Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.

Introduction: Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy 60Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta®, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP. Methods: B6D2F1 female mice were exposed to 60Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3). Results: CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased. Discussion: CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.

A rare case of fetal extensive intracranial hemorrhage and whole-cerebral hypoplasia due to latent maternal vitamin K deficiency.

We present here a late preterm infant with extensive brain lesions resulting from vitamin K deficiency. A female infant was born after 35 weeks of gestation by emergent cesarean section because of non-reassuring fetal status. Her mother had severe eating disorder and recurrent vomiting since early pregnancy. She was immediately intubated and ventilated because she was extremely pale, hypotonic, and non-reactive. Cerebral magnetic resonance imaging immediately after birth showed intraparenchymal hemorrhage in the left frontal lobe and cerebellum, marked cerebral edema, and cerebellar hypoplasia. Coagulation studies of the infant showed hepaplastin test <5%, prolonged PT and APTT, and a marked elevation of protein induced by vitamin K absence or antagonist-II. This case highlighted a potential risk of intracranial bleeding due to maternal vitamin K deficiency and difficulty in its prediction before delivery. Vitamin K supplementation to high risk mothers might be indispensable for preventing severe fetal vitamin K deficiency. Even when coagulation studies in mothers is normal, it is imperative to provide vitamin K supplementation for total protection.

Management of pulmonary embolism after recent intracranial hemorrhage: A case report.

RATIONALE: Venous thromboembolism may result from prolong immobilization following intracerebral hemorrhage. Massive pulmonary embolism with associated right heart failure is life-threatening, requiring treatment with anticoagulants or even thrombolytic agents. However, these drugs are contraindicated after a recent hemorrhagic episode, as they may induce further hemorrhage. There are no guidelines for treatment in these circumstances. PATIENT CONCERNS: A 57-year-old man experienced massive pulmonary embolism and shock 18 days after an intracerebral hemorrhage. DIAGNOSES: Tachycardia and high D-dimer (21.27 mg/L fibrinogen-equivalent units) were noted. Chest computed tomography showed bilateral pulmonary trunk embolism. INTERVENTIONS: Heparinization were used and activated partial thromboplastin time therapeutic range was 50 to 70 seconds. Fortunately, shock status and shortness of breath improved two days later. Continuing high dose Rivaroxaban was administrated for three weeks. OUTCOMES: There was no recurrent intracranial hemorrhage (ICH) following treatment for three-weeks with high-dose and one-year with standard dose of rivaroxaban. This report presents a treatment option in the management of these difficult clinical situations. LESSONS: The combination of unfractionated heparin infusion and continuing non-Vitamin K antagonist oral anticoagulants use could manage life-threatening pulmonary embolism following recent ICH. Theoretically, the use of NOAC is a safer strategy if the patient with previous history of major ICH.

Effects of the blood components on the AMPA and NMDA synaptic responses in brain slices in the onset of hemorrhagic stroke.

Blood-borne events play a major role in post bleeding disturbances of the neuronal network. However, very little is known about the early effects of blood plasma, leucocytes, and the red blood cells on the AMPA and NMDA-mediated synaptic responses in the onset of experimental intracranial hemorrhage (ICH). In this study, we used the technique of on-line monitoring of electrophysiological parameters referred to synaptic activity in piriform cortex of SHR rat slice. We exposed the olfactory cortex slices to diluted autologous blood or its components and compared with effects of ferric chloride. Whole blood exerted a total inhibition of synaptic activity in piriform cortex within first 5 min. Dilution of blood induced prolonged epileptic synaptic activation of NMDA receptors. Blood plasma and fraction of leucocytes induced hyperactivation of neurons transforming to epileptiform discharges. Fraction of red blood cells acted biphasic, an initial sharp activity of AMPA- and NMDA-mediated receptors replaced by a following total depression. Our slice-based models of experimental stroke revealed the mechanism of the earliest pathophysiologic events occur in brain tissue during bleeding that may be relevant to the human ICH.

Clinical analysis of electrolyte imbalance in thalamic hemorrhage patients within 24 h after admission.

We have observed that patients with thalamic hemorrhage are more likely to have electrolyte disturbances than those with non-thalamic hemorrhage. Here, we are attempting to provide some comprehensive information on electrolyte disturbances in patients with thalamic hemorrhage. Retrospectively, 67 patients with thalamic hemorrhage (TH group) and 256 with non-thalamic hemorrhage (N-TH group) were found from computer tomography images. Electrolytes of these patients were tested within 24 h after hospitalization. Chi-square test was used to compare the incidence of electrolyte imbalance. Serum K+ levels were found to be abnormal in 37.31% of the patients in the TH group and 24.21% in the N-TH group, and the difference was significant (p<0.05). Such a difference was also observed for the levels of serum Na+ and Cl+. Incidences of abnormal serum K+ (p<0.05), Na+ (p<0.01) and Cl(-) (p<0.01) levels were different among thalamic hemorrhage, basal ganglia area hemorrhage and lobar hemorrhage patients. In the TH group, the mortality of patients with electrolyte disturbances (42.50%) was higher than that of patients with normal electrolyte levels (14.81%, p<0.05). The incidence of electrolyte imbalance is higher in patients with thalamic hemorrhage than in those with non-thalamic hemorrhage. The reason may be partly related to the location of the hemorrhage. Electrolyte disturbance may contribute to the higher mortality of patients with thalamic hemorrhage.

Low level of n-3 polyunsaturated fatty acids in erythrocytes is a risk factor for both acute ischemic and hemorrhagic stroke in Koreans.

Evidence suggesting an association between n-3 polyunsaturated fatty acids (PUFA) and stroke risk has been inconsistent, possibly because previous studies have not differentiated between different stroke types. The present study investigated the hypothesis that tissue levels of n-3 PUFA are positively associated with hemorrhagic stroke and negatively associated with ischemic stroke. We recruited 120 subjects for this case-control study, with 40 cases each of hemorrhagic stroke, ischemic stroke, and unaffected controls. Patients with a family history of hemorrhagic stroke had a significantly increased risk for hemorrhagic stroke. Omega-3 Index (20:5n3 + 22:6n3 in erythrocytes) and 22:6n3 were negatively (P < .01) associated with the risk of both hemorrhagic and ischemic stroke in multivariate analyses. Saturated fatty acids 16:0 and 18:0 were positively associated, whereas 18:2n6 and 18:3n6 were negatively (P < .05) associated with risk of ischemic stroke. Monounsaturated fatty acid, 18:1n9, increased (P = .03) the odds of hemorrhagic stroke. Omega-3 Index and docosahexaenoic acid were significantly lower in patients with both subtypes of hemorrhagic stroke, subarachnoid and intracerebral hemorrhage, but only in one subtype of ischemic stroke, small-artery occlusion. Saturated fatty acids 16:0 and 18:0 were significantly higher, but 20:4n6 was significantly lower, in patients with small-artery occlusion. Linoleic acid was significantly lower in patients with small-artery occlusion and large-artery atherosclerosis, whereas 18:1n9 was higher in both subgroups of hemorrhagic stroke. In conclusion, the results of our case-control study suggest that erythrocyte n-3 PUFA may protect against hemorrhagic stroke and ischemic stroke, particularly in the case of small-artery occlusion.

The significance of measurement of serum unbound bilirubin concentrations in high-risk infants.

BACKGROUND: In the management of neonatal hyperbilirubinemia, total bilirubin (TB) concentration is not specific enough to predict the brain damage caused by bilirubin toxicity. Unbound bilirubin (UB) easily passes the blood-brain barrier and causes neurotoxicity. We aimed to evaluate whether serum UB concentration would be a useful predictor of bilirubin encephalopathy in high-risk infants. METHODS: We measured the serum TB and UB concentrations of 388 newborn infants treated with phototherapy or exchange transfusion for their hyperbilirubinemia at Takatsuki General Hospital between January 2002 and October 2003. Peak serum TB and UB levels and UB/TB ratios were studied on each birthweight group: below 1500 g (very low birthweight), 1500 g-2499 g (low birthweight), above 2500 g (normal birthweight); and several clinical factors influencing hyperbilirubinemia were also studied. RESULTS: Peak serum TB and UB levels increased with increasing birthweight, while UB/TB ratios decreased. The very low birthweight group showed higher UB levels and UB/TB ratios despite lower TB levels in intraventricular hemorrhage or severe infection compared to those in the others. The low birthweight and normal birthweight groups showed higher TB and UB levels in cases of hemolytic disease of the newborn compared to non-hemolytic disease of the newborn cases. Eight of 44 cases showed high UB levels accompanied by abnormal auditory brainstem responses, one of whom subsequently developed ataxic cerebral palsy with hearing loss, whereas the other seven showed transient abnormalities of auditory brainstem responses by the treatment of exchange transfusion or phototherapy. CONCLUSION: The UB measurement was considered to be significant for the assessment of the risk of bilirubin neurotoxicity and the appropriate intervention for hyperbilirubinemia in high-risk infants.

[Effect and mechanism of rhubarb on fibrinolysis in secondary damaged central nerve system of rats with acute hemorrhagic stroke].

OBJECTIVE: To observe the effect of rhubarb in treating secondary damage of central nerve system (CNS) in rats with acute hemorrhagic stroke (AHS) and to explore the possible mechanism. METHODS: The rat's AHS model was established by autologous blood injection, the effect of rhubarb on the secondary damage of CNS, plasminogen (PLG) in brain and tissue type plasminogen activator (t-PA) were observed. RESULTS: (1) The nerve function deficit signs reappeared in about 70% model rats 4 - 6 days after modeling and reached the peak at day 6 - 8, scored as 1.63 +/- 0.72 on day 4 and as 2.32 +/- 1.12 on day 7; (2) Rhubarb could effectively improve the secondary nerve function damage, with the nerve deficit scores kept to 1.24 +/- 0.19 from day 4 on, and no sign of secondary CNS damage was shown. The nerve deficit score was 1.22 +/- 0.15 on day 7 in the rhubarb treated group, showing significant difference as compared with that in the model group (P<0.05); (3) The specific amplified products of t-PA mRNA on day 3 and that of PLG mRNA on day 7 in CNS of model group were significantly higher than those in the sham operated group and the rhubarb treated group. CONCLUSION: Rhubarb could effectively reduce the secondary CNS damage in rats with AHS, it might be related with the suppressive effect of rhubarb on tPA mRNA and PLG mRNA expression in CNS.

Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma.

BACKGROUND AND PURPOSE: Free radical hyperproduction may play an important role in brain hemorrhage and ischemia/reperfusion injury. The aims of this study were to assess whether antioxidant depletion occurs after intracranial hemorrhage (ICH) and head trauma (HT) and to evaluate the relation between the diameter of the brain lesion, the degree of the neurological impairment, and any observed antioxidant changes. METHODS: We measured plasma levels of vitamin C (ascorbic acid, AA), uric acid (UA), vitamin E (alpha-tocopherol), and ubiquinol-10 in 13 patients with ICH and 15 patients with HT on the day of the brain injury and subsequently every other day up to 1 week. Patients were compared with 40 healthy control subjects. RESULTS: ICH and HT patients had significantly lower plasma levels of AA compared with healthy subjects, in contrast to plasma levels of UA, alpha-tocopherol, and ubiquinol-10. AA levels were significantly inversely correlated with the severity of the neurological impairment as assessed by the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. AA levels were also significantly inversely correlated with the major diameter of the lesion. In addition, mean plasma AA levels were lower in jugular compared with peripheral blood samples obtained from 5 patients. CONCLUSIONS: These findings suggest that a condition of oxidative stress occurs in patients with head trauma and hemorrhagic stroke of recent onset. The consequences of early vitamin C depletion on brain injury as well as the effects of vitamin C supplementation in ICH and HT patients remain to be addressed in further studies.

Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants.

BACKGROUND AND PURPOSE: Blood pressure is an important risk factor for stroke, but the roles of serum total and HDL cholesterol, alpha-tocopherol, and beta-carotene are poorly established. We studied these factors in relation to stroke subtypes. METHODS: Male smokers (n=28 519) aged 50 to 69 years without a history of stroke participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a controlled trial to test the effect of alpha-tocopherol and beta-carotene supplementation on cancer. From 1985 to 1993, a total of 1057 men suffered from primary stroke: 85 had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. RESULTS: Systolic blood pressure > or = 160 mm Hg increased the risk of all stroke subtypes 2.5 to 4-fold. Serum total cholesterol was inversely associated with the risk of intracerebral hemorrhage, whereas the risk of cerebral infarction was raised at concentrations > or = 7.0 mmol/L. The risks of subarachnoid hemorrhage and cerebral infarction were lowered with serum HDL cholesterol levels > or = 0.85 mmol/L. Pretrial high serum alpha-tocopherol decreased the risk of intracerebral hemorrhage by half and cerebral infarction by one third, whereas high serum beta-carotene doubled the risk of subarachnoid hemorrhage and decreased that of cerebral infarction by one fifth. CONCLUSIONS: The risk factor profiles of stroke subtypes differ, reflecting different etiopathology. Because reducing atherosclerotic diseases, including ischemic stroke, by lowering high serum cholesterol is one of the main targets in public health care, further studies are needed to distinguish subjects with risk of hemorrhagic stroke. The performance of antioxidants needs confirmation from clinical trials.