Long latency postural reflexes are under supraspinal dopaminergic control

Scaling of posturally stabilizing long latency (LL) reflexes in tibialis anterior muscles induced by "toe-up" rotational perturbations is abnormal in standing patients with Parkinson's disease. To investigate the contribution of dopaminergic pathways to abnormal scaling, we studied LL reflexes in 22 patients with selective hypodopaminergic syndromes: 10 psychiatric patients taking chronic neuroleptic medication (7 with mild parkinsonism), 8 patients with young-onset Parkinson's disease, and 4 patients with MPTP-induced parkinsonism. Results were compared with those of 10 healthy controls. Stimuli consisted of (a) 10 serial (predictable) perturbations of 4 degrees amplitude, (b) 10 serial (predictable) perturbations of 10 degrees amplitude, and (c) 20 randomly mixed (unpredictable) perturbations of either 4 or 10 degrees amplitude. In normal subjects, LL reflex amplitudes were adapted to match predictable variations in stimulus size, whereas under unpredictable conditions a "default" response emerged that anticipated the 10 degrees perturbation. LL reflex scaling under predictable conditions was intact in patients with neuroleptic-induced parkinsonism and young-onset Parkinson's disease, but the large default LL response under unpredictable conditions was absent. In patients with MPTP-induced parkinsonism, LL reflex scaling was absent during both predictable and unpredictable conditions. We conclude that abnormal scaling of posturally stabilizing LL reflexes is related to decreased supraspinal dopaminergic influence.     

Arginine 206 of the C5a receptor is critical for ligand recognition and receptor activation by C-terminal hexapeptide analogs

C5a is a 74-amino-acid glycoprotein whose receptor is a member of the rhodopsin superfamily. While antagonists have been generated to many of these receptors, similar efforts directed at family members whose natural ligands are proteins have met with little success. The recent development of hexapeptide analogs of C5a has allowed us to begin elucidation of the molecular events that lead to activation by combining a structure/activity study of the ligand with receptor mutagenesis. Removal of the hexapeptide's C-terminal arginine reduces affinity by 100-fold and eliminates the ability of the ligand to activate the receptor. Both the guanidino side chain and the free carboxyl of the arginine participate in the interaction. The guanidino group makes the energy-yielding contact with the receptor, while the free carboxylate negates "electrostatic" interference with Arg-206 of the receptor. It is the apparent movement Arg-206 induced by this set of interactions that is responsible for activation, since conversion of Arg-206 to alanine eliminates the agonist activity of the hexapeptides. Surprisingly, activation is a nearly energy-neutral event and may reflect the binding process rather than the final resting site of the ligand.     

The unanticipated difficult airway with recommendations for management

PURPOSE: To review the current literature and generate recommendations on the role of newer technology in the management of the unanticipated difficult airway. METHODS: A literature search using key words and filters of English language and English abstracted publications from 1990-96 contained in the Medline, Current Contents and Biological Abstracts databases was carried out. The literature was reviewed and condensed and a series of evidence-based recommendations were evolved. CONCLUSIONS: The unanticipated difficult airway occurs with a low but consistent incidence in anaesthesia practice. Difficult direct laryngoscopy occurs in 1.5-8.5% of general anaesthetics and difficult intubation occurs with a similar incidence. Failed intubation occurs in 0.13-0.3% general anaesthetics. Current techniques for predicting difficulty with laryngoscopy and intubation are sensitive, non-specific and have a low positive predictive value. Assessment techniques which utilize multiple characteristics to derive a risk factor tend to be more accurate predictors. Devices such as the laryngeal mask, lighted stylet and rigid fibreoptic laryngoscopes, in the setting of unanticipated difficult airway, are effective in establishing a patient airway, may reduce morbidity and are occasionally lifesaving. Evidence supports their use in this setting as either alternatives to facemask and bag ventilation, when it is inadequate to support oxygenation, or to the direct laryngoscope, when tracheal intubation has failed. Specifically, the laryngeal mask and Combitube have proved to be effective in establishing and maintaining a patent airway in "cannot ventilate" situations. The lighted stylet and Bullard (rigid) fibreoptic scope are effective in many instances where the direct laryngoscope has failed to facilitate tracheal intubation. The data also support integration of these devices into strategies to manage difficult airway as the new standard of care. Training programmes should ensure graduate physicians are trained in the use of these alternatives. Continuing medical education courses should allow physicians in practice the opportunity to train with these alternative devices.     

Focus groups reveal perils and promises of managed care for nurse practitioners

Decades of practice and research suggest that nurse practitioners (NPs) provide cost-effective and high-quality care. Managed care's emphasis on prevention and cost savings led some policy makers to view NPs as a way to meet the need for primary care providers. However, access to and utilization of NPs has increasingly been controlled by managed care organizations (MCOs) through their selection of providers for primary care panels. This study employed qualitative methodology to examine NPs' experiences with MCOs. Three focus groups, comprising 27 NPs in New York and Connecticut, revealed NPs' mixed reactions to managed care and a range of sentiments regarding NPs' efforts to be listed as primary care providers. The results reflected NPs' concerns about their perceived "invisibility," as well as their sense of "invincibility" in the ways in which NPs are responding to the barriers posed by MCOs. They identified barriers to, as well as ways to facilitate, being listed by MCOs, and described the importance of NPs working individually and collectively in negotiating with MCOs.     

Sprained ankle syndrome: prevalence and analysis of 639 acute injuries

OBJECTIVE: To document injury rates in professional rugby players in the Rugby Super 12 competition and to act as a pilot study for future studies of rugby injuries. DESIGN: Prospective longitudinal study encompassing the 1997 Super 12 rugby season. SETTING: A New Zealand Super 12 rugby squad. PATIENTS AND PARTICIPANTS: 25 professional rugby players (replacement players were used for unavailable players, so although 30 different players were used during the season, there were only 25 in the squad at any one time). OUTCOME MEASURES: An "injury" was defined as something that prevented a player from taking part in two training sessions, from playing the next week, or something requiring special medical treatment (suturing or special investigations). An injury was "significant" if it prevented the player from being able to play one week after sustaining it (that is, if it made the player miss the next match). RESULTS: The overall injury rate was 120/1000 player hours. The rate of significant injuries was 45/1000 player hours. Those playing the position of "forward" had a higher overall injury rate than other players, but there was no difference in significant injury rate between the forwards and the backs. Injuries that caused players to miss game time occurred almost exclusively during the pre-season program or in the final third of the season. The majority of injuries were musculo-tendinous sprains or strains. The phase of play responsible for the majority of injuries was the tackle. The most frequently injured body part was the head and face. No catastrophic injuries occurred during the study period. CONCLUSIONS: Injury rates increase with increasing grade of rugby, injury rates in the Super 12 competition being higher than in first grade rugby. There is very little quality data on rugby injuries, and the few studies available use different methods of data collection and injury definition. There is a pressing need for the collection of accurate ongoing epidemiological data on injuries in rugby.     

The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein

Flavin-containing monooxygenases (FMOs) are NADPH-dependent flavoenzymes that catalyze the oxidation of heteroatom centers in numerous drugs and xenobiotics. FMO2, or "pulmonary" FMO, one of five forms of the enzyme identified in mammals, is expressed predominantly in lung and differs from other FMOs in that it can catalyze the N-oxidation of certain primary alkylamines. We describe here the isolation and characterization of cDNAs for human FMO2. Analysis of the sequence of the cDNAs and of a section of the corresponding gene revealed that the major FMO2 allele of humans encodes a polypeptide that, compared with the orthologous protein of other mammals, lacks 64 amino acid residues from its C terminus. Heterologous expression of the cDNA revealed that the truncated polypeptide was catalytically inactive. The nonsense mutation that gave rise to the truncated polypeptide, a C --> T transition in codon 472, is not present in the FMO2 gene of closely related primates, including gorilla and chimpanzee, and must therefore have arisen in the human lineage after the divergence of the Homo and Pan clades. Possible mechanisms for the fixation of the mutation in the human population and the potential significance of the loss of functional FMO2 in humans are discussed.     

Comparison of CT and MR imaging in staging of neck metastases

OBJECTIVE: To determine whether adaptive cytoprotection exists in human intestinal cells under in vitro conditions and what role, if any, endogenous prostaglandins or calcium may play in mediating this protective response. SUMMARY BACKGROUND DATA: Adaptive cytoprotection can be defined as that process whereby the administration of a low concentration of a damaging agent, termed a "mild irritant," which by itself is not injurious, can attenuate gastrointestinal mucosal injury subsequently induced by the application of higher concentrations of the same or other necrotizing agents. Despite substantial investigation, the mediator or mediators of adaptive cytoprotection remain poorly understood. METHODS: Postconfluent Caco-2 cells were used in all experiments. Cellular death was quantitated using a dual-component fluorescent assay. Changes in intracellular calcium concentration were quantitated by measuring fluorescent signal changes of the single wavelength calcium indicator (Fluo-3). Finally, prostaglandin E2 release into the media was quantitated by radioimmunoassay. RESULTS: Pretreatment of Caco-2 cells with low concentrations of ethanol (mild irritant) significantly attenuated injury induced by higher damaging concentrations of ethanol. The protection conferred by the mild irritant was directly dependent on both the concentration of the irritant used and the duration of exposure and was abrogated when cells were pretreated with an endogenous prostaglandin inhibitor (indomethacin) or if the mild irritant was administered in calcium-free media. Cells exposed to ethanol had a significant and concentration-dependent increase in intracellular calcium concentration, an effect that was highly related to cellular injury. Pretreatment with a mild irritant significantly decreased intracellular calcium increases induced by not only ethanol but also by a calcium ionophore (A23187). Cells treated with low concentrations of ethanol demonstrated no significant elevation in prostaglandin E2 release. CONCLUSIONS: Adaptive cytoprotection induced by ethanol exists in human colonocytes under in vitro conditions independent of mucosal blood flow, neural innervation, or circulating humoral factors. The authors' data suggest that this response does not require endogenous prostaglandin synthesis but may involve processes whereby intracellular calcium accumulation is prevented.     

Protein topology of presenilin 1

Mutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.     

Effects of metal-contaminated soils on the growth, sexual development, and early cocoon production of the earthworm Eisenia fetida, with particular reference to zinc

Juvenile Eisenia fetida (Savigny) were exposed for 20 weeks to an uncontaminated soil and to soils contaminated with cadmium, copper, lead, and zinc collected from seven sites at different distances from a smelting works at Avonmouth, southwest England. The survival, growth (= weight after 5 weeks exposure), time to sexual maturation (= percentages of adults present after 8 weeks), and reproduction (= number of cocoons produced by the worms) were compared with soil metal concentrations. Of the parameters measured, growth and sexual maturation time had the lowest EC50 values. The effects of metal-contaminated soils could be attributed both to the direct toxicity of the metals and to changes in the "scope for growth" of the exposed worms. A comparison of the results with those of an earlier toxicity test conducted with adult worms indicated that juveniles are more sensitive to metals than adults. Significant toxic effects on the growth and sexual maturation times of juveniles were detected in soils from sites for which no significant effects on the cocoon production of adults could be detected. The greater sensitivity of juvenile worms indicates the importance of considering effects on a variety of life history stages when conducting a risk assessment of the effects of pollutants in soils. Although E. fetida does not occur naturally in soils at Avonmouth, the present study provides evidence to support the suggestion that pollution from the smelter is responsible for the absence of worms within 2 km of the factory. Results presented in this paper, and from previous studies, suggest the observed absence is due to the effects of zinc on the growth and maturation of juveniles and the cocoon production rate of adult worms.