Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis.

Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.

The Effects of Symptoms on Quality of Life during Chemotherapy in African-American Women with Breast Cancer.

Little is known about the effects of burdensome symptoms dur- ing chemotherapy treatment in African-American women. This study explored the symptom burden occurring during chemotherapy treatment and how these symptoms impacted functional well-being and quality of life (QOL). A sample of 30 African-American women with breast cancer (BC) completed a battery of questionnaires that were used to collect the data at baseline, midpoint, and at the completion of chemotherapy. There were significant differences in the severity of symptoms for worse pain, pain inteiference with activities of daily living (ADLs), present fatigue and history offatigue, present nausea and history of nausea and insomnia as well as lower intensity of QOL measures over the course of chemotherapy treatment. All symptoms had greater intensity at midpoint and completion than at baseline. Worst pain had a significant negative effect on functional well-being. Both pain and depression each had significant negative effects on QOL.

Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV.

Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [(11)C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [(11)C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test-retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.

Neuropsychiatric complications of aging with HIV.

Persons over age 50 are not only aging with human immunodeficiency virus (HIV) infection but also represent a high proportion of new HIV infections. Neuropsychiatric symptoms, including depression, cognitive impairment, and substance abuse, are very common in individuals infected with HIV. However, there is little understanding of the relationship between these HIV-related comorbid conditions in newly infected elderly patients compared to uninfected elderly and those who have survived after 20 years of HIV/AIDS. We summarize the current theories and research that link aging and HIV with psychiatric illnesses and identify emerging areas for improved research, treatment, and patient care.

Physicians' and nurses' experiences of the influence of race and ethnicity on the quality of healthcare provided to minority patients, and on their own professional careers.

This qualitative content analysis examines data from African-American and Hispanic physician and nurse focus groups conducted by the Institute of Medicine (IOM). Participants discussed the influence of race and ethnicity regarding perspectives on healthcare provided to ethnic minority patients, and on the professional careers of ethnic minority physicians and nurses. A majority of responses related to Racism and Prejudice, which affected ethnic minority patients and health-care providers at three levels (health-care system to patient, provider to patient, and provider to provider). Racism and Prejudice interfered with promotions, obtaining hospital privileges, and advancement in careers. Communication and Culture was important among patients who preferred racially concordant care providers. Role Modeling was found to be important as participants entered and matured in their professional careers. Findings provide compelling evidence that racism and prejudice are shared experiences between ethnic minority physicians and nurses throughout their careers. One concerning finding was that perceived prejudice materialized at the onset of medical and nursing education and remained a predominant theme throughout the professionals' careers. Research should be directed towards providing equity in care and on the careers of ethnic minority health-care professionals.

Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans.

UNLABELLED: Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, (11)C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide ((11)C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of (11)C-DPA-713 in human subjects using PET. METHODS: Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity (11)C-DPA-713. For comparison, 2 additional healthy controls were studied with (11)C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model. RESULTS: In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for (11)C-R-PK11195. Accordingly, dose-normalized time-activity curves showed that (11)C-DPA-713 gives a larger brain signal. CONCLUSION: Studies in patient populations will help determine whether (11)C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that (11)C-DPA-713 is a promising ligand for evaluating TSPO binding with PET.

Differences in Coping Among African American Women With Breast Cancer and Triple-Negative Breast Cancer.

PURPOSE/OBJECTIVES: To determine differences in psychological distress, symptoms, coping capacity, and coping abilities among African American (AA) women with triple-negative breast cancer (TNBC) and non-TNBC and to explore differences in relationships among these variables.
. DESIGN: A prospective, descriptive, comparative, and correlational design.
. SETTING: Johns Hopkins Hospital in Baltimore, Maryland.
. SAMPLE: 30 AA women with breast cancer.
. METHODS: Patients completed questionnaires during chemotherapy. The Transactional Model of Stress and Coping was used to guide the research.
. MAIN RESEARCH VARIABLES: Psychological distress, symptoms, coping capacity, and coping ability.
. FINDINGS: Patients with non-TNBC reported more intense present total pain, nausea and vomiting, better emotional functioning, lower cognitive functioning, use of significantly more prayer and hope, and more coping self-statements. A lower coping capacity score was associated with psychological distress in the TNBC group at midpoint and in both groups at completion of chemotherapy treatment. Patients in both groups used a higher level of positive religious coping.
. CONCLUSIONS: AA women with TNBC and non-TNBC might benefit (reduced psychological distress and improved coping skills) from receiving a comprehensive psychological care program. The findings can be incorporated and tested in a comprehensive coping strategy program.
. IMPLICATIONS FOR NURSING: Nurses should work closely with AA women with breast cancer undergoing chemotherapy to help them identify and consciously use coping strategies associated with increased coping capacity.

Clinical studies of neuroinflammatory mechanisms in schizophrenia.

Schizophrenia is a pervasive neurodevelopmental disorder that appears to result from genetic and environmental factors. Although the dopamine hypothesis is the driving theory behind the majority of translation research in schizophrenia, emerging evidence suggests that aberrant immune mechanisms in the peripheral and central nervous system influence the etiology of schizophrenia and the pathophysiology of psychotic symptoms that define the illness. The initial interest in inflammatory processes comes from epidemiological data and historical observations, dating back several decades. A growing body of research on developmental exposure to infection, stress-induced inflammatory response, glial cell signaling, structural and functional brain changes and therapeutic trials demonstrates the impact that inflammation has on the onset and progression of schizophrenia. Research in animal models of psychosis has helped to advance clinical and basic science investigations of the immune mechanisms disrupted in schizophrenia. However, they are limited by the inability to recapitulate the human experience of hallucinations, delusions and thought disorder that define psychosis. To date, translational studies of inflammatory mechanisms in human subjects have not been reviewed in great detail. Here, we critically review clinical studies that focus on inflammatory mechanisms in schizophrenia. Understanding the neuroinflammatory mechanisms involved in schizophrenia may be essential in identifying potential therapeutic targets to minimize the morbidity and mortality of schizophrenia by interrupting disease development.

Cognitive impairment in patients with AIDS - prevalence and severity.

The advent of highly active antiretroviral therapy has prolonged the life expectancy of HIV patients and decreased the number of adults who progress to AIDS and HIV-associated dementia. However, neurocognitive deficits remain a pronounced consequence of HIV/AIDS. HIV-1 infection targets the central nervous system in subcortical brain areas and leads to high rates of delirium, depression, opportunistic central nervous system infections, and dementia. Long-term HIV replication in the brain occurs in astrocytes and microglia, allowing the virus to hide from antiviral medication and later compromise neuronal function. The associated cognitive disturbance is linked to both viral activity and inflammatory and other mediators from these immune cells that lead to the damage associated with HIV-associated neurocognitive disorders, a general term given for these disturbances. We review the severity and prevalence of the neuropsychiatric complications of HIV including delirium, neurobehavioral impairments (depression), minor cognitive-motor dysfunction, and HIV-associated dementia.

Radiation dosimetry and biodistribution of the TSPO ligand 11C-DPA-713 in humans.

UNLABELLED: Whole-body PET/CT was used to characterize the radiation dosimetry of (11)C-DPA-713, a specific PET ligand for the assessment of translocator protein. METHODS: Six healthy control subjects, 3 men and 3 women, underwent whole-body dynamic PET scans after bolus injection of (11)C-DPA-713. Subjects were scanned from head to mid thigh with 7 passes performed, with a total PET acquisition of approximately 100 min. Time-activity curves were generated in organs with visible tracer uptake, and tissue residence times were calculated. Whole-body dosimetry was calculated using OLINDA 1.1 software, assuming no voiding. RESULTS: The absorbed dose is highest in the lungs, spleen, kidney, and pancreas. The lungs were determined to be the dose-limiting organ, with an average absorbed dose of 2.01 × 10(-2) mSv/MBq (7.43 × 10(-2) rem/mCi). On the basis of exposure limits outlined in the U.S. Food and Drug Administration Code of Federal Regulations (21CFR361.1), the single-dose limit for (11)C-DPA-713 radiotracer injection is 2,487.6 MBq (67.3 mCi). CONCLUSION: (11)C-DPA-713 has an uptake pattern that is consistent with the biodistribution of translocator protein and yields a dose burden that is comparable to that of other (11)C-labeled PET tracers.

Safety considerations in drug treatment of depression in HIV-positive patients: an updated review.

Major depressive disorder (MDD) is one of the most prevalent illnesses associated with HIV infection, and negatively affects medication adherence, disease progression and mortality in HIV disease. Co-morbid treatment of major depression in HIV disease is the optimal therapeutic approach, but discriminating MDD from normal fluctuations in mood state, personality or physiology is difficult. Definitive diagnosis of MDD is critical for drug safety and for avoiding unnecessary exposure to psychotropic medications. HIV patients respond to antidepressant treatment like the general population, and medication adverse effects and patient adherence are the best predictors of treatment outcome. This review attempts to assist the medical provider with the diagnosis and treatment of MDD in HIV patients. We outline the initial steps in screening and psychiatric referral, the antidepressants that are particularly useful in HIV-infected patients, and the adverse effects and pharmacological strategies for overcoming potential barriers to medication adherence. Potential interactions between the various classes of antidepressants and HIV/antiretroviral therapy, as well as management of HIV medication-related psychiatric adverse effects, are also discussed.

Carbon monoxide mediates vasoactive intestinal polypeptide-associated nonadrenergic/noncholinergic neurotransmission.

Carbon monoxide (CO) synthesized by heme oxygenase 2 (HO2) and nitric oxide (NO) produced by neuronal NO synthase (nNOS) mediate nonadrenergic/noncholinergic (NANC) intestinal relaxation. In many areas of the gastrointestinal tract, NO and CO function as coneurotransmitters. In the internal anal sphincter (IAS), NANC relaxation is mediated primarily by CO. Vasoactive intestinal polypeptide (VIP) has also been shown to participate in NANC relaxation throughout the intestine, including the IAS. By using a combination of pharmacology and genetic knockout of the biosynthetic enzymes for CO and NO, we show that the physiologic effects of exogenous and endogenous VIP in the IAS are mediated by HO2-synthesized CO.