Maternal care behavior and physiology moderate offspring outcomes following gestational exposure to opioids.

The opioid epidemic has resulted in a drastic increase in gestational exposure to opioids. Opioid-dependent pregnant women are typically prescribed medications for opioid use disorders ("MOUD"; e.g., buprenorphine [BUP]) to mitigate the harmful effects of abused opioids. However, the consequences of exposure to synthetic opioids, particularly BUP, during gestation on fetal neurodevelopment and long-term outcomes are poorly understood. Further, despite the known adverse effects of opioids on maternal care, many preclinical and clinical studies investigating the effects of gestational opioid exposure on offspring outcomes fail to report on maternal care behaviors. Considering that offspring outcomes are heavily dependent upon the quality of maternal care, it is important to evaluate the effects of gestational opioid exposure in the context of the mother-infant dyad. This review compares offspring outcomes after prenatal opioid exposure and after reduced maternal care and integrates this information to potentially identify common underlying mechanisms. We explore whether adverse outcomes after gestational BUP exposure are due to direct effects of opioids in utero, deficits in maternal care, or a combination of both factors. Finally, suggestions for improving preclinical models of prenatal opioid exposure are provided to promote more translational studies that can help to improve clinical outcomes for opioid-dependent mothers.

Health equity in the implementation of genomics and precision medicine: A public health imperative.

Recent reviews have emphasized the need for a health equity agenda in genomics research. To ensure that genomic discoveries can lead to improved health outcomes for all segments of the population, a health equity agenda needs to go beyond research studies. Advances in genomics and precision medicine have led to an increasing number of evidence-based applications that can reduce morbidity and mortality for millions of people (tier 1). Studies have shown lower implementation rates for selected diseases with tier 1 applications (familial hypercholesterolemia, Lynch syndrome, hereditary breast and ovarian cancer) among racial and ethnic minority groups, rural communities, uninsured or underinsured people, and those with lower education and income. We make the case that a public health agenda is needed to address disparities in implementation of genomics and precision medicine. Public health actions can be centered on population-specific needs and outcomes assessment, policy and evidence development, and assurance of delivery of effective and ethical interventions. Crucial public health activities also include engaging communities, building coalitions, improving genetic health literacy, and building a diverse workforce. Without concerted public health action, further advances in genomics with potentially broad applications could lead to further widening of health disparities in the next decade.

Acute exposure to abuse-like concentrations of toluene induces inflammation in mouse lungs and brain.

Toluene is an aromatic hydrocarbon commonly abused by young adolescents for its central nervous system depressant effects. Although toluene's pharmacological effects at high concentrations are relatively well-known, few studies have assessed toluene's effects on lung and brain tissues. The present study characterized the pathological effects of acute inhaled toluene exposure in the lungs and brains of male Swiss-Webster mice (N = 68). Using a static vapor exposure chamber, mice (PND 28) received a single 30-min toluene administration (0, 1000, 2000, or 4000 ppm). Lung and brain tissues were extracted 24-h post-exposure. Histology results revealed significant changes in the morphology of lung tissue (e.g., irregular cellular architecture) with the 2000- and 4000-ppm exposures expressing greater signs of pathology than control 0-ppm exposure. Markers of immune system activity (F4/80 and Ly-6G) and cellular proliferation (Ki-67) in the lung revealed no significant differences. Additionally, brain tissues were analyzed for changes of astrogliosis (glial fibrillary acidic protein [GFAP]) and oxidative stress (glutathione peroxidase [GPx]). GFAP showed increased astrogliosis in the striatum with 2000-ppm toluene showing significantly higher expression than control (p < 0.05) and a marginal effect in the hippocampus. No other markers showed significant changes. The increased signs of inflammation and cellular damage suggest that exposure to a single high concentration of toluene, typical of abuse, is capable of producing pathology in both lung and brain tissue.

Repeated toluene exposure leads to neuroadaptation in dopamine release mechanisms within the nucleus accumbens core.

BACKGROUND: Intentionally inhaling volatile organic solvent like toluene for its intoxicating effects continues to be a public health concern. While repeated abuse of toluene has deleterious behavioral and health effects, little is known about the actions of toluene on the dopaminergic neurotransmitter system within the central nervous system. METHOD: The present study employed complementary neurochemical techniques of slice fast-scan cyclic voltammetry (FSCV) and in vivo microdialysis, to assess dopamine (DA) dynamics immediately after repeated exposure to 2000- or 4000-ppm toluene. DA D3 autoreceptor functionality, measured by FSCV with pharmacological manipulations and brain tissue content analysis with high performance liquid chromatography, were also used to account for the changes in the DA dynamics. RESULTS: Toluene-exposed mice had decreased stimulated DA release only in the nucleus accumbens core immediately after seven days of repeated exposure. DA uptake was decreased in the core only after 2000-ppm exposure. The differences in stimulated DA release were not attributed to alterations in intraneuronal DA levels as measured by tissue content analysis. Basal extracellular DA levels were not significantly different between the air- and toluene-treated mice. However, following an additional toluene exposure, mice had elevated extracellular DA levels in the nucleus accumbens during recovery. This potentiation in extracellular accumbal DA levels was further heightened following potassium stimulation. The accumbal DA D3 autoreceptor function did not appear to play a role as a potential mediator for these differences. CONCLUSION: Our FSCV and microdialysis results suggest a neuroadaptation in DA release mechanics within the nucleus accumbens, but the exact neuronal mechanism of toluene's impact remains elusive.

Evaluating the role of public health in implementation of genomics-related recommendations: a case study of hereditary cancers using the CDC Science Impact Framework.

Public health plays an important role in ensuring access to interventions that can prevent disease, including the implementation of evidence-based genomic recommendations. We used the Centers for Disease Control and Prevention (CDC) Science Impact Framework to trace the impact of public health activities and partnerships on the implementation of the 2009 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Lynch Syndrome screening recommendation and the 2005 and 2013 United States Preventive Services Task Force (USPSTF) BRCA1 and BRCA2 testing recommendations.The EGAPP and USPSTF recommendations have each been cited by >300 peer-reviewed publications. CDC funds selected states to build capacity to integrate these recommendations into public health programs, through education, policy, surveillance, and partnerships. Most state cancer control plans include genomics-related goals, objectives, or strategies. Since the EGAPP recommendation, major public and private payers now provide coverage for Lynch Syndrome screening for all newly diagnosed colorectal cancers. National guidelines and initiatives, including Healthy People 2020, included similar recommendations and cited the EGAPP and USPSTF recommendations. However, disparities in implementation based on race, ethnicity, and rural residence remain challenges. Public health achievements in promoting the evidence-based use of genomics for the prevention of hereditary cancers can inform future applications of genomics in public health.

Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).

In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.

Lead identification and characterization of hTrkA type 2 inhibitors.

Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.

Pro region engineering of nerve growth factor by deep mutational scanning enables a yeast platform for conformational epitope mapping of anti-NGF monoclonal antibodies.

Nerve growth factor (NGF) plays a central role in multiple chronic pain conditions. As such, anti-NGF monoclonal antibodies (mAbs) that function by antagonizing NGF downstream signaling are leading drug candidates for non-opioid pain relief. To evaluate anti-canine NGF (cNGF) mAbs we sought a yeast surface display platform of cNGF. Both mature cNGF and pro-cNGF displayed on the yeast surface but bound conformationally sensitive mAbs at most 2.5-fold in mean fluorescence intensity above background, suggesting that cNGF was mostly misfolded. To improve the amount of folded, displayed cNGF, we used comprehensive mutagenesis, FACS, and deep sequencing to identify point mutants in the pro-region of canine NGF that properly enhance the folded protein displayed on the yeast surface. Out of 1,737 tested single point mutants in the pro region, 49 increased the amount of NGF recognized by conformationally sensitive mAbs. These gain-of-function mutations cluster around residues A-61-P-26. Gain-of-function mutants were additive, and a construct containing three mutations increased amount of folded cNGF to 23-fold above background. Using this new cNGF construct, fine conformational epitopes for tanezumab and three anti-cNGF mAbs were evaluated. The epitope revealed by the yeast experiments largely overlapped with the tanezumab epitope previously determined by X-ray crystallography. The other mAbs showed site-specific differences with tanezumab. As the number of binding epitopes of functionally neutralizing anti-NGF mAbs on NGF are limited, subtle differences in the individual interacting residues on NGF that bind each mAb contribute to the understanding of each antibody and variations in its neutralizing activity. These results demonstrate the potential of deep sequencing-guided protein engineering to improve the production of folded surface-displayed protein, and the resulting cNGF construct provides a platform to map conformational epitopes for other anti-neurotrophin mAbs.

A knowledge base for tracking the impact of genomics on population health.

PURPOSE: We created an online knowledge base (the Public Health Genomics Knowledge Base (PHGKB)) to provide systematically curated and updated information that bridges population-based research on genomics with clinical and public health applications. METHODS: Weekly horizon scanning of a wide variety of online resources is used to retrieve relevant scientific publications, guidelines, and commentaries. After curation by domain experts, links are deposited into Web-based databases. RESULTS: PHGKB currently consists of nine component databases. Users can search the entire knowledge base or search one or more component databases directly and choose options for customizing the display of their search results. CONCLUSION: PHGKB offers researchers, policy makers, practitioners, and the general public a way to find information they need to understand the complicated landscape of genomics and population health.Genet Med 18 12, 1312-1314.

Prevalence and morbidity of primary immunodeficiency diseases, United States 2001-2007.

PURPOSE: Few studies have estimated population prevalence and morbidity of primary immunodeficiency diseases (PIDD). We used administrative healthcare databases to estimate the prevalence of PIDD diagnoses in the United States from 2001 to 2007. METHODS: MarketScan databases compile claims from commercial health insurance plans and Medicaid, recording individual diagnoses for outpatient encounters and hospital stays. We used a cross sectional survey to estimate prevalence of PIDD using related ICD-9 codes (279.0, 279.1, 279.2, 279.8, 279.9, 288.1 and 288.2). Persons with secondary immunodeficiency diagnoses were excluded from analysis. RESULTS: Between 2001 and 2007, prevalence of any PIDD diagnosis increased from 38.9 to 50.5 per 100,000 among privately insured and from 29.1 to 41.1 per 100,000 among publicly insured persons. B cell defects predominated. Prevalence was more than twice as high among Whites as among Blacks or Hispanics. CONCLUSION: In this large database, we found a higher prevalence of diagnosed PIDD than has been reported previously from registries. Increased awareness may have contributed to the increasing prevalence.

Strategies, actions, and outcomes of pilot state programs in public health genomics, 2003-2008.

State health departments in Michigan, Minnesota, Oregon, and Utah explored the use of genomic information, including family health history, in chronic disease prevention programs. To support these explorations, the Office of Public Health Genomics at the Centers for Disease Control and Prevention provided cooperative agreement funds from 2003 through 2008. The 4 states' chronic disease programs identified advocates, formed partnerships, and assessed public data; they integrated genomics into existing state plans for genetics and chronic disease prevention; they developed projects focused on prevention of asthma, cancer, cardiovascular disease, diabetes, and other chronic conditions; and they created educational curricula and materials for health workers, policymakers, and the public. Each state's program was different because of the need to adapt to existing culture, infrastructure, and resources, yet all were able to enhance their chronic disease prevention programs with the use of family health history, a low-tech "genomic tool." Additional states are drawing on the experience of these 4 states to develop their own approaches.

Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice.

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28-32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

The effects of buprenorphine and morphine during pregnancy: Impact of exposure length on maternal brain, behavior, and offspring neurodevelopment.

The escalating incidence of opioid-related issues among pregnant women in the United States underscores the critical necessity to understand the effects of opioid use and Medication for Opioid Use Disorders (MOUDs) during pregnancy. This research employed a translational rodent model to examine the impact of gestational exposure to buprenorphine (BUP) or morphine on maternal behaviors and offspring well-being. Female rats received BUP or morphine before conception, representing established use, with exposure continuing until postnatal day 2 or discontinued on gestational day 19 to mimic treatment cessation before birth. Maternal behaviors - including care, pup retrieval, and preference - as well as hunting behaviors and brain neurotransmitter levels were assessed. Offspring were evaluated for mortality, weight, length, milk bands, surface righting latency, withdrawal symptoms, and brain neurotransmitter levels. Our results reveal that regardless of exposure length (i.e., continued or discontinued), BUP resulted in reduced maternal care in contrast to morphine-exposed and control dams. Opioid exposure altered brain monoamine levels in the dams and offspring, and was associated with increased neonatal mortality, reduced offspring weight, and elevated withdrawal symptoms compared to controls. These findings underscore BUP's potential disruption of maternal care, contributing to increased pup mortality and altered neurodevelopmental outcomes in the offspring. This study calls for more comprehensive research into prenatal BUP exposure effects on the maternal brain and infant development with the aim to mitigate adverse outcomes in humans exposed to opioids during pregnancy.

Older adults are not more susceptible to acute muscle atrophy after immobilisation compared to younger adults: a systematic review.

PURPOSE: To identify if older adults are more susceptible to acute muscle atrophy compared to younger adults. METHODS: All studies whose design involved a period of enforced immobilisation and a comparison between an older (> 40) and a younger cohort (< 40) were included. Outcome of interest was change in muscle mass, measured by radiological techniques or histological analysis of fibre size. Medline, Embase and Cochrane databases were systematically searched and records screened by two independent reviewers. Studies selected for inclusion were critically appraised and individually assessed for risk of bias. GRADE framework guided the assessment of quality of studies. RESULTS: Eight articles were included (193 participants). 14 (7.3%) were female and 102 (52.8%) were in older groups. Mean age for older adults was 66.3 years and for younger adults 23.3 years. Immobilisation periods spanned 4-14 days as simulated by bed rest, limb brace or limb cast. Studies measured muscle mass by DXA, CT, MRI or fibre cross-sectional area, or a combination of each. Muscles studied included quadriceps, adductor pollicis, vastus lateralis or combined lean leg mass. Of the radiological measures, three studies (74 participants) reported greater atrophy in the older group, three studies (76 participants) reported greater atrophy in the younger group. Reduction in muscle mass varied in older adults between 0.19 and 0.76% per day, and for younger adults between 0.06 and 0.70% per day. Due to substantial heterogeneity, a meta-analysis was not performed. Five studies reported fibre size. Change in fibre size varied considerably between each study, with no convincing overall trend for either older or younger groups. CONCLUSION: The current literature suggests that there is no difference in the rate of muscle atrophy after immobilisation in older people compared to younger people, and therefore that older people are not more susceptible to atrophy in the acute setting. However, the findings are inconsistent and provide statistically significant but opposing results. There is a lack of high-quality research available on the topic, and there is a paucity of literature regarding atrophy rates in women.

A novel preclinical model of environment-like combined benzene, toluene, ethylbenzene, and xylenes (BTEX) exposure: Behavioral and neurochemical findings.

Environmental exposure to toxicants is a major health issue and a leading risk factor for premature mortality worldwide, including environmental exposures to volatile organic compounds (VOCs), specifically Benzene, Toluene, Ethylbenzene, and Xylene (BTEX). While exposure to these compounds individually has shown behavioral and neurochemical effects, this investigation examined the impact of exposure to combined BTEX using a preclinical model. Male Swiss Webster mice were exposed to BTEX vapors designed to approximate environmental levels in urban communities. Animals were exposed to one of four treatment conditions: a 0-ppm (air control), two BTEX groups representing levels of environmental-like exposure, and a fourth group modeling occupational-like exposure. These exposures were conducted in 1.5-h sessions, 2 sessions/day, 5 days/week, for 3 weeks. Effects on coordination (i.e., rotarod and inverted screen test), learning and memory (i.e., Y-maze), and locomotor behavior (i.e., movement during exposure) were assessed during and after exposure. Monoamine levels in the medial prefrontal cortex and nucleus accumbens were assessed immediately following exposure. Effects of BTEX exposure were found on the variance of locomotor activity but not in other behavioral or neurochemical assessments. These results indicate that the combination of inhaled BTEX at environmentally representative concentrations has demonstrable, albeit subtle, effects on behavior.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: identification of 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds.

Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.

Two serious and challenging medical complications associated with volatile substance misuse: sudden sniffing death and fetal solvent syndrome.

Volatile substance misuse is a prevalent and often overlooked behavior among adolescents, including reported use among young pregnant women. Several medical repercussions can arise from the improper use of volatile substances, yet they are often underappreciated among scientists and health professionals. This brief review reports on the recent advances made in the preclinical and clinical data about two serious medical complications surrounding volatile substance misuse: sudden sniffing death and fetal solvent syndrome. Suggestions for treatment interventions are discussed. The paper's limitations are noted.

The last two decades on preclinical and clinical research on inhalant effects.

This paper reviews the scientific evidence generated in the last two decades on the effects and mechanisms of action of most commonly misused inhalants. In the first section, we define what inhalants are, how they are used, and their prevalence worldwide. The second section presents specific characteristics that define the main groups of inhalants: (a) organic solvents; (b) aerosols, gases, and volatile anesthetics; and (c) alkyl nitrites. We include a table with the molecular formula, structure, synonyms, uses, physicochemical properties and exposure limits of representative compounds within each group. The third and fourth sections review the direct acute and chronic effects of common inhalants on health and behavior with a summary of mechanisms of action, respectively. In the fifth section, we address inhalant intoxication signs and available treatment. The sixth section examines the health effects, intoxication, and treatment of nitrites. The seventh section reviews current intervention strategies. Finally, we propose a research agenda to promote the study of (a) solvents other than toluene; (b) inhalant mixtures; (c) effects in combination with other drugs of abuse; (d) age and (e) sex differences in inhalant effects; (f) the long-lasting behavioral effects of animals exposed in utero to inhalants; (g) abstinence signs and neurochemical changes after interrupting inhalant exposure; (h) brain networks involved in inhalant effects; and finally (i) strategies to promote recovery of inhalant users.

Opioid use during pregnancy can impair maternal behavior and the Maternal Brain Network: A literature review.

Opioid Use Disorder (OUD) is a global epidemic also affecting women of reproductive age. A standard form of pharmacological treatment for OUD is Opioid Maintenance Therapy (OMT) and buprenorphine has emerged as the preferred treatment for pregnant women with OUD relative to methadone. However, the consequences of BUP exposure on the developing Maternal Brain Network and mother-infant dyad are not well understood. The maternal-infant bond is dependent on the Maternal Brain Network, which is responsible for the dynamic transition from a "nulliparous brain" to a "maternal brain". The Maternal Brain Network consists of regions implicated in maternal care (e.g., medial preoptic area, nucleus accumbens, ventral pallidum, ventral tegmentum area) and maternal defense (e.g., periaqueductal gray). The endogenous opioid system modulates many of the neurochemical changes in these areas during the transition to motherhood. Thus, it is not surprising that exogenous opioid exposure during pregnancy can be disruptive to the Maternal Brain Network. Though less drastic than misused opioids, OMTs may not be without risk of disrupting the neural and molecular structures of the Maternal Brain Network. This review describes the Maternal Brain Network as a framework for understanding how pharmacological differences in exogenous opioid exposure can disrupt the onset and maintenance of the maternal brain and summarizes opioid and OMT (in particular buprenorphine) use in the context of pregnancy and maternal behavior. This review also highlights future directions for evaluating exogenous opioid effects on the Maternal Brain Network in the hopes of raising awareness for the impact of the opioid crisis not only on exposed infants, but also on mothers and subsequent mother-infant bonds.