Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirus-related sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction-related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired β2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.

The aim of this study was to determine the value of C-reactive protein (CRP) in the diagnosis of patients with neonatal sepsis by a meta-analysis. Potential relevant studies were searched through the PubMed, Embase, and Cochrane Library databases before February 2016. We combined estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with their 95% confidence intervals (CIs) of CRP for neonatal sepsis diagnosis. Summary receiver operating characteristic (SROC) curve was applied to evaluate the diagnostic value of CRP. The meta-regression and subgroup analysis were performed when heterogeneity was significant. In total, 31 studies were included in our meta-analysis with 5698 participants. The overall estimates for CRP in the diagnosis of neonatal sepsis were: sensitivity 0.69 (95% CI, 0.66-0.71), specificity 0.77 (95% CI, 0.76-0.78), PLR 3.83 (95% CI, 3.03-4.84), NLR 0.38 (95% CI, 0.31-0.45), and DOR 12.65 (95% CI, 8.91-17.94). The area under the curve (AUC) and Q* index were 0.8458 and 0.7773. Meta-regression analysis showed that heterogeneity was irrelevant to test time, cutoff value, assay method of CRP, neonates, and sepsis type. Heterogeneity still existed but decreased after subgroup analysis. CRP might be a valuable approach for the diagnosis of neonatal sepsis.

Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up-and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.

Rationale: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid, amino acid, and choline metabolism. The clinical manifestation of MADD is heterogeneous, from severe neonatal forms to mild late-onset forms. Patient concerns: Here, we report a patient who presented with severe hypoglycemia and exercise intolerance suggestive of MADD. Serum tandem mass spectrometry analysis indicated elevated levels of various acyl carnitines at 25 days of age. Exome sequencing of the proband revealed compound heterozygous mutations, c. 413T>G (p.Leu138Arg) and c.1667C > G (p.Pro556Arg), in the ETFDH gene as the probable causative mutations. Diagnoses: Based on the patient's clinical presentation and test results, the patient was diagnosed with MADD. Interventions: A high-calorie and reduced-fat diet was given together with oral supplements of L-carnitine (150 mg/day). Outcomes: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. Lessons: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD and may not only prevent the need for invasive testing but also allow for timely initiation of treatment.

Rationale:Autosomal-recessive dopa-responsive dystonia (DRD) is a rare clinical disorder presenting as bradykinesia, dystonia, tremor and even severe encephalopathy, and caused by tyrosine hydroxylase deficiency (THD). We report a case of compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive DRD herein.Patient concerns:A 16-month-old Chinese boy presented with symptoms of movement disorder and growth retardation in his infant period.Diagnoses:The genetic test revealed compound heterozygous mutations in the TH gene at c.457C>T and c.698G>A, which are pathogenic of DRD.Interventions:The patient was administrated low-dose levodopa.Outcomes:The treatment resulted in the substantial improvement of dystonia. His long-term neurological outcome need follow-up for years.Lessons:Gene mutation analysis is helpful and necessary to diagnose DRD and has important guiding significance for the subsequent treatment.