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Poverty threatens child health. In the United States, financial strain, which encompasses income and asset poverty, is common with many complex etiologies. Even relatively successful antipoverty programs and policies fall short of serving all families in need, endangering health. We describe a new approach to address this pervasive health problem: antipoverty medicine. Historically, medicine has viewed poverty as a social problem outside of its scope. Increasingly, health care has addressed poverty's downstream effects, such as food and housing insecurity. However, strong evidence now shows that poverty affects biology, and thus, merits treatment as a medical problem. A new approach uses Medical-Financial Partnerships (MFPs), in which healthcare systems and financial service organizations collaborate to improve health by reducing family financial strain. MFPs help families grow assets by increasing savings, decreasing debt, and improving credit and economic opportunity while building a solid foundation for lifelong financial, physical, and mental health. We review evidence-based approaches to poverty alleviation, including conditional and unconditional cash transfers, savings vehicles, debt relief, credit repair, financial coaching, and employment assistance. We describe current national MFPs and highlight different applications of these evidence-based clinical financial interventions. Current MFP models reveal implementation opportunities and challenges, including time and space constraints, time-sensitive processes, lack of familiarity among patients and communities served, and sustainability in traditional medical settings. We conclude that pediatric health care practices can intervene upon poverty and should consider embracing antipoverty medicine as an essential part of the future of pediatric care.

Advancing Health Equity Through Innovations and Technology This year’s summit was unique given the COVID-19 pandemic: a major global outbreak that has imposed severe restrictions in all aspects of our life. At the outset, we were faced with three mutually exclusive options. First option was to cancel the summit in its entirety: this was the easiest and most obvious choice once the COVID-19 pandemic forced a near total lockdown all over the country with unprecedented disruptions of normal daily activities as the disease announced its thunderous touchdown on United States (US) soil. It was also the most-logical response faced with uncertainty regarding summit logistics and expected poor attendance due to the raging pandemic. Second option was to conduct a digital summit restricted to local audiences at Baylor College of Medicine: this option entailed implementing a virtual summit with attendance restricted to participants from our institution only. It sounded like a reasonable choice but that would impede the presence of diversity of topics, perspectives, insights and experiential learning opportunities, which are what render the summit exciting and worth attending. And finally, the last option was to conduct a digital unrestricted summit open to all interested audiences throughout the US. The conduct of a virtual summit open to all participants from around the country was initially considered daunting given the likelihood of amplified technical problems associated with an array of internet access differentials around the country, which would require a strong Information Technology (IT) presence throughout the sessions. Nonetheless, the attractiveness of going national with a virtual summit, despite the pandemic and logistical challenges, slowly gained converts and became the dominant choice. The response and level of participation in this first virtual summit showed an unanticipated surge despite the increase in registration fees to cover IT costs. This year, we had attendees from all regions of the US as well as from the United Kingdom. The range of topics was quite diverse encompassing health disparities in relation to cancers, nutrition, musculo-skeletal disorders, amputation rates, vaccination uptakes and COVID-19 infections. Various solutions were passionately presented to address these disparities including novel health technologies, community engagement and partnerships, improvement in health literacy and alternative therapeutics. There were no hitches despite the complex breakout sessions, and above all, attendees were satisfied and offered outstanding evaluation scores. This was definitely a summit that metamorphosed from pessimism to a triumphant success! Copyright © 2020 Salihu et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

The non-offending caregiver (NOC) population is under studied despite their role in the recovery of child victim-survivors of sexual abuse. Research suggests that NOCs experience significant distress following a child's disclosure of sexual abuse. Trauma has been demonstrated to negatively impact the caregiver-child relationship. This study informs about common NOC stress reactions in response to child sexual abuse (CSA) disclosures and has clinical implications for treating families affected by CSA. Participants included 66 NOCs (age 23-66, M = 41.09, SD = 10.26) who participated in clinical intakes at a CSA treatment program and completed a self-report measure of parenting stress. Depending on the child's age, NOCs were administered either the Parenting Stress Index-fourth edition, Short Form (PSI-4-SF) or the Stress Index for Parents of Adolescents (SIPA). NOCs reported higher than average parenting stress. Statistically significant differences between the clinical and normative samples were found on all PSI-4-SF domains and on majority of SIPA domains. High to Clinically Significant scores were reported by 42% of NOCs for Parent-Child Dysfunctional Interaction. Stress related to their child's social withdrawal was reported by 56% of NOCs. This study provides comparison data for evaluations of NOCs. NOCs may require treatment and family-based approaches are implicated.

214 Background: A wealth of published data exists highlighting the benefits of alternative and supportive therapies when used in combination with traditional medical approaches for individuals diagnosed with cancer. Many physical and emotional symptoms, along with quality of life, can be improved through exercise, artistic expression, mind-body practices and support group participation. While many of these services are offered through healthcare systems or large national foundations, fewer community-run organizations exist. The Gather Place (TGP) uniquely serves the Greater Cleveland area at two stand-alone locations. A wide variety of programs and services are offered, free-of-charge, to those affected by cancer. Since spring of 2020, most services have been provided virtually due to the COVID-19 pandemic. While few studies have evaluated predictors of support group utilization, there is limited data on the demographics of participants at individual support communities. Methods: De-identified, retrospective data was gathered from 04/01/2021 to 03/31/2022. Participant data including age, gender, ethnicity, residential zip code, cancer type, treatment center, date of first attendance, programs attended, and frequency of program attendance were collected and analyzed. Results: 1,494 participants with cancer utilized services at TGP with varying rates of unknown data among each category. Educational opportunities, support groups and one-on-one emotional support sessions were most frequently attended. Female involvement was greater than males (83.9% v. 15.7%), with higher participation among Caucasians compared to African Americans (79.5% v. 16.2%). 67.1% of participants resided in zip codes above the median household income of Cuyahoga County. Participants with breast and gynecologic cancers made up the majority (44.3% & 10.1%), while those with cutaneous, head/neck and hepatobiliary malignancies comprised the smallest distribution (1.6%, 1.7% & 1.8%). Conclusions: TGP is a unique organization unaffiliated with a major healthcare system providing nutrition, fitness, healing arts, education and individual/group support programs. Despite a high incidence of prostate and lung cancer diagnoses in Northeast Ohio, participants with these malignancies were a small percentage of total attendees, differing from the high disease incidence and program participation seen in patients with breast cancer. As information was gathered solely during the COVID-19 pandemic when program delivery shifted to the virtual setting, racial or income disparities reported here may reflect similar disparities seen in tele-health during the pandemic. The gaps in utilization we identified highlight opportunities for targeted areas of improved education and referral.

Background: Prior to COVID-19, two out of ve people in the US could not cover a $400 emergency Now,many more families are struggling nancially Families with low income often don't seek needed healthcare,risking poor health outcomes Minority families, in particular, suffer health inequities stemming fromdisparities in social capital, income, and education Higher education improves long-term economic success,but low-income families have difficulty saving for their children's futures Children's Savings Account (CSA)programs, which provide higher education savings to children in early childhood, have increased families'college expectations and improved mothers' mental health and children's socio-emotional development Methods: We assessed parents' perceptions of and access to preventive healthcare, as well as the educationalgoals they have for their children We conducted qualitative interviews with 13 parents meeting the followingcriteria: (1) at least one child age 3 or younger, (2) maximum income at 185% of the federal poverty level, and(3) no parent with an advanced degree (e g master's) We will interview seven more parents by December 2020 Meanwhile, we designed Early Bird, a rst-of-its-kind health clinic-based CSA program that rewardsfamilies for achieving healthy milestones-such as attending pediatrician and dentist appointments, meetingwith a nancial coach, and enrolling in pre-Kindergarten-with scholarship funds in their children's CSAs Weare launching a 3-year longitudinal randomized study to evaluate this novel model Results: All parentsinterviewed would participate in a milestone-based CSA program through their health clinic All hoped theirchild(ren) would attend college, 85% perceived nancial barriers to higher education, and 69% worried thatnot attending college would limit their child's career Only 23% of participants had savings for college Participants' self-described ethnicities were 85% Hispanic or Latino, 7 5% Black or African American, 7 5%American Indian or Alaska Native, and 7 5% White/Caucasian (1) Philanthropic funds were raised to supportthe launch of Early Bird's pilot serving 300 children, including scholarships up to $500 per child Contractedpartners include a federally-qualied health center, a nancial coaching service provider, a 529 accountmanagement system provider, and a local nonprot that will administer the scholarship accounts Theprogram will launch in 2020 Discussion: Parents with low income desire higher education for their childrenbut struggle to save money This new model aligns short-term achievements during early childhood in health,education, and family nances with long-term goals for higher education and career success This studyinforms a replicable model with potential to improve health, education, and nancial outcomes nationally Early Bird aligns many milestone achievements with the priorities of health insurance payers, which may aidlong-term nancial sustainability Feasibility studies are needed to further assess the model's viability indiffering clinical settings (1) Totals more than 100% due to multi-select answer format

We have been using the Inbred Long- and Short-Sleep mouse strains (ILS, ISS) and a recombinant inbred panel derived from them, the LXS, to investigate the genetic underpinnings of acute ethanol tolerance which is considered to be a risk factor for alcohol use disorders (AUDs). Here, we have used RNA-seq to examine the transcriptome of whole brain in 40 of the LXS strains 8 hours after a saline or ethanol "pretreatment" as in previous behavioral studies. Approximately 1/3 of the 14,184 expressed genes were significantly heritable and many were unique to the pretreatment. Several thousand cis- and trans-eQTLs were mapped; a portion of these also were unique to pretreatment. Ethanol pretreatment caused differential expression (DE) of 1,230 genes. Gene Ontology (GO) enrichment analysis suggested involvement in numerous biological processes including astrocyte differentiation, histone acetylation, mRNA splicing, and neuron projection development. Genetic correlation analysis identified hundreds of genes that were correlated to the behaviors. GO analysis indicated that these genes are involved in gene expression, chromosome organization, and protein transport, among others. The expression profiles of the DE genes and genes correlated to AFT in the ethanol pretreatment group (AFT-Et) were found to be similar to profiles of HDAC inhibitors. Hdac1, a cis-regulated gene that is located at the peak of a previously mapped QTL for AFT-Et, was correlated to 437 genes, most of which were also correlated to AFT-Et. GO analysis of these genes identified several enriched biological process terms including neuron-neuron synaptic transmission and potassium transport. In summary, the results suggest widespread genetic effects on gene expression, including effects that are pretreatment-specific. A number of candidate genes and biological functions were identified that could be mediating the behavioral responses. The most prominent of these was Hdac1 which may be regulating genes associated with glutamatergic signaling and potassium conductance.

This study evaluated the use of short-scrotum castration to create sterile ram lambs. East Friesian x Lacaune male lambs born in February on a commercial sheep dairy were left intact (n = 19; IN) or rendered short-scrotum (n = 17; SS) within 10 d of birth. At 3 mo of age lambs were transferred to the study site and grazed as one group, while being supplemented with a grain mixture at 0.7 kg/d. Lambs were harvested at 6 mo of age, and reproductive tract of 5 IN and 5 SS lambs collected at random and shipped cold overnight for processing. Testis and epididymis were weighed. Segments of the left testis and epididymis were processed for histology, while a subsample of testicular parenchyma and epididymal segments of the right side were used to determine sperm reserves by tissue homogenization. Differences between testis types were determined using GLM of SAS. Testes and epididymal weights were reduced (P < 0.001) in SS (115 and 22 g) compared to IN (364 and 50 g) lambs. Seminiferous tubule diameter was also smaller (P < 0.001) in SS (142 µm) than IN (234 µm) lambs. Daily sperm production per gram testicular parenchyma (DSPG) was not different between types (3.8 vs. 2.3 million sperm/g; P = 0.06), but total daily sperm production was lower (P < 0.01) in SS (0.23 billion) than IN (1.34 billion) ram lambs. Considerable variation was noted in DSPG in IN lambs suggesting still incomplete development at this age, and accounting for the lack of a significant difference. Epididymal sperm reserves were markedly reduced (P < 0.001) in SS (0.1 billion) compared to IN (10.5 billion), and decreased along the epididymis, supported by evidence of phagocytic action by the epididymal epithelium. Data suggest that ram lambs rendered short-scrotum shortly after birth develop smaller testes with reduced sperm production, making them effectively infertile.

Short-scrotum (induced cryptorchid) rams can retain growth and performance characteristics of intact-rams while making them sterile and facilitating co-grazing with ewe-lambs. East Friesian x Lacaune male lambs left intact (n = 19; IN), rendered short-scrotum (n = 17; SS) or neutered (n = 25; WE) by 10 d of age, were used to evaluate libido and semen quality at 7-mo old. Lambs were managed as one group on a forage-based diet supplemented with a grain mixture (barley and soybean meal at 0.7 kg/d). Four CIDR-treated estrus-induced ewes were placed two/pen in adjacent 2.5x2.5 m pens for libido testing. Males were introduced individually to ewe pens for 5 min and reproductive behaviors recorded (anogenital sniffs, foreleg kicks, flehmen, false mounts, and service). Semen was collected from 6 random IN and SS lambs via artificial vaginas using estrus-induced ewes as teasers. Volume was recorded, and ejaculate extended in milk/egg yolk, packaged into straws, and stored at 5°C for analysis with a CASA system the following day. Behavior measurements were compared between types using PROC GLM. Ejaculate characteristics are presented as mean±SD due to insufficient sperm concentrations of SS ejaculates. Anogential sniffs, foreleg kicks, and mounts were similar in IN and SS, and higher (P < 0.05) than in WE (7.44 and 6.34 vs. 4.76; 1.72 and 1.60 vs. 0.17; 1.78 and 2.05 vs. 0.22; respectively). Number of services were higher (P < 0.001) in IN than SS (1.11 vs. 0.53), but time to service (112 sec) was not different. Ejaculate volume was similar in IN and SS (0.51 mL), but SS ejaculates were essentially devoid of sperm. Ejaculates from IN lambs had 0.69x109±0.48 x109 sperm, with 68.9±12.5% progressive motility, 81.8±6.1% viability and 87.1±6.1% morphologic normality. Ram lambs rendered short-scrotum by 10 d of age had reproductive behavior similar to intact post-pubertal rams, but ejaculate characteristics showed them to be sterile

This was the second year of a study comparing the growth and carcass characteristics of (intact) ram, wether, and short-scrotum lambs from a commercial sheep dairy in Maryland. East Friesian x Lacaune lambs were left intact (RAM, n = 21), castrated (WETHER, n = 25), or made short-scrotum (SS, n = 18). All banding of WETHER and SS lambs was done by d 10. When the lambs averaged 65±17 d and 44.5±10.6 lbs., they were transported to the Western Maryland Research & Education Center, where they grazed cool season pastures and were supplemented with grain (3 lb/d) for 107 d, before being harvested to collect carcass data. Data were analyzed using the MIXED procedure of SAS, with statistical significance set at P ≤ 0.05. Fixed effects included sex and birth type; starting weight was included as a covariate. There was an effect of birth type on final BW, ADG, HCW, CCW, and body wall thickness (BWT), favoring twin-born lambs. RAM and SS lambs had heavier final BW (P < 0.0001) and ADG (P < 0.0001) than WETHER lambs. RAM lambs had heavier hot (P < 0.01) and cold carcass (P < 0.005) weights than WETHER lambs; SS lambs were intermediate. Dressing percentage was higher (P < 0.004) for WETHER lambs and similar for RAM and SS lambs. RAM and SS lambs had larger REA than WETHER lambs (P < 0.03), but not when adjusted to a common weight (P < 0.71). WETHER lambs produced the fattest carcasses, as evidenced by greater BF (3.8±0.2 mm) than RAM and SS lambs (2.2±0.2 mm and 2.7±0.2 mm, respectively). Sex did not influence BWT, KPH, or leg conformation score. RAM lambs yielded a higher percentage of BCTRC (49.9±0.2%) than WETHER lambs (49.1±0.2%); SS lambs were intermediate (49.6±0.3%). For the second year in a row, RAM and SS lambs demonstrated superior growth and carcass composition compared to WETHER lambs.

e24052 Background: We conducted an exercise study to IMPROVE health outcomes in older breast cancer survivors (BCS) from diverse racial and socioeconomic backgrounds. Here, we report cohort recruitment strategies and baseline characteristics. Methods: ‘IMPROVE’ is a randomized trial, designed to evaluate a group-based exercise intervention compared to support group. Participants were ≥ 65 years, had stage I-III breast cancer and within five years of treatment completion. Enrollment target was 220 participants, 25% in each of four strata defined by race (AA versus Non-Hispanic Whites [NHW]) and SES (low vs. high). Participants were recruited through hospital-based tumor registries, the state tumor registry or direct referrals. Results: Between October 2016 and November 2019, 7487 patients were screened, 4790 were potentially eligible, 230 were consented and 213 randomized into the study. The Eligible-to-Randomization rates were 4.4% overall, and 84%, 8%, and 2% for recruitment utilizing direct referrals, hospital and state registries, respectively. Median age of the randomized cohort was 70 years (range: 65-88 years) and included 25% AA/Low SES, 20% AA/High SES, 19% NHW/Low SES and 36% NHW/High SES Older BCS. Compared with registry-eligible patients, directly referred patients were more likely to be AA vs. NHW (41% vs. 19%, p = 0.003) and to accept study participation (88% vs. 16%, p < 0.0001). Conclusions: Direct referrals resulted in the highest recruitment yield and was the most effective strategy for recruiting AA patients. Behavioral intervention studies seeking to target older BCS from racial minority and SES disadvantaged backgrounds should focus on strategies that foster direct referrals to study participation. Clinical trial information: NCT02763228 .

Gastro-intestinal parasites, especially Haemonchus contortus, limit the profitability and expansion of the meat goat industry in many states. The objective of the Western MD Pasture Based Meat Goat Production test was to evaluate the performance of meat goat bucklings (mostly Kiko and Kiko crosses), consuming a pasture-based diet, with natural exposure to gastro-intestinal parasites. From 2006–2016, the FAMACHA© system was used to determine need for deworming (scores of 4 and 5) in all kids. Therefore, goats were handled bi-weekly to determine body weights (BW), FAMACHA© scores (FAM) and fecal egg counts (FEC) in eggs per gram (epg), as well as other possible indicators of internal parasitism. Adjacent FAMACHA© scores were used to form 3 groups; kids not requiring treatment (FAM1; FAM 1 and 2), kids intermediate (FAM 3) and kids requiring treatment (FAM 5; FAM 4 and 5). Differences in mean log-transformed FEC (LFEC) and ADG were determined using the PROC MIXED procedure of SAS and included year, FAMACHA© score and FAMACHA© score by year interaction effects. There was an exponential increase in LFEC and decrease in ADG with increasing FAM score groups for most years of the test. LFEC were significantly different for FAM1, FAM3, and FAM5 groups (P

A pasture-based meat goat performance test was conducted at the University of Maryland’s Western Maryland Research & Education Center (39º 30’ N/77º 44’ W) from 2007–2016. The purpose of the test was to evaluate the performance of meat goat bucklings (mostly Kiko and Kiko crosses), consuming a pasture-based diet, with natural exposure to gastro-intestinal parasites. While on test, the goats were handled bi-weekly to determine body weights (BW), FAMACHA© scores (FAM) and body condition (BCS) scores. Coat condition (COAT), dag (DAG) and diarrhea scores (DISCO) and deworming frequency (TX) were also recorded from 2012–2016. Fecal samples were collected bi-weekly to determine individual fecal eggs counts (FEC; 2007–2016) and pooled samples were collected every 28 days for larvae ID (2009–2016). Data came from 811 meat goat kids representing 100 herds in 20 states. Residual correlations among log-transformed FEC (LFEC), FAMACHA© scores, BW, ADG, BCS, coat condition, dag and fecal consistency scores were determined. In addition, deworming frequency by year was determined by PROC FREQ in SAS. The predominant genera of gastrointestinal nematode cultured was Haemonchus contortus ranging from 70–95% over the 10-yrs. Overall, residual correlations (r) of FAMACHA scores with ADG (-0.15), LFEC (0.24), BCS (-0.09), COAT (-0.06), DAG (0.12) and DISCO (0.04) were significant (P

Background We previously reported that acute functional tolerance (AFT) to the hypnotic effects of alcohol was significantly correlated with drinking in the dark (DID) in the LXS recombinant inbred panel, but only in mice that had been pretreated with alcohol. Here, we have conducted quantitative trait locus (QTL) mapping for AFT. DNA sequencing of the progenitor ILS and ISS strains and microarray analyses were also conducted to identify candidate genes and functional correlates. Methods LXS mice were given either saline or alcohol (5 g/kg) on day 1 and then tested for loss of righting reflex AFT on day 2. QTLs were mapped using standard procedures. Two microarray analyses from brain were conducted: (i) naive LXS mice and (ii) an alcohol treatment time course in the ILS and ISS. The full genomes of the ILS and ISS were sequenced to a depth of approximately 30×. Results A significant QTL for AFT in the alcohol pretreatment group was mapped to distal chromosome 4; numerous suggestive QTLs were also mapped. Preference drinking and DID have previously been mapped to the chromosome 4 locus. The credible interval of the significant chromosome 4 QTL spanned 23 Mb and included 716 annotated genes of which 150 had at least 1 nonsynonymous single nucleotide polymorphism or small indel that differed between the ILS and ISS; expression of 48 of the genes was cis-regulated. Enrichment analysis indicated broad functional categories underlying AFT, including proteolysis, transcription regulation, chromatin modification, protein kinase activity, and apoptosis. Conclusions The chromosome 4 QTL is a key region containing possibly pleiotropic genes for AFT and drinking behavior. Given that the region contains many viable candidates and a large number of the genes in the interval fall into 1 or more of the enriched functional categories, we postulate that many genes of varying effect size contribute to the observed QTL effect.

The ILSXISS (LXS) recombinant inbred (RI) panel of mice is a valuable resource for genetic mapping studies of complex traits, due to its genetic diversity and large number of strains. Male and female mice from this panel were used to investigate genetic influences on alcohol consumption in the “drinking in the dark” (DID) model. Male mice (38 strains) and female mice (36 strains) were given access to 20 % ethanol during the early phase of their circadian dark cycle for four consecutive days. The first principal component of alcohol consumption measures on days 2, 3, and 4 was used as a phenotype (DID phenotype) to calculate QTLs, using a SNP marker set for the LXS RI panel. Five QTLs were identified, three of which included a significant genotype by sex interaction, i.e., a significant genotype effect in males and not females. To investigate candidate genes associated with the DID phenotype, data from brain microarray analysis (Affymetrix Mouse Exon 1.0 ST Arrays) of male LXS RI strains were combined with RNA-Seq data (mouse brain transcriptome reconstruction) from the parental ILS and ISS strains in order to identify expressed mouse brain transcripts. Candidate genes were determined based on common eQTL and DID phenotype QTL regions and correlation of transcript expression levels with the DID phenotype. The resulting candidate genes (in particular, Arntl/Bmal1) focused attention on the influence of circadian regulation on the variation in the DID phenotype in this population of mice.

It has been well documented that genetic factors can influence predisposition to develop alcoholism. While the underlying genomic changes may be of several types, two of the most common and disease associated are copy number variations (CNVs) and sequence alterations of protein coding regions. The goal of this study was to identify CNVs and single-nucleotide polymorphisms that occur in gene coding regions that may play a role in influencing the risk of an individual developing alcoholism. Toward this end, two mouse strains were used that have been selectively bred based on their differential sensitivity to alcohol: the Inbred long sleep (ILS) and Inbred short sleep (ISS) mouse strains. Differences in initial response to alcohol have been linked to risk for alcoholism, and the ILS/ISS strains are used to investigate the genetics of initial sensitivity to alcohol. Array comparative genomic hybridization (arrayCGH) and exome sequencing were conducted to identify CNVs and gene coding sequence differences, respectively, between ILS and ISS mice. Mouse arrayCGH was performed using catalog Agilent 1 × 244 k mouse arrays. Subsequently, exome sequencing was carried out using an Illumina HiSeq 2000 instrument. ArrayCGH detected 74 CNVs that were strain-specific (38 ILS/36 ISS), including several ISS-specific deletions that contained genes implicated in brain function and neurotransmitter release. Among several interesting coding variations detected by exome sequencing was the gain of a premature stop codon in the alpha-amylase 2B (AMY2B) gene specifically in the ILS strain. In total, exome sequencing detected 2,597 and 1,768 strain-specific exonic gene variants in the ILS and ISS mice, respectively. This study represents the most comprehensive and detailed genomic comparison of ILS and ISS mouse strains to date. The two complementary genome-wide approaches identified strain-specific CNVs and gene coding sequence variations that should provide strong candidates to contribute to the alcohol-related phenotypic differences associated with these strains.

Sixty male lambs (East Friesian x Lacaune) from a commercial sheep dairy were used to compare growth and carcass characteristics of short-scrotum (SS), ram (R), and wether (W) lambs. By d 10, every third single, twin, and triplet male was left entire (ram, n = 19), castrated (n = 24), or made short-scrotum (n = 17). After weaning and transport to the Western Maryland Research & Education Center, lambs were maintained as a single group on pasture, with supplemental feeding at 2–3% of BW. Lambs were weighed biweekly. Ultrasonic measurements were determined at d 102. The lambs were slaughtered at d 110. Growth and carcass data were analyzed using PROC GLM and carcass data correlations with PROC CORR. SS lambs had heavier final BW (53.5±1.0 kg) and higher ADG (0.25±0.001 kg/d) than W lambs (50.2±0.6 kg and 0.22±0.001 kg/d, respectively). R lambs were intermediate (51.6±1.0 kg and 0.23±0.001 kg/d, respectively). Sex did not influence ultrasonic backfat (BF), but there was a tendency to influence rib eye area (REA), with W lambs REA smaller than both R and SS lambs (P = 0.07). There was no influence of sex on dressing percentage, body wall thickness, REA, percent kidney and heart fat, leg conformation, or percent boneless closely trimmed retail cuts. There was a tendency (P = 0.10) for SS lambs to have heavier HCW (26.3±0.6 kg) compared to R (24.8±0.6 kg) and W lambs (24.7±0.25 kg). W lambs were fatter (P < 0.02), having greater BF (3.8 ± 0.6 mm) and yield grade (1.9 ± 0.1) than SS (3.0±0.6 mm and 1.6±0.1, respectively) and R lambs (2.8±0.6 mm and 1.5±0.1, respectively). There was strong correlation between ultrasonic and actual carcass measurements (r = 0.7, P < 0.0001), except for REA in SS lambs (r = 0.4; P = 0.1). Compared to W lambs, SS lambs had superior growth and produced leaner carcasses. The short-scrotum procedure may offer a viable alternative to castration.

In prior work, congenic strains carrying the DBA/2Igb (D2) region of chromosome 2 (Chr2) for alcohol preference were bred onto a C57BL/6Ibg (B6) background and as predicted were found to reduce voluntary consumption. Subsequently, interval-specific congenic recombinant strains (ISCRS) were generated and also tested. These ISCRS strains reduced the quantitative trait loci (QTL) interval to a comparatively small 3.4 Mb region. Here, we have exploited an integrative approach using both murine and human populations to critically evaluate candidate genes within this region. First, we used bioinformatics tools to search for genes relevant to alcohol preference within the QTL region. Second, we searched for single nucleotide polymorphisms (SNPs) within exons of every gene in this region. Third, we conducted follow-up microarray analyses to identify differentially expressed genes between the B6 and ISCRS strains in mice from each group. Fourth, we analyzed correlations between the expression level of candidate genes and phenotypes of alcohol preference in a large family of BXD recombinant inbred strains derived from B6 and D2. Finally, we evaluated SNP segregation in both BXD mouse strains and in humans who were heavy alcohol drinkers or non-drinkers. Among several potential candidate genes in this region, we identified activating transcription factor 2 (Atf2) as the most plausible gene that would influence alcohol preference. However, the candidacy of Atf2 was only weakly supported when we used a genetic network approach and by focused reanalysis of genome-wide association study data from European-American and African-American populations. Thus, we cannot conclude that Atf2 plays a role in the regulation of the QTL of mouse Chr2.

The US meat goat industry lags behind other livestock industries in the use of quantitative genetic evaluation. The Western Maryland Pasture-Based Meat Goat Performance Test was initiated in 2006 at the University of Maryland’s Western Maryland Research & Education Center (39º 30’ N/77º 44’ W). The purpose of the test was to identify genetically-superior meat goat bucks, especially those which exhibited resistance and resilience to internal parasites. From 2006–2016, 736 bucklings, of various breeds and crosses, were evaluated. One hundred producers from 20 states consigned one or bucks. Bi-weekly progress reports, summaries, and other information and data were shared via a blog (https://mdgoattest.blogspot.com), which has 218,346 cumulative page views from 523 blog posts. Many other programs were held in conjunction with the test, including sales, field days, youth programs, and carcass evaluation. Each year, top-performing bucks were identified and sold or retained for breeding, with 86% of consigners using the genetics from top-performing bucks in their breeding programs. Many more producers used the genetics from top-performing bucks by purchasing breeding stock and/or semen from consigners. Per survey data, consigning to the Maryland test improved the reputation of participating herds (80%), increased the demand and selling price for breeding stock (66–72%), and enabled the sale of semen from top-performers (38%). The test enabled participating producers to develop more parasite resistant herds (76%), improve the health and performance of their herds (73%), and improve their knowledge of parasite control (80%). The Western Maryland Pasture-Based Meat Goat Performance Test provided economic value to producers (71%), while contributing to the genetic improvement of the meat goat industry and serving as a valuable resource to producers.

The identification of genes that contribute to polygenic (complex) behavioral phenotypes is a key goal of current genetic research. One approach to this goal is to combine gene expression information with genetic information, i.e., to map chromosomal regions that regulate gene expression levels. This approach has been termed “genetical genomics”, and, when used in conjunction with the identification of genomic regions (QTLs) that regulate the complex physiological trait under investigation, provides a strong basis for candidate gene discovery. In this paper, we describe the implementation of the genetical genomic/phenotypic approach to identify candidate genes for sensitivity to the analgesic effect of morphine in BXD recombinant inbred mice. Our analysis was performed “in silico”, using an online interactive resource called PhenoGen (http://phenogen.ucdenver.edu). We describe in detail the use of this resource, which identified a set of candidate genes, some of whose products regulate the cellular localization and activity of the mu opiate receptor. The results demonstrate how PhenoGen can be used to identify a novel set of genes that can be further investigated for their potential role in pain, morphine analgesia and/or morphine tolerance.

Most reading disabilities can be traced to difficulties acquiring oral language during preschool years due to insufficient linguistic stimulation. The present 2-year project aimed to improve the literacy-related oral language skills of 48 low-income, primarily ELL 4-year-old children in local public preschool by providing for individual conversational experiences with trained university students. Their results were compared to 48 peers at two comparable preschools. Children were tested in the fall and spring on multiple measures. Throughout the year, intervention children met with volunteers each week (26 weeks) for 20 minutes to dictate personal narratives. The control group received the regular public school preschool curriculum only. The improvement of intervention children on multiple measures of oral language ability—notably vocabulary and quality of narrative—was significantly greater than that of their peers.

Measures of genetic relatedness are essential to models of evolution by kin selection and determinations of inclusive fitness. Under a kin selection paradigm, individuals are expected to distribute actions influencing the fitness of relatives based on the relatedness of these relatives. In addition, it is necessary to have an accurate measure of relatedness to estimate heritability (h2) of phenotypic characters and to predict the efficacy of selection. Relatedness is often defined as the genotypic correlation between individuals. Assessed on the basis of common ancestry, relatedness can only be determined sensu strictu from pedigree analysis. Recent methodological and statistical advances allow the estimation of relatedness from allele frequency data. Many coefficients of relatedness can be found in the literature; I review and evaluate these, with emphasis on situations for which each is appropriate.

Interval-specific congenic strains (ISCS) allow fine mapping of a quantitative trait locus (QTL), narrowing its confidence interval by an order of magnitude or more. In earlier work, we mapped four QTL specifying differential ethanol sensitivity, assessed by loss of righting reflex because of ethanol (LORE), in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, accounting for approximately 50% of the genetic variance for this trait. Subsequently, we generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa. An earlier paper reported construction and results of the ISCS on the ISS background; here, we describe this process and report results on the ILS background. We developed multiple ISCS for each Lore QTL in which the QTL interval was broken into a number of smaller intervals. For each of the four QTL regions (chromosomes 1, 2, 11 and 15), we were successful in reducing the intervals significantly. Multiple, positive strains were overlapped to generate a single, reduced interval. Subsequently, this reduced region was overlaid on previous reductions from the ISS background congenics, resulting in substantial reductions in all QTL regions by approximately 75% from the initial mapping study. Genes with sequence or expression polymorphisms in the reduced intervals are potential candidates; evidence for these is presented. Genetic background effects can be important in detection of single QTL; combining this information with the generation of congenics on both backgrounds, as described here, is a powerful approach for fine mapping QTL.

BACKGROUND Acute functional tolerance (AFT) develops shortly after ethanol administration, and is determined as the change in brain or blood ethanol concentration (BEC) measured at 2 behavioral or physiological endpoints. Acute functional tolerance studies in some rodent strains support a long-held hypothesis that more sensitive strains develop more within-session tolerance. We used the new, 74-strain L x S recombinant inbred (RI) panel, developed from inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, to revisit this hypothesis and to map quantitative trait loci (QTLs) for AFT. We report replication of QTL regions reported by earlier studies of AFT and preliminary application of a coarse single nucleotide polymorphism map analysis to limit QTL intervals for subsequent candidate gene hypotheses. METHODS Acute functional tolerance was assayed using a test of ataxia: loss and regain of balance on a stationary wooden dowel. Following an initial dose of 1.75 g/kg, BEC was measured at initial loss (BEC(0)) and regain of balance (BEC(1)). A second injection (2.0 g/kg) was administered and blood taken at the second regain of balance (BEC(2)). Acute functional tolerance was calculated as a difference score in 2 ways: (1) between BEC at the 2 successive regains of balance (AFT(1)), or (2) as the difference in BEC at final regain and at initial loss of balance (AFT(2)). We mapped QTLs for BEC(0), a measure of initial sensitivity, and both AFT scores. RESULTS All 4 parental strains (LS, SS, ILS, and ISS) developed tolerance, replicating previous published reports. There were significant sex effects for 3 of these strains. The L x S panel showed a 128-fold range in tolerance, with a few strains showing negative tolerance (sensitization). The ISS surpassed the next highest RI strain by 55% and was more than 4 times greater than SS. Heritability estimates for both AFT measures were close to 0.25 for both sexes. One significant QTL accounting for approximately 18% of phenotypic variance (V(P)), on chromosome 12 (AFT(1)), and 1 suggestive QTL (16% V(P)), on chromosome 16 (AFT(2)), were identified. These QTLs replicated regions reported in other studies. A multiple QTL model incorporating the effects of all significant interacting QTLs was developed, explaining almost 60% of V(P). The chromosome 12 region was further investigated by haplotype analysis, which identified many nonpolymorphic regions within the confidence interval, and possible candidate genes in the polymorphic regions. CONCLUSIONS Both SS and ISS developed greater AFT, assessed by both methods, than LS and ILS; this difference was significant in virtually all sex by strain comparisons. In the L x S RI, there was no correlation between initial sensitivity, measured by BEC at initial loss of balance, and either measure of AFT, on a stationary dowel. These results indicate that in this model system, initial sensitivity does not predict tolerance. Several QTLs for tolerance were identified; candidates in the narrowed chromosome 12 region, which has been reported in 2 other mapping studies, merit additional study.

African-American (AA) breast cancer (BCa) survivors have higher mortality rates, more comorbidities and are less likely to meet national physical activity guidelines after diagnosis compared to Caucasian BCa survivors. We previously reported that a 20-week resistance exercise intervention coupled with a support group and home walking program, conducted using facilities and personnel at a community cancer support center, in Stage I–III AA BCa survivors improved strength, fitness and circulating C-peptide levels. Here, we report our findings on changes in quality of life (QoL) and other behavioral measures associated with this 20-week intervention and, discuss findings from a qualitative analysis of semi-structured patient interviews. We found a clinically relevant improvement in QoL using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) (Baseline, B: 101.1 ± 21.5; End-of-Intervention, EOI: 108.5 ± 21.6; p = 0.05) and, a significant decrease in depression using the Beck Depression Inventory-II (B: 11.9 ± 8.1; EOI: 9.0 ± 5.5; p = 0.03). Our analysis of the patient interviews support improvements in these behavioral measures in that participants stated that they “feel better”, were “more motivated” and “uplifted” after the program. The patient interviews also provided insights to the primary motivators (e.g., social support, improvements in strength and function, weight loss) and barriers (e.g., family and health issues) in adhering to the program and provided suggestions for improving the program (e.g., incorporating nutritional and treatment related side-effect discussions). Our results suggest that community-based lifestyle interventions may improve QoL and depression in AA BCa survivors and lend insights for improving future programs.

Background: Most mouse quantitative trait loci (QTLs) for behavioral traits have been mapped using populations of mice derived from C57BL/6J (B6) and DBA/2J (D2). It is also important to identify QTLs for behavior in populations derived from other progenitors. We report results from QTL mapping for low-dose (ethanol) locomotor activation (LDA) using the recently developed LXS recombinant inbred (RI) strains, derived from Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) progenitors. The LXS RI panel has additional genetic variation, and greater power due to a larger number of strains, compared with other RI panels and strain crosses. Methods: Mice were tested using a 3-day protocol in which activity levels were monitored for 15 minutes each day. On day 1, baseline activity was recorded; on day 2, mice were injected with saline before testing; and on day 3, mice were injected with 1.8 g/kg ethanol and tested. Results: Several suggestive QTLs were found, on chromosomes 2, 3, 4, 7, 8, 12, and 13; 3 of these QTLs were sex-specific. Conclusions: Two apparently novel LDA QTLs were identified, on chromosomes 4 and 8. The other QTLs appear to replicate previously identified LDA QTLs. These replicated QTLs will be pursued in subsequent studies designed to identify candidate genes.

Animal models offer several advantages for the study of complex human disorders such as alcoholism. No animal model replicates all aspects of alcoholism but different components of the disorder can be investigated using various rodent models. In this article, we review a select subset of the most widely used mouse genetic models in alcohol research. Different genetically defined strains and stocks of mice are useful for genetic, physiologic, behavioral and pharmacological studies of this devastating disorder. In the past decade, numerous genomic regions associated with a tendency for various behavioral components of alcoholism have been identified; recent applications of new methods are shedding light on quantitative trait genes. Many of the underlying genes should be identified in the near future.

In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F(2) backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity.

Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum ( C max ) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum ( T max ) was 1.0 h for each dose. The mean elimination half-life ( t 1/2 ) was approximately 22 days. The volume of distribution ( V ) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact potygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Background The inbred long-sleep (ILS) and inbred short-sleep (ISS) strains of mice are widely studied as a model of initial sensitivity to alcohol. Recently, a large comparative DNA sequencing study of candidate genes located within the four Lore quantitative trait loci (QTLs) associated with the ethanol-induced loss of righting reflex in ILS and ISS mice has identified eight genes that contain coding region differences corresponding to amino acid changes. Here, recently developed interval-specific congenic recombinant mice (ISCRs) have been used to map these genes in relationship to newly narrowed QTL regions. Methods Regions of candidate genes containing DNA differences corresponding to previously identified amino acid changes between ISS and ILS mice were amplified from either genomic DNA or complementary DNA from ISCR mice using polymerase chain reaction. The products were purified and directly sequenced to determine the genotypes for each polymorphism. On the basis of these genotypic data, each candidate gene was determined to be located either within or outside of recently narrowed Lore QTL intervals. Results Of these eight candidates with protein-coding differences, five are now excluded from their respective Lore intervals. The other three (Znf142, Ptprn, and Znf133) have been localized to the narrowed QTL intervals. Conclusions These three central nervous system genes (Znf142, Ptprn, and Znf133) represent promising candidates for involvement in the differential sensitivity to alcohol exhibited between ILS and ISS mice. This study also demonstrates how the combination of high-throughput comparative gene sequencing and concomitant genetic fine mapping of QTL regions with ISCRs can be an effective tool for accelerating the process of moving from QTL to gene.

Background: We have identified four major genes or quantitative trait loci (QTLs) that determine duration of loss of righting reflex (LORR), induced by sedative doses of ethanol:Lore1, Lore2, Lore4, and Lore5. Together these genes explain more than 50% of the phenotypic variance for sensitivity to the sedative/hypnotic effects of ethanol between the Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) strains of mice. The derivation of these strains is reviewed here. Methods: Each QTL has been bred onto the opposite background (ILS or ISS) through 10 rounds of backcrossing by using QTL-marker-assisted counter selection to produce reciprocal congenic strains. Mice were genotyped for markers that flanked each of the QTLs. Selection for the donor at the desired QTL, and against donor markers at the other four QTLs, allowed rapid fixation of the genetic background. Phenotypic assessment in the ISS-recipient congenic strains was conducted throughout the backcross. Results: By the N5 generation, phenotypic assessments failed to detect significant effects in some sublines; these sublines were discarded and positive lines split to create new replicate sublines. In the N10, all sublines retained the phenotypic difference between heterozygotes and ISS homozygotes; however, the expected additive effect was not found in the Lore1 congenics. On the ILS background, each Lore was captured, as shown by the expected differential LORR. Two strains on the ILS background, and one on the ISS, exhibited the differential effect on blood ethanol concentration associated with the donor strain. Conclusions: Congenic strains represent an important resource for confirmation of previously identified QTLs, for identification and mapping of additional phenotypes, and for exclusion of candidate genes. QTL-marker-assisted selection rapidly stabilized the genetic background within four generations (based on phenotypic assessments); however, phenotypic selection during the backcrossing to generate congenic strains did not contribute to the successful capture of the ISS QTLs.

Background: Low-dose ethanol-induced activation (LDA) and initial sensitivity to alcohol are both predictors of alcohol abuse in human populations. Our hypothesis is that one or more genes specifying hypnotic sensitivity also specify LDA. We tested this hypothesis by using congenic mice derived from the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, which carry an ILS region introgressed onto an ISS background. Methods: LDA was assessed by assigning mice randomly to receive one of five doses of ethanol ranging from 1.2 to 2.4 g/kg. On day 1, animals were injected with saline and placed in a brightly lit activity monitor for 30 min, after which they were returned to their home cages. On day 2, mice were injected with ethanol (20% w/v), their activity was monitored for a 30-min period, and LDA was determined by subtracting day 1 activity. The blood ethanol concentration of each animal was then assessed at 30 min by retro-orbital collection of 25 μl of blood. Results: Ethanol had a significant effect on the activity of ISS mice, but ILS mice showed no activation at any dose, similar to the activities of the outbred lines. All three congenic strains were activated at several doses. Lore-2 and Lore-5 were not ILS-like (less active than ISS) at any dose. In contrast, ISS.ILS-Lore-1 congenics (carrying an ILS-derived Lore-1 allele on the ISS background) were significantly less activated than the ISS controls at 1.8 and 2.4 g/kg of ethanol. Conclusions: The Lore-2 and Lore-5 congenic regions do not affect LDA. In contrast, the Lore-1 congenic region carries one or more genes specifying both initial hypnotic sensitivity to ethanol and LDA.

Low initial response to alcohol has been shown to be among the best predictors of development of alcoholism. A similar phenotypic measure, difference in initial sensitivity to ethanol, has been used for the genetic selection of two mouse strains, the Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice, and for the subsequent identification of four quantitative trait loci (QTLs) for alcohol sensitivity. We now report the application of high throughput comparative gene sequencing in the search for genes underlying these four QTLs. To carry out this search, over 1.7 million bases of comparative DNA sequence were generated from 68 candidate genes within the QTL intervals, corresponding to a survey of over 36,000 amino acids. Eight central nervous system genes, located within these QTLs, were identified that contain a total of 36 changes in protein coding sequence. Some of these coding variants are likely to contribute to the phenotypic variation between ILS/ISS animals, including sensitivity to alcohol, providing specific new genetic targets potentially important to the neuronal actions of alcohol.

Mouse strains congenic for individual quantitative trait loci (QTLs) conferring hypnotic sensitivity to ethanol were constructed by backcrossing genotypically selected ILS × ISS N2 individuals to either inbred Long Sleep (ILS) or inbred Short Sleep (ISS) mice. We used a novel ``speed congenic'' approach in which N2 mice were genotyped for markers flanking each of the five originally identified QTLs. Genotypic selection for ISS regions at four of the five QTLs, and for ILS/ISS at the fifth QTL, allowed rapid fixation of the genetic background. We call this strategy ``QTL-Marker-Assisted Counter Selection'' or QMACS. By the N4 generation, phenotypic assessments showed that in some sublines the QTL had not been captured; these sublines were discarded and positive lines split to create new replicate sublines. One QTL, on Chromosome (Chr) 8, was not confirmed. At the N8, virtually all sublines on the remaining QTLs retained the phenotypic difference between heterozygotes and ISS homozygotes. Small numbers of interim congenics were produced at the N6 and later generations in which the ILS QTL was made homozygous on the ISS background; as expected, these congenic mice showed an increased sleep time. For later backcrosses (after the N4), the parents were selected on the basis of phenotype as well as genotype. The parent-offspring correlation over all QTLs was significant, supporting the use of phenotypic selection in congenic construction.

The purpose of this study is to investigate whether expression profiles of alcoholism-relevant genes in different parts of the brain are correlated differently with those in the liver. Four experiments were conducted. First, we used gene expression profiles from five parts of the brain (striatum, prefrontal cortex, nucleus accumbens, hippocampus, and cerebellum) and from liver in a population of recombinant inbred mouse strains to examine the expression association of 10 alcoholism-relevant genes. Second, we conducted the same association analysis between brain structures and the lung. Third, using five randomly selected, nonalcoholism-relevant genes, we conducted the association analysis between brain and liver. Finally, we compared the expression of 10 alcoholism-relevant genes in hippocampus and cerebellum between an alcohol preference strain and a wild-type control. We observed a difference in correlation patterns in expression levels of 10 alcoholism-relevant genes between different parts of the brain with those of liver. We then examined the association of gene expression between alcohol dehydrogenases (Adh1, Adh2, Adh5, and Adh7) and different parts of the brain. The results were similar to those of the 10 genes. Then, we found that the association of those genes between brain structures and lung was different from that of liver. Next, we found that the association patterns of five alcoholism-nonrelevant genes were different from those of 10 alcoholism-relevant genes. Finally, we found that the expression level of 10 alcohol-relevant genes is influenced more in hippocampus than in cerebellum in the alcohol preference strain. Our results show that the expression of alcoholism-relevant genes in liver is differently associated with the expression of genes in different parts of the brain. Because different structural changes in different parts of the brain in alcoholism have been reported, it is important to investigate whether those structural differences in the brains of those with alcoholism are due to the difference in the associations of gene expression between genes in liver and in different parts of the brain.

Numerous algorithms for the identification and genetic mapping of quantitative trait loci (QTL) have been developed. Methods for confirming QTL maps involve either examination of independent segregating populations or the construction of congenic lines differing only in the QTL of interest. Because these projects require a minimum of several years or thousands of marker assessments in laboratory mice, an alternative, faster congenic method has been proposed. In a preliminary study, we tested this method for confirming QTLs identified in crosses between the ILS and ISS selected lines of mice for differential sensitivity to the hypnotic effects of ethanol. Herein, we report the construction of "segregating congenic" strains in which each QTL is made homozygous in a single generation, whereas the remainder of the genetic background is allowed to segregate. Sensitivity to ethanol among the progeny of such mice is consistent with predictions. Phenotypic variation is high, as expected, due to the background segregation, and statistical significance was attained in only 2 of 7 comparisons. Such segregating congenic populations may be a valuable research tool for confirming QTL map positions and for subsequent assessment of individual pathways and mechanisms of action of individual QTLs.

Initial insensitivity to alcohol is a strong predictor of human alcoholism, a widespread and heritable health problem. The Long Sleep and Short Sleep lines of mice were developed by genetic selection for high or low alcohol sensitivity. We have identified seven quantitative trait loci (QTLs) specifying differences in alcohol sensitivity using intercross progeny from these selected strains. These QTLs (Lorel-Lore7) together account for approximately 60% of the total genetic variance for this trait. This represents the first report of linkages for genes influencing alcohol action in any mammalian system using stringent, genome-wide mapping criteria.

We are mapping the genes (quantitative trait loci or QTLs) that are responsible for individual differences in ethanol sensitivity, measured as the duration of loss of righting, reflex (LORR) and blood ethanol concentrations upon recovery of the righting reflex (BEC). The Long-Sleep (LS) and Short-Sleep (SS) selected lines of mice manifest an 18-fold difference in LORR and serve as a rodent model for ethanol sensitivity. The LS x SS recombinant inbred (RI) series, developed from LS and SS lines, are an important resource for QTL mapping of ethanol-related responses. The current report summarizes the initial QTL analysis of LORR and BEC in the LS x SS strains and compares the results of correlational analysis with an interval-mapping approach. The data provide strong evidence for QTLs that influence ethanol sensitivity on mouse chromosomes 1 and 2 and possible QTLs on chromosomes 1, 3, 4, 5, 6, 7, 12, 13, 16, and 18. These results are compared to those from an F2 cross which confirms QTLs on chromosomes 1, 2, 4, and 18.

Background We hypothesized that rapid tolerance (1-day tolerance) for the duration of the loss of righting reflex (“sleep time” [ST]) was mediated by an increase in acute functional tolerance (AFT). We also hypothesized that increased AFT would correspond to increased drinking. These questions were addressed using the LXS recombinant inbred mouse strain panel. Methods Mice were given a pretreatment dose of either saline or 5 g/kg alcohol on day 1. On day 2, mice were tested for ST (4.1 g/kg) using a method with which it is possible to accurately assess AFT. Genetic correlation analysis was conducted among the ST-related variables and also with “drinking in the dark” (DID) which was previously measured by Saba and colleagues (2011). Results Saline-pretreated mice showed a continuous distribution of ST ranging from ~40 minutes to over 3 hours. Of the 43 strains tested, 9 showed significantly decreased ST after alcohol pretreatment, while in 3 strains, ST was significantly increased. AFT scores ranged from 0 to over 200 mg% in the saline group, and in the alcohol group, 8 strains showed a significant increase in AFT and 2 strains showed significant decrease in AFT. In the saline group, AFT was significantly correlated with ST (r = −0.47), but not in the alcohol group (r = −0.22). DID was significantly correlated with only AFT in the alcohol pretreated group (r = 0.64). Conclusions The results suggest that AFT is an important component of the overall ST response, but that the alcohol pretreatment–induced change in AFT does not contribute to rapid ST tolerance. The significant correlation between DID and AFT in the alcohol group suggests that AFT may be a more relevant predictor of drinking behavior than the static measurement of ST. Moreover, preexposure to alcohol seems to change AFT in a way that makes it an even stronger predictor of drinking behavior.

Animal Welfare – Food Safety – Consumer Confidence – these terms represent important concerns in animal agriculture and will be determinants of continued or increased use of animal products in the future. Essentially all animal commodity organizations have implemented quality assurance education programs (QAEPs) designed to maintain or increase food safety, wholesomeness, and quality. QAEPs are generally based on total quality management (TQM) or hazard analysis and critical control points concepts (HACCP). The programs are producer driven and funded; they are designed to reinforce the attitude whereby animal producers accept responsibility as food producers. But QAEPs also enhance animal well-being by necessitating an even greater direct consideration of the animal. Essentially each step in QAEPs, although primarily oriented toward increasing food safety and carcass quality, also positively influences some aspect of animal well-being. The interdisciplinary approach in the formulation and conduct of QAEPs is essential: it involves engineers, nutritionists, animal handling and care specialists, meat scientists, management specialists, and veterinarians. All of the programs are based on increasing the use and effectiveness of the veterinarian/client/patient relationship. Regardless of the depth and breadth of these programs, success will be measured by increased safety, wholesomeness, and quality of the products. There are definite indications in the beef, veal, and swine industries that the programs are being used effectively.