Increased Sociability in Mice Lacking Intergenic Dlx Enhancers.

The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters (Dlx1/2, Dlx3/4, and Dlx5/6) with cis-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and Dlx5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams-Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i(-/-), I12b(-/-)). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2. The loss of the I56i enhancer resulted in a transient decrease in GABA+ cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development.

Premedications for infliximab infusions do not impact the risk of acute adverse drug reactions.

OBJECTIVE: The purpose of this study was to identify the association of premedication with the adverse drug reaction (ADR) rate in infliximab infusions. DESIGN: A retrospective chart review of 684 patients who received 4077 infusions in a network of community clinics over 16.5 months. Data collected included age, weight, sex, diagnosis, dose, premedications and ADR information, which was coded for time of onset, severity and outcome. SETTING: Community infusion clinics located in Ontario, Canada. PATIENTS: Patients aged 12-91 years who receive regular infliximab infusions to treat their autoimmune condition, mainly either Crohn's disease or rheumatoid arthritis. MAIN OUTCOME MEASURES: The number of infusions to the occurrence of an acute ADR by presence of premedication. RESULTS: ADRs are not significantly different (χ2(1, n=644, p=0.651)=0.204) between those who always received premedications and those who never did. When controlling for age, sex, weight and diagnosis, patients receiving premedications were just as likely to experience an ADR as patients who never received any (OR 1.1, 95% CI 0.7 to 1.9, p=0.5). When assessing the number of infusions to the occurrence of an ADR using the Kaplan-Meier method, no significant difference was found between the two groups. CONCLUSIONS: The use of premedications is not associated with a decreased risk of ADR in patients receiving infliximab. This held true for patients who had never had an ADR prior to receiving premedications and while controlling for age, sex, weight and diagnosis.

An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain.

Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.

The safety of infliximab infusions in the community setting.

BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has an important role in the pathogenesis of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and psoriasis. Infliximab, a chimeric anti-TNFalpha monoclonal antibody, has been shown to reduce the severity of symptoms or induces remission of active disease. Infusions have generally been limited to the hospital setting due to cost and concerns for patient safety. Studies defining its efficacy and safety have, therefore, originated almost exclusively from hospital settings. OBJECTIVE: To evaluate the safety of infliximab in a community clinic environment, across all types of patients. METHODS: A retrospective chart review of 3161 patients who received a combined 20,976 infusions at a network of community clinics over 16.5 months was conducted. Adverse drug reaction (ADR) information was retrieved and coded for time of onset, severity and outcome. Only ADRs that occurred during or within the first 24 h of the infusion were included. RESULTS: A total of 524 (2.5% of all infusions) acute ADRs in 353 patients (11.2%) were recorded. Most reactions (ie, ADRs) were mild (n=263 [50.2%, 1.3% of all infusions]) or moderate (n=233 [44.5%, 1.1% of all infusions]). Twenty-eight reactions (5.3%, 0.1% of all infusions) were severe. Emergency medical services were called to transport patients to hospital for seven of the severe reactions, of which none required admission. As per pre-established medical directives, adrenaline was administered three times. CONCLUSIONS: Infliximab infusions are safe in the community setting. Severe ADRs were rare. None required active physician intervention; nurses were able to treat all reactions by following standardized medical directives.

The impact on patient flow after the integration of nurse practitioners and physician assistants in 6 Ontario emergency departments.

OBJECTIVE: We sought to assess the impact of the integration of the new roles of primary health care nurse practitioners (NPs) and physician assistants (PAs) on patient flow, wait times and proportions of patients who left without being seen in 6 Ontario emergency departments (EDs). METHODS: We performed a retrospective review of health records data on patient arrival time, time of initial assessment by a physician, time of discharge from the ED and discharge status. RESULTS: Whether a PA or NP was directly involved in the care of patients or indirectly involved by being on duty, the wait times, lengths of stay and proportion of patients who left without being seen were significantly reduced. When a PA or NP were directly involved in patients' care, patients were 1.6 (95% confidence interval [CI] 1.3-2.1, p < 0.05) and 2.1 (95% CI 1.6-2.8, p < 0.05) times more likely to be seen within the wait time benchmarks, respectively. Lengths of stay were 30.3% (95% CI 21.6%-39.0%, p < 0.01) and 48.8% (95% CI 35.0%-62.7%, p < 0.01) lower when PAs and NPs, respectively, were involved. When PAs and NPs were not on duty, the proportion of patients who left without being seen were 44% (95% CI 31%-63%, p < 0.01) and 71% (95% CI 53%-96%, p < 0.05), respectively. CONCLUSION: The addition of PAs or NPs to the ED team can improve patient flow in medium-sized community hospital EDs. Given the ongoing shortage of physicians, use of alternative health care providers should be considered. These results require validation, as their generalizability to other locations or types of EDs is not known.

The application of change management principles to facilitate the introduction of nurse practitioners and physician assistants into six Ontario emergency departments.

In a project funded by the Ontario Ministry of Health and Long-Term Care, MedEmerg facilitated the introduction of three new providers into six emergency departments. A managed change process that included team development was carried out. Increased team awareness and a higher acceptance of the provider roles were some of the key successes. Challenges included role confusion and the learning curve for the new providers. While overall the project was a success, lessons learned included the need for physician buy-in, communication, planning for unintended consequences and management of expectations. The project emphasized the importance of a managed process, including team development, in the implementation of change.