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Abstract Background Among the neurological complications of influenza in children, the most severe is acute necrotizing encephalopathy (ANE), with a high mortality rate and neurological sequelae. ANE is characterized by rapid progression to death within 1–2 days from onset. However, the knowledge about the early diagnosis of ANE is limited, which is often misdiagnosed as simple seizures/convulsions or mild acute influenza-associated encephalopathy (IAE). Objective To develop and validate an early prediction model to discriminate the ANE from two common neurological complications, seizures/convulsions and mild IAE in children with influenza. Methods This retrospective case-control study included patients with ANE (median age 3.8 (2.3,5.4) years), seizures/convulsions alone (median age 2.6 (1.7,4.3) years), or mild IAE (median age 2.8 (1.5,6.1) years) at a tertiary pediatric medical center in China between November 2012 to January 2020. The random forest algorithm was used to screen the characteristics and construct a prediction model. Results Of the 433 patients, 278 (64.2%) had seizures/convulsions alone, 106 (24.5%) had mild IAE, and 49 (11.3%) had ANE. The discrimination performance of the model was satisfactory, with an accuracy above 0.80 from both model development (84.2%) and internal validation (88.2%). Seizures/convulsions were less likely to be wrongly classified (3.7%, 2/54), but mild IAE (22.7%, 5/22) was prone to be misdiagnosed as seizures/convulsions, and a small proportion (4.5%, 1/22) of them was prone to be misdiagnosed as ANE. Of the children with ANE, 22.2% (2/9) were misdiagnosed as mild IAE, and none were misdiagnosed as seizures/convulsions. Conclusion This model can distinguish the ANE from seizures/convulsions with high accuracy and from mild IAE close to 80% accuracy, providing valuable information for the early management of children with influenza.

ObjectiveAcute necrotizing encephalopathy (ANE) is a rare but severe encephalopathy and is associated with a high morbidity and mortality. We aimed to analyze and compare the clinical features and predictive indicators of pediatric ANE.Materials and methodsThis retrospective study included children with ANE diagnosed at Guangzhou Women and Children’s Medical Center between November 2018 and January 2020. Pediatric patients’ information, including clinical characteristics, laboratory tests, neuroelectrophysiology and brain magnetic resonance imaging (MRI) findings, MRI score, brainstem auditory evoked potential (BAEP) grades, ANE severity scores (ANE-SS), and modified Rankin scale (mRS), were collected.ResultsTwelve ANE patients were included. Among them, one patient (8.3%) died from brainstem dysfunction, one (8.3%) recovered and 10 (83.3%) experienced neurological sequelae. All patients had an initial viral infection and neurological symptoms such as acute disturbance of consciousness (ADOC) or seizure, and the interval from onset of the disease to neurological manifestations was 3 (1.25–3) days. MRI score-I ranged from 1 to 3 (1.8 ± 0.7), MRI score-II ranged from 1 to 4 (2.5 ± 1.1). ANE-SS varied from 1 to 6 (3.9 ± 1.3). The scores of mRS were from 0 to 6 (2.9 ± 1.7). Higher MRI score were associated with worse outcomes, while the BAEP grade and ANE-SS score were not significantly associated with mRS.ConclusionANE is a severe encephalopathy syndrome with rapid progression, resulting in serious neurological sequelae. Compared with BAEP grade and ANE-SS, brain MRI shows more comprehensive advantages in predicting the prognosis of ANE patients. More in-depth research and better indicators are still needed to support the evaluation and treatment of ANE.

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.

Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockout mice showed worse glucose tolerance, lower locomotor activity and lower metabolic rate than wildtype mice. Additionally, GDF15 deficiency increased occurrences of high fat diet-induced skin lesions. Our data suggests that endogenous GDF15 has a protective role in obesity development and lack of GDF15 aggravates the progression of obesity and associated pathological conditions. Elevated GDF15 levels in obesity may have resulted from a response to overcome GDF15 resistance.

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake. Overexpression of TFF3 using a recombinant adeno-associated virus (AAV) vector, or daily administration of recombinant TFF3 protein in vivo improved glucose tolerance in a diet-induced obesity mouse model. Body weight, fasting insulin, triglyceride, cholesterol and leptin levels were not affected by TFF3 treatment. Induction of mucinous metaplasia was observed in mice with AAV-mediated TFF3 overexpression, however, no such adverse histological effect was seen after the administration of recombinant TFF3 protein. Altogether these results suggest that the therapeutic potential of targeting TFF3 to treat T2D may be limited.

The article looks at a microarray study that compares gene expression in major metabolic issues of fed and fasted ob/ob mice and C57BL/6 mice in search of metabolically-regulated secreted proteins. Topics covered include challenges in the clinical development of GDF15 as a therapeutic, testing of recombinant GDF15 proteins and antibodies in a variety of disease models, and the effect of GDF15 on gastric emptying, food preference, and activation of area postrema neurons.

Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity. Thus, we generated a monoclonal antibody (mAb) against SFRP5 to ascertain the effect of SFRP5 inhibition in vivo. Congruent with SFRP5 overexpression worsening blood glucose levels and glucose intolerance, anti-SFRP5 mAb therapy improved these phenotypes in vivo. The results from both the overexpression and mAb inhibition studies suggest a role for SFRP5 in glucose metabolism and pancreatic ß-cell function and thus establish the use of an anti-SFRP5 mAb as a potential approach to treat type 2 diabetes. [ABSTRACT FROM AUTHOR]

A study of orexin knockout mice reveals a phenotype that has a striking resemblance to humans suffering from narcolepsy. They also exhibit similarities with canarc-1 mutant dogs, narcolepsy's only known monogenic model. The findings, which also include the activation of orexin-containing neuron with the use of modafinil, provide evidence of orexin's function in the regulation of the state of wakefulness and sleep and provides a useful model for human narcolepsy.

Leptin is an adipose-derived hormone that regulates a wide variety of physiological processes, including feeding behavior, metabolic rate, sympathetic nerve activity, reproduction. and immune response. Circulating leptin levels are tightly regulated according to energy homeostasis in vivo. Although mechanisms for the regulation of leptin production in adipocytes are not well understood, G protein-coupled receptors may play an important role in this adipocyte function. Here we report that C2-C6 short-chain fatty acids, ligands of an orphan G protein-coupled receptor GPR41, stimulate leptin expression in both a mouse adipocyte cell line and mouse adipose tissue in primary culture. Acute oral administration of propionate increases circulating leptin levels in mice. The concentrations of short-chain fatty acids required to stimulate leptin production are within physiological ranges, suggesting the relevance of this pathway in vivo. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase IV (DPP-IV) degrades the incretin hormone glucagon-like peptide 1 (GLP-1). Small molecule DPP-IV inhibitors have been used as treatments for type 2 diabetes to improve glucose tolerance. However, each of the marketed small molecule drugs has its own limitation in terms of efficacy and side effects. To search for an alternative strategy of inhibiting DPP-IV activity, we generated a panel of tight binding inhibitory mouse monoclonal antibodies (mAbs) against rat DPP-IV. When tested in vitro, these mAbs partially inhibited the GLP-1 cleavage activity of purified enzyme and rat plasma. To understand the partial inhibition, we solved the co-crystal structure of one of the mAb Fabs (Ab1) in complex with rat DPP-IV. Although Ab1 does not bind at the active site, it partially blocks the side opening, which prevents the large substrates such as GLP-1 from accessing the active site, but not small molecules such as sitagliptin. When Ab1 was tested in vivo, it reduced plasma glucose and increased plasma GLP-1 concentration during an oral glucose tolerance test in rats. Together, we demonstrated the feasibility of using mAbs to inhibit DPP-IV activity and to improve glucose tolerance in a diabetic rat model. [ABSTRACT FROM AUTHOR]