| BackgroundFebrile seizures (FS) is a disease which is starting at the age between3months to5years old in the upper respiratory infection or other infectious diseases early.when the body temperature is above38℃,the convulsions are suddenly occurring having excluded previous afebrile seizures history intracranial infection and of other diseases caused by structural or metabolic abnormalities. The disease is common ofter the acute upper respiratory tract infections, acute otitis media or child care rash. The non-complex seizures occurred in a short period of time during the heating process quickly,without a history of epilepsy, nervous system lesions.It is the most common paroxysmal emergency disease in children,also considered as a special type of epilepsy syndrome with a significant age-dependent, and genetic predisposition. It is common in the children between6months to6years after birth and accounting for30%of the various types of seizures in children.The incidence of2%to5%under the age of five with boys slightly more than girls.It will be rare after the age of seven.The incidence rate of5%to6%in China,2%to5%in the United States and Western Europe,6%to9%in Japan,11.4%in the the West Pacific Maia Islands.The recurrence rate is30%to40%,even up to1/3after the first episode of febrile seizure.The prognosis of children with FS is generally good. They also can cause irreversible brain damage when the repeated convulsions are occurring,leaving the nerve-mental disorders. Its exact pathogenesis is not very clear.There is still clinically a lack of effective interventions. In recent years, the pathogenesis of FS was researching extensively at home and abroad.The people for the study of hydrogen sulfide (hudrogen sulfide, H2S) is limited to its toxic effects before. Goodwin and other scientists have found a endogenous H2S with relatively high concentration in the human brain tissue of the rats, bovines humans and speculated that it may be involved in the pathophysiological process of multiple system diseases in mammals and the human nervous system, digestive system and cardiovascular system, endocrine system and urinary system in1989.Abe K found the endogenous H2S existing as a neuroactive substances in the human body through experiments in the first time in the1990s.The physiological and pathological role of H2S in the past10years, especially in the central nervous system and cardiovascular system has conducted a lot of research. Some data indicate that endogenous H2S are closely linked with Alzheimer’s disease (AD), FS, ischemic perfusion brain injury (GIRI)、Down’s syndrome and other neurological diseases.Han Y found that the NaHS donor of exogenous gaseous signal molecule H2S can significantly reduced hippocampal neuronal damage caused by recurrent FS.But the hydroxylamine (HA) which is CBS inhibitor significantly increased hippocampal neuronal damage. With the deepening of the experimental study,the endogenous H2S has been recognized another new gas signal medium following nitrogen monoxidum (NO) and carbon monoxide (CO),playing an important regulation role in the function of the central nervous system,such as the regulation of synaptic activity, affect hippocampal long-term potentiation. Endogenous H2S has become the hotspot of the medical research in the field, and its relationship with brain injury caused by the great attention of medical researchers now.Neuron-specific enolase (NSE) as a dimeric protein, which is neuropeptide, existed specifically in the neurons and cytoplasm of the neuroendocrine cells, accounting for1.5%of the soluble proteins in the brain. It was a specific marker of neuronal injury,also a key enzyme during the glycolytic pathway, and closely relating to the judgement making in the braininjury severity of the disease early. When the brain damage occurs,the nerve cells are necrosis dissolved.Then the NSE enter into from the cells into the cerebrospinal fluid resulting the changes in CSF NSE concentrations.At the same time, the blood-brain barrier is of damage, the cell permeability increasing.The NSE released from the cells into the blood, resulting in serum NSE concentration also increaseing.Chilean scholars observed CSF NSE concentrations have no significant difference comparing with normal children after one seizure for1h, Also some Scholar reported that serum and CSF NSE levels were significantly higher than that of the control group in24h,suggesting that seizures can lead to neuronal function injury.Brain-derived neurotrophic factor was extracted from porcine brain extract for the first time Barde, widely presenting in the central nervous system tissue and as an important biological role. Subsequent studies found that BDNF may promote neuronal survival, differentiation and growth, resistance to the noxious stimuli and maintain its normal physiological function. At present, a large number of studies have shown that BDNF played an important role of neuroprotection during the process of FS. But now there was other sense,such as excitotoxiciry in the convulsive diseases at home and abroad.Scharfman proposed endogenous BDNF exist double meaning, not only the protective effect to the neurons, may also be related to the formation of human temporal lobe epilepsy. Some scholars injected intrathecally the BDNF into adult rat. Early gene c-fos was significantly increased in the spinal cord dorsal horn surface after3h. C-fos is a sensitive indicator of neuronal excitability injury.High mobility group box1(HMGB1) was widely present in the in the chromatin nucleoprotein of non-histone proteins in eukaryotic cells.They usually stored in the nucleus, but they also could transferred to the extracellular for mediating in-flammatory reaction through the active secretion of the innate immune cells and the passive release of necrotic cells when infected in the body.lt was an important late inflammatory factors involved in the occurence and development of a variety of inflammatory diseases. Some scholars found the HMGB1of high expression from human brain epilepsy tissue.It had been demonstrated that HMGB1、TLR4antagonist could prevent or delay the occurrence of seizures, also decreasing acute and chronic recurrence of epilepsy.It was suggested that HMGB1promote seizures in epilepsy.So we can infer that there have be the existence of common pathological role of HMGB1 between FS and epilepsy. Also studies reported that HMGB1involved in the pathophysiological process of brain damage, but the few studies.IL-6was a cytokine with a wide range of regulatory role synthetized by brain neurons and glial cells. It was of a dual role in the central nervous system that had been confirmed in animal experiments.Past studies showed that overexpressing IL-6in the mice could increase the release of neuronal excitatory substances and the correspondingly enhanced the susceptibility to seizures in mice. One reason was that the GABA receptor activity mediated neuronal inhibition was decreased,then the inhibition attenuated. In addition, IL-6also enabled the development of mouse to delay seizures occurring and short the duration of the seizures.It was of an important anticonvulsant effect. C-reactive protein, white blood cell count, and calcitonin was the most common laboratory parameters whihch reflected the severity of the inflammatory. Such inflammatory factors often increased in the early period of children with FS.Based on the above theory, the study detected the concentration of serum H2S、 NSE BDNF、HMGB1、IL-6、WBC、CRP and PCT in the children with FS by ELISA, and combine the EEG and pediatric neuropsychological development scale, exploring the clinical significance of such indicators to the brain damage after FS. It could find a new target for the prevention and treatment of FS,also to offer help for its clinical diagnosis, treatment and prognosis.ObjectiveIn this study, serum H2S content and serum NSE、BDNF、HMGB1、IL-6concentration was measured by enzyme-linked immunosorbent assay (ELISA),and clinically recording the seizures time and the number of seizures with FS, combining with EEG and intellectual development of children with FS, analysing the changes of various serum indicators levels.Primary discussion for effects during the occurrence and development about changes of serum H2S、NSE、BDNF、HMGB1、IL-6、WBC、 CRP and PCT levels and its correlations.It can provide some theoretical basis for the assessment and judgment in seizures brain injury early, also a new concept for the treatment. MethodsSixty-five children with FS、fifty-one with acute upper respiratory infection associated with fever and forty-three in Child health section for physical examination were respectively chosen as the experimental group、the fever without convulsion control group、the healthy control group.65cases and53cases of children with FS was chosen as another experimental group.All children came from Department of Pediatrics Zhujiang Hospital, Southern Medical University from March15,2012to November10,2012.The serum H2S、NSE、BDNF、HMGB1、IL-6、WBC、CRP、 PCT levels of all groups were measured by Microplate Reader. The brain activity was examined by EEG; The mental development index(DQ) was assessed by development scale.Results(1) compared between serum H2Sand serum NSE The serum concentration of H2S in children with FS is (30.30±13.15) umol/L, serum NSE concentration (12.22±2.87) ng/ml. The serum concentration of H2S in children with upper respiratory tract infection is (43.38±11.14) umol/L, serum NSE concentrations (10.93±2.66) ng/ml.The serum concentration of H2S in healthy group is (45.60±9.98) umol/L, serum NSE concentration (10.00±2.47) ng/ml. There were both statistically significant differences about serum H2S content and serum NSE concentration compared FS goup with the two control group.(P<0.05, P<0.01).The serum NSE differences have no statistical significance in two control goups (P>0.05). There were all no statistically differences among different EEG groups(P>0.05).(2) The serum BDNF levels in experimental group were greatly higher than thecontrol groups(P<0.01). The serum BDNF levels were significantly increased in children with abnormal EEG(P<0.01; P<0.05), especially the children with seizure abnormal EEG (3) Comparisons of cytokine levels among3groupsThere were statistically significant differences of serum HMGB1, IL-6, WBC, CRP, PCT between FS group、upper respiratory infection and normal control group (HMGB1:P<0.01, P=0.044<0.05; IL-6:P<0.01, P<0.01; WBC:P<0.01, P<0.01; CRP:P<0.01, P<0.01; PCT:P<0.01, P<0.01). There were no statistically significant differences of serum HMGB1levels between FS group (P=0.04<0.05),but no significant differences of serum IL-6. WBC. CRP and PCT levels(IL-6:P=0.219>0.05; P=0.481>0.05); P=0.98>0.05; P=0.976>0.05).(4) Comparisons of HMGB1among3groups There were no statistically significant differences of serum HMGB1levels between SFS group、CFS group and nomal group (P=0.01<0.01, P=0.02<0.01).There were no statistically significant differences of serum HMGB1levels between SFS group and CFS group (P=0.496>0.05).(5) The compared between serum H2S and NSE levels in the different number of seizures and the number of seizures The serum concentration of H2S in the children with The number of seizures<2times is (31.88±12.76) umol/L, serum NSE concentration (11.67±2.78) ng/ml.The serum concentration of H2S in children with the number seizures≥2times is (25.01±13.45) umol/L, serum NSE concentration (14.03±2.47) ng/ml. The serum concentration of H2S with the seizure time<5min is (31.82±12.97) umol/L, serum NSE concentration (11.85±2.99) ng/ml. There were significant differences of serum NSE concentrations between convulsive seizures(<2times) and convulsive seizures(<2times)(t=-2.955,P=0.004).There were no significant differences of serum H2S concentrations between convulsive seizures(<2times) and convulsive seizures(<2times)(t=1.808, P=0.075). There were no significant differences of serum H2S and serum NSE concentrations between convulsive seizures(<5min) and convulsive seizures (t=1.464, P=0.148, t=-1.629, P=0.108).(6) Correlation analysis The correlation coefficient for serum H2S content and serum NSE concentration was r=-0.279,P=0.024. The correlation coefficient for convulsive seizures and serum H2S levels was r=-0.269, P=0.03, and for convulsive seizures and serum NSE concentrations(r=0.322, P=0.009).Although there had no correlation among convulsions time、the serum H2S levels and serum NSE from overall statistical analysis (correlation coefficient r=-0.194, P=0.122, r=0.102, P=0.417), the correlation coefficient for seizure durations (≥5min) and serum H2S levels was r=-0.532, P=0.019,without correlation with serum NSE concentrations(r=0.246, P=0.310). There was no significant correlation between DQ and the serum BDNF or H2S(P=0.144; P=0.0.948). Serum HMGB1was no significantly correlate with serum IL-6. PCT levels(r=0.131, P=0.348; r=0.036, P=0.799), but related to H2S、WBC、CRPlevels(r=-0.301, P=0.029; r=0.283, P=0.04; r=0.331, P=0.016). Serum IL-6was significantly no correlate with WBC、PCT levels(r=0.196, P=0.16; r=0.131, P=0.348),but related to serum CRP levels(r=0.276, P=0.046).Conclusions(1) Endogenous H2S, NSE, BDNF, HMGB1, IL-6may all participate in the pathogenesis of FS,and serum BDNF、HMGB1及IL-6probably be the important occurrence and recurrence factors of FS.(2) The serum H2S levels in experimental group was significantly decreased in the process of FS early,also related to serum NSE levels convulsive seizures and seizure durations. The Serum H2S levels was expected to be a objective index for evaluating the seizure brain injury early, the important occurrence and recurrence factors of FS.(3) H2S、BFNF、HMGB and IL-6can be used as the potential therapeutic targets resisting FS.(4) There was no significant correlation between serum BDNF and DQ. |
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