Persistent intracranial hyper-inflammation in ruptured cerebral aneurysm after COVID-19: case report and review of the literature.

BACKGROUND: The systemic manifestations of coronavirus disease 2019 (COVID-19) include hyperinflammatory reactions in various organs. Recent studies showed evidence for the frequent involvement of central nervous system in affected patients; however, little is known about clinical features of cerebrovascular diseases in childhood-onset COVID-19. CASE PRESENTATION: A 10-year-old boy recovered from SARS-CoV-2 infection without complication. On 14 days after infection, he presented with loss of consciousness. A head computed tomography detected a ruptured cerebral aneurysm at the left posterior cerebral artery accompanying subarachnoid hemorrhage (SAH). Immediate surgical intervention did not rescue the patient, resulting in the demise 7 days after admission. Serological and genetic tests excluded the diagnosis of vasculitis and connective tissue disorders. Retrospective analysis showed markedly higher levels of interleukin (IL)-1ß, IL-6 and IL-8 in the cerebrospinal fluid than the serum sample concurrently obtained. A review of literature indicated that adult patients with COVID-19 have a risk for the later development of SAH during the convalescent phase of COVID-19. CONCLUSIONS: SAH is a severe complication of COVID-19 in children and adults who have asymptomatic cerebrovascular aneurysms. The markedly high levels of cytokines detected in the cerebrospinal fluid suggested that intracranial hyperinflammatory condition might be one of the possible mechanisms involved in the rupture of a preexisting cerebrovascular aneurysms.

Recovery of respiratory muscle strength, physical function, and dyspnoea after lobectomy in lung cancer patients undergoing pulmonary rehabilitation: A retrospective study.

OBJECTIVE: To characterise changes in respiratory muscle strength, physical function, and dyspnoea in patients who underwent pre- and post-operative exercise intervention following lobectomy for non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included NSCLC patients who underwent lobectomy via video-assisted thoracoscopic surgery (VATS) or posterolateral thoracotomy (PLT) and pre- and post-operative exercise intervention consisting of breathing, flexibility, resistance, aerobic exercises, coughing/huffing techniques, and early mobilisation. Maximum mouth inspiratory (Pimax) and expiratory pressures (Pemax), 6-min walk distance (6MWD), quadriceps force (QF), and modified Medical Research Council (mMRC) dyspnoea scale were evaluated preoperatively, at hospital discharge, and post-lobectomy 1 and 3 months. RESULTS: Data from 41 patients were analysed. At hospital discharge, the Pimax, Pemax, 6MWD, and mMRC dyspnoea scores were lower than pre-operatively; QF remained unchanged; Pimax and 6MWD recovered to pre-operative values at post-lobectomy 1 month; and Pemax and mMRC dyspnoea scores recovered at 3 months. During sub-analysis, Pimax and mMRC dyspnoea scores in the VATS (n = 24) and PLT groups (n = 17) recovered to pre-operative values at post-lobectomy 1 and 3 months. CONCLUSION: After lobectomy, respiratory muscle strength, physical function, and dyspnoea in patients who underwent exercise intervention returned to pre-operative values at post-lobectomy 3 months.

Intranasal administration of 40 and 80 units of insulin does not cause hypoglycemia during cardiac surgery: a randomized controlled trial.

PURPOSE: Intranasal insulin administration may improve cognitive function in patients with dementia and may prevent cognitive problems after surgery. Although the metabolic effects of intranasal insulin in non-surgical patients have been studied, its influence on glucose concentration during surgery is unknown. METHODS: We conducted a randomized, double-blind, placebo-contolled trial in patients scheduled for elective cardiac surgery. Patients with type 2 diabetes mellitus (T2DM) and non-T2DM patients were randomly allocated to one of three groups (normal saline, 40 international units [IU] of intranasal insulin, and 80 IU intranasal insulin). Insulin was given after the induction of general anesthesia. Glucose and plasma insulin concentrations were measured in ten-minute intervals during the first hour and every 30 min thereafter. The primary outcome was the change in glucose concentration 30 min after intranasal insulin administration. RESULTS: A total of 115 patients were studied, 43 of whom had T2DM. In non-T2DM patients, 40 IU intranasal insulin did not affect glucose concentration, while 80 IU intranasal insulin led to a statistically significant but not clinically important decrease in blood glucose levels (mean difference, 0.4 mMol·L-1; 95% confidence interval, 0.1 to 0.7). In T2DM patients, neither 40 IU nor 80 IU of insulin affected glucose concentration. No hypoglycemia (< 4.0 mMol·L-1) was observed after intranasal insulin administration in any patients. In non-T2DM patients, changes in plasma insulin were similar in the three groups. In T2DM patients, there was an increase in plasma insulin concentrations ten minutes after administration of 80 IU of intranasal insulin compared with saline. CONCLUSIONS: In patients with and without T2DM undergoing elective cardiac surgery, intranasal insulin administration at doses as high as 80 IU did not cause clinically important hypoglycemia. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02729064); registered 5 April 2016.

RéSUMé: OBJECTIF: L'administration intranasale d'insuline pourrait améliorer la fonction cognitive des patients souffrant de démence et pourrait prévenir les problèmes cognitifs après une chirurgie. Bien que les effets métaboliques de l'insuline intranasale chez les patients non chirurgicaux aient été étudiés, son influence sur la glycémie pendant une chirurgie est inconnue. MéTHODE: Nous avons réalisé une étude randomisée, à double insu, contrôlée par placebo auprès de patients devant subir une chirurgie cardiaque non urgente. Des patients atteints de diabète de type 2 et des patients non diabétiques ont été randomisés dans l'un de trois groupes (solution physiologique salée, 40 unités internationales [UI] d'insuline intranasale et 80 UI d'insuline intranasale). La solution intranasale a été administrée après l'induction de l'anesthésie générale. Les concentrations de glucose et d'insuline plasmatique ont été mesurées à des intervalles de dix minutes pendant la première heure et toutes les 30 minutes par la suite. Le critère d'évaluation principal était le changement de glycémie 30 min après l'administration intranasale d'insuline. RéSULTATS: Un total de 115 patients ont été étudiés, dont 43 souffraient de diabète de type 2. Chez les patients non diabétiques, 40 UI d'insuline intranasale n'ont pas affecté la glycémie, alors que 80 UI d'insuline intranasale ont entraîné une réduction statistiquement significative mais non cliniquement importante de la glycémie (différence moyenne, 0,4 mMol·L−1; intervalle de confiance de 95 %, 0,1 à 0,7). Chez les patients diabétiques, ni 40 UI ni 80 UI d'insuline n'ont affecté la glycémie. Aucune hypoglycémie (< 4,0 mMol·L−1) n'a été observée après administration intranasale d'insuline chez les patients diabétiques ou non diabétiques. Chez les patients non diabétiques, les changements de l'insuline plasmatique étaient semblables dans les trois groupes. Chez les patients diabétiques, une augmentation des concentrations d'insuline plasmatique a été observée dix minutes après l'administration de 80 UI d'insuline intranasale comparée à la solution saline. CONCLUSION: Chez les patients diabétiques et non diabétiques subissant une chirurgie cardiaque non urgente, l'administration intranasale d'insuline à des doses allant jusqu'à 80 UI n'a pas causé d'hypoglycémie cliniquement importante. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Accuracy of blood glucose measurements using the NOVA StatStrip® glucometer during cardiac surgery: a prospective observational study.

PURPOSE: The Nova StatStrip® Glucose Hospital Meter System (Nova Biomedical, Waltham, MA, USA) is United States Food and Drug Administration approved for point-of-care use in critically ill patients, but its use during cardiac surgery has not been evaluated. In this study, we compare glucose values obtained during cardiac surgery by StatStrip® with values obtained by a blood gas analyzer. METHODS: Blood glucose concentrations were analyzed in 121 patients by the StatStrip point- of-care test (POCT) glucose monitor and the GEM® Premier™ 3000 blood gas analyzer (Instrumentation Laboratory Company, Bedford MA, USA). Arterial blood samples were taken at baseline (before surgery), before cardiopulmonary bypass (CPB), during early and late CPB, and 30 min after CPB. Accuracy of the StatStrip glucometer was analyzed using the Clinical and Laboratory Standards Institute (CLSI) POCT12-A3 criteria (criterion 1; 95% of samples should be ± 0.66 mMol·L-1 of reference glucose values < 5.5 mMol·L-1 and ± 12.5% for reference glucose values > 5.5 mMol·L-1, criterion 2; 98% of samples should be ± 0.83 mMol·L-1 of reference glucose values < 4.1 mMol·L-1 or 20% of the reference glucose for values > 4.1 mMol·L-1). RESULTS: The accuracy of StatStrip glucose measurements at baseline (99%, 100%) and before CPB (95%, 98%), but not during (early: 84%, 97%; late: 83%, 96%) and after (92%, 100%) CPB, satisfied the CLSI POCT12-A3 criteria. CONCLUSION: Arterial blood glucose measurement by StatStrip was accurate before CPB, but lacked accuracy during and after CPB. Glucose values should be interpreted with caution when intensive glucose control protocols are being used during cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02729064); registered 5 April, 2016.

RéSUMé: OBJECTIF: Le glucomètre hospitalier StatStrip® de Nova (Nova Biomedical, Waltham, MA, É.-U.) est approuvé par la FDA (Food and Drug Administration) américaine pour une utilisation au chevet chez les patients en état critique, mais son utilisation n'a pas été évaluée en chirurgie cardiaque. Dans cette étude, nous avons comparé les valeurs glycémiques obtenues par le lecteur StatStrip® et les valeurs obtenues par un analyseur des gaz du sang pendant une chirurgie cardiaque. MéTHODE: Les concentrations glycémiques de 121 patients ont été analysées en utilisant le moniteur glycémique StatStrip et l'analyseur de gaz sanguins GEM® Premier™ 3000 (Instrumentation Laboratory Company, Bedford, MA, É.-U.). Des échantillons de sang artériel ont été prélevés avant la chirurgie, avant la circulation extracorporelle (CEC), au début et à la fin de la CEC et 30 min après la CEC. La précision du glucomètre StatStrip a été analysée à l'aide des critères de l'Institut des normes cliniques et de laboratoire (Clinical and Laboratory Standards Institute (CLSI)) POCT12-A3 (1er critère; 95 % des échantillons doivent être à l'intérieur de ± 0,66 mMol·L−1 des valeurs glycémiques de référence < 5,5 mMol·L−1 et ± 12,5 % pour les valeurs glycémiques de référence > 5,5 mMol·L−1, 2ème critère; 98 % des échantillons doivent être à l'intérieur de ± 0,83 mMol·L−1 des valeurs glycémiques de référence < 4,1 mMol·L−1 ou 20 % du taux glycémique de référence pour les valeurs > 4,1 mMol·L−1). RéSULTATS: La précision des mesures glycémiques prises par le StatStrip avant l'opération (99 %, 100 %) et avant la CEC (95 %, 98 %), mais non durant (début : 84 %, 97 %; fin : 83 %, 96 %) et après (92 %,100 %) la CEC, respectait les critères POCT12-A3 du CLSI. <0} CONCLUSION: La mesure de la glycémie artérielle réalisée avec le StatStrip était précise avant la CEC mais a manqué de précision pendant et après la CEC. Les valeurs glycémiques devraient donc être interprétées avec prudence lorsque des protocoles intensifs de contrôle glycémique sont utilisés pendant une chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Glycemia and the cardioprotective effects of insulin pre-conditioning in the isolated rat heart.

BACKGROUND: While acute hyperglycemia has been shown to mitigate the beneficial effects of ischemic preconditioning, its effect on insulin-induced preconditioning remains unclear. METHODS: The study was designed to test the hypothesis that acute hyperglycemia diminishes the cardioprotective effects following a 20-min pre-ischemic pre-conditioning with insulin in the isolated rat heart using the Langendorff system. Forty hearts were assigned to receive modified Krebs-Henseleit (KH) buffer containing 0.5 U/L insulin and 100 mg/dL glucose (InsG100, n = 10), KH buffer with 100 mg/dL glucose (G100, n = 10), KH buffer supplemented with 0.5 U/L insulin and 600 mg/dL glucose (InsG600, n = 10), or with 600 mg/dL glucose (G600, n = 10). To match the osmotic pressure of the InsG600 group, 27.5 mmol/L of mannitol was added to KH solution in the InsG100 and G100 group. The four groups were perfused with each solution for 20 min prior to 15 min of no-flow ischemia, and during 20 min of reperfusion. Only during the ischemic period the heart was paced at 222 beats/min. Measurements of heart rate, coronary flow and maximum of LV derivative of pressure development (dP/dt max) were recorded. Myocardial phospho-protein kinase B (p-Akt) and tumor necrosis factor-α (TNF-α) levels were assayed by enzyme-linked immunosorbent assay and sandwich ELISA, respectively following reperfusion. RESULTS: After reperfusion, LV dP/dt max and heart rate in the InsG100 group was significantly higher than that in the other three groups. The myocardial p-Akt level in the InsG100 group was significantly elevated when compared to the InsG600 group at the end of reperfusion. The p-Akt levels in the InsG600 and InsG100 group were significantly higher than in the corresponding non-insulin groups. CONCLUSIONS: Acute hyperglycemia diminishes the cardioprotective effects of insulin preconditioning in the isolated rat heart, possibly mediated through the suppression of myocardial Akt phosphorylation.

Safety of intranasal insulin administration in patients undergoing cardiovascular surgery: An open-label, nonrandomized, dose-escalation study.

Objective: This study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. Methods: This open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. Results: In total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. Conclusions: The administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model.

OBJECTIVE: Lactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. METHODS: Hearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. RESULTS: LV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. CONCLUSIONS: Enteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

Sniff and reverse-sniff nasal respiratory pressures after exacerbation of chronic obstructive pulmonary disease: A single-center prospective study.

BACKGROUND: and objective: This study examined the validity of sniff nasal inspiratory (SNIP) and reverse-sniff nasal expiratory pressures (RSNEP) for estimating respiratory muscle strength and for predicting poor life expectancy following exacerbation in patients with chronic obstructive pulmonary disease (COPD). METHODS: This prospective study included patients who were admitted for COPD exacerbation and underwent rehabilitation. At hospital discharge, SNIP, RSNEP, and maximum mouth inspiratory (MIP) and expiratory pressures (MEP) were measured, and the body mass index, degree of airflow obstruction, dyspnea, and exercise capacity (BODE) index was calculated by evaluating body mass index, forced expiratory volume in 1 s (FEV1), the Modified Medical Research Council Dyspnea Scale, and 6-min walk distance. RESULTS: Data from 43 patients (mean age 76.8 years, FEV1 42.8 % predicted) were analyzed. SNIP and RSNEP were moderately correlated with MIP and MEP, respectively. Bland-Altman plot means of SNIP (48.3 ± 17.5) and RSNEP (44.7 ± 23.8 cmH2O) were lower than those of MIP (54.8 ± 19.9) and MEP (76.4 ± 31.2 cmH2O), respectively, and the SNIP-MIP and RSNEP-MEP 95 % limits of agreement were wide. Logistic regression showed that SNIP and RSNEP were significantly associated with BODE score ≥7 (poor life expectancy), and predictive accuracy was 81.4 % when combining SNIP ≤49 and RSNEP ≤42 cmH2O. CONCLUSION: After exacerbation in patients with COPD, SNIP and RSNEP are useful indicators that complement MIP and MEP. Furthermore, a combined SNIP and RSNEP test may be beneficial in predicting poor life expectancy.

[Massive bleeding during and after cesarean section in a patient receiving frozen-thawed embryo transfer].

A 30-year-old pregnant woman (151 cm, 49 kg) with twin gestation who had got pregnant with frozen-thawed embryo transfer was scheduled to undergo cesarean section at 37 weeks of gestation. Combined spinal and epidural anesthesia was performed separately at the T12-L1 (epidural) and at the L3-4 interspace (spinal). The sensory anesthesia was extended to T2 and the operation was started. The cesarean delivery was uneventful and healthy 2,370 g and 2,334 g neonates were delivered. Five minutes after the delivery, placenta was removed manually from the uterus. Despite using oxytocin, methylergometrine and prostaglandin F2alpha, uterine contraction was severely impaired and massive bleeding occurred. General anesthesia was not commenced and packed red blood cells, fresh frozen plasma and cryoprecipitate were given. Uterus gradually contracted and the patient was transferred to the ward. However, massive bleeding continued postoperatively, and magnetic resonance imaging indicated retained placenta. Total hysterectomy was performed on the second postoperative day. Atonic bleeding and placental invasion should be the main causes of massive bleeding. Frozen-thawed embryo transfer might be one of the important factors for placental invasion. We have to prepare for massive bleeding during and after the cesarean section in patients receiving frozen-thawed embryo transfer.

PaO2 / FiO2 ratio responsiveness to prone positioning in intubated patients with severe COVID-19: a retrospective observational study.

Aim: Prone positioning of coronavirus disease 2019 (COVID-19) patients could improve oxygenation. However, clinical data on prone positioning of intubated COVID-19 patients are limited. We investigated trends of PaO2 / FiO2 ratio values in patients during prone positioning to identify a predictive factor for early detection of patients requiring advanced therapeutic intervention such as extracorporeal membrane oxygenation (ECMO). Methods: This retrospective, observational cohort study was undertaken between April 2020 and May 2021 in a tertiary referral hospital for COVID-19 in Osaka, Japan. We included intubated adult COVID-19 patients treated with prone positioning within the first 72 h of admission to the intensive care unit and followed them until hospital discharge or death. Primary outcomes were in-hospital mortality and escalation of care to ECMO. We used unsupervised k-means clustering modeling to categorize COVID-19 patients by PaO2 / FiO2 ratio responsiveness to prone positioning. Results: The final study cohort comprised 54 of 155 consecutive severe COVID-19 patients. Three clusters were generated according to trends in PaO2 / FiO2 ratios during prone positioning (cluster A, n = 16; cluster B, n = 24; cluster C, n = 14). Baseline characteristics of all clusters were almost similar. Cluster A (no increase in PaO2 / FiO2 ratio during prone positioning) had a significantly higher proportion of patients placed on ECMO or who died (6/16, 37.5%). Numbers of patients with ECMO and with in-hospital death were significantly different between the three groups (p = 0.017). Conclusion: In Japanese patients intubated due to COVID-19, clinicians should consider earlier escalation of treatment, such as facility transfer or ECMO, if the PaO2 / FiO2 ratio does not increase during initial prone positioning.

PI3K/Akt pathway mediates the positive inotropic effects of insulin in Langendorff-perfused rat hearts.

Insulin exerts positive inotropic effects on cardiac muscle; however, the relationship between cardiac contractility and phosphoinositol-3-kinase/Akt (PI3K/Akt) activation remains unclear. We hypothesized that the positive inotropic effects of insulin are dose-dependent and mediated via the PI3K/Akt pathway in isolated normal rat hearts. The Institutional Animal Investigation Committee approved the use of hearts excised from rats under pentobarbital anesthesia. The hearts were perfused at a constant pressure using the Langendorff technique. After stabilization (baseline), the hearts were randomly divided into the following four insulin (Ins) groups: 1) Ins0 (0 IU/L), 2) Ins0.5 (0.5 IU/L), 3) Ins5 (5 IU/L), and 4) Ins50 (50 IU/L) (n = 8 in each group). To clarify the role of the PI3K/Akt pathway in insulin-dependent inotropic effects, we also treated the insulin groups with the PI3K inhibitor wortmannin (InsW): 5) InsW0 (0 IU/L), 6) InsW0.5 (0.5 IU/L), 7) InsW5 (5 IU/L), and 8) InsW50 (50 IU/L). Hearts were perfused with Krebs-Henseleit buffer solution with or without wortmannin for 10 min, followed by 20 min perfusion with the solution containing each concentration of insulin. The data were recorded as the maximum left ventricular derivative of pressure development (LV dP/dt max). Myocardial p-Akt levels were measured at 3 min, 5 min, and at the end of the perfusion. In the Ins groups, LV dP/dt max in Ins5 and Ins50 increased by 14% and 48%, respectively, 3 min after insulin perfusion compared with the baseline. Tachyphylaxis was observed after 10 min in the Ins5 and Ins50 treatment groups. Wortmannin partially inhibited the positive inotropic effect of insulin; although insulin enhanced p-Akt levels at all time points compared with the control group, this increase was suppressed in the presence of wortmannin. The positive inotropic effect of insulin is dose-dependent and consistent with Akt activation. This effect mediated by high doses of insulin on cardiac tissue was temporary and caused tachyphylaxis, potentially triggered by Akt overactivation, which leads beta 1 deactivation.

Difference between delayed anastomosis and early anastomosis in damage control laparotomy affecting the infusion volume and NPWT output volume: is infusion restriction necessary in delayed anastomosis? A single-center retrospective analysis.

Objectives: During temporary abdominal closure (TAC) with damage control laparotomy (DCL), infusion volume and negative-pressure wound therapy (NPWT) output volume are associated with the success and prognosis of primary fascial closure. The same may also hold true for anastomosis. The aim of this research is to evaluate whether the difference between early anastomosis and delayed anastomosis in DCL is related to infusion volume and NPWT output volume. Methods: This single-center retrospective analysis targeted patients managed with TAC during emergency surgery for trauma or intra-abdominal sepsis between January 2011 and December 2019. It included patients who underwent repair/anastomosis/colostomy in the first surgery and patients who underwent intestinal resection in the first surgery followed by delayed anastomosis with no intestinal continuity. Results: Seventy-three patients were managed with TAC using NPWT, including 19 cases of repair, 17 of colostomy, and 37 of anastomosis. In 16 patients (trauma 5, sepsis 11) with early anastomosis and 21 patients (trauma 16, sepsis 5) with delayed anastomosis, there was no difference in the infusion volume (p=0.2318) or NPWT output volume (p=0.7128) 48 hours after surgery. Additionally, there was no difference in the occurrence of suture failure (p=0.8428). During the second-look surgery after 48 hours, the anastomosis was further postponed for 48% of the patients who underwent delayed anastomosis. There was no difference in the infusion volume (p=0.0783) up to the second-look surgery between the patients whose delayed anastomosis was postponed and those who underwent delayed anastomosis, but there was a tendency toward a large NPWT output volume (p=0.024) in the postponed delayed anastomosis group. Conclusion: Delayed anastomosis may be managed with the same infusion volume as that used for early anastomosis. There is also the option of postponing anastomosis if the planned delayed anastomosis is complicated. Level of evidence: Therapeutic/Care Management, Level IV.

Cardioprotective effects of enteral vs. parenteral lactoferrin administration on myocardial ischemia-reperfusion injury in a rat model of stunned myocardium.

BACKGROUND: Lactoferrin, an iron-binding glycoprotein, is known to have protective effects against intestinal and cerebral ischemia-reperfusion (IR) injuries; however, its cardioprotective effects against the stunned myocardium are unknown. This study aimed to test the hypothesis that lactoferrin has cardioprotective effects against stunned myocardium. METHODS: Using isolated rat hearts (Langendorff system), we determined the effects of lactoferrin administered enterally and by direct cardiac perfusion. Rat hearts were perfused using the Langendorff system, and two experiments were performed. In experiment 1, the hearts were divided into the enteral lactoferrin (E-LF) 7.5 m, 15 m, 30 m, and 60 m groups, where lactoferrin (1000 mg/kg) was administered enterally 7.5, 15, 30, and 60 min, respectively, before perfusion; and a control group, where saline was administered 30 min before perfusion. In experiment 2, hearts were allocated to the perfusate lactoferrin (P-LF) 15 and 100 groups, where 15 mg/L and 100 mg/L lactoferrin were respectively added to the perfusate, and a control group. Each group was perfused for 20 min prior to 15 min of no-flow ischemia with pacing, followed by 20 min of reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (LV dP/dt max) 15 min after reperfusion. Myocardial phospho-protein kinase B (p-Akt) was assayed using western blotting. RESULTS: The LV dP/dt max 15 min after reperfusion in the E-LF 15 and 30 m groups was significantly higher than that in the control group. However, the effects disappeared in the E-LF 60 m group. In the second experiment, there were no significant differences in LV dP/dt max. Myocardial p-Akt was not significantly activated in any lactoferrin group. CONCLUSION: Cardioprotection was observed 15-30 min after enteral lactoferrin but not by direct cardiac perfusion with lactoferrin. Myocardial p-Akt was not associated with the cardioprotective effect. The cardioprotective effect may be induced by enteral lactoferrin-induced substances.

Transient global amnesia with bilateral hippocampal lesions during the COVID-19 global outbreak.

This manuscript presents a case report of transient global amnesia with bilateral hippocampal lesions which might be triggered by the fear of getting infected by coronavirus disease 2019 (COVID-19). The purpose of this article is to facilitate the clinicians in understanding that an increasing number of patients with transient global amnesia have been reported during the COVID-19 global outbreak.

Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1.

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model.

To ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the antitumor effects of trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TSA and vorinostat both displayed strong antitumor activities in 50% of NSCLC cell lines, suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the support vector machine model was validated by an additional nine cell lines, resulting in a prediction value of 100% with respect to determining response to TSA and vorinostat. Our results suggested that (a) HDAC inhibitors may be promising anticancer drugs to NSCLC and (b) the nine-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients.

In vitro simulation study of individualized chemotherapy in lung cancer.

The primary aim of this in vitro simulation study was to evaluate the utility of gene expression profile analysis in predicting the effect of varying drug combinations for the treatment of lung cancer. Using 10 human cancer cell lines, we focused our gene expression analysis on a cohort of candidate sensitivity-prediction factors, previously reported using cDNA filter arrays, with a view to predicting the ability of a set of anti-cancer drugs commonly used to treat lung cancer, namely cisplatin, 5-fluorouracil (5FU), SN38, docetaxel, gemcitabine, and vinorelbine. Altered expression of genes for glutathione-S-transferase-pi, uridine phosphorylase, O-6-methylguanine-DNA methyltransferase, and multidrug resistance 1 was identified in lung cancer cell lines. Drug sensitivity testing, in the form of methylthiotetrazol analysis, was performed using these six anti-cancer drugs against the panel of 10 lung cancer cell lines. We compared the predicted chemosensitivity based on the gene expression pattern of 19 well-known sensitivity-related genes with the cytotoxic activity of each of these anti-cancer drugs. Molecular profiling data predicted resistance to CDDP in LK-2 cells, 5FU in LK-2, PC7, A549, NCI-N231, Lu135 cells, irinitecan in PC9 cells, and VNR in PC7 cells. However, the prediction efficacy (number of predicted inactive drugs by gene expression analysis/number of inactive drugs by methylthiotetrazol assay) was 21.6% (8 of 37). No false-positive findings in relation to sensitivity-related genes were obtained on the basis of this molecular analysis. Thus, prediction of sensitivity to lung cancer by molecular analysis appears possible. With elucidation of additional drug sensitivity factors, selection of appropriate anticancer drugs by gene expression profiling may make it possible to increase the response rate in lung cancer chemotherapy.

Anticancer drug clustering in lung cancer based on gene expression profiles and sensitivity database.

BACKGROUND: The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer. METHODS: We related the cytotoxic activity of each of commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin (CDDP), and carboplatin (CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program. RESULTS: We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster. CONCLUSION: These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types.