bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report
Authors: Kelly Daniel F. , Gaw Gonzalo Irene T. , Cohan Pejman , Berman Nancy , Swerdloff Ronald , Wang Christina 
Published: May 2009

Object. Recognition of pituitary hormonal insufficiencies after head injury and aneurysmal subarachnoid hemorrhage (SAH) may be important, especially given that hypopituitarism-related neurobehavioral problems are typically alleviated by hormone replacement. In this prospective study the authors sought to determine the rate and risk factors of pituitary dysfunction after head injury and SAH in patients at least 3 months after insult.Methods. Patients underwent dynamic anterior and posterior pituitary function testing. Results of the tests were compared with those of 18 age-, sex-, and body mass index—matched healthy volunteers. The 22 head-injured patients included 18 men and four women (mean age 28 ± 10 years at the time of injury) with initial Glasgow Coma Scale (GCS) scores of 3 to 15. Eight patients (36.4%) had a subnormal response in at least one hormonal axis. Four were growth hormone (GH) deficient. Five patients (four men, all with normal testosterone levels, and one woman with a low estradiol level) exhibited an inadequate gonadotroph response. One patient had both GH and thyrotroph deficiency and another had both GH deficiency and borderline cortisol deficiency. At the time of injury, all eight patients with pituitary dysfunction had an initial GCS score of 10 or less and, compared with the 14 patients without dysfunction, were more likely to have had diffuse swelling, seen on initial computerized tomography scans (p < 0.05), and to have sustained a hypotensive or hypoxic insult (p = 0.07). Of two patients with SAH who were studied (Hunt and Hess Grade IV) both had GH deficiency.Conclusions. From this preliminary study, some degree of hypopituitarism appears to occur in approximately 40% of patients with moderate or severe head injury, with GH and gonadotroph deficiencies being most common. A high degree of injury severity and secondary cerebral insults are likely risk factors for hypopituitarism. Pituitary dysfunction also occurs in patients with poor-grade aneurysms. Postacute pituitary function testing may be warranted in most patients with moderate or severe head injury, particularly those with diffuse brain swelling and those sustaining hypotensive or hypoxic insults. The neurobehavioral effects of GH replacement in patients suffering from head injury or SAH warrant further study.
High level of extracellular potassium and its correlates after severe human head injury: relationship to high intracranial pressure
Authors: Reinert Michael , Khaldi Ahmad , Zauner Alois , Doppenberg Egon , Choi Sung , Bullock Ross 
Published: May 2009

Object. Disturbed ionic and neurotransmitter homeostasis are now recognized as probably the most important mechanisms contributing to the development of secondary brain swelling after traumatic brain injury (TBI). Evidence obtained in animal models indicates that posttraumatic neuronal excitation by excitatory amino acids leads to an increase in extracellular potassium, probably due to ion channel activation. The purpose of this study was therefore to measure dialysate potassium in severely head injured patients and to correlate these results with measurements of intracranial pressure (ICP), patient outcome, and levels of dialysate glutamate and lactate, and cerebral blood flow (CBF) to determine the role of ischemia in this posttraumatic ion dysfunction.Methods. Eighty-five patients with severe TBI (Glasgow Coma Scale Score < 8) were treated according to an intensive ICP management-focused protocol. All patients underwent intracerebral microdialyis. Dialysate potassium levels were analyzed using flame photometry, and dialysate glutamate and dialysate lactate levels were measured using high-performance liquid chromatography and an enzyme-linked amperometric method in 72 and 84 patients, respectively. Cerebral blood flow studies (stable xenon computerized tomography scanning) were performed in 59 patients.In approximately 20% of the patients, dialysate potassium values were increased (dialysate potassium > 1.8 mM) for 3 hours or more. A mean amount of dialysate potassium greater than 2 mM throughout the entire monitoring period was associated with ICP above 30 mm Hg and fatal outcome, as were progressively rising levels of dialysate potassium. The presence of dialysate potassium correlated positively with dialysate glutamate (p < 0.0001) and lactate (p < 0.0001) levels. Dialysate potassium was significantly inversely correlated with reduced CBF (p = 0.019).Conclusions. Dialysate potassium was increased after TBI in 20% of measurements. High levels of dialysate potassium were associated with increased ICP and poor outcome. The simultaneous increase in dialysate potassium, together with dialysate glutamate and lactate, supports the concept that glutamate induces ionic flux and consequently increases ICP, which the authors speculate may be due to astrocytic swelling. Reduced CBF was also significantly correlated with increased levels of dialysate potassium. This may be due to either cell swelling or altered vasoreactivity in cerebral blood vessels caused by higher levels of potassium after trauma. Additional studies in which potassium-sensitive microelectrodes are used are needed to validate these ionic events more clearly.
Cerebral microdialysis monitoring: determination of normal and ischemic cerebral metabolisms in patients with aneurysmal subarachnoid hemorrhage
Authors: Schulz Mette K. , Wang Lars Peter , Tange Mogens , Bjerre Per 
Published: May 2009

Object. The success of treatment for delayed cerebral ischemia is time dependent, and neuronal monitoring methods that can detect early subclinical levels of cerebral ischemia may improve overall treatment results. Cerebral microdialysis may represent such a method. The authors' goal was to characterize patterns of markers of energy metabolism (glucose, pyruvate, and lactate) and neuronal injury (glutamate and glycerol) in patients with subarachnoid hemorrhage (SAH), in whom ischemia was or was not suspected.Methods. By using low-flow intracerebral microdialysis monitoring, central nervous system extracellular fluid concentrations of glucose, pyruvate, lactate, glutamate, and glycerol were determined in 46 patients suffering from poor-grade SAH. The results in two subgroups were analyzed: those patients with no clinical or radiological signs of cerebral ischemia (14 patients) and those who succumbed to brain death (five patients).Significantly lower levels of energy substrates and significantly higher levels of lactate and neuronal injury markers were observed in patients with severe and complete ischemia when compared with patients without symptoms of ischemia (glucose 0 compared with 2.12 ± 0.15 mmol/L; pyruvate 0 compared with 151 ± 11.5 µmol; lactate 6.57 ± 1.07 compared with 3.06 ± 0.32 mmol/L; glycerol 639 ± 91 compared with 81.6 ± 12.4 µmol; and glutamate 339 ± 53.4 compared with 14 ± 3.33 µmol). Immediately after catheter placement, glutamate concentrations declined over the first 4 to 6 hours to reach stable values. The remaining parameters exhibited stable values after 1 to 2 hours.Conclusions. The results confirm that intracerebral microdialysis monitoring of patients with SAH can be used to detect patterns of cerebral ischemia. The wide range from normal to severe ischemic values calls for additional studies to characterize further incomplete and possible subclinical levels of ischemia.
Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats
Authors: Berman Robert F. , Verweij Bon H. , Muizelaar J. Paul 
Published: May 2009

Object. Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects.Methods. The authors report that the acceleration—deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7, 14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze.Conclusions. These results demonstrated that the acceleration—deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.
Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose—response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury
Authors: Verweij Bon H. , Muizelaar J. Paul , Vinas Federico C. , Peterson Patti L. , Xiong Ye , Lee Chuan P. 
Published: May 2009

Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose—response curves in preclinical drug testing. This idea was tested in a model of TBI in rats.Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose.Conclusions. The authors established these time-window profiles and dose—response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose—response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.
No additional neuroprotection provided by barbiturate-induced burst suppression under mild hypothermic conditions in rats subjected to reversible focal ischemia
Authors: Westermaier Thomas , Zausinger Stefan , Baethmann Alexander , Steiger Hans-Jakob , Schmid-Elsaesser Robert 
Published: May 2009

Object. Mild-to-moderate hypothermia is increasingly used for neuroprotection in humans. However, it is unknown whether administration of barbiturate medications in burst-suppressive doses—the gold standard of neuroprotection during neurovascular procedures—provides an additional protective effect under hypothermic conditions. The authors conducted the present study to answer this question.Methods. Thirty-two Sprague—Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion and randomly assigned to one of four treatment groups: 1) normothermic controls; 2) methohexital treatment (burst suppression); 3) induction of mild hypothermia (33°C); and 4) induction of mild hypothermia plus methohexital treatment (burst suppression). Local cerebral blood flow was continuously monitored using bilateral laser Doppler flowmetry and electroencephalography. Functional deficits were quantified and recorded during daily neurological examinations. Infarct volumes were assessed histologically after 7 days. Methohexital treatment, mild hypothermia, and mild hypothermia plus methohexital treatment reduced infarct volumes by 32%, 71%, and 66%, respectively, compared with normothermic controls. Furthermore, mild hypothermia therapy provided the best functional outcome, which was not improved by additional barbiturate therapy.Conclusions. The results of this study indicate that barbiturate-induced burst suppression is not required to achieve maximum neuroprotection under mild hypothermic conditions. The magnitude of protection afforded by barbiturates alone appears to be modest compared with that provided by mild hypothermia.
Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53
Authors: Kraus Alison , Gross Markus W. , Knuechel Ruth , Münkel Kristin , Neff Frauke , Schlegel Jürgen 
Published: May 2009

Object. A clearer understanding of the cellular mechanisms involved in the response to ionizing radiation is pivotal to the development of new therapeutic strategies for glioblastoma multiforme (GBM). To gain insight into dynamic functional aspects of cell cycle regulation and the control of apoptosis in GBMs, the authors investigated the molecular changes induced by ionizing radiation in genetically characterized primary GBMs in vitro compared with secondary GBMs, Grades II and III gliomas, and three GBM cell lines.Methods. Irradiation of primary GBMs bearing wild-type (wt) p53 invariably fails to invoke the G1 checkpoint and apoptosis in vitro. In approximately half of these primary GBMs a defect lies at or above the level of p53 because transcriptional activation of p21 and bax after irradiation does not occur. The failure of a p21 response to irradiation is invariably accompanied by overexpression of p21 mRNA under nonirradiated conditions. In all remaining primary GBMs transcriptional activation of p21 after irradiation does occur, suggesting that a defect downstream from p21 prevents G1 arrest.Conclusions. These results show that the G1 checkpoint and the p53 pathway are dysfunctional in primary GBMs in vitro, despite the presence of an intact p53 gene. The data also suggest that primary GBMs may be divided into two categories on the basis of their p21 response to irradiation.
Cortical reorganization after digit-to-hand replantation
Authors: Wiech Katja , Preißl Hubert , Lutzenberger Werner , Kiefer Ralph-Thomas , Töpfner Stephanie , Haerle Max , Schaller Hans-Eberhard , Birbaumer Niels 
Published: May 2009

✓ Functional recovery after digit-to-hand replantation depends on the interaction of various factors. In addition to peripheral mechanisms, cortical and subcortical reorganization of digit representation may play a substantial role in the recovery process. However, cortical processes during the first months after replantation are not well understood.In this 25-year-old man who had traumatically lost digits II to V (DII—V) on his right hand, the authors used magnetoencephalographic source imaging to document the recovery of somatosensory cortical responses after tactile stimulation at four sites on the replanted digits. Successful replantation of DIV and DV was accomplished at the original position of DIII and DIV with mixed innervation. Cortical evoked fields could be recorded starting from the 10th week after digit-to-hand replantation. Initially, signals from all sites showed decreased amplitudes and prolonged latencies. In the subsequent six recordings obtained between the 12th and 55th week postreplantation, a continuous increase in amplitude but only a slight recovery of latencies were observed. Components of the recorded somatosensory evoked fields were localized in the primary somatosensory cortex (SI). The localizations of the replanted DIV showed a gradual lateral-inferior shift in the somatosensory cortex over time, indicating cortical reorganization caused by altered peripheral input. The authors infer from this shift that the original cortical area of the missing finger (DII) was taken over by the replanted finger.From these data the authors conclude that magnetic source imaging might be a reliable noninvasive method to evaluate surgical nerve repair and that cortical reorganization of SI is involved in the regeneration process following peripheral nerve injury.
Primary intracerebral and aneurysmal subarachnoid hemorrhage in Izumo City, Japan. Part 1: incidence and seasonal and diurnal variations
Authors: Inagawa Tetsuji , Takechi Akihiko , Yahara Kaita , Saito Jun , Moritake Kouzo , Kobayashi Shotai , Fujii Yoshito , Sugimura Chie 
Published: May 2009

Object. The purpose of this community-based study was first to estimate the incidence rates of primary intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH) in Izumo City, Japan, and second to investigate whether there were seasonal and diurnal periodicities in their onset.Methods. During 1991 through 1996, 267 patients with primary ICH and 123 with aneurysmal SAH were treated in Izumo City. The crude and the age- and sex-adjusted annual incidence rates per 100,000 population for all ages were 52 and 48 for ICH and 24 and 23 for SAH, respectively. These incidence rates were higher than those previously published for any other geographical region. The incidence rates of both ICH and SAH increased almost linearly with age. For ICH, a significant seasonal pattern was observed in men and in patients younger than 65 years, with a peak in winter and a trough in summer. However, no significant seasonal fluctuation was found in women or in individuals aged 65 years or older. There was no significant seasonal periodicity for SAH, even when patients were analyzed according to sex and age. Diurnal variations in the onset of both ICH and SAH were significant (except in men with SAH), with a nadir between midnight and 6:00 a.m.Conclusions. The actual incidence rates of both primary ICH and aneurysmal SAH seem to be much higher than have been reported so far. In addition, the data indicate the existence of seasonal periodicity for men and younger patients with ICH, and that the risk of both ICH and SAH is lower during nighttime.
An efficacy and safety study of the ETA/B receptor antagonist TAK-044 in subarachnoid hemorrhage
Authors: Shaw Malcolm D. M. , Vermeulen Marinus , Murray Gordon D. , Pickard John D. , Bell B. Anthony , Teasdale Graham M. 
Published: May 2009

Object. Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ETA/B receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients.Methods. Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events.There was a lower incidence of delayed ischemic events at 3 months in the TAK-044—treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo—treated and TAK-044—treated groups.Conclusions. The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache—side effects compatible with the drug's vasodilatory properties—occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.
Irregular-shaped ruptured aneurysms: pseudoaneurysm formation in a thrombus at rupture site
Authors: Nomura Motohiro , Kida Sinya , Uchiyama Naoyuki , Yamashima Tetsumori , Yoshikawa Jun , Yamashita Junkoh , Matsui Osamu 
Published: May 2009

Object. The authors describe the clinical, radiological, and pathological findings of ruptured cerebral aneurysms with irregular configurations.Methods. Eight patients with subarachnoid hemorrhage due to ruptured irregularly shaped aneurysms were examined. The preoperative radiological findings in these cases were compared with the pathological and operative findings of endovascular or open surgery.All of the aneurysms exhibited delayed opacification and delayed washout of contrast medium from the irregularly shaped portion of the aneurysm on digital subtraction angiography and/or helical computerized tomography scanning. Endovascular embolization with platinum coils was attempted in the first four patients who underwent treatment. In three of these patients the aneurysm ruptured again during the endovascular procedure. In the fourth patient an intraaneurysm thrombus was observed during the procedure and clipping was performed. In the subsequent four patients, three underwent clipping without complication and one underwent partial aneurysm embolization because of poor general status. A thrombus adjacent to the aneurysm dome was observed in the patients who underwent open surgery. Pathological examination of the operative specimens revealed a pseudoaneurysm-like cavity in the thrombus that was adherent to the aneurysm.Conclusions. Ruptured irregularly shaped aneurysms may be accompanied by fragile pseudoaneurysm-like cavities located at the rupture point. Because these aneurysms have a high risk of repeated rupture during an endovascular procedure, advancing microinstruments to the weaker portion of the aneurysm should be avoided.