Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of ...the
(
) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA.
Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of astrocyte dysfunction in SMA and indicates a possible approach for improving motor neuron growth and survival in this disease.
There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism ...by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.
Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics.
Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism.
In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.
Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes ...such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD.
C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C16:0-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls.
After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C16:0-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C16:0-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression.
Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.
•CerS6 deletion improved glucose control and showed sex-dependent effect on ethanol-induced weight gain and liver fat in mice.•CerS6 deletion down-regulated lipid droplet-associated proteins in ethanol-fed mice.•In human patients, progression of alcoholic-associated liver disease was associated with increased hepatic CerS6 expression.•CerS6 may be a potential therapeutic target for early stage alcoholic-associated liver disease.
Aims
Acute kidney injury (AKI) during acute heart failure (AHF) is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanism appears to have prognostic ...relevance; however, the differentiation of true, structural AKI from hemodynamic pseudo‐AKI remains a clinical challenge.
Methods and results
The Basics in Acute Shortness of Breath Evaluation Study (NCT01831115) prospectively enrolled adult patients presenting with AHF to the emergency department. Mortality of patients was prospectively assessed. Haemoconcentration, transglomerular pressure gradient (n = 231) and tubular injury patterns (n = 253) were evaluated to investigate pathophysiological mechanisms underlying AKI timing (existing at presentation vs. developing during in‐hospital period). Of 1643 AHF patients, 755 patients (46%) experienced an episode of AKI; 310 patients (19%; 41% of AKI patients) presented with community‐acquired AKI (CA‐AKI), 445 patients (27%; 59% of AKI patients) developed in‐hospital AKI. CA‐AKI but not in‐hospital AKI was associated with higher mortality compared with no‐AKI (adjusted hazard ratio 1.32 95%‐CI 1.01–1.74; P = 0.04). Independent of AKI timing, haemoconcentration was associated with a lower two‐year mortality. Transglomerular pressure gradient at presentation was significantly lower in CA‐AKI compared to in‐hospital AKI and no‐AKI (P < 0.01). Urinary NGAL ratio concentrations were significantly higher in CA‐AKI compared to in‐hospital AKI (P < 0.01) or no‐AKI (P < 0.01).
Conclusions
CA‐AKI but not in‐hospital AKI is associated with increased long‐term mortality and marked by decreased transglomerular pressure gradient and tubular injury, probably reflecting prolonged tubular ischemia due to reno‐venous congestion. Adequate decongestion, as assessed by haemoconcentration, is associated with lower long‐term mortality independent of AKI timing.
Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is ...common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This "syndrome of metabolic and alcoholic steatohepatitis" (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.
Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF).
To evaluate the effect of a strategy that emphasized ...early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF.
Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019.
Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan.
The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days.
Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths 14.4%) and in 111 patients (27.8%) in the usual care group (including 61 deaths 15.3%) (absolute difference for the primary end point, 2.8% 95% CI, -3.7% to 9.3%; adjusted hazard ratio, 1.07 95% CI, 0.83-1.39; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%).
Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.
ClinicalTrials.gov Identifier: NCT00512759.
Takotsubo cardiomyopathy (TSC) is a transient cardiac condition brought on by physical and emotional distress causing left ventricular akinesis. Typically, patients are older females that present ...with substernal chest pain radiating to the left arm, presenting similarly to acute coronary syndrome. In addition, the elevated troponins and EKG changes such as ST elevations and T wave inversions seen in acute coronary syndrome may also be appreciated in TSC. While there have been many reports of TSC presenting in a similar manner to acute coronary syndrome, this case report will describe an atypical presentation of Takotsubo cardiomyopathy. The patient we are presenting is an African American middle-aged female who presented to the emergency department with a four-day history of non-bilious, non-bloody vomiting. Chief complaint denied any chest pain, shortness of breath, or recent physical and emotional stressors. Her past medical history was significant for Chronic Obstructive Pulmonary Disease Gold Criteria 2, controlled Hypertension, and Human Immunodeficiency Virus for which she is on antiretroviral therapy. Her hospital course was complicated by shortness of breath beginning on day two as well as elevated troponin levels and global T wave inversions on EKG. Patient underwent cardiac catheterization, which revealed left ventricular akinesis with an ejection fraction of <30%. Catherization also revealed no obstructive coronary artery disease, thus the diagnosis of Takotsubo cardiomyopathy was made.
Aims
Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) for obesity could further ...increase its clinical utility in the early diagnosis of acute heart failure (AHF).
Methods and results
This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT‐proBNP plasma concentrations were applied: first, using currently recommended cut‐offs; second, using cut‐offs lowered by 33% with body mass index (BMI) of 30–34.9 kg/m2 and by 50% with BMI ≥ 35 kg/m2. Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT‐proBNP as quantified by the area under the receiver‐operating characteristic curve was lower in obese versus non‐obese patients (0.890 vs. 0.938). For rapid AHF rule‐out in obese patients, the currently recommended cut‐off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval CI 93.8–98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule‐in, the age‐dependent cut‐off concentrations (age <50 years: 450 pg/ml; age 50–75 years: 900 pg/ml; age >75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8–88.9%). Proportionally lowering the currently recommended cut‐offs by BMI increased sensitivity to 98.2% (95% CI 95.8–99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the ‘gray zone’ (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7–81.4%).
Conclusions
Adjusting NT‐proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF.
Obese patients ruled out and ruled in or remaining in the ‘gray zone’ after: (A) applying the currently recommended N‐terminal pro‐B‐type natriuretic peptide cut‐offs, or (B) reducing these cut‐offs by one third in patients with a body mass index 30–34.9 kg/m2 and by half in those with a body mass index ≥35 kg/m2. Red figures represent patients with acute heart failure (AHF) and black figures show patients without AHF as a final diagnosis. One full figure represents 2% of all obese patients. Golden arrows indicate the number (and %) of reclassified patients. For instance, when applying the reduced cut‐offs, 37 AHF patients (7.2% of the overall patient population) in the ‘gray zone’ were ruled in with their correct diagnosis. The red arrow represents the most common immediate consequences of ‘rule‐in’ of AHF in the emergency department; specifically, bolus of 40 mg intravenous furosemide and ordering an echocardiogram.
Zusammenfassung
Je nach Diabetesform und -therapie sollen alle Menschen mit Diabetes eine individuelle ernährungsmedizinische Beratung und Schulung durch Fachpersonal erhalten. Im Vordergrund sollte ...eine patientinnen- und patientenzentrierte, individualisierte Beratung stehen, angepasst an die jeweiligen Bedürfnisse und Lebensumstände der Menschen mit Diabetes. Neben der Unterstützung zur Umsetzung einer ausgewogenen Ernährung gilt es, gemeinsam mit Patient:innen individuelle Stoffwechselziele und Gewichtsziele zu definieren, um mithilfe der Ernährung den Krankheitsverlauf positiv zu beeinflussen und mögliche Spätfolgen zu vermeiden. Dabei sollten vor allem praxisbezogene Empfehlungen unter Berücksichtigung der persönlichen Nahrungsmittel-Präferenzen ausgesprochen werden und Hilfsmittel zur Planung von geeigneten Portionsgrößen und der geeigneten Mahlzeitenzusammenstellung zum Einsatz kommen. Entsprechend aktueller internationaler und nationaler Standards sollen Menschen mit Diabetes im Diabetes-Selbstmanagement unterstützt werden (DSMES) und erlernen, die postprandiale Reaktion auf Speisen und Getränke besser einschätzen und durch die geeignete Lebensmittel- und Getränkeauswahl positiv beeinflussen zu können. Alle Menschen mit Diabetes sollten regelmäßig, je nach individuellem Bedarf, die Möglichkeit haben, eine ernährungstherapeutische Beratung oder Schulung in Anspruch nehmen zu können.Diese Praxisempfehlung stellt eine Zusammenfassung der aktuellen Literatur zu ernährungsrelevanten Aspekten bei Diabetes dar.
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