A pilot study of hyperoxemia on neurological injury, inflammation and oxidative stress.

BACKGROUND: Normobaric hyperoxia is used to alleviate secondary brain ischaemia in patients with traumatic brain injury (TBI), but clinical evidence is limited and hyperoxia may cause adverse events. METHODS: An open label, randomised controlled pilot study comparing blood concentrations of reactive oxygen species (ROS), interleukin 6 (IL-6) and neuron-specific enolase (NSE) between two different fractions of inspired oxygen in severe TBI patients on mechanical ventilation. RESULTS: We enrolled 27 patients in the Fi O2 0.40 group and 38 in the Fi O2 0.70 group; 19 and 23 patients, respectively, completed biochemical analyses. In baseline, there were no differences between Fi O2 0.40 and Fi O2 0.70 groups, respectively, in ROS (64.8 nM [22.6-102.1] vs. 64.9 nM [26.8-96.3], P = 0.80), IL-6 (group 92.4 pg/ml [52.9-171.6] vs. 94.3 pg/ml [54.8-133.1], P = 0.52) or NSE (21.04 ug/l [14.0-30.7] vs. 17.8 ug/l [14.1-23.9], P = 0.35). ROS levels did not differ at Day 1 (24.2 nM [20.6-33.5] vs. 29.2 nM [22.7-69.2], P = 0.10) or at Day 2 (25.4 nM [21.7-37.4] vs. 47.3 nM [34.4-126.1], P = 0.95). IL-6 concentrations did not differ at Day 1 (112.7 pg/ml [65.9-168.9) vs. 83.9 pg/ml [51.8-144.3], P = 0.41) or at Day 3 (55.0 pg/ml [34.2-115.6] vs. 49.3 pg/ml [34.4-126.1], P = 0.95). NSE levels did not differ at Day 1 (15.9 ug/l [9.0-24.3] vs. 15.3 ug/l [12.2-26.3], P = 0.62). There were no differences between groups in the incidence of pulmonary complications. CONCLUSION: Higher fraction of inspired oxygen did not increase blood concentrations of markers of oxidative stress, inflammation or neurological injury or the incidence of pulmonary complications in severe TBI patients on mechanical ventilation.

Chronic subdural haematoma after endoscopic treatment of a supracellar arachnoid cyst.

Neuroendoscopy is considered a safe treatment option for intracranial arachnoid cysts. However a variety of complications has been reported after such interventions. Here we present the first case of a chronic subdural hematoma two months after the combined treatment of a supracellar arachnoid cyst with endoscopic third ventriculostomy and cyst fenestration.

Heterogeneity of cerebral perfusion 1 week after haemorrhage is an independent predictor of clinical outcome in patients with aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid haemorrhage (aSAH) can be associated with acute global and regional decrease in cerebral perfusion. Furthermore, cerebral vasospasm may lead to development of delayed ischaemic deficits. The aim of the study was to find out whether cerebral perfusion heterogeneity, an indicator of cerebral microvascular function and autoregulation, measured by single-photon emission tomography (SPET), is able to predict the long-term clinical outcome of aSAH. METHODS: The perfusion SPET data of 55 patients with aSAH were analysed by dividing the brain into 384 regions of interest. Spatial perfusion heterogeneity was assessed by calculating the relative dispersions (RD, coefficient of variation) from the SPETs performed before treatment (RD1) and 1 week after early surgical or endovascular treatment of the ruptured aneurysm (RD2). Both RDs were compared to the clinical outcome (Glasgow Outcome Scale, GOS), neuropsychological test scores and late ischaemic findings in MRI 1 year after SAH. RESULTS: High RD2 (OR 1.96; 95% CI 1.18-3.26; p = 0.009) and poor clinical condition (Hunt and Hess grade) on admission (OR 6.60; 95% CI 1.78-24.52; p = 0.005) proved to be independent predictors of poor or moderate clinical outcome (GOS 1-4). RD2 was higher in patients with ischaemic findings in 12-month MRI than in those without ischaemic findings (p = 0.008). RD2 also correlated with neuropsychological outcome 1 year after aSAH. CONCLUSIONS: Perfusion heterogeneity is an independent predictor of the clinical outcome of aSAH and may thus be a valuable measure in the assessment of the disease.

Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa.

BACKGROUND: The tumor-promoting effect of ethanol on cancer of the upper respiratory-digestive tract is not well understood. Although ethanol itself is not carcinogenic, the first product of ethanol metabolism-acetaldehyde is. Acetaldehyde can be produced from ethanol by oral bacteria, and high concentrations have been observed in human saliva after ethanol consumption. The purpose of this study was to investigate whether acetaldehyde administered orally to rats induces altered differentiation and proliferation in the animals' upper gastrointestinal tracts. METHODS: Twenty Wistar rats were given either water containing acetaldehyde at a concentration of 120 mM or tap water to drink for 8 months. Tissue specimens were then taken from the tongue, epiglottis, and forestomach of each animal and immunohistochemically stained for markers of cellular proliferation (Ki67 nuclear antigen) or differentiation (cytokeratins 1, 4, 10, 11, 14, and 19). The mean epithelial thickness of each sample was measured via light microscopy, using an eyepiece containing grid lines. Differences between the control and acetaldehyde-treated groups were analyzed by use of the unpaired Student's t test. All reported P values are two-sided. RESULTS: Although no tumors were observed, staining for cytokeratins 4 and 14 revealed an enlarged basal layer of squamous epithelia in the rats receiving acetaldehyde. In these animals, cell proliferation was significantly greater than that observed in the control animals for samples from the tongue (P<.0001), epiglottis (P<.001), and forestomach (P<.0001). In addition, the epithelia from acetaldehyde-treated rats were significantly thicker than in epithelia from control animals (P<.05 for all three sites). CONCLUSIONS: Acetaldehyde, administered orally to rats, can cause hyperplastic and hyperproliferative changes in epithelia of the upper gastrointestinal tract. This finding suggests that microbially produced acetaldehyde in saliva may explain the tumor-promoting effect of ethanol on these epithelia.

First-line eradication therapy for Helicobacter pylori in primary health care based on antibiotic resistance: results of three eradication regimens.

AIM: To determine the efficacy of three Helicobacter pylori eradication regimens and factors affecting the eradication results in Finland. METHODS: A total of 342 H. pylori-positive adult patients from primary health care referred for gastroscopy at 23 centres in different parts of Finland were randomized to receive either (i) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and metronidazole 400 mg t.d.s. (LAM), (ii) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC), or (iii) ranitidine bismuth citrate 400 mg b.d., metronidazole 400 mg t.d.s. and tetracycline 500 mg q.d.s. (RMT). A (13)C-urea breath test was performed 4 weeks after therapy. RESULTS: The eradication result could be assessed in 329 cases. Intention-to-treat cure rates of LAM, LAC, and RMT were 78, 91 and 81%. The difference was significant between LAM and LAC (P = 0.01) and between LAC and RMT (P = 0.04). The eradication rates in cases with metronidazole-susceptible vs. -resistant isolates were for LAM 93% vs. 53% (P = 0.00001), for LAC 95% vs. 84%, and for RMT 91% vs. 67% (P = 0.002). Previous antibiotic use, smoking, and coffee drinking reduced the efficacy of therapy. CONCLUSIONS: In unselected patients in primary health care, LAC was the most effective first-line eradication.

Outcomes of early endovascular versus surgical treatment of ruptured cerebral aneurysms. A prospective randomized study.

BACKGROUND AND PURPOSE: This prospective study was conducted to compare the outcomes of surgical clipping and endovascular treatment in acute (<72 hours) aneurysmal subarachnoid hemorrhage (SAH). METHODS: One hundred nine consecutive patients were randomly assigned to either surgical (n=57) or endovascular (n=52) treatment. Clinical and neuropsychological outcome was assessed at 3 and 12 months after treatment; MRI of the brain was performed at 12 months. Follow-up angiography was scheduled after clipping and 3 and 12 months after endovascular treatment. RESULTS: One year postoperatively, 43/41 (surgical/endovascular) patients had good or moderate recovery, 5/4 had severe disability or were in a vegetative state, and 9/7 had died (NS) according to intention to treat. Patients with good clinical recovery did not differ in their neuropsychological test scores. Symptomatic vasospasm (OR 2.47; 95% CI 1.45 to 4.19; P<0.001), poorer Hunt and Hess grade (OR 2.50; 95% CI 1.31 to 4.75; P=0.005), need for permanent shunt (OR 8.90; 95% CI 1.80 to 44.15; P=0.008), and larger size of the aneurysm (OR 1. 22; 95% CI 1.02 to 1.45; P=0.032) independently predicted worsened clinical outcome regardless of the treatment modality. In MRI, superficial brain retraction deficits (P<0.001) and ischemic lesions in the territory of the ruptured aneurysm (P=0.025) were more frequent in the surgical group. Kaplan-Meier analysis (mean+/-SD follow-up 39+/-18 months) revealed equal survival in both treatment groups. No late rebleedings have occurred. CONCLUSIONS: One-year clinical and neuropsychological outcomes seem comparable after early surgical and endovascular treatment of ruptured intracranial aneurysms. The long-term efficacy of endovascular treatment in preventing rebleeding remains open.

Evidence for excess long-term mortality after treated subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the long-term mortality rate of patients with aneurysmal subarachnoid hemorrhage (SAH) compared with that of the general population. METHODS: Aneurysmal SAH patients who were treated for ruptured aneurysm from 1977 through 1998 in a tertiary referral center (n=1537) were followed up for a median of 7.5 years. Dates and causes of death were determined. Standardized mortality ratios (observed/expected deaths) according to age, sex, and Glasgow Outcome Scale at 12 months after surgery were calculated. RESULTS: The mortality rate among patients with good recovery at 12 months was twice that of the general population. The excess mortality appeared to be most evident in younger age groups. Cerebrovascular and cardiovascular diseases were the principal causes of premature death. The result was similar among patients without preexisting cardiovascular diseases at the time of SAH. CONCLUSIONS: Aneurysmal SAH patients have an excess mortality rate even after successful treatment of ruptured aneurysms. Therefore, aneurysmal SAH should be viewed more as one aspect of a chronic general vascular disease, and more attention should be given to treatment of risk factors and long-term follow-up of these patients.

Hepatic aldehyde and alcohol dehydrogenases in alcohol-preferring and alcohol-avoiding rat lines.

The alcohol-avoiding ANA (Alko, Non-Alcohol) and alcohol-preferring AA (Alko, Alcohol) rat lines are known to differ in their acetaldehyde metabolism and were originally found to differ in hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities in the 1970s. At the beginning of the 1980s, these rat lines were revitalized and some previously found line differences were lost. Thus, the purpose of this study was to determine whether these enzymatic line differences still exist and, if so, to study them further at the isoenzyme level. ADH and ALDH activities were measured from liver homogenates and different subcellular fractions of the rats. The ANA rats were found to have lower hepatic ALDH and higher ADH activities than AA rats, in accordance with the previous study. The line difference in ALDH activity was observed in all fractions, but was more apparent with millimolar than micromolar substrate concentrations and generally more pronounced in females than in males. The line difference in the microsomal ALDH activity was found to be quantitative, and it seemed to concern both microsomal ALDH isoenzymes. A qualitative line difference concerning mitochondrial high Km ALDH isoenzyme was found, and three different cytosolic ALDH isoenzyme patterns were observed, the frequencies of which were found to be different in the two lines. In conclusion, the results of the present study support the assumption that line differences in hepatic ADH and ALDH activities may be relevant to the acetaldehyde accumulation and the particularly low ethanol consumption of the ANA rats.

No significant expression of CYP2E1 in rat liver stellate cells.

The putative role of the ethanol-inducible cytochrome P450(CYP)2E1 in stimulating collagen synthesis by rat liver stellate cells was studied. Analysis of carefully isolated stellate cells revealed that their content of immunoreactive CYP2E1 protein and of CYP2E1 mRNA, as determined by reverse transcription, polymerase chain reaction (RT-PCR), was very low, i.e. only 0-4% of that in hepatocytes. We conclude that it is improbable that such low expression of CYP2E1 in stellate cells would have functional importance.

Primary Helicobacter pylori resistance to metronidazole and clarithromycin in the Finnish population.

AIM: To systematically determine Helicobacter pylori primary antimicrobial resistance in Finland and the associated demographic and clinical features. METHODS: A total of 342 adult patients referred for gastroscopy at 23 centres in different parts of Finland and positive for the rapid biopsy urease test were recruited. Clinical and demographic data were collected via a structured questionnaire. Patients with positive H. pylori culture and successful antibiotic sensitivity determination by the E-test method (n = 292) were included in the present analysis. RESULTS: The study population consisted of 134 men and 158 women, mean age 56 years (95% CI, 55-58 years). Resistance to metronidazole was 38% (110 of 292) and to clarithromycin 2% (seven of 292). Resistance to metronidazole was higher in women than in men (48% vs. 25%, P < 0.001). Previous use of antibiotics for gynaecological infections predicted metronidazole resistance (P = 0.01), and previous use of antibiotics for respiratory (P = 0.02) and dental infections (P = 0.02) the clarithromycin resistance. We observed no major geographical variations in metronidazole resistance. CONCLUSIONS: The primary metronidazole resistance of H. pylori was 38% and was common in women previously treated for gynaecological infections. Primary clarithromycin resistance was uncommon (2%) and may associate with previous dental and respiratory infections.

Gastric tonometry after subarachnoid hemorrhage.

OBJECTIVE: To evaluate splanchnic tissue perfusion, assessed by gastric tonometry, in patients with subarachnoid hemorrhage (SAH) and to study the effect of treatment, either surgical or endovascular, and the severity of initial SAH on splanchnic tissue perfusion. DESIGN: Prospective observational substudy, part of a randomised controlled trial of early treatment of ruptured intracranial aneurysms. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: A consecutive sample of 26 patients [13 surgical (7/6 Hunt & Hess Grade I-II/H & H Gr IV-V) and 13 endovascular (3/10 H & H Gr I-II/H & H Gr IV-V)] out of 56 SAH patients randomly assigned to either endovascular or surgical treatment during the substudy period between 1 May 1995 and 31 August 1996. All patients were treated within 72 h after SAH. MEASUREMENTS AND RESULTS: After treatment of a ruptured aneurysm, hemodynamics and gastric intramucosal pCO2 were measured during the first 4 h and between 6 h and 12 h after aneurysm treatment. In the whole sample, neither the gastric intramucosal-arterial pCO2 difference (pCO2 gap) (1.5+/-1.9 kPa and 1.7+/-1.2 kPa, NS) nor gastric intramucosal pH (7.28+/-0.12 and 7.29+/-0.08, NS) changed during the study. There were no differences in pCO2 gap or gastric intramucosal pH between treatment groups or Hunt & Hess grade groups during the study period. CONCLUSIONS: Splanchnic tissue perfusion may be insufficient even though there is no systemic hemodynamic disturbance in patients after SAH. Neither the therapeutic treatment nor pre-treatment Hunt & Hess grade is associated with a specific pattern of pCO2 gap.

Dissecting aneurysms of all four cervicocranial arteries in fibromuscular dysplasia: treatment with self-expanding endovascular stents, coil embolization, and surgical ligation.

A patient with cervicocranial fibromuscular dysplasia (FMD) presented with subarachnoid hemorrhage. A ruptured dissecting distal vertebral artery aneurysm required clip ligation of the parent artery; a contralateral dissecting proximal vertebral aneurysm was occluded with detachable coils. Progressive dissecting, extracranial aneurysms of the internal carotid artery were treated with self-expanding stents. Subsequent angiography and intravascular sonography revealed patent stents, a smooth luminal surface, and total occlusion of the aneurysm. Clinical outcome was excellent.

Acetaldehyde induces histamine release from purified rat peritoneal mast cells.

Acetaldehyde is a widely distributed compound in the human environment and it is also formed in the human body from various endogenous and exogenous sources, exogenous ethanol being the most important one. Many alcohol-associated hypersensitivity reactions, e.g. Oriental flushing reaction, appear to be attributable to acetaldehyde rather than to ethanol itself. The pathogenetic mechanism behind such hypersensitivity reactions has been suggested to be histamine release from mast cells or blood basophils. However, the direct effects of acetaldehyde on mast cells, the main source of histamine in a mammalian body, have not been studied. The aim of the present study was, thus, to evaluate whether physiological concentrations of acetaldehyde could release histamine from purified rat peritoneal mast cells. The effects of ethanol were studied similarly. The results show that acetaldehyde, already at a concentration of 50 microM, significantly increases the release of histamine from mast cells. Ethanol has a similar effect but only at molar concentrations. These results indicate that acetaldehyde may contribute to the development of various hypersensitivity reactions by directly increasing histamine release from mast cells.

Inhibition of bacteriocolonic pathway for ethanol oxidation by ciprofloxacin in rats.

Many colonic bacteria possess marked alcohol dehydrogenase (ADH) activity and are capable of oxidizing ethanol to acetaldehyde both in vitro and in vivo. We have recently shown that part of ingested ethanol is metabolized to acetaldehyde in the colon during normal alcohol metabolism. To assess the contribution of this bacteriocolonic pathway for ethanol oxidation to total ethanol metabolism, the elimination rate of ethanol, faecal aerobic flora and faecal ADH activity were determined in rats before and after the treatment with ciprofloxacin (200 mg/kg/day) for four days. Ciprofloxacin treatment decreased ethanol elimination rate from 310+/-9 to 282+/-13 mg/kg/h (mean+/-SE; p<0.02), markedly reduced faecal aerobic flora, and also lowered faecal ADH activity from 63+/-17 to 17+/-7 nmol/min/mg faeces (p<0.05). Neither hepatic ADH nor microsomal ethanol oxidizing system activities were affected by the ciprofloxacin treatment. On the contrary, an acute intraperitoneal dose of ciprofloxacin had no effect on the rate of ethanol elimination. These results support the significant role of the bacteriocolonic pathway in total ethanol elimination, and open a new, microbiological, perspective for studies on ethanol metabolism and pathogenesis of alcohol related organ damages.

Voluntary alcohol drinking and acetaldehyde metabolism in F2 hybrid crosses of AA and ANA rat lines.

Alcohol-preferring AA and alcohol-avoiding ANA rat lines differ in their acetaldehyde metabolism and this has been suggested to be one reason for their different ethanol drinking behavior. To study whether acetaldehyde accumulation is indeed associated with alcohol drinking behavior and to evaluate which enzymatic differences previously observed in these rat lines are of importance in this regard, we produced an F2 generation from them. ADH and ALDH activities, and ALDH patterns were then assessed from these hybrids and correlated with their voluntary ethanol drinking and blood acetaldehyde concentrations measured during ethanol metabolism. A significant negative correlation between voluntary ethanol intake and blood acetaldehyde concentration was observed in F2 females drinking less than 17% of the total fluid as ethanol. In F2 males, hepatic microsomal high Km ALDH activities correlated negatively with blood acetaldehyde concentrations, indicating that low activity of this isoenzyme in ANA rats could be at least in part responsible for the accumulation of acetaldehyde in their blood. Finally, F2 rats that possessed the cytosolic ALDH isoenzyme pattern most frequently found in the AA rat line drank significantly more ethanol than the animals with typical ANA pattern, suggesting that this polymorphism might also be relevant in the regulation of voluntary ethanol drinking although it is probably not associated with acetaldehyde metabolism.

Mitochondrial aldehyde dehydrogenase (ALDH2) polymorphism in AA and ANA rats: lack of genotype and phenotype line differences.

Polymorphism of the gene coding for mitochondrial ALDH2 in humans is known to be associated with differences in alcohol drinking behavior. Recently, two different alleles of the ALDH2 gene, ALDH2R and ALDH2Q, have been found in rats also and a possible relationship between the frequencies of the two alleles and drinking behavior has been proposed. In this study, we examined whether this polymorphism of ALDH2 was the underlying cause for the previously reported acetaldehyde accumulation in the alcohol-avoiding ANA rat line and, thus, could be one of the factors explaining the differences in alcohol drinking behavior between the ANA and the alcohol-preferring AA rat lines. The experimental animals were genotyped and their mitochondrial ALDH activities and blood acetaldehyde concentrations after ethanol injection were measured. The two lines did not differ in their frequencies of ALDH2R and ALDH2Q alleles. Thus, the polymorphism in the ALDH2 gene does not explain the acetaldehyde accumulation in ANA rats and it does not seem to be associated with differences in the alcohol drinking behavior in these rat lines.

Regional cerebral blood flow in aneurysmal subarachnoid hemorrhage: single photon emission tomography evaluation of endovascular versus surgical treatment.

Since February 1995, 59 patients with recent aneurysmal SAH have been randomised in our study program, either for surgical aneurysm clipping or for endovascular treatment with Guglielmi detachable coils, to compare the safety and long-term efficacy of these methods. Patients with expansive haematomas or those in a moribund state were excluded, as well as those with aneurysms unsuitable for treatment with both methods. We used single photon emission tomography (SPET) to compare regional cerebral blood flow (rCBF) in surgically and in endovascularly-treated patients. In a sub-study presented in this paper, we analysed the data of patients in Grade I-III (Hunt & Hess) with anterior circulation aneurysms (n = 21). When changes between the pre- and post-treatment rCBF were compared, the surgically treated group showed a tendency towards improved rCBF (change in different vascular territories varied from +4% to +12%) while the endovascularly-treated group showed no consistent change (changes varied from -3% to +6%). There was, however, no significant statistical difference between the changes in the groups. Our results are preliminary, but they suggest that endovascular treatment of anterior circulation aneurysms may not have any advantage over surgical treatment in respect to disturbances in the rCBF.

Atrophic enlargement of CSF volume after subarachnoid hemorrhage: correlation with neuropsychological outcome.

BACKGROUND AND PURPOSE: Ventricular dilation and sulcal enlargement are common sequelae after aSAH. Our aim was to quantify the late ventricular dilation and volumes of the CSF spaces after aSAH and to determine if they correlate with neurologic and cognitive impairments frequently detected in these patients. MATERIALS AND METHODS: 3D T1-weighted images needed for volumetry were available in 76 patients 1 year after aSAH, along with 75 neuropsychological assessments. Volumes of CSF segments and ICV were quantified by SPM in 76 patients and 30 control subjects to determine CSF/ICV ratios. The mCMI was calculated to roughly evaluate the ventricular dilation. The contributing factors for enlarged ventricles and CSF volumes were reviewed from radiologic, clinical, and neuropsychological perspectives. RESULTS: The mCMI was higher in patients with aSAH (0.23 +/- 0.06) compared with control subjects (0.20 +/- 0.04; P = .020). In line with these planimetric measurements, the SPM-based CSF/ICV ratios were higher in patients with aSAH (35.58 +/- 7.0) than in control subjects (30.36 +/- 6.25; P = .001). Preoperative hydrocephalus, higher HH and Fisher grades, and focal parenchymal lesions on brain MR imaging, but not the treatment technique, were associated with ventricular enlargement. The clinical outcome and presence of neuropsychological deficits correlated significantly with CSF enlargement. CONCLUSIONS: Ventricular and sulcal enlargement, together with reduced GM volumes, after aSAH may indicate general atrophy rather than hydrocephalus. Enlarged CSF spaces correlate with cognitive deficits after aSAH. A simple measure, mCMI proved to be a feasible tool to assess the diffuse atrophic brain damage after aSAH.