Chemogenetic stimulation of proprioceptors remodels lumbar interneuron excitability and promotes motor recovery after SCI.

Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

Procedural Pain in Hospitalized Children in a Chinese Children's Hospital.

BACKGROUND: Pain prevalence in pediatric hospitals has been investigated in many developed countries, but little is known about this topic in China. AIMS: This study sought to describe the frequency and pain intensity of procedures for medical care in hospitalized children in a Chinese children's hospital. DESIGN: A cross-sectional study was designed to include interviews with children, their parents and the nurses. SETTINGS: This survey was administered in a teaching hospital in southeast China. PARTICIPANTS/SUBJECTS: Infants and children up to 16 years old who were admitted to the study units for more than 6 days were eligible for inclusion. METHODS: Information regarding patient demographics, painful procedures and pain management strategies was obtained during the day shifts of the children's hospitalization. RESULTS: A total of 3886 procedures were performed on 342 children during the data collection period. The reuse of intravenous indwelling needles ( n = 577), removal of tape from the skin (n = 420) and venipuncture on the back of the hand ( n = 401) were the most frequently performed procedures on children. A total of 1941 procedures, accounting for 49.9% (1941/3886) of painful procedures caused moderate to severe pain (pain score ≥4.0). However, only 25.3% (984/3886) received a valid pain assessment, and only 14.4% (560/3886) received pain interventions. CONCLUSIONS: Most children, especially those who are younger (<4 years old), experienced moderate or severe pain during their hospitalization, but did not receive appropriate interventions.

Diagnostic value of TWEAK for predicting active lupus nephritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis.

PURPOSE: Accumulative studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was up-regulated in the blood and urine from patients diagnosed with lupus nephritis (LN) and that it might be used as a novel biomarker for active LN. This meta-analysis aimed to determine the diagnostic value of TWEAK in active LN. METHODS: We searched the Cochrane Library, Embase, PubMed, Springer, Wanfang and CNKI databases for articles published up to 20 August 2020. The diagnostic capacity of TWEAK for active LN was assessed using pooled sensitivity and specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC). Quality assessment and publication bias were also evaluated. STATA 11.0 and Meta-Disc 1.4 were used to perform these analyses. RESULTS: Nine cross-sectional studies were included in this meta-analysis. The overall pooled sensitivity of TWEAK for the diagnosis of active LN was 0.69 (95% CI, 0.63-0.75), and specificity was 0.77 (95% CI, 0.71-0.82). The overall pooled PLR and NLR were 3.31 (95% CI, 2.05-5.35) and 0.38 (95% CI, 0.26-0.55), respectively, with a DOR of 10.89 (95% CI, 6.73-17.63) and AUC (SE) of 0.8276 (0.0289). Deeks' funnel plot revealed that the publication bias was insignificant in the study (p = .32). CONCLUSIONS: Our results suggest that TWEAK might be a potential biomarker for patients with active LN. Future cross-sectional and longitudinal studies are needed to confirm its diagnostic value, as well as to establish more definite cutoff for active LN.

Effects of different types of neonatal pain on somatosensory and cognitive development in male juvenile rats.

BACKGROUND: Premature infants are inevitably exposed to painful events, including repetitive procedures, inflammation, or mixed stimulation that may induce long-term behavioral outcomes. Here, we set up three neonatal painful models to investigate their long-term effect on somatosensation and cognition. METHODS: Three types of neonatal pain models in rat were set up. Rat pups were randomly assigned to four groups. The needling pain (NP) group received repetitive needle pricks on the paws from the day of birth (PD0) to postnatal day 7 (PD7) to mimic the diagnostic and therapeutic procedures. The inflammatory pain (IP) group received the injection of carrageenan into the left hindpaw at PD3 to induce IP in peripheral tissues. The mixed pain group received a combination of the NP and IP (NIP). The control (CON) group was untreated. We performed behavioral and biochemical testing of juvenile rats (PD21-PD26). RESULTS: The NIP group showed a longer hypersensitivity than the NP group, when given a secondary inflammatory stimulation. NP led to insensitivity to anxiety-causing stimuli and impairment of fear memory both aggravated by NIP. NP reduced the expression of synapse-related molecules (GluN1/PSD95/GFAP) in the medial prefrontal cortex, and NIP exacerbated this decrease. The corticosterone secretion in the NIP group increased after the behavioral task, compared with those in other three groups. CONCLUSION: A combination of NP with inflammation occurring in the neonatal period might aggravate the adverse effects of each on somatosensory and cognitive development of rats, the mechanism of which might be associated with the increase of corticosterone secretion and the dysregulation of synaptic molecules.

Enriched environment rescues neonatal pain induced cognitive deficits and the impaired hippocampal synaptic plasticity later in life.

Although extensive and untreated pain that occurs during a critical developmental window may impair cognition later in life, environmental interventions early in life might promote cognition. However, the underlying mechanism is poorly understood. Our current study utilized a rat model of "repetitive needle pricks" from the day of birth (P0) to postnatal day 7 (P7) to mimic the painful experience of preterm neonates in the neonatal intensive care unit. Enriched environment (EE) during development period (from P15 to P70) was implemented as a nonpharmacological intervention approach. Electrophysiological recording, behavioral tests, and biochemical analysis were performed after the end of EE (between P71 and P80). The results showed neonatal repetitive pain resulted in a reduction in mechanical withdrawal thresholds by the von Frey test in P70 (p < .001). Furthermore, neonatal repetitive pain impaired spatial learning and memory (p < .05) and even led to dysfunction in fear memory (p < .01). In contrast, EE rescued neonatal pain-induced cognitive deficits and normalized hippocampal long-term potentiation in rats exposed to neonatal pain (p << .05). The beneficial effect of EE might be the improvements in hippocampal synaptic plasticity via upregulating neurotrophic factors and N-methyl-d-aspartate (NMDA) receptors in the hippocampus. Our findings provide evidence that early environmental intervention might be a safe strategy to overcome neurodevelopmental abnormalities in preterm infants who experienced multiple procedural painful events during the early critical period.

Dietary curcumin supplementation promotes browning and energy expenditure in postnatal overfed rats.

BACKGROUND: Early postnatal overfeeding could result in metabolic imprinting that decreases energy expenditure following white adipose tissue (WAT) gain throughout life. This research investigated whether curcumin (CUR) supplementation could promote WAT browning and activate thermogenesis in postnatal overfed rats. METHODS AND RESULTS: This study adjusted the size of litters to three (small litters, SL) or ten (normal litters, NL) to mimic early postnatal overfeeding or normal feeding from postnatal day 3. From postnatal week 3 (weaning period), SL rats were fed a standard diet (SL) or a diet supplemented with 1% (SL1% CUR) or 2% (SL2% CUR) CUR for ten weeks. At postnatal week 13, SL rats with 1% or 2% CUR supplementation had lower body weight and less WAT gain and had an increased lean mass ratio, and their glucose tolerance and blood lipid levels had recovered to normal when compared to SL rats that did not receive the supplement. Moreover, the increased heat generation were consistent with the expression levels of uncoupling protein 1 (UCP1) and other browning-related genes in the subcutaneous adipose tissue (SAT) of the SL2% CUR rats but not in the SL1% CUR rats. In addition, 2% CUR dietary supplementation enhanced the serum norepinephrine levels in SL rats, with upregulated mRNA levels of ß3-adrenergic receptor (ß3-AR) in SAT. CONCLUSION: Dietary CUR supplementation attenuates body fat gain and metabolic disorders in SL, which might be induced by promoting browning of SAT and energy expenditure. Moreover, the benefits were more obvious in SL with 2% CUR supplementation.

n-3 PUFAs protect against adiposity and fatty liver by promoting browning in postnatally overfed male rats: a role for NRG4.

Early-life nutrition plays an important role in regulating adult metabolism. This study evaluated the effects of early nutrition during the suckling and postweaning periods on expression of the adipocytokine Neuregulin 4 (Nrg4) and its relationship with nonalcoholic fatty liver disease (NAFLD) in adulthood. In vivo, male rats were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3. Pups were fed control chow (NL and SL groups) or a high-fat diet (NL-HF and SL-HF groups), and SL pups specifically were fed a fish oil diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs) (SL-FO group), from postnatal weeks 3 to 13. The results demonstrated that postnatal overnutrition increased weight, hepatic de novo lipogenesis (DNL) gene expression and NAFLD and decreased body temperature and Nrg4, Ucp1 and Pgc1a mRNA expression in adipose tissues in SL, SL-HF and NL-HF rats compared to NL rats in adulthood. The opposite trends were observed in SL-FO rats. Moreover, in vitro, recombinant NRG4 protein reduced lipid accumulation by inhibiting DNL gene expression in fatty HepG2 cells stimulated with sodium oleate. In HPAs, eicosapentaenoic acid (EPA) treatment elevated NRG4 production and caused adipocyte browning, and these effects were abrogated by PPARG antagonism. In conclusion, a postweaning n-3 PUFA diet enhanced Nrg4 expression in adipose tissues, associated with attenuation of NAFLD induced by SL rearing. Additionally, external NRG4 reduced lipogenesis in steatotic hepatocytes. Thus, white adipose tissue browning induced by n-3 PUFAs may promote NRG4 production through the PPARG pathway.

Repetitive Pain in Neonatal Male Rats Impairs Hippocampus-Dependent Fear Memory Later in Life.

Preterm infants in neonatal intensive care units are inevitably subjected to numerous painful procedures. However, little is known about the consequences of early pain experience on fear memory formation later in life. We hypothesized that exposure to repetitive pain in early life triggered hippocampal synaptic plasticity and resulted in memory deficiency in prepubertal and adult rats. From the day of birth (P0) to postnatal day 7 (P7), neonatal male rat pups were randomly assigned to either needle pricks or tactile touches repetitively every 6 h. Trace fear conditioning was performed on rats on P24-P26 and P87-P89. On P24 and P87, rats were sacrificed for molecular and electrophysiological studies. On P24-26 and P87-89, rats that experienced neonatal needle treatment showed a significant reduction in freezing time in the contextual fear conditioning (P < 0.05) and trace fear conditioning tests (P < 0.05). Moreover, repetitive neonatal procedural pain caused a significant decrease in the magnitude of hippocampal long-term potentiation induced by high-frequency stimulation. Furthermore, rats that experienced neonatal needle treatment demonstrated sustained downregulation of NR1, NR2A, NR2B, and GluR1 expression in the hippocampus. Therefore, neonatal pain is related to deficits in hippocampus-related fear memory later in life and might be caused by impairments in hippocampal synaptic plasticity.

TNFR2 knockdown triggers apoptosis-induced proliferation in primarily cultured Schwann cells.

After sciatic nerve injury, Schwann cells in the distal segments of injury site undergo apoptosis and meanwhile proliferation. Although apoptosis-induced proliferation (AiP) has been characterized in various models, whether the proliferation of Schwann cells in the distal segments is triggered by apoptosis remains unelucidated. In this study, we used small interfering RNA to knock down the expression of TNFR1 and TNFR2 in primarily cultured Schwann cells, respectively and observed its effects on apoptosis and proliferation. The downregulation of TNFR1 or TNFR2 resulted in a remarkable decrease of cell viability and dramatically increased the apoptosis of Schwann cells. In contrast, the cell apoptosis induced by the knockdown of TNFR2, but not TNFR1, promoted the Schwann cell proliferation. Together, these observations indicated that Schwann cells can undergo AiP, and TNFR2 knockdown triggers the process. Additionally, we established the sciatic nerve injury model on TNF-α knock-out (KO) mice, and found that the Schwann cells of KO mice occurred significantly less apoptosis and proliferation than that of wild-type mice in the distal segments, which indicated TNF-α and its receptors were essential in the massive apoptosis and the apoptosis-induced proliferation of Schwann cells after sciatic nerve injury. The finding of AiP in Schwann cells may be beneficial to develop new approaches to promote axon regeneration and thereby improve the functional recovery after peripheral nerve injury.

Neonatal overfeeding induced glucocorticoid overexposure accelerates hepatic lipogenesis in male rats.

BACKGROUND: Postnatal overfeeding activates tissue glucocorticoid (GC) activity by up-regulating 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) and increasing sensitivity to high-fat (HF) diet-induced non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate the effects of postnatal overfeeding on GC regulation and lipogenesis in the liver and to observe the impact of GC on hepatocyte lipid metabolism. METHODS: In vivo, Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litter, SL) or ten (normal litter, NL) on postnatal day 3 and then given standard chow from postnatal week 3 (W3) to W13. In vitro, HepG2 cells were stimulated by GC, mifepristone (Mi) or GC + Mi within 48 h, followed by sodium oleate (OA) intervention (or not) for 24 h. Intracellular lipid droplets, triglyceride (TG) concentrations and gene expression related to lipid metabolism were measured in hepatic tissues or HepG2 cells. RESULTS: In vivo, weight gain in the body and liver and TG concentrations in the liver were significantly increased in the SL rats compared to the NL rats at W3 and W13 (p < 0.05); mRNA expression of hepatic 11ß-HSD1, acetyl-CoA carboxylase 1 (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FASN) and their nuclear transcription factor, sterol regulatory element binding protein-1c (SREBP-1c) (p < 0.05), was also increased. In vitro, intracellular lipid droplets and TG content in HepG2 cells increased under stimulation with GC or OA (p < 0.05); the increase was more significant following treatment with GC and OA together (p < 0.05). The ACC, SCD1, FASN and SREBP-1c mRNA expression changes were highly similar to the changes in TG content in cells. All the changes induced by GC disappeared when the glucocorticoid receptor (GR) was blocked by Mi. CONCLUSIONS: Postnatal overfeeding induced GC overexposure through 11ß-HSD1 up-regulation in the liver. GC activated hepatic de novo lipogenesis (DNL) via GR and led to hepatic lipid accumulation, which increased the risk of NAFLD during adulthood.

Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life.

Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life.