A massive binary black-hole system in OJ 287 and a test of general relativity.

Tests of Einstein's general theory of relativity have mostly been carried out in weak gravitational fields where the space-time curvature effects are first-order deviations from Newton's theory. Binary pulsars provide a means of probing the strong gravitational field around a neutron star, but strong-field effects may be best tested in systems containing black holes. Here we report such a test in a close binary system of two candidate black holes in the quasar OJ 287. This quasar shows quasi-periodic optical outbursts at 12-year intervals, with two outburst peaks per interval. The latest outburst occurred in September 2007, within a day of the time predicted by the binary black-hole model and general relativity. The observations confirm the binary nature of the system and also provide evidence for the loss of orbital energy in agreement (within 10 per cent) with the emission of gravitational waves from the system. In the absence of gravitational wave emission the outburst would have happened 20 days later.

[Principles of revascularization in treatment of giant intracranial aneurysms].

During recent decades extra-intracranial and intra-intracranial bypasses have deserved high interest among neurosurgeon, especially in management of giant cerebral aneurysms. Development of microsurgery and neuroanesthesiological techniques, advances in neuroradiology and neurophysiology prerequisite improvement of revascularization surgery. Evolution of competitive endovascular methods pushes the surgeons to improve microneurosurgical technique of revascularization and elaboration of new approaches to management of intracranial aneurysms. In this review we discuss principles of surgery of cerebrovascular bypasses in management of giant aneurysms applied in our clinic.

Microsurgical technique for previously coiled aneurysms.

Since the introduction of Guglielmi detachable coils to treat intracranial aneurysms in 1991, the number of patients undergoing endovascular coiling has continuously risen as well as the number of those residual and recurrent previously coiled aneurysms that necessitate a microsurgical occlusion. Between July 1995 and August 2009 we retrospectively analyzed 81 patients with 82 previously coiled aneurysms treated microsurgically at two Finnish Neurosurgical University Hospitals, Helsinki and Kuopio. Fifty-eight aneurysms (71%) were located at anterior circulation and 24 (29%) at posterior circulation. Fifteen patients were operated on within the first month (early surgery) after coiling, whereas 66 were treated later (late surgery). Complete or partial removal of coils during surgery may facilitate clipping, but is significantly (P<0.001) more difficult to accomplish in late surgery. Removal of coils may also increase the chance for poor outcome. Chance of poor outcome increased also with intraoperative aneurysm rupture, size of the aneurysm and posterior circulation location. Good clinical outcome, three months after surgery, was achieved in 71 patients (88%); four patients were severely disabled, and six patients died (three of them due to poor clinical condition). Complete microsurgical occlusion of the residual previously coiled aneurysm is a high-risk procedure in large and giant aneurysms, and these patients should be referred to a dedicated neurovascular center to minimize surgical complications. Bypass procedures may be the best option for demanding growing lesions, especially those in posterior circulation.

Local Hemodynamic Conditions Associated with Focal Changes in the Intracranial Aneurysm Wall.

BACKGROUND AND PURPOSE: Aneurysm hemodynamics has been associated with wall histology and inflammation. We investigated associations between local hemodynamics and focal wall changes visible intraoperatively. MATERIALS AND METHODS: Computational fluid dynamics models were constructed from 3D images of 65 aneurysms treated surgically. Aneurysm regions with different visual appearances were identified in intraoperative videos: 1) "atherosclerotic" (yellow), 2) "hyperplastic" (white), 3) "thin" (red), 4) rupture site, and 5) "normal" (similar to parent artery), They were marked on 3D reconstructions. Regional hemodynamics was characterized by the following: wall shear stress, oscillatory shear index, relative residence time, wall shear stress gradient and divergence, gradient oscillatory number, and dynamic pressure; these were compared using the Mann-Whitney test. RESULTS: Hyperplastic regions had lower average wall shear stress (P = .005) and pressure (P = .009) than normal regions. Flow conditions in atherosclerotic and hyperplastic regions were similar but had higher average relative residence time (P = .03) and oscillatory shear index (P = .04) than thin regions. Hyperplastic regions also had a higher average gradient oscillatory number (P = .002) than thin regions. Thin regions had lower average relative residence time (P < .001), oscillatory shear index (P = .006), and gradient oscillatory number (P < .001) than normal regions, and higher average wall shear stress (P = .006) and pressure (P = .009) than hyperplastic regions. Thin regions tended to be aligned with the flow stream, while atherosclerotic and hyperplastic regions tended to be aligned with recirculation zones. CONCLUSIONS: Local hemodynamics is associated with visible focal wall changes. Slow swirling flow with low and oscillatory wall shear stress was associated with atherosclerotic and hyperplastic changes. High flow conditions prevalent in regions near the flow impingement site characterized by higher and less oscillatory wall shear stress were associated with local "thinning" of the wall.

A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder.

BACKGROUND: The objective of this study was to evaluate the efficacy and tolerability of citalopram in the long-term treatment of adult outpatients with panic disorder with or without agoraphobia. METHOD: Patients in this double-blind, parallel-group trial were assigned to 1 of 3 fixed dosage ranges of citalopram (10 or 15 mg/day, 20 or 30 mg/day, or 40 or 60 mg/day), 1 dosage range of clomipramine (60 or 90 mg/day), or placebo. After the completed 8-week acute treatment period, the eligible patients could continue the treatment for up to 1 year. Of the 475 patients who were randomly assigned for the short-term trial, 279 agreed to continue double-blind treatment at their assigned doses. The primary efficacy measure used was the Clinical Anxiety Scale panic attack item, and the response was defined as no panic attacks (score of 0 or 1). The other key measures used were the Physician's Global Improvement Scale, the Patient's Global Improvement Scale, and the Hamilton Rating Scale for Anxiety (HAM-A). RESULTS: In all drug-treated groups, except the group receiving the lowest citalopram dose, the treatment outcome was generally better than with placebo. As determined by a life table analysis of response, the probability of response during the 12 months was significantly greater with all treatment regimens than with placebo (p < .05), with citalopram 20 or 30 mg/day demonstrating the best response. Panic attacks tended to disappear in all patients remaining in the study until the end of follow-up. Analysis of the difference in the number of patients in different treatment groups remaining in the study (perhaps the best measure of long-term efficacy) also demonstrated that the patients treated with citalopram in dosage ranges of 20 or 30 mg/day and 40 or 60 mg/day had better response than placebo-treated patients (p < .0002 and p < .004, respectively). HAM-A and Global Improvement Scale scores also showed that patients treated with active drug showed greater improvement than placebo-treated patients. All treatment groups showed no new or exceptional adverse event clusters. CONCLUSION: Citalopram in the dosage range of 20 to 60 mg/day is effective, well tolerated, and safe in the long-term treatment of patients who have panic disorder.

Effect of smoking on neuroleptics in schizophrenia.

OBJECTIVE: The effect of smoking on daily doses and plasma levels of neuroleptics prescribed for schizophrenic patients was studied. METHODS: 90 outpatients with schizophrenic disorder (DSM-III-R) who were on a stable regimen of psychotropic medication and showed a stable clinical state were included in a double-blind placebo-controlled trial. Data were collected and blood tests taken at the baseline interview. The plasma levels were obtained for 52 patients. RESULTS: Daily neuroleptic doses converted to chlorpromazine equivalents correlated significantly (r = 0.436) with the plasma levels of their unmetabolised fractions. The neuroleptic doses increased with age in smokers, while in nonsmokers they decreased. Neither sex, age nor smoking had a significant association with the neuroleptic plasma levels. CONCLUSIONS: Smoking seems to lead to increased neuroleptic dosages in postmenopausal schizophrenics by increasing hepatic metabolism and renal excretion of the drugs and possibly enhancing dopamine release. It is also possible that older smoking patients form a selected group of heavy smoker and they, therefore, need exceptionally high neuroleptic doses.

Reduction of dosing frequency of carbamazepine with a slow-release preparation.

The occurrence of side effects and epileptic seizures and the pharmacokinetics of carbamazepine (CBZ) and carbamazepine-10,11-epoxide were studied using a slow-release CBZ preparation, Neurotol slow, and a conventional CBZ preparation, Tegretol. The study was an open, randomized cross-over trial, with a 2 week study period for each preparation. Tegretol was given 3 times and Neurotol slow twice a day. The earlier CBZ dose was kept unchanged. The initial sample consisted of 24 adult epileptic patients receiving CBZ treatment of whom 20 patients were evaluable. The fluctuation in serum CBZ concentrations did not differ significantly between the 2 treatment periods, even though the interdose interval of Neurotol slow was 4 h longer than that of Tegretol. The switch-over from conventional CBZ to the slow-release formulation did not seem to alter the efficacy and side effects of CBZ. By using Neurotol slow instead of a conventional CBZ preparation, Tegretol, it is evidently possible to reduce the dosing frequency from 3 times a day to twice daily administrations.

Multiple-dose pharmacokinetic study with a slow-release carbamazepine preparation.

The pharmacokinetics, clinical efficacy and side effects of carbamazepine (CBZ) in the steady-state condition were studied using a slow-release preparation (SR), Neurotol Slow, and a conventional preparation (C), Tegretol. Eighteen adult epileptic patients under CBZ therapy were evaluated in this single-blind, randomized cross-over study. The previous daily CBZ dose was kept unchanged and divided into 2 daily doses during two 2 week study periods. At the end of each period blood samples were drawn at frequent intervals for 12 h after the administration of the morning CBZ dose. Serum concentrations of unchanged CBZ and its main metabolite, carbamazepine-10,11-epoxide (CBZE), were determined by HPLC. Peak concentrations of CBZ and CBZE were significantly lower, and the time-lapse before CBZ reached its peak was significantly longer during SR treatment. The fluctuations in serum CBZ and CBZE were significantly lower during SR treatment. There was no significant difference in bioavailability between the 2 preparations. The number of epileptic seizures was 31 during SR and 57 during C treatment. Side effects were more common during C treatment. The occurrence of dizziness was significantly lower with SR treatment than with C treatment. We conclude that greater stability in serum CBZ and CBZE concentrations can be obtained by using an SR of CBZ, without reducing the bioavailability of the drug.

Citalopram as an adjuvant in schizophrenia: further evidence for a serotonergic dimension in schizophrenia.

There is increasing evidence suggesting that symptoms of depression and anxiety may also be associated with serotonergic dysfunction in schizophrenic patients. The effect of the adjuvant selective serotonin reuptake inhibitor citalopram was assessed regarding the symptom dimensions of schizophrenia measured with the Positive and Negative Syndrome Scale (PANSS) and with the Hamilton Rating Scale for Depression (HRSD). Citalopram alleviated symptoms of the depression/anxiety dimension of the PANSS, but not the symptoms of the four other PANSS domains or depressive symptoms measured with the HRSD. The results support the hypothesis of a serotonergic dimension in schizophrenia.

Effect of ibopamine on the failing heart at rest and during isometric exercise: a noninvasive study.

Eleven patients suffering from heart failure were treated with oral ibopamine, a di-isobutyric ester of N-methyldopamine, 100 mg three times a day for 1 week and 200 mg three times a day for 3 weeks. Therapy was discontinued by one patient because of tachycardia. Left ventricular performance was evaluated with echocardiography and systolic time intervals at rest and after 3 minutes of isometric exercise using a handgrip. Six of 10 patients completing the study were in New York Heart Association (NYHA) functional class III, 2 in class IV, and 2 in class II. All patients, except one who remained stable in class II, improved their subjective condition by one functional class during 4 weeks of therapy (p less than 0.01). There were no changes in heart rate, blood pressure, rate-pressure product, cardiac index, or total peripheral vascular resistance. The left ventricular end-systolic diameter decreased after four weeks from 71.2 +/- 12.7 (SD) to 65.9 +/- 13.0 mm (p less than 0.001); the left ventricular end-diastolic diameter did not change. The ejection fraction increased from 26 +/- 8 to 32 +/- 9% (p less than 0.01). Afterload, that is, left ventricular circumferential systolic wall stress, declined as a result of decreased systolic diameter. Systolic time intervals did not vary. There were no changes due to ibopamine during isometric exercise probably owing to increased beta-adrenergic stimulation induced by the handgrip. Neither urine volume nor body weight changed. Side effects were mild except for tachycardia of one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Smoking and cognitive deficits in schizophrenia: a pilot study.

The cross-sectional study assessed the associations among smoking status, number of cigarettes smoked per day, and psychiatric symptoms in 88 chronic schizophrenic outpatients with a stable psychic condition. Among the 49 smokers, the number of cigarettes smoked per day was associated with the severity of cognitive symptoms of the Positive and Negative Syndrome Scale. The authors suggest that smoking may alleviate cognitive deficits in schizophrenia by increasing dopaminergic neurotransmission in the prefrontal areas of the brain.

Citalopram in patients with unsatisfactory response to neuroleptics: an open follow-up study.

There is clinical evidence that antidepressants have beneficial effects on certain symptom clusters of psychotic patients. Specific serotonin reuptake inhibitors like citalopram provide a new possibility to selectively influence brain neurotransmission. We studied the effects of citalopram (20-60 mg daily) in 36 psychotic or borderline patients receiving neuroleptic treatment without satisfactory response. Particular attention was paid to negative symptomatology, anxiety, and impulsiveness. 22 of the patients (65%) were assessed to react to citalopram treatment in a clinically significant manner. Initially, the responders tended to have higher scores in withdrawal-retardation, anxious-depression, and hostile-suspiciousness factors of the Brief Psychiatric Rating Scale (BPRS), with a lower degree of thinking disturbances. In the responder group, a significant decline in all symptom clusters was recorded. The mean decrease was 38% in Clinical Global Impression (CGI) and BPRS scales. The most prominent change (52%) was seen in hostile-suspiciousness factor of the BPRS inventory. In light of the positive results achieved in this open-label trial, controlled trials with patients not responding satisfactorily to neuroleptics are warranted.

Citalopram causes no significant alterations in plasma neuroleptic levels in schizophrenic patients.

Steady-state plasma concentrations of commonly used neuroleptic drugs were measured in 90 schizophrenic patients before and after adding placebo or citalopram (40 mg/day) to their treatment regimen. Plasma concentrations of citalopram and its main metabolite, desmethylcitalopram, were also measured. In addition, patients with exceptionally high neuroleptic levels or an increase in adverse effects during the 12-week study period were evaluated for their debrisoquine/sparteine hydroxylase (CYP2D6) genotype, an enzyme responsible for oxidative metabolism of several neuroleptics and selective serotonin re-uptake inhibitors. There were no significant changes in plasma concentrations of haloperidol, chlorpromazine, zuclopenthixol, levomepromazine, thioridazine or perphenazine during the study. Plasma concentrations of citalopram and desmethylcitalopram were well within the levels reported previously with monotherapy, and remained stable throughout the study. None of the 15 patients analysed for the CYP2D6 genotype was a poor metabolizer. It is concluded that clinically important pharmacokinetic drug interactions do not play a crucial role when citalopram is used as an augmentation therapy in neuroleptic-treated schizophrenic patients.

Post-traumatic frontal and parieto-occipital extradural haematomas: a retrospective analysis of 41 patients and review of the literature.

BACKGROUND: The purpose of this study was to analyse the differences between patients with frontal (FEDH) or parieto-occipital (POEDH) epidural haematomas and evaluate possible statistically significant prognostic factors. MATERIAL AND METHODS: In this retrospective study of a group of 41 patients with a FEDH (17) or POEDH (24 individuals), the authors analysed the influence of gender, age, type of injury, clinical presentation, Glasgow coma scale (GCS) score on admission, radiological findings, and time interval from trauma to surgery on outcomes. A good recovery and moderate disability were considered a "good" or "favourable outcome", whereas severe disability, a vegetative state or death was a "poor outcome". RESULTS: In the POEDH subgroup, a higher GCS score on admission and a younger age were statistically significant prognostic factors for a better outcome (p=0.006, rs=0.702). In the subgroup of patients with FEDHs, the results were not significant. However, patients with FEDHs more frequently had "good outcomes" than members of the POEDH subgroup (88.2 vs. 70.9%). Children (≤ 18 years old) constituted a smaller portion of the POEDH subgroup (12.5%) than those in the FEDH subgroup (41.2%). The evaluation of time intervals between the accident and surgery (≤ 24 h vs. > 24 h) showed no significant influence on outcomes in any of the studied subgroups. However, patients undergoing surgery within 24 h of their injury had a less favourable GCS score on admission than those operated on more than 24 h after their injury. Subacute and chronic clinical courses predominated in patients with a FEDH (10/17 FEDH vs. 11/22 POEDH). Different accompanying intradural lesions occurred in 12 patients of the POEDH subgroup, but only in 2 of the FEDH subgroup (50 vs. 11.8%). However, the presence of such lesions did not significantly deteriorate surgical outcomes in either of the subgroups.

Posterior fossa extradural haematomas.

BACKGROUND: Posttraumatic epidural haematoma (EDH) of the temporal region is the most common site of supratentorial extradural bleeding; other locations are considered atypical. We reviewed 24 patients with EDH located in the posterior cranial fossa (PFEDH) treated at two neurosurgical centres between January 2000 and November 2006. MATERIAL AND METHODS: In the retrospective study we analysed gender and age distribution, type of injury, clinical presentation, Glasgow Coma Scale (GCS) score on admission, radiological images, interval between trauma and surgery, and outcome. RESULTS: 24 patients with PFEDH constituted 11.5% of 209 surgically treated individuals with EDH. The best outcomes were obtained by patients with GCS scores of 15-14 on admission. Patients in the fourth to seventh decade of life had less favourable outcomes than younger ones. More than half of the patients with PFEDH had associated intradural lesions. Only patients with concomitant brain contusion had a more favourable recovery. The 3 worst levels on the Glasgow Outcome Scale (GOS) were observed in patients suffering from subdural or intracerebral haematoma, or both, associated with the PFEDHs. The majority of patients with concurrent lesions and supratentorial extension of the haemorrhage were in the subgroup undergoing craniotomy between 24 and 72 h after injury. Patients treated in this time interval also had the most unfavourable outcomes. A classical lucid interval was observed only in one patient. The mortality rate in the series was 4.2%. CONCLUSION: The most significant factors influencing outcome in our patients were GCS on admission, age, and associated intradural lesions.

Characterization of contractions in mechanically disaggregated myocardial cells from the rat.

Myocardial cell groups, mechanically disaggregated from the rat heart, beat spontaneously in a medium which resembles intracellular fluid. The cells, initially functioning in an uncoordinated way, i.e. each cell in its own rhythm, gradually become coordinated as a function of time. After 90 min of incubation at 15 degrees C all the cell groups were functioning in a coordinated way. The initiation of coordination was temperature-dependent. Lowering the temperature from 15 degrees C to 10 degrees C significantly delays the coordination, only 75% of the cell groups being coordinated after 90 min. The contraction wave in coordinated cell groups was very slow; 90 +/- 7 micrometers/s at 20 degrees C, 100 +/- 6 micrometers/s at 30 degrees C and 100 +/- 7 micrometers/s at 35 degrees C. The velocity of contraction waves was not significantly temperature-dependent, suggesting a neonenzymatical type of propagation. It also seems too slow to be an electrical event. Apparently the contraction waves are propagated by diffusion of Ca2+. The addition of caffeine to the medium hastened the coordination of contractions, but Na-azide strongly inhibited it. The results indicate that the sarcoplasmic reticulum functions in the coordination of contractions, probably by releasing Ca2+ for the activation of the myofilaments.

Alpha and beta adrenergic control of contraction force of perch heart (Perca fluviatilis) in vitro.

Noradrenaline showed a negative inotropic effect on the isolated electrically triggered atrium of the perch. The effect was stronger at lower temperature and was antagonized by an alpha adrenergic blocker, phentolamine. The inotropic effect of adrenaline was dependent on incubation temperature. The effect was negative at 15 C but biphasic at 24 C, where with increasing adrenaline concentration a positive inotropic effect was followed by negative inotropy. Phentolamine not only antagonized the negative inotropic effect of adrenaline at 15 degrees C but changed it to positive. This positive inotropic effect was antagonized by a beta adrenergic blocker, propranolol. On the triggered ventricular strip adrenaline had no effect at 6 or 15 C, but increased contraction force at 24 C. It can be suggested that in the perch heart atrium there is an activity balance of alpha and beta receptors, which mediate the negative and positive inotropic control, respectively. As in higher vertebrates, alpha adrenergic activation decreases and beta activation increases by agonists in the following order: noradrenaline, adrenaline and isoprenaline. The balance changes towards increased beta activity when temperature rises.

Characterization of contractions in mechanically and enzymatically isolated myocardial cells from the rat heart ventricles.

Single spontaneously beating myocardial cells were prepared by mechanical or enzymatical isolation. Using a TV camera and videotape recorder, beating parameters were characterized in different buffer solutions in regard to temperature and integrity of sarcolemma, which was tested by ability of cells to exclude a vital stain, Evans blue. The mechanically disaggregated cells were totally permeable to this stain, but about 60% of the enzymatically isolated myocytes were able to exclude the stain. The myocytes prepared in the presence of calcium were most tolerant to physiological concentration of calcium. Contractions were mainly of phasic type where the velocity of contraction wave was very slow (50-330 microns/s). The velocity was not correlated to the beat rate. Temperature dependence of the velocity was positively correlated with the integrity of sarcolemma. Beat rate was inversely related to the integrity of sarcolemma being slowest in calcium tolerant enzymatically isolated cells. Beat rate of calcium sensitive myocytes was higher but unstable and the temperature dependence of the rate was steeply reduced and even reversed during the incubation. Some calcium tolerant myocytes generated occasionally an electric type of contraction which came in bursts and was characterized by synchronous sarcomere shortening without any contraction wave.

The effect of nifedipine on plasma lipids in patients with essential hypertension.

The effect of nifedipine on plasma lipids given over a period of one month to 14 patients with essential hypertension was studied. There were no significant changes in the concentrations of plasma total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol and triglycerides during treatment. Nifedipine appears to be preferable to diuretic agents and to beta-blockers without ISA as nifedipine has no untoward effects on lipid metabolism.