Results from a randomised controlled pilot study of the Better Conversations with Primary Progressive Aphasia (BCPPA) communication partner training program for people with PPA and their communication partners.

BACKGROUND: There has been a growing focus on functional communication interventions for primary progressive aphasia (PPA). These interventions aim to support individuals to participate in life situations. One such intervention, communication partner training (CPT) aims to change conversation behaviours in both the person with PPA and their communication partner (CP). CPT has a growing evidence base in stroke aphasia; however, these programmes are not designed to meet the needs of people with progressive communication difficulties. To address this, the authors developed a CPT program entitled Better Conversations with PPA (BCPPA) and undertook a pilot trial to establish for a future full trial; predicted recruitment rates, acceptability, an assessment of treatment fidelity and an appropriate primary outcome measure. METHODOLOGY: This was a single-blind, randomised controlled pilot study comparing BCPPA to no treatment, delivered across 11 National Health Service Trusts in the UK. A random sample of eight recordings of local collaborators delivering the intervention were analysed to examine fidelity. Participants completed feedback forms reporting on acceptability. Pre- and post-intervention measures targeted conversation behaviours, communication goals and quality of life. RESULTS: Eighteen people with PPA and their CPs (9 randomised to BCPPA, 9 randomised to no treatment) completed the study. Participants in the intervention group rated BCPPA positively. Treatment fidelity was 87.2%. Twenty-nine of 30 intervention goals were achieved or over-achieved and 16 of 30 coded conversation behaviours demonstrated change in the intended direction. The Aphasia Impact Questionnaire was identified as the preferred outcome measure. CONCLUSION: The first randomised controlled UK pilot study of a CPT program for people with PPA and their families demonstrates BCPPA is a promising intervention. The intervention was acceptable, treatment fidelity high and an appropriate measure identified. Results of this study indicate a future RCT of BCPPA is feasible. TRIAL REGISTRATION: Registered 28/02/2018 ISRCTN10148247 .

Validation of the cognitive stimulation therapy (CST) program for people with dementia in Portugal.

BACKGROUND: Cognitive Stimulation Therapy (CST) is considered a gold-standard, evidence-based and cost-effective approach to improve cognitive function and quality of life of people with mild to moderate dementia. AIMS: To validate CST for the Portuguese population and test its effectiveness. METHODS: A single-blind, multi-center, randomized controlled trial recruited 112 older people with dementia. The primary outcome measure was cognition and secondary measures were quality of life, communication, autonomy, anxiety, depression, and global functioning. We also explored whether CST benefits people differently according to context, gender and level of cognitive reserve. RESULTS: Fifty-five people were randomized to the intervention and 57 to the control group. In the post-test, the intervention group significantly improved relative to controls in cognition (ADAS-Cog, p = 0.013), communication (HCS, p = 0.045), behaviour (CAPE-BRS, p = 0.017) and in global dementia rating (CDR, p = 0.008). Quality of life, depression and anxiety had no significant differences. The estimated number needed to treat was four for one to benefit a cognitive improvement (ADAS-Cog). CONCLUSIONS: Group CST is valid for the Portuguese population with benefits for people with mild to moderate dementia.

An adapted mindfulness intervention for people with dementia in care homes: feasibility pilot study.

OBJECTIVE: Depression and anxiety are common in dementia. There is a need to develop effective psychosocial interventions. This study sought to develop a group-based adapted mindfulness programme for people with mild to moderate dementia in care homes and to determine its feasibility and potential benefits. METHODS: A manual for a 10-session intervention was developed. Participants were randomly allocated to the intervention plus treatment as usual (n = 20) or treatment as usual (n = 11). Measures of mood, anxiety, quality of life, cognitive function, stress and mindfulness were administered at baseline and 1 week post-intervention. RESULTS: There was a significant improvement in quality of life in the intervention group compared to controls (p = 0.05). There were no significant changes in other outcomes. CONCLUSIONS: The intervention was feasible in terms of recruitment, retention, attrition and acceptability and was associated with significant positive changes in quality of life. A fully powered randomised controlled trial is required. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of high-fat diet and gastric bypass on neurons in the caudal solitary nucleus.

Bariatric surgery is an effective treatment for obesity that involves both peripheral and central mechanisms. To elucidate central pathways by which oral and visceral signals are influenced by high-fat diet (HFD) and Roux-en-Y gastric bypass (RYGB) surgery, we recorded from neurons in the caudal visceral nucleus of the solitary tract (cNST, N=287) and rostral gustatory NST (rNST,N=106) in rats maintained on a HFD and lab chow (CHOW) or CHOW alone, and subjected to either RYGB or sham surgery. Animals on the HFD weighed significantly more than CHOW rats and RYGB reversed and then blunted weight gain regardless of diet. Using whole-cell patch clamp recording in a brainstem slice, we determined the membrane properties of cNST and rNST neurons associated with diet and surgery. We could not detect differences in rNST neurons associated with these manipulations. In cNST neurons, neither the threshold for solitary tract stimulation nor the amplitude of evoked EPSCs at threshold varied by condition; however suprathreshold EPSCs were larger in HFD compared to chow-fed animals. In addition, a transient outward current, most likely an IA current, was increased with HFD and RYGB reduced this current as well as a sustained outward current. Interestingly, hypothalamic projecting cNST neurons preferentially express IA and modulate transmission of afferent signals (Bailey, '07). Thus, diet and RYGB have multiple effects on the cellular properties of neurons in the visceral regions of NST, with potential to influence inputs to forebrain feeding circuits.

Cognitive stimulation therapy (CST) for people with dementia--who benefits most?

BACKGROUND: The efficacy of cognitive stimulation therapy (CST) has been demonstrated, but little is known about the characteristics of people with dementia, which may predict a more positive response to CST. This study sought to investigate which factors may predict response to CST. METHODS: Two hundred and seventy-two participants with dementia took part in a 7-week CST intervention. Assessments were carried out pre-treatment and post-treatment. The results were compared with those of a previous comparable CST randomised control trial. A comparison of mean scores pre-CST and post-CST groups was undertaken, and contributing factors that predicted change in outcomes were examined. RESULTS: CST improved cognition and quality of life, and the results showed that the benefits of CST were independent of whether people were taking acetylcholinesteraseinhibitor (AChEI) medication. Increasing age was associated with cognitive benefits, as was female gender. Care home residents improved more than community residents on quality of life, but the community sample seemed to benefit more in relation to behaviour problems. CONCLUSIONS: These results demonstrate that CST improves cognition and quality of life for people with dementia including those already on AChEIs. Older age and being female were associated with increased cognitive benefits from the intervention. Consideration should be given to aspects of CST, which may enhance the benefits for people with dementia who are male and those younger than 80 years.

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation.

Roux-en-Y gastric bypass (RYGB) surgery has been shown to decrease consummatory responsiveness of rats to high sucrose concentrations, and genetic deletion of glucagon-like peptide-1 receptors (GLP-1R) has been shown to decrease consummatory responsiveness of mice to low-sucrose concentrations. Here we assessed the effects of RYGB and pharmacological GLP-1R modulation on sucrose licking by chow-fed rats in a brief-access test that assessed consummatory and appetitive behaviors. Rats were tested while fasted presurgically and postsurgically and while nondeprived postsurgically and 5 h after intraperitoneal injections with the GLP-1R antagonist exendin-3(9-39) (30 µg/kg), agonist exendin-4 (1 µg/kg), and vehicle in 30-min sessions during which a sucrose concentration series (0.01-1.0 M) was presented in 10-s trials. Other rats were tested postsurgically or 15 min after peptide or vehicle injection while fasted and while nondeprived. Independent of food-deprivation state, sucrose experience, or GLP-1R modulation, RYGB rats took 1.5-3× as many trials as sham-operated rats, indicating increased appetitive behavior. Under nondeprived conditions, RYGB rats with presurgical sucrose experience licked more to sucrose relative to water compared with sham-operated rats. Exendin-4 and exendin-3(9-39) impacted 0.3 M sucrose intake in a one-bottle test, but never interacted with surgical group to affect brief-access responding. Unlike prior reports in both clearly obese and relatively leaner rats given RYGB and in GLP-1R knockout mice, we found that neither RYGB nor GLP-1R blockade decreased consummatory responsiveness to sucrose in our less obese chow-fed rats. Collectively, these results highlight the fact that changes in taste-driven motivated behavior to sucrose after RYGB and/or GLP-1R modulation are very model and measure dependent.

Alterations of sucrose preference after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass.

Carbon fiber reinforced polymer dimensional stability investigations for use on the laser interferometer space antenna mission telescope.

The laser interferometer space antenna (LISA) is a mission designed to detect low frequency gravitational waves. In order for LISA to succeed in its goal of direct measurement of gravitational waves, many subsystems must work together to measure the distance between proof masses on adjacent spacecraft. One such subsystem, the telescope, plays a critical role as it is the laser transmission and reception link between spacecraft. Not only must the material that makes up the telescope support structure be strong, stiff, and light, but it must have a dimensional stability of better than 1 pm Hz(-1/2) at 3 mHz and the distance between the primary and the secondary mirrors must change by less than 2.5 µm over the mission lifetime. Carbon fiber reinforced polymer is the current baseline material; however, it has not been tested to the pico meter level as required by the LISA mission. In this paper, we present dimensional stability results, outgassing effects occurring in the cavity and discuss its feasibility for use as the telescope spacer for the LISA spacecraft.

WITHDRAWN: Reality orientation for dementia.

BACKGROUND: Reality Orientation (RO) was first described as a technique to improve the quality of life of confused elderly people, although its origins lie in an attempt to rehabilitate severely disturbed war veterans, not in geriatric work. It operates through the presentation of orientation information (eg time, place and person-related) which is thought to provide the person with a greater understanding of their surroundings, possibly resulting in an improved sense of control and self-esteem. There has been criticism of RO in clinical practice, with some fear that it has been applied in a mechanical fashion and has been insensitive to the needs of the individual. There is also a suggestion that constant relearning of material can actually contribute to mood and self-esteem problems. There is often little consistent application of psychological therapies in dementia services, so a systematic review of the available evidence is important in order to identify the effectiveness of the different therapies. Subsequently, guidelines for their use can be made on a sound evidence base. OBJECTIVES: To assess the evidence of effectiveness for the use of Reality Orientation (RO) as a classroom-based therapy on elderly persons with dementia. SEARCH STRATEGY: Computerised databases were searched independently by 2 reviewers entering the terms 'Reality Orientation, dementia, control, trial or study'. Relevant web sites were searched and some hand searching was conducted by the reviewer. Specialists in the field were approached for undocumented material, and all publications found were searched for additional references. SELECTION CRITERIA: All randomized controlled trials (RCTs), and all controlled trials with some degree of concealment, blinding or control for bias (second order evidence) of Reality Orientation as an intervention for dementia were included. The criteria for inclusion/exclusion involved systematic assessment of the quality of study design and the risk of bias, using a standard data extraction form. A measure of cognitive and/or behavioural change was needed. DATA COLLECTION AND ANALYSIS: Data were extracted independently by both reviewers, using a previously tested data extraction form. Authors were contacted for data not provided in the papers. Psychological scales measuring cognitive and behavioural changes were examined. MAIN RESULTS: 6 RCTs were entered in the analysis, with a total of 125 subjects (67 in experimental groups, 58 in control groups). Results were divided into 2 subsections: cognition and behaviour. Change in cognitive and behavioural outcomes showed a significant effect in favour of treatment. AUTHORS' CONCLUSIONS: There is some evidence that RO has benefits on both cognition and behaviour for dementia sufferers. Further research could examine which features of RO are particularly effective. It is unclear how far the benefits of RO extend after the end of treatment, but and it appears that a continued programme may be needed to sustain potential benefits.

Improved quality of life and cognitive stimulation therapy in dementia.

Quality of life (QoL) is now seen as a key outcome in many aspects of dementia care. In a recent randomized controlled trial of Cognitive Stimulation Therapy (CST) groups, significant improvements in self-reported QoL were identified as well as changes in cognitive function. This further analysis of results from the trial examines whether the changes in these two domains occurred independently, perhaps for different reasons, or whether the effect of treatment on QoL was mediated by the changes in cognition. In all, 201 people with dementia living in residential homes or attending day centres were assessed using the Quality of Life-Alzheimer's Disease (QOL-AD) scale and a range of measures of cognition, dementia level, mood, dependency and communication. Participants were randomized to receive an intervention programme of CST or to receive treatment as usual. The QoL-AD and other measures were repeated eight weeks later. At baseline, higher QoL in dementia was significantly correlated with lower levels of dependency and depression, but not with cognitive function or dementia severity. Improvement in quality of life was associated with being female, low quality of life at baseline, reduced depression and increased cognitive function. Changes in cognitive function mediated the effects of treatment in improving QoL. These results suggest that whilst QoL in dementia appears to be independent of level of cognitive function, interventions aimed at improving cognitive function can, nonetheless, have a direct effect on QoL.

Electromechanical models of the outer hair cell composite membrane.

The outer hair cell (OHC) is an extremely specialized cell and its proper functioning is essential for normal mammalian hearing. This article reviews recent developments in theoretical modeling that have increased our knowledge of the operation of this fascinating cell. The earliest models aimed at capturing experimental observations on voltage-induced cellular length changes and capacitance were based on isotropic elasticity and a two-state Boltzmann function. Recent advances in modeling based on the thermodynamics of orthotropic electroelastic materials better capture the cell's voltage-dependent stiffness, capacitance, interaction with its environment and ability to generate force at high frequencies. While complete models are crucial, simpler continuum models can be derived that retain fidelity over small changes in transmembrane voltage and strains occurring in vivo. By its function in the cochlea, the OHC behaves like a piezoelectric-like actuator, and the main cellular features can be described by piezoelectric models. However, a finer characterization of the cell's composite wall requires understanding the local mechanical and electrical fields. One of the key questions is the relative contribution of the in-plane and bending modes of electromechanical strains and forces (moments). The latter mode is associated with the flexoelectric effect in curved membranes. New data, including a novel experiment with tethers pulled from the cell membrane, can help in estimating the role of different modes of electromechanical coupling. Despite considerable progress, many problems still confound modelers. Thus, this article will conclude with a discussion of unanswered questions and highlight directions for future research.

Reminiscence therapy for dementia.

BACKGROUND: Reminiscence Therapy (RT) involves the discussion of past activities, events and experiences with another person or group of people, usually with the aid of tangible prompts such as photographs, household and other familiar items from the past, music and archive sound recordings. Reminiscence groups typically involve group meetings in which participants are encouraged to talk about past events at least once a week. Life review typically involves individual sessions, in which the person is guided chronologically through life experiences, encouraged to evaluate them, and may produce a life story book. Family care-givers are increasingly involved in reminiscence therapy. Reminiscence therapy is one of the most popular psychosocial interventions in dementia care, and is highly rated by staff and participants. There is some evidence to suggest it is effective in improving mood in older people without dementia. Its effects on mood, cognition and well-being in dementia are less well understood. OBJECTIVES: The objective of the review is to assess the effects of reminiscence therapy for older people with dementia and their care-givers. SEARCH STRATEGY: The trials were identified from a search of the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group on 4 May 2004 using the term "reminiscence". The CDCIG Specialized Register contains records from all major health care databases (MEDLINE, EMBASE, PsycLIT, CINAHL) and many ongoing trials databases and is regularly updated. We contacted specialists in the field and also searched relevant Internet sites. We hand-searched Aging and Mental Health, the Gerontologist, Journal of Gerontology, Current Opinion in Psychiatry, Current Research in Britain: Social Sciences, British Psychological Society conference proceedings and Reminiscence database. SELECTION CRITERIA: Randomised controlled trials and quasi-randomized trials of reminiscence therapy for dementia. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Five trials are included in the review, but only four trials with a total of 144 participants had extractable data. The results were statistically significant for cognition (at follow-up), mood (at follow-up) and on a measure of general behavioural function (at the end of the intervention period). The improvement on cognition was evident in comparison with both no treatment and social contact control conditions. Care-giver strain showed a significant decrease for care-givers participating in groups with their relative with dementia, and staff knowledge of group members' backgrounds improved significantly. No harmful effects were identified on the outcome measures reported. AUTHORS' CONCLUSIONS: Whilst four suitable randomized controlled trials looking at reminiscence therapy for dementia were found, several were very small studies, or were of relatively low quality, and each examined different types of reminiscence work. Although there are a number of promising indications, in view of the limited number and quality of studies, the variation in types of reminiscence work reported and the variation in results between studies, the review highlights the urgent need for more and better designed trials so that more robust conclusions may be drawn.

Whose quality of life is it anyway? The validity and reliability of the Quality of Life-Alzheimer's Disease (QoL-AD) scale.

Quality of life (QoL) is becoming an increasingly used outcome measure in both clinical practice and research. There are now more than 1000 scales available to measure QoL, and it is important that they are assessed for reliability and validity. This study aims to assess the reliability and validity of the Quality of Life-Alzheimer's Disease (QoL-AD) scale, which is dementia specific and brief and uses the patient's own responses. Two separate samples of people with dementia (sample 1, n = 60; sample 2, n = 201) were assessed. Five focus groups were conducted involving both people with dementia and their caregivers; the focus groups showed that people with dementia had higher hopes for their QoL than their caregivers did for them. Questionnaires about the scale were completed by 71 health care professionals working with people with dementia. The scale was found to have good content validity with no additional items required and all items necessary. It also correlated well with the Dementia Quality of Life scale (0.69) and with the Euroqol-5D scale (0.54), indicating good criterion concurrent validity. Construct validity was also good with the principal components analysis showing all 13 items of the QoL-AD loaded on component 1. Interrater reliability was excellent with all Cohen's kappa values >0.70. Internal consistency was excellent with a Cronbach's alpha coefficient of 0.82. Some people with severe dementia and a Mini-Mental State Examination score as low as 3 were able to satisfactorily complete the QoL-AD. The QoL-AD has very good psychometric properties and can be completed with people with a wide range of severity of dementia.

Cognitive rehabilitation and cognitive training for early-stage Alzheimer's disease and vascular dementia.

BACKGROUND: Memory problems are a defining feature of the early stages of Alzheimer's disease (AD) and vascular dementia. Cognitive training and cognitive rehabilitation are specific approaches designed to address everyday memory difficulties. OBJECTIVES: The main aim was to evaluate the effectiveness and impact of cognitive training and cognitive rehabilitation interventions aimed at improving memory functioning for people in the early stages of Alzheimer's disease or vascular dementia. The two types of intervention were considered separately. SEARCH STRATEGY: The CDCIG Specialized Register, which contains records from MEDLINE, EMBASE, CINAHL, PsycINFO and many other databases, was searched on 9 April 2003. SELECTION CRITERIA: RCTs comparing cognitive rehabilitation or cognitive training interventions with comparison conditions, and reporting outcomes for the person with dementia and/or the family caregiver, were considered for inclusion. DATA COLLECTION AND ANALYSIS: Six studies reporting cognitive training interventions were included. Statistical analyses were conducted to provide an indication of intervention effect sizes. Data from ordinal scales was treated as continuous, and a fixed effects model was applied in calculating weighted mean differences and 95% confidence intervals. No studies were found that reported a fully individualised cognitive rehabilitation approach. MAIN RESULTS: None of the six studies reporting cognitive training interventions demonstrated any statistically significant effects in any domain, although there were indications of some modest, non-significant effects in various domains of cognitive functioning. REVIEWER'S CONCLUSIONS: The present findings do not provide strong support for the use of cognitive training interventions for people with early-stage AD or vascular dementia, although these findings must be viewed with caution due to the limited number of RCTs available and to the methodological limitations identified, and further well-designed trials would help to provide more definitive evidence. Due to a complete absence of RCTs evaluating an individualised cognitive rehabilitation approach, It is not possible at present to draw conclusions about the efficacy of individualised cognitive rehabilitation interventions for people with early-stage dementia, and further research is required in this area.

Aroma therapy for dementia.

BACKGROUND: Complementary therapies have become more commonly used over the last decade and have been applied to a range of health problems, including dementia. Of these, aroma therapy is reported to be the most widely used in the British National Health Service (Lundie 1994) and might be of use for people with dementia for whom verbal interaction may be difficult and conventional medicine of only marginal benefit. Aroma therapy has been used for people with dementia to reduce disturbed behaviour (e.g. Brooker 1997), promote sleep (e.g. Wolfe 1996), and stimulate motivational behaviour (e.g. MacMahon 1998). OBJECTIVES: To assess the efficacy of aroma therapy as an intervention for people with dementia. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 29 October 2002 to find all relevant trials using the terms: aroma therap*, "aroma therap*", "complementary therap*", "alternative therap*" and "essential oil". The CDCIG Register contains records from all major health care databases and is updated regularly. Additionally, relevant journals were hand searched, and 'experts' in the field of complementary therapies and dementia contacted. SELECTION CRITERIA: All relevant randomized controlled trials (RCTs) were considered. A minimum length of trial and requirements for a follow-up were not included, and participants in included studies had a diagnosis of dementia of any type and severity. The review considered all trials using fragrance from plants defined as aroma therapy as an intervention with people with dementia. Several outcomes were considered in this review, including cognitive function, quality of life, and relaxation. DATA COLLECTION AND ANALYSIS: The titles and abstracts extracted by the searches were screened for their eligibility for potential inclusion in the review, which revealed 2 RCTs of aroma therapy for dementia. Neither of these had published results in a form that we could use. However, individual patient data from one trial were obtained (Ballard 2002) and additional analyses performed. Analysis of co-variance was used for all outcomes, using a random effects model. MAIN RESULTS: The additional analyses conducted revealed a statistically significant treatment effect in favour of the aroma therapy intervention on measures of agitation and neuropsychiatric symptoms. REVIEWER'S CONCLUSIONS: Aroma therapy showed benefit for people with dementia in the only trial that contributed data to this review, but there were several methodological difficulties with this study. More well designed large-scale RCTs are needed before conclusions can be drawn on the effectiveness of aroma therapy. Additionally, several issues need to be addressed, such as whether different aroma therapy interventions are comparable and the possibility that outcomes may vary for different types of dementia.

Comparison of 20-, 22-, and 24-carbon n-3 and n-6 polyunsaturated fatty acid utilization in differentiated rat brain astrocytes.

Astrocytes convert n-6 fatty acids primarily to arachidonic acid (20:4n-6), whereas n-3 fatty acids are converted to docosapentaenoic (22:5n-3) and docosahexaenoic (22:6n-3) acids. The utilization of 20-, 22- and 24-carbon n-3 and n-6 fatty acids was compared in differentiated rat astrocytes to determine the metabolic basis for this difference. The astrocytes retained 81% of the arachidonic acid ([(3)H]20:4n-6) uptake and retroconverted 57% of the docosatetraenoic acid ([3-(14)C]22:4n-6) uptake to 20:4n-6. By contrast, 68% of the eicosapentaenoic acid ([(3)H]20:5n-3) uptake was elongated, and only 9% of the [3-(14)C]22:5n-3 uptake was retroconverted to 20:5n-3. Both tetracosapentaenoic acid ([3-(14)C]24:5n-3) and tetracosatetraenoic acid ([3-(14)C]24:4n-6) were converted to docosahexaenoic acid (22:6n-3) and 22:5n-6, respectively. Therefore, the difference in the n-3 and n-6 fatty acid products formed is due primarily to differences in the utilization of their 20- and 22-carbon intermediates. This metabolic difference probably contributes to the preferential accumulation of docosahexaenoic acid in the brain.

Modeling 3-D deformation of outer hair cells and their production of the active force in the cochlea.

We analyze the deformation of the outer hair cell and its production of active force under physiological conditions. The active force has two components. One results from the strain caused by loading in the organ of Corti in the cochlea and depends on the level of the acoustic signal; the other is related to the intrinsic active properties of the cell membrane. We demonstrate our approach by considering, as a basic model of an outer hair cell in the organ of Corti, a cylindrical shell that is filled with an incompressible fluid and located between two planes that move relative to each other. These planes represent the basilar membrane and tectorial membrane complexes. We show that the deformed state of the cell has a 3-D nature, including bending and twisting components. This is different from the experimental conditions in which the active force is usually measured. We estimate the active force as a function of the relative position of the planes, angle of the cell's inclination, and the cell length.

Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid.

DHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes. For a long time, the exact mechanism of DHA formation has remained unclear, but now it is known that it involves the production of tetracosahexaenoic acid (C24:6n-3) from dietary linolenic acid (C18:3n-3) via a series of elongation and desaturation reactions, followed by beta-oxidation of C24:6n-3 to C22:6n-3. Although DHA is deficient in patients lacking peroxisomes, the intracellular site of retroconversion of C24:6n-3 has remained controversial. By making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this article that peroxisomes, and not mitochondria, are involved in DHA formation by catalyzing the beta-oxidation of C24:6n-3 to C22:6n-3. Additional studies of fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, and of fibroblasts from l-bifunctional protein and sterol carrier protein X (SCPx) knockout mice, show that the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of importance for the treatment of patients with a defect in peroxisomal beta-oxidation.

ATP causes small heat shock proteins to release denatured protein.

Small heat-shock proteins (sHSPs) are a ubiquitous family of low molecular mass (15-30 kDa) stress proteins that have been found in all organisms. Under stress, sHSPs such as alpha-crystallin can act as chaperones binding partially denatured proteins and preventing further denaturation and aggregation. Recently, it has been proposed that the function of sHSPs is to stabilize stress-denatured protein and then act cooperatively with other HSPs to renature the partially denatured protein in an ATP-dependent manner. However, the process by which this occurs is obscure. As no significant phosphorylation of alpha-crystallin was observed during the renaturation, the role of ATP is not clear. It is now shown that ATP at normal physiological concentrations causes sHSPs to change their confirmation and release denatured protein, allowing other molecular chaperones such as HSP70 to renature the protein and renew its biological activity. In the absence of ATP, sHSPs such as alpha-crystallin are more efficient than HSP70 in preventing stress-induced protein aggregation. This work also indicates that in mammalian systems at normal cellular ATP concentrations, sHSPs are not effective chaperones.

Activation of ATP-sensitive K(+) channels by epoxyeicosatrienoic acids in rat cardiac ventricular myocytes.

1. We examined the effects of epoxyeicosatrienoic acids (EETs), which are cytochrome P450 metabolites of arachidonic acid (AA), on the activities of the ATP-sensitive K(+) (K(ATP)) channels of rat cardiac myocytes, using the inside-out patch-clamp technique. 2. In the presence of 100 microM cytoplasmic ATP, the K(ATP) channel open probability (P(o)) was increased by 240 +/- 60 % with 0.1 microM 11,12-EET and by 400 +/- 54 % with 5 microM 11,12-EET (n = 5-10, P < 0.05 vs. control), whereas neither 5 microM AA nor 5 microM 11,12-dihydroxyeicosatrienoic acid (DHET), which is the epoxide hydrolysis product of 11,12-EET, had any effect on P(o). 3. The half-maximal activating concentration (EC(50)) was 18.9 +/- 2.6 nM for 11,12-EET (n = 5) and 19.1 +/- 4.8 nM for 8,9-EET (n = 5, P = n.s. vs. 11,12-EET). Furthermore, 11,12-EET failed to alter the inhibition of K(ATP) channels by glyburide. 4. Application of 11,12-EET markedly decreased the channel sensitivity to cytoplasmic ATP. The half-maximal inhibitory concentration of ATP (IC(50)) was increased from 21.2 +/- 2.0 microM at baseline to 240 +/- 60 microM with 0.1 microM 11,12-EET (n = 5, P < 0.05 vs. control) and to 780 +/- 30 microM with 5 microM 11,12-EET (n = 11, P < 0.05 vs. control). 5. Increasing the ATP concentration increased the number of kinetically distinguishable closed states, promoting prolonged closure durations. 11,12-EET antagonized the effects of ATP on the kinetics of the K(ATP) channels in a dose- and voltage-dependent manner. 11,12-EET (1 microM) reduced the apparent association rate constant of ATP to the channel by 135-fold. 6. Application of 5 microM 11,12-EET resulted in hyperpolarization of the resting membrane potential in isolated cardiac myocytes, which could be blocked by glyburide. 7. These results suggest that EETs are potent activators of the cardiac K(ATP) channels, modulating channel behaviour by reducing the channel sensitivity to ATP. Thus, EETs could be important endogenous regulators of cardiac electrical excitability.