The serum anion gap is associated with the prognosis of coronary artery bypass grafting (CABG): analysis based on the MIMIC-IV database.

OBJECTIVE: The serum anion gap (AG) has been reported to be an important prognostic indicator for patients in intensive care units. To explore the potential relationship between the serum AG and 30-day mortality in patients who underwent CABG. PATIENTS AND METHODS: All data were collected from the Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) database. We divided patients into 3 groups according to AG tertiles. The primary outcome of our study was the 30-day mortality of patients who underwent CABG. The relationship between the serum AG and mortality in individuals who underwent CABG was estimated using Cox proportional hazard models. Subgroup analysis for effect modification was conducted with a likelihood ratio test. RESULTS: A total of 5,102 eligible subjects were included in our analysis. After adjusting for confounding factors, every unit increase in the AG was associated with a 22% higher odds of 30-day mortality in patients who underwent CABG [hazard ratio (HR), 95% confidence interval (CI): 1.22, 1.13-1.33] When the AG was converted into a categorical variable, the high AG group had a higher risk of 30-day mortality than the low AG group in the fully adjusted model (HR, 95% CI: 3.99, 1.35-11.76). Tests for trends were statistically significant (p-value < 0.05). Subgroup analysis demonstrated that higher mortality was related to the subgroups of people ≥ 70 years and females. CONCLUSIONS: The serum AG was an independent predictor of short-term prognosis in patients who underwent CABG. A high AG was associated with an increased risk of 30-day mortality after CABG.

[Association analysis between genetic variants of matrix metalloproteinase enzyme 2 gene and the blood pressure of children and adolescents].

Objective: To explore the association between genetic variants of matrix metalloproteinase enzyme 2 (MMP2) gene and the blood pressure of children and adolescents. Methods: This cross-sectional study was performed in 2016 and included 4 155 children and adolescents in the urban area of Guangzhou. Physical examinations (including body height, weight, and blood pressure), questionnaires (including general characteristics, physical exercise, parental educational level, household income, etc.), and blood sampling were performed. Multivariable linear regression models were used to investigate the associations of MMP2 genetic variations (rs243865, rs7201) and the genetic risk score (GRS) level with standardized blood pressure. Mediating effect of standardized body mass index (BMI) was further assessed by process analysis in the association between GRS level and blood pressure, and potential additive interaction between physical activity and GRS level was analyzed using the product term in the regression model. Results: A total of 4 155 primary and secondary schoolchildren were finally included in the analysis, consisting of 1 401 (33.7%) second grade pupils of primary school, 1 422 (34.2%) first grade pupils of middle school, and 1 332 (32.1%) first-grade students of senior high school. After adjusting for age, sex, parental educational level, and family income, as compared to the rs243865 TT genotype, the CC/CT genotype increased diastolic blood pressure (DBP) by 0.461 standard deviations (SD) (ß for dominant model=0.461, 95%CI 0.199-0.723). When compared to the rs7201 CC genotype, the AA/AC genotype showed 0.147 SD higher systolic blood pressure (SBP) (ß for recessive model=0.147, 95%CI 0.014-0.279) and 0.171 SD increased DBP (ß for recessive model=0.171, 95%CI 0.039-0.304). For each increment of GRS level, SBP and DBP increased by 0.151 SD (ß for dominant model=0.151, 95%CI 0.029-0.272) and 0.242 SD (ß=0.242, 95%CI 0.120-0.363), respectively. The mediating effect of BMI accounted for 28.3% and 12.6% of the total effect of GRS on SBP and DBP, respectively. After controlling BMI, the direct effect of GRS on DBP remained statistically significant (P<0.001). The insufficient moderate-to-vigorous physical activity (<0.5 h/d) showed a significant interaction with GRS on SBP under additive scale (ß for interaction=0.518, 95%CI 0.088-0.949, P=0.018). Conclusions: rs243865 and rs7201 variants in MMP2 gene are associated with the elevated blood pressure of children and adolescents. Obesity may yield a mediation role in the associations, while insufficient physical activity may have a positively additive interaction with MMP2 genetic variants.

Value of three biopsy methods in prostate cancer detection: a meta-analysis and systematic review.

OBJECTIVE: The study aimed at investigating the value of systemic biopsy (sysPbx), magnetic resonance imaging/ultrasound fusion targeted biopsy (fusPbx) and fusPbx combined with sysPbx (comPbx) for prostate cancer (PCa) detection. MATERIALS AND METHODS: Data from the PubMed, Cochrane, and Embase databases were searched from inception until March 23, 2020. Prospective studies comparing the detection rates of sysPbx, fusPbx and comPbx were identified. We pooled the detection rates for all PCa, clinically significant prostate cancer (csPCa), and clinically insignificant prostate cancer (cinsPCa) of fusPbx, sysPbx, and comPbx. Risk ratios (RRs) were calculated for the meta-analysis. Then, analyses were performed to identify the possible sources of heterogeneity. RESULTS: Seventeen studies, including 18 cohorts with 3035 men, were included. No patients had previous evidence of PCa. Each patient had one or more suspicious lesions found on multiparametric magnetic resonance imaging (mpMRI) and received both fusPbx and sysPbx. The results showed that fusPbx and sysPbx did not differ significantly in detecting all PCa (RR=1.00, 95% CI: 0.95-1.05, p>0.05). However, fusPbx provided a higher detection rate for csPCa (RR=1.24, 95% CI: 1.14-1.34, p<0.05) and a lower detection rate for cinsPCa (RR=0.68, 95% CI: 0.61-0.76, p<0.05) than sysPbx. In addition, comPbx detected more PCa (RR=1.22, 95% CI: 1.16-1.29, p<0.05) and csPCa cases (RR=1.13, 95% CI: 1.05-1.21, p<0.05) than fusPbx. CONCLUSIONS: In men with positive mpMRI findings, compared to sysPbx, fusPbx had significantly increased the detection rates for csPCa and decreased those for cinsPCa. The combination of fusPbx with sysPbx outperformed fusPbx in detecting both overall PCa and csPCa.

The interplay of transcriptional and post-transcriptional regulation of migration of mesenchymal stem cells during early stages of bone fracture healing.

Bone fractures are a medical condition where the continuity of the bone is broken due to a fall or accident. The fracture may also be the result of medical conditions such as osteoporosis, cancers of bone or osteogenesis imperfect. During the bone fracture healing process, the mesenchymal stem cells (undifferentiated connective tissue cells) are recruited from local and systemic sources. The modulation of mesenchymal cell migration to the fractured site is the desired goal. Still, there are many processes that are still required to be studied and analyzed. We aimed to consolidate and review the available information on this topic.

Lack of effects of transforming growth factor-alpha gene knockout on peripheral nerve regeneration may result from compensatory mechanisms.

Transforming growth factor-alpha (TGF-alpha), previously identified as a major member of the epidermal growth factor (EGF) family of growth factors, plays a role in proliferation, differentiation, and survival of neuronal and glial precursors and is implicated in development of the nervous system. However, its roles in nerve injury-induced responses remain obscure. The current study examined roles of endogenous TGF-alpha in peripheral nerve regeneration using sciatic nerve injury models with TGF-alpha knockout mice. Three weeks after a sciatic nerve crush, no significant differences were found between TGF-alpha wild-type and mutant mice in the number of retrogradely labeled L5 dorsal root ganglion (DRG) sensory neurons and L5 spinal cord motor neurons and in the morphology of myelinated regenerating nerve fibers, indicating that TGF-alpha is not essential for sensory and motor nerve regeneration. To assess a possible functional redundancy among TGF-alpha-related ligands in response to a nerve injury, mRNA expression of the EGF family was analyzed by RT-PCR in L4/L5 DRG pools and distal degenerating sciatic nerve segments after sciatic nerve ligation. Prior to and 1 day after ligation, there was a higher level of EGF-R mRNA in DRGs and in nerve in TGF-alpha null mice compared to wild types, and there was an induction of ligand amphiregulin mRNA in DRGs in mutant mice in place of the TGF-alpha upregulation present in wild types. These results indicate that TGF-alpha gene knockout does not affect peripheral nerve regeneration, probably due to a functional redundancy within the EGF family through a compensatory expression mechanism at both the receptor and ligand levels in TGF-alpha knockout mice.

Downregulation of TrkA expression in primary sensory neurons after unilateral lumbar spinal nerve transection and some rescuing effects of nerve growth factor infusion.

Peripheral nerve injury results in sprouting of sympathetic and sensory nerve terminals around large diameter neurons in the dorsal root ganglia (DRG), but the underlying mechanism is not clear. Current study sought to examine changes of the nerve growth factor (NGF) receptor TrkA in DRG and spinal cord after a spinal nerve transection by an immunohistochemical technique and to investigate effects of NGF on the expression of TrkA protein in the same animal model. In the control rat, TrkA immunoreactivity was localized to about 55 +/ -1% of total neurons in DRG and to laminae I and II of the spinal cord. The percentage of TrkA immunoreactive neurons in DRG and TrkA staining intensity of spinal cord were reduced 1 week after the nerve lesion. The changes became maximal 2 weeks, but recovered partially 4 weeks after the lesion. The size of TrkA immunoreactive neurons dramatically shifted to smaller sizes, becoming more remarkable 4 weeks after the lesion. In the contralateral DRG, the percentage of TrkA immunoreactive neurons also decreased significantly. Exogenous NGF delivered to DRG for 2 weeks partially reversed the reduction of TrkA expression as well as atrophy of TrkA immunoreactive neurons. No TrkA immunoreactive basket was found around neuronal somata. Our data show that unilateral peripheral nerve injury results in dynamic downregulation of TrkA in sensory neurons in bilateral DRG and spinal cord, and that TrkA expression in sensory neurons is partially regulated by target-derived NGF.

Effects of endogenous neurotrophins on sympathetic sprouting in the dorsal root ganglia and allodynia following spinal nerve injury.

Peripheral nerve injury is often complicated by a chronic pain syndrome that is difficult to treat. In animal models of peripheral nerve injury, sympathetic nerve terminals in the dorsal root ganglia (DRG) sprout to form baskets around large diameter neurons, an anatomical change that has been implicated in the induction of neuropathic pain. In the present study, we have investigated whether neurotrophins derived from peripheral sources play any roles in sympathetic sprouting and neuropathic pain in a rat model of peripheral nerve injury. After transection of the left lumbar (L) 5 spinal nerve, antisera specific to neurotrophins were injected intraperitoneally twice a week for 2 weeks. The foot withdrawal response to von Frey hairs was examined on days 1, 3, 7, 10, and 14 postlesion. After completion of behavioral tests, sympathetic sprouting in DRG was examined by tyrosine hydroxylase (TH) immunohistochemistry. The number of TH-immunoreactive (ir) fibers and baskets around large neurons within the lesioned DRG was dramatically increased in the rats treated with control normal sheep serum. Antisera specific to nerve growth factor (NGF), neurotrophin-3 (NT3), and brain-derived neurotrophic factor (BDNF) significantly reduced the sympathetic sprouting and the formation of baskets. L5 spinal nerve lesion induced a significant increase in foot withdrawal responses to von Frey hair stimuli, which was attenuated by treatment of antisera to neurotrophins with a different time sequential. The effect of BDNF antiserum occurred earlier and lasted longer than those of NGF and NT3 antisera. These results implicate that peripherally derived neurotrophins are involved in the induction of sympathetic sprouting and neuropathic pain following peripheral nerve injury.

Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats.

Injury to peripheral nerves often results in chronic pain which is difficult to relieve. The mechanism underlying the pain syndrome remains largely unknown. In previous studies we showed that neurotrophins are up-regulated in satellite cells around sensory neurons following sciatic nerve lesion. In the present study, we have examined whether the neurotrophins in the dorsal root ganglia play any role in allodynia after nerve injury. Antibodies to different neurotrophins, directly delivered to injured dorsal root ganglia, significantly reduced (with different time sequences) the percentage of foot withdrawal responses evoked by von Frey hairs. The antibodies to nerve growth factor acted during the early phase but antibodies to neurotrophin-3 and brain-derived neurotrophic factor were effective during the later phase. Exogenous nerve growth factor or brain-derived neurotrophic factor, but not neurotrophin-3, directly delivered to intact dorsal root ganglia, trigger a persistent mechanical allodynia. Our results showed that neurotrophins within the dorsal root ganglia after peripheral nerve lesion are involved in the generation of allodynia at different stages. These studies provide the first evidence that ganglia-derived neurotrophins are a source of nociceptive stimuli for neuropathic pain after peripheral nerve injury.

BDNF is involved in sympathetic sprouting in the dorsal root ganglia following peripheral nerve injury in rats.

Peripheral nerve injury results in sympathetic sprouting around large diameter sensory neurons in the dorsal root ganglia (DRG). The mechanism underlying this pathological phenomenon is not known. Brain-derived neurotrophic factor (BDNF) is up-regulated in large sensory neurons and ensheathing satellite cells following a sciatic nerve injury. In the present study, we investigated the effects of BDNF on the sympathetic sprouting in the DRG, by delivering BDNF antibody or antisense oligodeoxynucleotide to injured DRGs, or by delivering exogenous BDNF to intact DRGs. The sheep antibody to BDNF, characterized by bioassays and dot blots, specifically reacted with BDNF but not other neurotrophins. Noradrenergic fibers were visualized by immunostaining of tyrosine hydroxylase (TH) and quantified by an NIH Imaging program. Two weeks following L5 spinal nerve lesion, a dramatic increase in TH-immunoreactive (-ir) fibres was observed in both ipsi- and contralateral DRGs in normal sheep IgG treated rats. BDNF antibody significantly reduced the sprouting of sympathetic nerves in both ipsi- and contra-lateral DRGs by 67% and 42% respectively. BDNF antisense oligodeoxynucleotide, by inhibiting BDNF synthesis in DRGs, also significantly suppressed the sprouting by 67% and 60% respectively in the ipsi- and contra-lateral DRGs. Delivery of exogenous BDNF into an intact L5 DRGs resulted in an increase in the sprouting by 4.2-fold. Our results clearly indicate that BDNF, synthesized in and secreted from the DRGs, is involved in the sympathetic sprouting in the DRG following the peripheral nerve injury.

Measurement of neurotrophin 4/5 in rat tissues by a sensitive immunoassay.

Neurotrophin 4/5 (NT4/5) is a member of the neurotrophin family known to exert survival and other effects on a variety of neurons including those within the motor, sensory and central populations. Although mRNA(NT4/5) has been found in various effector tissues of the rat and human, the concentration of NT4/5 protein in tissues has not been reported previously due to lack of suitable methodology. We present here a quantitative two-site enzyme-linked immunosorbent assay for the estimation of NT4/5 in pre- and postnatal rat tissues. The assay was performed using a combination of polyclonal and monoclonal antibodies to recombinant human NT4/5. Tissue samples were extracted at neutral pH. Results show that the assay is highly specific for NT4/5 with a sensitivity of 1 pg/ml, and reproducible with intra- and inter-assay variation coefficients of 3.0 and 6.3%, respectively. NT4/5 was found in most embryonic tissues examined at gestation day 17 and 21, but was rarely detectable in postnatal tissues, with the notable exception of the testis. The availability of an immunoassay for the estimation of NT4/5 protein in rat tissues should contribute to the understanding of the physiology of this little understood neurotrophic factor.

Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat.

Peripheral nerve injury results in plastic changes in the dorsal root ganglia and spinal cord, and is often complicated with neuropathic pain. The mechanisms underlying these changes are not known. We have now investigated the expression of brain-derived neurotrophic factor in the dorsal root ganglia with histochemical and biochemical methods following sciatic nerve lesion in the rat. The percentage of neurons immunoreactive for brain-derived neurotrophic factor in the ipsilateral dorsal root ganglia was significantly increased as early as 24 h after the nerve lesion and the increase lasted for at least two weeks. The level of brain-derived neurotrophic factor messenger RNA was also significantly increased in the ipsibut not contralateral dorsal root ganglia. Both neurons and satellite cells in the lesioned dorsal root ganglia synthesized brain-derived neurotrophic factor messenger RNA after the nerve lesion. There was a dramatic shift in size distribution of positive neurons towards large sizes seven days after sciatic nerve lesion. Morphometric analysis and retrograde tracing studies showed that no injured neurons smaller than 600 microm2 were immunoreactive for brain-derived neurotrophic factor, whereas the majority of large injured neurons were immunoreactive in the ipsilateral dorsal root ganglia seven days postlesion. The brain-derived neurotrophic factor-immunoreactive nerve terminals in the ipsilateral spinal cord were reduced in the central region of lamina II, but increased in more medial regions or deeper into laminae III/IV. These studies indicate that sciatic nerve injury results in a differential regulation of brain-derived neurotrophic factor in different subpopulations of sensory neurons in the dorsal root ganglia. Small neurons switched off their normal synthesis of brain-derived neurotrophic factor, whereas larger ones switched to a brain-derived neurotrophic factor phenotype. The phenotypic switch may have functional implications in neuronal plasticity and generation of neuropathic pain after nerve injury.

Satellite-cell-derived nerve growth factor and neurotrophin-3 are involved in noradrenergic sprouting in the dorsal root ganglia following peripheral nerve injury in the rat.

Injury to a peripheral nerve induces in the dorsal root ganglia (DRG) sprouting of sympathetic and peptidergic terminals around large-diameter sensory neurons that project in the damaged nerve. This pathological change may be implicated in the chronic pain syndromes seen in some patients with peripheral nerve injury. The mechanisms underlying the sprouting are not known. Using in situ hybridization and immunohistochemical techniques, we have now found that nerve growth factor (NGF) and neurotrophin-3 (NT3) synthesis is upregulated in satellite cells surrounding neurons in lesioned DRG as early as 48 h after nerve injury. This response lasts for at least 2 months. Quantitative analysis showed that the levels of mRNAs for NT3 and NGF increased in ipsilateral but not contralateral DRG after nerve injury. Noradrenergic sprouting around the axotomized neurons was associated with p75-immunoreactive satellite cells. Further, antibodies specific to NGF or NT3, delivered by an osmotic mini-pump to the DRG via the lesioned L5 spinal nerve, significantly reduced noradrenergic sprouting. These results implicate satellite cell-derived neurotrophins in the induction of sympathetic sprouting following peripheral nerve injury.

Rat mature sympathetic neurones derive neurotrophin 3 from peripheral effector tissues.

In a previous study we have demonstrated that endogenous neurotrophin 3 (NT3) is required for the survival of most sympathetic neurones in postnatal rats. However, the mechanisms underlying the action of NT3 on sympathetic neurones is not known. Neither is it understood whether NT3 is retrogradely transported from peripheral tissues or acts locally in an autocrine fashion. In the present study, NT3-mRNA was quantified in sympathetic effector tissues and NT3 protein was localized in intact and lesioned sympathetic nerves in rats. NT3-mRNA is expressed and developmentally regulated in many effector tissues including mesenteric arteries, salivary gland, heart and kidney but hardly detectable in the superior cervical ganglia of adult animals. The majority of sympathetic neurones express immunoreactivity for TrkA and TrkC in both neonatal and adult rats. Sympathetic somata are normally immunoreactive for NT3, but the immunoreactivity is abolished by systemic administration of NT3 antibodies or axotomy of postganglionic neurones, suggesting an accumulation of NT3 from extraneuronal sources. Furthermore, the detection of NT3-immunoreactivity in the internal carotid nerve as early as 3 h following a compression and only on the distal side indicates endogenous NT3 is retrogradely transported by sympathetic neurones. These studies provide evidence indicating that NT3, like nerve growth factor, is an effector tissue-derived neurotrophic factor for sympathetic neurones both during development and in the adult animal. Thus, we have provided a clear example that one type of neurone derives, through a retrograde transport mechanism, two neurotrophic factors simultaneously from its peripheral effector tissues.