A rapid realist review of clinical neuropsychology rehabilitation programmes to improve psychological wellbeing and quality of life for people with acquired brain injuries.

Approximately 20% of acquired brain injury (ABI) survivors experience reduced psychological wellbeing (PWB). Neuropsychological rehabilitation (NPR) is one approach supporting people with ABI to participate meaningfully in activities despite challenges. Although literature supports NPR effectiveness, little is known about change mechanisms. This systematic realist review identifies what NPR programmes have been designed, delivered, and evaluated for people with ABI to improve PWB and/or quality of life (QOL), as well as providing a context-relevant understanding of what NPR includes and how NPR might lead to positive outcomes. A rapid realist review was conducted in three phases: (1) structured retrieval and evidence extraction; (2) stakeholder consultation; (3) analysis and synthesis. Searches were completed, and findings from 35 publications and one stakeholder consultation were synthesized into a refined logic model. Six context-mechanism-outcome chains (CMOCs) were identified. Participants' relationships to internal experiences, and feelings of self-worth, mastery, and connection appeared to be mechanisms that led to improved PWB and QOL. Adaptation and individualized programmes were also key mechanisms to explain successful NPR. Embedding CMOCs into NPR could improve PWB and/or QOL for people with ABI. The logic model will inform ongoing development of a new online, group-based, NPR programme.

Optimal care for the management of older people non-weight bearing after lower limb fracture: a consensus study.

BACKGROUND: Older people who are non-weight-bearing after a lower limb fracture are at risk of poor outcomes but there are no clinical guidelines for this group of patients. Given the paucity of the research evidence base, we conducted a consensus exercise to ascertain expert opinion about the management of this group. METHODS: A three-round e-Delphi technique was planned to use the online JISC survey tool with a multidisciplinary panel of health professionals. Panellists were invited by email via professional organisations and UK NHS Trusts. The initial statements for this study were prepared by the authors based upon the findings of their scoping review. Consensus required >/= 70% agreement with statements. RESULTS: Only 2 survey rounds were required. Ninety panellists, representing seven clinical disciplines, reached consensus for 24 statements about general issues (osteoporosis detection and management, falls risk reduction and nutrition) and specific non-weight bearing issues (such as the need for activity to be promoted during this period). CONCLUSIONS: These findings can be used in the generation of a clinical guideline for this group of patients.

Hippocampal theta power pressure builds over non-REM sleep and dissipates within REM sleep episodes.

The theta rhythm during waking has been associated with voluntary motor activity and learning processes involving the hippocampus. Theta also occurs continuously during rapid eye movement (REM) sleep where it likely serves memory consolidation. Theta amplitude builds across wakefulness and is the best indicator of the homeostatic need for non-REM (NREM) sleep. Although REM sleep is homeostatically regulated independently of NREM sleep, the drivers of REM sleep regulation are under debate. The dynamics of theta within REM sleep bouts have not been thoroughly explored. We equipped 20 male rats with sleep instrumentation and hippocampal electrodes to measure theta across normal sleep/waking periods over the first 4 h of the sleep phase on two consecutive days. We found that theta power decreased by a third, on average, within individual REM sleep bouts, but recovered between bouts. Thus, there was no general decline in theta power across the duration of the recording period or between days. The time constant of theta power decline within a REM sleep bout was the same whether the bout was short, midlength, or long, and did not predict the behavioral state immediately following the REM sleep bout. Interestingly, the more time spent in NREM sleep prior to REM sleep, the larger the decline in theta power during REM sleep, indicating that REM sleep theta may be homeostatically driven by NREM sleep just as NREM delta power is driven by the length of prior waking and by waking theta. Potential causes and implications for this phenomenon are discussed.

Effect of AMPs MSI-78 and BP100 on the lipid acyl chains of 2H-labeled intact Gram positive bacteria.

The lipid bilayer disrupting effect of antimicrobial peptides (AMPs) has been widely studied in model-lipid systems by applying biophysical techniques such as 2H NMR spectroscopy. Real bacteria cell envelopes contain non-lipid components, such as peptidoglycan, and thus it is important to assess the effects of such non-lipid components on the lipid-disrupting effects of AMPs. To this end, our group and other have developed methods that promote uptake of deuterium-labeled acyl chains in bacterial cells to produce 2H-membrane-enriched Bacillus subtilis. In this work, we studied changes in the static 2H NMR spectra of B. subtilis induced by the AMPs MSI-78 and BP100. Addition of both AMPs resulted in the increase of lipid acyl chain disorder consistent with disruption of the bacterial membrane. In addition, the peptide to lipid molar ratios (P:L) that give rise to observable effects fall between the P:L molar ratios necessary to generate membrane disruption in model-lipid-only systems and the P:L molar ratios needed to inhibit bacterial cell growth. This observation supports a role for the non-lipid components in modulating the AMP-lipid interactions.

A pilot study of the gingival response when smokers switch from smoking to vaping.

Introduction Tobacco smoking is one of the most important risk factors for periodontitis as it alters the host response to plaque. Although the prevalence of tobacco smoking has declined in recent years, the use of electronic-cigarettes (vaping) has increased. The effect of vaping on the gingiva is unknown and an evidence-base needs to be established before providing dental advice about the use of these products.Objective To compare the gingival health of a group of established smokers before and after substituting vaping for smoking tobacco.Design Pilot.Setting Guy's Dental Hospital (England) from April-December 2015.Materials and methods Twenty established smokers (all staff members at Guy's Hospital) with mild periodontal disease replaced their regular smoking habits with the use of e-cigarettes for two weeks.Main outcome measure The primary outcome measure of gingival inflammation was bleeding on probing. Levels of selected pro-inflammatory cytokines in GCF, saliva and serum samples were also determined.Results and conclusions There was a statistically significant increase in gingival inflammation when tobacco smokers switched from smoking to vaping for two weeks. However, this result must be interpreted with extreme caution since this is only a pilot study. Nonetheless, this study should provide a stepping stone to encourage further investigation of the effects of vaping on periodontal health.

The solution structure of bacteriophage lambda protein W, a small morphogenetic protein possessing a novel fold.

Protein W (gpW) from bacteriophage lambda is required for the stabilization of DNA within the phage head and for attachment of tails onto the head during morphogenesis. Although comprised of only 68 residues, it likely interacts with at least two other proteins in the mature phage and with DNA. Thus, gpW is an intriguing subject for detailed structural studies. We have determined its solution structure using NMR spectroscopy and have found it to possesses a novel fold consisting of two alpha-helices and a single two-stranded beta-sheet arranged around a well-packed hydrophobic core. The 14 C-terminal residues of gpW, which are essential for function, are unstructured in solution.

What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study.

BACKGROUND: The presentation of symptoms for multiple system atrophy (MSA) varies. Because there are no specific markers for its clinical diagnosis, the diagnosis rests on the results of the neuropathologic examination. Despite several clinicopathologic studies, the diagnostic accuracy for MSA is unknown. OBJECTIVES: To determine the accuracy for the clinical diagnosis of MSA and to identify, as early as possible, those features that would best predict MSA. DESIGN: One hundred five autopsy-confirmed cases of MSA and related disorders (MSA [n=16], non-MSA [n=89]) were presented as clinical vignettes to 6 neurologists (raters) who were unaware of the study design. Raters identified the main clinical features and provided a diagnosis based on descriptions of the patients' first and last clinic visits. METHODS: Interrater reliability was evaluated with the use of kappa statistics. Raters' diagnoses and those of the primary neurologists (who followed up the patients) were compared with the autopsy-confirmed diagnoses to estimate the sensitivity and positive predictive values at the patients' first and last visits. Logistic regression analysis was used to determine the best predictors to diagnose MSA. RESULTS: For the first visit (median, 42 months after the onset of symptoms), the raters' sensitivity (median, 56%; range, 50%-69%) and positive predictive values (median, 76%; range, 61%-91%) for the clinical diagnosis of MSA were not optimal. For the last visit (74 months after the onset of symptoms), the raters' sensitivity (median, 69%; range, 56%-94%) and positive predictive values (median, 80%; range, 77%-92%) improved. Primary neurologists correctly identified 25% and 50% of the patients with MSA at the first and last visits, respectively. False-negative and -positive misdiagnoses frequently occurred in patients with Parkinson disease and progressive supranuclear palsy. Early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait disturbances were identified as the best predictive features to diagnose MSA. CONCLUSIONS: The low sensitivity for the clinical diagnosis of MSA, particularly among neurologists who followed up these patients in the tertiary centers, suggests that this disorder is underdiagnosed. The misdiagnosis of MSA is usually due to its confusion with Parkinson disease or progressive supranuclear palsy, thus compromising the research on all 3 disorders.

Radioprotective thiolamines WR-1065 and WR-33278 selectively denature nonhistone nuclear proteins.

Differential scanning calorimetry was used to study the interactions of nuclei isolated from Chinese hamster V79 cells with the radioprotector WR-1065, other thiol compounds, and polyamines. Differential scanning calorimetry monitors denaturation of macromolecules and resolves the major nuclear components (e.g. constrained and relaxed DNA, nucleosome core, and nuclear matrix) of intact nuclei on the basis of thermal stability. WR-1065 treatment (0.5-10 mM) of isolated nuclei led to the irreversible denaturation of nuclear proteins, a fraction of which are nuclear matrix proteins. Denaturation of 50% of the total nonhistone nuclear protein content of isolated nuclei occurred after exposure to 4.7 mM WR-1065 for 20 min at 23 degrees C. In addition, a 22% increase in the insoluble protein content of nuclei isolated from V79 cells that had been treated with 4 mM WR-1065 for 30 min at 37 degrees C was observed, indicating that WR-1065-induced protein denaturation occurs not only in isolated nuclei but also in the nuclei of intact cells. From the extent of the increase in insoluble protein in the nucleus, protein denaturation by WR-1065 is expected to contribute to drug toxicity at concentrations greater than approximately 4 mM. WR-33278, the disulfide form of WR-1065, was approximately twice as effective as the free thiol at denaturing nuclear proteins. The proposed mechanism for nucleoprotein denaturation is through direct interactions with protein cysteine groups with the formation of destabilizing protein-WR-1065 disulfides. In comparison to its effect on nuclear proteins in isolated nuclei, WR-1065 had only a very small effect on non-nuclear proteins of whole cells, isolated nuclear matrix, or the thiol-rich Ca(2+)ATPase of sarcoplasmic reticulum, indicating that WR-1065 can effectively denature protein only inside an intact nucleus, probably due to the increased concentration of the positively charged drug in the vicinity of DNA.

A perspective of gene therapy in the glaucomas.

Gene therapy in the anterior and posterior segment tissues may have the potential to favorably influence aqueous hydrodynamics and retinal ganglion cell biology, thereby preventing, delaying, or minimizing glaucomatous damage to the optic nerve. We demonstrated the feasibility of using a herpes viral vector (ribonucleotide reductase defective HSV-1, hrR3) to deliver the lacZ reporter gene to living cat and rat eyes. Cats received injections into the anterior chamber and rats into the vitreous cavity. In cats, lacZ expression was detectable at 1 to 2 days in the anterior outer portion of the ciliary muscle and the lining of the intertrabecular spaces of the corneoscleral and uveal meshwork. Rat eyes showed lacZ expression in the retinal pigment epithelium and photoreceptor outer segments 2 days after injection.

Effects of tetrodotoxin treatment in LGN on neuromodulatory receptor expression in developing visual cortex.

The expression and distribution patterns of transmitter receptors change dramatically during pre- and post-natal development of the visual cortex, but the factors that control these processes are largely unknown. We have tested the hypothesis that input activity from the lateral geniculate nucleus (LGN), one major input source to visual cortex, may contribute to the processes underlying transmitter receptor redistributions in the visual cortex during development. We found that a short period of tetrodotoxin (TTX) treatment in LGN retarded the developmental expression and age-dependent reorganization of neuromodulatory receptors, including muscarinic, serotonergic and adrenergic receptors, in kitten primary visual cortex. The visual cortices ipsilateral to the TTX infusion site displayed a 'younger' receptor pattern than that of their contralateral control counterparts in the same animals. The results suggest that active input from LGN regulates the expression profile of a broad range of receptors in the developing visual cortex.

The oral health of a group of 15-17 year old British school children of different ethnic origin.

The influence of ethnic origin on the oral health of a group of 472 British schoolchildren aged 15-17 years attending two adjacent schools was investigated. Ethnic origin was assessed as European (E; n = 197), Afro-Caribbean (AC; n = 97) and Asian (As; n = 140) leaving 38 subjects of other or mixed origin. Plaque, bleeding on probing and subgingival retentive factors, together with probing depths and attachment loss were recorded at the four approximal sites of teeth 16, 11, 26, 36, 31, 46. DMFT scores were collected for the whole mouth. Socio-economic status was assessed using a Classification of Residential Neighbourhoods (ACORN). Multiple regression analysis indicated that ethnic origin had a significant influence on plaque, subgingival calculus, gingivitis, pockets and DMFT scores. The overall prevalence of periodontitis was 11.2 per cent; European, Afro-Caribbean and Asian groups had prevalences of 3, 21 and 14 per cent respectively.

Serum IgG1 and IgG2 antibody responses to Porphyromonas gingivalis in patients with periodontitis.

BACKGROUND/AIMS: Protein and carbohydrate antigens of Porphyromonas gingivalis interact with the host to produce antibody of different subclasses. IgG1 and IgG2 antibodies frequently account for approximately 90% of the total serum IgG. This work aimed to investigate serum IgG1 and IgG2 antibody responses of periodontitis patients to protein and carbohydrate-rich antigens of P. gingivalis. METHODS: Sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blots of P. gingivalis antigens and proteinase K digested antigens rich in carbohydrates were used to investigate the molecular weight of antigen recognised by serum IgG1 and IgG2. Enzyme-linked immunosorbent assay was used to measure levels of IgG1 and IgG2 antibody to P. gingivalis and radial immunodiffusion was used to estimate the total concentration of IgG1 and IgG2 in serum. RESULTS: Serum IgG antibodies bound to antigens of molecular weights 47, 39 and 32 kDa. Antigen most frequently recognised by both IgG1 and IgG2 antibody had a molecular weight of 47 kDa. Serum IgG2 antibody bound to carbohydrate antigen with a molecular weight of 32 kDa but there was no recognition of carbohydrate antigens by IgG1 antibodies. There was no correlation between the titre of anti-P. gingivalis IgG1 or IgG2 antibody and the total concentration of serum IgG1 or IgG2 antibodies of all specificities. CONCLUSION: Both IgG1 and IgG2 antibodies recognised a dominant antigen of 47 kDa, probably Arg-gingipain. Much of the response to carbohydrate antigen is of the IgG2 subclass. Neither the level of IgG1 nor the IgG2 antibody specific to P. gingivalis was related to the total serum concentration of that antibody.

Secretory leukocyte protease inhibitor and its potential interactions with elastase and cathepsin B in gingival crevicular fluid and saliva from patients with chronic periodontitis.

BACKGROUND AND OBJECTIVE: Elastase is carried into the oral cavity by gingival crevicular fluid (GCF) from periodontal lesions. Our study investigated the regulation of elastase activity by secretory leukocyte protease inhibitor (SLPI) and the possible action of another GCF protease on this protective salivary component. MATERIAL AND METHODS: Whole-mouth saliva (WMS), parotid saliva (PS) and GCF were obtained from 19 patients with periodontitis. The concentrations of active elastase and cathepsin B were determined using peptide substrates. SLPI and alpha1-proteinase inhibitor (alpha1PI) concentrations were determined using enzyme-linked immunosorbent assays (ELISAs). The molecular forms of SLPI were examined by immunoblotting. RESULTS: The molar concentrations of elastase, cathepsin B and alpha1PI were higher in GCF than in WMS and especially PS (p < 0.0002). The GCF SLPI concentrations were also higher than the WMS SLPI concentrations (p < 0.05). All WMS components increased with GCF content, significantly for elastase and SLPI (p < 0.002). In GCF, the concentration of alpha1PI was higher than the concentration of SLPI (p < 0.0002), while there was no significant difference for WMS. SLPI and elastase levels in GCF and WMS were inversely related (p < 0.005). In SLPI immunoblots, PS contained only the intact 14-kDa molecule of SLPI, while WMS also contained an 8-kDa fragment. For WMS there was a positive correlation between SLPI degradation and cathepsin B (p < 0.002). Incubation of WMS alone or of PS with GCF in the presence of cysteine proteinase activators caused SLPI immunoreactivity to shift to 8 kDa. CONCLUSION: For GCF, serum-derived alpha1PI is the major elastase inhibitor, but in WMS SLPI probably reduces activity. The inflamed gingivae can be an additional source of SLPI in the oral cavity, but here the molecule is apparently cleaved by GCF cysteine proteinases, such as cathepsin B.

Effectiveness, efficiency, excellence: can they coexist in health care?

The conference certainly provided a great deal of food-for-thought for participants. From the imperatives of funding restraint, presented by Dr Scully and Professor Manga, to the public attitudes and opinions research presented by Allan Gregg and the anticipated public policy initiatives presented by Senator Kirby, the audience was challenged to take a new look at health care. Chief Ovide Mercredi presented a very earnest plea on behalf of the aboriginal people of Canada for restoration of their dignity and self-determination, as a key to better mental and physical health. The message to health care leaders was that quality improvement not only works, but also leads to more efficient use of resources. Dr Donald Berwick blew away the myths that often prevent organizations from establishing quality improvement programs and presented a blueprint for success. Other speakers gave examples of successful QI programs they were personally involved in. One of the most interesting presentations was Dr Naylor's able exposition of the role of research in assuring quality. This must have opened many eyes to how resources can be used without real benefit to patients, when proper outcome measurement is not used. Indeed, outcome measures may be an important key to dealing with some of the problems facing health care.

Characterization of the Porphyromonas gingivalis antigen recognized by a monoclonal antibody which prevents colonization by the organism.

Monoclonal antibody (MAb) 61BG1.3 prevented recolonization of deep pockets by Porphyromonas gingivalis in patients with periodontitis. The aim of this work was to identify the antigen recognized by the MAb. This was carried out by dose-dependent inhibition with materials extracted from P. gingivalis and assessed by a radioimmunoassay. A protease preparation and a capsular extract inhibited about 95% of the binding activity, whereas LPS or fimbriae had no effect. However, about 125 times greater concentration of the capsular than the protease material was needed to inhibit 50% of the antibody activity, suggesting that the MAb recognizes the protease preparation and that the capsular extract contained some protease. Western blotting of MAb 61BG1.3 with recombinant prpR1 protein expressed in Escherichia coli confirmed that MAb 61BG1.3 recognizes the haemagglutinating protease and mapped its epitope to residues 748-1130 of the beta component of the polyprotein. Three major bands of M(r) 45,000, 38,300 and 31,400 were detected in native whole cells of the virulent P. gingivalis strain W50 by Western blotting with MAb 61BG1.3. The MAb inhibited haemagglutination of human red blood cells by P. gingivalis or by a native protease extract. Blocking adhesion of P. gingivalis to the receptors on erythrocytes might be a mechanism by which the MAb inhibits recolonization by the microorganism.

Neural mechanisms for generating rate and temporal codes in model CA3 pyramidal cells.

The effect of synaptic inhibition on burst firing of a two-compartment model of a CA3 pyramidal cell is considered. We show that, depending on its timing, a short dose of fast decaying synaptic inhibition can either delay or advance the timing of firing of subsequent bursts. Moreover, increasing the strength of the inhibitory input is shown to modulate the burst profile from a full complex burst, to a burst with multiple spikes, to single spikes. We additionally show how slowly decaying inhibitory input can be used to synchronize a network of pyramidal cells. Implications for the phase precession phenomenon of hippocampal place cells and for the generation of temporal and rate codes are discussed.

A minimal, compartmental model for a dendritic origin of bistability of motoneuron firing patterns.

Various nonlinear regenerative responses, including plateau potentials and bistable repetitive firing modes, have been observed in motoneurons under certain conditions. Our simulation results support the hypothesis that these responses are due to plateau-generating currents in the dendrites, consistent with a major role for a noninactivating calcium L-type current as suggested by experiments. Bistability as observed in the soma of low- and higher-frequency spiking or, under TTX, of near resting and depolarized plateau potentials, occurs because the dendrites can be in a near resting or depolarized stable steady state. We formulate and study a two-compartment minimal model of a motoneuron that segregates currents for fast spiking into a soma-like compartment and currents responsible for plateau potentials into a dendrite-like compartment. Current flows between compartments through a coupling conductance, mimicking electrotonic spread. We use bifurcation techniques to illuminate how the coupling strength affects somatic behavior. We look closely at the case of weak coupling strength to gain insight into the development of bistable patterns. Robust somatic bistability depends on the electrical separation since it occurs only for weak to moderate coupling conductance. We also illustrate that hysteresis of the two spiking states is a natural consequence of the plateau behavior in the dendrite compartment.

A temporal mechanism for generating the phase precession of hippocampal place cells.

The phase relationship between the activity of hippocampal place cells and the hippocampal theta rhythm systematically processes as the animal runs through the region in an environment called the place field of the cell. We present a minimal biophysical model of the phase precession of place cells in region CA3 of the hippocampus. The model describes the dynamics of two coupled point neurons--namely, a pyramidal cell and an interneuron, the latter of which is driven by a pacemaker input. Outside of the place field, the network displays a stable, background firing pattern that is locked to the theta rhythm. The pacemaker input drives the interneuron, which in turn activates the pyramidal cell. A single stimulus to the pyramidal cell from the dentate gyrus, simulating entrance into the place field, reorganizes the functional roles of the cells in the network for a number of cycles of the theta rhythm. In the reorganized network, the pyramidal cell drives the interneuron at a higher frequency than the theta frequency, thus causing a systematic precession relative to the theta input. The frequency of the pyramidal cell can vary to account for changes in the animal's running speed. The transient dynamics end after up to 360 degrees of phase precession when the pacemaker input to the interneuron occurs at a phase to return the network to the stable background firing pattern, thus signaling the end of the place field. Our model, in contrast to others, reports that phase precession is a temporally, and not spatially, controlled process. We also predict that like pyramidal cells, interneurons phase precess. Our model provides a mechanism for shutting off place cell firing after the animal has crossed the place field, and it explains the observed nearly 360 degrees of phase precession. We also describe how this model is consistent with a proposed autoassociative memory role of the CA3 region.

Compartmental model of vertebrate motoneurons for Ca2+-dependent spiking and plateau potentials under pharmacological treatment.

In contrast to the limited response properties observed under normal experimental conditions, spinal motoneurons generate complex firing patterns, such as Ca2+-dependent regenerative spiking and plateaus, in the presence of certain neurotransmitters and ion-channel blockers. We have developed a quantitative motoneuron model, based on turtle motoneuron data, toinvestigate the roles of specific ionic currents and the effects of their soma and dendritic distribution in generating these complex firing patterns. In addition, the model is used to explore the effects of multiple ion channel blockers and neurotransmitters that are known to modulate motoneuron firing patterns. To represent the distribution of ionic currents across the soma and dendrites, the model contains two compartments. The soma compartment, representing the soma and proximal dendrites, contains Hodgkin-Huxley-like sodium (INa) and delayed rectifier K+ (IK-dr) currents, an N-like Ca2+ current (ICa-N), and a calcium-dependent K+ current [IK(Ca)]. The dendritic compartment, representing the lumped distal dendrites, contains, in addition to ICa-N and IK(Ca) as in the soma, a persistent L-like calcium current (ICa-L). We determined kinetic parameters for INa, IK-dr, ICa-N, and IK(Ca) in order to reproduce normal action-potential firing observed in turtle spinal motoneurons, including fast and slow afterhyperpolarizations (AHPs) and a linear steady-state frequency-current relation. With this parameter set as default, a sequence of pharmacological manipulations were systematically simulated. A small reduction of IK-dr [mimicking the experimental effect of tetraethylammonium (TEA) in low concentration] enhanced the slow AHP and caused calcium spiking (mediated by ICa-N) when INa was blocked. Firing patterns observed experimentally in high TEA [and tetrodotoxin (TTX)], namely calcium spikes riding on a calcium plateau, were reproduced only when both IK-dr and IK(Ca) were reduced. Dendritic plateau potentials, mediated by ICa-L, were reliably unmasked when IK(Ca) was reduced, mimicking the experimental effect of the bee venom apamin. The effect of 5-HT, which experimentally induces the ability to generate calcium-dependent plateau potentials but not calcium spiking, was reproduced in the model by reducing IK(Ca) alone. The plateau threshold current level, however, was reduced substantially if a simultaneous increase in ICa-L was simulated, suggesting that serotonin (5-HT) induces plateau potentials by regulating more than one conductance. The onset of the plateau potential showed significant delays in response to near-threshold, depolarizing current steps. In addition, the delay times were sensitive to the current step amplitude. The delay and its sensitivity were explained by examining the model's behavior near the threshold for plateau onset. This modeling study thus accurately accounts for the basic firing behavior of vertebrate motoneurons as well as a range of complex firing patterns invoked by ion-channel blockers and 5-HT. In addition, our computational results support the hypothesis that the electroresponsiveness of motoneurons depends on a nonuniform distribution of ionic conductances, and they predict modulatory effects of 5-HT and properties of plateau activation that have yet to be tested experimentally.

Passive immunization with monoclonal antibodies against Porphyromonas gingivalis in patients with periodontitis.

Selective inhibition of recolonization of Porphyromonas gingivalis was investigated by topical application of monoclonal antibody (MAb). To select a MAb to P. gingivalis with the potential for recognizing most strains of P. gingivalis, we examined seven MAbs, one of which (MAb 61BG 1.3) recognized all 22 laboratory strains and serotypes of P. gingivalis tested as well as 105 human clinical isolates. A comparative study of the number of P. gingivalis bacteria identified by conventional culture and immunofluorescence with MAb 61BG 1.3 showed a very significant correlation between the two methods (Spearman r = 0.85, P < 0.001). Fourteen patients with periodontitis, who harbored P. gingivalis in their subgingival plaque, were treated by root planing and with metronidazole to suppress any detectable P. gingivalis. In this double-blind study, the patients were then divided randomly into two groups; one was treated with MAb to P. gingivalis, and the other was treated with saline. Each patient had four subgingival applications of 3 micrograms of MAb (or saline) per tooth at 1, 3, 7, and 10 days after P. gingivalis was suppressed. The number of P. gingivalis bacteria was then monitored, and significantly less recolonization of the sites with the most severe periodontitis was found in the MAb-treated patients than in the control patients (P < 0.01). This was evident at 6 and 9 months after the application of MAb, but by 12 months, P. gingivalis, was also found to recolonize these sites in two of the MAb-treated patients. The effect of MAb was specific to P. gingivalis, since the numbers of spirochetes were not significantly different between the two groups. However, no significant difference in any clinical periodontal indices between the immunized and control patients at 6 and 12 months was observed. This is the first demonstration that a putative periodontal pathogen can be selectively prevented from recolonization for up to 9 months in sites with the most severe periodontitis. This strategy could be used to establish directly in humans whether a microorganism is involved in the pathogenesis of periodontitis, by repeated application of the corresponding MAb at about 6-month intervals and by comparing the clinical indices between the MAb-treated and control patients.