The effects of surgical levels of sevoflurane and propofol anaesthesia on heart rate variability.

BACKGROUND AND OBJECTIVE: We compared heart rate dynamics during surgical levels of propofol and sevoflurane anaesthesia in a highly standardized setting. METHODS: We recorded electrocardiography from 24 anaesthetized healthy male subjects. In the first parallel part of the study, the subjects were anaesthetized either with sevoflurane (n = 8) or propofol (n = 8) targeted to match 1.0, 1.5 and 2.0 minimal alveolar concentration/effective concentration 50. In the second part, a separate group (n = 8) underwent four different anaesthetic regimens targeted to bispectral index 40: sevoflurane alone, sevoflurane + 70% nitrous oxide, propofol alone and propofol + 70% nitrous oxide. The electrocardiography data were analysed using conventional time and frequency domain methods, and the approximate entropy method, which estimates the complexity of the data. RESULTS: The induction of anaesthesia was followed by an overall reduction of heart rate variability, evident in all frequency bands in the spectral analysis, and also in the time domain measures. Approximate entropy decreased at 1 effective concentration 50 with propofol and at 2 minimal alveolar concentration with sevoflurane. In the second part of the study, the time domain variables and high-frequency spectral power were all similarly reduced by sevoflurane and propofol anaesthesia, with and without nitrous oxide. Approximate entropy tended to decrease during propofol anaesthesia. CONCLUSIONS: Hypnotic levels of sevoflurane and propofol anaesthesia suppressed the heart rate variability measured using conventional analysis methods. Deeper surgical levels of anaesthesia also reduce the complexity of heart rate variability.

Correlation of EEG spectral entropy with regional cerebral blood flow during sevoflurane and propofol anaesthesia.

ENTROPY index monitoring, based on spectral entropy of the electroencephalogram, is a promising new method to measure the depth of anaesthesia. We examined the association between spectral entropy and regional cerebral blood flow in healthy subjects anaesthetised with 2%, 3% and 4% end-expiratory concentrations of sevoflurane and 7.6, 12.5 and 19.0 microg.ml(-1) plasma drug concentrations of propofol. Spectral entropy from the frequency band 0.8-32 Hz was calculated and cerebral blood flow assessed using positron emission tomography and [(15)O]-labelled water at baseline and at each anaesthesia level. Both drugs induced significant reductions in spectral entropy and cortical and global cerebral blood flow. Midfrontal-central spectral entropy was associated with individual frontal and whole brain blood flow values across all conditions, suggesting that this novel measure of anaesthetic depth can depict global changes in neuronal activity induced by the drugs. The cortical areas of the most significant associations were remarkably similar for both drugs.

APOE-epsilon4 predicts dementia but not other psychiatric disorders after traumatic brain injury.

The authors studied the association between APOE-epsilon4 genotype and axis I and II psychiatric disorders an average of 30 years after traumatic brain injury. Sixty patients were dichotomized into subjects with and without APOE-epsilon4 allele. Dementia and subclinical dementia were significantly more common with the presence of APOE-epsilon4. The occurrence of other psychiatric disorders did not differ between patients with and without APOE-epsilon4 allele.

Osteoblastic activity and neoangiogenesis in distracted bone of irradiated rabbit mandible with or without hyperbaric oxygen treatment.

The effects of irradiation and hyperbaric oxygenation (HBO) on osteoblastic activity and angiogenesis in rabbit mandibular distraction (DO) were evaluated. Three groups were studied. The mandible of two groups received a 22.4Gy dose of irradiation. One of the irradiated groups was also given HBO, 18 times at 2.5ATA for 90min per day preoperatively. The third group was given neither radiotherapy nor HBO. Mandibular lengthening was performed unilaterally. Osteoblastic activity was assessed ex vivo by [18F]fluoride digital autoradiography. Neovascularization of distracted bone was evaluated histomorphometrically. Osteoblastic activity was higher in non-irradiated than irradiated animals. In non-irradiated rabbits, the activity was evenly distributed over the distraction area. In the irradiated groups, the activity was greater in the central third of the lengthened bone than the peripheral thirds. HBO changed the osteogenic pattern towards that of non-irradiated bone. In the non-irradiated group the number of blood vessels was 1.7-fold as compared to irradiated rabbits without HBO (P=0.0012), and the fewest number of vessels was found in irradiated rabbits without HBO. Blood vessels were more numerous in the central region than in peripheral regions in non-irradiated animals and irradiated animals with HBO, but not in irradiated rabbits without HBO therapy. It is concluded that radiotherapy disturbs distraction bone formation and neovascularization related to DO. HBO increases osteoblastic activity, but not to the level of non-irradiated bone. Angiogenic response is markedly increased by HBO.

Sevoflurane is epileptogenic in healthy subjects at surgical levels of anesthesia.

OBJECTIVE: To investigate EEG effects of three escalating concentrations of sevoflurane and propofol in single-agent anesthesia on healthy subjects. METHODS: Four-channel EEG was continuously recorded at 1, 1.5, and 2 minimum alveolar concentration (MAC)/effective plasma concentration 50 (EC50) levels of either sevoflurane or propofol anesthesia in 16 men, 8 subjects in each group. Each concentration level lasted for 30 minutes. EEG was first visually analyzed. In quantitative EEG analysis, the 95% spectral edge frequency (SEF95) and peak frequency (PF) were determined after fast Fourier transformation. RESULTS: Epileptiform discharges occurred in all eight subjects at 1.5 and 2 MAC levels of sevoflurane anesthesia. Three subjects showed electrographic seizures at 2 MAC level, in one case accompanied with clinical seizures despite muscle relaxation. Propofol did not produce remarkable epileptiform EEG phenomena at any level of anesthesia. Suppression and slowing of EEG activity were evident for both drugs with increasing concentration. Owing to the high incidence of epileptiform events in the sevoflurane group at 1.5 and 2 MAC, the SEF95 and PF values were higher (p < 0.001) compared with propofol. Within the sevoflurane group, these values were higher at the 2 than at the 1.5 MAC level (p values ranged between <0.001 and 0.019). CONCLUSIONS: Sevoflurane consistently produces epileptiform discharges and is dose dependently epileptogenic at surgical levels of anesthesia.

Debulking or biopsy of malignant glioma in elderly people - a randomised study.

BACKGROUND: Patients with radiologically (MRI and/or CT images) suspected malignant glioma is referred to radiotherapy after craniotomy and resection of the tumour or after diagnostic biopsy. Patients with poor preoperative status and elderly patients are diagnosed more often by biopsy and treated by radiotherapy rather than by craniotomy and tumour resection. However, based on previous retrospective studies it is not possible to conclude which procedure is better for elderly patients. Thus a prospective study comparing these two procedures with elderly patients was planned. METHODS: 30 patients older than 65 years with radiologically (CT and/or MRI) obvious malignant glioma were randomised into two groups: I) stereotactic biopsy and II) open craniotomy and resection of the tumour. Nineteen patients were diagnosed to have grade IV glioma and four patients grade III glioma. Seven out of 30 (23%) were followed in the "intention-to-treat" group with diagnosis of stroke (n=3), metastasis (n=2), malignant lymphoma (n=1) and one with out histological diagnosis. Patients with histologically verified malignant glioma (grade III-IV) were diagnosed by stereotactic biopsy (n=13) or by open craniotomy and resection (n=10) and all the patients were referred to radiotherapy. Survival and time of deterioration were followed. FINDINGS: The overall median survival time was 146 (95% CI 89-175) days after the procedure. The estimated median survival time was 171 (95% CI 146-278) days after the craniotomy versus 85 (95% CI 55-157) days after the biopsy (p=0.035). The estimated survival time was 2.757 times longer (95% CI 1.004-7.568, p=0.049) after craniotomy. However, there was no significant difference in the time of deterioration between these two treatments (p=0.057). Amount of radiotherapy given had a significant effect on survival (p=0.001). INTERPRETATION: Longer survival time is achieved after open craniotomy and resection of tumour. However, overall benefit of open surgery to patient seems to be modest, while time of deterioration did not differ between two treatment groups. Our results support previous studies on the benefit of radiotherapy in the treatment of malignant glioma.

Effect of mandibular distraction osteogenesis on temporomandibular joint after previous irradiation and hyperbaric oxygenation.

The purpose was to evaluate the effect of mandibular distraction osteogenesis (DO) on condylar cartilage after radiotherapy and hyperbaric oxygenation (HBO). Unilateral DO was performed on low- and high-dose irradiated rabbits with or without accompanying HBO, and non-irradiated animals. High-dose irradiated animals were given irradiation in the temporomandibular joint (TMJ) equivalent to 50 Gy in 25 fractions. Low-dose irradiated rabbits received scattered irradiation of 10% of that of high-dose irradiated animals. After radiotherapy, some of the animals were given HBO 18 times at 2.5 ATA for 90 min/day. One month after completion of radiotherapy, distraction osteotomy with distractor placement was performed. After a latency period, distraction was started at the rate of 1 mm/day, continued for 2 weeks, and the regenerate was allowed to consolidate for 1 month. Condyles of non-operated rabbits served as controls. Histological changes were more evident on the distracted than on the non-distracted side. In distracted, non-irradiated animals, condylar cartilage changes were minor and probably clinically insignificant. In irradiated rabbits, condylar cartilage changes on the lengthened side were severe, and often cartilage was either totally or partially sealed off by bone. Condylar heads were morphologically deformed. Even low doses of irradiation resulted in notable changes on the operated side, and HBO did not prevent disadvantageous effects.

Epirubicin/docetaxel regimen in progressive breast cancer-a phase II study.

The purpose of this investigation was to evaluate the efficacy and toxicity of 6 months' treatment with the combination of epirubicin and docetaxel in metastatic breast cancer. Thirty-eight women (mean age 51 years, range 35-72) with metastatic breast cancer were treated with a regimen of epirubicin 75 mg/m and docetaxel 75 mg/m every 3 weeks, given 4 times if progression was seen upon evaluation after 4 courses or 8 times in responding/stable patients. The patients received 285 cycles of combination treatment and two treatments with docetaxel or epirubicin alone. When neutropenia with fever was observed, further cycles were given with dose reduction. The median cumulative docetaxel dose was 462 mg/m (range 199-600) and that of epirubicin 476 mg/m (range 199-740). The overall response rate was 54% (95% CI 37-71), with a median duration of response of 14.8 months (95% CI 8.8-27.8). Median time to progression was 12 months, median survival 26 months. Neutropenia below 0.5 x 10 /l occurred following 113 (39%) of the total of 285 cycles given; 21 patients (55%) were hospitalized for febrile neutropenia. We conclude that dose tailoring is required in treatment with an epirubicin and docetaxel regimen to avoid grade 3/4 adverse effects in a significant number of patients treated for metastatic breast cancer.

Childhood cancer patients at school.

The aim of this study was to assess the school-related problems of childhood cancer patients. A cross-sectional questionnaire study for school-aged children with extracranial malignancies, in the area of Turku University Hospital serving around 1000000 people. Siblings, healthy pupils and teachers were studied as controls. 43 patients responded. None of the patients or controls was placed in special educational programmes. However, 30.8% of the patients, 15.7% of the controls and 3.7% of the siblings had required extra tutoring. The patients' results differed statistically from both the siblings' (P=0.022) and the controls' (P=0.041) results. The school marks in mathematics (P=0.05) and in foreign languages (P=0.06) tended to be worse for the patients than for the healthy controls. Bullying was reported by 31.7% of the patients, 10.9% of controls (P=0.0012) and 8.3% of the siblings (P=0.056). The biggest problem faced by the cancer patients was bullying-the patients reported approximately 3 times as much bullying as the healthy children did. It seems that there are still several aspects which need to be reconsidered when these children return to school or start their school-life as survivors of childhood cancer. Some proposals are presented.

Unbiased morphological measurements show no neuronal loss in the substantia nigra in Alzheimer's disease.

This is the first study to use the unbiased stereological method, the disector, to estimate the total number of pigmented neurons in the pars compacta of the substantia nigra (SNpc) in Alzheimer's disease (AD) patients as compared to healthy controls. The right half of the SNpc of 11 AD patients and 24 controls was studied. We also used single sections to determine the neuronal number and area in different subregions of the SNpc. The results showed that there was no significant difference in the total number of pigmented neurons in the SNpc (154,415+/-13,593 for AD and 160,163+/-8027 for controls) or in the volume of the SNpc between the patients with AD and controls. Studies on single sections revealed that even subregionally there was no significant difference in the neuronal number or area in the SNpc between AD patients and controls.

Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect.

1. In this study, the analysis of spontaneous baroreflex sensitivity (BRS) was applied to the dynamic assessment of cardiac anticholinergic drug effect in healthy male volunteers. 2. The anticholinergic effects of single intravenous (i.v.) injections of atropine (10 microg kg(-1)), glycopyrrolate (5 microg kg(-1)) and scopolamine (5 microg kg(-1)), as well as a 2-h infusion of glycopyrrolate (5 microg kg(-1) h(-1)) were investigated. Baroreflex sensitivity, a validated measure of cardiac parasympathetic reflex regulation, was repeatedly measured from 5-min recordings of electrocardiogram (ECG) and continuous blood pressure by using the sequence technique, a method based on detection of spontaneous fluctuations in blood pressure and heart rate. 3. Single injections of atropine, glycopyrrolate and scopolamine decreased the mean BRS by 71 +/- 32, 68 +/- 23 and 27 +/- 45%, respectively, whereas the slow glycopyrrolate infusion gradually decreased BRS (up to 83 +/- 11% reduction) and increased both systolic (SAP) and diastolic arterial pressures (DAP) (on an average, by 9 mmHg). 4. During the withdrawal of the parasympathetic blockade (indicated by increasing BRS), the proportion of baroreflex sequences in the recordings increased transiently from 10 up to 20-25%, probably reflecting the restoration of the baroreflex integrity and the baroreflex-induced attempt to counteract the blood pressure increase. 5. The sequence method to study BRS seems to be feasible in the assessment of cardiac anticholinergic drug effects, and it also provides good time resolution for the dynamic measurements.

The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.

Expression of fibroblast growth factor (FGF)-8 isoforms and FGF receptors in human ovarian tumors.

FGF-8 is a mitogenic growth factor, which is widely expressed during embryonic development but only at a very low level in adult tissues. Alternative splicing of the human FGF-8 gene potentially allows coding for 4 protein isoforms (a, b, e, f), which differ in their transforming capacity. The FGF-8 isoforms preferentially activate the receptors FGFR1IIIc, FGFR2IIIc, FGFR3IIIc and FGFR4. FGF-8 is over-expressed in human breast and prostate cancers. Expression has also been found in RT-PCR studies of human ovarian and testicular cancers. The present study was undertaken to examine which FGF-8 isoforms are expressed in ovarian cancer and whether FGF-8 receptors are also expressed. Specimens from 5 normal human ovaries and 51 ovarian tumors (1 benign tumor, 8 borderline malignancies, 42 malignant tumors of different histopathological types) were studied by RT-PCR and immunohistochemistry. FGF-8 isoform b was expressed in all ovarian tumors and in all 7 ovarian-cancer cell lines studied. Isoform a was co-expressed in 9 malignant ovarian tumors. FGF-8 mRNA was not detected by RT-PCR of 3 normal ovary samples. Immunohistochemical staining localized FGF-8 protein to cancer cells. In general, the increased intensity of FGF-8 staining was associated with loss of differentiation within the tumors (Bowker's test, p = 0.37). FGF-8 staining of surface epithelium observed on 2 normal ovaries was very faint. RT-PCR showed that FGFR1IIIc, FGFR2IIIc and FGFR4 were the FGF-8 receptors expressed in normal ovaries and in ovarian tumors. FGF-8 receptor immunoreactivity was preferentially found in normal ovary surface epithelium and tumor cells but also in some stromal cells. Collectively, our results show that ovarian cancers of a wide variety of histological types expressing receptors for FGF-8 have acquired the capacity of expressing FGF-8. This suggests that FGF-8 has an important role in ovarian tumorigenesis.

Reproducibility and effect of levodopa on dopamine transporter function measurements: a [18F]CFT PET study.

The objective of this article was to study the reproducibility and effect of levodopa on dopamine transporter function measurements using 2beta-carbomethoxy-3beta-(4-[18F]fluorophenyl)tropane ([18F]CFT) positron emission tomography (PET). Seven de novo patients with Parkinson's disease (PD) were studied twice, before and after three months of levodopa medication. Eight healthy volunteer subjects participated in the reproducibility study. The [18F]CFT PET scan was done twice with an interval of approximately 2.5 months. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. The [18F]CFT uptake was calculated as the region-cerebellum:cerebellum ratio at 180 to 210 minutes. Three-month levodopa treatment in PD patients had no significant effect on [18F]CFT uptake in any striatal subregion between the two PET scans. In PD patients, the percent change from baseline was 4.1% in the anterior putamen, 1.9% in the posterior putamen, and 4.0% in the caudate nucleus. No significant differences in [18F]CFT uptake between the first and second PET scan in any striatal subregion occurred in healthy controls. The intraclass correlation, indicating the reproducibility of the PET scan within subjects, was 0.94 for the anterior putamen, 0.86 for the posterior putamen, and 0.91 for the caudate nucleus. The percent change from baseline was 4.0% in the anterior putamen, 1.1% in the posterior putamen, and 2.8% in the caudate nucleus. Long-term levodopa treatment in PD patients had no effect on the [18F]CFT uptake in the striatum and the test-retest reproducibility was very high. These findings confirm [18F]CFT as a suitable ligand to monitor progression of PD.

The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial.

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

Carboplatin and etoposide in extensive small cell lung cancer.

The combination of carboplatin and etoposide was evaluated in 61 previously untreated patients with extensive small cell lung cancer. Treatment was given at four-week intervals with 450 mg/m2 of carboplatin intravenously (i.v.) on day 1 and etoposide 100 mg/m2 i.v. on days 1-3. The response was complete in 5 (9%) and partial in 28 (50%) of the 56 evaluable patients (overall response rate 59%). The median time to progression after response as well as the median survival time in all evaluable patients was 4.6 months. WHO grade 3 and 4 leukopenia and thrombocytopenia occurred in 8% and 11% of the courses respectively. Two treatment-related deaths were registered. The combination of carboplatin and etoposide used in the present study produced acceptable response rate and toxicity, but duration of response and median survival were shorter than expected from earlier studies.

Risk factors for screen-detected breast cancer. A case-control study.

Risk factors for breast cancer (BC) detected in mammography screening were sought using a questionnaire among 31,927 women aged from 40 to 74 years who attended screening. Data from 204 women with screen-detected BC were compared with those of 612 controls who did not have BC in screening. Mothers of women with BC had more often BC than those of the controls (8% vs. 3%, odds ratio, OR, 3.18, 95% CI 1.59-6.35). Women with screen-detected BC were older at their first childbirth (25.7 years vs. 24.7 years, OR 1.61, 1.14-2.33), and younger at menarche (13.6 years vs. 13.8 years, OR 1.38, 1.00-1.91), but there was no significant difference in the body mass index, number of pregnancies, breast size, smoking, or in the use of contraceptive pills between the cases and the controls. In multivariate logistic regression analyses, late age at the first childbirth, BC in the mother, and early age at menarche were independent risk factors for screen-detected BC but they appear to be of limited value in targeting screening in the female population aged from 40 to 74 in order to improve its cost-effectiveness.