Exploring the cancer caregiver's journey through web-based Meaning-Centered Psychotherapy.

OBJECTIVE: Psychosocial interventions are historically underutilized by cancer caregivers, but support programs delivered flexibly over the Internet address multiple barriers to care. We adapted Meaning-Centered Psychotherapy for cancer caregivers, an in-person psychotherapeutic intervention intended to augment caregivers' sense of meaning and purpose and ameliorate burden, for delivery in a self-administered web-based program, the Care for the Cancer Caregiver (CCC) Workshop. The present study evaluated the feasibility, acceptability, and preliminary effects of this program. METHODS: Eighty-four caregivers were randomized to the CCC Workshop or waitlist control arm. Quantitative assessments of meaning, burden, anxiety, depression, benefit finding, and spiritual well-being were conducted preintervention (T1), within 2-weeks postintervention (T2), and 2- to 3-month follow-up (T3). In-depth semistructured interviews were conducted with a subset of participants. RESULTS: Forty-two caregivers were randomized to the CCC Workshop. Attrition was moderate at T2 and T3, with caregiver burden and bereavement as key causes of drop-out. At T2 and T3, some observed mean change scores and effect sizes were consistent with hypothesized trends (eg, meaning in caregiving, benefit finding, and depressive symptomatology), though no pre-post significant differences emerged between groups. However, a longitudinal mixed-effects model found significant differential increases in benefit finding in favor of the CCC arm. CONCLUSIONS: The CCC Workshop was feasible and acceptable. Based on effect sizes reported here, a larger study will likely establish the efficacy of the CCC Workshop, which has the potential to address unmet needs of caregivers who underutilize in-person supportive care services.

CHiCP: a web-based tool for the integrative and interactive visualization of promoter capture Hi-C datasets.

UNLABELLED: Promoter capture Hi-C (PCHi-C) allows the genome-wide interrogation of physical interactions between distal DNA regulatory elements and gene promoters in multiple tissue contexts. Visual integration of the resultant chromosome interaction maps with other sources of genomic annotations can provide insight into underlying regulatory mechanisms. We have developed Capture HiC Plotter (CHiCP), a web-based tool that allows interactive exploration of PCHi-C interaction maps and integration with both public and user-defined genomic datasets. AVAILABILITY AND IMPLEMENTATION: CHiCP is freely accessible from www.chicp.org and supports most major HTML5 compliant web browsers. Full source code and installation instructions are available from http://github.com/D-I-L/django-chicp CONTACT: ob219@cam.ac.uk.

Non-specific symbiotic germination of Cynorkis purpurea (Thouars) Kraezl., a habitat-specific terrestrial orchid from the Central Highlands of Madagascar.

Orchids, particularly terrestrial taxa, rely mostly on basidiomycete fungi in the Cantharellales and Sebacinales that trigger the process of seed germination and/or initiate the full development of the seedling. During the course of development, orchids may associate with the same fungus, or they may enlist other types of fungi for their developmental needs leading to resilience in a natural setting. This study examined in vitro seed germination and seedling developmental behavior of Cynorkis purpurea, a terrestrial orchid from the Central Highlands of Madagascar. This species is mostly restricted to gallery forests in the Itremo Massif, in moist substrate between rocks bordering streams. The main objective was to understand the influence of diverse mycorrhizal fungi on seed germination and further development of C. purpurea. The study aims to compare symbiotic versus asymbiotic germination and seedling development with seeds and fungi collected from a 13-km(2) area in the Itremo region. Seeds collected from the wild were sown with diverse orchid mycorrhizal fungi (OMF) spanning 12 operational taxonomic units (OTUs) in three genera (Tulasnella, Ceratobasidium, and Sebacina) acquired from different habitats. Treatments were assessed in terms of the percentage of germinated seeds and fully developed seedlings against those in asymbiotic control media treatments. Overall, OMF significantly improved seedling development within the 12-week experiment period. Sebacina as a genus was the most effective at promoting seedling development of C. purpurea, as well as having the ability to enter into successful symbiotic relationships with orchids of different life forms; this new knowledge may be especially useful for orchid conservation practiced in tropical areas like Madagascar. A Sebacina isolate from an epiphytic seedling of Polystachya concreta was the most effective at inducing rapid seedling development and was among the five that outperformed fungi isolated from roots of C. purpurea. C. purpurea was found to be a mycorrhizal generalist, despite its specific habitat preference, highlighting the complex interaction between the plant, fungi, and the environment. The potential impact on conservation strategies of understanding the requirements for orchid seed germination and development by identifying and using OMF from diverse sources is discussed in detail.

Elevated levels of soluble total and hyperphosphorylated tau result in early behavioral deficits and distinct changes in brain pathology in a new tau transgenic mouse model.

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr(181), Ser(199), Thr(231) and Thr(235)), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser(396) and Ser(404) in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

An siRNA screen identifies RSK1 as a key modulator of lung cancer metastasis.

We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagen-based three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

Association of white matter hyperintensity measurements on brain MR imaging with cognitive status, medial temporal atrophy, and cardiovascular risk factors.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimer's Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

Association between late-life body mass index and dementia: The Kame Project.

OBJECTIVE: To examine the association between body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) and risk of dementia and its subtypes in late life. METHODS: Participants were members of the Kame Project, a population-based prospective cohort study of 1,836 Japanese Americans living in King County, WA, who had a mean age of 71.8 years and were dementia-free at baseline (1992-1994), and were followed for incident dementia through 2001. Cox proportional hazards models were used to estimate the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD) controlling for demographic and lifestyle characteristics and vascular comorbidities as a function of baseline BMI, WC, and WHR and change in BMI over time. RESULTS: Higher baseline BMI was significantly associated with a reduced risk of AD (hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.33-0.97) in the fully adjusted model. Slower rate of decline in BMI was associated with a reduced risk of dementia (HR = 0.37, 95% CI = 0.14-0.98), with the association stronger for those who were overweight or obese (HR = 0.18, 95% CI = 0.05-0.58) compared to normal or underweight (HR = 1.00, 95% CI = 0.18-5.66) at baseline. CONCLUSION: Higher baseline body mass index (BMI) and slower declining BMI in late life are associated with a reduced risk of dementia, suggesting that low BMI or a faster decline in BMI in late life may be preclinical indicators of an underlying dementing illness, especially for those who were initially overweight or obese.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.

Cycad exposure and risk of dementia, MCI, and PDC in the Chamorro population of Guam.

OBJECTIVE: To study cycad-derived products as possible risk factors for dementia, mild cognitive impairment (MCI), and parkinsonism-dementia complex (PDC) on Guam. METHODS: Complete risk factor data from in-person interviews of 166 cases of Guam dementia, 50 cases of amnestic MCI, and 21 cases of PDC were compared with 1,581 controls in the base population regarding exposure to cycad-derived products from a traditional food (fadang), consumption of fruit bats, and use of cycad-derived topical medicine. RESULTS: Adjusted odds ratios (ORs) and 95% CIs for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05 to 1.91) to 2.87 (1.48 to 5.56) and were consistently elevated and significant across all three diagnostic outcomes. Associations independent of exposure in young adulthood were for picking (OR 0.78, 95% CI 0.64 to 0.96) and processing (OR 0.77, 95% CI 0.63 to 0.94) fadang in childhood with Guam dementia. Men showed stronger and more consistent relations across exposure groups in young adulthood compared with women. No associations were found for consumption of fruit bats or exposure to cycad used as a topical medicine for any of the outcomes. Estimated adjusted population attributable risks suggest that exposure to eating fadang in young adulthood incurred the highest attributable risk percent. CONCLUSIONS: Environmental lifestyle and diet may contribute to the etiology of neurodegenerative diseases in the native population of Guam.

GAP-43 immunoreactivity of subepithelial and detrusor muscle nerve fibres in patients with refractory idiopathic detrusor overactivity.

AIMS: To determine the relative density of nerve fibres immunoreactive to growth associated protein-43 (GAP-43, an indicator of neuronal sprouting) in the subepithelium and detrusor of patients with idiopathic detrusor overactivity (IDO). To investigate the effect, if any, of age and previous recurrent bacterial cystitis on neuronal sprouting in such patients. MATERIALS AND METHODS: A series of 18 women with urodynamically proven IDO (median age 62 years, range 39-85), who were refractory to treatment, underwent cystoscopy and cold cup biopsy. Controls (n=26, median age 65, range 32-79) were females without urgency/urge incontinence, undergoing cystoscopy for other indications. Recurrent proven bacterial cystitis (rUTI) was documented. Frozen sections were stained with specific antibodies to GAP-43 and protein gene product 9.5 (PGP, a general neuronal marker). The area represented by immunoreactive (ir) subepithelial or muscle nerve fibres was measured. RESULTS: The density of GAP-43ir and PGPir nerves did not differ significantly between IDO patients and controls, in either subepithelium or detrusor. The GAP-43ir nerve density (as percent of PGPir) increased significantly with advancing age amongst patients with IDO in the detrusor muscle but not in the subepithelium; density in controls was unaltered. In IDO patients with rUTI, a significant increase in GAP-43 (as percent of PGPir) was observed in the subepithelium. CONCLUSIONS: Although we found no evidence of increased neuronal proliferation in patients with IDO generally, the increase in GAP-43 with age and with previous cystitis history suggests that neuronal sprouting is important in some subsets of patients with IDO.

Staging disease severity in pathologically confirmed cases of frontotemporal dementia.

OBJECTIVE: To devise a staging scheme for addressing the severity of atrophy in patients with pathologically proven frontotemporal dementia (FTD) and determine any relationship with clinical indices. METHODS: Twenty-four cases with clinical and pathologic features of FTD were selected using standard inclusion and exclusion criteria from 125 dementia cases collected in Sydney, Australia, over an 8.5-year period. Patterns of gross atrophy were determined in two coronal brain slices. Reproducibility of a four-stage severity scheme was tested. Nonparametric statistics were used to determine relationships between the stage of atrophy and clinical indices (age at death, duration from diagnosis, and clinical severity at death). RESULTS: The FTD cases studied could be reliably grouped (kappa = 0.97) into four progressively severe stages of global atrophy. Initial mild atrophy occurred in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressed to involve the other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), then involved all remaining tissue in these coronal slices (stage 3), until very marked atrophy was observed in all areas (stage 4). These stages correlated with disease duration and clinical dementia severity, lending validity to the progressive nature of the staging scheme. CONCLUSIONS: The authors have identified a reproducible staging system for the severity of gross atrophy in cases of FTD. This staging scheme provides the required framework to compare different research indices and determine correlates relating to time and disease progression in FTD-information necessary to determine core disease processes and etiologic factors.

Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') ingestion.

BACKGROUND: Life-threatening and fatal hyponatraemic complications following ecstasy use have previously been documented. AIM: To define clinical features of hyponatraemia following the ingestion of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). DESIGN: Retrospective case series. METHODS: All enquiries to the London centre of the National Poisons Information Service (NPIS) between December 1993 and March 1996 were screened for cases of MDMA use associated with hyponatraemia (serum sodium <130 mmol/l). History of fluid consumption, presenting features and subsequent clinical course were recorded. RESULTS: Seventeen patients, aged 15-26 years, were identified. Serum sodium levels ranged between 107 mmol/l and 128 mmol/l. In six patients, biochemical results were consistent with inappropriate secretion of antidiuretic hormone (SIADH). Analytical confirmation of MDMA ingestion was obtained in 10 patients. Ten patients were known to have ingested a large amount of non-alcoholic or alcoholic fluid. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed in 11 patients by seizures. Drowsiness, a mute state and disorientation were observed for up to 3 days. Two patients died; 14 made a complete recovery. DISCUSSION: MDMA can cause life-threatening hyponatraemic encephalopathy when accompanied by excessive fluid ingestion. The mechanism involves inappropriate secretion of antidiuretic hormone.

Setting and evaluating the energy content of emergency rations.

This paper examines the setting and evaluation of emergency rations for refugees and displaced people. After defining the purpose for which rations are designed, the variables affecting their quantification are discussed. The debate concerning the use of one as opposed to a range of energy levels for different populations is highlighted in a review of recent proposals for ration levels. It is demonstrated that up to a twofold range occurs if different combinations of the main parameters are used. This has important implications for the large-scale provision of food. The use of one figure for the setting and evaluation of rations for all populations is inappropriate; figures should be set according to specific context and need. To achieve this, a practical two-stage approach is proposed. Stage 1, probably a desk exercise, uses pre-calculated 'look-up' tables which provide energy values for each country. These figures are for immediate use as 'rule-of-thumb' estimates, based on clearly defined parameters. The second stage involves refining the values using improved information on local conditions collected by field assessment.

The clinical picture of the depressed form of puerperal psychosis.

The clinical features of 104 patients admitted to a mother and baby unit over a 5-year period with RDC diagnoses of depression or schizoaffective depression were studied by self-ratings, measurements of non-verbal behaviour from standardised videotaped interviews, and observer ratings based on multiple information sources. The hypothesis was tested that they included a large subset which represented the depressed form of a bipolar puerperal psychosis. It was deduced that these illnesses would start early in the puerperium, and would have some specific clinical features. A comparison of patients with onset of depression within 2 weeks of delivery with those with onset during pregnancy or much later in the postnatal period showed a number of significant differences. A discriminant function analysis using serial reclassification of atypical patients refined the early-onset group by the exclusion of about one third of the patients who had an atypical clinical picture; the patients who remained, who are considered to represent the depressed form of puerperal psychosis, showed less anger, less self-rated emotion and more animation than the other depressed patients.

Is the message getting through? Nutritional knowledge of pregnant women in Edinburgh and London.

This paper reports the results of a survey in which pregnant women in London and Edinburgh were asked about their knowledge and understanding of the recent recommendations of expert committees (James, 1983; DHSS, 1984). In general, Londoners had a better understanding, although in both regions manual groups were less knowledgeable, with the Edinburgh manual group the least well informed.

Salt intake and blood pressure in young adults from hypertensive and normotensive families.

Young adults with both parents in either the upper or lower quartile of blood pressure for their age groups were monitored for 13 d to assess whether there was a selective relationship between blood pressure and sodium excretion in the adults from the hypertensive but not from the normotensive families. Twelve 24-h urine measurements of sodium and potassium excretion were related to the mean of daily blood pressure measurements. Although a significant correlation between sodium excretion and blood pressure was found for the whole group, this related to the co-correlation of blood pressure and sodium excretion with the body weights of the subjects, no links being found in adults of either parental type once an allowance was made for body weight differences.