Frontal delta power associated with negative symptoms in ultra-high risk individuals who transitioned to psychosis

It has recently been shown that treatment with long-chain omega-3 polyunsaturated fatty acids (PUFAs) could decrease the rate of transition to psychosis, and improve psychiatric symptoms and global functioning in people at ultra-high risk (UHR) for psychosis. Previous studies have suggested that resting state brain activity measured with electroencephalography (EEG) may represent an objective biomarker of changes in neural function associated with supplementation with omega-3 PUFAs. It has also been proposed that although resting state EEG cannot, by itself, predict transition to psychosis in UHR individuals, the combination of resting state EEG with negative symptoms may be a valid predictor of transition. The present study investigated whether treatment with omega-3 PUFAs influenced resting state EEG in UHR participants, and whether or not the association of the participants' resting state EEG with their levels of negative symptoms was dependent on their transition status. The brain activity of 73 UHR participants was recorded in the context of a randomized, placebo-controlled trial of the effects of supplementation with omega-3 PUFAs. The UHR participants who subsequently transitioned to psychosis (UHR+) did not differ from those who did not transition (UHR-) in terms of resting state EEG power in any frequency band. However, negative symptom scores were associated with increased delta activity in the frontal region of the UHR+ participants, but not in the UHR- participants. Treatment with omega-3 PUFAs did not induce changes in resting state EEG in either group. The results suggest that decreased frontal delta activity, in combination with high levels of negative symptoms, may be a risk factor for subsequent transition to psychosis in UHR individuals.     

Chronic rhinosinusitis and nasal polyposis in cystic fibrosis: update on diagnosis and treatment

Although cystic fibrosis (CF) is an irreversible genetic disease, advances in treatment have increased the life expectancy of CF patients. Upper airway involvement, which is mainly due to pathological changes in the paranasal sinuses, is prevalent in CF patients, although many are only mildly symptomatic (with few symptoms). The objective of this literature review was to discuss the pathophysiology and current therapeutic management of chronic rhinosinusitis (CRS) in CF patients. The review was based on current evidence, which was classified in accordance with the Oxford Centre for Evidence-Based Medicine criteria. When symptomatic, CRS with nasal polyps can affect quality of life and can lead to pulmonary exacerbations, given that the paranasal sinuses can be colonized with pathogenic bacteria, especially Pseudomonas aeruginosa. Infection with P. aeruginosa plays a crucial role in morbidity and mortality after lung transplantation in CF patients. Although clinical treatment of the upper airways is recommended as initial management, this recommendation is often extrapolated from studies of CRS in the general population. When sinonasal disease is refractory to noninvasive therapy, surgery is indicated. Further studies are needed in order to gain a better understanding of upper airway involvement and improve the management of CRS in CF patients, with the objective of preserving lung function and avoiding unnecessary invasive procedures.     

Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputation: A practical guide

Missing data due to loss to follow-up or intercurrent events are unintended, but unfortunately inevitable in clinical trials. Since the true values of missing data are never known, it is necessary to assess the impact of untestable and unavoidable assumptions about any unobserved data in sensitivity analysis. This tutorial provides an overview of controlled multiple imputation (MI) techniques and a practical guide to their use for sensitivity analysis of trials with missing continuous outcome data. These include δ- and reference-based MI procedures. In δ-based imputation, an offset term, δ, is typically added to the expected value of the missing data to assess the impact of unobserved participants having a worse or better response than those observed. Reference-based imputation draws imputed values with some reference to observed data in other groups of the trial, typically in other treatment arms. We illustrate the accessibility of these methods using data from a pediatric eczema trial and a chronic headache trial and provide Stata code to facilitate adoption. We discuss issues surrounding the choice of δ in δ-based sensitivity analysis. We also review the debate on variance estimation within reference-based analysis and justify the use of Rubin's variance estimator in this setting, since as we further elaborate on within, it provides information anchored inference.     

Identifying an outcome measure to assess the impact of Mobility Dogs

Purpose: Mobility Dogs® trains dogs to work with people with physical disabilities to increase independence, confidence, self-esteem and participation. Mobility Dogs® seeks to critically evaluate and improve its services as it grows. This study aimed to identify and implement a standardised outcome measure into practice at Mobility Dogs®. Method: Based on the Consolidated Framework for Implementation Research and guided by a steering group of key stakeholders, a three-phase approach was developed to identify and assess an outcome measure. The steering group highlighted the organisation’s specific needs, selected participation as the assessment domain and identified core utility requirements of the measure. A comprehensive review of evidence was undertaken to identify and rank potential measures according to the specified needs.

Results: Of the seven participation outcome measures that met inclusion criteria, the three highest ranked measures were critically evaluated by the steering group to determine suitability against the organisation’s needs. The Impact on Participation and Autonomy (IPA) was selected for implementation into practice at Mobility Dogs®. Conclusion: Use of the IPA is an important first step for Mobility Dogs® to test the benefits of trained service dogs. This process could be replicated by other service dog organisations to identify outcome measures to assess their own services.

• Implications for Rehabilitation

• Service dogs (such as Mobility Dogs® in New Zealand) assist people living with physical impairments by performing tasks, however there is limited evidence on outcomes.

• The process for selecting an appropriate outcome measure for Mobility Dogs® involving partnership between Mobility Dogs® personnel and academics was an effective way to steer the project by determining important properties of the measure, before a search of the literature was undertaken.

• While the IPA was selected as the most appropriate outcome measure for use at Mobility Dogs®, it was the process that is valuable to replicate if other organisations wish to select an outcome measure for use in their own practice.

     

Metabotropic glutamate receptors (mGlus) and cellular transformation

Although the glutamatergic system usually functions in the CNS, expression has been observed in non-neuronal tissues and a subset of cancers. Metabotropic glutamate receptors (mGlus) are highly "druggable" GPCRs and thus a priority for validation as therapeutic targets. We have previously reported that the aberrant expression of mGlu1 is sufficient to induce spontaneous melanoma development in vivo. We isolated and characterized several stable mGlu1-mouse melanocytic clones and demonstrated that these clones are transformed and tumorigenic. We hypothesize that expression of mGlus may not be uncommon in the pathogenesis of tumors other than melanoma, and that activity of an otherwise normal glutamate receptor in an ectopic cellular environment involves signaling pathways which dysregulate cell growth, ultimately leading to tumorigenesis. As most human cancers are of epithelial origin (carcinomas), in this review, the possibility that mGlu1 could function as a complete oncogene and transform epithelial cells is also discussed.     

Antiprotozoal,antimycobacterial and cytotoxic potential of twenty‐three British and Irish red algae

As part of our continuing research on seaweeds, we have screened the crude extracts of 23 red marine algae collected from England and Ireland. The clinically important blood‐stage life forms of Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani and Mycobacterium tuberculosis were used as test organisms in the in vitro assays. The selectivity of the extracts was determined by using mammalian skeletal myoblast (L6) cells. All algal extracts showed activity against T. brucei rhodesiense, with Corallina officinalis and Ceramium virgatum being the most potent (IC₅₀ values 4.8 and 5.4 μg/ml), whilst none of the algal extracts inhibited the growth of T. cruzi. Except for Porphyra leucosticta, extracts from all seaweeds also showed leishmanicidal activity with IC₅₀ values ranging from 16.5 to 85.6 μg/ml. Only the crude extract of Calliblepharis jubata showed some weak activity against Mycobacterium tuberculosis (MIC value 256 μg/ml), while the others were inactive at this concentration. Corallina officinalis was the only seaweed that displayed some marginal cytotoxicity (IC₅₀ value 88.6 μg/ml), and all remaining extracts were non‐toxic towards L6 cells at 90 μg/ml concentration. To our knowledge, this is the first study reporting antiprotozoal and antimycobacterial activity of British and Irish red algae. Copyright © 2010 John Wiley & Sons, Ltd.     

Improved clinical outcomes for multiple myeloma patients treated at a single specialty clinic

Despite recent advances made in its treatment, multiple myeloma (MM) remains an incurable B cell malignancy. Thus, the objective for treating these patients is to prolong overall survival (OS) and preserve patients’ quality of life. We have analyzed data from 264 consecutive MM patients who had their initial visit between July 1, 2004 and December 1, 2014 and have received treatment in a single clinic specializing in MM. We determined their progression-free survival (PFS, OS, and 5-year OS). The PFS for frontline (n = 165 treatments), salvage (n = 980), and all treatments (n = 1145) were 13.9, 4.6, and 5.5 months, respectively. The median OS of all patients was 98 months with a 5-year survival of 74%. The results of this study show a marked improvement in OS for unselected MM patients compared with historical data. There were no significant differences in OS between patients with different International Staging System (ISS) stages. Younger patients (<65 years old) showed a longer OS. The results of this study should help physicians predict outcomes for MM patients and be encouraging for patients with this B cell malignancy.     

Filamentous, mixed micelles of triblock copolymers enhance tumor localization of indocyanine green in a murine xenograft model

Polymeric micelles formed by the self-assembly of amphiphilic block copolymers can be used to encapsulate hydrophobic drugs for tumor-delivery applications. Filamentous carriers with high aspect ratios offer potential advantages over spherical carriers, including prolonged circulation times. In this work, mixed micelles composed of poly(ethylene oxide)-poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127 (PF-127) were used to encapsulate a near-infrared fluorophore. The micelle formulations were assessed for tumor accumulation after tail vein injection to xenograft tumor-bearing mice by noninvasive optical imaging. The mixed micelle formulation that facilitated the highest tumor accumulation was shown by cryo-electron microscopy to be filamentous in structure compared to spherical structures of pure PF-127 micelles. In addition, increased dye loading efficiency and dye stability were attained in this mixed micelle formulation compared to pure PEO-PHB-PEO micelles. Therefore, the optimized PEO-PHB-PEO/PF-127 mixed micelle formulation offers advantages for cancer delivery over micelles formed from the individual copolymer components.     

In vivo simultaneous intra- and extracellular potassium recordings using a micro-optrode

This technique proposes a new approach to correlate intra- and extracellular variations of the ionic concentrations in vivo by means of tapered optical waveguides coupled to standard electrophysiological electrodes to monitor in vivo simultaneously the intracellular and extracellular K(+) concentration as well as the neighboring field potential. The optical fibers were tapered to a final diameter of approximately 10 μm and were used to guide the excitation light deep into the tissue and to collect the fluorescence emanating from the intracellular milieu. This fiber was coupled to a double barrel ion-sensitive electrode forming a micro-optrode with a final diameter around 15 μm. The method was successfully used to record the intracellular K(+) evolution with the fluorescent indicator PBFI during three states: normal sleep-like patterns, paroxysmal seizures, and coma. While we could not disclose any phasic fluctuations of the intracellular K(+) during normal sleep patterns, they were clearly present during seizures and coma. In the majority of cases (58%), paroxysmal discharges were associated with positive variations of the intracellular fluorescence of 62±5% corresponding to extracellular K(+) increases of 2.04±0.4 mM. In the remaining cases (42%) intracellular K(+) dropped by 44.4±12% for an extracellular K(+) increase of 2.62±0.47 mM. We suggest that this differential behavior might reflect different cellular populations (glia vs. neurons, respectively). Comatose states were accompanied by an extracellular drop of K(+) of 1.31±0.13 mM, which was reflected, in all cases, by an intracellular K(+) increase of 39±4%.