Impaired communication ability in SOX11 syndrome.

BACKGROUND: Speech and language skills are important for social interaction and learning. This study characterised the communication abilities of verbal individuals with SOX11 syndrome using a standardised parent/carer questionnaire, the Children's Communication Checklist (CCC-2). METHOD: Thirteen parent/carers of verbal individuals (aged 5-19 years) diagnosed with SOX11 syndrome completed the CCC-2. In order to contextualise findings, responses were compared to norms and to data from Noonan syndrome, a relatively well-known genetic diagnosis associated with communication impairment. RESULTS: For all individuals, the CCC-2 composite score indicated significant communication difficulties. Language structure (speech, syntax, semantics and coherence), pragmatic language (inappropriate initiation, stereotyped language use of context and non-verbal communication) and autistic features (social relations and interests) scores were lower than typically developing norms. Subscale comparisons revealed relative difference in use of context compared to other pragmatic domains (stereotyped language and inappropriate initiation). Individual scores showed substantial variation, particularly in regard to language structure profile. Differences were more pronounced than for Noonan syndrome, specifically in domains of speech, syntax, non-verbal communication and social relations. CONCLUSIONS: SOX11 syndrome is associated with communication impairment. It is important to assess communication abilities as part of the management of individuals with SOX11 syndrome and understand individual strengths and difficulties in order to provide targeted support.

Association of a P2RX7 gene missense variant with brachycephalic dog breeds.

Missense variants are associated with various phenotypic traits and disorders in dogs. The canine P2RX7 gene, coding the ATP-gated P2X7 receptor ion channel, contains four known missense variants. The current study aimed to examine the presence of these variants in a random sample of pedigree and mixed-pedigree dogs. Exons 3, 8, 11 and 13 of the P2RX7 gene, encoding these four respective variants, in 65 dogs were assessed by Sanger sequencing and combined with existing sequencing data from another 69 dogs. The distribution of these variants was then evaluated in all 134 dogs combined and separately within individual breeds including 35 different pure breeds. The rs23314713 (p.Phe103Leu) and rs23315462 (p.Pro452Ser) variants were present in 47 and 40% of all dogs studied respectively, with the rs23314713 variant associated with brachycephalic breeds. Among pedigree dogs, the rs23314713 and rs23315462 variants were associated with brachycephalic and non-brachycephalic breeds respectively. The rs851148233 (p.Arg270Cys) and rs850760787 (p.Arg365Gln) variants were present only in dogs of Cocker Spaniel and Labrador Retriever pedigrees respectively. No other missense variants were found in exons 3, 8, 11 and 13 of the P2RX7 gene within the dogs. In conclusion, the rs23314713 and rs23315462 missense variants of the P2RX7 gene are present in a large proportion of dogs, with the rs23314713 variant associated with a number of brachycephalic breeds. However, the association of this variant with dogs of bulldog ancestry, not brachycephaly per se, cannot be excluded.

Goal-setting and attainment in prolonged disorders of consciousness - development of a structured approach.

Aims: To develop a structured goal-set for use in programs for the assessment and management of prolonged disorders of consciousness (PDOC).Methods: A retrospective analysis of goals from a consecutive cohort of patients (n = 162) admitted to a specialist in-patient PDOC program in the UK from 2007 to 2018. Overall goal attainment was examined with Goal Attainment Scaling (GAS) using the GAS-Light method. Rates of individual goal-setting and achievement were examined for both standardized objectives (n = 2959) and personalized goals (n = 661). Goal statements from the personalized goals were independently reviewed and mapped to the domains of the existing structured objective set to identify any missing goal areas.Results: Mean outcome GAS T-scores were 47.2 (95% CI: 46.7, 47.6) and 47.7 (95% CI: 46.7, 48.8), respectively, for the standardized and personally set goals. These were closely correlated (r = 0.482, p < .001) with no significant difference between them. Analysis of goal achievement within each domain identified goals that were/were not likely to be achieved. An initial structured set of 20 standardized objectives in 12 domains was expanded and re-organized to produce a final-structured goal-set of 36 objectives in 18 domains.Conclusions: Developed through real-life clinical practice, this first published structured goal-set for PDOC programs now requires testing in other services/settings.

Nucleotides regulate secretion of the inflammatory chemokine CCL2 from human macrophages and monocytes.

CCL2 is an important inflammatory chemokine involved in monocyte recruitment to inflamed tissues. The extracellular nucleotide signalling molecules UTP and ATP acting via the P2Y2 receptor are known to induce CCL2 secretion in macrophages. We confirmed this in the human THP-1 monocytic cell line showing that UTP is as efficient as LPS at inducing CCL2 at early time points (2-6 hours). Expression and calcium mobilisation experiments confirmed the presence of functional P2Y2 receptors on THP-1 cells. UTP stimulation of human peripheral CD14+ monocytes showed low responses to LPS (4-hour stimulation) but a significant increase above background following 6 hours of treatment. The response to UTP in human monocytes was variable and required stimulation >6 hours. With such variability in response we looked for single nucleotide polymorphisms in P2RY2 that could affect the functional response. Sequencing of P2RY2 from THP-1 cells revealed the presence of a single nucleotide polymorphism altering amino acid 312 from arginine to serine (rs3741156). This polymorphism is relatively common at a frequency of 0.276 (n = 404 subjects). Finally, we investigated CCL2 secretion in response to LPS or UTP in human macrophages expressing 312Arg-P2Y2 or 312Ser-P2Y2 where only the latter exhibited significant UTP-induced CCL2 secretion (n = 5 donors per group).

CAY10593 inhibits the human P2X7 receptor independently of phospholipase D1 stimulation.

The P2X7 receptor is a trimeric ATP-gated cation channel important in health and disease. We have observed that the specific phospholipase D (PLD)1 antagonist, CAY10593 impairs P2X7-induced shedding of the 'low affinity' IgE receptor, CD23. The current study investigated the mode of action of this compound on P2X7 activation. Measurements of ATP-induced ethidium(+) uptake revealed that CAY10593 impaired P2X7-induced pore formation in human RPMI 8226 B cells, P2X7-transfected HEK-293 cells and peripheral blood mononuclear cells. Concentration response curves demonstrated that CAY10593 impaired P2X7-induced pore formation in RPMI 8226 cells more potently than the PLD2 antagonist CAY10594 and the non-specific PLD antagonist halopemide. Electrophysiology measurements demonstrated that CAY10593 also inhibited P2X7-induced inward currents. Notably, RT-PCR demonstrated that PLD1 was absent in RPMI 8226 cells, while choline-Cl medium or 1-butanol, which block PLD stimulation and signalling respectively did not impair P2X7 activation in these cells. This data indicates that CAY10593 impairs human P2X7 independently of PLD1 stimulation and highlights the importance of ensuring that compounds used in signalling studies downstream of P2X7 activation do not affect the receptor itself.

The human P2X7 receptor and its role in innate immunity.

The human P2X7 receptor is a two-transmembrane ionotropic receptor which has a ubiquitous distribution and is most highly expressed on immune cells. In macrophages and similar myeloid cells primed by lipopolysaccharide (LPS), activation of P2X7 by extracellular ATP opens a cation channel/pore allowing massive K+ efflux associated with processing and secretion of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. A variety of other downstream effects follows P2X7 activation over several minutes including shedding of certain surface molecules, membrane blebbing, microvesicle/exosome release and apoptosis of the cell. High concentrations of ATP (>100 µM) are required to activate P2X7 but it remains unclear where these levels exist, other than in inflammatory foci or confined spaces such as in bone. A variety of potent selective antagonists of P2X7 activation have recently become available, allowing clinical trials to be undertaken in inflammatory and immune-mediated disorders. Proteomic studies have shown that P2X7 exists as a large multiprotein complex which includes non-muscle myosin heavy chain and other elements of the cytoskeleton. In the absence of its ATP ligand and serum, P2X7 has an alternate function in the recognition and phagocytosis of non-opsonized foreign particles, including bacteria and apoptotic cells. The P2RX7 gene has many polymorphic variants and isoforms which increase or decrease function of the receptor. Genetic association studies have linked loss-of-function polymorphisms with reactivation of latent tuberculosis as well as symptomatic infection with certain other obligate intracellular pathogens. The many roles involving P2X7 suggest that this receptor is essential to fundamental aspects of the innate immune response.

Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement.

Upper limb spasticity affecting elbow, wrist, and finger flexors can be safely and effectively reduced with injections of botulinum toxin type-A (BoNT-A). It has been best studied in adults in the context of post-stroke spasticity. The clinical benefits include reduction in pain and deformity, improvement in washing and dressing the upper limb, and a reduction in caregiver burden (Class I evidence, recommendation level A). Some patients show improvement in function performed by active movement of the affected upper limb (Class III evidence, recommendation C), but predicting and measuring this is difficult, and further research is needed. An individually based approach to treatment and outcome measurement is preferred (Class IV, recommendation U). More research is needed to resolve many unknown issues of assessment and treatment, using research methods appropriate to the question.

Functional disability in paediatric patients with recurrent abdominal pain.

BACKGROUND: Recurrent abdominal pain (RAP) is common in childhood, affecting approximately 12% of children and adolescents. Children with RAP tend to experience impairments in functioning, such as increased school absences, anxiety and depression. METHODS: The current study investigated the potential influences on the relation between functional disability and RAP in 100 school-aged children. A series of hierarchical regression analyses were conducted to test two models: main effects and moderation of the relation between abdominal pain symptoms, child anxiety, child depression, maternal emotional distress, maternal encouragement of child illness behaviour and functional disability. RESULTS: The results indicated support for abdominal pain symptoms and child depression in predicting functional disability. The results also indicated that child anxiety and child depression each moderated the relation between pain symptoms and functional disability. CONCLUSIONS: Implications of the findings are discussed in terms of potential influences on the development of functional disability in youth.

Sex-dependent behavioral effects of cerebral cortical lesions in the developing rhesus monkey.

Male rhesus monkeys with orbital prefrontal lesions were imtpaired on behavioral tests at 2(1/2) months of age whereas similar deficits were not detected in females with comparable lesions until 15 to 18 months of age. The results suggest that the maturation of a cortical region in the primate brain proceeds at different tempos in males and females.

Multidisciplinary rehabilitation programmes following joint replacement at the hip and knee in chronic arthropathy.

BACKGROUND: Joint replacements are common procedures and treatment of choice for those with intractable joint pain and disability arising from arthropathy of the hip or knee. Multidisciplinary rehabilitation is considered integral to the outcome of joint replacement. OBJECTIVES: To assess the evidence for effectiveness of multidisciplinary rehabilitation on activity and participation in adults following hip or knee joint replacement for chronic arthropathy. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and CINAHL up to September 2006. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared organised multidisciplinary rehabilitation with routine services following hip or knee replacement, and included outcome measures of activity and participation in accordance with the International Classification of Functioning, Health and Disability (ICF). DATA COLLECTION AND ANALYSIS: Four authors independently extracted data and assessed methodological quality of included trials. MAIN RESULTS: Five trials (619 participants) met the inclusion criteria; two addressed inpatient rehabilitation (261 participants) and three (358 participants) home-based settings. There were no trials addressing outpatient centre-based programmes. Pooling of data was not possible due to differences in study design and outcomes used. Methodological assessment showed all trials were of low quality. For inpatient settings early commencement of rehabilitation and clinical pathways led to more rapid attainment of functional milestones (disability) (Functional Independence Measure (FIM) transfer WMD 0.5, 95% CI 0.15, 0.85, number needed to treat to benefit (NNTB) = 6, FIM ambulation WMD 1.55 (95%CI 0.96, 2.14), NNTB = 3), shorter hospital stay, fewer post-operative complications and reduced costs in the first three to four months. Home-based multidisciplinary care improved functional gain (Oxford Hip Score (OHS) WMD at 6 months -7.00 (95%CI -10.36, -3.64), NNT = 2 and quality of life (QoL) and reduced hospital stay in the medium term (six months). No trials addressed longer-term outcomes following hip replacement only. AUTHORS' CONCLUSIONS: Based on the heterogeneity and the low quality of the included trials that precluded pooled meta-analysis, there is silver level evidence that following hip or knee joint replacement, early multidisciplinary rehabilitation can improve outcomes at the level of activity and participation. The optimal intensity, frequency and effects of rehabilitation over a longer period and associated social costs need further study. Future research should focus on improving methodological and scientific rigour of clinical trials, and use of standardised outcome measures, so that results can be pooled for statistical analysis.

P2X receptor characterization and IL-1/IL-1Ra release from human endothelial cells.

BACKGROUND AND PURPOSE: The pro-inflammatory cytokine, interleukin-1beta (IL-1beta), has been implicated in the pathogenesis of atherosclerosis, potentially via its release from vascular endothelium. Endothelial cells (EC) synthesize IL-1beta in response to inflammatory stimuli, but the demonstration and mechanism of release of IL-1 from ECs remains unclear. In activated monocytes, efficient release of bioactive IL-1beta occurred via activation of ATP-gated P2X(7) receptors (P2X(7)Rs). Activation of P2X(7)R in ECs from human umbilical vein (HUVECs) released IL-1 receptor antagonist (IL-1Ra). The purpose of this study was to provide a quantitative investigation of P2XR expression and function, in parallel with IL-1beta and IL-1Ra synthesis, processing and release, in HUVECs under pro-inflammatory conditions. EXPERIMENTAL APPROACH: Quantitative RT-PCR, immunoblotting, ELISA, flow cytometry, and whole-cell patch clamp recordings were used to determine protein expression and receptor function. IL-8-luciferase-reporter was used as an IL-1 sensitive bioassay. KEY RESULTS: HUVECs expressed P2X(4)R and P2X(7)R subtypes and both were significantly up-regulated under inflammatory conditions. P2X(7)R currents were increased 3-fold by inflammatory stimuli, whereas no P2X(4)R-mediated currents were detected. Caspase-1, but not IL-1beta, was present intracellularly under basal conditions; inflammatory stimuli activated the synthesis of intracellular pro-IL-1beta and increased caspase-1 levels. Activation of P2X(7)Rs resulted in low-level release of bioactive IL-1beta and simultaneous release of IL-1Ra. The net biological effect of release was anti-inflammatory. CONCLUSIONS AND IMPLICATIONS: Endothelial P2X(7)Rs induced secretion of both pro- and anti-inflammatory IL-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the arterial vessel wall.

Multidisciplinary rehabilitation for adults with multiple sclerosis.

BACKGROUND: Multidisciplinary rehabilitation (MD) is an important component of symptomatic and supportive treatment for Multiple sclerosis (MS), but evidence base for its effectiveness is yet to be established. OBJECTIVES: To assess the effectiveness of organized MD rehabilitation in adults with MS. To explore rehabilitation approaches that are effective in different settings and the outcomes that are affected. SEARCH STRATEGY: The sources used included: Cochrane Central Register of Controlled Trials "CENTRAL", MEDLINE (1966- 2005), CINAHL (1982- 2005), PEDro (1990- 2005), EMBASE (1988- 2005), the Cochrane Rehabilitation and Related Therapies Field trials Register and the National Health Service National Research Register (NRR). SELECTION CRITERIA: Randomized and controlled clinical trials that compared MD rehabilitation with routinely available local services or lower levels of intervention; or trials comparing interventions in different settings or at different levels of intensity. DATA COLLECTION AND ANALYSIS: Three reviewers selected trials and rated their methodological quality independently. A 'best evidence' synthesis based on methodological quality was performed. Trials were grouped in terms of setting and type of rehabilitation and duration of patient follow up. MAIN RESULTS: Eight trials (7 RCTs; 1 CCT) (747 participants and 73 caregivers) were identified. Seven RCTs scored well and one CCT scored poorly on the methodological quality assessment. There was 'strong evidence' that despite no change in the level of impairment, inpatient MD rehabilitation can produce short-term gains at the levels of activity (disability) and participation for patients with MS. For outpatient and home-based rehabilitation programmes there was 'limited evidence' for short-term improvements in symptoms and disability with high intensity programmes, which translated into improvement in participation and quality of life. For low intensity programmes conducted over a longer period there was strong evidence for longer-term gains in quality of life; and also limited evidence for benefits to carers. Although some studies reported potential for cost-savings, there is no convincing evidence regarding the long-term cost-effectiveness of these programmes. It was not possible to suggest best 'dose' of therapy or supremacy of one therapy over another. This review highlights the limitations of RCTs in rehabilitation settings and need for better designed randomized and multiple centre trials. AUTHORS' CONCLUSIONS: MD rehabilitation programmes do not change the level of impairment, but can improve the experience of people with MS in terms of activity and participation. Regular evaluation and assessment of these persons for rehabilitation is recommended. Further research into appropriate outcome measures, optimal intensity, frequency, cost and effectiveness of rehabilitation therapy over a longer time period is needed. Future research in rehabilitation should focus on improving methodological and scientific rigour of clinical trials.

Rehabilitation interventions for foot drop in neuromuscular disease.

BACKGROUND: "Foot drop" or "Floppy foot drop" is the term commonly used to describe weakness or contracture of the muscles around the ankle joint. It may arise from many neuromuscular diseases. OBJECTIVES: To conduct a systematic review of randomised trials of treatment for footdrop resulting from neuromuscular disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (July 2005), MEDLINE (January 1966 to July 2005), EMBASE (January 1980 to July 2005), AMED (January 1985 to July 2005) and CINAHL databases (January 1982 to July 2005). SELECTION CRITERIA: Randomised and quasi-randomised trials of physical, orthotic and surgical treatments for footdrop resulting from lower motor neuron or muscle disease and related contractures were included. People with primary joint disease were excluded. Interventions included a 'wait and see' approach, physiotherapy, orthotics, surgery and pharmacological therapy. The primary outcome measure was ability to walk whilst secondary outcome measures included dorsiflexor torque and strength, measures of 'activity' and 'participation' and adverse effects. DATA COLLECTION AND ANALYSIS: Methodological quality was evaluated by two authors using the van Tulder criteria. Three studies with altogether 139 participants were included in the review. Heterogeneity of the studies precluded pooling the data. MAIN RESULTS: Early surgery did not significantly affect walking speed in a trial including 20 children with Duchenne muscular dystrophy. After one year, the mean difference (MD) of the 28 feet walking time was 0.00 seconds (95% confidence interval (CI) -0.83 to 0.83) and the MD of the 150 feet walking time was -2.88 seconds, (95% CI -8.18 to 2.42). In a trial with altogether 26 participants with Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy), long-term strength training significantly increased walking speed on a 6 metre timed walk (MD -0.70 seconds, 95% CI -1.17 to -0.23) but not on a 50 metre timed walk (MD -1.9 seconds, 95% CI -4.09 to 0.29). In a trial of a 24-week strength training programme in 28 participants with myotonic dystrophy, there was no significant change in walking speed on either a 6 or 50 metre walk. AUTHORS' CONCLUSIONS: Using the primary outcome of ability to walk, only one study demonstrated a positive effect and that was an exercise programme for people with Charcot-Marie-Tooth disease. Surgery was not significantly effective in children with Duchenne Muscular Dystrophy. More evidence generated by methodologically sound trials is required.

Neonatal overfeeding by small-litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline.

The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data.

Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373.

BACKGROUND AND PURPOSE: The ATP-gated P2X(7) receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X(7) receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized. EXPERIMENTAL APPROACH: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1beta release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP). KEY RESULTS: AZ11645373 up to 10 microM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X(1), rat P2X(2), human P2X(3), rat P2X(2/3), human P2X(4), or human P2X(5) receptors expressed in HEK cells. AZ11645373 inhibited human P2X(7) receptor responses in HEK cells in a non-surmountable manner with K (B) values ranging from 5 - 20 nM, with mean values not significantly different between assays. K (B) values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1beta release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC(50) = 90 nM. AZ11645373 was > 500-fold less effective at inhibiting rat P2X(7) receptor-mediated currents with less than 50% inhibition occurring at 10 microM. CONCLUSIONS AND IMPLICATIONS: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X(7) receptors and will have much practical value in studies of human cells.

Multi-disciplinary rehabilitation for acquired brain injury in adults of working age.

BACKGROUND: Evidence from systematic reviews demonstrates that multi-disciplinary rehabilitation is effective in the stroke population, where older adults predominate. However, the evidence base for the effectiveness of rehabilitation following acquired brain injury (ABI) in younger adults is not yet established, perhaps because there are different methodological challenges. OBJECTIVES: To assess the effects of multi-disciplinary rehabilitation following ABI in adults, 16 to 65 years. To explore approaches that are effective in different settings and the outcomes that are affected. SEARCH STRATEGY: We used a wide range of sources including: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966-2004), EMBASE (1988-2004), CINAHL (1983-2004), PsycLIT (1967-2004), AMED, the National Research Register 2004 and ISI Science Citation Index (1981-2004). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing multi-disciplinary rehabilitation with either routinely available local services or lower levels of intervention; or trials comparing intervention in different settings or at different levels of intensity. Quasi-randomised and quasi-experimental designs were also included, providing they met pre-defined methodological criteria. DATA COLLECTION AND ANALYSIS: Trials were selected by two authors independently, and their methodological quality rated, again by two independent authors. A third reviewer arbitrated when disagreements could not be resolved by discussion. A 'best evidence' synthesis was performed by attributing levels of evidence, based on methodological quality. Trials were sub-divided in terms of severity of ABI and the setting and type of rehabilitation offered. MAIN RESULTS: Ten trials were identified of good methodological quality and four of lower quality. Within the subgroup of predominantly mild brain injury, 'strong evidence' suggested that most patients make a good recovery with provision of appropriate information, without additional specific intervention. For moderate to severe injury, there is 'strong evidence' of benefit from formal intervention. For patients with moderate to severe ABI already in rehabilitation, there is strong evidence that more intensive programmes are associated with earlier functional gains, and 'moderate evidence' that continued outpatient therapy can help to sustain gains made in early post-acute rehabilitation. There is 'limited evidence' that specialist in-patient rehabilitation and specialist multi-disciplinary community rehabilitation may provide additional functional gains, but the studies serve to highlight the particular practical and ethical restraints on randomisation of severely affected individuals for whom there are no realistic alternatives to specialist intervention. AUTHORS' CONCLUSIONS: Problems following ABI vary; different services are required to suit the needs of patients with different problems. Patients presenting acutely to hospital with moderate to severe brain injury should be routinely followed up to assess their need for rehabilitation. Intensive intervention appears to lead to earlier gains. The balance between intensity and cost-effectiveness has yet to be determined. Patients discharged from in-patient rehabilitation should have access to out-patient or community-based services appropriate to their needs. Those with milder brain injury benefit from follow-up, and appropriate information and advice. Not all questions in rehabilitation can be addressed by traditional research methodologies. There are important questions still to be answered and future research should employ the most appropriate methodology.

Dinitrogen oxide detection for nitrification failure early warning systems.

Experiments were conducted in order to establish whether N2O could be used to predict nitrification failure (through non-invasive means). Previous research had shown a strong correlation between N2O gas and NH3 in the effluent, giving rise to the possibility N2O can be used as an indicator for failure in the nitrification process. Two pilot-scale activated sludge plants were used, each with two lanes. The smaller consisted of a 601 aeration tank and a 201 clarifier; the larger pilot plant had an aeration tank of 3151 and a clarifier of 1001. The small pilot plant experiments showed that N2O gas was given off almost immediately from O2 deprivation/NH3 shock loads, but did not follow the expected trend of the time lag of NH3 in the effluent. This led to further investigation in the hydrodynamics and mixing characteristics of aeration basins, where a second larger pilot plant was used. Further experiments were conducted of high NH3 loadings and O2 deprivation, showed that work of was reproducible. However, it was also shown that with partial nitrification failure, a different N2O response of a continual rise was observed.

Selected ginsenosides of the protopanaxdiol series are novel positive allosteric modulators of P2X7 receptors.

BACKGROUND AND PURPOSE: The P2X7 receptor is an ATP-gated ion channel predominantly expressed in immune cells and plays a key role in inflammatory processes. Ginseng is a well-known Chinese herb with both pro- and anti-inflammatory properties and many of its actions have been ascribed to constituent ginsenosides. We screened a number of ginsenoside compounds for pharmacological activity at P2X7 receptors, that might contribute to the reported immunomodulatory actions of ginseng. EXPERIMENTAL APPROACH: We used several assays to measure responses of P2X7 receptors, ATP-mediated dye uptake, intracellular calcium measurement and whole-cell patch-clamp recordings. HEK-293 cells stably expressing human P2X7 receptors were used in addition to mouse macrophages endogenously expressing P2X7 receptors. KEY RESULTS: Four ginsenosides of the protopanaxdiol series, Rb1, Rh2, Rd and the metabolite compound K (CK) potentiated the dye uptake responses of P2X7 receptors, whereas other ginsenosides tested were ineffective (1-10 µM). The potentiation was rapid in onset, required a threshold concentration of ATP (>50 µM) and had an EC50 of 1.08 µM. CK markedly enhanced ATP-activated P2X7 currents, probably via an extracellular site of action. One of the consequences of this potentiation effect is a sustained rise in intracellular Ca(2+) that could account for the decrease in cell viability in mouse macrophages after a combination of 500 µM ATP and 10 µM CK that are non-toxic when applied alone. CONCLUSIONS AND IMPLICATIONS: This study identifies selected ginsenosides as novel potent allosteric modulators of P2X7 channels that may account for some of the reported immune modulatory actions of protopanaxdiol ginsenosides in vivo.

A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors.

A previous study of twins with Parkinson's disease (PD) revealed low concordance, suggesting that genetic factors play a minor role in the etiology of PD. To identify possible environmental determinants of PD while maximally controlling for hereditary factors, 31 monozygotic twin pairs discordant for PD were interviewed by telephone. Information about possible risk factors was obtained from systematic and uniform interviews with cases and controls. The only statistically significant result was less cigarette smoking by PD patients (p less than 0.05). Thirteen dizygotic discordant twin pairs were evaluated with the same techniques, but there were no statistically significant differences between affected and unaffected twins.

Anticonnective tissue and other antitissue 'antibodies' in the sera of patients with coeliac disease compared with the findings in a mixed hospital population.

Serum IgG specificities directed against various components of basement membrane and reticulin have been described, and their incidence in 138 patients with coeliac disease has been compared with that in 110 hospital inpatients, 100 normal blood donors, and 1441 other patients. A wide variety of antitissue specificities were observed but only a few appeared to be of any significance. The 'antireticulin' specificities have been subdivided into different groups according to their distinctive histological staining patterns. Specificity directed primarily against endothelial basement membrane was found most frequently in the sera of patients with hiatus hernia (35%) or coeliac disease (22%). The same specificity was also observed in patients with myasthenia gravis and to a lesser extent in Crohn's disease and in a mixed group of patients with unspecified organic gastrointestinal disease. An epithelial basement membrane reactivity was found in patients with rheumatoid arthritis but only rarely in other conditions. Staining of perivascular connective tissue represented a third type of 'antireticulin' specificity. It was found only rarely, although in coeliac disease this reactivity was found more frequently in combination with other connective tissue specificities.