Prednisolone Versus Colchicine for Acute Gout in Primary Care: statistical analysis plan for the pragmatic, multicenter, randomized, and double-blinded COPAGO non-inferiority trial.

BACKGROUND: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. STUDY DESIGN: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. STATISTICAL ANALYSIS PLAN: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes. DISCUSSION: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

From Maltreatment to Psychiatric Disorders in Childhood and Adolescence: The Relevance of Emotional Maltreatment.

Different forms of maltreatment are thought to incur a cumulative and non-specific toll on mental health. However, few large-scale studies draw on psychiatric diagnoses manifesting in early childhood and adolescence to identify sequelae of differential maltreatment exposures, and emotional maltreatment, in particular. Fine-grained multi-source dimensional maltreatment assessments and validated age-appropriate clinical interviews were conducted in a sample of N = 778 3 to 16-year-olds. We aimed to (a) substantiate known patterns of clinical outcomes following maltreatment and (b) analyse relative effects of emotional maltreatment, abuse (physical and sexual), and neglect (physical, supervisory, and moral-legal/educational) using structural equation modeling. Besides confirming known relationships between maltreatment exposures and psychiatric disorders, emotional maltreatment exerted particularly strong effects on internalizing disorders in older youth and externalizing disorders in younger children, accounting for variance over and above abuse and neglect exposures. Our data highlight the toxicity of pathogenic relational experiences from early childhood onwards, urging researchers and practitioners alike to prioritize future work on emotional maltreatment.

Being an Infant in a Pandemic: Influences of the COVID-19 Pandemic on Infants, Toddlers and Their Mothers in a Clinical Population.

The COVID-19 pandemic and the ongoing lockdowns might have had a strong impact on mental health of mothers and their infants/toddlers. For example, families had to deal with health issues and social isolation, which might have affected mental health and parent-child interactions. The aim of this study is to evaluate differences in (1) infantile regulatory disorders, (2) maternal mental health, (3) the impact of maternal mental health on infantile regulatory disorders, and (4) alterations in the mother-child interaction for participants recruited before versus after the onset of the first German lockdown. For this reason, mother-child dyads have been divided into two groups and were compared by analyzing clinical interviews on psychopathology of mother and child (M.I.N.I. & DC:05) and mother-child-interactions (Emotional Availability Scales). Results showed that (1) differences in infantile sleeping disorders emerged (phi = 0.243; p = 0.016) compared to the pre-lockdown group, while (2) the occurrence of maternal panic and anxiety increased in the post-lockdown group (phi = 0.229; p = 0.022). Moreover, there was (3) an association for maternal panic and child's sleep disorder, and (4) specific associations with maternal non-hostility in the mother-child-interaction. In conclusion, the present study highlights the differences of maternal mental health occurrences and infants' regulatory problems, as well as the possible effects of the COVID-19 pandemic for infants. In the pre-lockdown group, maternal non-hostility might have acted as a promotive factor against regulatory disorders, while this mechanism was mitigated in the post-lockdown group.

Assessment and Diagnostic Classification Using DC:0-5 in Early Childhood Mental Health Clinics: The Protocol for the Developmental Psychiatry Diagnostic Challenges Study (DePsy).

Mental health problems in early childhood are common, but there is a lack of psychiatric research on this age group. DC:0-5 is a multiaxial classification system for mental disorders in early childhood, providing a framework for standardizing clinical practice and research. However, research on the validity of DC:0-5 is scarce. The Developmental Psychiatry Diagnostic Challenges Study (DePsy) is a multi-site, prospective clinical study including six German early childhood mental health (ECMH) clinics. The main objective of the study is to contribute to the validation of Axis I and Axis II of DC:0-5. A second aim of the study is to describe the population of the participating clinics regarding diagnoses, family context, and treatment outcomes. Additionally, the impact of environmental risk factors, including parental Adverse Childhood Experiences (ACEs) and media use, on child psychopathology and caregiver-child relationships will be examined. Over two years, patients aged 0.0-5.9 years old will be enrolled in the study. Assessments include ICD-10 and DC:0-5 diagnoses, developmental tests, video-based observations of caregiver-child interactions, and questionnaires on child psychopathology, media use, parental stress, and treatment satisfaction. Study results will promote the standardization of assessment and treatment in ECMH clinics aiming to improve the development of patients and their families.

Birth-related, medical, and diagnostic characteristics in younger versus older children with avoidant/restrictive food intake disorder (ARFID).

BACKGROUND: Although avoidant/restrictive food intake disorder (ARFID) presents the replacement and extension of feeding disorders of infancy and childhood, previous research into ARFID concentrated mainly on older patients. While birth-related characteristics play an etiologic role in feeding disorders, virtually nothing is known so far in ARFID. Therefore, the first aim of the study was to identify differences in birth-related characteristics in younger vs. older children with ARFID. Second, differences in physical and mental comorbidities, and third, diagnostic features between age groups were analysed. METHODS: Among N = 51 in- and outpatient treatment-seeking patients, n = 23 patients aged 0-5 years (30% girls) and n = 28 patients aged 6-17 years (57% girls), with an interview-based diagnosis of ARFID were included. Data on the pre- and perinatal period and mental and physical comorbidities were derived from patients' medical records, while diagnostic criteria, main ARFID presentation, and sociodemographic variables were collected through diagnostic interview. RESULTS: Significantly, younger patients with ARFID were born more often preterm and had more pre- and perinatal complications and a higher incidence of postnatal invasive procedures. Patients with ARFID aged 0-5 years presented significantly more physical comorbidities and conditions, especially congenital anomalies, while mental comorbidities, especially mood disorders, were significantly more common in patients with ARFID aged 6-17 years. No age differences were found for the distribution of diagnostic criteria and main ARFID presentation. CONCLUSION: This is the first study which aimed to identify age-specific characteristics in patients with ARFID with potential relevance for diagnosis and treatment. Especially birth-related complications, including invasive procedures postnatally, may be associated with developing ARFID, highlighting the importance of a closer view on these potential risk factors of the disorder. Future research with longitudinal design and larger samples may allow more detailed information on further age-specific associations, symptom trajectories, and age-specific risk factors for ARFID.

Avoidant/restrictive food intake disorder (ARFID) is a feeding and eating disorder characterized by a highly limited amount and/or variety of food intake accompanied by weight loss or reduced growth, nutritional deficiencies, the dependency on enteral nutrition or oral nutritional supplements, or psychosocial impairment. Although the knowledge about ARFID is currently expanding, there is still a lack of information whether the disorder presents differentially among younger and older youths. The present study examined n = 23 children aged 0­5 years in comparison to n = 28 patients aged 6­17 years in birth-related, medical, and diagnostic features. ARFID was assessed by clinical interview and questionnaire data, and medical records were used to derive clinical information. While younger patients with ARFID were more likely to be born preterm, had complications after birth and more co-occurring physical diseases, older patients with ARFID showed more mental illnesses. These findings underline the relevance of further investigations on age-dependent characteristics of ARFID to adapt diagnostic assessment and treatment of the disorder. No significant age differences were found for diagnostic criteria and presentations of ARFID, indicating that these features are applicable for patients of all child ages.

Prednisolone Versus Colchicine for Acute Gout in Primary Care (COPAGO): protocol for a two-arm multicentre, pragmatic, prospective, randomized, double-blind, controlled clinical trial of prednisolone and colchicine for non-inferiority with a parallel group design.

BACKGROUND: Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen. METHODS: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients' global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed. DISCUSSION: This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680.

Past attachment experiences, the potential link of mentalization and the transmission of behavior to the child by mothers with mental health problems: cross-sectional analysis of a clinical sample.

Maternal capacity to mentalize (= reflective functioning, RF), secure attachment and emotionally available parenting has an impact on the child's development. The transmission of mothers' past attachment experiences gained with both her caregivers in her own childhood and the impact on current mother-child interaction is part of the 'transmission gap.' This study explores the transgenerational transmission mechanisms and the potential moderating effect of RF in a clinical sample of 113 mother-child dyads suffering from mental health problems. In a cross-sectional study, the associations between maternal attachment experiences, RF (coded based on Adult Attachment Interviews) and current mother-child interaction (Emotional Availability Scales) were examined with univariate correlation, moderator analyses, and structural equation models. We found relationships between attachment experiences and mother-child interaction, but RF had no moderating effect. Past loving experiences and perceived neglection, particularly with the own father in childhood, were predictors for the present mother-child interaction. There seems to be an intergenerational transmission of attachment experiences to the ongoing generation. Particularly past adverse childhood experiences with the own father seem to explain currently disruptive interactions with the child.Trial registration: DRKS00017008 and DRKS00016353.

Distribution and clinical comparison of restrictive feeding and eating disorders using ICD-10 and ICD-11 criteria.

OBJECTIVE: Within the eleventh edition of the International Classification of Diseases (ICD-11), diagnostic criteria for feeding and eating disorders were revised and new diagnoses including avoidant/restrictive food intake disorder (ARFID) are classifiable; however, nothing is known about how these changes affect the prevalence of feeding and eating disorders. This study compared the distribution and clinical characteristics of restrictive feeding and eating disorders between ICD-10 and ICD-11. METHOD: The Eating Disorder Examination (EDE), its child version, and the EDE ARFID module were administered to N = 82 patients (0-17 years) seeking treatment for restrictive feeding and eating disorders and their parents. Clinical characteristics were derived from medical records, questionnaires, and objective anthropometrics. RESULTS: The number of residual restrictive eating disorders (rrED) significantly decreased from ICD-10 to ICD-11 due to a crossover to full-threshold disorders, especially anorexia nervosa (AN) or ARFID. Patients reclassified to ICD-11 ARFID were younger, had an earlier age of illness onset, more restrictive eating behaviors, and tended to have more somatic comorbidities compared to those reclassified to ICD-11 AN. Patients with rrED according to both ICD-10 and ICD-11 were younger, had an earlier age of illness onset, less shape concern, and more somatic comorbidities than patients who were reclassified from ICD-10 rrED to ICD-11 AN or ARFID. DISCUSSION: This study highlights the inclusive approach of ICD-11 criteria, paving the way for more targeted treatment, and ARFID's high clinical relevance. Future studies considering nonrestrictive feeding and eating disorders across the life span may allow further analyses on diagnostic crossover. PUBLIC SIGNIFICANCE: Changes in diagnostic criteria for restrictive eating disorders within the newly published ICD-11 led to an increase in full-threshold disorders, while the number of rrED was significantly lowered compared to ICD-10 criteria. The results thus highlight the diagnostic utility of ICD-11 criteria and may help providing adequate treatment to children and adolescents with rrED.

Validation study on the child, adult, and parent version of the ARFID module 2.0 for the Eating Disorder Examination.

OBJECTIVE: This study presents a psychometric evaluation of the avoidant/restrictive food intake disorder (ARFID) module 2.0 for the Eating Disorder Examination (EDE), its child (ChEDE), and parent version. Within a pediatric sample seeking treatment for restrictive feeding or eating disorders and non-treatment-seeking controls, the module's interrater reliability, parent-child agreement, and its convergent, divergent, and discriminant validity were examined. METHOD: The child, adult, and/or parent version of the German ARFID module was administered to N = 176 children and adolescents (0-17 years) and their parents, as were the (Ch)EDE, well-established measures on food-avoidance behaviors, food variety, and body esteem, and objective anthropometric measures. RESULTS: Across all versions of the ARFID module, substantial to almost perfect interrater reliability was shown. Parent-child agreement for ARFID diagnosis was substantial. Based on medium-to-large associations between interview-assessed avoidant/restrictive food intake and questionnaire-assessed food-avoidance behaviors, food variety, and objective weight status, the module showed high convergent validity, especially for the child and parent version. Low associations of avoidant/restrictive food intake with weight and shape concern demonstrated divergent validity. Individuals with ARFID differed significantly from those with anorexia nervosa and individually matched controls in a range of clinical characteristics, indicating discriminant validity. DISCUSSION: This comprehensive validation supports the EDE ARFID module to be a valuable measure for the assessment and diagnosis of ARFID in 0-17-year-olds based on self- and parent-report. Validation of the ARFID module against other interview-based measures on ARFID and its evaluation in an adult sample are pending. PUBLIC SIGNIFICANCE: Based on good reliability and validity of the avoidant/restrictive food intake disorder (ARFID) module for the Eating Disorder Examination (EDE) in its child, adult, and parent version, the present study paves the way for the clinical and research use of the interview-based EDE ARFID module for assessing ARFID across childhood and adolescence.

Maternal sensitivity and intrusiveness in early childhood as predictors of children's weight at school age.

BACKGROUND: While previous research indicates that low maternal sensitivity in mother-child interactions puts children at risk of overweight and obesity, maternal intrusiveness has rarely been investigated in association with children's weight. We investigated whether maternal sensitivity and intrusiveness in early childhood predict children's increased body mass index standard deviation scores (BMI-SDS) at school age. BMI-SDS are standardized for age and gender with respect to a reference standard. METHODS: At baseline (t1), we assessed maternal sensitivity and (non-)intrusiveness of 116 mothers with their children (48.3% female) aged 5-47 months (M = 24.00, SD = 11.36) using the emotional availability scales. We obtained anthropometric data for mothers at t1 by measuring height and weight in the laboratory and for children at birth assessed by medical staff. Six years later (t2) we obtained anthropometric data for children in the laboratory or based on parental report. Linear regression analyses were run with child BMI-SDS at t2 as outcome and sensitivity and (non-)intrusiveness as predictors, adjusting for confounders and exploring child age and gender as moderators. RESULTS: Maternal sensitivity only negatively predicted children's BMI-SDS in girls, while maternal intrusiveness predicted higher child BMI-SDS at school age regardless of child gender. The effect of maternal non-intrusiveness remained significant when controlling for confounders. CONCLUSION: Maternal intrusiveness in early childhood seems to represent a risk factor for increased BMI-SDS in children, while lower maternal sensitivity tends to be a risk factor for increased BMI-SDS in girls. This may have implications for prevention or intervention programmes.

"Our difficult job is to take a unified view of the patient " (Winnicott) Psychosomatic work in a children's hospital.

We present our work as psychoanalysts in the interdisciplinary psychosomatic unit of a paediatric hospital. As the starting point for our work we use Winnicott's understanding of the psychosomatic dilemma delineated in his paper on psychosomatic illness in its positive and negative aspects. The central hypothesis is that splitting the medical field into many highly specialized fields can be understood as a display of the psychosomatic patients' inner need for splitting and their defence against integration. Based on four case examples from different developmental periods, we demonstrate the interconnectedness of the relational environment, developmental processes, and psychic and biological conditions, and show how early experiences of threat and deprivation can cause the soma-psyche unit to fragment. Drawing on several psychoanalytic psychosomatic schools, we delineate treatment principles of the psychoanalytic contribution to the interdisciplinary work and of the individual psychoanalytic treatment.

Efficacy of parent-infant psychotherapy compared to care as usual in children with regulatory disorders in clinical and outpatient settings: study protocol of a randomised controlled trial as part of the SKKIPPI project.

BACKGROUND: The first years of life are a significant period for child development, when children are particularly sensitive and prone to crises. This early phase lays the foundation for healthy growth. Clinical assessment of psychological symptoms in early infancy and adequate treatment are both important in improving the diagnostic outcome and preventing later long-term developmental consequences. The most common psychological problems in the first 3 years of life are regulatory disorders. The aim of this trial is to investigate the efficacy of Parent-Infant Psychotherapy (PIP) for infants and young children (aged 0-36 months, diagnosed with at least one regulatory disorder) and their mothers, compared to care as usual (CAU). METHODS: In this open multicentre randomised controlled trial, 160 mother-infant dyads are randomised to receive PIP or CAU for 6 weeks of intervention in clinical or outpatient (including home treatment) settings. The primary outcome is the maternal sensitivity (sensitivity scale of the Emotional Availability Scales (EAS)) after 6 weeks. Secondary outcomes include assessment of interaction, mental health problems, attachment, development, psychological factors, treatment adherence, health care system utilisation, and costs, after 6 weeks and 12 months. DISCUSSION: This study will evaluate whether a manualised focus-based short-term psychodynamic psychotherapeutic intervention in mother-child dyads improves the care situation for families of children diagnosed with regulatory disorders, and helps prevent long-term psychopathologies. Assessment of the intervention in different settings will support the development of more tailored interventions for affected infants and their mothers. TRIAL REGISTRATION: German Clinical Trial Register, ID: DRKS00017008 . Registered 03/20/2019.

Macro- and Micronutrient Intake in Children with Avoidant/Restrictive Food Intake Disorder.

Although case studies in avoidant/restrictive food intake disorder (ARFID) indicate severe nutritional deficiencies in those with a highly limited amount or variety of food intake, systematic analyses on food intake in treatment-seeking children and adolescents with ARFID are lacking. Within this study, n = 20 patients with an interview-based diagnosis of ARFID (0-17 years) were included and compared to n = 20 healthy controls individually matched for age and sex. Children or parents completed three-day food diaries and a food list. Macronutrient, vitamin, and mineral supply was determined based on the percentage of their recommended intake. The results showed a significantly lower total energy and protein intake in ARFID versus controls, with trends for lower fat and carbohydrate intake. ARFID subtypes of limited amount versus variety of food intake significantly differed in macro-, but not micronutrient intake. Those with ARFID met only 20%-30% of the recommended intake for most vitamins and minerals, with significantly lower intake relative to controls for vitamin B1, B2, C, K, zinc, iron, and potassium. Variety of food intake was significantly reduced in ARFID versus controls in all food groups except carbohydrates. This study demonstrated that ARFID goes along with reduced everyday life macro- and micronutrient intake, which may increase the risk for developmental and health problems. Future studies additionally assessing serum nutrient levels in a larger sample may further explore differences in food intake across diverse ARFID presentations.

[Postpartum mental health problems: healthcare service situation and effectiveness of parent-infant psychotherapy. Presentation of the SKKIPPI project funded by the German Innovationsfonds]. / Postpartale psychische Erkrankungen: Versorgungslage und Wirksamkeit der Eltern-Säugling-Kleinkind-Psychotherapie. Vorstellung des Innovationsfondprojektes SKKIPPI.

After the birth of a child, parents may experience episodes of stress and psychological strain. Some infants show psychological or somatic stress in the form of early regulatory disorders. While the close connection between parental psychological stress, early regulatory disorders, and the development of the parent-child relationship is well documented, current data on effective treatment options are lacking. Previous care services mostly operate on a preventive basis; evidence-based psychotherapeutic services with a special focus on the parent-child relationship are rare.SKKIPPI is a multicenter research project (Berlin, Flensburg, Hamburg, Leipzig) and consists of several study parts with a mixed methods approach: an epidemiological cohort study, two randomized controlled intervention studies (RCTs), and a qualitative study. A population-based cohort study records the occurrence and determinants of psychosocial stress and mental health disorders, as well as the use of health and social services by parents and their children within the first two years of life, using online questionnaires and telephone interviews. The aim of the two RCTs is to evaluate the efficacy of a focused, dyadic parent-infant psychotherapy (Eltern-Säugling-Kleinkind-Psychotherapie, ESKP) compared to routine treatment in inpatient and outpatient settings. The focus of these RCTs is on the improvement of maternal sensitivity and on mother-child attachment, as well as child development and the reduction of mother-child psychopathological symptoms. The qualitative study intends to reconstruct the perspectives of parents on the assistance system and to explore reasons for underuse. The results are expected to help develop preventive as well as therapeutic strategies in the German health system.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets.

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.

Simplified approach to least-square fitting of fluorescence lifetime ophthalmoscopy (FLIO) data by fixating lifetimes.

Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a new imaging modality in ophthalmology. For clinical investigations, the amplitude-weighted mean of two or three lifetime components is usually analyzed. In this study, we investigated the effects of fixation of lifetime components. This resulted in slightly higher fit errors but mean lifetimes were highly correlated to those from fits with variable individual lifetimes. Furthermore, this approach resulted in a similarly good discrimination of diabetic retinopathy patients from controls, a reduction of the computational workload, a de-noising of the mean lifetime images and allows higher local resolution. Thus, fixation of lifetimes in the fit of FLIO data could be superior for clinical routine analysis of FLIO data.

The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas.

We recently showed that the antiobese efficacy of the AT1 receptor blocker telmisartan (TEL) is at least partially related to an Ang(1-7)-dependent mechanism. Ang(1-7) acts via Mas, thus raising the question of whether Mas-deficient (Mas-ko) mice are likewise predisposed to develop diet-induced obesity and, further, whether this can be prevented by TEL treatment. Mas-ko mice and FVB/N wild-type (wt) animals were treated with TEL (8 mg/kg/day) or vehicle while they were fed with high-fat diet (HFD) or chow. Mice were phenotyped regarding body weight, fat mass, insulin sensitivity, and leptin sensitivity. In response to HFD feeding, gain in body weight and impairment of leptin sensitivity were similar between wt and Mas-ko mice. TEL reduced body weight in both strains but effects were stronger in Mas-ko mice. TEL diminished fat mass and restored leptin sensitivity only in Mas-ko mice. Blood glucose was higher in wt than Mas-ko mice fed with HFD while not differing when they were fed with chow. Insulin challenge confirmed that wt mice became insulin resistant when fed with HFD while HFD feeding did not impair insulin sensitivity in Mas-ko mice. TEL had no further effect. Our findings on the influence of TEL on growth and metabolism in Mas-ko mice conflict with our previous findings in rats. We assume that the FVB/N background of the mice may partly explain these inconsistent data. Moreover, it also seems feasible that the MrgD receptor compensates for Mas deficiency.

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation.

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice.

Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.

Development of obesity can be prevented in rats by chronic icv infusions of AngII but less by Ang(1-7).

Considering that obesity is one of the leading risks for death worldwide, it should be noted that a brain-related mechanism is involved in AngII-induced and AT1-receptor-dependent weight loss. It is moreover established that activation of the Ang(1-7)/ACE2/Mas axis reduces weight, but it remains unclear whether this Ang(1-7) effect is also mediated via a brain-related mechanism. Additionally to Sprague Dawley (SD) rats, we used TGR(ASrAOGEN) selectively lacking brain angiotensinogen, the precursor to AngII, as we speculated that effects are more pronounced in a model with low brain RAS activity. Rats were fed with high-calorie cafeteria diet. We investigated weight regulation, food behavior, and energy balance in response to chronic icv.-infusions of AngII (200 ng•h-1), or Ang(1-7) (200/600 ng•h-1) or artificial cerebrospinal fluid. High- but not low-dose Ang(1-7) slightly decreased weight gain and energy intake in SD rats. AngII showed an anti-obese efficacy in SD rats by decreasing energy intake and increasing energy expenditure and also improved glucose control. TGR(ASrAOGEN) were protected from developing obesity. However, Ang(1-7) did not reveal any effects in TGR(ASrAOGEN) and those of AngII were minor compared to SD rats. Our results emphasize that brain AngII is a key contributor for regulating energy homeostasis and weight in obesity by serving as a negative brain-related feedback signal to alleviate weight gain. Brain-related anti-obese potency of Ang(1-7) is lower than AngII but must be further investigated by using other transgenic models as TGR(ASrAOGEN) proved to be less valuable for answering this question.