Efficacy of tumor necrosis factor α and eicosanoid inhibitors in experimental models of neonatal sepsis

Abstract The potential role of tumor necrosis factor α (TNFα) and eicosanoids in the pathogenesis of experimental neonatal sepsis models was investigated. Lethality was induced in neonatal rats by administration of heat killed group B streptococci (GBS, 7 mg kg⁻¹ intracardially) or Salmonella enteritidis endotoxin (0.35 mg kg⁻¹ intracardially). The relative efficacy of six compounds with putative TNFα and eicosanoid inhibitory actions were tested. These were: ibuprofen (3 and 20 mg kg⁻¹), a cyclo-oxygenase inhibitor; CGS85515 (30 mg kg⁻¹), a lipoxygenase inhibitor; LY203647 (30 mg kg⁻¹), a leukotriene D₄ receptor antagonist; pentoxifylline (10, 50 and 100 mg kg⁻¹), a TNF inhibitor; cloricromene (2 and 10 mg kg⁻¹), a thromboxane A₂ synthetase inhibitor with TNFα inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg⁻¹), a dual cyclo-oxygenase/lipoxygenase inhibitor with TNFα inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNFα at 2.5 h post-injection with killed GBS ( P < 0.05). On the contrary, pretreatment with ibuprofen, CGS85515 or LY203647 did not significantly affect TNFα levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNFα and eicoisanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.     

肺表面活性物质治疗新生儿呼吸窘迫综合征前给予nCPAP呼吸支持最佳时间窗的临床研究

摘要 目的：探讨肺表面活性物质（PS）治疗新生儿呼吸窘迫综合征（NRDS）前给予经鼻持续气道正压通气（nCPAP）呼吸支持的最佳时间窗。方法：选择2017年1月至2019年12月期间我院收治的NRDS患儿100例。根据随机数字表法分为A组（给予PS前预先进行小于2 h的nCPAP,n=33）、B组（给予PS前预先进行2-4 h的nCPAP,n=33）和C组（立即给予PS,n=34）。对比三组患儿的血气分析指标、肺功能指标、临床指标和并发症发生率。结果：A组、B组给予PS后4h、给予PS后24 h动脉血氧分压（PaO₂）、pH值高于C组,且B组高于A组（P<0.05）,而动脉二氧化碳分压（PaCO₂）低于C组,且B组低于A组（P<0.05）。A组、B组给予PS后4 h、给予PS后24 h潮气量（VT）、肺动态顺应性（CD）高于C组,且B组高于A组（P<0.05）,而吸气阻力（Raw）低于C组,且B组低于A组（P<0.05）。B组用药后3天内需气管插管行机械通气例数少于A组和C组,住院时间短于A组和C组（P<0.05）,A组、C组的用药后3天内需气管插管行机械通气例数、住院时间对比无明显差异（P>0.05）。三组患儿并发症发生率未见统计学差异（P>0.05）。结论：给予PS前预先进行2-4h的nCPAP,可较好地改善患儿血气分析指标和肺功能,有助于改善患儿预后。     

Protein Tyrosine Kinases in Human Brain and Gliomas

Tyrosine kinase activity was determined in neonatal and adult human brain, oligodendrogliomas, and astrocytomas. The astrocytomas were divided into low- (grade I and grade II) and high-grade (grade III and grade IV) tumors. We measured the tyrosine kinase activity in the cytosolic and membrane fraction using poly(glutamic acid:tyrosine, 4:1) as an artificial substrate. The cytosolic activity in oligodendrogliomas (n = 7), low-grade astrocytomas (n = 7), and neonatal brain (n = 1) was increased, on average, two- to fourfold compared with that in normal adult brain (n = 14). The cytosolic activities of high-grade astrocytomas (n = 11) were in approximately the same range as found in normal adult brain. The absence of an increase in cytosolic activity in high-grade astrocytomas compared with adult brain is likely due to the occurrence of necrosis in these tumors. In contrast to the cytosolic activity, no differences were found in the membrane-bound activity. By fast protein liquid chromatography, at least three forms of cytosolic protein tyrosine kinase could be separated, which eluted at 0, 115, and 210 mM NaCl. In most cases the highest amount of activity eluted at 210 mM NaCl. However, in oligodendrogliomas, high-grade astrocytomas, and neonatal brain, more activity eluted at 115 mM NaCl than in normal adult brain (p = 0.043). Nevertheless, protein tyrosine kinases from all three peaks contributed to the elevated levels of total cytosolic activity of oligodendrogliomas and low-grade astrocytomas.     

Neonatal coagulopathies: A review of established and emerging treatments

Despite the relative frequency of both bleeding and clotting disorders among patients treated in the neonatal intensive care unit, few clear guidelines exist for treatment of neonatal coagulopathies. The study and treatment of neonatal coagulopathies are complicated by the distinct hemostatic balance and clotting components present during this developmental stage as well as the relative scarcity of studies specific to this age group. This mini-review examines the current understanding of neonatal hemostatic balance and treatment of neonatal coagulopathies, with particular emphasis on emerging treatment methods and areas in need of further investigative efforts.     

Predation processes: behavioural interactions between red fox and roe deer during the fawning season

Predation by red fox (Vulpes vulpes) is the most important mortality cause for neonatal roe deer (Capreolus capreolus) in Scandinavia. With the objective of investigating how the fox finds fawns and how antipredatory behaviour of roe deer females influences choice of hunting method, I analysed observations of interactions between red fox and roe deer females. The observations were collected over 14 years in a mixed forest/agricultural landscape in Sweden. Of 49 fox–doe encounters, the doe attacked the fox in 59%. In 90% of these attacks the fox was successfully deterred. In two observations a doe saved a fawn attacked by a fox. Two hunting methods used by the fox were discerned. In 28 cases foxes searched the ground, and in 18 cases they surveyed open areas, often from a forest edge. The latter behaviour seemed more directed at fawns and was seen leading to a capture attempt. Searching seemed less efficient and also difficult to conduct due to the aggressiveness of does. A surveying sit-and-wait type of hunting method thus appeared as the most successful. The possibility to use this method could explain why roe deer fawns are more vulnerable to fox predation in open habitats.     

Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain

Poly(ADP-ribose) synthase (PARS), an abundant nuclear protein, has been described as an important candidate for mediation of neurotoxicity by nitric oxide. However, in cerebral ischemia, excessive PARS activation may lead to energy depletion and exacerbation of neuronal damage. We examined the effect of inhibiting PARS on the (a) degree of cerebral injury, (b) process of inflammatory responses, and (c) functional outcomes in a neonatal rat model of focal ischemia. We demonstrate that administration of 3-aminobenzamide, a PARS inhibitor, leads to a significant reduction of infarct volume: 63 +/- 2 (untreated) versus 28 +/- 4 mm(3) (treated). The neuroprotective effects currently observed 48 h postischemia hold up at 7 and 17 days of survival time and attenuate neurological dysfunction. Inhibition of PARS activity, demonstrated by a reduction in poly(ADP-ribose) polymer formation, also reduces neutrophil recruitment and levels of nitrotyrosine, an indicator of peroxynitrite generation. Taken together, our results demonstrate that PARS inhibition reduces ischemic damage and local inflammation associated with reperfusion and may be of interest for the treatment of neonatal stroke.     

Building a better neonatal mouse model to understand infant respiratory syncytial virus disease

Background

Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infection in infants; and severe RSV infection in infants is associated with asthma development. Today, there are still no vaccines or specific antiviral therapies against RSV. The mechanisms of RSV pathogenesis in infants remain elusive. This is partly due to the fact that the largely-used mouse model is semi-permissive for RSV. The present study sought to determine if a better neonatal mouse model of RSV infection could be obtained using a chimeric virus in which the F protein of A2 strain was replaced with the F protein from the line 19 clinical isolate (rA2-19F).

Methods

Five-day-old pups were infected with the standard laboratory strain A2 or rA2-19F and various immunological and pathophysiological parameters were measured at different time points post infection, including lung histology, bronchoalveolar lavage fluid (BALF) cellularity and cytokines, pulmonary T cell profile, and lung viral load. A cohort of infected neonates were allowed to mature to adulthood and reinfected. Pulmonary function, BALF cellularity and cytokines, and T cell profiles were measured at 6 days post reinfection.

Results

The rA2-19F strain in neonatal mice caused substantial lung pathology including interstitial inflammation and airway mucus production, while A2 caused minimal inflammation and mucus production. Pulmonary inflammation was characterized by enhanced Th2 and reduced Th1 and effector CD8⁺ T cells compared to A2. As with primary infection, reinfection with rA2-19F induced similar but exaggerated Th2 and reduced Th1 and effector CD8⁺ T cell responses. These immune responses were associated with increased airway hyperreactivity, mucus hyperproduction and eosinophilia that was greater than that observed with A2 reinfection. Pulmonary viral load during primary infection was higher with rA2-19F than A2.

Conclusions

Therefore, rA2-19F caused enhanced lung pathology and Th2 and reduced effector CD8⁺ T cell responses compared to A2 during initial infection in neonatal mice and these responses were exacerbated upon reinfection. The exact mechanism is unknown but appears to be associated with increased pulmonary viral load in rA2-19F vs. A2 infected neonatal lungs. The rA2-19F strain represents a better neonatal mouse model of RSV infection.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0244-0) contains supplementary material, which is available to authorized users.     

Gut microbial alterations in neonatal jaundice pre- and post-treatment

Neonatal jaundice is a common disease that affects up to 60% of newborns. Herein, we performed a comparative analysis of the gut microbiome in neonatal jaundice and non-neonatal jaundice infants (NJIs) and identified gut microbial alterations in neonatal jaundice pre- and post-treatment. We prospectively collected 232 fecal samples from 51 infants at five time points (0, 1, 3, 6, and 12 months). Finally, 114 samples from 6 NJIs and 19 non-NJI completed MiSeq sequencing and analysis. We characterized the gut microbiome and identified microbial differences and gene functions. Meconium microbial diversity from NJI was decreased compared with that from non-NJI. The genus Gemella was decreased in NJI versus non-NJI. Eleven predicted microbial functions, including fructose 1,6-bisphosphatase III and pyruvate carboxylase subunit B, decreased, while three functions, including acetyl-CoA acyltransferase, increased in NJI. After treatments, the microbial community presented significant alteration-based β diversity. The phyla Firmicutes and Actinobacteria were increased, while Proteobacteria and Fusobacteria were decreased. Microbial alterations were also analyzed between 6 recovered NJI and 19 non-NJI. The gut microbiota was unique in the meconium microbiome from NJI, implying that early gut microbiome intervention could be promising for the management of neonatal jaundice. Alterations of gut microbiota from NJI can be of great value to bolster evidence-based prevention against ‘bacterial dysbiosis’.     

Identification of MRI1, encoding translation initiation factor eIF-2B subunit alpha/beta/delta-like protein,as a candidate locus for infantile epilepsy with severe cystic degeneration of the brain

Several neurodegenerative disorders are known to predominantly affect the white matter of the brain including vanishing white matter disease (VWMD), an autosomal recessive disorder characterized by leukodystrophy of varying severity in addition to variable systemic involvement. We report a consanguineous Arab family with three affected children, all of whom presented with severe neonatal epilepsy and profound neurodegenerative disease characterized by marked leukodystrophy with white matter cavitation mimicking VWMD. We combined autozygome and exome analysis to identify a novel variant in the gene encoding a member of the eIF2B-related family of proteins (MRI1). This is a poorly understood family of proteins of unclear function. Our results represent the first link between a variant in a member of this family and a human disease, and suggest that it converges with the highly homologous eIF2B, known to be mutated in VWMD, on the molecular pathogenesis of neurodegeneration.     

De novo trisomy 20p characterized by array comparative genomic hybridization: Report of a novel case and review of the literature

We report on a boy with speech delay, mental retardation, motor clumsiness, hyperactivity, dysmorphic facial features, brachytelephalangy and short stature. Electrocardiogram, echocardiography, renal ultrasound, electroencephalogram, fundoscopic exam and auditory brainstem responses were all normal. Brain magnetic resonance imaging showed a left temporal arachnoid cyst and a small pineal gland cyst.