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Hülya Bayir

Publications and source records attributed to Hülya Bayir.

17 recordsLinked to original sources
PubMed2007

Nitrosative stress inhibits the aminophospholipid translocase resulting in phosphatidylserine externalization and macrophage engulfment: implications for the resolution of inflammation.

Macrophage recognition of apoptotic cells depends on externalization of phosphatidylserine (PS), which is normally maintained within the cytosolic leaflet of the plasma membrane by aminophospholipid translocase (APLT). APLT is sensitive to redox modifications of its -SH groups. Because activated macrophages produce reactive oxygen and nitrogen species, we hypothesized that macrophages can directly participate in apoptotic cell clearance by S-nitrosylation/oxidation and inhibition of APLT causing PS externalization. Here we report that exposure of target HL-60 cells to nitrosative stress inhibited APLT, induced PS externalization, and enhanced recognition and elimination of "nitrosatively" modified cells by RAW 264.7 macrophages. Using S-nitroso-L-cysteine-ethyl ester (SNCEE) and S-nitrosoglutathione (GSNO) that cause intracellular and extracellular trans-nitrosylation of proteins, respectively, we found that SNCEE (but not GSNO) caused significant S-nitrosylation/oxidation of thiols in HL-60 cells. SNCEE also strongly inhibited APLT, activated scramblase, and caused PS externalization. However, SNCEE did not induce caspase activation or nuclear condensation/fragmentation suggesting that PS externalization was dissociated from the common apoptotic pathway. Dithiothreitol reversed SNCEE-induced S-nitrosylation, APLT inhibition, and PS externalization. SNCEE but not GSNO stimulated phagocytosis of HL-60 cells. Moreover, phagocytosis of target cells by lipopolysaccharide-stimulated macrophages was significantly suppressed by an NO. scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation.

Animals↗
PubMed2006

Heme oxygenase 1 in cerebrospinal fluid from infants and children after severe traumatic brain injury.

Heme oxygenase 1 (HO-1) is an enzyme important in the catabolism of heme that is induced under conditions of oxidative stress. HO-1 degradation of heme yields biliverdin, bilirubin, carbon monoxide and iron. HO-1 is thought to serve a protective antioxidant function, and upregulation of HO-1 has been demonstrated in experimental models of neurodegeneration, subarachnoid hemorrhage, cerebral ischemia and traumatic brain injury (TBI). We measured HO-1 concentration in cerebral spinal fluid samples from 48 infants and children following TBI and 7 control patients by ELISA. Increased HO-1 was seen in TBI versus control patients--mean 2.75+/-0.63, peak 4.17+/-0.96 ng/ml versus control (<0.078 ng/ml, not detectable) (p<0.001). Increased HO-1 concentration was associated with increased injury severity and unfavorable neurological outcome (both p<0.05). Increased HO-1 concentration was independently associated with younger age; however, statistical analysis could not rule out the possibility that the effect of age was related to inflicted TBI from child abuse. HO-1 increases after TBI and appears to be more prominent in infants compared with older children after injury.

Age Factors↗
PubMed2006

Oxidative stress in immature brain after traumatic brain injury.

High oxygen demand along with the abundance of readily oxidizable substrates yielding productive oxidative metabolism are required for the normal function of the brain. This necessitates the existence of the complex and multicomponent antioxidant system in the brain for protection against oxidative damage. However, during development, individual components of the antioxidant system are not equally expressed and not always sufficient to fulfill their tasks in a coordinated way. As a result, the developing brain may be more vulnerable to oxidative insults than the adult brain. Traumatic brain injury is one of the damaging acute impacts that challenge the brain antioxidant reserves by exposing them to a number of decompartmentalized prooxidant molecules. This review focuses on the sources and assessment of oxidative stress and the link between oxidative stress and cell death pathways in the immature brain after experimental and clinical traumatic brain injury.

Animals↗
PubMed2005

Enhanced oxidative stress in iNOS-deficient mice after traumatic brain injury: support for a neuroprotective role of iNOS.

Studies in experimental traumatic brain injury (TBI) suggest both deleterious and protective effects of inducible nitric oxide synthase (iNOS). Early after injury, iNOS may be detrimental via formation of peroxynitrite and iNOS inhibitors are protective. In contrast, we reported impaired long-term functional outcome after TBI in iNOS knockout (ko) versus wild-type (wt) mice. To elucidate potential neuroprotective and neurotoxic mechanisms for iNOS, we studied nitric oxide formation by electron paramagnetic resonance (EPR) spectroscopy using diethyldithiocarbamate-iron (DETC-Fe) as a spin trap and markers of nitrosative (S-nitrosothiol (RSNO, Fluorescent assay); nitrotyrosine (3NT, ELISA)) and oxidative stress (ascorbate, HPLC) at 72 h after controlled cortical impact (CCI) in iNOS ko and wt and in uninjured iNOS ko and wt mice. 3NT immunostaining with macrophage and myeloperoxidase (MPO) dual labeling was also assessed in brain sections. Brain DETC-Fe-NO low-temperature EPR signal intensity was approximately 2-fold greater in wt versus iNOS ko at 72 h after CCI. Ascorbate levels decreased in injured hemisphere in wt and iNOS ko versus uninjured -this decrease was more pronounced in iNOS ko. In wt mice, RSNO and 3NT levels were increased after CCI versus uninjured (50% and 400%, respectively, P < 0.05). RSNO levels were not increased in iNOS ko after CCI. Nitrotyrosine levels increased after CCI in wt and ko versus respective uninjured -this increase was more pronounced in wt (2.34 +/- 0.95 versus 1.27 +/- 0.49 pmol/mg protein, P < 0.05). Increased 3NT immunoreactivity was detected in wt versus iNOS ko at 72 h after CCI, and colocalized with macrophage marker and MPO. Our data support a role for iNOS-derived NO as an endogenous antioxidant after CCI. iNOS also contributes protein nitrosylation and nitration. Colocalization of 3NT with macrophages and MPO suggests generation of nitrating agents by macrophages and/or phagocytosis of nitrated proteins.

Animals↗
PubMed2005

Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system.

OBJECTIVE: In response to the landmark 1999 report by the Institute of Medicine and safety initiatives promoted by the Leapfrog Group, our institution implemented a commercially sold computerized physician order entry (CPOE) system in an effort to reduce medical errors and mortality. We sought to test the hypothesis that CPOE implementation results in reduced mortality among children who are transported for specialized care. METHODS: Demographic, clinical, and mortality data were collected of all children who were admitted via interfacility transport to our regional, academic, tertiary-care level children's hospital during an 18-month period. A commercially sold CPOE program that operated within the framework of a general, medical-surgical clinical application platform was rapidly implemented hospital-wide over 6 days during this period. Retrospective analyses of pre-CPOE and post-CPOE implementation time periods (13 months before and 5 months after CPOE implementation) were subsequently performed. RESULTS: Among 1942 children who were referred and admitted for specialized care during the study period, 75 died, accounting for an overall mortality rate of 3.86%. Univariate analysis revealed that mortality rate significantly increased from 2.80% (39 of 1394) before CPOE implementation to 6.57% (36 of 548) after CPOE implementation. Multivariate analysis revealed that CPOE remained independently associated with increased odds of mortality (odds ratio: 3.28; 95% confidence interval: 1.94-5.55) after adjustment for other mortality covariables. CONCLUSIONS: We have observed an unexpected increase in mortality coincident with CPOE implementation. Although CPOE technology holds great promise as a tool to reduce human error during health care delivery, our unanticipated finding suggests that when implementing CPOE systems, institutions should continue to evaluate mortality effects, in addition to medication error rates, for children who are dependent on time-sensitive therapies.

Child Mortality↗
PubMed2004

Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway.

Many central nervous system (CNS) diseases display sexual dimorphism. Exposure to circulating sex steroids is felt to be a chief contributor to this phenomenon; however, CNS diseases of childhood and the elderly also demonstrate gender predominance and/or a sexually dimorphic response to therapies. Here we show that XY and XX neurons cultured separately are differentially susceptible to various cytotoxic agents and treatments. XY neurons were more sensitive to nitrosative stress and excitotoxicity versus XX neurons. In contrast, XX neurons were more sensitive to etoposide- and staurosporine-induced apoptosis versus XY neurons. The responses to specific therapies were also sexually dimorphic. Moreover, gender proclivity in programmed cell death pathway was observed. After cytotoxic challenge, programmed cell death proceeded predominately via an apoptosis-inducing factor-dependent pathway in XY neurons versus a cytochrome c-dependent pathway in XX neurons. This gender-dependent susceptibility is related to the incapacity of XY neurons to maintain intracellular levels of reduced glutathione. In vivo studies further demonstrated an incapacity for male, but not female, 17-day-old rats to maintain reduced glutathione levels within cerebral cortex acutely after an 8-min asphyxial cardiac arrest. This gender difference in sensitivity to cytotoxic agents may be generalized to nonneuronal cells, as splenocytes from male and female 16-18-day-old rats show similar gender-dependent responses to nitrosative stress and staurosporine-induced apoptosis. These data support gender stratification in the evaluation of mechanisms and treatment of CNS disease, particularly those where glutathione may play a role in detoxification, such as Parkinson's disease, traumatic brain injury, and conditions producing cerebral ischemia, and may apply to non-CNS diseases as well.

Animals↗
PubMed2004

Relationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age, and hypothermia.

Excitotoxicity and ischemia can result in oxidative stress after TBI. Female sex hormones are hypothesized to be neuroprotective after TBI by affecting multiple mechanisms of secondary injury, including oxidative damage, excitotoxicity and ischemia. Ca2+ mediated oxidative stress increases with age, and hypothermia is known to attenuate secondary injury. The purpose of this study was to determine if the relationship between cerebral spinal fluid (CSF) markers of excitotoxicity, ischemia, and oxidative damage are gender and age specific and the role of hypothermia in affecting these relationships. F2-isoprostane, glutamate, and lactate/pyruvate, were assessed in CSF from adults (n = 68) with severe TBI (Glasgow coma scale [GCS] score </= 8) using ventricular CSF samples (n = 207) collected on days 1, 2, and 3 post-injury. F2-isoprostane/glutamate and F2-isoprostane/lactate/pyruvate ratios were determined for patients at each time point. Six-month Glasgow Outcome Scores (GOS) were also obtained. Repeated measures multivariate analysis showed a significant gender effect (p < 0.002) and gender*time interaction (p = 0.012) on F2-isoprostane/glutamate ratios. A significant gender effect (p = 0.050) and gender*time interaction (p = 0.049) was also seen with F2-isoprostane/lactate/pyruvate. Hypothermia (p = 0.001) and age (p = 0.026) significantly increased F2-isoprostane/glutamate ratios. Females had a significant inverse relationship between day 1 F2-isoprostane/glutamate ratios and GOS scores (r =- 0.43; p = 0.05) as well as day 1 F2-isoprostane/lactate/pyruvate ratio (r =- 0.46; p = 0.04) and GOS scores. These results indicate that females have smaller oxidative damage loads than males for a given excitotoxic or ischemic insult and female gonadal hormones may play a role in mediating this neuroprotective effect. These results also suggest that susceptibility to glutamate mediated oxidative damage increases with age and that hypothermia differentially attenuates CSF glutamate versus F2-isoprostane production. Gender and age differences in TBI pathophysiology should be considered when conducting clinical trials in TBI.

Adult↗
PubMed2004

Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients.

Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F(2)-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F(2)-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score </= 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33 degrees C (within approximately 6 h) for either 24 or 48 h and then re-warmed. F(2)-isoprostane levels were assessed by ELISA in ventricular CSF samples (n = 199) on day 1, 2, and 3. The association between age, GCS score, time, gender, treatment, duration of treatment, core temperature at the time of CSF sampling, secondary hypoxemia, and CSF F(2)-isoprostane level was assessed by multivariate and dichotomous analyses. F(2)-isoprostane was approximately 2-fold higher in males than females (145.8 +/- 39.6 versus 75.4 +/- 16.6 pg/mL, day 1 p = 0.018). An effect of time after injury (p = 0.007) was reflected by a marked early peak in F(2)-isoprostane (day 1). CSF F(2)-isoprostane was also associated with hypoxemia (p = 0.04). Hypothermia tended to decrease F(2)-isoprostane levels only in males on d1 after TBI. To our knowledge, this is the first study showing gender differences in lipid peroxidation after clinical TBI. Lipid peroxidation occurs early after severe TBI in adults and is more prominent in males vs females. These results established that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.

Adult↗
PubMed2004

Continuous versus intermittent cerebrospinal fluid drainage after severe traumatic brain injury in children: effect on biochemical markers.

Drainage of cerebrospinal fluid (CSF) is routinely used in the treatment of severe traumatic brain injury (TBI), either continuously or intermittently in response to increases in intracranial pressure (ICP). There has been little study of the effect of CSF drainage method on the biochemistry, pathophysiology or outcome of TBI in adults or children. Having previously reported that a variety of markers of injury or repair increase in CSF after severe TBI, we chose to evaluate directly the effect of CSF drainage method on the biochemistry and volume of CSF drained as well as ICP. We hypothesized that concentrations of these markers would be similar in CSF drained continuously vs intermittently. We compared CSF levels of markers of neuronal injury (neuron specific enolase, [NSE]), glial injury (s100B), inflammation (interleukin-6 [IL-6]), and regeneration (vascular endothelial growth factor [VEGF]) (measured by ELISA) in 80 CSF samples from 19 severely injured children whose CSF was drained continuously (n = 13) versus intermittently (n = 6) as part of standard care in two institutions. Compared to continuous CSF drainage, intermittent drainage of CSF was associated with twofold greater CSF concentrations of NSE, s100B, IL-6 and VEGF (p < 0.05) and with about half the volume of CSF removal than continuous drainage (p = 0.002). The resulting elimination (concentration x volume) of these biochemicals, however, was not influenced by drainage method. Patients treated with continuous drainage had lower mean ICPs than those with intermittent drainage (13.6 +/- 0.69 vs. 21.8 +/- 0.95 mm Hg, p < 0.0001). We conclude that the method of CSF drainage greatly affects concentrations of CSF markers after TBI and may influence ICP. The influence of method on CSF marker concentration must be kept in mind when interpreting studies of CSF biomarkers. The striking difference in biomarker concentration, CSF volume drained, and ICP suggests the need for a randomized trial directly comparing these two approaches in infants and children with severe TBI.

Adolescent↗
PubMed2003

Traumatic brain injury in infants and children: mechanisms of secondary damage and treatment in the intensive care unit.

Unfortunately no specific pharmacologic therapies are available for the treatment of TBI in patients. Current investigation of contemporary therapies for the treatment of TBI consists of recycling of previously tested therapies in the era of contemporary neurointensive care. These therapies include hypothermia, decompressive craniectomy, osmotherapy, and controlled hyperventilation. It is hoped that more detailed knowledge regarding the dominant pathophysiologic mechanisms associated with TBI-excitotoxicity, CBF dysregulation, oxidative stress, and programmed cell death-will catapult an efficacious intervention from the laboratory bench to the bedside. This intervention may be a potent agent targeting a single dominant pathway, a broad-spectrum intervention such as hypothermia, or, more likely, a combination of therapies. Meanwhile, practitioners must offer meticulous supportive neurointensive care using clinically proven therapies aimed at minimizing cerebral swelling for the management of pediatric patients who are victims of TBI.

Apoptosis↗
PubMed2003

F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children.

It has been hypothesized that oxidative stress plays an important role in mediating secondary damage after traumatic brain injury (TBI). To study the relationship between lipid peroxidation, clinical variables, and neuronal damage in pediatric TBI, we measured levels of F2-isoprostane, a marker of lipid peroxidation, and neuron-specific enolase (NSE), a marker of neuronal damage, in serial cerebrospinal fluid (CSF) samples from 23 infants and children with severe TBI (Glasgow Coma Scale score <8). These were compared to CSF samples from 10 uninjured pediatric controls. On d1 after injury, F2-isoprostane was increased 6-fold vs. control (36.59+/-8.96 pg/ml vs. 5.64+/-8.08 pg/ml, p=0.0035) and NSE was increased 10-fold (100.62+/-17.34 ng/ml vs. 8.63+/-2.76 ng/ml, p=0.0002). Multivariate analysis of F2-isoprostane levels and selected clinical variables showed a trend toward an inverse association with time after injury (p=0.0708). Multivariate analysis of NSE levels and selected variables showed a positive association between d1 NSE and F2-isoprostane (p=0.0426). CSF F2-isoprostane increases early after TBI in infants and children and is correlated with NSE, supporting a role for oxidative stress in the evolution of secondary damage early after severe TBI in infants and children.

Adolescent↗
PubMed2003

Promising strategies to minimize secondary brain injury after head trauma.

OBJECTIVE: To review novel therapeutic approaches in the treatment of severe traumatic brain injury. DESIGN: Eighty-three studies were reviewed specific to the treatment of traumatic brain injury, in either experimental models or in patients. CONCLUSION: Four therapeutic strategies appear to be the most promising approaches currently in clinical trials for severe traumatic brain injury: a) the novel pharmacologic agent dexanabinol; b) hypertonic saline; c) mild hypothermia; and d) decompressive craniectomy. Each of these therapies share the common feature of targeting multiple mechanisms, suggesting this may be an important factor to the development of a successful approach to severe traumatic brain injury.

Brain Injuries↗
PubMed2003

Increased S-nitrosothiols and S-nitrosoalbumin in cerebrospinal fluid after severe traumatic brain injury in infants and children: indirect association with intracranial pressure.

Nitric oxide (NO) is implicated in both secondary damage and recovery after traumatic brain injury (TBI). Transfer of NO groups to cysteine sulfhydryls on proteins produces S-nitrosothiols (RSNO). S-nitrosothiols may be neuroprotective after TBI by nitrosylation of N-methyl-D-aspartate receptor and caspases. S-nitrosothiols release NO on decomposition for which endogenous reductants (i.e., ascorbate) are essential, and ascorbate is depleted in cerebrospinal fluid (CSF) after pediatric TBI. This study examined the presence and decomposition of RSNO in CSF and the association between CSF RSNO level and physiologic parameters after severe TBI. Cerebrospinal fluid samples (n = 72) were obtained from 18 infants and children on days 1 to 3 after severe TBI (Glasgow Coma Scale score < 8) and 18 controls. Cerebrospinal fluid RSNO levels assessed by fluorometric assay peaked on day 3 versus control (1.42 +/- 0.11 micromol/L vs. 0.86 +/- 0.04, P< 0.05). S-nitrosoalbumin levels were also higher after TBI (n = 8, 0.99 +/- 0.09 micromol/L on day 3 vs. n = 6, 0.42 +/- 0.02 in controls, P< 0.05). S-nitrosoalbumin decomposition was decreased after TBI. Multivariate analysis showed an inverse relation between CSF RSNO and intracranial pressure and a direct relation with barbiturate treatment. Using a novel assay, the presence of RSNO and S-nitrosoalbumin in human CSF, an approximately 1.7-fold increase after TBI, and an association with low intracranial pressure are reported, supporting a possible neuroprotective role for RSNO. The increase in RSNO may result from increased NO production and/or decreased RSNO decomposition.

Adolescent↗