P =.004). RESULTS: Ten subjects were diagnosed with GERD and 10 subjects had manometry scores below the level indicating GERD. Overall, subjects diagnosed with GERD had significantly higher TWI scores compared with control subjects (mean difference = 0.6554; P =.004). GERD subjects had higher TWI scores in all quadrants, except in the mandibular anterior region where there was no difference. CONCLUSION: The results indicated that a relationship exists between loss of tooth structure, as measured by the TWI index, and the occurrence of GERD in this group of subjects.

Two-step pick-up impression procedure for implant-retained overdentures.

This article describes a procedure that permits careful border correction and impression fabrication of an edentulous arch, followed by pick-up of implant impression copings. The resultant master cast is accurate in terms of soft tissue detail, position of implant components, and relationship between soft tissue and implants.

Patients and the Internet: guidance for evidence-based choices.

This paper discusses the uses of the Internet by the public to gather healthcare information. It reviews the types of information available and the pitfalls of random searches. It provides guidance for directed searches and advice for patients and practitioners seeking evidence-based sources. It discusses future directions and the growing responsibilities of professions to stay educated with regard to Internet technology.

The nursing outcomes taxonomy: development and coding.

Interest in the theoretical knowledgebase of nursing has increased over the last 25 years and has led to the current interest in middle-range theory development to describe the essence of nursing. This article describes the creation of a three-level taxonomy and coding structure for the Nursing Outcomes Classification (NOC) based on methods developed by the Nursing Interventions Classification (NIC) work. A model is presented depicting the importance of standardized nursing diagnoses, interventions, and outcomes in the development of the substantive component of nursing practice and to enable nurses to be accountable for care of their clients.

Outcomes for home and community nursing in integrated delivery systems.

In these tumultuous times in health care, nursing providers are under pressure to capture data that demonstrate the effectiveness of nursing interventions on client health. At the University of Iowa, researchers are attempting to develop a client outcome classification system that uses a standardized language across different health care settings to capture this vital information.

Erosion caused by gastroesophageal reflux: diagnostic considerations.

Dental erosion occurs with a high prevalence in the general population, but its impact on prosthodontic care is often unrecognized. The etiology of dental erosion is difficult to establish because it may result from a variety of causes and may have different presentations. Our purpose was to review the literature relevant to dental erosion and to report a patient presentation in which an unusual pattern of severe erosion was the dental manifestation of asymptomatic gastroesophageal reflux disease.