Investigating the efficacy of a combination Aß-targeted treatment in a mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aß) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we explored the use of a combination treatment to reduce amyloid load through microglial phagocytosis in a mouse model of AD. We hypothesized that using an initial treatment of magnetic resonance image guided focused ultrasound (MRIgFUS) to transiently increase the blood-brain barrier (BBB) permeability and enhance the delivery of an Aß-antibody (BAM-10), followed by scyllo-inositol treatment would result in accelerated clearance. TgCRND8 mice expressing both Swedish (KM670/671NL) and Indiana (V717F) APP mutations under the hamster prion (PrP) promoter at 5 months of age were either treated with scyllo-inositol or received an initial MRIgFUS treatment delivering BAM-10 prior to scyllo-inositol treatment for one month. Treated animals and untreated TgCRND8 littermates were then sacrificed at 6 months of age, and their brains were processed for immunohistochemistry and immunofluorescence. Amyloid load was quantified and analyzed through immunohistochemical staining. Astrocyte and microglial activation were quantified and analyzed through immunofluorescent staining. We found that both the scyllo-inositol treatment and combination treatment, MRIgFUS/BAM10+scyllo-inositol, significantly reduced amyloid load and astrocyte activation in the hippocampus and the cortex. Furthermore, in both treatment paradigms microglial activation and phagocytosis was increased in comparison to the untreated mice. There were no differences detected between the two treatment paradigms. We propose that the 30-day scyllo-inositol treatment saturated the early benefit of the MRIgFUS/BAM-10 treatment. In the future, multiple FUS treatments combined with BAM-10 throughout the duration of scyllo-inositol treatment may lead to more effective amyloid clearance.

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions.

Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

Preclinical MRI-Guided Focused Ultrasound: A Review of Systems and Current Practices.

Effective preclinical research is a vital component in the development of MRI-guided focused ultrasound (MRgFUS) and its translation to clinic. In this review, we seek to outline the challenges at hand for effective preclinical research, survey different solutions, and underline best practices. Furthermore, we summarize efforts to build and characterize dedicated preclinical MRgFUS equipment, including lab prototypes and available commercial products. Finally, we discuss constraints and considerations specific to using clinical MRgFUS equipment in preclinical research. Specifically, we examine additional hardware that has been used to adapt clinical MRgFUS equipment to better position, constrain, and image preclinical subjects, as well as software solutions that have been used to extend the potential and capabilities of clinical devices.

MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound.

PURPOSE: A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain. PROCEDURES: Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding. RESULTS: Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ∼1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ∼4:1 at 45 min to ∼7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS. CONCLUSIONS: MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.

A novel, flat, electronically-steered phased array transducer for tissue ablation: preliminary results.

Flat, λ/2-spaced phased arrays for therapeutic ultrasound were examined in silico and in vitro. All arrays were made by combining modules made of 64 square elements with 1.5 mm inter-element spacing along both major axes. The arrays were designed to accommodate integrated, co-aligned diagnostic transducers for targeting and monitoring. Six arrays of 1024 elements (16 modules) and four arrays of 6144 elements (96 modules) were modelled and compared according to metrics such as peak pressure amplitude, focal size, ability to be electronically-steered far off-axis and grating lobe amplitude. Two 1024 element prototypes were built and measured in vitro, producing over 100 W of acoustic power. In both cases, the simulation model of the pressure amplitude field was in good agreement with values measured by hydrophone. Using one of the arrays, it was shown that the peak pressure amplitude dropped by only 24% and 25% of the on-axis peak pressure amplitude when steered to the edge of the array (40 mm) at depths of 30 mm and 50 mm. For the 6144 element arrays studied in in silico only, similarly high steerability was found: even when steered 100 mm off-axis, the pressure amplitude decrease at the focus was less than 20%, while the maximum pressure grating lobe was only 20%. Thermal simulations indicate that the modules produce more than enough acoustic power to perform rapid ablations at physiologically relevant depths and steering angles. Arrays such as proposed and tested in this study have enormous potential: their high electronic steerability suggests that they will be able to perform ablations of large volumes without the need for any mechanical translation.

Depressive symptoms, self-esteem, HIV symptom management self-efficacy and self-compassion in people living with HIV.

The aims of this study were to examine differences in self-schemas between persons living with HIV/AIDS with and without depressive symptoms, and the degree to which these self-schemas predict depressive symptoms in this population. Self-schemas are beliefs about oneself and include self-esteem, HIV symptom management self-efficacy, and self-compassion. Beck's cognitive theory of depression guided the analysis of data from a sample of 1766 PLHIV from the USA and Puerto Rico. Sixty-five percent of the sample reported depressive symptoms. These symptoms were significantly (p ≤ 0.05), negatively correlated with age (r = -0.154), education (r = -0.106), work status (r = -0.132), income adequacy (r = -0.204, self-esteem (r = -0.617), HIV symptom self-efficacy (r = - 0.408), and self-kindness (r = - 0.284); they were significantly, positively correlated with gender (female/transgender) (r = 0.061), white or Hispanic race/ethnicity (r = 0.047) and self-judgment (r = 0.600). Fifty-one percent of the variance (F = 177.530 (df = 1524); p < 0.001) in depressive symptoms was predicted by the combination of age, education, work status, income adequacy, self-esteem, HIV symptom self-efficacy, and self-judgment. The strongest predictor of depressive symptoms was self-judgment. Results lend support to Beck's theory that those with negative self-schemas are more vulnerable to depression and suggest that clinicians should evaluate PLHIV for negative self-schemas. Tailored interventions for the treatment of depressive symptoms in PLHIV should be tested and future studies should evaluate whether alterations in negative self-schemas are the mechanism of action of these interventions and establish causality in the treatment of depressive symptoms in PLHIV.

Innovations in low input and organic dairy supply chains--what is acceptable in Europe?

The growth in organic and low-input farming practices is driven by both market demand for high quality, safe food, and European Union policy support, and these types of farming practices are considered in European Union policies for sustainable production, food quality, healthy life, and rural development. However, many constraints to the development of low-input and organic dairy farming supply chains have been identified, including economic, political, and technical constraints. In order for these types of supply chains to develop and provide further benefits to society, innovations are required to improve their sustainability. However, an innovation will only be taken up and result in desirable change if the whole supply chain accepts the innovation. In this paper, Q methodology is used to identify the acceptability of dairy supply chain innovations to low-input and organic supply chain members and consumers in Belgium, Finland, Italy, and the United Kingdom. A strong consensus existed across all respondents on innovations that were deemed as unacceptable. The use of genetically modified and transgenic organisms in the farming system and innovations perceived as conflicting with the naturalness of the production system and products were strongly rejected. Innovations that were strongly liked across all participants in the study were those related to improving animal welfare and improving forage quality to be able to reduce the need for purchased concentrate feeds. Only minor differences existed between countries as to where the priorities lay in terms of innovation acceptability.

Mediators of antiretroviral adherence: a multisite international study.

The purpose of this study was to investigate the effects of stressful life events (SLE) on medication adherence (3 days, 30 days) as mediated by sense of coherence (SOC), self-compassion (SCS), and engagement with the healthcare provider (eHCP) and whether this differed by international site. Data were obtained from a cross-sectional sample of 2082 HIV positive adults between September 2009 and January 2011 from sites in Canada, China, Namibia, Puerto Rico, Thailand, and US. Statistical tests to explore the effects of stressful life events on antiretroviral medication adherence included descriptive statistics, multivariate analysis of variance, analysis of variance with Bonferroni post-hoc analysis, and path analysis. An examination by international site of the relationships between SLE, SCS, SOC, and eHCP with adherence (3 days and 30 days) indicated these combined variables were related to adherence whether 3 days or 30 days to different degrees at the various sites. SLE, SCS, SOC, and eHCP were significant predictors of adherence past 3 days for the United States (p = < 0.001), Canada (p = 0.006), and Namibia (p = 0.019). The combined independent variables were significant predictors of adherence past 30 days only in the United States and Canada. Engagement with the provider was a significant correlate for antiretroviral adherence in most, but not all, of these countries. Thus, the importance of eHCP cannot be overstated. Nonetheless, our findings need to be accompanied by the caveat that research on variables of interest, while enriched by a sample obtained from international sites, may not have the same relationships in each country.

Prevalence, correlates, and self-management of HIV-related depressive symptoms.

Depressive symptoms are highly prevalent yet undertreated in people living with HIV/AIDS (PLHAs). As part of a larger study of symptom self-management (N=1217), this study examined the prevalence, correlates, and characteristics (intensity, distress, and impact) of depressive symptoms, and the self-care strategies used to manage those symptoms in PLHAs in five countries. The proportion of respondents from each country in the total sample reporting depressive symptoms in the past week varied and included Colombia (44%), Norway (66%), Puerto Rico (57%), Taiwan (35%), and the USA (56%). Fifty-four percent (n=655) of the total sample reported experiencing depressive symptoms in the past week, with a mean of 4.1 (SD 2.1) days of depression. Mean depression intensity 5.4 (SD 2.7), distressfulness 5.5 (SD 2.86), and impact 5.5 (SD 3.0) were rated on a 1-10 scale. The mean Center for Epidemiologic Studies Depression Scale score for those reporting depressive symptoms was 27 (SD 11; range 3-58), and varied significantly by country. Respondents identified 19 self-care behaviors for depressive symptoms, which fell into six categories: complementary therapies, talking to others, distraction techniques, physical activity, medications, and denial/avoidant coping. The most frequently used strategies varied by country. In the US sample, 33% of the variance in depressive symptoms was predicted by the combination of education, HIV symptoms, psychological and social support, and perceived consequences of HIV disease.

HIV illness representation as a predictor of self-care management and health outcomes: a multi-site, cross-cultural study.

Research has shown that the perceptions that form the cognitive representation of an illness (illness representation) are fundamental to how persons cope with illness. This study examined the relationship of illness representation of HIV with self-care behavior and health outcomes. Data were collected at 16 sites in the United States, Taiwan, Norway, Puerto Rico and Colombia via survey. HIV seropositive participants (n = 1,217, 31% female, 38% African-American/Black, 10% Asian/Pacific Islander and 26% White/Anglo) completed measures of illness representation based on the commonly accepted five-component structure: identity, time-line, consequences, cause, and cure/controllability (Weinman et al. 1996, Psychology and Health, 11, 431-445). Linear regression analyses were conducted to investigate relationships among illness representation, self-care behaviors and quality-of-life outcomes. Components of illness representation were associated with self-care and health outcomes, indicating that the cognitive representation of HIV has consequences for effective illness management. For example, perception that there is little that can be done to control HIV was significantly associated with fewer and less effective self-care activities (F = 12.86, P < .001) and poorer health function in the domain of quality-of-life (F = 13.89, P < .001). The concept of illness representation provides a useful framework for understanding HIV symptom management and may be useful in directing development of effective patient-centered interventions.

Unhealthy behaviours for self-management of HIV-related peripheral neuropathy.

The prevalence of peripheral neuropathy is frequent in HIV disease and is often associated with antiretroviral therapy. Unhealthy behaviours, particularly substance-use behaviours, are utilized by many HIV-positive individuals to manage neuropathic symptoms. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of unhealthy behaviours to self-manage peripheral neuropathy in HIV disease. Sociodemographic and disease-related correlates and unhealthy behaviours were examined in a convenience sample of 1,217 respondents who were recruited from data collection sites in several US cities, Puerto Rico, Colombia, and Taiwan. Results of the study indicated that respondents with peripheral neuropathy (n=450) identified a variety of unhealthy self-care behaviours including injection drug use, oral drug use, smoking cigarettes and alcohol ingestion. Specific unhealthy behaviours that participants reported to alleviate peripheral neuropathy included use of marijuana (n=67), smoking cigarettes (n=139), drinking alcohol (n=81) and street drugs (n=30). A subset of those individuals (n=160), who identified high levels of neuropathy (greater than five on a scale of 1-10), indicated significantly higher use of amphetamines and injection drug use in addition to alcohol use and cigarette smoking. For participants from Norway, substance use (using alcohol: 56%) was one of the most frequent self-management strategies. Implications for clinical practice include assessment and education of persons with HIV for self-care management of the complex symptom of peripheral neuropathy.

Symptom management and self-care for peripheral neuropathy in HIV/AIDS.

Peripheral neuropathy is the most common neurological complication in HIV and is often associated with antiretroviral therapy. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of peripheral neuropathy in HIV disease, sociodemographic and disease-related correlates and self-care strategies. A convenience sample of 1,217 respondents was recruited from data collection sites in several US cities, Puerto Rico, Colombia and Taiwan. Results of the study indicated that respondents with peripheral neuropathy (n=450) identified 20 self-care behaviors including complementary therapies, use of medications, exercise and rest and/or elevation of extremities. Ratings of frequency and effectiveness were also included. An activities checklist summarized into five categories of self-care behaviors including activities/thoughts, exercise, medications, complementary therapies and substance was used to determine self-care behaviors. Taking a hot bath was the most frequent strategy used by those with peripheral neuropathy (n=292) and received the highest overall rating of effectiveness of any self-management strategies included in this study at 8.1 (scale 1-10). Other self-care strategies to manage this symptom included: staying off the feet (n=258), rubbing the feet with cream (n=177), elevating the feet (n=236), walking (n=262), prescribed anti-epileptic agent (n=80), prescribed analgesics (n=84), over-the-counter medications (n=123), vitamin B (n=122), calcium supplements (n=72), magnesium (n=48), massage (n=156), acupuncture (n=43), reflexology (n=23) and meditation (n=80). Several behaviors that are often deemed unhealthy were included among the strategies reported to alleviate peripheral neuropathy including use of marijuana (n=67), cigarette smoking (n=139), drinking alcohol (n=81) and street drugs (n=30).

The impact of meaning in life and life goals on adherence to a tuberculosis medication regimen in South Africa.

SETTING: Out-patient tuberculosis (TB) clinics in Durban, South Africa. OBJECTIVE: Health care provider concerns about persons with active TB defaulting on medications led to a study of adherence among persons receiving anti-tuberculosis therapy and, specifically, the relationships between meaning in life, life goals, sense of coherence, social support, symptom presence and intensity, and adherence in individuals diagnosed with TB. DESIGN: A cross-sectional, descriptive design was used to gather self-reported data from TB-infected individuals who were enrolled in out-patient clinics. Data were collected from 159 Zulu and/or English-speaking persons who agreed to participate in the study. RESULTS: A significant relationship was found between higher life goals and adherence to TB treatment (P = 0.027). Analysis of variance revealed that higher meaning in life ratings were significantly associated with older age (P = 0.007). Having children and children living in the same household were significantly associated with low meaning in life ratings (P = 0.006 and P < or = 0.001, respectively), indicating that these individuals were more concerned about basic matters of home and sustenance. CONCLUSIONS: The results of this study indicate that meaning in life and life goals may be useful for identifying individuals who will require additional support in adhering to anti-tuberculosis treatment.

Strategies for self-management of HIV-related anxiety.

This study examines the frequency and effectiveness of commonly used strategies for self management of anxiety in an international sample of 502 participants from Norway (n=42, 8%), Taiwan (n=35, 7%), and the US (n=426, 85%). An activities checklist summarized into five categories of self-care behaviours including activities/thoughts, exercise, medications, complementary therapies, and substance use determined self-care behaviours. Ratings of frequency and effectiveness for each self-care activity were also included. Praying received the highest overall rating of effectiveness of any self-management strategies included in this study at 8.10 (scale 1 to 10), followed by meditation (7.37), exercising (7.32), using relaxation techniques (7.22), cooking (6.98), and walking (6.90). An analysis of effectiveness scores for each self-care strategy by country reflected a wide variation. The three most effective anxiety self-care strategies reported by participants from Norway included exercise (7.31), walking (6.96), and reading (6.44). Highest ratings of effectiveness by participants from Taiwan included talking with others with HIV (6.0), attending support groups (6.0), and exercising (6.0). US participants allocated highest ratings of effectiveness to complementary/alternative therapies, including praying (8.10), meditating (7.43), and using relaxation techniques (7.35). Regardless of the country, watching television and talking with family and friends were the two most frequently reported strategies. These strategies for self-management of HIV-related anxiety are important for clinicians to be aware of in the care of persons with HIV/AIDS.

Self-care management for neuropathy in HIV disease.

Peripheral neuropathy is the most common neurological complication in HIV and is often associated with antiretroviral therapy. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of peripheral neuropathy in HIV disease, the self-care strategies, and sources of information for self-care utilized by the sample. A convenience sample of 422 respondents was recruited from an Internet web-based site developed by the University of California, San Francisco International HIV/AIDS Research Network and from five geographic data collection sites (Boston, New York City, San Francisco and Paterson in the USA, and Oslo, Norway). Results of the study indicated that respondents with peripheral neuropathy identified 77 self-care behaviours including complementary therapies, use of medications, exercise and rest and/or elevation of extremities. Sources of information included health care providers, informal networks and media sources.

Issues in cross-cultural quality-of-life research.

PURPOSE: To examine cross-cultural measurement of quality of life (QOL) and issues to consider in adapting quality-of-life instruments. ORGANIZING CONSTRUCT: Health-related quality of life. METHODS: Review of the literature on cross-cultural QOL using the Cumulative Index to Nursing & Allied Health Literature (CINAHL), 1982 to February 2000, and Medline, 1966 to May 2000, databases. FINDINGS: Use of research instruments beyond the samples with which they were initially tested, particularly if the new samples are cross-cultural, presents considerable challenges. The findings indicate consideration of these problems: phenomenon of interest, cross-cultural versus cross-national, salience, conceptual equivalence, cultural hegemony versus cultural validity, cultural equivalence versus verbal equivalence, fidelity versus appropriateness, privacy versus disclosure, appropriateness of format, and resource utilization for translation. Although the literature indicates increased discussion of theoretical, conceptual, and operational approaches to measuring cross-cultural QOL, problems continue in adapting instruments from one culture to another. CONCLUSIONS: Many issues about cross-cultural QOL were identified. By addressing these issues, researchers can develop appropriately translated and validated quality-of-life instruments to advance knowledge about cross-cultural QOL.

Adolescent violence. Assessment of nurses' attitudes and educational needs.

Adolescent violence is a major public health problem. Because of their roles in community and hospital settings, nurses have an opportunity to limit the epidemic of violence. The purpose of this study was to examine the perceived levels of knowledge, the value of further education, resource utilization, and attitudes of nurses caring for adolescent victims of violence. Data were collected from 60 nurses employed at an urban public hospital. Results of the study indicate that 50% of the respondents had high scores on the perceived knowledge section of the survey. However, the majority of nurses (82.5%) felt inadequately educated about violence. The attitudes reported with the most frequency were frustration (78%), anger (59%), and powerlessness (58%). The results of this study indicate a need for additional violence education for nurses, particularly in the areas of available resources and intervention for adolescent victims of violence.

The use of complementary and alternative therapies.

The National Center for Complementary and Alternative Medicine (NCCAM) was created by Congress in 1998 as part of the National Institutes of Health. As interest in alternative and complementary therapies among healthcare providers and consumers has increased in recent years, the NCCAM has provided research funding to determine the efficacy of various types of unconventional treatments. The Center also provides research training and acts as a clearing-house for information dissemination to practitioners and the general public. Inclusion and exclusion criteria for alternative and complementary medicine as defined by the NCCAM are provided. Interest in these non-traditional treatments will likely continue to increase over the next few years. The NCCAM is playing a vital role as it provides avenues to determine how these therapies can lead to enhanced quality of life for individuals as we enter the new millennium.

Long-term continuum of care for people living with HIV/AIDS.

The introduction of highly active antiretroviral therapy (HAART), has created new options for those infected and affected by human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS). Most HIV-infected persons no longer die within months of diagnosis. There is now a long-term continuum of care that can end in misery or relative comfort. The introduction of palliative care in concert with curative therapies throughout the disease trajectory should be the standard of care for all persons. At the very least, the introduction of palliative care and hospice at the end of life is important to the holistic care of persons living with HIV/AIDS.

Predictors of perception of cognitive functioning in HIV/AIDS.

This is a descriptive, correlational study of the predictors of perceived cognitive functioning. The convenience sample of 728 nonhospitalized persons receiving health care for HIV/AIDS was recruited from seven sites in the United States. All measures were self-reported. Self-perception of cognitive functioning, the dependent variable, was composed of three items from the Medical Outcomes Study HIV scale: thinking, attention, and forgetfulness. Data related to age, gender, ethnicity, education, injection drug use, CD4 count, and length of time known to be HIV-positive were collected on a demographic questionnaire. The scale from the Sign and Symptom Checklist for Persons with HIV Disease was used to measure self-reported symptoms. Data were analyzed using hierarchical multiple regression analysis. Predictors of perception of cognitive functioning explained a total of 36.3% of the variance. Four blocks--person variables (1.5%) (age, gender, education, history of injection drug use), disease status (2.3%), symptom status (26.5%), and functional status (5.4%)--significantly contributed statistically to the total variance. Among those individuals who completed the questions related to depression (n = 450), 28% of the variance in cognitive functioning was explained by this variable. The findings in this multi-site study indicate that symptom status explained the largest amount of variance in perceived cognitive functioning. Early identification of cognitive impairment can result in appropriate clinical interventions in remediable conditions and in the improvement of quality of life.