Complex chronic conditions among children born to women with schizophrenia.

PURPOSE: Maternal schizophrenia is linked to complications in offspring near the time of birth. Whether there is also a higher future risk of the child having a complex chronic condition (CCC) - a pediatric condition affecting any bodily system expected to last at least 12 months that is severe enough to require specialty care and/or a period of hospitalization - is not known. METHODS: In this population-based health administrative data cohort study (Ontario, Canada, 1995-2018), the risk for CCC was compared in 5066 children of women with schizophrenia (the exposed) vs. 2,939,320 unexposed children. Adjusted hazard ratios (aHR) were generated for occurrence of any CCC, by CCC category, and stratified by child sex, and child prematurity. RESULTS: CCC was more frequent in the exposed (7.7 per 1000 person-years [268 children]) than unexposed (4.2 per 100 person-years [124,452 children]) - an aHR of 1.25 (95% CI 1.10-1.41). aHRs were notably higher in 5 of 9 CCC categories: neuromuscular (1.73, 1.28-2.33), cardiovascular (1.94, 1.64-2.29), respiratory (1.83, 1.32-2.54), hematology/immunodeficiency (2.24, 1.24-4.05) and other congenital or genetic defect (1.59, 1.16-2.17). The aHR for CCC was more pronounced among boys (1.32, 1.13-1.55) than girls (1.16, 0.96-1.40), and of similar magnitude in term (1.22, 1.05-1.42) and preterm infants (1.18, 0.95-1.46). CONCLUSIONS: The risk for a CCC appears to be higher in children born to women with schizophrenia. This finding introduces opportunities for targeted preconception counselling, optimization of maternal risk factors, and intervention to support a vulnerable parent population who will experience unique challenges caring for a child with CCCs.

Selected medical interventions in women with a deleterious BRCA mutation: a population-based study in British Columbia.

Background: We examined the uptake of risk-reducing interventions, including bilateral mastectomy, risk-reducing salpingo-oophorectomy, oral contraceptive pills, tamoxifen, and raloxifene, for the entire population of women with a deleterious BRCA1 or BRCA2 mutation in the Canadian province of British Columbia. Methods: This retrospective population-based study used data available in British Columbia for all women who, between 1996 and 2014, were tested and found to have a BRCA mutation. Rates of risk-reducing interventions stratified according to the type of BRCA mutation and prior history of breast or gynecologic cancer (ovary, fallopian tube, peritoneal) are presented. Cancers diagnosed in women with a BRCA mutation after disclosure of their mutation status are also presented. Results: The final study cohort consisted of 885 patients with a deleterious BRCA1 (n = 474) or BRCA2 (n = 411) mutation. Of the women with no prior breast cancer, 30.8% carrying a BRCA1 mutation and 28.3% carrying a BRCA2 mutation underwent bilateral mastectomy. Of women with no prior gynecologic cancer, 64.7% carrying a BRCA1 mutation and 62.2% carrying a BRCA2 mutation underwent risk-reducing bilateral salpingo-oophorectomy. Rates of chemoprevention with oral contraceptive pills and tamoxifen or raloxifene were low in all groups. In this cohort, 23 gynecologic and 70 breast cancers were diagnosed after disclosure of BRCA mutation status. Conclusions: Our results suggest reasonable uptake of risk-reducing interventions in high-risk women. To minimize the occurrence of breast and ovarian cancer in women with a BRCA1 or BRCA2 mutation, more attention could be paid to ensuring that affected women receive proper counselling and follow-up.

Examination of the pharmacodynamics and pharmacokinetics of a diclofenac poly(lactic-co-glycolic) acid nanoparticle formulation in the rat.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assembled into two categories; cyclooxygenase (COX-1) sparing inhibitors of COX-2 and non-selective NSAIDs. Diclofenac (DICLO) is a non-selective NSAID that has been linked to serious side effects including gastric ulcers and renal injury. In this study, we examine the effect of poly(lactic-co-glycolic) acid nanoformulation on DICLO-associated adverse events and pharmacokinetics using a nanoparticle (NP) formulation previously developed in our laboratory. MATERIALS AND METHODS: Rats were administered a single dose of methylcellulose (VEH), blank NP, DICLO (10 mg/kg), or a DICLO-NP suspension equivalent to the DICLO dose. Urinary and blood parameters were measured at baseline and following treatment. Duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) were collected to assess inflammation at 24 hrs post-treatment. RESULTS: The mean percent change from baseline in sodium excretion rate (µmol/min/100 g body weight) differed significantly from VEH in the NP (p < 0.0001), DICLO (p < 0.0001), and DICLO-NP (p = 0.0001) groups. The differences among groups did not reach significance for plasma sodium or potassium concentrations, potassium excretion rate, gastric PGE2, or intestinal biomarker concentrations. Regarding renal histopathology, DICLO produced considerably more necrosis compared to VEH; while DICLO-NP did not elicit notable differences from VEH. CONCLUSIONS: Our results suggest that over the duration and dosage examined, DICLO-NP may reduce renal necrosis without influencing other side effects or drug characteristics.

Assessment of celecoxib poly(lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats.

OBJECTIVE: Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP). MATERIALS AND METHODS: Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma and urine were assessed based on 100 g body weight. Using tissues collected 24 hrs post-treatment, gastrointestinal inflammation was estimated through duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) levels; while kidney tissue was examined for dilatation and necrosis. CEL concentration was assayed in renal tissue and plasma utilizing high-performance liquid chromatography. RESULTS: Although there were significant changes when comparing CEL and CEL-NP to VEH in plasma sodium concentration and potassium excretion rate, there was no significant variation between CEL and CEL-NP. There was a significant reduction of protective duodenal PGE2 in CEL compared to VEH (p = 0.0088) and CEL-NP (p = 0.02). In the CEL-NP formulation, t1/2, Cmax, AUC0-∞, and Vd/F increased significantly when compared to CEL. CONCLUSIONS: At the observed dosage and duration, CEL-NP may not affect CEL-associated electrolyte parameters in either plasma or urine; however, it does provide increased systemic exposure while potentially alleviating some gastrointestinal outcomes related to inflammation.

beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways.

UNLABELLED: beta-arrestins, a family of regulatory and scaffold proteins, are well-known negative regulators of G-protein-coupled receptors (GPCRs) including opioid receptors. Recent studies have shown that beta-arrestin2 plays a potential role in inhibiting cell death. It has been reported that opioids such as morphine induce cell death at high concentrations (>500 microM for 24 hours), which is similar to morphine plasma concentrations in cancer patients receiving chronic morphine treatment for pain relievers. However, the role of beta-arrestin2 in opioid-induced cell death remains to be elucidated. We report here that beta-arrestin2 significantly blocks morphine-induced number of cell death in human breast cancer MCF-7 and MDA-MB231 cells. Suppression of endogenous beta-arrestin2 by specific RNA interfering (RNAi) and morphine treatment significantly attenuates the levels of phosphorylated Akt compared with inhibition of beta-arrestin2 or morphine treatment alone. However, blockade of morphine-induced cell death by beta-arrestin2 seems to be dependent on the inhibition of caspase-8, as inhibition of beta-arrestin2 and morphine treatment significantly enhanced the levels of cleaved caspase-8. These studies show for the first time that beta-arrestin2 blocks morphine-induced cell death through anti-apoptotic Akt and pro-apoptotic caspase-8 pathways. Therefore, targeting beta-arrestin2 may be useful for treating side effects of opioids as pain relievers for cancer patients. KEYWORDS: Breast cancer, beta-arrestin, opioid. Akt, caspase-8,cell death.

Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction.

Matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2) are expressed in both sporadic and familial adenomatous colonic polyps and tumours and have been independently shown to play causal roles in intestinal tumour formation in mouse models of colon cancer. The apparent roles of these enzymes in intestinal tumorigenesis led us to examine, in the Min mouse model of colon cancer, if selective COX-2 and MMP inhibitors provide additive or synergistic therapeutic benefits in intestinal tumour prevention. The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice. Using suboptimal doses, the MMPI reduced tumour multiplicity by 32%, the COX-2I by 48% and, both agents in combination resulted in a 67% decrease compared to control demonstrating a cooperative effect on intestinal tumorigenesis. Apoptosis, proliferation, and angiogenesis were assayed in tumors from each treatment group. These agents in combination allowed for a lowered dosage to be administered to achieve significant biological effects. Clinically, this could potentially reduce side effects associated with currently used MMP and COX-2 inhibitors. Together, these compounds could represent an easily tolerated chemopreventive approach.

MERLOT: a faculty-focused Web site of educational resources.

The Multimedia Educational Resource for Learning and Online Teaching (MERLOT) is a community of academic institutions, professional discipline organizations, and individual people building a collection of Web-based teaching and learning resources where faculty can easily find peer-reviewed materials for use in their classes. The MERLOT project is currently supported by 23 systems and institutions of higher education and by the National Science Foundation. MERLOT is developing collections of learning materials from many academic disciplines, including psychology.

Reinforcement schedule thinning following treatment with functional communication training.

We evaluated four methods for increasing the practicality of functional communication training (FCT) by decreasing the frequency of reinforcement for alternative behavior. Three participants whose problem behaviors were maintained by positive reinforcement were treated successfully with FCT in which reinforcement for alternative behavior was initially delivered on fixed-ratio (FR) 1 schedules. One participant was then exposed to increasing delays to reinforcement under FR 1, a graduated fixed-interval (FI) schedule, and a graduated multiple-schedule arrangement in which signaled periods of reinforcement and extinction were alternated. Results showed that (a) increasing delays resulted in extinction of the alternative behavior, (b) the FI schedule produced undesirably high rates of the alternative behavior, and (c) the multiple schedule resulted in moderate and stable levels of the alternative behavior as the duration of the extinction component was increased. The other 2 participants were exposed to graduated mixed-schedule (unsignaled alternation between reinforcement and extinction components) and multiple-schedule (signaled alternation between reinforcement and extinction components) arrangements in which the durations of the reinforcement and extinction components were modified. Results obtained for these 2 participants indicated that the use of discriminative stimuli in the multiple schedule facilitated reinforcement schedule thinning. Upon completion of treatment, problem behavior remained low (or at zero), whereas alternative behavior was maintained as well as differentiated during a multiple-schedule arrangement consisting of a 4-min extinction period followed by a 1-min reinforcement period.

A component analysis of "stereotypy as reinforcement" for alternative behavior.

Results from several studies have suggested that the opportunity to engage in stereotypic behavior may function as reinforcement for alternative, more socially desirable behaviors. However, the procedural components of this intervention include several distinct operations whose effects have not been analyzed separately. While measuring the occurrence of stereotypy and an alternative behavior (manipulation of leisure materials), we exposed 3 participants to three or four components of a "stereotypy as reinforcement" contingency: (a) continuous access to materials, (b) prompts to manipulate materials, (c) restricted access to stereotypy (i.e., response blocking), and (d) access to stereotypy contingent on manipulating the materials. Continuous access to materials and prompting (a and b) produced negligible results. Restriction of stereotypy (c) produced a large increase in the alternative behavior of 2 participants, suggesting that response restriction per se may occasion alternative behavior. However, contingent access to stereotypy (d) was necessary to increase the 3rd participant's object manipulation; this finding provided some support for the use of stereotypy as reinforcement for alternative behavior. Finally, when transfer of the effects of intervention was assessed during periods in which active intervention components were withdrawn, the alternative behavior was maintained for 1 participant.

Differential responding in the presence and absence of discriminative stimuli during multielement functional analyses.

We evaluated the extent to which discriminative stimuli (S(D)s) facilitate differential responding during multielement functional analyses. Eight individuals, all diagnosed with mental retardation and referred for assessment and treatment of self-injurious behavior (SIB) or aggression, participated. Functional analyses consisted of four or five assessment conditions alternated in multielement designs. Each condition was initially correlated with a specific therapist and a specific room color (S(D)s), and sessions continued until higher rates of target behaviors were consistently observed under a specific test condition. In a subsequent analysis, the programmed S(D)s were removed (i.e., all conditions were now conducted by the same therapist in the same room), and sessions continued until differential responding was observed or until twice as many sessions were conducted with the S(D)s absent (as opposed to present), whichever came first. Results indicated that the inclusion of programmed S(D)s facilitated discrimination among functional analysis conditions for half of the participants. These results suggest that the inclusion of salient cues may increase either the efficiency of functional analyses or the likelihood of obtaining clear assessment outcomes.

Effects of continuous and intermittent reinforcement for problem behavior during functional communication training.

We evaluated the effectiveness of functional communication training (FCT) in reducing problem behavior and in strengthening alternative behavior when FCT was implemented without extinction. Following the completion of functional analyses in which social-positive reinforcement was identified as the maintaining variable for 5 participants' self-injurious behavior (SIB) and aggression, the participants were first exposed to FCT in which both problem behavior and alternative behavior were reinforced continuously (i.e., on fixed-ratio [FR] 1 schedules). During subsequent FCT conditions, the schedule of reinforcement for problem behavior was made more intermittent (e.g., FR 2, FR 3, FR 5, etc.), whereas alternative behavior was always reinforced according to an FR 1 schedule. Results showed that 1 participant's problem behavior decreased and alternative behavior increased during FCT when both behaviors were reinforced on FR 1 schedules. The remaining 4 participants shifted response allocation from problem to alternative behavior as the schedule of reinforcement for problem behavior became more intermittent. These results suggest that individuals might acquire alternative responses during FCT in spite of inconsistencies in the application of extinction, although even small errors in reinforcement may compromise treatment effects.

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.

Assessment of patient waiting times for vascular surgery.

OBJECTIVES: To assess patient waiting times for vascular surgery and to determine if complications of the disease develop while the patients are awaiting surgery. DESIGN: Prospective cohort study. SETTING: A university-affiliated tertiary care institution. PATIENTS: All 554 patients who underwent scheduled vascular surgical procedures between April 1995 and October 1996. OUTCOME MEASURES: A literature review carried out to develop guidelines for acceptable waiting times for surgery associated with various vascular disorders based on their natural history (benchmark target); actual waiting times, defined as the interval from the date each patient was booked for surgery to the date of admission to hospital for the procedure; the proportion of patients admitted within the benchmark targets; and whether prolonged waiting time placed patients at risk for complications of their disease. RESULTS: Of the 554 patients, 382 (69%) were admitted within the benchmark waiting times. Of 84 patients having an abdominal aortic aneurysm, the aneurysm ruptured during the waiting period in 6, and 4 of them died, for a complication rate of 7% and a death rate of 5%. Two of the 6 aneurysms ruptured after the patient had waited longer than the target time. Three of 100 patients with symptomatic carotid artery stenosis awaiting admission for carotid endarterectomy suffered ischemic stroke, for a 3% complication rate; all had waited longer than the target period. One patient suffered occlusion of a femoropopliteal bypass graft while awaiting revision of a stenosed bypass graft. CONCLUSIONS: This study suggests that although most patients are admitted for operation within the benchmark time, one-third are admitted late and may suffer serious complications of their disease while awaiting admission for the procedure.

An evaluation of the effects of matched stimuli on behaviors maintained by automatic reinforcement.

The purpose of the current investigation was to extend the literature on matched stimuli to three dissimilar forms of aberrant behavior (dangerous climbing and jumping, saliva manipulation, and hand mouthing). The results of functional analyses suggested that each behavior was automatically reinforced. Preference assessments were used to identify two classes of stimuli: items that matched the hypothesized sensory consequences of aberrant behavior (matched stimuli) and items that produced sensory consequences that were not similar to those produced by the aberrant behavior (unmatched stimuli). The effects of providing continuous and noncontingent access to either the most highly preferred matched or the most highly preferred unmatched stimuli were assessed relative to a condition in which no stimuli were available. Overall results suggested that providing access to items that matched the hypothesized sensory consequences of aberrant behavior may be more effective than simply selecting stimuli either arbitrarily or based on the results of preference assessments alone.

A method for identifying satiation versus extinction effects under noncontingent reinforcement schedules.

We evaluated one method for determining whether response suppression under noncontingent reinforcement (NCR) is a function of satiation or extinction. Three individuals with developmental disabilities who engaged in self-injurious behavior (SIB) or aggression participated. Results of functional analyses indicated that their problem behavior was maintained by social-positive reinforcement. NCR procedures, individualized for each participant, were implemented in a multiple baseline across subjects design and were associated with decreases in all participants' problem behavior. Identification of the mechanism by which NCR produced these effects was based on examination of cumulative records showing response patterns during and immediately following each NCR session. Satiation during NCR should lead to a temporary increase in responding during the post-NCR (extinction) period due to a transition from the availability to the unavailability of reinforcement (satiation to deprivation). Alternatively, extinction during NCR should reveal no increase in responding during the extinction period because the contingency for the problem behavior would remain unchanged and the transition from satiation to deprivation conditions would be irrelevant. Results suggested that the operative mechanisms of NCR were idiosyncratic across the 3 participants and appeared to change during treatment for 1 of the participants.

Analysis of activity preferences as a function of differential consequences.

Individuals who do not possess the verbal skills to express meaningful choice in the absence of its consequences may have difficulty indicating their preference for protracted activities that are unavailable until some time in the future (e.g., taking a walk, riding a bike). When we examined the preferences of 4 individuals with developmental disabilities by showing them pictorial representations of various activities, their initial choices showed no clear preferences. In a subsequent condition, selecting a photograph resulted in brief access to the depicted activity. When selections produced differential consequences (i.e., access to the activity), clear preferences emerged. In addition, 3 individuals' preferences were later shifted to an initially less preferred but more socially desirable option by superimposing additional reinforcement contingencies for engaging in the less preferred activity. Results are discussed in terms of the conditions under which choice functions as an indicator of preference and how those conditions may be altered to improve the quality of choice making without limiting access to preferred options.

On the establishing and reinforcing effects of termination of demands for destructive behavior maintained by positive and negative reinforcement.

The results of functional analyses suggested that the destructive behavior of two individuals was sensitive to escape and attention as reinforcement. In an instructional context, we evaluated the effects of reinforcing compliance with functional reinforcers when destructive behavior produced a break. For one participant we also evaluated the effects of reinforcing compliance with functional reinforcers when destructive behavior produced no differential consequence (escape extinction). We hypothesized that destructive behavior failed to decrease in an instructional context when compliance resulted in a break because presentation of a break evoked attention-maintained destructive behavior. The results of a reinforcer assessment supported this hypothesis by demonstrating that demands functioned as positive reinforcement when no alternative activities were available. These results are discussed in terms of the importance of establishing operations in determining the appetitive or aversive properties of stimuli when destructive behavior is multiply controlled.

Resistance to HgCl2-induced autoimmunity in haplotype-heterozygous mice is an intrinsic property of B cells.

Exposure to low doses of mercury chloride induces autoantibodies to the nucleolar protein fibrillarin in H-2s, but not in H-2b, mice. Surprisingly, F1 crosses between resistant and sensitive haplotypes are resistant. Previously, we have shown that the resistance in these F1 mice was due to coexpression of the resistant class II allele. Using adoptive transfer techniques we have examined several mechanisms by which the resistant haplotype could be down-regulating the antifibrillarin response in F1 (s/b) mice. Similar to other autoimmune models, mercury-induced autoimmunity requires cognate MHC-restricted T cell help. The absence of autoantibody production in F1 mice was not due to a difference in thymic education or to the absence of antifibrillarin-specific T cell help. These results suggest that the resistance is due to an intrinsic property of the haplotype-heterozygous B cells.

Treatment of pica through multiple analyses of its reinforcing functions.

We conducted functional analyses of the pica of 3 participants. The pica of 1 participant appeared to be maintained by automatic reinforcement; that of the other 2 participants appeared to be multiply controlled by social and automatic reinforcement. Subsequent preference and treatment analyses were used to identify stimuli that would complete with the automatic function of pica for the 3 participants. These analyses also identified the specific aspect of oral stimulation that served as automatic reinforcement for 2 of the participants. In addition, functional analysis-based treatments were used to address the socially motivated components of 2 of the participants' pica. Results are discussed in terms of (a) the importance of using the results of functional analyses to develop treatments for pica and (b) the advantages of developing indirect analyses to identify specific sources of reinforcement for automatically reinforced behavior.

Effects of wrist weights on self-injurious and adaptive behaviors.

The effects of wrist weights on the self-injurious and adaptive behaviors of a young boy with profound mental retardation were evaluated. Application of wrist weights reduced SIB by 92% and was associated with either increases or stable levels of multiple novel and preexisting adaptive behaviors.