Although recreational drug use is uncommon among older adults, recent research has shown that recreational drug use patterns and misuse of alcohol and prescription medications among baby boomers are increasing (Barry and Blow 2016;Caputo et al. 2012;Oslin 2004).As older adults generally have chronic conditions that lead to the use of prescription drugs and over-the-counter (OTC) medications, they are more at risk for dangerous alcohol-medication interactions (Breslow et al. 2015).Also, recent increases in rates of death and use of prescription opioids with suicidal intent among older adults have important implications as the USA undergoes rapid expansion of this population (West et al. 2015;Lippold et al. 2019).Despite their heightened vulnerability, few older adults are screened, and most older adults do not receive needed preventive services or early interventions even though evidence-based programs exist.Screening, Brief Intervention, and Referral to Treatment (SBIRT) is considered an evidence-based public health approach for addressing this gap but has rarely been used in the aging network of care (Blow and Barry 2000;Kuerbis et al. 2015).Thus, the focus of this brief report is to document the barriers and facilitators of implementing SBIRT in nonmedical organizations serving older adults and to assess whether older adults can be recruited and retained into this program.This study did not involve randomization of study participants to an experimental condition, and consequently, it is not possible to draw causal inferences about program impact.

Sickle cell disease is a hemoglobinopathy that causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. The development and treatment of pain, in particular, neuropathic pain in sickle cell disease patients is poorly understood and impedes our progress toward the development of novel therapies to treat pain associated with sickle cell disease. The orexin/hypocretin system offers a novel approach to treat chronic pain and hyperalgesia. These neuropeptides are synthesized in three regions: perifornical area (PFA), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH). Data suggest that orexin-A neuropeptide has an analgesic effect on inflammatory pain and may affect mechanisms underlying the maintenance of neuropathic pain. The purpose of this study was to determine whether there are neuronal activation differences in the orexin system as a result of neuropathic pain testing in a mouse model of sickle cell disease. Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS-BERK) and age-/gender-matched controls (HbAA-BERK mice; n = 10/group, 20-30 g) expressing normal human hemoglobin A were habituated to each test protocol and environment before collecting baseline measurements and testing. Four measures were used to assess pain-related behaviors: thermal/heat hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and deep-tissue hyperalgesia. Hypothalamic brain sections from HbAA-BERK and HbSS-BERK mice were processed to visualize orexin and c-Fos immunoreactivity and quantified. The percentage of double labeled neurons in the PFA was significantly higher than the percentage of double labeled neurons in the LH orexin field of HbAA-BERK mice (* p < 0.05). The percentages of double labeled neurons in PFA and DMH orexin fields are significantly higher than those neurons in the LH of HbSS-BERK mice (* p < 0.05). These data suggest that DMH orexin neurons were preferentially recruited during neuropathic pain testing and a more diverse distribution of orexin neurons may be required to produce analgesia in response to pain in the HbSS-BERK mice. Identifying specific orexin neuronal populations that are integral in neuropathic pain processing will allow us to elucidate mechanisms that provide a more selective, targeted approach in treating of neuropathic pain in sickle cell disease.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

The dose-dependent effects of alcohol, where the initial euphoric and stimulant effects initiated by the exposure to low ethanol levels can quickly lead to a deadly consequence are well established. Thus, high blood alcohol concentration (BAC), as seen in alcoholics, can cause significant damage to various organs. At low concentrations (e.g., 10 mg% or lower), however, beneficial effects of alcohol, particularly on cardiovascular function have been reported. Although, the latter assertion has been challenged by recent epidemiological studies, protective effects of low alcohol concentrations in vitro and in vivo relevant to the central nervous system (CNS) is well documented. In this review, the mechanism(s) leading to the detrimental effects of high BAC, as well as the beneficial effects of low BAC will be discussed. In addition, gender consideration is touched upon. Although further investigation is clearly warranted, it may be concluded that at least some of the beneficial outcomes of low BAC, including possible neuroprotection and antidepressant-like effects, may be due to elevation of the neurotropic factors and reduction of inflammatory mediators, whereas detrimental outcomes associated with high BAC, including neurotoxicity and depressive-like behavior may be due to reduction in neurotropic factors and elevation of inflammatory mediators. Furthermore, new research strategies are suggested.

Fast beta (20–28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10−8. The most significantly associated SNP, rs11720469 (β: −0.124; P<4.5 × 10−9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

The orexins are neuropeptides that are synthesized in the perifornical area (PFA), lateral hypothalamus (LH) and dorsomedial hypothalamus (DMH) and mediate arousal, sleep, energy balance, food and drug reward. The LH region is associated with reward, while the PFA and DMH are more associated with stress and arousal. Data suggest that orexin-A has an analgesic effect on inflammatory pain and it may affect mechanisms underlying the maintenance of neuropathic pain. To date, there have been no published studies to investigate this system as a potential target to treat neuropathic pain in a mouse model of sickle cell disease (SCD). Therefore, we seek to determine activational and topographical differences in neuronal activation of the orexin system in a mouse model of SCD by using an array of behavioral measures to characterize pain in transgenic mice expressing human hemoglobin.

Introduction: Although a role for alpha-2 adrenoceptors (alpha-2 ARs) in alcohol use disorder (AUD) and depression is suggested, very little information on a direct interaction between alcohol and these receptors is available.Methods: In this study adult female Wistar and Wistar-Kyoto (WKY) rats, a putative animal model of depression, were exposed to alcohol vapor 3 h daily for 10 days (blood alcohol concentration similar to 150 mg%) followed by daily injection of 10 mg/kg of imipramine (IMP, a selective norepinephrine NE/serotonin reuptake inhibitor) or nomifensine (NOMI, a selective NE/dopamine reuptake inhibitor). On day 11 animals were tested for open field locomotor activity (OFLA) and forced swim test (FST) and were sacrificed 2 h later for measurement of alpha-2 Ails densities in the frontal cortex and hippocampus using [3H]RX 821002 as the specific ligand.Results: Chronic alcohol treatment increased the immobility in the FST, without affecting OFLA in both Wistar and WKY rats, suggesting induction of depressive-like behavior in Wistar rats and an exacerbation of this behavior in WKY rats. Alcohol treatment also resulted in an increase in cortical but not hippocampal alpha-2 ARs densities in both Wistar and WKY rats. The behavioral effects of alcohol were completely blocked by IMP and NOMI and the neurochemical effects (increases in alpha-2 ARs) were significantly attenuated by both drugs in both strains.Conclusions: The results suggest a role for cortical alpha-2 ARs in alcohol withdrawal-induced depression and that selective subtype antagonists of these receptors may be of adjunct therapeutic potential in AUD-depression co-morbidity.

Background Heavy use of alcohol is commonly associated with heavy smoking (nicotine intake). Although many factors, including mood effects of these two drugs may contribute to their co-use, the exact neurobiological underpinnings are far from clear. It is well known that chronic alcohol exposure induces neuroinflammation that may precipitate depressive-like behavior, which is considered an important factor in alcohol relapse. Nicotine, on the other hand, possesses anti-inflammatory and antidepressant effects. Purpose In this study, we sought to determine which proinflammatory markers may be associated with the depressogenic effects of chronic alcohol and whether nicotine pretreatment may normalize these changes. Study design For this purpose, we treated adult male Wistar rats with alcohol (1.0 g/kg, IP), nicotine (0.3 mg/kg, IP) or their combination once daily for 14 days. Two prominent proinflammatory cytokines (IL-1β and TNF-α) in two primary brain regions, namely the hippocampus and frontal cortex that are intimately involved in mood regulation, were evaluated. Results Chronic alcohol resulted in increases in both cytokines in both regions as determined by Western blot. Nicotine completely blocked alcohol-induced effects in the hippocampus, but not in the frontal cortex. These data suggest that nicotine may mitigate the inflammatory effects of alcohol in brain-selective region. Hence, the previously observed depressogenic effects of alcohol and the antidepressant effects of nicotine may at least be partially mediated through manipulations of proinflammatory cytokines in the hippocampus. Conclusion These findings suggest possible therapeutic potential of anti-inflammatory cytokines in combating alcohol-induced depression and/or relapse.

American Journal of HematologyVolume 92, Issue 1 p. E10-E11 CorrespondenceFree Access Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer Yan Dai, Yan Dai Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Cancer Center, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorJose Sangerman, Jose Sangerman Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorMehdi Nouraie, Mehdi Nouraie Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PennsylvaniaSearch for more papers by this authorAidan D. Faller, Aidan D. Faller Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorPatricia Oneal, Patricia Oneal Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorAngela Rock, Angela Rock Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorOluwakemi Owoyemi, Oluwakemi Owoyemi Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorXiaomei Niu, Xiaomei Niu Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorSergei Nekhai, Sergei Nekhai Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorDashmeet Maharaj, Dashmeet Maharaj Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorShauiying Cui, Shauiying Cui Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorRobert Taylor, Robert Taylor Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorMartin Steinberg, Martin Steinberg Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorSusan Perrine, Corresponding Author Susan Perrine sperrine@bu.edu Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Cancer Center, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of Columbia Phoenicia Biosciences, Weston, MassachusettsCorrespondence to: Susan Perrine, MD, Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, 72 East Concord Street, L909, Boston, MA 02118. E-mail: sperrine@bu.eduSearch for more papers by this author Yan Dai, Yan Dai Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Cancer Center, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorJose Sangerman, Jose Sangerman Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorMehdi Nouraie, Mehdi Nouraie Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PennsylvaniaSearch for more papers by this authorAidan D. Faller, Aidan D. Faller Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorPatricia Oneal, Patricia Oneal Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorAngela Rock, Angela Rock Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorOluwakemi Owoyemi, Oluwakemi Owoyemi Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorXiaomei Niu, Xiaomei Niu Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorSergei Nekhai, Sergei Nekhai Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorDashmeet Maharaj, Dashmeet Maharaj Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorShauiying Cui, Shauiying Cui Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorRobert Taylor, Robert Taylor Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of ColumbiaSearch for more papers by this authorMartin Steinberg, Martin Steinberg Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MassachusettsSearch for more papers by this authorSusan Perrine, Corresponding Author Susan Perrine sperrine@bu.edu Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Cancer Center, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of Columbia Phoenicia Biosciences, Weston, MassachusettsCorrespondence to: Susan Perrine, MD, Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, 72 East Concord Street, L909, Boston, MA 02118. E-mail: sperrine@bu.eduSearch for more papers by this author First published: 20 October 2016 https://doi.org/10.1002/ajh.24590Citations: 7 Conflict of interest: S. Perrine: Inventor on patents related to this work. Contract grant sponsor: NIH; Contract grant numbers: 1P50 HL-118006, R01 DK-52962, R41 HL-108516, R42 HL-110727. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: Biochemical, epidemiologic, clinical, and genetic research over several decades has shown that any increment in fetal hemoglobin (HbF) reduces the clinical severity of sickle cell anemia, with significantly improved survival in US patients with HbF levels above the 75% percentile (8.6%) or with an absolute HbF ≥ 0.5 g/dL with hydroxyurea (HU) treatment 1, 2. While having 100% F-cells results in a benign condition in compound heterozygotes for HbS and hereditary persistence of HbF (HPFH), a level of 70–75% F-cells has been observed in the milder haplotypes, such as the Arabian-Indian haplotype 3-5. Perhaps the most important protector of the sickle erythrocyte from deoxy HbS polymer-induced injury is the concentration of HbF/F-cell. A recent analysis of a population of African patients found low concentrations of HbF/F-cells in sickle cell patients in Tanzania, supporting the importance of this parameter 6. The amount of HbF/F-cell required to entirely prevent HbS polymerization was recently proposed as a therapeutic target 1. To investigate the impact of HU on HbF expression parameters other than total HbF in adult patients, we analyzed F-cells and HbF/F-cell in 56 adult sickle cell disease patients attending a sickle cell clinic for routine care, of whom 33 (60%) were taking HU at modest stable doses of 1,000–1,500 mg/day. Subjects were 20–65 years of age, with median age 31 years; 45% were females. Patients with an acute illness or transfusion within 4 weeks were not included. Proportions of F-cells and mean fluorescent intensity (MFI) of F-cells were analyzed from heparinized peripheral blood by flow cytometry. Cells were stained with a specific HbF antibody (Becton–Dickinson). F-cells and mean fluorescence intensity of positive cells was determined using Cell Quest software and used as an estimate of HbF/F-cell. HbF was analyzed by HPLC (Variant). The mean HbF in HU-treated subjects was 8.8% compared to 5.0% in untreated subjects (Fig. 1A), a level nearly identical to that observed in the Multi-Center Study of Hydroxyurea that led to its FDA approval. Mean % F-cells was 34% in HU-treated subjects compared to 22.9% in untreated subjects (P = 0.01, t-test), shown in Fig. 1B. Fourteen of the 33 (42%) of HU-treated subjects demonstrated F-cell proportions ≥ 40%. Mean fluorescent intensity of F-cells in untreated patients compared to HU-treated patients was 37 vs. 48 fluorescence units, respectively, shown in Fig. 1B (P = 0.01). Several recently identified targeted HbF therapeutic inducing agents which act through differing mechanisms to increase fetal globin mRNA, HbF, and F-cells in vitro and in vivo, including sodium 2,2 dimethylbutyrate (ST20), benserazide (BEN), and the LSD-1 inhibitor RN-1 were evaluated for effects on HbF expression in erythroid progenitor cells cultured from at least 10 sickle cell patients 3. All therapeutic candidates significantly induced fetal globin mRNA levels by 2.5- to 10-fold above untreated control cells from the same patients (Fig. 1C); mean increases above control were 2.5- to 2.8-fold with HU, RN-1, or ST20 (all, P < 0.01); 5.8-fold with BEN (P < 0.001); and 7-fold with combined treatment with BEN and HU (P = 0.01), analyzed by a nonparametric test. Figure 1Open in figure viewerPowerPoint A,B: Mean levels of HbF, F-cells, or MFI in sickle cell patients who were taking HU (dark bars) were significantly higher in treated than in untreated patients. C: Fetal (γ)-globin mRNA in erythroid progenitors cultured from sickle cell patients is significantly increased (*) with added therapeutics compared to untreated controls from the same patient, from 2.5- to 2.8-fold with ST20, RN-1, or HU, 5.8-fold with BEN (P < 0.001), and 7-fold with BEN + HU (n = 10, P = 0.011). Standard deviation is shown by the vertical bars. D: Diagram of the Pathway analysis, demonstrating that the main effect of hydroxyurea (HU) is due to increases in % F-cells, which in turn contribute to total HbF. Therapeutic targets for amelioration of clinical severity of sickle cell disease have been proposed as 20–30% HbF, 70–75% F-cells, and 10 pg HbF/cell, twice the threshold of 4–6 pg/cell which is the minimum previously detectable in flow cytometry assays 1. F-cells undergo selective survival and have longer lifespans than non-F cells 3-5. We used a pathway analysis to deconstruct the total effects of HU as either direct (HbF) or indirect (mediated by F-cell percentage). Pathway analysis tests a hypothetical pathway from predictors to responses against observed data using multiple regression equations. Standardized regression coefficients are computed for each relationship, adjusted for the other relationships, and shown next to each line connecting predictors to responses, and is shown for the patient data in Fig. 1D. This analysis indicates that HU contributes first to higher proportions of F-cells (r = 0.47, P < 0.001), and secondly to the amount of HbF (r = 0.85, P < 0.01), whereas, in contrast, a direct effect of HU to HbF was not statistically significant (r = 0.09, P = 0.3). In this analysis, 82% of the total effect of HU on HbF is an indirect effect mediated by F-cells. These data suggest that addition of a second, or perhaps multiple, HbF inducers may produce higher concentrations of HbF content in erythroid cells which differentiate with, or are primed by, HU. The findings here particularly suggest that addition of benserazide as a second therapeutic with HU may induce HbF expression closer to therapeutic targets proposed. As individual patients have highly variable baseline HbF expression patterns, monitoring these parameters may guide treatments to ameliorate clinical severity and indicate when multiple therapies are warranted. Author Contributions Y. Dai, J. Sangerman, A. D. Faller, D. Maharaj and X. Niu performed assays; A. Rock, O. Owoyemi, and P. Oneal obtained clinical correlations; S. Perrine, M. Nouraie, M. Steinberg, analyzed results and wrote the paper. M. Nouraie performed statistical analyses. S. Nekhai, S. Cui, and R. Taylor reviewed the manuscript. Yan Dai,1,2 Jose Sangerman,3 Mehdi Nouraie,4 Aidan D. Faller,3 Patricia Oneal,5 Angela Rock,5 Oluwakemi Owoyemi,5 Xiaomei Niu,5 Sergei Nekhai,5 Dashmeet Maharaj,3 Shauiying Cui,6 Robert Taylor,5 Martin Steinberg,6,7 And Susan Perrine1,2,3,5,8 1Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; 2Cancer Center, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; 3Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts; 4Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 5Center for Hemoglobin Research in Minorities (CHaRM), Howard University, Washington, District of Columbia; 6Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; 7Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; 8Phoenicia Biosciences, Weston, Massachusetts References 1Steinberg MH, Chui DHK, Dover GJ, et al. Fetal hemoglobin in sickle cell anemia: A glass half full? Blood 2014; 123: 481– 485. 2Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010; 85: 403– 408. 3Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin N Am 2014; 28: 233– 248. 4Boyer SH, Dover GJ, Serjeant GR, et al. Production of F-cells in sickle cell anemia: Regulation by a genetic locus or loci separate from the beta globin cluster. Blood 1984; 64: 1053– 1058. 5Franco RS, Yasin Z, Palascak MB, et al. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood 2006; 108: 1073– 1076. 6Urio F, Lyimo M, Mtatiro SN, et al. High prevalence of individuals with low concentration of fetal hemoglobin in F-cells in sickle cell anemia in Tanzania. Am J Hematol 2016; 91: E323– E324. Citing Literature Volume92, Issue1January 2017Pages E10-E11 FiguresReferencesRelatedInformation

BACKGROUND:Substance-related disorders are a growing problem in the United States. The patient-provider setting can serve as a crucial environment to detect and prevent at-risk substance use. Screening, brief intervention, and referral to treatment (SBIRT) is an integrated approach to deliver early intervention and treatment services for persons who have or are at risk for substance-related disorders. SBIRT training components can include online modules, in-person instruction, practical experience, and clinical skills assessment. This paper will evaluate the impact of multiple modes of training on acquisition of SBIRT skills as observed in a clinical skills assessment.METHODS:Residents were part of an SBIRT training program, from 2009 through 2013, consisting of lecture, role-play, online modules, patient encounters, and clinical skills assessment (CSA). Differences were assessed across satisfactory and unsatisfactory CSA performance.RESULTS:Seventy percent of the residents satisfactorily completed CSA. Demographics, type of components completed, and number of components completed were similar among residents who demonstrated satisfactory clinical skills compared with those who did not. All components of the training program were accepted equally across specialties and resident matriculation cohorts.CONCLUSION:The authors conclude that the components employed in SBIRT training do not have to be numerous or of a particular mode of training in order to see observable demonstration of SBIRT skills among medical residents. Thus, residency educators who have limited time or resources may utilize as few as 1 mode of training to effectually disseminate SBIRT skills among health care providers. As SBIRT continues to evolve as a promising tool to address at-risk substance-related disorders, it is critical to train medical residents and other health professionals.

Background and Objectives Numerous factors contribute to underrepresentation of African-Americans in medical research, including beliefs, historical events, structural, and health access obstacles. This study examined beliefs about medical research and the types of study methods preferred among potential African-American research participants.Methods A sample of 304 African-American participants from the Washington, DC Metropolitan area, completed a survey evaluating beliefs about medical research and preferred research study methods. Multiple Regression analyses were performed to examine how age, gender, and education may influence these beliefs and preferences for research study methods.Results The beliefs and preferences surveyed did not differ by age, gender, or educational attainment. There was an overwhelmingly favorable belief (90 %) that medical research was necessary and assists in finding a cure for a disease. Most respondents preferred participating in research related to issues with which they were familiar (e.g., diabetes, hypertension) or working with researchers of a similar ethnic background to themselves. Interestingly, though nonsignificant, those with higher levels of educational trended toward the belief that participation in research was risky.Conclusion The findings of this study indicate that certain beliefs about medical research participation and preferred study methodologies reported by African-Americans did not differ by age, gender, or level of education. This information about African-American's beliefs and preferences regarding medical research should lead to an awareness of potential gains in African-American participation through the development of culturally sensitive medical research studies and methodologies.

Complete eradication of HIV-1 infection is impeded by the existence of latent HIV-1 reservoirs in which the integrated HIV-1 provirus is transcriptionally inactive. Activation of HIV-1 transcription requires the viral Tat protein and host cell factors, including protein phosphatase-1 (PP1). We previously developed a library of small compounds that targeted PP1 and identified a compound, SMAPP1, which induced HIV-1 transcription. However, this compound has a limited bioavailability in vivo and may not be able to reach HIV-1-infected cells and induce HIV-1 transcription in patients. We packaged SMAPP1 in polymeric polyethylene glycol polymethyl methacrylate nanoparticles and analyzed its release and the effect on HIV-1 transcription in a cell culture. SMAPP1 was efficiently packaged in the nanoparticles and released during a 120-hr period. Treatment of the HIV-1-infected cells with the SMAPP1-loaded nanoparticles induced HIV-1 transcription. Thus, nanoparticles loaded with HIV-1-targeting compounds might be useful for future anti-HIV-1 therapeutics.

Sleep-disordered breathing (SDB) is reported in up to 69% of adolescents and children with sickle cell disease (SCD) [1], but data regarding the prevalence of SDB in adults with SCD are limited. In order to obtain a preliminary assessment of the frequency and degree of sleep-related hypoxemia and potential associations with cardiovascular function in adults with SCD, we conducted overnight sleep studies, 6-min walk tests, echocardiograms, and hematologic and chemistry panels, calculated the Pittsburgh sleep quality index (PSQI), and conducted fatigue-and health-related quality-of-life measurement in 20 young adults with SCD visiting a sickle cell clinic for routine care. Sleep apnea, defined as an apnea-hypopnea index (AHI) > 5 events/h, was found in 50% of patients. Traditional clinical indicators, such as obesity, the presence of snoring, and reported sleep complaints, did not reliably differentiate them. The patients with AHI > 5 had higher mean systolic blood pressure (p = 0.03), evidence of impaired left ventricular diastolic function (i.e., increased mitral valve E/A ratio, p = 0.05), a trend toward higher reduction in 6-min walk distances (p = 0.06), and lower health-related quality-of-life scores (p <= 0.01). Three of nine patients with more severe anemia (total Hb < 9.0) showed nocturnal hypoxemia in the absence of sleep apnea. As prolonged and frequent hypoxemic episodes likely increase risks for vaso-occlusive, cardiovascular, and neurologic complications of SCD, these results suggest that the prevalence and severity of SDB should be investigated further in studies of larger patient populations. If confirmed, these findings could identify opportunities to prevent or reduce nocturnal hypoxia and improve outcomes. (C) 2016 Elsevier B.V. All rights reserved.

Background: Chronic pain, along with the other physical, emotional, and cognitive manifestations of Sickle Cell Disease (SCD) increases the risk of developing psychological disorders. Studies with limited sample size have suggested that depression occurs at a significantly higher proportion in SCD patients than control groups. In this study we assessed the burden of mood and alcohol dependence disorders in SCD adult patients and their effect on healthcare utilization using a nationwide sample.

Sickle cell disease (SCD) is the most common monogenic disorder, afflicting millions worldwide, and causing hemolytic anemia and chronic organ damage from vaso-occlusion. Fetal hemoglobin (HbF) is an endogenous type of hemoglobin present in all humans during development, which is normally suppressed in infancy. Biochemical and clinical studies have shown that increased synthesis of HbF inhibits sickle hemoglobin (HbS) polymerization and reduces clinical severity. Concerted efforts have been made to induce the synthesis of HbF in adult erythroid cells with chemical inducers of HbF and through disruption of transcription factors in repressor complexes. As wide variability in individual responses to drug candidates have been observed in clinical trials, consistently effective HbF inducers are highly desired. We previously identified that Lysine-specific histone demethylase 1 (LSD1) is involved in the regulation of the fetal γ-globin genes, and inhibition of LSD1 using either RNAi or by the momoamine oxidase inhibitor tranylcypromine (TC) in primary human erythroid progenitor cells induces HbF to therapeutic levels. However, TC treatment has potentially problematic side effects, and at high concentrations decreases adult b-globin mRNAs and impairs erythroid maturation. We have now investigated another LSD1 inhibitor, RN-1, which is a cell-permeable TC analog that acts as a potent, irreversible inhibitor of LSD1 with a lower IC50 than TC. We investigated in vivo effects of RN-1 on γ-globin gene expression and erythroid physiology in a transgenic mouse model of SCD which expresses human α- and sickle β-globin, and has many genetic, hematologic, and pathophysiological features found in SCD patients, including irreversibly sickled RBCs, hemolytic anemia, high reticulocyte counts, hepatosplenomegaly and organ pathology. We found a robust increase in human fetal γ-globin (15-fold) and murine embryonic εY- and βH1-globin mRNAs (36 and 54-fold) and 4-fold increases in human HbF in SCD mice following repeated RN-1 treatment (at 10 μg/g body weight) within 4 weeks. Further, irreversibly sickled RBCs were significantly reduced, and RBC lifespan increased markedly in RN-1-treated SCD mice, leading to significantly decrease pathophysiologic indicators (hemolysis, splenomegaly, and organ necrosis) compared to untreated SCD mice. To begin to evaluate potential effects of RN-1 on erythroid progenitor cells from patients with SCD, peripheral blood from 5 adult SCD patients was cultured with RN-1 (0.07 to 0.25 μM) in a 2-phase progenitor assay, with mRNA analyzed on day 12 and F-reticulocytes on day 13-14 of the erythroid differentiation phase. RN-1 treated progenitors demonstrated a mean 3.4-fold higher g-globin mRNA (p=0.04) and 5% higher absolute F-reticulocytes than were observed in untreated progenitors from the same subject, with responses occurring in 5/5 subjects' assays. These preclinical studies provide additional evidence that modulating LSD-1 activity is a promising approach to inducing HbF expression as a mechanism to reduce clinical severity of SCD.