The oxygen isotopic composition of the Sun inferred from captured solar wind.

All planetary materials sampled thus far vary in their relative abundance of the major isotope of oxygen, (16)O, such that it has not been possible to define a primordial solar system composition. We measured the oxygen isotopic composition of solar wind captured and returned to Earth by NASA's Genesis mission. Our results demonstrate that the Sun is highly enriched in (16)O relative to the Earth, Moon, Mars, and bulk meteorites. Because the solar photosphere preserves the average isotopic composition of the solar system for elements heavier than lithium, we conclude that essentially all rocky materials in the inner solar system were enriched in (17)O and (18)O, relative to (16)O, by ~7%, probably via non-mass-dependent chemistry before accretion of the first planetesimals.

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors.

Eighteen patients with refractory and progressive solid tumors were treated with a single round of triple modified oncolytic adenovirus (Ad5/3-Cox2L-D24). Ad5/3-Cox2L-D24 is the first non-Coxsackie-adenovirus receptor-binding oncolytic adenovirus used in humans. Grades 1-2 flu-like symptoms, fever, and fatigue were seen in most patients, whereas transaminitis or thrombocytopenia were seen in some. Non-hematological grades 3-5 side effects were seen in one patient with grade 3 ileus. Treatment resulted in high neutralizing antibody titers within 3 weeks. Virus appeared in serum 2-4 days after treatment in 83% of patients and persisted for up to 5 weeks. One out of five radiologically evaluable patients had partial response (PR), one had minor response (MR), and three had progressive disease (PD). Two patients scored as PD had a decrease in tumor density. Tumor reductions not measurable with Response Evaluation Criteria In Solid Tumors (RECIST) were seen in a further four patients. PR, MR, stable disease, and PD were seen in 12, 23.5, 35, and 29.5% of tumor markers analyzed, respectively (N=17). Ad5/3-Cox2L-D24 appears safe for treatment of cancer in humans and extended virus circulation results from a single treatment. Objective evidence of anti-tumor activity was seen in 11/18 (61%) of patients. Clinical trials are needed to extend these findings.

Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells.

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.

The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.

UNLABELLED: We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia. IMPLICATIONS: The alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.

Exposure and effect monitoring: a critical appraisal of their practical application.

The prerequisite for the use of biomarkers of exposure as indicators of health risk is that the relationship between the biomarker and the health effects and the representation in time of the biomarker level are known. Some exposure biomarkers may be applied for the quantitative assessment of the amount of exposure. In this task, the half-time of the parameter measured is crucial, since it determines what length of time of exposure the result reflects. For reliable assessment of the exposure the species (e.g. metal, oxide or salt) has to be known. For some chemicals the estimation of exposure from biomonitoring is based on several studies with uniform results and is quite reliable, while for others the uncertainty is wide. Exposure biomarkers have been successfully used in the identification of exposed individuals and follow-up of exposure. For example, macromolecule adducts and mutagenicity in urine have been successfully applied to the identification of workers exposed to carcinogens and as indicators of changes of exposure. Biomarkers of renal effects of cadmium, lead effects on haemoglobin synthesis and organophosphate effects on cholinesterase activities have been well validated and are widely used in routine monitoring activities. However, effect markers for lead and cadmium offer little advantage over the analysis of the chemical itself and where accurate metal analysis is readily available, they have a limited use today. For the analysis of chromosomal aberrations, limited data are available suggesting that elevated frequencies may indicate a carcinogenic risk. In several instances, genotoxic effect monitoring has been used to identify groups of people exposed to hazardous chemicals and in the follow-up of improvements in industrial hygiene.

Results of biomonitoring analyses in Biomonitoring Laboratory, Helsinki, Finland in 1997.

In 1997 a total of 4848 results of 47 different analytes from blood or urine specimens, were performed in the Finnish Institute of Occupational Health, Biomonitoring Laboratory, Helsinki, Finland. The results of these service analyses were registered in a database with additional information concerning the worker and the work place. The biomonitoring register, containing one or more results of about 30,000 workers, enables the follow-up of chemical exposure on individual or working group levels. In general, the levels of chemicals or their metabolites in biological specimens have been slowly but continuously declined in Finland during the last decade. In 1997 the decrease in the levels of heavy metals was particularly important. The most problematic organic solvent in Finland is styrene. Styrene exposures have remained in unacceptable levels in work places and still in 1997 more than a third of the workers analysed had very high concentrations of styrene metabolites in their urine. In most major analyte groups studied, there were workers whose exposure level exceeded the Finnish biomonitoring action level (BAL), and in about half of the specimens the level exceeded the upper reference limits (URL), of the non-exposed persons.

Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine.

BACKGROUND: alpha 2-Adrenergic agonists have been shown to reduce anesthetic requirements of other anesthetics, and they may even act as complete anesthetics by themselves at high doses in animal models. The present study was designed to define the interaction of intravenous infusion of dexmedetomidine, an alpha 2-adrenergic agonist, and isoflurane in patients having surgery by using the minimum alveolar concentration (MAC) of isoflurane as the measure of anesthetic potency. METHODS: Forty-nine women scheduled for abdominal hysterectomy were randomly allocated to receive either a placebo infusion (n = 16) or a two-stage infusion of dexmedetomidine with target plasma concentration of 0.3 ng/ml (n = 17) or 0.6 ng/ml (n = 16). The study drug infusion was commenced 15 min before induction of anesthesia with thiopental and alfentanil and was continued until skin incision. The end-tidal concentration of isoflurane for each patient was predetermined according to the "up-down" method of Dixon, and it was maintained for at least 15 min before the patient's response to skin incision was assessed. RESULTS: The MAC of isoflurane was 0.85% end-tidal in the control group, 0.55% end-tidal with the low dose of dexmedetomidine, and 0.45% end-tidal with the high dose of dexmedetomidine. CONCLUSIONS: The MAC of isoflurane in the control group was lower than that reported previously in similar patients having surgery, probably due to anesthesia induction with thiopental and alfentanil. Nevertheless, with the high dose of dexmedetomidine, the MAC of isoflurane was still 47% less than that without dexmedetomidine.

Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.

BACKGROUND: Alpha 2-adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific alpha 2-adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting. METHODS: Eighty patients scheduled for elective coronary artery bypass grafting received, in a double-blind manner, either a saline placebo or a dexmedetomidine infusion, initially 50 ng.kg-1.min-1 for 30 min before induction of anesthesia with fentanyl, and then 7 ng.kg-1.min-1 unit the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs. RESULTS: Compared with placebo, dexmedetomidine decreased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia (3 vs. 24 mmHg) and surgery (2 vs. 14 mmHg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine decreased the incidence of intraoperative (2 vs. 13 patients) and postoperative (5 vs. 16 patients) tachycardia. Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increments of enflurane (4.4 vs. 5.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl-induced muscle rigidity (15 vs. 33 patients) and postoperative shivering (13 vs. 23 patients). CONCLUSIONS: Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.

Multivariant confirmation of sickle cell disease using a non-radioactive minisequencing reaction.

A non-radioactive solid-phase minisequencing method for confirmation of abnormal hemoglobin variants causing sickle cell disease has been developed. In this method amplified 5'-biotinylated target sequences containing normal and mutation sites are immobilized onto streptavidin-coated microplates. Detection primers corresponding to target sequences are annealed immediately adjacent to the mutation site and single-step, hapten-labeled nucleotide primer extension reactions are performed. The incorporation of the labeled nucleotide is detected through immunological reaction with an enzyme-labeled anti-hapten conjugate and a substrate. The method enables confirmation of mutations of the beta-globin gene variants (Hbs S, C, E D-Punjab, O-Arab) and the alpha-globin gene variant (Hb G-Philadelphia). The test was evaluated using characterized dried blood spot specimens (n = 100) The advantages of the procedure are easy performance and objectiveness. The non-radioactive minisequencing assay will prove helpful for genotyping in neonatal screening for hemoglobinopathies and in prenatal and pre-implantational diagnostics.

Luminometric microplate hybridization for detection of varicella-zoster virus PCR product from cerebrospinal fluid.

We modified and optimized a new microplate hybridization assay to detect the varciella-zoster virus (VZV) PCR product, and studied cerebrospinal fluid (CSF) samples of 287 patients with meningitis, encephalitis or other neurological diseases or symptoms. Specific antibodies to VZV and reference antigens were determined by enzyme immunoassay from serum and CSF, they were then compared with clinical findings and with the results obtained by VZV-PCR using different detection methods for VZV-specific amplified DNA. VZV DNA was found in the CSF of 25 patients using the microplate hybridization assay and chemiluminescence detection for amplified DNA. All 25 CSF samples were also positive in Southern blotting. Among the patients, 10 had chickenpox, 4 had shingles, and 11 had no rash at all. The detection rate of VZV-specific DNA by microplate hybridization was 30% higher than that obtained by conventional agarose gel electrophoresis. In most patients the diagnosis was confirmed by demonstrating specific intrathecal antibody production to VZV but not to other viruses. These results indicate the presence of VZV in the central nervous system (CNS) in many patients with chickenpox or shingles, and even in patients without a rash. The microplate hybridization assay based on chemiluminescence detection improves considerably the detection rate of the VZV-PCR product compared to agarose gel electrophoresis and will add to the list of recognized VZV infections in the CNS. It is especially useful in cases where there is no cutaneous manifestation.

Strabismus in children with cerebral palsy.

In 48 children with cerebral palsy the characteristics of the squint and amblyopia were analyzed, also with respect to the features of cerebral palsy and to birth weight. Strabismus of congenital esotropia type was found to be common, as was also exotropia of early onset. Spontaneous alternation or an accommodative component of the squint was present only in a few cases. There was no evidence of an accumulation of any strabismus type in the different subgroups of cerebral palsy, whereas amblyopia or an obvious risk for amblyopia was found in the great majority of the cases. Some kind of amblyopia treatment was given to 34. Most of them showed improvement of the visual capacity which encourages treatment of amblyopia, even in children with cerebral palsy.

Detection of herpes simplex virus DNA in cerebrospinal fluid samples using the polymerase chain reaction and microplate hybridization.

As conventional polymerase chain reaction (PCR) procedures are time-consuming and laborious, we developed and evaluated a rapid semi-automatic microplate method to detect the amplified PCR products. The use of PCR, with subsequent hybridization in microplates, is described for the detection of herpes simplex virus (HSV) DNA in cerebrospinal fluid samples. The principle of the method is based on two phases. Firstly, the amplification of the viral DNA in the sample is undertaken using a pair of primers of which one is biotinylated. Secondly, the amplified viral genomic sequences are bound to the wells of streptavidin-coated microplates and hybridized with digoxigenin-labeled oligonucleotide probes which are then detected using anti-digoxigenin antibody enzyme conjugates and either a photometric, fluorometric or luminometric substrate and microplate reader. The method is highly sensitive allowing the detection of as few as five purified DNA molecules. Compared to conventional gel electrophoresis followed by Southern blotting the established microplate hybridization is also much less time-consuming and involves less manual work. The applicability of the method is described for use as a routine diagnostic procedure for detection of early central nervous system infections caused by HSV-1 and HSV-2.

Comparison of intramuscular dexmedetomidine and midazolam premedication for elective abdominal hysterectomy.

The purpose of this study was to compare the perioperative effects of the intramuscular (i.m.) alpha 2 agonist, dexmedetomidine (DEX), and midazolam (MID) premedication. The study comprised 192 women (64 per group) scheduled for abdominal hysterectomy. The doses of the study drugs were chosen to obtain equal sedative effects. The three groups were: 1) i.m. DEX (2.5 micrograms/kg) and intravenous (i.v.) placebo (DexPla group), 2) i.m. DEX and i.v. fentanyl (FENT) (1.5 micrograms/kg) (DexFent group), and 3) i.m. MID (0.08 mg/kg) and i.v. FENT (MidFent group). I.m. drugs were administered 45-90 min before induction of anesthesia. Preoperative sedation and anxiolysis after DEX was comparable to that after MID. The maximum arterial blood pressure response to endotracheal intubation was blunted in the DexFent group, while in the two other groups blood pressure increased 30-34 mm Hg after endotracheal intubation. The mean isoflurane concentration during surgery was 0.14% in the DexFent group, 0.24% in the DexPla group, and 0.34% in the MidFent group (P < 0.001). During surgery, bradycardia (heart rate < 40 bpm) was observed in 6.2% of DEX patients, and no MID patients, whereas postoperatively 14.1% of DEX patients and 1.6% of MID patients had bradycardia. Fewer patients suffered from postoperative shivering after DEX (10%) than after MID (52%). We conclude that DEX has many desirable effects, but side effects such as bradycardia may limit its routine use in ASA physical status I-II patients.

Pharmacokinetics and pharmacodynamics of intraspinal dexmedetomidine in sheep.

INTRODUCTION: Epidural and spinal injection of alpha 2-adrenergic agonists causes analgesia and hypotension. For opioids, relative analgesic potency of epidural to intravenous administration decreases with increasing lipophilicity, but such pharmacodynamic studies have been performed with only one alpha 2-adrenergic agonist, clonidine, of moderate lipophilicity. This study examines antinociception, transfer to cerebrospinal fluid (CSF), and CSF pharmacokinetics in sheep of the selective alpha 2-adrenergic agonist dexmedetomidine, with lipophilicity 3.5 times greater than clonidine, and correlates CSF concentrations to hemodynamic effects. METHODS: Six sheep with chronically implanted epidural, intrathecal, and vascular catheters received, on separate days, 100 micrograms dexmedetomidine intravenously, epidurally, or intrathecally. Cerebrospinal fluid and blood were sampled at specified intervals for dexmedetomidine assay. Pharmacokinetics of dexmedetomidine in CSF were determined using a NONMEM approach. Hemodynamic effects were measured and correlated to CSF concentrations. A second group of four sheep received intrathecal dexmedetomidine to define its time course for antinociception. RESULTS: Intrathecal dexmedetomidine decreased blood pressure within 1 min, with a maximum reduction of -22 +/- 3%. Epidural injection decreased blood pressure with a slower onset (11 min) and to a lesser degree (-14 +/- 4%), whereas intravenous injection did not affect blood pressure (-8 +/- 6%). Dexmedetomidine absorption in CSF after epidural injection was rapid (Tmax = 5-20 min), although pharmacokinetic modeling suggested a biphasic absorption process. Only 22% of the injected dose was identified in the CSF. There was a delay of at least 30 min between peak CSF concentrations and time of maximal reduction in blood pressure. At times of identical CSF dexmedetomidine concentrations, blood pressure decreased more after epidural than after intrathecal administration. Intrathecal dexmedetomidine injection produced maximum antinociception within 20-30 min of injection. CONCLUSIONS: These data support a primary spinal site of action for decreased blood pressure after intraspinal dexmedetomidine injection. Dexmedetomidine appears rapidly in CSF after epidural administration and decreases blood pressure. The relationship between CSF dexmedetomidine concentrations and drug effect may require more complex modeling tools than those used to relate plasma drug concentrations to effects of systemically administered opioids or neuromuscular blockers.

Intramuscular dexmedetomidine premedication--an alternative to midazolam-fentanyl-combination in elective hysterectomy?

Sedation, anxiolysis, intubation responses and fentanyl anaesthetic requirements were investigated in a double-blind, randomized study in twenty ASA I-II elective hysterectomy patients. Ten patients received dexmedetomidine 2.5 micrograms kg-1 i.m. 60 min before induction and saline placebo i.v. 2 min prior to induction (= DP group). Ten patients received midazolam 0.08 mg kg-1 i.m. 60 min and fentanyl 1.5 micrograms kg-1 i.v. (= MF group) 2 min before induction of anaesthesia with thiopentone 4 mg kg-1. Anaesthesia was maintained with 70% nitrous oxide in oxygen and with fentanyl 2 micrograms kg-1 i.v. increments according to predetermined criteria. Both premedications induced sedation (P < 0.01 in both groups) and anxiolysis (P < 0.01 in DP vs P < 0.05 in MF group) without any differences between the groups. Haemodynamic changes following tracheal intubation did not significantly differ between the groups. Intraoperatively systolic and diastolic arterial pressure were 15% and 13% lower in DP group (P < 0.01 and P < 0.05 for drug effect), the mean heart rate was approximately 9 beats min-1 lower in DP group (n.s.). Fentanyl was required more often in MF group: median 3.5 (QD 1.5) vs. 2.5 (QD 0.5) times in DP group (P < 0.05), the total amount being 57% smaller in DP group: 0.03 (QD 0.01) vs. 0.07 (QD 0.02) micrograms kg-1 min-1 (P < 0.05). Postoperative course and analgesic requirements were similar in both groups. Dexmedetomidine premedication may offer an alternative to current anaesthesia practice in elective hysterectomy.

Detection of human papillomavirus DNA by AffiProbe HPV-DNA test kit in cervical scrapes or biopsies-histopathologic correlates.

OBJECTIVE: The aim of this study was to evaluate and compare the efficacy of punch biopsies and cervical scrapes in the detection of human papillomavirus (HPV) DNA from the cervix and compare the results with the histopathologic diagnosis. METHODS: The specimens were collected simultaneously, and HPV DNA was detected using a liquid hybridization test. RESULTS: Biopsies and scrapes were equally efficient, but each detected only two-thirds of all HPV-DNA-positive patients. Thus, the positivity rate increased when both tests were used. Overall, 13% of patients with normal histopathology, 38% of patients with benign atypia, and 66% of patients with squamous intraepithelial lesions (SIL) were HPV-DNA positive. HPV-DNA 16 was found in 54% of HPV-DNA-positive patients with SIL, in 20% of HPV-DNA-positive patients with atypia, and in none of patients with normal histopathology. CONCLUSIONS: The liquid hybridization test used in this study detects HPV DNA equally efficiently from both biopsies and scrapes. The test can be performed in 1 working day. However, the sensitivity of the test is low, and it only detects a limited number of HPV types.

Pharmacokinetics and pharmacodynamics of transdermal dexmedetomidine.

Dexmedetomidine is a novel alpha 2-adrenoceptor agonist that may provide beneficial effects as premedication for anesthesia. The pharmacokinetics and pharmacodynamics of transdermal (TD) and intravenous (i.v.) dexmedetomidine were studied in nine healthy male subjects in a crossover trial. The TD preparation, containing 625 micrograms of dexmedetomidine base, was applied on the forehead and left in place for 12 h. The i.v. dose (2.0 micrograms.kg-1 as dexmedetomidine hydrochloride) was administered as an infusion over 5 min. Dose-normalized total AUC values were used to calculate dexmedetomidine bioavailability. The bioavailability of dexmedetomidine from the TD preparation was 51%. However, the bioavailability of dexmedetomidine released from the preparation was 88%. The mean terminal half-life was 3.1 h after i.v. and 5.6 h after TD administration. After TD administration, the mean maximal reductions in blood pressure (systolic/diastolic) and heart rate were 28/20 mmHg, and 19 beats.min-1. A sedative effect was obvious within 5 min and 1-2 h after i.v. and TD administration, respectively.

Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease.

We report the clinical findings in 19 Finnish patients, including six pairs of siblings, with a new, early onset spinocerebellar ataxia. The slowly progressive clinical symptoms manifested between one and two years of age in previously healthy infants. The first manifestation of children at that age was clumsiness and loss of ability to walk. Ataxia, athetosis and muscle hypotonia with loss of deep tendon reflexes were discovered on clinical examination. By school age ophthalmoplegia and hearing loss were diagnosed, while sensory neuropathy developed by adolescence. In addition, an acute crisis with status epilepticus was a late manifestation. We found a marked decrease in sensory nerve condition velocities, a progressive loss of myelinated fibers in sural nerve specimen, and abnormal background activity in EEG with advancing age. The main finding in neuroradiological investigations was cerebellar atrophy. The occurrence of the disease in siblings and lack of manifestations in parents indicate recessive inheritance.