Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome.

Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.

Validation of Self-Management Screening (SeMaS), a tool to facilitate personalised counselling and support of patients with chronic diseases.

BACKGROUND: A rising number of people with chronic conditions is offered interventions to enhance self-management. The responsiveness of individuals to these interventions depends on patient characteristics. We aimed to develop and validate a tool to facilitate personalised counselling and support for self-management in patients with chronic diseases in primary care. METHODS: We drafted a prototype of the tool for Self-Management Screening (SeMaS), comprising 27 questions that were mainly derived from validated questionnaires. To reach high content validity, we performed a literature review and held focus groups with patients and healthcare professionals as input for the tool. The characteristics self-efficacy, locus of control, depression, anxiety, coping, social support, and perceived burden of disease were incorporated into the tool. Three items were added to guide the type of support or intervention, being computer skills, functioning in groups, and willingness to perform self-monitoring. Subsequently, the construct and criterion validity of the tool were investigated in a sample of 204 chronic patients from two primary care practices. Patients filled in the SeMaS and a set of validated questionnaires for evaluation of SeMaS. The Patient Activation Measure (PAM-13), a generic instrument to measure patient health activation, was used to test the convergent construct validity. RESULTS: Patients had a mean age of 66.8 years and 46.6 % was female. 5.9 % did not experience any barrier to self-management, 28.9 % experienced one minor or major barrier, and 30.4 % two minor or major barriers. Compared to the criterion measures, the positive predictive value of the SeMaS characteristics ranged from 41.5 to 77.8 % and the negative predictive value ranged from 53.3 to 99.4 %. Crohnbach's alpha for internal consistency ranged from 0.56 to 0.87, except for locus of control (α = 0.02). The regression model with PAM-13 as a dependent variable showed that the SeMaS explained 31.7 % (r(2) = 0.317) of the variance in the PAM-13 score. CONCLUSIONS: SeMaS is a short validated tool that can signal potential barriers for self-management that need to be addressed in the dialogue with the patient. As such it can be used to facilitate personalised counselling and support to enhance self-management in patients with chronic conditions in primary care.

Diabetes self-management education after pre-selection of patients: design of a randomised controlled trial.

BACKGROUND: Many self-management programs have been developed so far. Their effectiveness varies. The program 'Beyond Good Intentions' (BGI) is based on proactive coping and has proven to be (cost-) effective in achieving reductions in BMI and blood pressure in screen-detected type 2 diabetes patients up until nine months follow-up. However, its long-term effectiveness in people already known with diabetes is lacking. In addition, its (cost-) effectiveness might increase if people who are likely not to be benefit from the program are excluded in a valid way. Therefore it was aimed to investigate the long-term effects of the educational program BGI on cardiovascular risk, quality of life and diabetes self-management behaviour in a pre-selected group of patients known with type 2 diabetes up to 5 years. METHODS: Randomised controlled trial with 2.5 year follow-up. Adults (≤75 years) with a type 2 diabetes duration between 3 months and 5 years will be included. With the use of a self-management screening tool (SeMaS) their potential barriers of self-management due to depression and/or anxiety will be determined. Based on the results of the SeMaS selection patients will be randomised (1:1) to the BGI-group (n = 53) or the control-group (n = 53). In addition to receiving usual care, patients in the BGI-group will follow the 12-week theory-based self-management program and a booster session a few months thereafter. The control-group will receive care as usual. The primary outcome is change in Body Mass Index after 2.5 years follow-up. Secondary outcomes are HbA1c, lipid profile and systolic blood pressure, (diabetes) quality of life, level of physical activity, dietary intake and medication adherence and proactive coping. Cost-effectiveness will be based on total use of health care resources during the entire study period. Difference between groups in change over time will be analysed according to intention-to-treat analysis. CONCLUSIONS: By differentiating between patients who will and those who are likely not to benefit from the educational program, a more (cost-) effective self-management program might be designed, also on the long-run. Trial registration NTR 5330.

Effectiveness of personalised support for self-management in primary care: a cluster randomised controlled trial.

BACKGROUND: Self-management support is an important component of the clinical management of many chronic conditions. The validated Self-Management Screening questionnaire (SeMaS) assesses individual characteristics that influence a patient's ability to self-manage. AIM: To assess the effect of providing personalised self-management support in clinical practice on patients' activation and health-related behaviours. DESIGN AND SETTING: A cluster randomised controlled trial was conducted in 15 primary care group practices in the south of the Netherlands. METHOD: After attending a dedicated self-management support training session, practice nurses in the intervention arm discussed the results of SeMaS with the patient at baseline, and tailored the self-management support. Participants completed a 13-item Patient Activation Measure (PAM-13) and validated lifestyle questionnaires at baseline and after 6 months. Data, including individual care plans, referrals to self-management interventions, self-monitoring, and healthcare use, were extracted from patients' medical records. Multilevel multiple regression was used to assess the effect on outcomes. RESULTS: The PAM-13 score did not differ significantly between the control (n = 348) and intervention (n = 296) arms at 6 months. In the intervention arm, 29.4% of the patients performed self-monitoring, versus 15.2% in the control arm (effect size r = 0.9, P = 0.01). In the per protocol analysis (control n = 348; intervention n = 136), the effect of the intervention was significant on the number of individual care plans (effect size r = 1.3, P = 0.04) and on self-monitoring (effect size r = 1.0, P = 0.01). CONCLUSION: This study showed that discussing SeMaS and offering tailored support did not affect patient activation or lifestyle, but did stimulate patients to self-monitor and use individual care plans.

Social support and self-management capabilities in diabetes patients: An international observational study.

OBJECTIVE: The objective of this study was to explore which aspects of social networks are related to self-management capabilities and if these networks have the potential to reduce the adverse health effects of deprivation. METHODS: In a cross-sectional study we recruited type 2 diabetes patients in six European countries. Data on self-management capabilities was gathered through written questionnaires and data on social networks characteristics and social support through subsequent personal/telephone interviews. We used regression modelling to assess the effect of social support and education on self-management capabilities. RESULTS: In total 1692 respondents completed the questionnaire and the interview. Extensive informational networks, emotional networks, and attendance of community organisations were linked to better self-management capabilities. The association of self-management capabilities with informational support was especially strong in the low education group, whereas the association with emotional support was stronger in the high education group. CONCLUSION: Some of the social network characteristics showed a positive relation to self-management capabilities. The effect of informational support was strongest in low education populations and may therefore provide a possibility to reduce the adverse impact of low education on self-management capabilities. PRACTICE IMPLICATIONS: Self-management support interventions that take informational support in patients' networks into account may be most effective, especially in deprived populations.

Implementation of personalized self-management support using the self-management screening questionnaire SeMaS; a study protocol for a cluster randomized trial.

BACKGROUND: The number of patients with one or more chronic diseases is rising. In several standards of care there is a focus on enhancing self-management. We applied the concept of personalization on self-management support and developed a self-management screening questionnaire (SeMaS). The main research objective is to assess the effectiveness of the SeMaS questionnaire and subsequent personalized self-management on patients' self-management behaviors. METHODS/DESIGN: A cluster randomized controlled trial will be set up in 15 general practices in the Netherlands. The practices are all group practices, and member of one care group. The practices will be assigned to the control or intervention arms by stratified randomization. The strata are determined by the participation of the practice nurses in a course for behavioral change, and the nurse's workload. Patients can be included if they are over 18 years of age, have at least one chronic condition and have a checkup appointment with the practice nurse in the inclusion period. The intervention consists of screening patients with the SeMaS questionnaire, producing a graphic profile with the abilities or barriers for self-management. Patients will receive tailored feedback. Practice nurses are trained in using the profile to enhance self-management of the patient and provide personalized self-management support. The use of individual care plans and self-management interventions is stimulated. In the control arm patients will receive care as usual. Patients of both trial arms will be asked to fill in the SeMaS questionnaire and additional questionnaires at inclusion and after 6 months. The primary outcome is the difference in the level of patient activation (PAM-13) between baseline and 6 months. Secondary outcomes include patient measures for lifestyle factors (exercise, diet, smoking), and process measures from medical record data analysis. DISCUSSION: This manuscript presents the protocol for a cluster randomized clinical trial of personalized self-management support using the SeMaS questionnaire in chronically ill patients in primary care. By carrying out this study, scientific evidence is built for the effectiveness of personalized self-management support. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR3960.

Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice.

The 9q34.3 subtelomeric deletion syndrome is a newly defined mental retardation syndrome, caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene. Patients also have childhood hypotonia, facial dysmorphisms, delay in reaching developmental milestones, and behavioral problems like aggressive outbursts, hypoactivity, or autistic-like features. Male and female heterozygous Ehmt1 knockout mice (Ehmt1(+/-), aged 1-20 months, kept on a C57BL/6J background), were used to investigate whether they mimic the patients behavioral characteristics by comparing their behavior to wildtype littermates. The Ehmt1(+/-) mice revealed reduced activity and exploration, with increased anxiety compared to wildtype mice when exposed to novel environments in the open field, object exploration, marble burying, light-dark box, mirrored chamber and T-maze tests. They also demonstrated diminished social play when encountering a mouse from a different litter, and a delayed or absent response to social novelty when exposed to a stranger mouse. However, no differences in phenotyper home cage locomotor activity or rotarod motor function were observed between Ehmt1(+/-) and wildtype mice. Together, these results indicate that the hypoactivity and the autistic-like features of 9q34.3 subtelomeric deletion syndrome patients are recapitulated in this Ehmt1(+/-) mouse model, and that the hypoactivity is apparently not caused by any motor dysfunction. Together, these observations make it plausible that the Ehmt1(+/-) mouse is a faithful mammalian model for the autistic-like behavioral features of patients with the 9q34.3 subtelomeric deletion syndrome.