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The last 25 years have seen significant growth in new therapeutic options for breast cancer, termed targeted therapies based on their ability to block specific pathways known to drive breast tumor growth and survival. Introduction of these drugs has been made possible through advances in the understanding of breast cancer biology. While the promise of targeted therapy for breast cancer has been clear for some time, the experience of the clinical use of multiple drugs and drug classes allows us to now present a summary and perspective as to the success and impact of this endeavor. Here we will review breast cancer targeted therapeutics in clinical use. We will provide the rationale for their indications and summarize clinical data in patients with different breast cancer subtypes, their impact on breast cancer progression and survival and their major adverse effects. The focus of this review will be on the development that has occurred within classes of targeted therapies and subsequent impact on breast cancer patient outcomes. We will conclude with a perspective on the role of targeted therapy in breast cancer treatment and highlight future areas of development.

Aim The purpose of this study was to identify quantitative instruments that measure characteristics that support nurse educator education, specifically social support, motivation, and work opportunity. Background Vacancies in nurse faculty positions have left nursing education unable to increase the number of nurses prepared to enter the workforce. Method A review of education, nursing, and psychological databases was undertaken to identify reported instruments. Identified instruments were analyzed to match three framework-derived concept categories: social support, internal motivators, and work opportunity. Search terms, retrievals, and quality assessments are discussed; identified instruments are ranked by concept categories. Results Of 98 articles retrieved, 85 underwent full review, and 7 met the inclusion criteria. From these reports, 20 unique instruments were identified and analyzed. Conclusions There are quantitative instruments that measure the concepts found in the Nurse Educator Retention Framework.

[Abstract] Objectives: To report a COVID-19 outbreak among workers and inpatients at a medical ward for especially vulnerable patients. Methods: Descriptive study of a nosocomial COVID-19 outbreak registered in March-April 2020 at medical ward of onco-hematological patients in an Spanish hospital. Confirmed cases were hospitalized patients, healthcare and non-healthcare workers who tested positive by PCR on a nasopharyngeal swab. Results: Twenty-two COVID-19 cases (12 workers and 10 inpatients) were laboratory-confirmed. Initial cases were a healthcare provider and a visitor who tested positive. The median patients age was 73 years (range 62-88). The main reason of admission was haematological in 8 patients and oncologic in 2. All patients followed an immunosuppressive treatment, 5/10 with high-flow oxygen nebulizations. Five patients presented a moderate/serious evolution, and 5 patients died. The mean workers age was 42.1±10.9. One healthworker required Intensive Care Unit admission, and all of them recovered completely. Conclusions: In the hospital setting, close patients surveillance for SARS-CoV-2 is essential, especially in immunosuppressed patients. Replacing nebulizations or high-flow oxygen therapies, when other equivalent options were available, to reduce dispersion, and controlling ventilation ducts, together with hygiene measures and an active follow-up on inpatients, visitors and workers appear to be important in preventing nosocomial outbreaks.

Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine.NM-MRI and TCompared with control subjects, cocaine users showed significantly increased NM-MRI signal in ventrolateral regions of the substantia nigra (area under the receiver operating characteristic curve=0.83). Exploratory analyses did not find a significant correlation of NM-MRI signal to activation of the ventral striatum during anticipation of monetary reward.Given that previous imaging studies show decreased dopamine signaling in the striatum, the finding of increased NM-MRI signal in the substantia nigra provides additional insight into the pathophysiology of cocaine use disorder. One interpretation is that cocaine use disorder is associated with a redistribution of dopamine between cytosolic and vesicular pools, leading to increased accumulation of neuromelanin. The study findings thus suggest that NM-MRI can serve as a practical imaging tool for interrogating the dopamine system in addiction.

Molecular imaging of the dopamine transporter (DAT) with Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) has been widely used in studies of neurological and psychiatric disorders. Nevertheless, there is a great interest in expanding molecular imaging to include magnetic resonance technology, because of the superior spatial resolution this technology may provide. Here we present a magnetic nanoparticle (NP) that specifically targets dopaminergic neurons and allows DAT imaging with magnetic resonance imaging (MRI). The nanoparticle (namely, NP-DN) is composed of an iron oxide core and a polyethylene glycol (PEG) coating to which a DAT specific dopaminergic neurolabeler (DN) is conjugated. NP-DN displayed long-term stability with favorable hydrodynamic size and surface charge suitable for in vivo application. In vitro studies showed NP-DN was non-toxic, displayed specificity towards DAT-expressing neurons, and demonstrated a 3-fold increase in DAT labeling over non-targeted NP. Our study shows NP-DN provides excellent contrast enhancement for MRI and demonstrates great potential for neuroimaging.

Background The goal of this study was to characterize cannabis use among patients with breast cancer, including their reasons for and timing of use, their sources of cannabis information and products, their satisfaction with the information found, their perceptions of its safety, and their dialogue about cannabis with their physicians. Methods United States-based members of the Breastcancer.org and Healthline.com communities with a self-reported diagnosis of breast cancer within 5 years (age ≥ 18 years) were invited to participate in an anonymous online survey. After informed consent was obtained, nonidentifiable data were collected and analyzed. Results Of all participants (n = 612), 42% (n = 257) reported using cannabis for relief of symptoms, which included pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea/vomiting (46%). Furthermore, 49% of cannabis users believed that medical cannabis could be used to treat cancer itself. Of those taking cannabis, 79% had used it during treatment, which included systemic therapies, radiation, and surgery. At the same time, few (39%) had discussed it with any of their physicians. Conclusions A significant percentage of survey participants (42%) used cannabis to address symptoms; approximately half of these participants believed that cannabis could treat cancer itself. Most participants used cannabis during active cancer treatment despite the potential for an adverse event during this vulnerable time. Furthermore, most participants believed that cannabis was safe and were unaware that product quality varied widely and depended on the source. This study reviews the research on medicinal cannabis in the setting of these findings to help physicians to recognize its risks and benefits for patients with cancer. Lay summary Almost half of patients with breast cancer use cannabis, most commonly during active treatment to manage common symptoms and side effects: pain, anxiety, insomnia, and nausea. However, most patient do not discuss cannabis use with their physicians. Instead, the internet and family/friends are the most common sources of cannabis information. Furthermore, most participants believe that cannabis products are safe and are unaware that the safety of many products is untested.

Background: The triad mentoring model was developed to frame the implementation of innovative student-centered academic–clinical partnerships for online graduate students in nursing leadership and administration practicums. Method: The nurse leader and faculty member jointly mentored each student to achieve the academic program's objectives through clinical learning experiences that were relevant and important to the clinical organization. Partnerships with nurse leaders within the student's locality were sought, and capstone practicum projects were developed and implemented during four courses. Results: Both formative and summative results were obtained from all members of the triad team throughout the practicum courses. The processes undertaken to establish, implement, and evaluate the student-centered academic–clinical partnerships identified project modifications throughout the course of study. Conclusion: Implementation of the triad mentoring model created academic–clinical partnerships that promoted a fusion of evidence-based practice, quality improvement, and clinical knowledge that produced positive outcomes for the health care setting and student learner. [ J Nurs Educ. 2019;58(8):463–467.]

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

The nucleus tractus solitarii (nTS) is the first central site for the termination and integration of autonomic and respiratory sensory information. Sensory afferents terminating in the nTS as well as the embedded nTS neurocircuitry release and utilize glutamate that is critical for maintenance of baseline cardiorespiratory parameters and initiating cardiorespiratory reflexes, including those activated by bouts of hypoxia. nTS astrocytes contribute to synaptic and neuronal activity through a variety of mechanisms, including gliotransmission and regulation of glutamate in the extracellular space via membrane-bound transporters. Here, we aim to highlight recent evidence for the role of astrocytes within the nTS and their regulation of autonomic and cardiorespiratory processes under normal and hypoxic conditions.

Background: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are common. These patients require an effective and safe analgesic alternative. Objective: The aim of the study was to demonstrate the safety of meloxicam and etoricoxib administered by open oral challenge in 2 equal steps in patients with NSAID hypersensitivity. Methods: A cross-sectional, descriptive study of patients with a diagnosis of NSAID hypersensitivity who underwent an oral drug provocation test (DPT) with meloxicam or etoricoxib between January 2011 and August 2017 was conducted. The analysis was performed from a database in BD Clinic. Results: Two hundred and twenty-eight oral provocations were performed with an alternative NSAID (203 with meloxicam and 25 with etoricoxib) in 217 patients with hypersensitivity to NSAIDs. The median age was 38 years. Ninety-eight percent of meloxicam and 100% of etoricoxib DPTs were performed in 2 steps (without previous placebo), and 52% and 64% of meloxicam and etoricoxib DPTs, respectively, were performed with 50% of the therapeutic dose in each step. Tolerance to meloxicam was demonstrated in 192 patients (94.5%) and in 100% of patients receiving etoricoxib. Conclusions: Open oral provocation with meloxicam and etoricoxib carried out in 2 steps without placebo seems to be safe and implies less costs and less time expenditure. Also, it could be performed with 2 equal doses.

The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30 mg, PO, QID) for two weeks and received placebo ibudilast (0 mg, PO, BID) during the 1st week (days 1–7). On day 8, participants (N = 10/group) were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50 mg/70 kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4 °C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40 mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p ≤ 0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p ≤ 0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

Background: Cow milk allergy (CMA) is the most common food allergy in breastfed infants. The aim of this study is to verify whether certain perinatal factors may influence the development of CMA immunoglobulin E (IgE)+. Methods: A retrospective, observational study of case and control groups was carried out. Information was collected of patients with CMA IgE+ from our department during the years 1990-2013. Patients of the same age and sex were recruited for the control group. Information on the following variables was collected: sex, age, pregnancy tolerance, duration of pregnancy, type of delivery, isolated doses of formula feeding in hospital (FFH), duration of breastfeeding, and family history of allergy (defined as ≥1 first-degree family member with allergic disease). Statistical analysis was performed using multivariate logistic regression techniques. Results: A total of 211 cases were included in this study. Multivariate analysis showed an influence of duration of breastfeeding, FFH to be a risk factor (OR 4.94; 95% CI 2.68-9.08), especially in caesarean delivery (OR 11.82; 95% CI 2.64-47.50), and prematurity (OR 0.29; 95% CI 0.09-0.92) to be a protective factor. Conclusions: Perinatal factors play a key role in the development of CMA IgE+, with an influence of breastfeeding duration, FFH and caesarean delivery as risk factors and prematurity as a protective factor. While family history had no important role, environmental factors were more decisive.

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self-administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC-501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double-blind, placebo-controlled, crossover study. Participants completed two 8-day treatment phases during which they received either CERC-501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18-hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self-administered during a 60-minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC-501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC-501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC-501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC-501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC-501 in the treatment of nicotine use disorder.

Substance use disorder is a leading causes of preventable disease and mortality. Drugs of abuse cause molecular and cellular changes in specific brain regions and these neuroplastic changes are thought to play a role in the transition to uncontrolled drug use. Neuroimaging has identified neural substrates associated with problematic substance use and may offer clues to reduce its burden on the patient and society. Here, we provide a narrative review of neuroimaging studies that have examined the structures and circuits associated with reward, cues and craving, learning, and cognitive control in substance use disorders. Most studies use advanced MRI or positron emission tomography (PET). Many studies have focused on the dopamine neurons of the ventral tegmental area, and the regions where these neurons terminate, such as the striatum and prefrontal cortex. Decreases in dopamine receptors and transmission have been found in chronic users of drugs, alcohol, and nicotine. Recent studies also show evidence of differences in structure and function in substance users relative to controls in brain regions involved in salience evaluation, such as the insula and anterior cingulate cortex. Balancing between reward-related bottom-up and cognitive-control-related top-down processes is discussed in the context of neuromodulation as a potential treatment. Finally, some of the challenges for understanding substance use disorder using neuroimaging methods are discussed.

Background/aims Cocaine use disorder (CUD) persists as a major public health problem in the United States. Response to evidence-based behavioral treatment has been shown to be predicted by dopaminergic dysfunction. Amphetamine formulations modulate dopaminergic systems and are one of the few agents with positive clinical findings but are associated with unique risks. We aimed to find a model for determining the most appropriate patients for treatment with mixed amphetamine salts-extended-release (MAS-ER) for CUD using an adaptive trial design. Methods We are enrolling treatment-seeking adults ages 18–60 years. All eligible participants receive bi-weekly individual counseling augmented with a computer-based intervention based on the community reinforcement approach with contingency management (CRA + CM) for 4 weeks. Participants who fail to achieve abstinence are additionally randomly assigned to 10 weeks of either MAS-ER, titrated up to 80 mg daily, or placebo. All participants complete a follow-up assessment after 12 weeks. Results Frequency and amount of cocaine use, cravings, retention, and quality of life will be compared between groups. The primary outcome will be having at least 3 weeks of urine toxicology-confirmed self-reported abstinence. Analyses will also be conducted to identify variables that may help identify who is more or less likely respond to the behavioral intervention during the first 4-weeks of treatment. Conclusions This trial more closely mimics a personalized medicine approach that is often used in clinical practice. It will help us understand who may be appropriate for psychostimulant therapy as an enhancement to evidence-based behavioral interventions, while limiting exposure to those who would respond to a psychosocial intervention alone. ClinicalTrials.gov Identifier: NCT01986075

Introduction: Cow’s milk allergy (CMA) is a common diagnosis in infants, requiring the exclusion of cow’s milk until tolerance is recovered. In the present study, we aim to determine which factors are associated with the development of tolerance. Methods: Retrospective, observational study of subjects who underwent the same clinical follow-up methodology. We studied 245 cases of CMA (125 IgE-mediated and 120 non-IgE-mediated). The following variables were analysed: age at diagnosis, gender, type of delivery, type of feeding received, feeding during the first months of life, clinical features, and type of feed received as treatment: casein hydrolysates or casein hydrolysates with Lactobacillus rhamnosus GG (LGG). Results: Factors associated with earlier tolerance were non-IgE-mediated CMA (HR = 2.92; 95% CI: 2.20–3.88) and patients receiving casein hydrolysate with LGG (HR = 1.79; 95% CI: 1.33–2.42). Later tolerance was associated with caesarean delivery (HR = 0.78; 95% CI: 0.58–1.05) and breastfeeding for a period of at least 3 days (HR = 0.64; 95% CI: 0.44–0.93). The multivariate study shows that the type of formula (HR = 1.61; 95% CI: 1.19–2.18) and the type of CMA (HR = 2.82; 95% CI: 2.12–3.85) have an effect on the recovery time. Casein hydrolysates with LGG reduces the recovery time in IgE-mediated (HR = 1.88; 95% CI: 1.17–3.01) and non-IgE-mediated CMA (HR = 1.46; 95% CI: 0.98–2.17). Conclusions: Tolerance acquisition is faster in non-IgE-mediated CMA subjects and in those who received casein hydrolysate with LGG.

Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [(11)C]GR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between [(11)C]GR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced [(11)C]GR103545 binding by 18% in the striatum and 14% across brain regions. No difference in [(11)C]GR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.

Background Previous imaging studies using Positron Emission Tomography (PET) have shown that alcohol use disorder (AUD) is associated with a decrease in dopamine type 2/3 receptor (D2/3) binding and dopamine transmission. Although binge drinking is a risk factor for future AUD, little is known about the neurobiology of binge drinking in young adults. This study measured D2/3 receptor binding and stimulant-induced dopamine release using PET and [11C]raclopride in binge drinkers without an AUD. Methods This study included 14 healthy controls (HC) and 14 young adult binge drinkers (BD), aged 18-25. The BD met National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for binge drinking and the HC subjects were social drinkers. The subjects were scanned with [11C]raclopride before and after the administration of oral methylphenidate (60 mg) to measure D2/3 binding and dopamine release. Results There was no significant difference in the PET measures of D2/3 binding or methylphenidate-induced dopamine release between the two groups. There was no significant association between Alcohol Use Disorders Identification Test (AUDIT) scores or 30-day drinking history and the imaging data. Conclusion In this sample of 18–25-year-old binge drinkers without a diagnosis of a substance use disorder, there were no significant differences in D2/3 receptor binding potential or methylphenidate-induced dopamine release relative to healthy controls.

Human adipose-derived stem cells (ASCs), despite being one of the most attractive cell populations for tissue engineering and regenerative medicine, currently have certain limitations that reduce their therapeutic efficacy. One of the most serious problems is the poor engraftment of cryopreserved ASCs at injured tissue, attributed to the diminished biological activity of ASCs immediately post-thaw and their poor survival under harsh conditions of oxidative stress. Seeking to address these issues, we have developed a hormetic strategy to preadapt human ASCs to oxidative stress based on a new hydrogen peroxide preconditioning procedure, resulting in cells we call HC016. These cells rapidly recover their biological activity and functionality after cryopreservation while maintaining their mesenchymal stem cell status. Compared with non-preconditioned ASCs, HC016 cells showed (a) faster in vitro adhesion capacity and cell cycle progression immediately post-thaw, (b) enhanced cell survival under oxidative stress in a serum-free environment, and (c) heightened chemotaxis towards damage signals of oxidized glial cells. In addition, compared with ASC-conditioned medium, HC016-conditioned medium showed a greater cytoprotective and pro-recovery effect on oxidized fibroblasts under serum-free conditions. Consistent with these results, in HC016 cells exposed to oxidative stress, we observed markedly higher expression of insulin-like growth factor-1 (a key factor in cell survival and migration) and of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 and pyruvate dehydrogenase kinase isozyme 1 (essential enzymes to upregulate glycolysis and downregulate oxidative phosphorylation) along with lower basal mitochondrial activity. Taking into account all the aforementioned advantages, HC016 cells might be considered an important breakthrough in ASC-based cell therapies.

BACKGROUND: Preclinical and human positron emission tomography (PET) studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here we quantify striatal DA release (measured by [(11)C]-raclopride displacement) in response to an intravenous infusion of morphine, and its relation with morphine-induced subjective effects, in healthy, non-dependent opioid-experienced participants. METHODS: Fifteen healthy male participants were initially included. Sessions were on separate days. On Session 1, participants received intravenous morphine (10 mg / 70 kg) in the clinic to ensure tolerability. Participants without adverse reactions (n=10) then received intravenous morphine and placebo (saline) sessions, in counter-balanced order, while undergoing [(11)C]-raclopride PET scans. Subjective and physiological responses were assessed. Region-of-interest and voxelwise image analyses were used to assess changes in [(11)C]-raclopride non-displaceable binding potential (ΔBPnd). RESULTS: Morphine produced marked subjective and physiological effects, and induced a significant decrease in [(11)C]-raclopride BPnd, particularly in the nucleus accumbens and globus pallidus, where ΔBPnd was approximately 9%. However, the subjective effects of morphine did not show a simple pattern of correlation with DA release. CONCLUSIONS: This is to our knowledge the first study providing in vivo human evidence that DA transmission in ventral striatum is affected by morphine. Further studies are required to fully delineate the DA contribution to the reinforcing effects of opioids.

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

This study assessed the effects of the diesel exhaust particles on ERK and JNK MAPKs activation, cell rheology (viscoelasticity), and cytotoxicity in bronchial epithelial airway cells (BEAS-2B). Crude DEP and DEP after extraction with hexane (DEP/HEX) were utilized. The partial reduction of some DEP/HEX organics increased the biodisponibility of many metallic elements. JNK and ERK were activated simultaneously by crude DEP with no alterations in viscoelasticity of the cells. Mitochondrial activity, however, revealed a decrease through the MTT assay. DEP/HEX treatment increased viscoelasticity and cytotoxicity (membrane damage), and also activated JNK. Our data suggest that the greater bioavailability of metals could be involved in JNK activation and, consequently, in the reduction of fiber coherence and increase in the viscoelasticity and cytotoxicity of BEAS cells. The adverse findings detected after exposure to crude DEP and to DEP/HEX reflect the toxic potential of diesel compounds. Considering the fact that the cells of the respiratory epithelium are the first line of defense between the body and the environment, our data contribute to a better understanding of the pathways leading to respiratory cell injury and provide evidence for the onset of or worsening of respiratory diseases caused by inorganic compounds present in DEP.

Since 2002, West Nile virus (WNV) has been detected every year in Houston and the surrounding Harris County, Texas. In 2014, the largest WNV outbreak to date occurred, comprising 139 cases and causing 2 deaths. Additionally, 1,286 WNV-positive mosquito pools were confirmed, the most reported in a single mosquito season.

Positron emission tomography (PET) imaging consistently shows blunted striatal dopamine release and decreased dopamine D2 receptor availability in addiction. Here, we review the preclinical and clinical studies indicating that this neurobiological phenotype is likely to be both a consequence of chronic drug consumption and a vulnerability factor in the development of addiction. We propose that, behaviorally, blunted striatal dopamine transmission could reflect the increased impulsivity and altered cost/benefit computations that are associated with addiction. The factors that influence blunted striatal dopamine transmission in addiction are unknown. Herein, we give an overview of various factors, genetic, environmental, and social, that are known to affect dopamine transmission and that have been associated with the vulnerability to develop addiction. Altogether, these data suggest that blunted dopamine transmission and decreased D2 receptor availability are biomarkers both for the development of addiction and resistance to treatment. These findings support the view that blunted dopamine reflects impulsive behavior and deficits in motivation, which lead to the escalation of drug use.

We investigated a multifacility outbreak of acute hepatitis B virus infection involving 21 residents across 10 assisted living facilities in Texas during the period January 2008 through July 2010. Epidemiologic and laboratory data suggested that these infections belonged to a single outbreak. The only common exposure was receipt of assisted monitoring of blood glucose from the same home health care agency. Improved infection control oversight and training of assisted living facility and home health care agency personnel providing assisted monitoring of blood glucose is needed.

Background Concern regarding the QTc interval in human immunodeficiency virus (HIV)-infected patients has been growing in recent years, and cases of prolonged QTc interval and torsades de pointes have been described in HIV-infected patients on methadone therapy. This study aimed to determine the prevalence and factors associated with long QTc interval in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. Methods A cross-sectional study was conducted in opioid-dependent HIV-infected patients on methadone maintenance therapy at a drug abuse outpatient center. Patients with any cardiac disease, drug-positive urine test, electrolyte abnormalities, and changes in their antiretroviral therapy (ART) or methadone doses in the last 2 months were excluded. Heart rate and QT interval in lead II were measured using the Bazett formula. Results Ninety-one patients were included: 58 (63.7%) were men with a median age of 44.5 years and 68 of 91 (74.7%) were on ART. Median methadone dose was 70 mg/day (range 15-250 mg/day) and mean QTc interval was 438 ± 34 ms. Prolonged QTc interval (>450 ms) was documented in 33 of 91(36.3%) patients, and 3 of 91 (3.2%) had QTc >500 ms. On multiple linear regression analysis, methadone doses (P = .005), chronic hepatitis C-induced cirrhosis (P = .008), and being ART-naive (P = .036) were predictive of prolonged QTc. Conclusions The prevalence of prolonged QTc interval in opioid-dependent HIV-infected patients on methadone maintenance therapy is high. Risk factors for prolongation of the QTc interval are chronic hepatitis C-induced cirrhosis, higher methadone doses, and being ART-naive. Thus, electrocardiographic monitoring is required to minimize cardiovascular morbidity and mortality in this specific HIV group.

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.

Background: Cognitive lifestyle may be an important modifiable risk factor for dementia but has not yet been comprehensively studied in healthy elderly. Objective: To examine gender- and lifespan-related differences in cognitive lifestyle in a population-based cohort. Methods: 872 individuals from the second wave of the Sydney Memory and Ageing Study (MAS) cohort were invited to complete the Lifetime of Experiences Questionnaire (LEQ), a validated measure of cognitive lifestyle. Of 555 questionnaires returned (64%), 253 were excluded due to prior diagnosis of mild cognitive impairment, leaving n = 302 cognitively-intact elders (mean age 80.1 years, ±SD 4.7, 40.1% men). Results: Total LEQ was significantly higher in men (97.9 ± 20.0) than women (90.0 ± 24.5), resulting mainly from midlife LEQ differences. Men were more likely to have worked in managerial or professional jobs (73.8% versus 39.5% women), and twice as likely to have supervised large groups of workers. In late life, women were significantly more likely to be living alone (68.1% versus 25.4% men), but otherwise significantly more engaged in specific cognitive activities, including reading novels (72.3% versus 52.0% men) and incorporating volunteer work (31.9% versus 19.7% men) and socializing (59.0% versus 37.0% men) into their typical day. Over the adult lifespan, it was more common for men and women to transition between LEQ tertiles than remain the same. Conclusions: Cognitive lifestyle changes over the adult lifespan and exhibits a range of gender-based differences. While older women are more likely to be living alone they generally lead a more active current cognitive lifestyle.

Project Panther LIFE is an inclusive postsecondary transition program for students with intellectual disabilities providing university access and participation with the primary goal of employment at program completion. Students in the program receive support from their academic mentors and peer coaches during the academic year. This study examines the skills and activities mentors use during their weekly sessions with students with intellectual disabilities and identifies areas in which mentors may require further support or training. Data analysis revealed major themes related to inclusion, self-determination, and adaptive behavior skills. Upon review of the data, we suggest that mentors need ongoing support from transition programs especially in areas related to encouraging self-advocacy and supporting time management.

Background Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D 2/3 receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior. Methods Heroin-dependent and healthy control subjects were scanned with [ 11 C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D 2/3 receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions. Results Both striatal D 2/3 receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin. Conclusions These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D 2/3 receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin.

Objective: Patients with limited health literacy (LHL) and limited English proficiency (LEP) experience suboptimal communication and health outcomes. Electronic health record implementation in safety net clinics may affect communication with LHL and LEP patients. We investigated the associations between safety net clinician computer use and patient-provider communication for patients with LEP and LHL. Materials and Methods: We video-recorded encounters at 5 academically affiliated US public hospital clinics between English- and Spanish-speaking patients with chronic conditions and their primary and specialty care clinicians. We analyzed changes in communication behaviors (coded with the Roter Interaction Analysis System) with each additional point on a clinician computer use score, controlling for clinician type and visit length and stratified by English proficiency and health literacy status. Results: Greater clinician computer use was associated with more biomedical statements (+12.4, P = .03) and less positive affect (−0.6, P Conclusion: Higher clinician computer use was associated with more biomedical focus with LEP/LHL patients, and clinician verbal dominance and lower ratings with patients with adequate English proficiency and health literacy. Discussion: Implementation research should explore interventions to enhance relationship-centered communication for diverse patient populations in the computer era.

Positron emission tomography (PET) studies performed with [(11) C]raclopride have consistently reported lower binding to D(2/3) receptors and lower amphetamine-induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D(2/3) antagonist radiotracers such as [(11) C]raclopride is the failure to provide information that is specific to D(2/3) receptors configured in a state of high affinity for the agonists (i.e., D(2/3) receptors coupled to G-proteins, D(2/3 HIGH) ). As the endogenous agonist DA binds with preference to D(2/3 HIGH) relative to D(2/3 LOW) receptors (i.e., D(2/3) receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D(2/3 HIGH) receptors in cocaine dependence. Thus, we measured the available fraction of D(2/3) (HIGH) receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D(2/3) antagonist and agonist PET radiotracers [(11) C]raclopride and [(11) C]NPA.[(11) C]raclopride and [(11) C]NPA binding potential (BP) (BP(ND) ) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D(2/3 HIGH) receptors, i.e., % R(HIGH) available = D(2/3 HIGH) /(D(2/3 HIGH) + D(2/3 LOW) ) was then computed as the ratio of [(11) C]NPA BP(ND) /[(11) C]raclopride BP(ND) .No differences in striatal [(11) C]NPA BP(ND) (HC = 1.00 ± 0.17; CD = 0.97 ± 0.17, P = 0.67) or available % R(HIGH) (HC = 39% ± 5%; CD = 41% ± 5%, P = 0.50) was observed between cocaine abusers and matched controls.The results of this [(11) C]NPA PET study do not support alterations in D(2/3 HIGH) binding in the striatum in cocaine dependence.

Sticholysin II (St II) is a toxin from the sea anemona Stichodactyla helianthus that produces erythrocytes lysis at low concentration and its activity depends on the presence of calcium. Calcium may act modifying toxin interaction with erythrocyte membranes or activating cellular processes which may result in a modified St II lytic action. In this study we are reporting that, in the presence of external K + , extracellular calcium decreased St II activity on erythrocytes. On the other hand an increase of intracellular calcium promotes Sty II lytic activity. The effect of intracellular calcium was specifically studied in relation to membrane lipid translocation elicited by scramblases and how this action influence St II lytic activity on erythrocytes. We used 0.5 mmol/L calcium and 10 mmol/L A23187, as calcium ionophore, for scramblases activation and found increased St II activity associated to increase of intracellular calcium. N -ethyl maleimide (activator) and 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (inhibitor) were used as scramblases modulators in the assays which produced an increase and a decrease of the calcium effect, respectively. Results reported suggest an improved St II membrane pore-forming capacity promoted by intracellular calcium associated to membrane phospholipids translocation.

Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects.Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole.Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum.The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Adoptive transfer of antitumor T cells is a promisingly effective therapy for various cancers, but its effect on endogenous antitumor immune mechanisms remains largely unknown. Here, we show that the administration of naive T cells de novo primed for only 7 days against tumor antigens resulted in the durable rejection of otherwise lethal ovarian cancers when coupled with the depletion of tumor-associated immunosuppressive dendritic cells (DC). Therapeutic activity required tumor antigen specificity and perforin expression by the adoptively transferred T cells, but not IFN-γ production. Importantly, these shortly primed T cells secreted large amounts of CCL5, which was required for their therapeutic benefit. Accordingly, transferred T cells recruited CCR5+ DCs into the tumor, where they showed distinct immunostimulatory attributes. Activated CCR5+ host T cells with antitumor activity also accumulated at tumor locations, and endogenous tumor-specific memory T cells remained elevated after the disappearance of transferred lymphocytes. Therefore, persistent, long-lived antitumor immunity was triggered by the administration of ex vivo activated T cells, but was directly mediated by immune cells of host origin. Our data unveil a CCL5-dependent mechanism of awakening endogenous antitumor immunity triggered by ex vivo expanded T cells, which is augmented by tumor-specific targeting of the cancer microenvironment. [Cancer Res 2009;69(15):6331–8]

Objective The goal of this study was to determine D1 receptor availability in human cocaine dependent (CD) subjects and matched healthy controls (HC). In addition, the cocaine dependent subjects performed cocaine self-administration sessions in order to explore the association between D1 receptor availability and cocaine seeking behavior. Methods 25 cocaine dependent subjects (40 ±4 yrs, 19M/6 F) and 23 matched healthy controls (38 ±4 yrs, 19M/4F) were scanned with PET and the radiotracer [11C]NNC 112. During the cocaine self-administration sessions, cocaine dependent volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D1 receptor availability was measured in the limbic, associative and sensori-motor striatum in addition to cortical brain regions. Results No difference in D1 receptor availability was seen between the two groups. A negative association was seen between D1 receptor BPND in the limbic striatum and the choice for the 6 mg dose of cocaine (r = - 0.47, p = 0.02, corrected for age). Conclusions These results do not support the hypothesis that cocaine dependence is associated with a reduction in D1 receptor availability in the striatum. However, within the cocaine-dependent subjects, low D1 receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D1 receptor availability may be associated with an increased risk of relapse in cocaine dependence.

Robust T-cell responses without autoimmunity are only possible through a fine balance between activating and inhibitory signals. We have identified a novel modulator of T-cell expansion named proliferation-induced lymphocyte-associated receptor (PILAR). Surface PILAR is markedly up-regulated on CD4 and, to a lesser extent, on CD8 T cells on T-cell receptor engagement. In absence of CD28 costimulation, PILAR signaling through CD161 supports CD3 antibody-dependent and antigen-specificT-cell proliferation by increasing the expression of antiapoptotic Bcl-xL and induces secretion of T helper type 1 cytokines. These effects are abrogated by PILAR blockade with specific antibodies, which decrease surface levels of CD28. In contrast, PILAR induces apoptotic death on naive and early activated T cells if CD161 engagement is blocked. PILAR is expressed by approximately 7% to 10% of CD4 T cells in 2 samples of inflammatory synovial fluid, suggesting a potential role in the pathogenesis of joint inflammation. In addition, in the ovarian cancer microenvironment, effector T cells express PILAR, but not CD161, although expression of both can be augmented ex vivo. Our results indicate that PILAR plays a central role in modulating the extent of T-cell expansion. Manipulation of PILAR signaling may be important for treatment of autoimmune diseases and cancer.

Dopamine D(2) receptor availability in the striatum has been reported to be low in generalized social anxiety disorder (GSAD) and obsessive-compulsive disorder (OCD), but it has not been studied in persons with comorbid OCD and GSAD (OCD+GSAD). D(2) receptor availability was assessed in 7 subjects with OCD+GSAD, 8 with OCD, and 7 matched healthy comparison (HC) subjects, all unmedicated adults. D(2) receptor availability was assessed with single-photon emission computerized tomography (SPECT) to measure binding potential (BP) of the D(2) receptor radiotracer [(123)I] iodobenzamide ([(123)I]IBZM). Mean striatal [(123)I]IBZM BP was significantly lower in the OCD+GSAD group (72.58 mL/g, SD=18.17) than in the HC group (118.41 mL/g, SD=45.40; P=.025). Mean BP in the OCD group (93.08 mL/g, SD=36.90) did not differ significantly from the HC group (P=.247). Trait detachment, as measured by the Detachment subscale of the Karolinska Scales of Personality, was negatively correlated with D(2) availability across all subjects (r(s)= -.55, P=.013). Comorbid GSAD and OCD may be associated with decreased availability of D(2) receptors in the striatum, consistent with prior findings in GSAD. Prior findings of decreased D(2) receptor availability in noncomorbid OCD were not confirmed. Decreased D(2) receptor availability was also associated with trait detachment, supporting prior findings in samples of healthy subjects.

Sticholysins I and II (St I and St II) are cytolysins produced by the sea anemone Stichodactyla helianthus. In spite of their 93% sequence homology, St II is more hemolytic against human erythrocytes than St I. In order to establish the possible causes of this difference, we studied the hemolytic activity of synthetic peptides containing sequences from the N-termini of both proteins. The results demonstrated that the differences in hemolytic activity of the toxins could be ascribed at least partly to differences in their N-termini.

The effect of three cationic surfactants bearing the same polar head group and different chain length (cetyltrimethyl ammonium bromide (CTAB); tetradecyltrimethylammonium bromide (TTAB); dodecyltrimethylammonium bromide (DTAB)) on the conformation and function of the sea anemone pore-forming toxins sticholysins I and II (St I and St II) was studied by fluorescence and circular dichroism spectroscopy and evaluation of hemolytic activity (HA). Preincubation of the toxins with the longer chain surfactants CTAB and TTAB at concentrations slightly above their critical micelle concentration (CMC) leads to an enhancement of their HA. Significant increases in the fluorescence intensity with a slightly red shift in lambda(max) were observed at concentrations close to the surfactants' CMC, suggesting changes in the environment of the tryptophan residues. The changes in the fluorescence intensity are more noticeable and take place at lower surfactant concentrations for St I, irrespective of the surfactant alkyl chain length, although the differences between St I and St II increase as the surfactant alkyl chain length increases. This is evinced not only by the higher fluorescence intensity values and the lower surfactant concentrations required to reach them, but also by the higher acrylamide-quenching constant values (Ksv) for St I. However, the surfactant's effects on the toxins' HA were not found to be directly related to the observed changes in fluorescence intensity, as well as near- and far-UV-CD spectra. In particular, the latter spectra indicate that changes in HA and in fluorescence behavior take place without noticeable modifications in St I and St II secondary and tertiary structures. The results suggest that the interaction with the surfactants induces only subtle conformational changes in the toxins that favor the formation of lytic competent structures.

Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction.

Continuous HIV treatment is necessary to ensure successful combined antiretroviral therapy (cART). The aim of this study was to evaluate the incidence of patient-initiated non-structured treatment interruptions in HIV-infected persons who inject drugs and who received a multidisciplinary comprehensive program, including medical HIV care, drug-dependence treatment and psychosocial support, at a drug outpatient addiction center. Non-structured treatment interruptions were defined as ≥30 consecutive days off cART without medical indication. During a median follow-up of 53.8 months, 37/132 (28 %) patients experienced the first non-structured treatment interruptions. The cumulative probability of cART interruption at 5 years was 31.2 % (95 % CI 22.4-40.0). Current drug use injection ≥1/day (HR 14.77; 95 % CI 5.90-36.96) and cART naive patients (HR 0.35, 95 % CI 0.14-0.93) were predictive factors for non-structured treatment interruptions. HIV care provided at a drug addiction center is a useful strategy to sustain continuous cART, however, drug abstinence is essential for the long-term maintenance of cART.

Although an ethnically diverse workforce is believed to enhance patient care quality, Hispanics are under-represented in the nursing workforce. Recruiting and retaining Hispanic students in nursing programs is essential for greater workforce participation. This grounded theory study explored practices used by Hispanic nursing students to promote their academic success during the first semester of a baccalaureate program. Fifteen Hispanic nursing students participated in focus groups and individual interviews. Students engaged in an adaption process composed of phases related to arrival, managing, and responding to evaluations. For entering Hispanic nursing students, recognizing the weight of different assignments and adjusting time and energy accordingly were essential in the process of arriving at success. Finances, family dynamics, dealing with potential failure, and time management were significant concerns.

Impressive progress has been made in the understanding of biological contributions to drug abuse and addiction. An area that has only recently begun to receive attention is potential ethnic and racial differences in biological systems that contribute to, or protect from, problem drug use. This article reviews recent research on drug abuse and addiction in Hispanics in which biological questions have been addressed, including work on genes, gene products (proteins), physiology and pharmacotherapy. Taken together, work to date suggests that there are both similarities and differences between Hispanics and other ethnic groups in biological factors related to drug abuse and addiction. Although the results are intriguing, relatively few studies have been done, and those that have been done have often been inconclusive due to low numbers of Hispanic subjects. Moreover, studies have often failed to recognize the complexity and heterogeneity of Hispanic populations in the United States and around the world. After reviewing the current status of the field, recommendations are given for future research in both humans and relevant animal models that will lead to a better understanding of drug abuse and addiction in Hispanics.

Background A decrease in dopamine type 2 receptors (D 2 ) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D 2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [ 11 C]raclopride. Methods Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D 2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V 3 ″). Amphetamine-induced [ 11 C]raclopride displacement was measured as the difference in V 3 ″ between the two scans. Results [ 11 C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [ 11 C]raclopride displacement was −5.2% ± 3.6% in AD subjects compared with −13.0% ± 8.8% in HC. However, no significant difference in [ 11 C]raclopride displacement was seen in the associative (−4.6% ± 5.8% in AD subjects vs. −6.7 ± 5.4% in HC) and sensorimotor (−12.3% ± 7.3% in AD subjects vs. −13.7 ± 7.5% in HC) subdivisions of the striatum between the two groups. Conclusions Alcohol dependence was associated with a decrease in D 2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.

Background Previous imaging studies demonstrated that schizophrenia is associated with increased amphetamine-induced dopamine (DA) release in the striatum, most pronounced during episodes of illness exacerbation. Schizotypal personality disorder (SPD) is a schizophrenia spectrum disorder, genetically related to schizophrenia. The goal of this study was to investigate striatal DA function in patients with SPD. Methods In our study, 13 SPD patients and 13 matched healthy control subjects underwent single photon emission computed tomography (SPECT) scan during bolus plus constant infusion of the D2/3 radiotracer [123I]iodobenzamide (IBZM). Striatal specific to nonspecific equilibrium partition coefficient (V3′′) was measured at baseline and following amphetamine administration (.3 mg/kg). Results No significant differences were observed in baseline V3′′ between groups. Amphetamine induced a larger decrease in [123I]IBZM V3′′ in SPD patients (−12 ± 5%) compared with control subjects (−7 ± 5%, p = .03). Conclusions The reduction in [123I]IBZM V3′′ induced by amphetamine in SPD was similar to that observed in remitted schizophrenia patients (−10 ± 9%, n = 17), but significantly lower than that observed during illness exacerbation (−24 ± 13%, n = 17). This suggests that DA dysregulation in schizophrenia spectrum disorders might have a trait component, present in remitted patients with schizophrenia and in SPD, and a state component, associated with psychotic exacerbations but not SPD.

Sticholysin II (St II) a potent cytolysin from the sea anemone Stichodactyla helianthus was obtained by recombinant procedures exhibiting six histidine residues in its N-terminus (St IIn6H) (De los Rios et al., 2000). The functional comparison between St II and St IIn6H showed a lesser pore-forming ability for the recombinant than for the native in human or rat red blood cells (RBC) and in large unilamellar vesicles (LUV) of different phospholipid composition. However, binding of St IIn6H to small unilamellar vesicles (SUV) was higher with regard to St II. The explanation to the different permeabilizing capacity of both protein variants is not clear, but a different anchoring of St IIn6H to the lipid bilayer could delay the organization of the competent pore into membrane.

The human striatum is functionally organized into limbic, associative, and sensorimotor subdivisions, which process information related to emotional, cognitive, and motor function. Dopamine projections ascending from the midbrain provide important modulatory input to these striatal subregions. The aim of this study was to compare activation of dopamine D2 receptors after amphetamine administration in the functional subdivisions of the human striatum. D2 receptor availability (V3″) was measured with positron emission tomography and [11C]raclopride in 14 healthy volunteers under control conditions and after the intravenous administration of amphetamine (0.3 mg/kg). For each condition, [11C]raclopride was administered as a priming bolus followed by constant infusion, and measurements of D2 receptor availability were obtained under sustained binding equilibrium conditions. Amphetamine induced a significantly larger reduction in D2 receptor availability (ΔV3″) in limbic (ventral striatum, −15.3 ± 11.8%) and sensorimotor (postcommissural putamen, −16.1 ± 9.6%) regions compared with associative regions (caudate and precommissural putamen, −8.1 ± 7.2%). Results of this region-of-interest analysis were confirmed by a voxel-based analysis. Correction for the partial volume effect showed even greater differences in ΔV3″ between limbic (−17.8 ± 13.8%), sensorimotor (−16.6 ± 9.9%), and associative regions (−7.5 ± 7.5%). The increase in euphoria reported by subjects after amphetamine was associated with larger ΔV3″ in the limbic and sensorimotor regions, but not in the associative regions. These results show significant differences in the dopamine response to amphetamine between the functional subdivisions of the human striatum. The mechanisms potentially accounting for these regional differences in amphetamine-induced dopamine release within the striatum remain to be elucidated, but may be related to the asymmetrical feed-forward influences mediating the integration of limbic, cognitive, and sensorimotor striatal function via dopamine cell territories in the ventral midbrain.