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AbstractThe distribution of glutamate receptor subtypes on the surface of neurons is highly relevant for synaptic activation and signal processing in the neocortex. As a novel approach we have used infra‐red videomicroscopy in combination with photostimulation or microiontophoresis in brain slices of rat neocortex to map the distribution of N‐methyl‐d‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors on pyramidal neurons of layer V. Both modes of application revealed a spatially distinct distribution of glutamate receptor subtypes: the soma and the proximal dendrite of neurons are highly sensitive to NMDA, whereas the more distal parts of the dendrite are more sensitive to AMPA. An implication is that NMDA receptors near the soma might regulate the amplification of synaptic signals resulting from AMPA receptor activation on remote dendritic sites. [ABSTRACT FROM AUTHOR]

In this article the author discusses rapid-onset motor plasticity in the multiple sclerosis (MS) patients, during which the MS patients show paired associative stimulation (PAS)-induced development of corticospinal excitability.

Background: Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants., Methods: We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis., Results: We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three., Conclusion: Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

The Child Oriented FamilyTherapy (COF) is a new therapeutic method aiming towards infants in the playing age group and their families. COF is - originally invented in Scandinavia - spreading over Germany since the beginning of the 21st century. The prevalence for psychiatric disorders in toddlers, preschoolers and young infants in Germany lies between 14 and 22 %. Treatment in an outpatients' clinic with partial hospitalization is indicated whenever the psychosocial resources are too low or the symptoms are too severe to be treated in an ambulant environment. The outpatients' department for pediatric psychiatry in Gelsenkirchen is the first institution in its field to use COF as one module to treat their young patients and their families. Due to the setting adjustments of the original method are necessary, for example a conceptualization of disease, the use of COF as a diagnostic method and the embedding of COF in an underlying treatment plan.

Background: Physiotherapy and occupational therapy are currently described using the duration of treatment (days or weeks), the frequency of therapy sessions (on a daily or 3-5 days per week basis) and considering the duration of a session (e.g., 30 or 45 min). The content is often poorly defined and the intensity is rarely reported. Using digital technology some of these shortcomings can be overcome. The cumulative parameters of walking and activity sessions, the duration of walking, the time spent in an upright or lying/sitting position and the number of steps can now be analyzed. In this study, we examined the parameters during non-treatment periods and therapy time in patients recovering from fragility fractures., Methods: The study is a secondary data analysis of a trial that examined the improvement of physical activity (PA) and self-efficacy of fragility fracture patients. Changes in mobility parameters were measured using the ActivPal3 sensor during the 1st and 3rd weeks of rehabilitation and 104 patients were analyzed (mean age 82.5 years). Parameters included the time during supervised treatment, the mean number of steps, cumulative time in an upright position and walking duration, the number of walking intervals of > 10 s and sit to stand transfers., Results: Patients received 3-4 therapy sessions adding up to 90-120 min per day. More than 50% of the daily walking activities were achieved in these sessions until discharge. With this amount of therapeutic input most parameters meaningfully improved from baseline to the second measurement. The number of steps increased by 30%, the mean time in an upright position increased by 26% and the mean time spent walking increased by 49%., Conclusion: The sensor-derived measurements describe the amount of walking activity administered during the supervised therapy sessions. This could be used as a starting point for future trials to improve the outcomes or as a standard of process evaluation for clinical services., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach., Methods: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping., Results: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants., Conclusion: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Physical exercise is associated with many health benefits. Especially for older adults it is challenging to achieve an appropriate adherence to exercise programs. The outcome expectations for exercise scale 2 (OEE-2) is a 13-item self-report questionnaire to assess negative and positive exercise outcome expectations in older adults. The aim of this study was to translate the OEE‑2 into German and to assess the psychometric properties of this version., Methods: The OEE‑2 was translated from English into German including a forward and backward translation process. Psychometric properties were assessed in 115 patients with hip/pelvic fractures (76% female, mean age 82.5 years) and fear of falling during geriatric inpatient rehabilitation., Results: Principal component analyses could confirm a two-factor solution (positive/negative OEE) that explained 58% of the total variance, with an overall internal reliability of α = 0.89. Cronbach's α for the 9‑item positive OEE subscale was 0.89, for the 4‑item negative OEE subscale 0.79. The two subscales were correlated with r s  = 0.49. Correlations of the OEE total score were highest with the perceived ability to manage falls, prefracture leisure time activities and prior training history (r s  = 0.35-0.41)., Conclusion: These results revealed good internal reliability and construct validity of the German version of the OEE‑2. The instrument is valid for measuring physical exercise outcome expectations in older, German-speaking patients with hip or pelvic fractures and fear of falling., (© 2020. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: A growing number of older adults suffer hip and pelvic fractures leading to hospital admission. They often result in reduced physical activity (PA) and impaired mobility. PA can be objectively measured with body-worn sensors. Usually, global cumulative PA parameters are analysed, such as walking duration, upright-time and number of steps. These traditional parameters mix different domains of PA, such as physical capacity (PC), behaviour and living environment. We examined the change of global cumulative PA measures during rehabilitation and after discharge in patients with hip or pelvic fracture and whether more 'in-depth' PA parameters, such as walking interval length, variability of interval length and sit-to-stand transitions and their changes during rehabilitation and 3 months after discharge might better reflect the above mentioned three clinically relevant domains of PA., Methods: This study is a secondary data analysis of a randomised controlled trial to improve PA and fall-related self-efficacy in hip or pelvic fracture patients (≥60 years) with concerns about falling. Changes of accelerometer-measured global cumulative and in-depth PA parameters (activPAL3) were analysed in an observational design before and after discharge combining both groups. For comparison, the same analyses were applied to the traditional PC measures gait speed and 5-chair-rise., Results: Seventy-five percent of the 111 study participants were female (mean age: 82.5 (SD = 6.76) years. Daily walking duration, upright time and number of steps as aspects of global PA increased during inpatient rehabilitation as well as afterwards. The in-depth PA parameters showed differing patterns. While the total number of walking bouts increased similarly, the number of longer walking bouts decreased by 50% after discharge. This pattern was also seen for the average walking interval length, which increased by 2.34 s (95% confidence interval (CI): 0.68; 4.00) during inpatient rehabilitation and decreased afterwards below baseline level (- 4.19 s (95% CI: - 5.56; - 2.82)). The traditional PC measures showed similar patterns to the in-depth PA parameters with improvements during rehabilitation, but not at home., Conclusion: Our findings suggest that the in-depth PA parameters add further information to the global cumulative PA parameters. Whereas global cumulative PA parameters improved significantly during inpatient rehabilitation and after discharge, in-depth PA parameters as well as PC did not continuously improve at home. In contrast to global cumulative PA parameters the in-depth parameters seem to reflect contextual factors such as the build environment and aspects of PC, which are traditionally assessed by clinical PC measures. These in combination with digital mobility measures can help clinicians to assess the health status of fragility fracture patients, individually tailor therapy measures and monitor the rehabilitation process.

Introduction: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure., Methods and Analysis: In this quality improvement strategy (QIS), a decision support system as a mobile application (ASIC app), which uses available clinical real-time data, is implemented to support physicians in timely diagnosis and improvement of adherence to established guidelines in the treatment of ARDS. ASIC is conducted on 31 intensive care units (ICUs) at 8 German university hospitals. It is designed as a multicentre stepped-wedge cluster randomised QIS. ICUs are combined into 12 clusters which are randomised in 12 steps. After preparation (18 months) and a control phase of 8 months for all clusters, the first cluster enters a roll-in phase (3 months) that is followed by the actual QIS phase. The remaining clusters follow in month wise steps. The coprimary key performance indicators (KPIs) consist of the ARDS diagnostic rate and guideline adherence regarding lung-protective ventilation. Secondary KPIs include the prevalence of organ dysfunction within 28 days after diagnosis or ICU discharge, the treatment duration on ICU and the hospital mortality. Furthermore, the user acceptance and usability of new technologies in medicine are examined. To show improvements in healthcare of patients with ARDS, differences in primary and secondary KPIs between control phase and QIS will be tested., Ethics and Dissemination: Ethical approval was obtained from the independent Ethics Committee (EC) at the RWTH Aachen Faculty of Medicine (local EC reference number: EK 102/19) and the respective data protection officer in March 2019. The results of the ASIC QIS will be presented at conferences and published in peer-reviewed journals., Trial Registration Number: DRKS00014330., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them  could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

Background: fear of falling and reduced fall-related self-efficacy are frequent consequences of falls and associated with poorer rehabilitation outcomes. To address these psychological consequences, geriatric inpatient rehabilitation was augmented with a cognitive behavioural intervention ("Step by Step") and evaluated in a RCT., Methods: one hundred fifteen hip and pelvic fracture patients (age = 82.5 years, 70% female) admitted to geriatric inpatient rehabilitation were randomly allocated to the intervention or control group. The intervention consisted of eight additional individual sessions during inpatient rehabilitation, one home visit and four telephone calls delivered over 2 months after discharge. Both groups received geriatric inpatient rehabilitation. Primary outcomes were fall-related self-efficacy (short falls efficacy scale-international) and physical activity as measured by daily walking duration (activPAL3™ sensor) after admission to rehabilitation, before discharge and 1-month post-intervention., Results: in covariance analyses, patients in the intervention group showed a significant improvement in fall-related self-efficacy (P = 0.025, d = -0.42), but no difference in total daily walking duration (P = 0.688, d = 0.07) 1-month post-intervention compared to the control condition. Further significant effects in favour of the intervention group were found in the secondary outcomes "perceived ability to manage falls" (P = 0.031, d = 0.41), "physical performance" (short physical performance battery) (P = 0.002, d = 0.58) and a lower "number of falls" (P = 0.029, d = -0.45)., Conclusions: the intervention improved psychological and physical performance measures but did not increase daily walking duration. For the inpatient part of the intervention further research on the required minimum intensity needed to be effective is of interest. Duration and components used to improve physical activity after discharge should be reconsidered., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To gain a better understanding about the nature of fear of falling, this study analyzed associations between psychological and physical aspects related to fear of falling and falls efficacy in hip/pelvic fracture patients., Design: Baseline data of a randomized controlled trial., Setting: Geriatric inpatient rehabilitation hospital., Subjects: In all, 115 geriatric patients with hip/pelvic fracture (mean age: 82.5 years) reporting fear of falling within first week of inpatient rehabilitation., Interventions: None., Main Measures: Falls efficacy (Short Falls Efficacy Scale-International; Perceived Ability to Manage Falls), fear of falling (one-item question), fall-related post-traumatic stress symptoms (six items based on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM -IV) criteria), physical performance (Short Physical Performance Battery) and psychological inflexibility (Acceptance and Action Questionnaire-II) were assessed., Results: Path analyses demonstrated that low falls efficacy (Short Falls Efficacy Scale International) was significantly related to poor physical performance ( β * = -.277, P  ⩽ .001), but not to psychological inflexibility and fall-related post-traumatic stress symptoms ( P  ⩾ .05.). Fear of falling was directly associated with fall-related post-traumatic stress symptoms ( β *= .270, P  = .007) and indirectly with psychological inflexibility ( β *= .110, P  = .022). Low perceived ability to manage falls was significantly related to previous falls ( β * = -.348, P  ⩽ .001), psychological inflexibility ( β * = -.216, P  = .022) and female gender ( β * = -.239, P  ⩽ .01)., Conclusion: Falls efficacy and fear of falling constitute distinct constructs. Falls efficacy measured with the Short Falls Efficacy Scale International reflects the appraisal of poor physical performance. Fear of falling measured by the single-item question constitutes a fall-specific psychological construct associated with psychological inflexibility and fall-related post-traumatic stress symptoms.

Background: Specific training reduces the risk of falls and fall-related injuries in older persons. The availability of specific exercise programs in Germany, especially in rural areas is scarce. Therefore, a healthcare fund driven program osteoporotic fracture prevention program in rural areas (OFRA) (German name: "Trittsicher durchs Leben") was implemented in rural areas in 47 counties of 5 federal states. The most important components of the program are the "Trittsicher" mobility course and falls prevention classes organized by members of the German Association of Rural Women and executed by exercise instructors of the German Gymnastics Association or physiotherapists. Since the start of the program in October 2015 more than 2300 classes have been carried out., Aim: The study analyzed the structural characteristics of the first 1092 "Trittsicher" mobility courses and the characteristics of the 12,246 participants., Method: The analysis is based on data of a standardized course documentation sheet and information from an internal database of a health insurance company. Additionally, the distance between the location of the course and place of residence was determined for a subgroup of the participants., Results: The classes were conducted in communal and confessional rooms, in sports associations, kindergartens and restaurants. The majority of the 12,246 participants were female (89.1%), the median age was 75 years. The average size of the classes was 11.2 participants per course. More than half of the participants attended all six sessions. Half of the participants of the courses had to travel less than 1.7 km between the place of residence and the location of the courses., Conclusion: "Trittsicher" mobility courses are a new specific offer to improve mobility and reduce the risk of falling. They contribute to a better care of older people in rural areas.

Objective: Based on a theoretical framework and sound evidence, this article describes a rehabilitation programme for patients with fear of falling after hip and pelvic fracture., Rationale: Based on exercise science principles, current knowledge from fall prevention, emotion regulation, and the Health Action Process Approach we developed a theoretical framework, from which the components of the intervention were derived. Description of the intervention: The intervention consists of 6 components: (1) relaxation, (2) meaningful activities and mobility-based goals, (3) falls related cognitions and emotions, coping with high risk tasks and situations, (4) individual exercise programme, (5) planning and implementing exercises and activities, and (6) fall risks and hazards. The intervention comprises of 8 individual sessions during 3 to 5 weeks of inpatient rehabilitation and 4 telephone calls and 1 home visit over a 2-month post-discharge period. Each session or telephone call takes about 30-60 minutes. It is provided to geriatric hip and pelvic fracture patients with concerns about falling and no cognitive impairment. To ensure completeness of reporting, the Template for Intervention Description and Replication (TIDierR) is used., Results: Fifty-seven patients were assigned to the intervention group. All 46 completers met all pre-defined criteria for an intervention per protocol., Conclusion: The programme is feasible to administer. We have completed a randomised controlled trial, which will be submitted in due time (for trial protocol: www.isrctn.org ; ISRCTN79191813).

Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1 β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1- β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF- α ), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1 β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1 β therapy for prevention and treatment of DN., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Fragility fractures are one of the leading causes for disability in old people. The main underlying mechanisms are osteoporosis and falls. Evidence-based measures to prevent either falls or fractures are available. However, coordinated preventive approaches combining bone health and fall prevention are rare. The objective of the study is to evaluate a health care fund driven program, which encourages insured persons to adhere to national guidelines regarding bone health and physical activity and falls prevention. The health care fund cooperates with the 'German Association of Rural Women' and the 'German Gymnastics Association'. The program consists of mobility and falls prevention classes, the examination of bone health by a DXA scan, and a consultation about 'safety in the living environment'., Methods: Cluster-randomized study in 47 intervention and 143 control districts in 5 federal states of Germany. The program is offered to a) community-living women and men aged 70 to <85 years with a prior fragility fracture or b) community-living women aged 75 to <80 years. Within two years more than 10,000 persons will be directly contacted and motivated to make use of the components of the program. The primary outcome is a combined measure of incident osteoporotic fractures. Secondary outcomes include the rate of referrals to a mobility and falls prevention class or a bone mass density measurement. An economic evaluation will be conducted., Discussion: The study evaluates a complex preventive intervention in a routine health care setting which may serve as model for similar approaches in other areas or countries., Trial Registration: DRKS-ID: DRKS00009000 ; date of registration: 06.08.2015.

Context: Patients with pancreatic neuroendocrine neoplasia (pNEN) show great variability in prognosis and treatment response. Additional prognostic markers might help in individual therapeutic decision making., Objective: The objective of the study was to investigate the association between preoperative plasma levels of C-reactive protein (CRP) and overall survival (OS) in pNEN., Design: This was a single-center, retrospective analysis of long-term prospective patient-database., Setting: The study was conducted at a tertiary referral center., Patients: All 149 patients with sporadic pNENs were eligible for retrospective analysis., Main Outcome Measure: Cumulative overall survival, compared between patients with elevated and normal CRP levels, was measured., Results: Median OS for patients with elevated CRP levels was 1093 days (SE 1261, 95% confidence interval [CI] 0-3565), compared with 6859 days (SE 1252, 95% CI 4405-9313) for patients with normal CRP levels. Log rank test showed a significant correlation between CRP and OS (P < .001). In univariate Cox regression, patients with elevated CRP levels had a significantly higher hazard ratio for death (3.27; 95%-CI 1.74-6.16; P < .001). This finding persisted after multivariable adjustment. Furthermore, OS was associated with the presence of liver metastases (hazard ratio 3.17; 95% CI 1.88-5.35; P < .001), incomplete resection (R1/R2 status; hazard ratio 3.99; 95% CI 2.16-7.35; P < .001) and Ki-67 percentage (hazard ratio 5.05; 95% CI 2.17-11.76; P < .001)., Conclusion: CRP is an independent prognostic marker in patients with pNEN. Pretreatment CRP measurements should be considered for incorporation into prospective studies of outcome in patients with pNENs and clinical trials of systemic therapies for these tumors.

Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances β-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1β antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1β antagonist., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)