First genome-wide association study investigating blood pressure and renal traits in domestic cats.

Hypertension (HTN) and chronic kidney disease (CKD) are common in ageing cats. In humans, blood pressure (BP) and renal function are complex heritable traits. We performed the first feline genome-wide association study (GWAS) of quantitative traits systolic BP and creatinine and binary outcomes HTN and CKD, testing 1022 domestic cats with a discovery, replication and meta-analysis design. No variants reached experimental significance level in the discovery stage for any phenotype. Follow up of the top 9 variants for creatinine and 5 for systolic BP, one SNP reached experimental-wide significance for association with creatinine in the combined meta-analysis (chrD1.10258177; P = 1.34 × 10-6). Exploratory genetic risk score (GRS) analyses were performed. Within the discovery sample, GRS of top SNPs from the BP and creatinine GWAS show strong association with HTN and CKD but did not validate in independent replication samples. A GRS including SNPs corresponding to human CKD genes was not significant in an independent subset of cats. Gene-set enrichment and pathway-based analysis (GSEA) was performed for both quantitative phenotypes, with 30 enriched pathways with creatinine. Our results support the utility of GWASs and GSEA for genetic discovery of complex traits in cats, with the caveat of our findings requiring validation.

Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress.

Defective DNA replication can result in genomic instability, cancer and developmental defects. To understand the roles of DNA damage response (DDR) genes on carcinogenesis in mutants defective for core DNA replication components, we utilized the Mcm4(Chaos3/Chaos3) ('Chaos3') mouse model that, by virtue of an amino-acid alteration in MCM4 that destabilizes the MCM2-7 DNA replicative helicase, has fewer dormant replication origins and an increased number of stalled replication forks. This leads to genomic instability and cancer in most Chaos3 mice. We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility. Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males. Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects. Hypomorphism for the 9-1-1 component Hus1 did not affect tumor latency or susceptibility in Chaos3 animals, and tumors in these mice did not exhibit impaired ATR pathway signaling. These and other data indicate that under conditions of systemic replication stress, the ATM pathway is particularly important both for cancer suppression and viability during development.

Skill acquisition in the implementation of functional analysis methodology.

Functional analysis methodology is a powerful assessment tool for identifying contingencies that maintain a wide range of behavior disorders and for developing effective treatment programs. Nevertheless, concerns have been raised about the feasibility of conducting functional analyses in typical service settings. In this study, we examined the issue of skill acquisition in implementing functional analyses by evaluating an instructional program designed to establish a basic set of competencies. Eleven undergraduate students enrolled in a laboratory course in applied behavior analysis served as participants. Their performance was assessed during scripted simulations in which they played the roles of "therapists" who conducted functional analyses and trained graduate students played the roles of "clients" who emitted self-injurious and destructive behaviors. To approximate conditions under which an individual might conduct an assessment with limited prior training, participants read a brief set of materials prior to conducting baseline sessions. A multiple baseline design was used to assess the effects of training, which consisted of reading additional materials, watching a videotaped simulation demonstrating correct procedural implementation, passing a written quiz, and receiving feedback on performance during sessions. Results showed that participants scored a relatively high percentage of correct therapist responses during baseline, and that all achieved an accuracy level of 95% or higher following training that lasted about 2 hr. These results suggest that basic skills for conducting functional analyses can be acquired quickly by individuals who have relatively little clinical experience.

A comparison of procedures for programming noncontingent reinforcement schedules.

We compared two methods for programming and thinning noncontingent reinforcement (NCR) schedules during the treatment of self-injurious behavior (SIB). The participants were 3 individuals who had been diagnosed with mental retardation. Results of functional analyses indicated that all participants' SIB was maintained by positive reinforcement (i.e., access to attention or food). Following baseline, the effects of two NCR schedule-thinning procedures were compared in multielement designs. One schedule (fixed increment) was initially set at fixed-time 10-s reinforcer deliveries and was also thinned according to fixed-time intervals. The other schedule (adjusting IRT) was initially determined by participants' baseline interresponse times (IRTs) for SIB and was thinned based on IRTs observed during subsequent treatment sessions. Results indicated that both schedules were effective in initially reducing SIB and in maintaining response suppression as the schedules were thinned.

Effects of session duration on functional analysis outcomes.

We examined the extent to which variations in session duration affected the outcomes of functional analyses. Forty-six individuals, all diagnosed with mental retardation and referred for assessment and treatment of self-injurious or aggressive behavior, participated in functional analyses, consisting of repeated exposure to multiple test conditions during 15-min sessions. For each set of assessment data, new data sets based on session durations of 10 and 5 min were prepared by deleting data from the last 5 and 10 min, respectively, of each session. Each graph (N = 138) was then reviewed individually by graduate students who had previous experience conducting and interpreting functional analyses, but who were blind to both participant identity and session duration. Interpretations of behavioral function based on the 10- and 5-min data sets were then compared with those based on the 15-min data sets. All of the 10-min data sets yielded interpretations identical to those based on 15-min data sets. Interpretations based on the 5-min and 15-min data sets yielded three discrepancies, all of which were the result of increased response rates toward the latter parts of sessions. These results suggest that the efficiency of assessment might be improved with little or no loss in clarity by simply reducing the duration of assessment sessions.

Side effects of extinction: prevalence of bursting and aggression during the treatment of self-injurious behavior.

Findings from basic and applied research suggest that treatment with operant extinction may produce adverse side effects; two of these commonly noted are an increase in the frequency of the target response (extinction burst) and an increase in aggression (extinction-induced aggression). Although extinction is often used to treat problem behavior in clinical settings, few applied studies have examined the prevalence of these side effects or their possible attenuation with other operant procedures. An analysis of 41 data sets for individuals who received treatment for self-injurious behavior indicated that extinction bursts or increases in aggression occurred in nearly one half of the cases. The prevalence of bursting and aggression was substantially lower when extinction was implemented as part of a treatment package rather than as the sole intervention.

Examination of ambiguous stimulus preferences with duration-based measures.

Items that produced ambiguous results in an approach-based preference assessment were reassessed using a duration-based assessment. The reinforcing effects of three items on free-operant responding were subsequently tested. The results suggested that the duration-based assessment produced slightly more differentiated results and that predictions about reinforcer value, based on this assessment, were accurate.

Rapid assessment of the effects of restraint on self-injury and adaptive behavior.

We evaluated the effects of restraint on occurrences of self-injurious behavior (SIB) and adaptive responses exhibited by 2 individuals across eight response-effort conditions: baseline (no restraints); restraint sleeves without stays; restraints with 5, 10, 15, 20, or 25 thin metal stays; and restraints with five thick metal stays. From this analysis, we identified a restraint level for each participant that reduced SIB but did not inhibit adaptive responding.

Level of involvement with alcohol and success at smoking cessation in the lung health study.

OBJECTIVE: This analysis examines the role of alcohol consumption in success at quitting smoking. METHOD: Participants were 3,977 men and women in the Lung Health Study, a prospective investigation of the effect of smoking cessation and an inhaled bronchodilator on the airways of smokers with mild lung function impairment. Participants reporting more than 25 drinks per week, or 8 or more drinks per occasion once a month or more, or alcoholics who drank in the past year were excluded from the sample. RESULTS: There was no relationship between amount of alcohol consumed at baseline and smoking status after 1 year. Among both men and women receiving a smoking cessation intervention, those who drank eight or more drinks per occasion (binge drinkers) were more likely to be current smokers after 1 year, and to smoke more cigarettes per day than those without a history of binge drinking. These relationships were largely absent among control participants. Participants who identified themselves as former or recovering alcoholics at baseline did not differ from the other participants in their smoking behavior after 1 year. When volume of drinking and drinking of eight or more drinks per occasion were compared in polychotomous ordinal logistic regressions, only binge drinking predicted failure at smoking cessation. CONCLUSIONS: Binge but not volume of drinking was related to failure in attempts to quit smoking. The common factor may be that binge drinking and relapse to smoking both represent loss of control.