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.

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.

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.

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.

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.

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.

Culture-independent identification of periodontitis-associated Porphyromonas and Tannerella populations by targeted molecular analysis.

Periodontitis is the commonest bacterial disease of humans and is the major cause of adult tooth loss. About half of the oral microflora is unculturable; and 16S rRNA PCR, cloning, and sequencing techniques have demonstrated the high level of species richness of the oral microflora. In the present study, a PCR primer set specific for the genera Porphyromonas and Tannerella was designed and used to analyze the bacterial populations in subgingival plaque samples from inflamed shallow and deep sites in subjects with periodontitis and shallow sites in age- and sex-matched controls. A total of 308 clones were sequenced and found to belong to one of six Porphyromonas or Tannerella species or phylotypes, one of which, Porphyromonas P3, was novel. Tannerella forsythensis was found in significantly higher proportions in patients than in controls. Porphyromonas catoniae and Tannerella phylotype BU063 appeared to be associated with shallow sites. Targeted culture-independent molecular ecology studies have a valuable role to play in the identification of bacterial targets for further investigations of the pathogenesis of bacterial infections.

Gram-positive anaerobic bacilli in human periodontal disease.

OBJECTIVE: The uncertain taxonomy of oral anaerobic gram-positive bacilli and their generally slow growing nature has limited the understanding of their role in periodontal disease. The current objective was to design and use species-specific oligonucleotide probes to investigate the relationship of selected gram-positive anaerobic bacilli to periodontal disease. METHODS: Plaque and clinical measurements were collected from 40 patients with periodontitis and from 40 matched controls. Oligonucleotide probes were designed for Bulleidia extructa, Eubacterium nodatum, Mogibacterium timidum and Slackia exigua and used to probe nucleic acids extracted from the samples with a chemiluminescent detection method. Species were quantified as absent or present at low (approximately 10(3)-10(4) cells), medium (approximately 10(4)-10(5) cells) or high levels (approximately 10(5)-10(6) cells). RESULTS: M. timidum and B. extructa were detected in only three and four samples, respectively. The level of both E. nodatum and S. exigua was significantly higher in deep than shallow pockets (Wilcoxon, p < 0.001). The level of E. nodatum, but not S. exigua, was higher in patients than matched controls (Mann-Whitney U, p < 0.03). Using an ordered logistic regression model, the probing depth of the sampled sites had the greatest influence on the level of both species and significant variations occurred between individuals. Bleeding also influenced the levels of both species, with supragingival plaque influencing S. exigua. CONCLUSION: Both E. nodatum and S. exigua were associated with clinical indicators of periodontal disease.

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.

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.

Structural proteomics of an archaeon.

A set of 424 nonmembrane proteins from Methanobacterium thermoautotrophicum were cloned, expressed and purified for structural studies. Of these, approximately 20% were found to be suitable candidates for X-ray crystallographic or NMR spectroscopic analysis without further optimization of conditions, providing an estimate of the number of the most accessible structural targets in the proteome. A retrospective analysis of the experimental behavior of these proteins suggested some simple relations between sequence and solubility, implying that data bases of protein properties will be useful in optimizing high throughput strategies. Of the first 10 structures determined, several provided clues to biochemical functions that were not detectable from sequence analysis, and in many cases these putative functions could be readily confirmed by biochemical methods. This demonstrates that structural proteomics is feasible and can play a central role in functional genomics.

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.

Solution structure of the RNA polymerase subunit RPB5 from Methanobacterium thermoautotrophicum.

RPB5 is an essential subunit of eukaryotic and archaeal RNA polymerases. It is a proposed target for transcription activator proteins in eukaryotes, but the mechanism of interaction is not known. We have determined the solution structure of the RPB5 subunit from the thermophilic archeon, Methanobacterium thermoautotrophicum. MtRBP5 contains a four-stranded beta-sheet platform supporting two alpha-helices, one on each side of the beta-sheet, resulting in an overall mushroom shape that does not appear to have any structural homologues in the structural database. The position and conservation of charged surface residues suggests possible modes of interaction with other proteins, as well as a rationale for the thermal stability of this protein.

Structure of a conserved domain common to the transcription factors TFIIS, elongin A, and CRSP70.

TFIIS is a transcription elongation factor that consists of three domains. We have previously solved the structures of domains II and III, which stimulate arrested polymerase II elongation complexes in order to resume transcription. Domain I is conserved in evolution from yeast to human species and is homologous to the transcription factors elongin A and CRSP70. Domain I also interacts with the transcriptionally active RNA polymerase II holoenzyme and therefore, may have a function unrelated to the previously described transcription elongation activity of TFIIS. We have solved the structure of domain I of yeast TFIIS using NMR spectroscopy. Domain I is a compact four-helix bundle that is structurally independent of domains II and III of the TFIIS. Using the yeast structure as a template, we have modeled the homologous domains from elongin A and CRSP70 and identified a conserved positively charged patch on the surface of all three proteins, which may be involved in conserved functional interactions with the transcriptional machinery.

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.

Detection of unculturable bacteria in periodontal health and disease by PCR.

Recently developed molecular methods have made it possible to characterize mixed microflora in their entirety, including the substantial numbers of bacteria which do not grow on artificial culture media. In a previous study, molecular analysis of the microflora associated with acute oral infections resulted in the identification of three phylotypes, PUS3.42, PUS9.170, and PUS9.180, representing as-yet-uncultured organisms. The aim of this study was to design and validate specific PCR primers for these phylotypes and to determine their incidences in samples collected from healthy and diseased periodontal tissues. Two specific reverse primers were devised for each phylotype, and these were used in duplex PCRs with universal forward and reverse primers. All three phylotypes were detected in periodontal sites; PUS9.170, related to oral asaccharolytic Eubacterium spp., was significantly associated with disease. This study demonstrates the possibility of using unculturable, and therefore uncharacterized, organisms as markers of disease.

Vascular endothelial growth factor in normal human salivary glands and saliva: a possible role in the maintenance of mucosal homeostasis.

Saliva is an enriched milieu containing biologically active proteins, including several different growth factors and cytokines. This study documents that vascular endothelial growth factor (VEGF), a potent, multifunctional, angiogenic cytokine, is a component of normal human saliva. VEGF was measured by ELISA in whole saliva (median concentration, 460 pg/ml) and in ductal secretions obtained from the parotid (277 pg/ml) and the submandibular-sublingual (80 pg/ml) salivary glands. VEGF seems to be synthesized endogenously by the salivary glands because both VEGF mRNA and protein (as revealed by in situ reverse transcriptase-PCR and by immunohistochemistry, respectively) colocalized to serous acinar cells and ductal epithelial cells within the parotid, submandibular, and minor salivary glands. These findings point to the existence of a "salivary VEGF system." It is possible that salivary VEGF plays a role in regulating physiologic and pathologic angiogenic and other vascular responses in salivary and mucosal tissues. And in particular, the presence of VEGF in saliva may contribute to the remarkable healing capacity of the oral mucosa as well as other regions of the digestive tract.

Retrospective application of a set of clinical diagnostic criteria for the diagnosis of multiple system atrophy.

We estimated the accuracy of a modified commonly used set of clinical diagnostic criteria for the diagnosis of multiple system atrophy (MSA) by retrospectively applying the criteria to the features recorded by six neurologists who had evaluated 105 autopsy-confirmed cases (16 MSA and 89 non-MSA disorders). Cases were abstracted from the records of the patients' first visit to an academic center, and were presented as clinical vignettes to six neurologists, each of whom recorded the main clinical features of the presented clinical vignette on a standardized form. Sensitivity and positive predictive values were chosen as validity outcome measures and were calculated by comparing the applied diagnostic criteria to the neuropathologic information. Of note, most MSA patients in this study (mainly those with Shy-Drager type) had not received levodopa therapy since the primary neurologists often had not perceived a need to administer this treatment. The validity of the retrospectively applied criteria for the diagnosis of possible MSA (sensitivity: median, 53%, range, 50-69%; positive predictive value: 30%, 28-39%) and probable MSA (sensitivity: 44%, 31-60%; positive predictive value: 68%, 54-80%) at the first visit was suboptimal. The best, still not perfect, accuracy for this set of diagnostic criteria was obtained when six out of eight features (sporadic adult onset, dysautonomia, parkinsonism, pyramidal signs, cerebellar signs, no levodopa response, no cognitive dysfunction, or no downward gaze supranuclear palsy) were present (median sensitivity, 59%; range, 50-75%; positive predictive value: 67%, 53-83%). This is the first study to validate criteria for the clinical diagnosis of MSA. Our data suggest that it is difficult to achieve an early and accurate clinical diagnosis of this disorder. The probability of correctly diagnosing MSA increases when at least six features of this modified set of criteria are present or when requiring the set for probable MSA.