Ailin Luo

Remote ischemic preconditioning fails to improve early renal function of patients undergoing living-donor renal transplantation: a randomized controlled trial.

and liver transplantation is indicated only for patients with end-stage liver and cardiac disease or familial amyloidosis, limiting its clinical use. Recent reports have described the use of a partial auxiliary liver in the context of kidney transplantation (15, 16), demonstrating that the auxiliary liver may offer a protective effect when transplanted together with a kidney from the same donor, despite a positive crossmatch between the donor and the recipient. The results of the antibody analyses in these reports have supported the hypothesis that even smaller liver grafts protect the transplanted kidneys by reducing the levels of specific DSA reactivity. Whether such partial auxiliary liver transplants may be performed in the context of heart transplantation in patients with high titers of DSA is speculative. In conclusion, transplantation of a liver graft immediately before heart transplantation can achieve profound and sustained decrease in DSA and protect the transplanted heart for celland antibody-mediated rejection, even in the presence of preformed high titers of such antibodies. Combined heart and liver transplantation in ‘‘reversed order’’ may become a therapeutic option for highly sensitized patients waiting for a heart transplant. Richard C. Daly Yan Topilsky Lyle Joyce Tal Hasin Manish Gandhi Charles Rosen Julie Heimbach Brooks S. Edwards Naveen Pereira John M. Stulak Christopher J. Arendt Soon J. Park Sudhir S. Kushwaha 1 Division of Cardiovascular Surgery Mayo Clinic Rochester, MN 2 Division of Cardiovascular Disease Mayo Clinic Rochester, MN 3 Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN 4 Division of Transplant Surgery Mayo Clinic Rochester, MN 5 Division of Pharmacy and Therapeutics Mayo Clinic Rochester, MN

Minocycline mitigates isoflurane-induced cognitive impairment in aged rats.

Postoperative cognitive dysfunction (POCD) is a severe neurological sequela that occurs in individuals who have undergone anesthesia and surgery, especially in the geriatric surgical population. Although it is known that isoflurane exposure impairs cognitive function in aged rodents, there are few clinical interventions for the prophylaxis and treatment of this disorder. Minocycline, a derivative of tetracycline, produces neuroprotection from several neurodegenerative diseases. Therefore, we set out to investigate the effects of minocycline pretreatment on isoflurane-induced cognitive impairment in aged rats. We found that pretreatment with minocycline remarkably alleviated isoflurane-induced cognitive dysfunction and inhibited the isoflurane-induced over expression of TNF-α, IL-1β, and IL-6, possibly by inhibiting the degradation of IκBα. In addition, minocycline downregulated the isoflurane-induced increase in the protein levels of cleaved caspase 3 and bax, and upregulated the bcl-2 protein level. These findings highlight the beneficial role of minocycline in preventing isoflurane-induced cognitive impairment and suggested that minocycline can be used as a clinical treatment to mitigate the cognitive impairment induced by isoflurane in elderly patients.

Dexmedetomidine Attenuates Myocardial Injury in Off-Pump Coronary Artery Bypass Graft Surgery

OBJECTIVE To investigate the cardioprotective effect of the continuous administration of dexmedetomidine using serum cardiac troponin I (cTnI) and creatine kinase MB (CK-MB) concentrations as biomarkers during off-pump coronary artery bypass grafting (OPCAB) surgery. DESIGN A prospective, randomized, parallel-group controlled study. SETTING A university hospital. PARTICIPANTS One hundred sixteen patients undergoing OPCAB surgery. INTERVENTIONS Patients were divided randomly into 3 experimental groups that were separated by the dexmedetomidine administration protocol: a high-dose group (loading dose, 1 μg/kg; maintenance dose, 0.6 μg/kg/h); low-dose group (loading dose, 0.6 μg/kg; maintenance dose, 0.3 μg/kg/h); and control group (the same amount of 0.9% saline as placebo). Serum cTnI and CK-MB levels were measured before surgery and 24 hours and 48 hours after surgery. MEASUREMENTS AND MAIN RESULTS Serum cTnI and CK-MB levels in patients of the high-dose group were less than those of the other 2 groups 48 hours after surgery. The administration of dexmedetomidine significantly decreased the heart rate. Compared with the control group, there was a significantly reduced requirement of sevoflurane in the other 2 groups (p<0.05). The intraoperative and postoperative cumulative volumes of urine output in the high-dose group were greater than those of the other 2 groups (p<0.05). The authors also found that the extubation time and length of stay in the intensive care unit were prolonged in the high-dose group. CONCLUSIONS Myocardial damage was reduced by the administration of a 1 μg/kg loading dose and a 0.6 μg/kg/h infusion dose of dexmedetomidine. However, further studies are needed to understand the underlying mechanism and to confirm that high doses of dexmedetomidine could be administered safely in patients undergoing OPCAB surgery.

Role of GSK-3β in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats

This study investigated the role of glycogen synthase kinase-3β (GSK-3β) in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. The hippocampi were dissected from aged rats which had been intraperitoneally administered lithium chloride (LiCl, 100 mg/kg) and then exposed to 1.4% isoflurane for 6 h. The expression of GSK-3β was detected by Western blotting. The mRNA and protein expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Morris water maze was employed to detect spatial memory ability of rats. The results revealed that the level of GSK-3β was upregulated after isofurane exposure. Real-time PCR analysis demonstrated that isoflurane anesthesia increased mRNA levels of TNF-α, IL-1β and IL-6, which was consistent with the ELISA results. However, these changes were reversed by prophylactic LiCl, a non-selective inhibitor of GSK-3β. Additionally, we discovered that LiCl alleviated isoflurane-induced cognitive impairment in aged rats. Furthermore, the role of GSK-3β in isoflurae-induced neuroinflammation and cognitive dysfunction was associated with acetylation of NF-κB p65 (Lys310). In conclusion, these results suggested that GSK-3β is associated with isoflurane-induced upregulation of proinflammatory cytokines and cognitive disorder in aged rats.SummaryThis study investigated the role of glycogen synthase kinase-3β (GSK-3β) in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. The hippocampi were dissected from aged rats which had been intraperitoneally administered lithium chloride (LiCl, 100 mg/kg) and then exposed to 1.4% isoflurane for 6 h. The expression of GSK-3β was detected by Western blotting. The mRNA and protein expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Morris water maze was employed to detect spatial memory ability of rats. The results revealed that the level of GSK-3β was upregulated after isofurane exposure. Real-time PCR analysis demonstrated that isoflurane anesthesia increased mRNA levels of TNF-α, IL-1β and IL-6, which was consistent with the ELISA results. However, these changes were reversed by prophylactic LiCl, a non-selective inhibitor of GSK-3β. Additionally, we discovered that LiCl alleviated isoflurane-induced cognitive impairment in aged rats. Furthermore, the role of GSK-3β in isoflurae-induced neuroinflammation and cognitive dysfunction was associated with acetylation of NF-κB p65 (Lys310). In conclusion, these results suggested that GSK-3β is associated with isoflurane-induced upregulation of proinflammatory cytokines and cognitive disorder in aged rats.

Pharmacological inhibition of PTEN attenuates cognitive deficits caused by neonatal repeated exposures to isoflurane via inhibition of NR2B-mediated tau phosphorylation in rats.

ABSTRACT Evidence has shown that children exposed to repeated anesthesia in early childhood display long‐term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane‐induced decrease of self‐renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimers disease model. Therefore, in the present in vivo study, we aimed to examine the effects of PTEN inhibition on the cognitive dysfunction and tau hyperphosphorylation caused by neonatal repeated exposures to isoflurane. Our results showed that the neonatal repeated exposures to isoflurane resulted in the activation of PTEN in the hippocampus. The treatment of PTEN inhibitor BPV (pic) restored PSD‐95 synthesis, and attenuated tau phosphorylation as well as the cognitive dysfunction caused by the repeated isoflurane exposures. In addition, BPV (pic) treatment reversed the activation of NR2B‐containing NMDARs induced by repeated isoflurane exposures, while in turn, the antagonism of NR2B subunit with ifenprodil alleviated tau phosphorylation, indicating a possible role of NR2B as the downstream of PTEN in mediating tau phosphorylation in the neonatal rats repeatedly exposed to isoflurane. In conclusion, our results reveal a novel role of PTEN in mediating tau phosphorylation and cognitive deficits caused by neonatal repeated exposures to isoflurane, implying that targeting on PTEN may be a potential therapeutic approach for the anesthetic‐related cognitive decline in the developing brain. HighlightsRepeated isoflurane exposures result in activation of PTEN in the hippocampus of neonatal rats.Inhibition of PTEN with BPV (pic) reduces cognitive deficits in the rats repeatedly exposed to isoflurane in neonatal age.Inhibition of PTEN restores synaptic protein synthesis and ameliorates tau phosphorylation in the hippocampus.NR2B‐containing NMDA receptor acts downstream of PTEN in regulating tau phosphorylation.

Ketamine: The best partner for isoflurane in neonatal anesthesia?

Isoflurane is one of the most commonly used inhalation anesthetic in neonatal anaesthesia. It has been suggested that isoflurane can induce caspase activation and apoptosis when applied in a clinically relevant concentration in the developing brain. Recent researches have indicated that a clinically relevant isoflurane treatment may induce neurodegeneration and apoptosis by activating the endoplasmic reticulum (ER) membrane inositol 1,4,5-trisphosphate (IP(3)) receptor, producing excessive calcium release from ER to the cytoplasm and triggering apoptosis. Although the exact mechanism by which isoflurane induces apoptosis still needs further study, it is generally accepted that the increase of cytosolic free calcium levels is the major risk factor. Previous studies have found that during early postnatal life, activation of gamma-aminobutyric acid (GABA(A)) receptor reduces the voltage-dependent Mg(2+) block of N-methyl-d-aspartate (NMDA) channels in neurons and increases cytosolic calcium levels by potentiated the Ca(2+) influx through NMDA channels; while in the adult, it may enhance the voltage-dependent Mg(2+) block of NMDA channels and decrease the Ca(2+) influx through NMDA channels. Since isoflurane acts at the GABA(A) receptor in an agonistic manner, here we presume that isoflurane increases intracellular calcium in neonatal neurons not only by activating IP(3) receptors in the endoplasmic reticulum (ER) membrane, but also by activating the GABA(A) receptor and depolarizing the postsynaptic membrane enough to facilitate NMDA receptor-mediated Ca(2+) influx. Meanwhile, we hypothesized that ketamine, a widely used pediatric anesthetic, acts as a noncompetitive antagonist of the NMDA type of glutamate receptors, which may be the best partner for isoflurane in neonatal anesthesia for it may attenuate isoflurane-induced caspase activation and apoptosis in the neonatal neurons by inhibiting the isoflurane-induced elevation in cytosolic calcium not only by blocking the NMDA receptors, but also by suppressing inositol triphosphate formation in the cytoplasm.

Involvement of caspase-3/PTEN signaling pathway in isoflurane-induced decrease of self-renewal capacity of hippocampal neural precursor cells.

Evidence has shown that children exposed to isoflurane anesthesia in early childhood display long-term cognitive abnormalities, and decreased self-renewal capacity of hippocampal neural precursor cells (NPCs), which are associated with cognition impairment. Caspase-3 has long been considered as a mediator in isoflurane-induced neuroapoptosis. However, accumulating data indicate that caspase-3 also plays a non-apoptotic negative regulatory role in NPCs self-renewal. In this study we used in vitro NPC cultures to test whether caspase-3 and its downstream signaling effectors were involved in isoflurane-induced impairment of the self-renewal capacity of hippocampal NPCs. We showed that isoflurane exposure induced a decrease in the self-renewal capacity of hippocampal NPCs by decreasing proliferation and increasing neuronal differentiation. Furthermore, we found that isoflurane exposure significantly increased the levels of active caspase-3 and decreased the levels of phospho-PTEN under both proliferation and differentiation conditions. Inhibition of either caspase-3 with Z-DEVD-fmk or PTEN with BPV (phen) in NPCs, attenuated the isoflurane-induced decrease of their proliferation and increase of neuronal differentiation. Application of Z-DEVD-fmk also attenuated isoflurane-induced decrease in phospho-PTEN expression. Taken together, our in vitro results reveal a previously uncharacterized involvement of caspase-3/PTEN signaling in the isoflurane-induced impairment of NPCs self-renewal, and contribute to the identification of novel targets for maintaining NPCs self-renewal in isoflurane-induced cognitive dysfunction.

Isoflurane enhances the expression of cytochrome C by facilitation of NMDA receptor in developing rat hippocampal neurons in vitro

SummaryThis study examined the effects of clinically relevant concentrations of isoflurane on the amplitude of NMDA receptor current (INMDA) and the expression of cytochrome C in cultured developing rat hippocampal neurons. The hippocampi were dissected from newborn Sprague-Dawley rats. Hippocampal neurons were primarily cultured for 5 days and then treated with different concentrations of isoflurane [(0.25, 0.5, 0.75, 1 minimum alveolar concentration (MAC))]. The peak of INMDA was recorded by means of the whole cell patch clamp technique. The cytochrome C level was detected by Western blotting and quantitative real-time PCR. Our results showed that isoflurane (0.25, 0.5, 0.75 and 1 MAC) potentiated the amplitude of INMDA by (116±8.8)%, (122±11.7)%, (135±14.3)% and (132±14.6)%, respectively, and isoflurane increased the mRNA expression of cytochrome C in a concentration-dependent manner. The cytochrome C mRNA expression reached a maximum after 0.5 MAC isoflurane stimulation for 6 h (P<0.05). It was concluded that isoflurane enhances the expression of cytochrome C in cultured rat hippocampal neurons, which may be mediated by facilitation of NMDA receptor.This study examined the effects of clinically relevant concentrations of isoflurane on the amplitude of NMDA receptor current (INMDA) and the expression of cytochrome C in cultured developing rat hippocampal neurons. The hippocampi were dissected from newborn Sprague-Dawley rats. Hippocampal neurons were primarily cultured for 5 days and then treated with different concentrations of isoflurane [(0.25, 0.5, 0.75, 1 minimum alveolar concentration (MAC))]. The peak of INMDA was recorded by means of the whole cell patch clamp technique. The cytochrome C level was detected by Western blotting and quantitative real-time PCR. Our results showed that isoflurane (0.25, 0.5, 0.75 and 1 MAC) potentiated the amplitude of INMDA by (116±8.8)%, (122±11.7)%, (135±14.3)% and (132±14.6)%, respectively, and isoflurane increased the mRNA expression of cytochrome C in a concentration-dependent manner. The cytochrome C mRNA expression reached a maximum after 0.5 MAC isoflurane stimulation for 6 h (P<0.05). It was concluded that isoflurane enhances the expression of cytochrome C in cultured rat hippocampal neurons, which may be mediated by facilitation of NMDA receptor.

Risk factors for acute kidney injury after orthotopic liver transplantation: A single-center data analysis

Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration (especially > 480 min), and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT.SummaryAcute kidney injury (AKI) is a common complication following orthotopic liver transplantation (OLT) and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration (especially > 480 min), and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT.

Overexpression cdc42 attenuates isoflurane-induced neurotoxicity in developmental brain of rats.

Nowadays many children receive operations with general anesthesia. Isoflurane is a commonly-used general anesthetic. Numbers of studies demonstrated that isoflurane induced neurotoxicity and neurobehavioral deficiency in young rats, however, the underlying mechanism remained unknown. Cell division cycle 42 (cdc42) played an important role in regulating synaptic vesicle trafficking and actin dynamics in neuron, which closely linked to synaptic plasticity and dendritic spine formation. Meanwhile, cdc42 also involved in many neurodegenerative diseases. However, whether cdc42 provided a protective role in isoflurane induced synaptogenesis dysfunction still unknown. As the upstream of cdc42, calcium/Calmodulin-dependent protein kinase II (CaMKII) interacts with ion channels such as VDCCs and N-methyl-d-aspartate receptors (NMDARs), which closely associated with neuroapoptosis and cognitive deficiency in developing brain. The phosphorylation of CaMKIIα at Thr 286 plays an important role in introduction and maintenance of long-term potentiation (LTP). Therefore, we investigated the effect of isoflurane on cdc42 and its upstream Calcium/Calmodulin-dependent protein kinase II (CaMKII) and its downstream p21 activated kinase 3 (PAK3), then determined whether CaMKIIα/cdc42/PAK3 signaling pathway was involved in neurotoxicity and cognitive deficiency induced by isoflurane. Our study found that isoflurane induced neurotoxicity and resulted in cognitive impairment in young rats through suppressed CaMKIIα/cdc42/PAK3 signaling pathway. Cdc42 over-expression could reverse neurotoxicity and improve cognitive impairment induced by isoflurane.