RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1.

The chromatin-binding protein 53BP1 promotes DNA repair by orchestrating the recruitment of downstream effectors including PTIP, RIF1, and shieldin to DNA double-strand break sites. While we know how PTIP recognizes 53BP1, the molecular details of RIF1 recruitment to DNA-damage sites remains undefined. Here, we report that RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes. The RIF1-binding sites on 53BP1 share an essential LxL motif followed by two closely apposed phosphorylated residues. Simultaneous mutation of these sites on 53BP1 abrogates RIF1 accumulation into ionizing-radiation-induced foci, but surprisingly, only fully compromises 53BP1-dependent DNA repair when an alternative mode of shieldin recruitment to DNA-damage sites is also disabled. Intriguingly, this alternative mode of recruitment still depends on RIF1 but does not require its interaction with 53BP1. RIF1 therefore employs phosphopeptide recognition to promote DNA repair but also modifies shieldin action independently of 53BP1 binding.

Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study.

OBJECTIVES: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population. METHODS: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas). RESULTS: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses. CONCLUSIONS: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA.

Vomeronasal organ volume increases with body size and is dissociated with the loss of a visual signal in Sceloporus lizards.

Many organisms communicate using signals in different sensory modalities (multicomponent or multimodal). When one signal or component is lost over evolutionary time, it may be indicative of changes in other characteristics of the signalling system, including the sensory organs used to perceive and process signals. Sceloporus lizards predominantly use chemical and visual signals to communicate, yet some species have lost the ancestral ventral colour patch used in male-male agonistic interactions and exhibit increased chemosensory behaviour. Here, we asked whether evolutionary loss of this sexual signal is associated with larger vomeronasal organ (VNO) volumes (an organ that detects chemical scents) compared with species that have retained the colour patch. We measured VNO coronal section areas of 7-8 adult males from each of 11 Sceloporus species (4 that lost and 7 that retained the colour patch), estimated sensory and total epithelium volume, and compared volumes using phylogenetic analysis of covariance, controlling for body size. Contrary to expectations, we found that species retaining the ventral patch had similar relative VNO volumes as did species that had lost the ancestral patch, and that body size explains VNO epithelium volume. Visual signal loss may be sufficiently compensated for by increased chemosensory behaviour, and the allometric pattern may indicate sensory system trade-offs for large-bodied species.

HELB Is a Feedback Inhibitor of DNA End Resection.

DNA double-strand break repair by homologous recombination is initiated by the formation of 3' single-stranded DNA (ssDNA) overhangs by a process termed end resection. Although much focus has been given to the decision to initiate resection, little is known of the mechanisms that regulate the ongoing formation of ssDNA tails. Here we report that DNA helicase B (HELB) underpins a feedback inhibition mechanism that curtails resection. HELB is recruited to ssDNA by interacting with RPA and uses its 5'-3' ssDNA translocase activity to inhibit EXO1 and BLM-DNA2, the nucleases catalyzing resection. HELB acts independently of 53BP1 and is exported from the nucleus as cells approach S phase, concomitant with the upregulation of resection. Consistent with its role as a resection antagonist, loss of HELB results in PARP inhibitor resistance in BRCA1-deficient tumor cells. We conclude that mammalian DNA end resection triggers its own inhibition via the recruitment of HELB.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Differences in children's exposure to television advertising of unhealthy foods and beverages in Spain by socio-economic level.

BACKGROUND: The influence of food advertising on food preferences and consumption could also contribute to the socio-economic inequalities among Spanish children in terms of eating habits and childhood obesity. Although the main food advertising channel targeted at children in Spain is television, available studies estimate exposure indirectly by combining content data with audience data. The aim of this study was therefore to describe the frequency of exposure to television advertising of unhealthy foods and drinks, measured directly, among Spanish children and adolescents, and analyse its socio-economic inequalities. METHODS: Observational study of television advertising impacts in a sample of 1590 children aged 4 to 16 years drawn from a consumer panel representative of the Spanish population in this age group, over the course of a full week of broadcasting in February 2022. The sample was obtained through stratified random sampling by Autonomous Region, with quotas being set by reference to socio-demographic variables. Exposure was measured with an audiometer, and the nutrient content of the food and drink advertised was analysed using the nutrient profile of the WHO Regional Office for Europe. We used the Chi-squared test to analyse possible differences in advertising coverage by socio-economic level. RESULTS: The participants saw a weekly mean of 82.4 food and drink commercials, 67.4 of which were for unhealthy products (81.8%), mostly outside the child-protection time slot. On average, low-social class participants received 94.4% more impacts from unhealthy food and drink advertising than did high-class participants (99.9 vs. 51.4 respectively). The mean advertising coverage of unhealthy foods and drinks was 71.6% higher in low-class than in high-class participants (10.9% vs. 18.7%; p = 0.01). CONCLUSION: Spanish children and adolescents received an average of 10 impacts per day from television spots for unhealthy foods and drinks. The exposure of low-class children is double that of high-class children, a finding compatible with the high prevalence of childhood obesity in Spain and the related socio-economic inequalities. To protect Spanish minors from the harmful effects of food advertising and reduce the related social health inequalities would require the implementation of a 24:00 watershed for unhealthy food advertising on television.

Non-human Clostridioides difficile Reservoirs and Sources: Animals, Food, Environment.

Clostridioides difficile is ubiquitous and is found in humans, animals and in variety of environments. The substantial overlap of ribotypes between all three main reservoirs suggests the extensive transmissions. Here we give the overview of European studies investigating farm, companion and wild animals, food and environments including water, soil, sediment, wastewater treatment plants, biogas plants, air, and households. Studies in Europe are more numerous especially in last couple of years, but are still fragmented in terms of countries, animal species, or type of environment covered. Soil seem to be the habitat of divergent unusual lineages of C. difficile. But the most important aspect of animals and environment is their role in C. difficile transmissions and their potential as a source for human infection is discussed.

Russell body duodenitis: a rare condition.

Russell bodies are accumulations of immunoglobulins within hyperstimulated plasma cells of the intestinal mucosa associated with chronic inflammation of benign progression, but may be confused with lymphoplasmacytic lymphoma, MALT lymphoma, multiple myeloma, or "signet-ring" cells, among others. There are few cases of gastric involvement, but duodenal involvement is even rarer with less than 10 published cases. Endoscopic examination with quality biopsies and anatomopathologic analysis with immunohistochemistry are essential to make an adequate differential diagnosis with other more severe processes. In any case, the treatment is that of the underlying disease.

Accuracy of estimating self and other body size among adolescent girls with anorexia nervosa.

This study aimed to analyze body size estimates of others by patients with anorexia nervosa (AN) and to identify any differences with the perception of their own body size. Adolescent females (age, 13-17 years) were enrolled into AN (n = 30) and control(n = 23) groups. The Subjective Body Dimensions Apparatus (SBDA) was used to evaluate body size estimates for oneself (self-estimation) and others (other-estimation). Participants also completed questionnaires assessing eating disorders and depressive symptoms. The AN and control groups scored significantly higher in self-estimation than in other-estimation. However, the AN group showed higher self-estimation scores than the control group for all the body parts and for the global silhouette (p < .001). Patients with more severe eating disorder symptomatology showed more distorted self-estimation (p < .05). No statistically significant differences were found in the other-estimation scores between the groups (p = .714), indicating that AN and control patients estimate the body sizes of others similarly. Eating disorder symptomatology correlates with self-estimation scores but not with other-estimation scores in adolescents with AN. No correlations existed between clinical symptomatology and other-estimation.

Family-Oriented Therapeutic Conversations: A Systematic Scoping Review.

There is increasing evidence that highlights the benefits of Family-oriented Therapeutic Conversations (FAM-TC) for the patient and the family; however, studies show variability regarding the content and the way these interventions are offered. This may hamper its further development in clinical practice. This review systematically maps the available literature on nurse-led FAM-TC and offers a solid synthesis of the characteristic, effectiveness, and feasibility of these interventions. A systematic search in PubMed, CINAHL, Cochrane, Web of Science, PsycINFO, Trip (Turning Research Into Practice), BASE (Bielefeld Academic Search Engine), OATD (Open Access Theses and Dissertations), and ProQuest databases identified 37 studies. The interventions varied in interventionist nurses' profile, the intervention content, or the duration of the sessions offered. Most of the interventions showed beneficial effects on perceived family support and family functioning. This review offers suggestions for future studies, such as the inclusion of specific theoretical frameworks for intervention design, targeting both the patient and the family and offered by nurses with family nursing competency.

Neuronal and astrocytic tetraploidy is increased in drug-resistant epilepsy.

AIMS: Epilepsy is one of the most prevalent neurological diseases. A third of patients with epilepsy remain drug-resistant. The exact aetiology of drug-resistant epilepsy (DRE) is still unknown. Neuronal tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE. METHODS: For that purpose, cortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Post-mortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases was used as control. RESULTS: The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100ß) followed by flow cytometry analysis. The results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests. A total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analysed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p = 0.020) and astrocytes (p = 0.002) in the hippocampus than controls. These results were validated by image cytometry. CONCLUSIONS: We demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects as well as increased levels of both cell populations in DRE patients. Herein, we describe for the first time the presence of tetraploid astrocytes in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment.

Oleic acid regulates the circadian rhythm of adipose tissue in obesity.

The effect of oleic acid (OA) on the regulation of the circadian rhythm present in human visceral (VAT) and subcutaneous (SAT) adipose tissue from patients with morbid obesity has not been analyzed yet. VAT and SAT explants from patients with morbid obesity were incubated with OA to analyze the circadian regulation of clock and other genes related to lipid metabolism (SREBP-1c, FAS, LPL and CPT1), and their association with baseline variables and the improvement of these patients after bariatric surgery. There were significant differences in amplitude and acrophase in VAT with respect to SAT. In VAT, body weight negatively correlated with BMAL1 and CRY1 amplitude, and REVERBα acrophase; body mass index (BMI) negatively correlated with REVERBα acrophase; and waist circumference negatively correlated with PER3 acrophase. In SAT, BMI negatively correlated with CLOCK amplitude, and CLOCK, REVERBα and CRY2 MESOR; and waist circumference negatively correlated with PER3 amplitude and acrophase. A greater short-term improvement of body weight, BMI and waist circumference in patients with morbid obesity after bariatric surgery was associated with a lower CRY1 and CRY2 amplitude and an earlier PER1 and PER3 acrophase in SAT. OA produced a more relevant circadian rhythm and increased the amplitude of most clock genes and lipid metabolism-related genes. OA regulated the acrophase of most clock genes in VAT and SAT, placing CLOCK/BMAL1 in antiphase with regard to the other genes. OA increased the circadian rhythmicity, although with slight differences between adipose tissues. These differences could determine its different behavior in obesity.

IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis.

Insulin and insulin-like growth factor type I (IGF-1) play prominent roles in brain activity throughout the lifespan. Insulin/IGF1 signaling starts with the activation of the intracellular insulin receptor substrates (IRS). In this work, we performed a comparative study of IRS1 and IRS2, together with the IGF1 (IGF1R) and insulin (IR) receptor expression in the hippocampus and prefrontal cortex during development. We found that IRS1 and IRS2 expression is prominent during development and declines in the aged hippocampus, contrary to IR, which increases in adulthood and aging. In contrast, IGF1R expression is unaffected by age. Expression patterns are similar in the prefrontal cortex. Neurite development occurs postnatally in the rodent hippocampus and cortex, and it declines in the mature and aged brain and is influenced by trophic factors. In our previous work, we demonstrated that knockdown of IRS1 by shRNA impairs learning and reduces synaptic plasticity in a rat model, as measured by synaptophysin puncta in axons. In this study, we report that shIRS1 alters spine maturation in adult hilar hippocampal neurons. Lastly, to understand the role of IRS1 in neuronal neurite tree, we transfect shIRS1 into primary neuronal cultures and observed that shIRS1 reduced neurite branching and neurite length. Our results demonstrate that IRS1/2 and insulin/IGF1 receptors display different age-dependent expression profiles and that IRS1 is required for spine maturation, demonstrating a novel role for IRS1 in synaptic plasticity.

Ultrasound findings in painful spastic hip. Muscle thickness in children with cerebral palsy.

BACKGROUND: In cerebral palsy (CP), spasticity is the dominant symptom and hip pain is one of the most common secondary conditions. Aetiology is not clear. Musculoskeletal ultrasound (MSUS) is a low-cost, non-invasive imaging technique that allows assessment of structural status, dynamic imaging, and quick contralateral comparison. OBJECTIVE: A retrospective case-matched-control study. To investigate associated factors with painful spastic hip and to compare ultrasound findings (focusing on muscle thickness) in children with CP vs. typically developing (TD) peers. SETTING: Paediatric Rehabilitation Hospital in Mexico City, from August to November 2018. PARTICIPANTS: 21 children (13 male, 7 + 4.26 years) with CP, in Gross Motor Function Classification System (GMFCS) levels IV to V, with spastic hip diagnosis (cases) and 21 children age- and sex-matched (7 + 4.28 years) TD peers (controls). CHARACTERISTICALLY DATA: Sociodemographic data, CP topography, degree of spasticity, mobility arch, contractures, Visual Analog Scale (VAS), GMFCS, measurements of the volumes of eight major muscles of the hip joint and MSUS findings of both hips. RESULTS: All children with CP group reported chronic hip pain. Associated factors for hip pain (high VAS hip pain score) were degree of hip displacement (percentage of migration), Ashworth Level, GMFCS level V. No synovitis, bursitis or tendinopathy was found. Significant differences (p < 0.05) were found in muscle volumes in all hip muscles (right and left) except in the right and left adductor longus. CONCLUSION: Though possibly the most important issue with diminished muscle growth in CP children is the influence on their long-term function, it is likely that training routines that build muscle size may also increase muscle strength and improve function in this population. To improve the choice of treatments in this group and maintain muscle mass, longitudinal investigations of the natural history of muscular deficits in CP as well as the impact of intervention are needed.

Psoas muscle analysis as a surrogate marker of sarcopenia and frailty: A multicenter analysis of predictive capacities over short- and long-term outcomes after abdominal aortic aneurysm repair.

OBJECTIVES: Several predictive models exist for estimating the postoperative risks of abdominal aortic aneurysm (AAA) repair, although no particular tool has seen widespread use. We present the results of a multicenter, historic cohort study comparing the predictive capacity of the psoas muscle area (PMA), radiodensity (PMD), and lean muscle area (LMA) as surrogate markers of sarcopenia, over short- and long-term outcomes after AAA repair, compared to the mFI-5 and American Society of Anesthesiologists (ASA) scales. METHODS: Retrospective review was conducted of all consecutive AAA elective repair cases (open or endovascular) in three tertiary-care centers from 2014 to 2019. Cross-sectional PMA, PMD, and LMA at the mid-body of the L3 vertebra were measured by two independent operators in the preoperative computed tomography. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values. Bivariate analysis, logistic regression, and Cox's proportional hazards models were built to examine the relationship between baseline variables and postoperative mortality, long-term mortality, and complications. RESULTS: 596 patients were included (mean age 72.7 ± 8 years, 95.1% male, 66.9% EVAR). Perioperative mortality was 2.3% (EVAR 1.2% vs open repair 4.6%, p = .015), and no independent predictors could be identified in the multivariate analysis. Conversely, an age over 74 years old (OR 1.84 95%CI 1.25-2.70), previous heart diseases (OR 1.62 95%CI 1.13-2.32), diabetes mellitus (OR 1.61 95%CI 1.13-2.32), and a PMD value over 66 HU (OR 0.58 95%CI 0.39-0.84) acted as independent predictors of long-term mortality in the Cox's proportional hazards model. Heart diseases (congestive heart failure or coronary artery disease), serum creatinine levels over 1.05 mg/dL, and an aneurysm diameter over 60 mm were independent predictors of major complications. CONCLUSION: Surrogate markers of sarcopenia had a poor predictive profile for postoperative mortality after AAA repair in our sample. However, PMD stood out as an independent predictor of long-term mortality. This finding can guide future research and should be confirmed in larger datasets.

Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by APOE4 Status.

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aß) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Depositions might be related to the circulating IAPP levels, but it warrants further investigation. Autoantibodies recognizing toxic IAPP oligomers (IAPPO) but not monomers (IAPPM) or fibrils have been found in T2D, but studies on AD are lacking. In this study, we have analyzed plasma from two cohorts and found that levels of neither immunoglobulin (Ig) M, nor IgG or IgA against IAPPM or IAPPO were altered in AD patients compared with controls. However, our results show significantly lower IAPPO-IgA levels in apolipoprotein E (APOE) 4 carriers compared with non-carriers in an allele dose-dependent manner, and the decrease is linked to the AD pathology. Furthermore, plasma IAPP-Ig levels, especially IAPP-IgA, correlated with cognitive decline, C-reactive protein, cerebrospinal fluid Aß and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPPO-IgA levels may be caused by increased plasma IAPPO levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPPO, which may influence the amount of IAPP deposition in the AD brain.

Role of Mitochondria in Inflammatory Bowel Diseases: A Systematic Review.

Mitochondria are key cellular organelles whose main function is maintaining cell bioenergetics by producing ATP through oxidative phosphorylation. However, mitochondria are involved in a much higher number of cellular processes. Mitochondria are the home of key metabolic pathways like the tricarboxylic acid cycle and ß-oxidation of fatty acids, as well as biosynthetic pathways of key products like nucleotides and amino acids, the control of the redox balance of the cell and detoxifying the cell from H2S and NH3. This plethora of critical functions within the cell is the reason mitochondrial function is involved in several complex disorders (apart from pure mitochondrial disorders), among them inflammatory bowel diseases (IBD). IBD are a group of chronic, inflammatory disorders of the gut, mainly composed of ulcerative colitis and Crohn's disease. In this review, we present the current knowledge regarding the impact of mitochondrial dysfunction in the context of IBD. The role of mitochondria in both intestinal mucosa and immune cell populations are discussed, as well as the role of mitochondrial function in mechanisms like mucosal repair, the microbiota- and brain-gut axes and the development of colitis-associated colorectal cancer.

The Metagenomic Composition and Effects of Fecal-Microbe-Derived Extracellular Vesicles on Intestinal Permeability Depend on the Patient's Disease.

The composition and impact of fecal-microbe-derived extracellular vesicles (EVs) present in different diseases has not been analyzed. We determined the metagenomic profiling of feces and fecal-microbe-derived EVs from healthy subjects and patients with different diseases (diarrhea, morbid obesity and Crohn's disease (CD)) and the effect of these fecal EVs on the cellular permeability of Caco-2 cells. The control group presented higher proportions of Pseudomonas and Rikenellaceae_RC9_gut_group and lower proportions of Phascolarctobacterium, Veillonella and Veillonellaceae_ge in EVs when compared with the feces from which these EVs were isolated. In contrast, there were significant differences in 20 genera between the feces and EV compositions in the disease groups. Bacteroidales and Pseudomonas were increased, and Faecalibacterium, Ruminococcus, Clostridium and Subdoligranum were decreased in EVs from control patients compared with the other three groups of patients. Tyzzerella, Verrucomicrobiaceae, Candidatus_Paracaedibacter and Akkermansia were increased in EVs from the CD group compared with the morbid obesity and diarrhea groups. Fecal EVs from the morbid obesity, CD and, mainly, diarrhea induced a significant increase in the permeability of Caco-2 cells. In conclusion, the metagenomic composition of fecal-microbe-derived EVs changes depending on the disease of the patients. The modification of the permeability of Caco-2 cells produced by fecal EVs depends on the disease of the patients.

Psychometric Evaluation of the Spanish Families Importance in Nursing Care: Nurses' Attitudes Scale Through Classical Test Theory and Rasch Analysis.

Nurses' attitudes toward families play an important role in improving relationships with patients' families. It is essential to have valid and reliable instruments to assess nurses' attitudes toward involving families. The aim of this study was to analyze the psychometric properties of the refined Spanish version of the Families' Importance in Nursing Care-Nurses' Attitudes (FINC-NA) according to classical test theory and the Rasch model (N = 263). Cronbach's alpha values were .73 to .87 and intraclass correlation coefficients ranged from .72 to .86. Rasch analysis results suggested that it was a multidimensional scale with four dimensions and a simpler response scheme than the original scale. Except for one item, the scale was free from bias regarding age and experience time. The FINC-NA is a reliable and valid measure showing a good fit to the Rasch model and is ready to map nurses' attitudes and measure the effectiveness of family nursing educational interventions.

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. METHODS: We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining. RESULTS: Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. CONCLUSIONS/INTERPRETATION: We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.