On the mechanism of carbon nanotube formation: the role of the catalyst.

This work examines the recent developments in non-traditional catalyst-assisted chemical vapour deposition of carbon nanotubes (CNTs) with a view to determining the essential role of the catalyst in nanotube growth. A brief overview of the techniques reliant on the structural reorganization of carbon to form CNTs is provided. Additionally, CNT synthesis methods based upon ceramic, noble metal, and semiconducting nanoparticle catalysts are presented. Experimental evidence is provided for CNT growth using noble metal and semiconducting nanoparticle catalysts. A model for CNT growth consistent with the experimental results is proposed, in which the structural reorganization of carbon to form CNTs is paramount.

Omalizumab therapy: patients who achieve greatest benefit for their asthma experience greatest benefit for rhinitis.

BACKGROUND: Asthma and rhinitis are considered components of a single IgE-mediated inflammatory disorder. However, despite being shown to often co-exist, they are typically treated as independent conditions. Omalizumab, an anti-IgE antibody, has proven effective in the treatment of both asthma and rhinitis. AIMS: To examine whether a response to omalizumab in terms of asthma control predicts a higher likelihood of rhinitis response in patients with concomitant allergic asthma and rhinitis. METHODS: This post hoc analysis was conducted on efficacy results from the SOLAR trial in which patients with moderate-to-severe asthma and rhinitis were randomized to receive omalizumab or placebo for 28 weeks. Patients were classified as asthma responders based on the physician's overall assessment (complete control or marked improvement in a five-level evaluation). Rhinitis responders were identified using the Rhinitis Quality of Life Questionnaire (RQLQ) questionnaire (> or = 1.0 point improvement in overall score). RESULTS: Data were available for 207 omalizumab-treated patients and 192 placebo patients. According to the physicians overall assessment, 123 (59.4%) of omalizumab-treated patients were asthma responders, with the likelihood of a rhinitis response significantly (P < 0.001) greater in these patients than in the placebo group. The odds ratio for rhinitis response in omalizumab-treated asthma responders vs nonresponders was 3.56 (95% CI: 1.94-6.54). CONCLUSIONS: A response in terms of asthma following omalizumab therapy is associated with a significantly increased probability of improvement in rhinitis.

Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment.

BACKGROUND: Anti-IgE, omalizumab, inhibits the allergen response in patients with asthma. This has not been directly related to changes in inflammatory conditions. We hypothesized that anti-IgE exerts its effects by reducing airway inflammation. To that end, the effect of anti-IgE on allergen-induced inflammation in bronchial biopsies in 25 patients with asthma was investigated in a randomized, double-blind, placebo-controlled study. METHODS: Allergen challenge followed by a bronchoscopy at 24 h was performed at baseline and after 12 weeks of treatment with anti-IgE or placebo. Provocative concentration that causes a 20% fall in forced expiratory volume in 1 s (PC(20)) methacholine and induced sputum was performed at baseline, 8 and 12 weeks of treatment. Changes in the early and late responses to allergen, PC(20), inflammatory cells in biopsies and sputum were assessed. RESULTS: Both the early and late asthmatic responses were suppressed to 15.3% and 4.7% following anti-IgE treatment as compared with placebo (P < 0.002). This was paralleled by a decrease in eosinophil counts in sputum (4-0.5%) and postallergen biopsies (15-2 cells/0.1 mm(2)) (P < 0.03). Furthermore, biopsy IgE+ cells were significantly reduced between both the groups, whereas high-affinity IgE receptor and CD4+ cells were decreased within the anti-IgE group. There were no significant differences for PC(20) methacholine. CONCLUSION: The response to inhaled allergen in asthma is diminished by anti-IgE, which in bronchial mucosa is paralleled by a reduction in eosinophils and a decline in IgE-bearing cells postallergen without changing PC(20) methacholine. This suggests that the benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE-bearing cells.

Effectiveness of omalizumab in patients with inadequately controlled severe persistent allergic asthma: an open-label study.

BACKGROUND: In a 1-year, randomized, open-label study in patients with moderate-to-severe allergic (immunoglobulin E (IgE)-mediated) asthma, adding omalizumab to best standard care (BSC) significantly improved efficacy outcomes compared with BSC alone (control). We assessed the efficacy of omalizumab in the subgroup of patients with inadequately controlled severe persistent allergic asthma despite high-dose inhaled corticosteroids (ICS) plus a long-acting beta(2)-agonist (LABA), which reflects the European Union (EU) label population. METHODS: Efficacy outcomes included annual asthma exacerbation rate, annual asthma deterioration-related incident (ADRI) rate, % predicted forced expiratory volume in 1 s (FEV(1)), asthma symptoms (Wasserfallen score) and quality of life (Mini Asthma Quality of Life Questionnaire (Mini-AQLQ)), which were compared in the omalizumab and control groups. Outcomes were also determined for omalizumab-treated patients judged to have responded to therapy (> or = 0.5-point improvement in Mini-AQLQ overall score at 27 weeks). RESULTS: In total, 164 patients (omalizumab, n=115; control, n=49) were receiving high-dose ICS plus a LABA. Annual asthma exacerbation rate was significantly reduced by 59% in the omalizumab group vs. control (1.26 vs. 3.06; P<0.001). ADRI rate was significantly reduced by 40% in the omalizumab group compared with control (5.61 vs. 9.40; P<0.05). Significant improvements were also seen in % predicted FEV(1) (71% vs. 60%; P<0.001), change from baseline in asthma symptom scores (-6.7 vs. 0.5; P<0.05) and Mini-AQLQ overall score (1.32 vs. 0.17; P<0.001). In omalizumab-treated patients, 71/102 (70%) were judged to have responded to therapy. In these Mini-AQLQ-assessed responders, exacerbation rate was reduced by 64% vs. control (1.12 vs. 3.06; P<0.001), ADRI rate was reduced by 50% vs. control (4.71 vs. 9.40; P<0.01). Percent predicted FEV(1) (73% vs. 60%; P<0.001), change from baseline in asthma symptom scores (-8.1 vs. 0.5; P<0.001) and Mini-AQLQ overall score (1.81 vs. 0.17; P<0.001) were also further significantly improved vs. control. CONCLUSIONS: Adding omalizumab to BSC is efficacious in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (EU label population), with further efficacy observed in patients judged to have responded to therapy which may more accurately illustrate the actual benefit of omalizumab therapy in clinical practice. The naturalistic setting of this study confirms the benefits observed in double-blind randomized clinical trials.

Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti-IgE treatment.

Geohelminth infections are major parasitic infections with a worldwide distribution. Immunoglobulin E (IgE) is considered to play a central role in protective immunity against these parasites although the evidence from experimental animal models infected with helminth parasites and treated with anti-IgE antibodies and from observational studies in human populations of the immunologic correlates of protective immunity against helminths do not support a critical role for IgE in mediating protection against helminths. Anti-IgE treatment of human allergic disorders using a humanized monoclonal IgE antibody (omalizumab, Xolair) has been approved for clinical use in the USA and Europe and there is concern that this treatment may be associated with increased morbidity in populations exposed to helminth infections. A recently published randomized controlled trial investigating the risk of geohelminth infections in allergic patients receiving omalizumab in Brazil has provided some evidence that omalizumab may not be associated with increased morbidity attributable to these parasites. This review examines the evidence for a role of IgE in protective immunity against helminth parasites, discusses the findings of the randomized controlled trial, assesses the potential risks and provides recommendations for anti-IgE treatment in groups of allergic patients with different exposure risks for helminth infections.

Predicting and evaluating response to omalizumab in patients with severe allergic asthma.

BACKGROUND: Omalizumab is a monoclonal antibody indicated for treatment of severe persistent allergic asthma inadequately controlled despite optimal controller therapy. We investigated whether patient selection could be targeted further. METHODS: Data from seven randomized controlled omalizumab trials were analyzed to investigate whether pre-treatment patient baseline clinical characteristics could be identified that were predictive of a superior response to omalizumab. We also studied whether patients who respond to omalizumab following a course of treatment could be reliably identified. Univariate/multivariate analyses of INNOVATE data were performed to identify predictive baseline measures and further investigated in efficacy analyses of pooled data from seven studies. The best method of identifying responders to omalizumab following treatment was determined by assessing the ability of various clinical response criteria to identify responders and discriminate patient exacerbation and other outcomes. RESULTS: Baseline total immunoglobulin E (IgE) was the only predictor of efficacy in INNOVATE. However, pooled analysis showed treatment benefits irrespective of IgE levels. In omalizumab-treated patients, physician's overall assessment following a course of treatment identified 61% as responders and best discriminated treatment outcomes. CONCLUSION: Baseline characteristics do not reliably predict benefit with omalizumab. Physician's overall assessment after 16 weeks of treatment is the most meaningful measure of response to therapy.

Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection.

BACKGROUND: Although the role of immunoglobulin E (IgE) in immunity against helminth parasites is unclear, there is concern that therapeutic antibodies that neutralize IgE (anti-IgE) may be unsafe in subjects at risk of helminth infection. OBJECTIVE: We conducted an exploratory study to investigate the safety of omalizumab (anti-IgE) in subjects with allergic asthma and/or perennial allergic rhinitis at high risk of intestinal helminth infection. The primary safety outcome was risk of infections with intestinal helminths during anti-IgE therapy. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 137 subjects (12-30 years) at high risk of geohelminth infection. All subjects received pre-study anthelmintic treatment, followed by 52 weeks' treatment with omalizumab or placebo. RESULTS: Of the omalizumab subjects 50% (34/68) experienced at least one intestinal geohelminth infection compared with 41% (28/69) of placebo subjects [odds ratio (OR) 1.47, 95% confidence interval (CI) 0.74-2.95, one-sided P=0.14; OR (adjusted for study visit, baseline infection status, gender and age) 2.2 (0.94-5.15); one-sided P=0.035], providing some evidence for a potential increased incidence of geohelminth infection in subjects receiving omalizumab. Omalizumab therapy was well tolerated, and did not appear to be associated with increased morbidity attributable to intestinal helminths as assessed by clinical and laboratory adverse events, maximal helminth infection intensities and additional anthelmintic requirements. Time to first infection (OR 1.30, 95% CI 0.79-2.15, one-sided P=0.15) was similar between treatment groups. Infection severity and response to anthelmintics appeared to be unaffected by omalizumab therapy. CONCLUSIONS: In this exploratory study of allergic subjects at high risk of helminth infections, omalizumab therapy appeared to be safe and well tolerated, but may be associated with a modest increase in the incidence of geohelminth infection.

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma.

BACKGROUND: Patients with poorly controlled asthma have greater morbidity and mortality. This study evaluated the efficacy and tolerability of omalizumab in patients with poorly controlled, moderate-to-severe allergic asthma. METHODS: This was a randomized, open-label, multicentre, parallel-group study. A total of 312 patients (12-73 years) receiving >/=400 microg/day (adolescent) or >/=800 microg/day (adult) inhaled beclomethasone dipropionate, or equivalent were included. Patients received best standard care (BSC) with or without omalizumab [at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks] for 12 months. RESULTS: The annualized mean number of asthma deterioration-related incidents was reduced from 9.76 with BSC alone (n = 106) to 4.92 per patient-year with omalizumab (n = 206) (P < 0.001). Mean clinically significant asthma exacerbation rates were 2.86 and 1.12 per patient-year, respectively (P < 0.001). Omalizumab-treated patients (41.4%) required rescue medication <1 day/week compared with 20.7% for BSC alone (P < 0.001). Omalizumab improved absolute forced expiratory volume in 1 s (FEV(1)) compared with BSC alone (2.48 and 2.28 l, respectively; P < 0.05) and reduced symptom scores relative to BSC alone (decrease of 6.5 and 0.7 respectively; P < 0.001). Omalizumab was well-tolerated. CONCLUSIONS: Omalizumab administered as add-on therapy to BSC benefits patients with poorly controlled, moderate-to-severe allergic asthma.

Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease.

BACKGROUND: Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis. METHODS: A detailed evaluation of attention and fluctuating attention was undertaken in 155 patients with dementia (85 with DLB and 80 with AD) from a representative hospital dementia case register and 35 elderly controls using the Cognitive Drug Research Computerized Assessment System for Dementia Patients computerized neuropsychological battery. Operationalized clinical diagnosis was made using the consensus criteria for DLB and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD. High levels of sensitivity and specificity have been achieved for the first 50 cases undergoing postmortem examination. RESULTS: The groups were well matched for severity of cognitive impairments, but the AD patients were older (mean age, 80 vs 78 years) and more likely to be female (55% vs 40%). Patients with DLB were significantly more impaired than patients with AD on all measures of attention and fluctuating attention (for all comparisons, t > or = 2.5, P<.001), and patients from both dementia groups were significantly more impaired than elderly controls for all comparisons other than cognitive reaction time, which was significantly more impaired in DLB patients than controls but was comparable in controls and AD patients. There were, however, significant associations between the severity of cognitive impairment and the severity of both attentional deficits and fluctuations in attention. CONCLUSIONS: This large prospective study confirms that slowing of cognitive processing, attention, and fluctuations of attention are significantly more pronounced in DLB and AD patients, although fluctuating attention is common in patients with moderate-to-severe AD. Deficits of cognitive reaction time appear to be specific to DLB, except in severe dementia. A detailed evaluation of attentional performance could make an important contribution to differential diagnosis, although the results need to be interpreted within the context of the overall severity of cognitive deficits.

Quantification and characterization of fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease.

Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia.

BACKGROUND: The identification of fluctuating confusion is central to improving the differential diagnosis of the common dementias. AIMS: To determine the value of two rating scales to measure fluctuating confusion. METHOD: The agreement between the clinician-rated scale and the scale completed by a non-clinician was determined. Correlations between the two scales were calculated; variability in attention was calculated on a computerised cognitive assessment and variability in delta rhythm on an electroencephalogram (EEG). RESULTS: The Clinician Assessment of Fluctuation and the computerised cognitive assessment were completed for 155 patients (61 Alzheimer's disease, 37 dementia with Lewy bodies, 22 vascular dementia, 35 elderly controls). A subgroup (n = 40) received a further evaluation using the One Day Fluctuation Assessment Scale and an EEG. The two scales correlated significantly with each other, and with the neuropsychological and electrophysiological measures of fluctuation. CONCLUSIONS: Both scales are useful instruments for the clinical assessment of fluctuation in dementia.

Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia.

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. METHOD: - A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.

Dose-dependent effects of flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers.

OBJECTIVES: To assess the possible effects of flumazenil on cognitive processing, physiology, and mood. Design A double-blind, placebo controlled, four-way cross-over study, using healthy volunteers. METHODS: On each of 4 separate visits, 16 participants received 0.5 mg, 2.5 mg, 5.0 mg of flumazenil, or normal saline. They then performed a computerised test battery assessing cognitive function. Measures of pulse rate, arterial oxygen saturation and mean arterial pressure were also taken. Finally, participants completed visual analogue scales assessing their subjective mood state. RESULTS: The majority of cognitive tasks showed dose-dependent declines in performance. Mean arterial pressure was significantly reduced, as was pulse rate. Subjective alertness showed a similar decline. CONCLUSIONS: Flumazenil has been clinically described as an agent with few intrinsic properties, whose primary effect lies in its ability to reverse benzodiazepine-induced states. This study has shown that flumazenil does possess intrinsic activity which have a significant effect on cognition, cardiovascular physiology and mood. Clinicians need to be aware of these effects.

Simple standardised neuropsychological assessments aid in the differential diagnosis of dementia with Lewy bodies from Alzheimer's disease and vascular dementia.

Consecutive patients from a dementia case register received a standardised evaluation which incorporated a neuropsychological assessment with the Cambridge Assessment for disorders in the elderly (CAMCOG). Operationalised clinical diagnoses were made (consensus criteria for dementia with Lewy bodies, DLB; NINCDS- ADRDA for Alzheimer's disease, AD, NINCDS AIRENS for vascular dementia, VaD). Two-hundred and twenty-eight patients were studied (DLB 54, AD102, VaD 72). DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis. DLB patients also had significantly better recent memory than those with VaD. Optimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.

Psychotic symptoms, aggression and restlessness in dementia.

The current article reviews the literature pertaining to psychosis, aggression and restlessness in dementia sufferers examining frequency, course and associations as well as treatment considerations. All of these problems are highly prevalent, with a high impact upon dementia sufferers and their carers. Although there has been an expansion in this literature over the last few years there are still very few studies describing the natural course of behavioural and psychological symptoms in dementia (BPSD) and a paucity of data relating to non-Alzheimer dementias. Several large treatment studies have recently been completed, but there are still very few double blind controlled trials focusing upon BPSD in particular respect to non-pharmacological interventions.

A prospective study of dementia with Lewy bodies.

BACKGROUND: little is known about the longitudinal course of dementia with Lewy bodies (DLB) and how this differs from Alzheimer's disease (AD). METHOD: standardized baseline and annual assessments of cognitive and non-cognitive symptoms are reported in a cohort of 72 patients with DLB or AD. AD was diagnosed using the NINCDS ADRDA criteria and DLB was diagnosed with the criteria of McKeith et al. Cognitive assessment was undertaken using the MMSE schedule and operationalized definitions were used to diagnose non-cognitive symptoms. RESULTS: 42 patients with DLB and 30 patients with AD were assessed. Of the 19 on whom post mortem examinations have been performed, 18 (95%) have had the clinical diagnosis confirmed. DLB patients were significantly more likely to experience visual hallucinations, disturbances of consciousness and parkinsonism at both baseline and at annual assessments. Of DLB patients exposed to neuroleptics, 33% developed sensitivity reactions. The magnitude and pattern of cognitive decline was similar in both groups. CONCLUSION: the importance of the core features highlighted in the newly proposed consensus DLB criteria is supported. These features appear to be stable over time.