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Abstract Objective The purpose of this study was to examine the effects of 10 weeks of high-intensity interval training (HIIT) and HIIT combined with circuit resistance training (HCRT) on selected measures of physical fitness, the expression of miR-9, -15a, -34a, -145, and − 155 as well as metabolic risk factors including lipid profiles and insulin resistance in middle-aged overweight/obese women. Methods Twenty-seven overweight/obese women aged 35–50 yrs. were randomized to HIIT (n = 14) or HCRT (n = 13) groups. The HIIT group performed running exercises (5 reps x 4 min per session) with active recovery between repetitions for 10 weeks with 5 weekly sessions. The HCRT group performed 10 weeks of HIIT and resistance training with 3 weekly HIIT sessions and 2 weekly HCRT sessions. Anthropometric measures (e.g., body mass), selected components of physical fitness (cardiovascular fitness, muscle strength), levels of miRNAs (miR-9, -15a, -34a, -145, and − 155), lipid profiles (total cholesterol; TC, Triglycerides; TG, low-density lipoprotein cholesterol; LDL-C and high-density lipoprotein cholesterol; HDL-C), and insulin resistance; HOMA-IR index, were measured at baseline and week 10. Results An ANOVA analysis indicated no significant group by time interactions (p > 0.05) for all anthropometric measures, and maximum oxygen consumption (VO2max). A significant group by time interaction, however, was found for the one-repetition maximum (IRM; p

Haitong Gong, 1 Stephen X Zhang, 2 Khaled Nawaser, 3 Asghar Afshar Jahanshahi, 4, 5 Xingzi Xu, 6 Jizhen Li, 6 Afsaneh Bagheri 7 1Collegue of Nursing and Health Sciences, Flinders University, Adelaide, SA, Australia; 2Faculty of Professions, University of Adelaide, Adelaide, SA, Australia; 3Universidad Católica Los Ángeles de Chimbote, Instituto de Investigación, Chimbote, Peru; 4CENTRUM Católica Graduate Business School (CCGBS), Lima, Peru; 5School of Economics and Management, Pontificia Universidad Católica del Perú (PUCP), Lima, Peru; 6School of Economics and Management, Tsinghua University, Beijing, People’s Republic of China; 7Faculty of Entrepreneurship, University of Tehran, Tehran, IranCorrespondence: Stephen X ZhangFaculty of Professions, University of Adelaide, 9-28 Nexus10 Tower, 10 Pulteney St, Adelaide, SA, 5000, AustraliaTel +61 8831 39310Email stephen.x.zhang@gmail.comPurpose: Healthcare staff operate at the forefront of the fight against COVID-19 and hence face enormous physical and mental pressures. We aim to investigate healthcare staff’s mental health issues and the associated predictors during the COVID-19 pandemic. Specifically, this paper aims to identify some unique predictors of healthcare staff’s mental health issues in Iran, the second country after China to experience a major COVID-19 crisis.Methods: An online survey of 280 healthcare staff in all 31 provinces of Iran assessed staff’s mental distress (K6), depression, and anxiety (PHQ-4) during April 5– 20, 2020 during the COVID-19 crisis.Results: Nearly a third of healthcare staff surpassed the cutoff for distress, depression, and anxiety symptoms. Females or more educated healthcare staff were more likely to experience distress. Those who were unsure whether they had COVID-19 were more likely to experience distress and depression symptoms. The number of COVID-19 cases among a healthcare worker’s colleagues or friends positively predicted the worker’s anxiety symptoms. Amongst healthcare staff, doctors were less likely than radiology technologists to experience distress and anxiety symptoms. Technicians and obstetrics staff experienced fewer anxiety symptoms. The age and the weekly working days of healthcare staff interacted such that age is asignificant predictor of mental health issues among younger but not older healthcare staff.Conclusion: The identification of the predictors of mental health issues can guide healthcare organizations to screen healthcare workers who are more likely to be mentally vulnerable in the ongoing COVID-19 pandemic.Keywords: healthcare staff, mental health, working time, age, COVID-19, epidemic, Iran

Stephen X Zhang,1 Shuhua Sun,2 Asghar Afshar Jahanshahi,3 Yifei Wang,4 Abbas Nazarian Madavani,5 Jizhen Li,6 Maryam Mokhtari Dinani7 1Faculty of the Professions, University of Adelaide, Adelaide, SA, Australia; 2A. B. Freeman School of Business, Tulane University, New Orleans, LA, USA; 3CENTRUM Católica Graduate Business School (CCGBS), Pontificia Universidad Católica del Perú (PUCP), Lima, Peru; 4School of Economics and Management, Tongji University, Shanghai, People’s Republic of China; 5Faculty of Sport Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran; 6School of Economics & Management, Tsinghua University, Beijing, People’s Republic of China; 7Faculty of Sport Sciences, Alzahra University, Tehran, IranCorrespondence: Stephen X ZhangFaculty of the Professions, University of Adelaide, 9-28 Nexus 10 Tower, 10 Pulteney St, Adelaide, SA 5000, AustraliaTel +61 8 8313 9310Fax +61 8 8223 4782Email stephen.x.zhang@gmail.comBackground: This study aims to identify individuals’ likelihood of being COVID negative or positive, enabling more targeted infectious disease prevention and control when there is a shortage of COVID-19 testing kits.Methods: We conducted a primary survey of 521 adults on April 1– 10, 2020 in Iran, where 3% reported being COVID-19 positive and 15% were unsure whether they were infected. This relatively high positive rate enabled us to conduct the analysis at the 5% significance level.Results: Adults who exercised more were more likely to be COVID-19 negative. Each additional hour of exercise per day predicted a 78% increase in the likelihood of being COVID-19 negative. Adults with chronic health issues were 48% more likely to be COVID-19 negative. Those working from home were the most likely to be COVID-19 negative, and those who had stopped working due to the pandemic were the most likely to be COVID-19 positive. Adults employed in larger organizations were less likely to be COVID-19 positive.Conclusion: This study enables more targeted infectious disease prevention and control by identifying the risk factors of COVID-19 infections from a set of readily accessible information. We hope this research opens a new research avenue to predict the individual likelihood of COVID-19 infection by risk factors.Keywords: individual infection prediction, COVID-19 infection, testing shortage, risk factors

Background: Based upon the anecdotal results about caffeine dose effects on exercise-induced inflammatory response, the present study was conducted to identify the effect of different doses of caffeine on acute inflammatory response following one-session exhaustive resistance training in male volleyball players. Materials & Methods: A total of 30 male elite volleyball players (aged 20-25 years and body fat 10-15%) in a quasi-experimental, randomized and double-blind design were allocated equally into three randomized homogeneous groups: supplement groups (Caffeine intake: 6 or 9 mg.kg-1) and placebo group (Dextrose intake: 6 mg.kg-1). After the supplementation, all subjects were participated in a one-session exhaustive resistance weight-training (with 80% of one repetition maximum). Changes in serum Tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP) were determined in three phases (Baseline, 45 min after the supplementation and 24 hours after the training protocol).The normal data were analyzed by repeated measure ANOVA at α≤0.05. Results: The serum TNF-α and CRP significantly increased 45 min after Caffeine intake (6 or 9 mg.kg-1) and 24 hours after one-session resistance training (P

Background: The aim of the present study was to evaluate the effect of natural antioxidant formula (blend of herbs: ginger root, cinnamon bark and raw almond fruit powder, rosemary leaf powder, and honey) on oxidative status, antioxidant enzyme activity, and relative heat shock protein (HSP-70) expression in recreational female athletes. Materials and Methods: Eighteen female participants trained for 4 weeks and randomly received either antioxidant formula (FormEX) (n = 8) or placebo (PlcEX) (n = 10) in a randomized controlled trial. Blood samples were obtained 1-h before, 1 h and 24 h postexercise to measure malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidases (GPx), and HSP70 mRNA expression. Data analysis was performed using 2 (treatment = grouping factor) ×6 (time = within-factor) repeated measurements analysis of variance or generalized estimating equations (GEE) test. We used the independent t-test to evaluate any significant differences for real-time polymerase chain reaction data. Results: Antioxidant formula increased the relative HSP-70 mRNA expression more than Plc-EX group in all time points (P = 0.001). The time main effect was significant with regard to TAC and SOD concentrations (P = 0.001 and 0.002, respectively). However, there were no statistically significant differences between groups for TAC, SOD, and MDA (P = 0.25, 0.06, and 0.38, respectively). Neither the time main effect for MDA nor time and intervention interaction was not statistically significant for MDA, TAC, and SOD (P = 0.19, 0.13, and 0.10, respectively). GEE results for GPx showed that there were no significant differences between the groups (P = 0.11). Conclusion: The results presented herein revealed that natural antioxidant rich formula had variable effects on oxidative status. However, in contrast to many antioxidant supplements, this formulation increases the HSP-70 mRNA expression which might improve the antioxidant ability of cells in the long-term period and exercise-induced adaptation.

Ebrahim Akhtari Shojaei1, Adalat Farajov2, Afshar Jafari31Tuberculosis and Lung Diseases Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran; 2Institute of Physiology, Baku National Academy of Sciences, Baku, Azerbaijan; 3Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, University of Tabriz, Tabriz, IranBackground: Based on the inconsistency of some previous results related to moderate exercise effects on systemic inflammatory responses, this study was conducted to determine the effects of 45 minutes of moderate aerobic cycling on inflammatory markers, interleukin-6 (IL-6), interleukin-10 (IL-10), C-reactive protein (CRP), and leucocyte counts in young active men.Methods: Ten healthy, active collegiate men (aged 21.03 ± 1.2 years, body fat 12.04 ± 2.72% and VO2max 59.6 ± 2.4 mL/kg/min) in a quasiexperimental pre/post design, participated in an acute, moderate cycling protocol at an intensity of 50% VO2max for 45 minutes. The inflammatory markers (serum IL-6, IL-10, CRP, and peripheral blood leucocyte counts), along with cortisol and epinephrine, were examined before and after the protocol. Data were expressed as mean (± SD) and analyzed by paired t-test using SPSS15 at α ≤ 0.05.Results: The results showed that serum IL-6, IL-10, CRP, total leukocyte counts, and stress hormones (epinephrine and cortisol) were significantly increased following 45 minutes of moderate cycling in active collegiate men (P < 0.001). However, all pre- and post-measurements were in the population range.Conclusion: Based on the present results, it can be concluded that moderate cycling is not only sufficient to induce systemic inflammation in active collegiate men, but also appears to be safe from an immunological point of view.Keywords: moderate cycling, pro- anti-inflammatory cytokines, C-reactive protein

BACKGROUND: The immune system in endurance athletes may be at risk for deleterious effects of gasous pollutants such as ambient ozone. Therefore, this study was performed to assess the effect of regular aerobic exercise with ozone exposure on peripheral leukocytes populations in male Wistar rats.METHODS: Twenty eight 8 weeks old rats were selected and randomly divided into four groups of ozone-unexposed anduntrained (control or group 1, n = 6), ozone-exposed and untrained (group 2, n = 6), ozone-unexposed and trained (group 3, n = 8), ozone-exposed and trained (group 4, n = 8). All animals in groups 3 and 4 were regularly running (20 m/min, 30 min/day) on a treadmill for 7 weeks (5 day/week). After the last ozone exposure [0.3 ppm, 30 min per sessions], blood samples were obtained from the cardiac puncture and hematological parameters as well as blood lactate were measured using automatic analyzers. Data were expressed as means (± SD) and analyzed by ANOVA and Pearson's correlation tests at p < 0.05.RESULTS: All the hematological parameters differences (except RBC and hemoglobin rate) were significantly higher in the trained groups (p < 0.001). However, ozone-induced leukocytosis in the trained (but not in the sedentary) rats was statistically higher than in the counterpart groups.CONCLUSIONS: Repeated acute ozone exposure has more additive effect on peripheral leukocyte counts in active animals. But, more researches are needed to identify effects of ozone exposure on other components of the immune system in athletes and non-athletes.KEYWORDS: Moderate Aerobic Exercise, Ozone Exposure, eukocytosis, Wistar Rats.

Programmed cell death protein-1 (PD-1), as an immune checkpoint molecule, attenuates T-cell activity and induces T-cell exhaustion. Although siRNA has a great potential in cancer immunotherapy, its delivery to target cells is the main limitation of using siRNA. This study aimed to prepare a liposomal formulation as a siRNA carrier to silence PD-1 expression in T cells and investigate it's in vivo antitumor efficacy. The liposomal siRNA was prepared and characterized by size, zeta potential, and biodistribution. Following that, the uptake assay and mRNA silencing were evaluated in vitro at mRNA and protein levels. siRNA-PD-1 (siPD-1)-loaded liposome nanoparticles were injected into B16F0 tumor-bearing mice to evaluate tumor growth, tumor-infiltrating lymphocytes, and survival rate. Liposomal siPD-1 efficiently silenced PD-1 mRNA expression in T cells (P < 0.0001), and siPD-1-loaded liposomal nanoparticles enhanced the infiltration of T-helper 1 (Th 1) and cytotoxic T lymphocytes into the tumor tissue (P < 0.0001). Liposome-PD-1 siRNA monotherapy and PD-1 siRNA-Doxil (liposomal doxorubicin) combination therapy improved the survival significantly, compared to the control treatment (P < 0.001). Overall, these findings suggest that immunotherapy with siPD-1-loaded liposomes by enhancing T-cell-mediated antitumor immune responses could be considered as a promising strategy for the treatment of melanoma cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Despite the tremendous efforts in finding a valuable markers for risk stratifying gastric cancer (GC) patients; still, management of this cancer faces multiple obstacles. Given this, we designed a study to explore the possible relationship between the tripartite motif-containing 44 (TRIM44) gene expression, and the outcome of the GC patients., Methods: The real-time quantitative PCR method was used to evaluate the mRNA expression level of TRIM44, and β-catenin in fresh primary tumor and adjacent normal tissues collected from 40 GC patients. The Pearson's correlation test, Kaplan-Meier method, and Cox proportional-hazards regression were performed to examine the association of TRIM44 expression with some clinicopathological data and the patients' overall survival (OS)., Results: The expression level of both TRIM44 and β-catenin was remarkably higher in GC tissues than in normal tissues (Fold change=1.71, p=0.004). In subgroup analysis based on the TRIM44 expression, pateints with high TRIM44 expression level exhibited poorer overall survival (HR = 1.46, 95% CI: 1.07-1.98, p=0.016). More strikingly, a positive correlation was also found between the expression of TRIM44 and β-catenin in GC, indicating that TRIM44 might exert its oncogenic activities probably through the β-catenin axis., Conclusion: This study highlighted the potent value of TRIM44 as an independent prognostic factor in gastric cancer and shed light on the probable interplay between this tripartite motif-containing protein and β-catenin. However, further investigations, especially with a larger sample size, are required to study the effect of TRIM44 in GC more precisely.

Aim: This meta-analysis aimed to evaluate the association of HIF-1α expression with clinicopathological features and overall survival (OS) of patients with digestive system malignancies., Background: Numerous studies have demonstrated that hypoxia-inducible factor-1α (HIF-1α) is abnormally expressed in various solid tumors. However, the clinicopathological features and prognostic value of HIF-1α expression in patients with digestive system malignancies remain controversial., Methods: A literature search in PubMed, Web of Science, and Scopus databases was performed to identify all relevant studies published in English until 15 October 2020. The pooled effect was calculated to evaluate the association between HIF-1α expression and clinicopathological features and overall survival in cancer patients. Pooled odds ratios (ORs) or hazard ratios (HRs) with a 95% confidence interval (CI) were calculated using fixed- or random-effects model based on between-study heterogeneity., Results: A total of 44 eligible studies with 5,964 patients were included. The pooled results indicated a positive association of HIF-1α overexpression with poor overall survival (OS) (HR=1.990, 95% CI: 1.615-2.453, p <0.001) and disease-free survival (DFS) (HR=1.90, 95% CI: 1.084-3.329, p =0.043). Meta-analysis results showed that HIF-1α level expression was significantly associated with positive lymph node metastasis (OR=1.869, 95% CI: 1.488-2.248, p <0.001), distance metastasis (OR=2.604, 95% CI: 1.500-4.519, p <0.001), tumor stage (OR=1.801, 95% CI: 1.437-2.257, p <0.001) and tumor size (OR=1.392. 95% CI: 1.068-1.815, p =0.014)., Conclusion: This meta-data suggest that HIF-1α expression might serve as an independent prognostic marker and a promising therapeutic target in patients with digestive system malignancies., Competing Interests: The authors declare that they have no conflict of interest., (©2022 RIGLD, Research Institute for Gastroenterology and Liver Diseases.)

Background and Aim: Tripartite Motif Containing 16 (TRIM16) is a member of the TRIM protein family which is known to play a suppressor role in development of numerous tumor types. However, a positive correlation between TRIM16 expression and gastric cancer (GC) progress has created a controversial situation that need to be fully delineated.  The aim of this study was to assess the expression level of TRIM16 mRNA and its relationship with β-catenin, CyclinD, and BCL2 expression in Iranian GC patients and to investigate its possible association with patients' overall survival.  Materials and Methods: The expression level of TRIM16 of fresh primary tumor and adjacent normal tissues in 40 GC patients was evaluated by real-time quantitative PCR method. Moreover, patients were subdivided into high or low expression subgroups based on the TRIM16 expression levels. The relationship between TRIM16 expression level, β-catenin, Cyclin D, BCL2, some clinicopathological data and prognosis of GC patients was also analyzed., Results: qPCR analysis showed a lower level of TRIM16 in GC tissues (fold change=0.351) in comparison to their matched adjacent noncancerous tissues (p <0.001). Contrary to this, the expression levels of β-catenin, Cyclin D, and BCL2 genes were up-regulated in cancerous samples. This may explain the tumor suppressive function of TRIM16 in GC; as reduction in TRIM16 expression leads to the accumulation of mRNAs from β-catenin, Cyclin D, and BCL2 genes and eventually cancer progression. We did not observe any significant correlation between TRIM16 expression and patients' overall survival. Univariate Cox regression analysis indicated that anemia, weight loss, bleeding, stomach ache, and smoking are statistically associated with overall survival; while, multivariate analysis did not support any correlation.  Conclusions: In sum, this study suggests a tumor suppressive role for TRIM16 in gastric cancer and proposes it as a potential candidate for GC prognosis., .

Background: Oleate-enriched triacylglycerides are well-suited for lubricant applications that require high oxidative stability. Fatty acid carbon chain length and degree of desaturation are key determinants of triacylglyceride properties and the ability to manipulate fatty acid composition in living organisms is critical to developing a source of bio-based oil tailored to meet specific application requirements., Results: We sought to engineer the oleaginous yeast Yarrowia lipolytica for production of high-oleate triacylglyceride oil. We studied the effect of deletions and overexpressions in the fatty acid and triacylglyceride synthesis pathways to identify modifications that increase oleate levels. Oleic acid accumulation in triacylglycerides was promoted by exchanging the native ∆9 fatty acid desaturase and glycerol-3-phosphate acyltransferase with heterologous enzymes, as well as deletion of the Δ12 fatty acid desaturase and expression of a fatty acid elongase. By combining these engineering steps, we eliminated polyunsaturated fatty acids and created a Y. lipolytica strain that accumulates triglycerides with > 90% oleate content., Conclusions: High-oleate content and lack of polyunsaturates distinguish this triacylglyceride oil from plant and algal derived oils. Its composition renders the oil suitable for applications that require high oxidative stability and further demonstrates the potential of Y. lipolytica as a producer of tailored lipid profiles.

Background: Microbial lipids are produced by many oleaginous organisms including the well-characterized yeast Yarrowia lipolytica, which can be engineered for increased lipid yield by up-regulation of the lipid biosynthetic pathway and down-regulation or deletion of competing pathways., Results: We describe a strain engineering strategy centered on diacylglycerol acyltransferase (DGA) gene overexpression that applied combinatorial screening of overexpression and deletion genetic targets to construct a high lipid producing yeast biocatalyst. The resulting strain, NS432, combines overexpression of a heterologous DGA1 enzyme from Rhodosporidium toruloides, a heterlogous DGA2 enzyme from Claviceps purpurea, and deletion of the native TGL3 lipase regulator. These three genetic modifications, selected for their effect on lipid production, enabled a 77 % lipid content and 0.21 g lipid per g glucose yield in batch fermentation. In fed-batch glucose fermentation NS432 produced 85 g/L lipid at a productivity of 0.73 g/L/h., Conclusions: The yields, productivities, and titers reported in this study may further support the applied goal of cost-effective, large -scale microbial lipid production for use as biofuels and biochemicals.

The reversed-phase preparative high performance liquid chromatographic purification of the methanol extract of the fruits of Ribes biebersteinii Berl. (Grossulariaceae) afforded five cyanidin glycosides, 3-O-sambubiosyl-5-O-glucosyl cyanidin (1), cyanidin 3-O-sambubioside (2), cyanidin 3-O-glucoside (3), cyanidin 3-O-(2(G)-xylosyl)-rutinoside (4) and cyanidin 3-O-rutinoside (5). They showed considerable free-radical-scavenging properties in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay with the RC(50) values of 9.29 x 10(-6), 9.33 x 10(-6), 8.31 x 10(-6), 8.96 x 10(-6) and 9.55 x 10(-6) mol L(-1), respectively. The structures of these compounds were elucidated by various chemical hydrolyses and spectroscopic means. The total anthocyanin content was 1.9 g per 100 g dried fruits on cyanidin 3-glucoside basis.

Object: The reduction in the level of nitric oxide (NO) is a purported mechanism of delayed vasospasm after subarachnoid hemorrhage (SAH). Evidence in support of a causative role for NO includes the disappearance of nitric oxide synthase (NOS) from the adventitia of vessels in spasm, the destruction of NO by hemoglobin released from the clot into the subarachnoid space, and reversal of vasospasm by intracarotid NO. The authors sought to establish whether administration of L-arginine, the substrate of the NO-producing enzyme NOS, would reverse and/or prevent vasospasm in a primate model of SAH., Methods: The study was composed of two sets of experiments: one in which L-arginine was infused over a brief period into the carotid artery of monkeys with vasospasm, and the other in which L-arginine was intravenously infused into monkeys over a longer period of time starting at onset of SAH. In the short-term infusion experiment, the effect of a 3-minute intracarotid infusion of L-arginine (intracarotid concentration 10(-6) M) on the degree of vasospasm of the right middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF) was examined in five cynomolgus monkeys. In the long-term infusion experiment, the effect of a 14-day intravenous infusion of saline (control group, five animals) or L-arginine (10(-3) M; six animals) on the occurrence and degree of cerebral vasospasm was examined in monkeys. The degree of vasospasm in all experiments was assessed by cerebral arteriography, which was performed preoperatively and on postoperative Days 7 (short and long-term infusion experiments) and 14 (long-term infusion experiment). In the long-term infusion experiment, plasma levels of L-arginine were measured at these times in the monkeys to confirm L-arginine availability. Vasospasm was not affected by the intracarotid infusion of L-arginine (shown by the reduction in the right MCA area on an anteroposterior arteriogram compared with preoperative values). However, intracarotid L-arginine infusion increased rCBF by 21% (p < 0.015; PCO2 38-42 mm Hg) in all vasospastic monkeys compared with rCBF measured during the saline infusions. In the long-term infusion experiment, vasospasm of the right MCA occurred with similar intensity with or without continuous intravenous administration of L-arginine on Day 7 and had resolved by Day 14. The mean plasma L-arginine level increased during infusion from 12.7+/-4 microg/ml on Day 0 to 21.9+/-13.1 microg/ml on Day 7 and was 18.5+/-3.1 microg/ml on Day 14 (p < 0.05)., Conclusions: Brief intracarotid and continuous intravenous infusion of L-arginine did not influence the incidence or degree of cerebral vasospasm. After SAH, intracarotid infusion of L-arginine markedly increased rCBF in a primate model of SAH. These findings discourage the use of L-arginine as a treatment for vasospasm after SAH.

Unlabelled: Hemoglobin released from hemolysed erythrocytes has been postulated to be responsible for delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the evidence is indirect and the mechanisms of action are unclear. Cerebrovascular tone is regulated by a dynamic balance of relaxing and contracting factors. Loss of the endothelium-derived relaxing factor-nitric oxide in the presence of oxyhemoglobin and overproduction of endothelin-1 stimulated by oxyhemoglobin have been postulated as causes of delayed cerebral vasospasm after SAH., Object: The authors aimed to investigate this hypothesis using in vivo microdialysis to examine time-dependent changes in the perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in a primate model of SAH., Methods: Nine cynomolgus monkeys underwent right-sided frontotemporal craniectomy and placement of a semipermeable microdialysis catheter adjacent to the right middle cerebral artery (MCA). Saline (control group, three animals) or an arterial blood clot (SAH group, six animals) was then placed around the MCA and the catheter. Arteriographically confirmed vasospasm had developed in all animals with SAH but in none of the control animals on Day 7. The dialysate was collected daily for 12 days. Levels of oxyhemoglobin, deoxyhemoglobin, and methemoglobin were measured by means of spectrophotometry. Perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin peaked on Day 2 in the control monkeys and could not be detected on Days 5 to 12. Perivascular concentrations of oxyhemoglobin and deoxyhemoglobin peaked on Day 7 in the SAH group, at which time the concentrations in the dialysate were 100-fold higher than in any sample obtained from the control animals. Methemoglobin levels increased only slightly, peaking between Days 7 and 12, at which time the concentration in the dialysate was 10-fold higher than in samples from the control animals., Conclusions: This study provides in vivo evidence that the concentrations of oxyhemoglobin and deoxyhemoglobin increase in the cerebral subarachnoid perivascular space during the development of delayed cerebral vasospasm. The results support the hypothesis that oxyhemoglobin is involved in the pathogenesis of delayed cerebral vasospasm after SAH and implicate deoxyhemoglobin as a possible vasospastic agent.

Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 microM), methemoglobin (10 microM), or hypoxia (11% oxygen). There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 +/- 2.2 pg/ml and ET-1 plasma levels were 1.2 +/- 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 +/- 1.7 pg/ml in CSF and 2.7 +/- 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 +/- 0.4 pg/ml at the occlusion vs. 3.1 +/- 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 +/- 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 +/- 0.8 pg/ml vs. 0.1 +/- 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 +/- 0.6 pg/ml vs. 0 +/- 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 +/- 0.6 vs. 6.4 +/- 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05). Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

The deep rostral piriform cortex contains a site (area tempestas) in which focal application of picomole amounts of bicuculline, a GABA antagonist, triggers limbic motor seizures which are dependent upon activation of both N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyloxole-4-proprionate subtypes of glutamate receptors. In the present study we determined whether nitric oxide can influence the local modulation of seizure initiation by bicuculline. Nitric oxide and the nitric oxide precursor L-arginine, alone or in combination with low doses of bicuculline were focally administered into the area tempestas of rats. While nitric oxide alone had no significant convulsant effect, L-arginine alone (30-240 nmol) induced brief myoclonic episodes. Nitric oxide (0.7 nmol) and L-arginine (30 nmol) markedly potentiated the seizures evoked by a low dose of bicuculline. The effect of L-arginine was prevented by focal pretreatment with an inhibitor of nitric oxide synthesis, N-nitro-L-arginine methyl ester. However, N-nitro-L-arginine methyl ester did not attenuate the convulsant effect of bicuculline or kainate alone when focally administered into area tempestas. The data demonstrate that exogenously applied nitric oxide or its precursors can enhance seizure triggering activity. However, the data also indicate that L-arginine-nitric oxide pathway does not normally contribute to seizure expression from area tempestas, as N-nitro-L-arginine methyl ester alone did not attenuate focally-evoked seizures.

The continuous release of nitric oxide (NO) is required to maintain basal cerebrovascular tone. Oxyhemoglobin, a putative spasmogen, rapidly binds NO, implicating loss of NO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). If vasospasm is mediated by depletion of NO in the vessel wall, it should be reversible by replacement with NO. To investigate this hypothesis, the authors placed blood clots around the right middle cerebral artery (RMCA) of four cynomolgus monkeys; four unoperated animals served as controls. Arteriography was performed before and 7 days after surgery to assess the presence and degree of vasospasm, which was quantified in the anteroposterior (AP) projection by computerized image analysis. On Day 7, cortical cerebral blood flow (CBF) in the distribution of the right MCA was measured during four to six runs in the right internal carotid artery (ICA) of brief infusions of saline followed by NO solution. Arteriography was performed immediately after completing the final NO infusion in three of the four animals with vasospasm. Right MCA blood flow velocities were obtained using transcranial Doppler before, during, and after NO infusion in two vasospastic animals. After ICA NO infusion, arteriographic vasospasm resolved (mean percent of preoperative AP area, 55.9%); that is, the AP areas of the proximal portion of the right MCA returned to their preoperative values (mean 91.4%; range 88%-96%). Compared to ICA saline, during ICA NO infusion CBF increased 7% in control animals and 19% in vasospastic animals (p < 0.002) without significant changes in other physiological parameters. During NO infusion, peak systolic right MCA CBF velocity decreased (130 to 109 cm/sec and 116 to 76 cm/sec) in two vasospastic animals. The effects of ICA NO on CBF and CBF velocity disappeared shortly after terminating NO infusion. Intracarotid infusion of NO in a primate model of vasospasm 1) increases CBF, 2) decreases cerebral vascular resistance, 3) reverses arteriographic vasospasm, and 4) decreases CBF velocity in the vasospastic artery without producing systemic hypotension. These findings indicate the potential for the development of targeted therapy to reverse cerebral vasospasm after SAH.

To establish if interruption of the intradural draining spinal vein or surgical excision are curative treatments for spinal dural arteriovenous fistulas (AVFs), the medical records and radiographic studies of 19 patients with spinal dural AVFs and progressive myelopathy were reviewed. Spinal arteriograms were obtained before and within 2 weeks after surgery in 19 patients, and after a delay of 4 months or more in 11 patients. The mean clinical and arteriographic follow up was at 37 and 35 months, respectively. In the 11 patients who underwent excision of the dural AVF there was no evidence of a residual lesion upon immediate or delayed postoperative arteriography. Surgery in eight patients consisted of simple interruption of the intradural draining vein as it entered the subarachnoid space. In six of these patients the vein draining the AVF intrathecally provided the only venous drainage of the AVF. In these six patients there was no immediate (six of six) or delayed (four of six) arteriographic evidence of residual or recurrent flow through the AVF. Two patients had an AVF with both intra- and extradural venous drainage; after intradural division of the draining vein there was residual flow through the AVF into the extradural venous system. In one of these two patients intrathecal venous drainage was reestablished, which required additional therapy. In the other patient the extradural AVF spontaneously thrombosed and was not evident on delayed follow-up arteriography. In patients with spinal dural AVFs with only intrathecal medullary venous drainage, which includes most patients with these lesions, surgical interruption of the intradural draining vein provides lasting and curative treatment. In patients with both intra- and extradural drainage of the AVF, complete excision of the fistula or interruption of the intra- and extradural venous drainage of the fistula is indicated. In patients in whom a common vessel supplies the spinal cord and the dural AVF, simple surgical interruption of the vein draining the AVF is the treatment of choice, as it provides lasting obliteration of the fistula and it is the only treatment that does not risk arterial occlusion and cord infarction. Simple interruption of the venous drainage of a spinal dural AVF provides lasting occlusion of the fistula, as it does for cranial dural AVFs, if all pathways of venous drainage are interrupted. This result provides further evidence that the venous approach to the treatment of dural AVFs can be used successfully.