Smoking, tobacco dependence, and neurometabolites in the dorsal anterior cingulate cortex.

Cigarette smoking has a major impact on global health and morbidity, and positron emission tomographic research has provided evidence for reduced inflammation in the human brain associated with cigarette smoking. Given the consequences of inflammatory dysfunction for health, the question of whether cigarette smoking affects neuroinflammation warrants further investigation. The goal of this project therefore was to validate and extend evidence of hypoinflammation related to smoking, and to examine the potential contribution of inflammation to clinical features of smoking. Using magnetic resonance spectroscopy, we measured levels of neurometabolites that are putative neuroinflammatory markers. N-acetyl compounds (N-acetylaspartate + N-acetylaspartylglutamate), glutamate, creatine, choline-compounds (phosphocholine + glycerophosphocholine), and myo-inositol, have all been linked to neuroinflammation, but they have not been examined as such with respect to smoking. We tested whether people who smoke cigarettes have brain levels of these metabolites consistent with decreased neuroinflammation, and whether clinical features of smoking are associated with levels of these metabolites. The dorsal anterior cingulate cortex was chosen as the region-of-interest because of previous evidence linking it to smoking and related states. Fifty-four adults who smoked daily maintained overnight smoking abstinence before testing and were compared with 37 nonsmoking participants. Among the smoking participants, we tested for associations of metabolite levels with tobacco dependence, smoking history, craving, and withdrawal. Levels of N-acetyl compounds and glutamate were higher, whereas levels of creatine and choline compounds were lower in the smoking group as compared with the nonsmoking group. In the smoking group, glutamate and creatine levels correlated negatively with tobacco dependence, and creatine correlated negatively with lifetime smoking, but none of the metabolite levels correlated with craving or withdrawal. The findings indicate a link between smoking and a hypoinflammatory state in the brain, specifically in the dorsal anterior cingulate cortex. Smoking may thereby increase vulnerability to infection and brain injury.

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.

Implementation of HIV Palliative Care: Interprofessional Education to Improve Patient Outcomes in Resource-Constrained Settings, 2004-2012.

Palliative care (PC), introduced early in the management of chronic illness, improves patient outcomes. Early integration of a palliative approach for persons with HIV has been documented to be effective in identifying and managing patient-level concerns over the past decade in African settings. The experience of implementing PC in multiple African and other resource-constrained settings (RCSs) emphasizes the need for essential palliative competencies that can be integrated with chronic disease management for patients and their families facing life-limiting illness. This article is an historical description of how basic palliative competencies were observed to be acceptable for health workers providing outpatient HIV care and treatment during eight years of U.S. implementation of "care and support," a term coined to represent PC for persons living with HIV in RCS. The need for team building and interprofessional education is highlighted. The model is currently being tested in one U.S. city and may represent a mechanism for expanding the palliative approach into management of chronic disease. Such competencies may play a role in the development of the patient-centered medical home, a critical component of U.S. health care reform.

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

BACKGROUND: The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. METHODS: We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. RESULTS: In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. CONCLUSIONS: Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.

Thalamic glutamate decreases with cigarette smoking.

RATIONALE: Findings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu. OBJECTIVE: To determine the effects of tobacco smoking on thalamic glutamate levels. METHODS: Thalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. RESULTS: Mean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r = -0.64, p = 0.006) and pack-years of smoking (r = -0.66, p = 0.005). CONCLUSIONS: Consistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain.

Effectiveness and safety of thiotepa as conditioning treatment prior to stem cell transplant in patients with central nervous system lymphoma.

BACKGROUND: Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This systematic review summarizes evidence on its effectiveness and safety, in patients with central nervous system [CNS] lymphoma. METHODS: We searched 3 databases for clinical studies. When feasible, we performed meta-analyses. RESULTS: We identified 13 eligible studies, none of which with a priori controls. So data synthesis focused on the 226 patients who received thiotepa. Based on pooled estimates, 75.9% of thiotepa-treated patients achieved a complete remission (95% confidence interval [CI] = 67.5-82.8), and 61.7% had a progression-free survival for up to 125 months post-treatment (95% CI = 49.4-72.7). However, 25.5% relapsed, 24.6% experienced infection, and 13.2% experienced neurotoxicity. DISCUSSION: Thiotepa-based conditioning followed by HSCT may be effective in most CNS lymphoma patients, with a manageable toxicity profile. But adequately powered randomized trials are needed to better evaluate and isolate the effects of thiotepa.

Gray-matter volume in methamphetamine dependence: cigarette smoking and changes with abstinence from methamphetamine.

BACKGROUND: Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants. METHODS: Gray matter was measured using voxel-based morphometry in three groups: 18 control nonsmokers, 25 control smokers, and 39 methamphetamine-dependent smokers (methamphetamine-abstinent 4-7 days). Subgroups of methamphetamine-dependent and control participants (n=12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence. RESULTS: Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than control nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease. CONCLUSIONS: Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.

Cigarette smoking and white matter microstructure.

RATIONALE: Diffusion tensor imaging has been used before in testing associations between cigarette smoking and white matter integrity, with inconsistent results. Published reports indicate higher fractional anisotropy (FA, a measure of linear water diffusion) in some brain regions and lower FA in others in adult smokers compared to nonsmokers. Adolescent smokers exhibited elevated FA at several brain regions and a positive correlation of FA in the genu corpus callosum with exposure to smoking (pack-years). OBJECTIVE: To help resolve prior discrepancies, we studied adults, sampling multiple brain regions, and testing for relationships to clinical features of nicotine dependence and exposure to smoking. METHODS: Brain MRI scans (1.5 T) were acquired, and FA and apparent diffusion coefficient (ADC, a measure of random diffusion) were assayed in corpus callosum and prefrontal white matter, corona radiata, internal capsule, cingulum bundle, and hippocampal perforant fibers in 18 smokers (33.7 ± 7.9 years of age) and 18 age- and gender-matched nonsmokers. RESULTS: ADC showed no group difference, but smokers had higher (4.3-21.1%) FA than nonsmokers. The differences were significant in right prefrontal white matter, cingulum, and genu corpus callosum. FA in several regions was negatively correlated with nicotine dependence or cigarettes/day. CONCLUSIONS: Combined with earlier findings, these results suggest a model of changing trajectories whereby FA is higher with tobacco exposure during adolescence and declines with continued smoking in adulthood. This notion is supported by the observation that, at multiple sampling sites, participants who had started smoking earlier in life had higher FA than those who had started later.

Magnetic resonance imaging studies of cigarette smoking.

This chapter reviews studies that have applied magnetic resonance imaging (MRI) toward a better understanding of the neurobiological correlates and consequences of cigarette smoking and nicotine dependence. The findings demonstrate that smokers differ from nonsmokers in regional brain structure and neurochemistry, as well as in activation in response to smoking-related stimuli and during the execution of cognitive tasks. We also review functional neuroimaging studies on the effects of nicotine administration on brain activity, both at rest and during the execution of cognitive tasks, independent of issues related to nicotine withdrawal and craving. Although chronic cigarette smoking is associated with poor cognitive performance, acute nicotine administration appears to enhance cognitive performance and increase neural efficiency in smokers.

Current HIV/AIDS end-of-life care in sub-Saharan Africa: a survey of models, services, challenges and priorities.

BACKGROUND: In response to increased global public health funding initiatives to HIV/AIDS care in Africa, this study aimed to describe practice models, strategies and challenges to delivering end-of-life care in sub-Saharan Africa. METHODS: A survey end-of-life care programs was conducted, addressing the domains of service aims and configuration, barriers to pain control, governmental endorsement and strategies, funding, monitoring and evaluation, and research. Both closed and qualitative responses were sought. RESULTS: Despite great structural challenges, data from 48 programs in 14 countries with a mean annual funding of US 374,884 dollars demonstrated integrated care delivery across diverse settings. Care was commonly integrated with all advanced disease care (67%) and disease stages (65% offering care from diagnosis). The majority (98%) provided home-based care for a mean of 301 patients. Ninety-four percent reported challenges in pain control (including availability, lack of trained providers, stigma and legal restrictions), and 77% addressed the effects of poverty on disease progression and management. Although 85% of programs reported Government endorsement, end-of-life and palliative care National strategies were largely absent. CONCLUSIONS: The interdependent tasks of expanding pain control, balancing quality and coverage of care, providing technical assistance in monitoring and evaluation, collaborating between donor agencies and governments, and educating policy makers and program directors of end-of-life care are all necessary if resources are to reach their goals.

Late temporal gene expression from the human cytomegalovirus pp28US (UL99) promoter when integrated into the host cell chromosome.

Toward understanding the temporal regulation of human cytomegalovirus (HCMV) late genes, we studied the regulation of the late gene promoter (pp28US, UL99) when outside the context of the viral genome and its response to the immediate early (IE) proteins. Expression of the luciferase reporter gene, regulated by the pp28US promoter, was synchronous with that of the endogenous viral pp28 gene, independently of whether the reporter was episomal or integrated into the glioblastoma cell line U373MG. Cotransfection of the reporter with expression vectors for each of the three major IE genes, IE72, IE86 and IE55, indicated that only IE86 transactivated the pp28US promoter. However, the magnitude of the promoter activation upon HCMV infection suggested that additional factors are also required for higher promoter activity. The promoter activation was specific to HCMV, as herpes simplex virus type 1 infection did not induce luciferase expression.