Allometric growth ratios are independent of Igf2 gene dosage during development.

In the mouse, allelic dosage of the paternally expressed gene coding for insulin-like growth factor II (Igf2), from null to bi-allelic, results in dose-dependent growth, an effect which appears to be fully established during a discrete period of embryogenesis that then persists throughout life. Here, we specifically quantify the influence of Igf2 allelic dosage on the proportionality of regional embryonic growth rather than overall growth. Remarkably, preservation of allometric growth ratios between head and body regions were observed throughout development, irrespective of the range of overall growth phenotype (60-130% of wild type). Evaluation of log-log plots suggests that each allele of Igf2 expressed corresponds to the equivalent of 2-4 days of relative growth. Igf2 is predominantly expressed in extra-embryonic mesoderm (E7.5-E8.25), 24 h before alterations in cell number are known to occur in embryos with disruption of the paternally expressed allele. We hypothesized that the preservation of proportionality may result from modification of extra-embryonic development and subsequent alteration of systemic nutritional supply. Morphological analyses of chorio-allantoic and placental development between E9 and E9.5 appeared Igf2 independent. This suggests either an intrinsic but systemic Igf2-dependent activity within the embryo or a more complex developmental mechanism accounts for the proportional phenotype. Allelic IGF2 expression is subject to stochastic variation in humans, with 10% of the population estimated to be functionally bi-allelic. Evaluation of allometric growth of normal and pathological human embryos, suggest intra-uterine growth phenotypes associated with altered IGF2 imprinting are also likely to be proportionate.

Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting.

The potent growth-promoting activity of insulin-like growth factor-II (IGF-II) is highly regulated during development but frequently up-regulated in tumors. Increased expression of the normally monoallelic (paternally expressed) mouse (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the Apc(Min/+) mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of Igf2 allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the Apc(Min/+) by breeding with mice with either disruption of Igf2 paternal allele or H19 maternal allele and used these models to evaluate an IGF-II-specific therapeutic intervention. Increased allelic Igf2 expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear beta-catenin staining. By introducing a transgene expressing a soluble form of the full-length IGF-II/mannose 6-phosphate receptor (sIGF2R) in the intestine, which acts as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), we show rescue of the Igf2-dependent intestinal and adenoma phenotype. This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand-specific therapeutic intervention in colorectal cancer.

Measuring patient acceptance of implantable cardiac device therapy: initial psychometric investigation of the Florida Patient Acceptance Survey.

INTRODUCTION: Patient acceptance of implantable device therapy has been established as an important outcome but the operationalization and validation of a measure of patient acceptance of implantable device therapy has not been fully completed. This study sought to validate a new measure of patient acceptance of cardiac implantable devices called the Florida Patient Acceptance Survey (FPAS). METHODS: The sample consisted of implantable cardioverter defibrillator (ICD; n = 58), and implantable atrioverter defibrillator (ICD-AT; n = 96), and pacemaker (PM, n = 84) patients. Mean age of all participants was 69 years; they were mostly male (62%) and married (75%). The final FPAS comprised 15 items with four consistent factors: Return to Function, Device-Related Distress, Positive Appraisal, and Body Image Concerns. RESULTS: The total FPAS demonstrated good internal consistency (Cronbach's alpha = 0.83), and internal consistency for each of the subscales ranged from 0.74 to 0.89. The FPAS demonstrated convergent, divergent, and discriminant validity when compared to other self-report measures of QOL, atrial symptoms, depression, and anxiety. A total FPAS score can be formed and between group comparisons with this sample indicated that ICD patients report a high level of acceptance (mean = 76), ICD-AT patients report a significantly higher level of acceptance (mean = 81.1), and PM patients reported the highest level of patient acceptance (mean = 85.4) of these implantable device groups. CONCLUSION: This initial psychometric investigation of the FPAS suggests that the FPAS may be useful in both clinical and research settings to assess patient acceptance of implantable cardiac devices.

Do patients accept implantable atrial defibrillation therapy? Results from the Patient Atrial Shock Survey of Acceptance and Tolerance (PASSAT) Study.

INTRODUCTION: The Medtronic Jewel AF 7250 is an implantable cardioverter defibrillator with atrial and ventricular therapies (ICD-AT). The ICD-AT is effective in managing atrial tachyarrhythmias (atrial fibrillation [AF]), but patient acceptance remains an issue. This aim of this study was to measure ICD-AT acceptance. METHODS AND RESULTS: ICD-AT acceptance was evaluated in 96 patients enrolled in the "Jewel AF-AF-Only Study" for > or =3 months of follow-up (mean 19 months). Patients were mostly men (72%; age 65 +/- 12 years). Clinical data and a written survey (75% response rate) were used to quantify demographics, AF frequency and symptoms, atrial defibrillation therapy, quality of life (QOL), psychosocial distress, and ICD-AT therapy acceptance. From implant to survey, AF symptom and severity scores decreased by 18% (P < or = 0.05), and QOL (SF-36) scores increased by 15% to 50% (P < or = 0.05). ICD-AT therapy acceptance was high, with 71.3% of patients scoring in the 75th percentile on the Florida Patient Acceptance Survey. ICD-AT acceptance was correlated with the Physical Component Scale and Mental Health Component Scale scores of the SF-36 (r = 0.28 and 0.35, respectively). ICD-AT acceptance was negatively correlated with depressive symptomatology (r =-0.59), trait anxiety (r =-0.48), illness intrusiveness (r =-0.55), and AF symptom and severity scores (r =-0.26). ICD-AT acceptance did not correlate with preimplant cardioversions, number of atrial shocks, AF episodes detected by the device, or device implant duration. CONCLUSION: Most patients accepted ICD-AT therapy. Patients were more likely to accept ICD-AT if they had less psychosocial distress, greater QOL, and lower AF symptom burden.

Sleep quality among patients treated with implantable atrial defibrillation therapy: effect of nocturnal shock delivery and psychological distress.

INTRODUCTION: The Medtronic ICD-AT has atrial/ventricular therapies, which can be programmed to deliver atrial defibrillation during sleep, intended to potentially decrease shock anxiety/pain and lifestyle disruption. However, these shocks may diminish sleep quality. This study examined atrial shock characteristics (i.e., mode, frequency), AF symptoms, and psychological factors as determinants of sleep quality. METHODS AND RESULTS: The 96 ICD-AT patients were mostly men (72%; M age 65 +/- 12 years) and implanted for 1.6 years (SD = 0.8 years). Patients were divided into shock groups based on the proportion of mode (> or =90%) of total atrial shocks received. Patients were grouped into either automatic-nocturnal shock group (8 P.M.-8 A.M.; n = 35) or manual-awake shock group (n = 42). Psychological measures included Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiology Studies-Depression Scale, State-Trait Anxiety Inventory, and Illness Intrusiveness Rating Scale. Atrial fibrillation disease burden was assessed via atrial symptom score and atrial shock use. PSQI global scores were similar between manual (7.67 +/- 2.53) and automatic shock (8.20 +/- 2.93) groups. A multiple hierarchical regression analysis indicated that no atrial shock variables were predictive of sleep quality; yet, both AF symptom (B = 0.226, P = 0.040) and depression (B = 0.392, P = 0.034) scores predicted diminished sleep quality, accounting for 42% of the variance in global sleep quality (P < 0.001). CONCLUSION: These results suggest that atrial defibrillation therapy does not have a deleterious impact on sleep. However, the significance of AF symptoms and depression indicate that comprehensive care of both physical and psychological symptomatology may improve sleep quality in ICD-AT patients.

The effects of different types of music on perceived and physiological measures of stress.

The effects of different types of music on perceived and physiological measures of stress were evaluated. Sixty undergraduate psychology students, 31 males and 29 females, rated their level of relaxation and completed the State-Trait Anxiety Inventory (STAI) after they were told that they would be taking a stressful, mental test. Participants were randomly assigned to listen to different types of music or silence while skin temperature, frontalis muscle activity, and heart rate were recorded. Participants rated their relaxation and anxiety levels after listening to music or silence and completed the Mental Rotations Task Test. MANOVA's resulted in significant differences between groups for trait anxiety, F(57, 3) = 3.058, p =.036, and postmusic phase heart rate, F(57, 3) = 3.522, p =.021. Significant differences were also found between groups on state anxiety when trait anxiety was used as a covariate, F(57, 3) = 3.95, p =.024. The results of the research suggest that music may have an effect on the cognitive component of the stress response.