[Local fibrinolisis in nontraumatic intraventricular hemorrhages]. / Lokal'nyi fibrinoliz pri netravmaticheskikh vnutrizheludochkovykh krovoizliyaniyakh.

The management of patients with hemorrhagic stroke is an important problem in modern neurology and neurosurgery. The proportion of hemorrhagic stroke is only 15% of all cases of acute cerebrovascular accident, but mortality reaches 50% (and with intraventricular hemorrhages up to 80%), and disability is over 75%. Minimally invasive methods are being developed to reduce intraoperative damage to brain and improve the prognosis for the patient. One of them is ventricular external drainage (EVD) in combination with local fibrinolysis (LF). Intraventricular injection of thrombolytics allows the acceleration of the process of lysis and evacuation of blood. In this clinical observation, a 52-year-old female patient was admitted to the clinic with intracerebral hematoma and intraventricular hemorrhage, complicated by acute occlusive hydrocephalus. In the case of this patient, the use of external ventricular drainage in combination with local fibrinolysis made it possible to quickly resolve occlusive hydrocephalus, reduce the risk of death and increase the patient's rehabilitation potential.

Specifics of Experimental Modeling 8-OH-DPAT-Induced Perseverative Behavior in Mice.

The effect of 5-HT1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances.

[Forensic chemical and chemicotoxicological examination of ricin poisoning by the HPLC-MS/MS method]. / Sudebno-khimicheskoe i khimiko-toksikologicheskoe issledovanie metodom VEZhKh-MS/MS pri otravlenii ritsinom.

THE AIM OF THE STUDY: Is to suggest the method of ricin determination in biological liquids during forensic medical and chemicotoxicological examination. This research describes the optimal conditions of sample processing of biological liquids, allowing to extract the components (ricinine and ricinoleic acid) of castor seeds. The recommended analysis conditions allow to perform research for 15 minutes by high resolution mass spectrometry method combined with high-value liquid chromatography on a chromato-mass spectrometer to detect ricinine and ricinoleic acid. The chromatographic (retention time) and mass-spectrometric parameters (mass spectra) were established for the exact high-quality determination of ricinine and ricinoleic acid.

[Measurement of benzodiazepine receptor agonists metabolites and their concentration in urine]. / Opredelenie metabolitov agonistov benzodiazepinovykh retseptorov i ustanovlenie ikh protsentnogo soderzhaniya v moche.

The study objective was to detect and measure the ratio of metabolites of benzodiazepine receptor agonists in urine during forensic chemical and chemical and toxicological studies, as well as to characterize the main metabolites to use them to confirm the oral intake of the test substances. Data on the presence of metabolites in the urine will allow us to reliably confirm the intake of zaleplon, zopiclone, clobazam, and phenazepam and determine the routes of administration (intake) into the body of the victim. Benzodiazepine derivatives (clobazam and phenazepam) and non-benzodiazepines (zaleplon and zopiclone) have different chemical structures and similar mechanisms of action resulting in a similar clinical presentation of side effects and the need for forensic chemical study according to poisoning symptoms. Metabolites of benzodiazepine receptor agonists and their ratio in urine after oral administration were measured: zaleplon (parent compound), deethylzaleplon, 5-oxozaleplon, 5-oxodeethylzaleplon, oxozaleplon glucuronide; zopiclone (parent compound), zopiclone-N-oxide, N-desmethylzopiclone; clobazam (parent compound), N-desmethylclobazam, 4-hydroxyclobazam, hydroxydesmethylclobazam; phenazepam (parent compound) and 3-hydroxyphenazepam. It is advisable to determine zaleplon in urine by the presence of 5-oxaleplon (97% of the total amount of metabolites), zopiclone by zopiclone-N-oxide (86% in urine), clobazam by the parent compound (61% in urine), phenazepam by the parent compound (90-100% in urine).

[Xalacom: possibilities and advantages of the drug in the treatment of patients with glaucoma]. / Ksalakom: vozmozhnosti i preimushchestva preparata v terapii glaukomy.

The strategy of glaucoma therapy is aimed at preserving visual functions and ensuring an acceptable quality of life for patients. To achieve this strategic goal, clinicians in their practice use drugs that affect the main factor in the progression of the disease - intraocular pressure (IOP), aiming to reduce it to an individual target level. It is not always possible to achieve optimal IOP values with monotherapy. Many patients require a combination of drugs from different pharmacological groups. Xalacom is a fixed drug with good tolerability and t hypotensive effect. This review focuses on the benefits of this drug for the treatment of glaucoma.

[Potential for the use of cards for sampling and transportation of biological material during forensic chemical and toxicological examinations]. / Vozmozhnost' ispol'zovaniya kart dlya zabora i transportirovki biologicheskogo materiala pri sudebno-khimicheskom i khimiko-toksikologicheskom issledovaniyakh.

The objective of the study is to evaluate the potential for the use of cards for sampling and transportation of biological material during forensic chemical and toxicological examinations by the example of a biological sample, urine containing zopiclone. Two methods of sample preparation were compared. The use of cards for the collection and transportation of biological material, such as urine, followed by high-resolution high-performance liquid chromatography-mass spectrometry (HPLC-MS) for the identification of zopiclone metabolites was shown to be beneficial in forensic chemical and toxicological examination. The validation evaluation of the proposed sample preparation and identification method met the acceptance criteria.

[Determination of zaleplon and clobazam by high performance liquid chromatography - high resolution tandem mass spectrometry using Orbitrap technology]. / Opredelenie zaleplona i klobazama metodom vysokoeffektivnoi zhidkostnoi khromatografii ­ tandemnoi mass-spektrometrii s vysokim razresheniem s ispol'zovaniem tekhnologii Orbitrap.

THE AIM OF THE STUDY: Was to develop a method for the qualitative and quantitative determination of benzodiazepine receptor agonists (zaleplon and clobazam), taking into account different chemical structures, by high-performance liquid chromatography-high-resolution tandem mass spectrometry using Orbitrap technology for the purposes and tasks of forensic medical examination. A method has been developed for the identification and quantitative determination of zaleplon and clobazam by high-performance liquid chromatography-high-resolution tandem mass spectrometry using Orbitrap technology. The proposed identification method can be used in the future to form a database of domestic mass spectra for potent and narcotic substances.

[Analysis of the feasibility of a forensic chemical investigation in clobazam poisoning]. / Analiz vozmozhnosti provedeniya sudebno-khimicheskogo issledovaniya pri otravlenii klobazamom.

The study objective was to determine the relevance of methods to detect clobazam poisoning during the forensic and chemical toxicological examination. The lack of a systematic approach to clobazam identification and assay as a part of forensic chemical and chemical toxicological analyses was demonstrated. The published data on the study of clobazam in biological objects are inconsistent and incomplete, precluding the conduction of focused forensic chemical and toxicological investigations on biological objects with required validity. Various methods of forensic chemical and toxicological investigation of clobazam in biological objects were studied and presented. Data are presented on various physicochemical test methods (TLC, HPLC, UV spectrometry, GC, and GC-MS) for clobazam detection.

A Low-Molecular-Weight BDNF Mimetic, Dipeptide GSB-214, Prevents Memory Impairment in Rat Models of Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) is known to be involved in the pathogenesis of Alzheimer's disease (AD). However, the pharmacological use of full-length neurotrophin is limited, because of its macromolecular protein nature. A dimeric dipeptide mimetic of the BDNF loop 1, bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylene diamide (GSB-214), was designed at the Zakusov Research Institute of Pharmacology. GSB-214 activates TrkB, PI3K/AKT, and PLC-γ1 in vitro. GSB-214 exhibited a neuroprotective activity during middle cerebral artery occlusion in rats when administered intraperitoneally (i.p.) at a dose of 0.1 mg/kg and improved memory in the novel object recognition test (0.1 and 1.0 mg/kg, i.p.). In the present study, we investigated the effects of GSB-214 on memory in the scopolamine- and steptozotocin-induced AD models, with reference to activation of TrkB receptors. AD was modeled in rats using a chronic i.p. scopolamine injection or a single streptozotocin injection into the cerebral ventricles. GSB-214 was administered within 10 days after the exposure to scopolamine at doses of 0.05, 0.1, and 1 mg/kg (i.p.) or within 14 days after the exposure to streptozotocin at a dose of 0.1 mg/kg (i.p.). The effect of the dipeptide was evaluated in the novel object recognition test; K252A, a selective inhibitor of tyrosine kinase receptors, was used to reveal a dependence between the mnemotropic action and Trk receptors. GSB-214 at doses of 0.05 and 0.1 mg/kg statistically significantly prevented scopolamine-induced long-term memory impairment, while not affecting short-term memory. In the streptozotocin-induced model, GSB-214 completely eliminated the impairment of short-term memory. No mnemotropic effect of GSB-214 was registered when Trk receptors were inhibited by K252A.

[Evaluation of the effectiveness of the third stage of rehabilitation after a knee joint injury in persons of older age groups by means of physiotherapy exercises.]

The main task in the rehabilitation of athletes with traumatic injuries of the knee joint and surrounding soft tissues is effective and painless recovery at all stages of treatment. The aim of this work is to introduce a set of physical exercises for the treatment and prevention of traumatic injuries of the knee joint in middle-aged and elderly patients at the third stage of rehabilitation treatment (ICD-10: S80-S89). To date, there is no single regulated program for the management of middle-aged and elderly patients at the outpatient stage. The article describes the third stage of the organization of medical rehabilitation assistance in the late rehabilitation period, the period of residual symptoms of the course of the disease, without relapses. Physical exercises, presented in this complex, give the patient independence in everyday life in the implementation of self-service, independent movement, in the presence of the prospect of restoration of function (rehabilitation potential) confirmed by the results of the examination. The proposed technique was tested on 148 patients who underwent all 3 stages of rehabilitation treatment, in whom the duration of remission was 12-36 months.

[Efficacy and safety of new oral anticoagulants as part of triple antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome. Data from an observational study].

Aim To study efficacy and safety of a triple antithrombotic therapy with direct oral anticoagulants (DOAC) versus warfarin in patients with atrial fibrillation after acute coronary syndrome, for 12 months following discharge from the hospital.Materials and methods This single-site cohort, prospective, observational study performed at the Regional Vascular Center 2 of the N.A. Semashko Nizhniy Novgorod Regional Clinical Hospital included 402 patients. It was possible to maintain contacts with 206 patients for 12 months. These patients were divided into two groups, the DOAC treatment (n=105) and the warfarin treatment (n=101) as a part of triple antithrombotic therapy upon discharge. Clinical observation was performed at 1, 3, 6, and 12 months after the discharge by structured telephone interview. Predetermined efficacy endpoints included cardiovascular death, myocardial infarction, stent thrombosis, and ischemic stroke. Safety endpoints included bleeding defined as small, medium (clinically significant), and major in accordance with the TIMI classification.Results At 12 months of follow-up, 80 patients (76.19%) continued taking DOAC and 39 patients (38.61%, p<0.001) continued taking warfarin; in this process, only 25 patients (24.75%) monitored their INR on a regular basis. With a regular INR monitoring and TTR >70%, death rate did not differ in the warfarin and the DOAC treatment groups. However, there was a difference in reaching the composite efficacy endpoint (p=0.048): ischemic events occurred statistically significantly more frequently in the warfarin treatment group than in the DOAC treatment group.Conclusions In 12 months after discharge from the hospital, compliance with the DOAC treatment as a part of the antithrombotic therapy was significantly higher than compliance with the warfarin treatment. The triple antithrombotic therapy with DOAC was safer than the warfarin treatment by the number of hemorrhagic complications and more effective in prevention of ischemic events, primarily due to no need for monitoring of lab test values.

The Behavioral and Neurochemical Aspects of the Interaction between Antidepressants and Unpredictable Chronic Mild Stress.

The behavioral and neurochemical effects of amitriptyline (10 mg/kg, i.p.) and fluoxetine (20 mg/kg, i.p.) after single and chronic administration in the setting of unpredictable mild stress in outbred ICR (CD-1) mice were studied. After a 28-day exposure to stress, we observed an increase in depressive reaction in a forced swim test in mice, as well as reduced hippocampal levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and an increased hypothalamic level of noradrenaline (NA). Single and chronic administration of amitriptyline and fluoxetine shortened the immobility period and increased the time corresponding to active swimming in the forced swim test. The antidepressant-like effect of fluoxetine - but not of amitriptyline - after a single injection coincided with an increase in the 5-HT turnover in the hippocampus. Chronic administration of the antidepressants increased the hypothalamic levels of NA. Thus, the antidepressant- like effect of amitriptyline and fluoxetine may result from an enhancement of the stress-dependent adaptive mechanisms depleted by chronic stress.

Psychotropic Effects of a New Pyrazolo[C]Pyridine Derivate GIZh-72 are Related to Functional Activity of Atp-Sensitive Potassium Channels.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

Role of GABAA Receptors in the Mechanism of In Vivo Psychotropic Activity of Amitriptyline in Rats.

Standard water-reinforced drug discrimination model was employed to train Wistar rats to discriminate the intraperitoneal injections of tricyclic antidepressant amitriptyline (5.4 mg/kg) and physiological saline. To examine the role of GABAA receptors in psychotropic action of amitriptyline, the substitution tests were performed with muscimol (0.1-1.0 mg/kg) and pregnenolone (30-50 mg/kg). Similar tests were carried out with amitriptyline interoceptive antagonists bicuculline (1 mg/kg), flumazenil (15 mg/kg), finasteride (5 mg/kg), and indomethacin (7.5 mg/kg). The study showed that interoceptive effects of amitriptyline depend on functional activity of GABAA receptors but not on the neurosteroid site of GABAA receptor complex.

A Nerve Growth Factor Dipeptide Mimetic Stimulates Neurogenesis and Synaptogenesis in the Hippocampus and Striatum of Adult Rats with Focal Cerebral Ischemia.

The nerve growth factor (NGF) and its mimetics, which have neuroprotective and neuroregenerative properties, are attractive candidates for developing new drugs for brain injury therapy. A dipeptide mimetic of NGF loop 4, bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), developed at the Zakusov Research Institute of Pharmacology, has the NGF-like ability to activate TrkA receptors, but unlike NGF, GK-2 activates mainly the PI3K/AKT pathway associated with neuroprotection and has no effect on the MAPK cascade associated with hyperalgesia, the main side effect of NGF. That GK-2 possesses neuroprotective activity has been observed in various models of cerebral ischemia. GK-2 was found to statistically significantly reduce the cerebral infarct volume in experimental stroke, even at treatment onset 24 h after injury. This suggests that GK-2 possesses neuroregenerative properties, which may be associated with the activation of neurogenesis and/or synaptogenesis. We studied the effect of GK-2 on neurogenesis and synaptogenesis in experimental ischemic stroke caused by transient occlusion of the middle cerebral artery in rats. GK-2 was administered 6 or 24 h after surgery and then once a day for 7 days. One day after the last administration, proliferative activity in the hippocampus and striatum of the affected hemisphere was assessed using Ki67 and synaptogenesis in the striatum was evaluated using synaptophysin and PSD-95. Ki67 immunoreactivity, both in the striatum and in the hippocampus of the ischemic rats, was found to have dropped by approximately 30% compared to that in the sham-operated controls. Synaptic markers - synaptophysin and PSD-95 - were also statistically significantly reduced, by 14 and 29%, respectively. GK-2 in both administration schedules completely restored the level of Ki67 immunoreactivity in the hippocampus and promoted its increase in the striatum. In addition, GK-2 restored the level of the postsynaptic marker PSD-95, with the therapeutic effect amounting to 70% at the start of its administration after 6 h, and promoted restoration of the level of this marker at the start of administration 24 h after an experimental stroke. GK-2 had no effect on the synaptophysin level. These findings suggest that the neurotrophin mimetic GK-2, which mainly activates one of the main Trk receptor signaling pathways PI3K/ AKT, has a stimulating effect on neurogenesis (and, probably, gliogenesis) and synaptogenesis in experimental cerebral ischemia. This effect may explain the protective effect observed at the start of dipeptide administration 24 h after stroke simulation.

Risk factors associated with portal vein thrombosis in liver cirrhosis: A case-control study.

AIM: To build a predictive model for PVT in cirrhotic patients. MATERIALS AND METHODS: A single centre case-control study was carried out. From the database of 1512 cirrhotic patients 94 with newly diagnosed PVT based on contrast-enhanced computed tomography were referred to the Case group. Malignant PVT was an exclusion criterion. Patients without PVT were stratified and matched according to sex, age and etiology of cirrhosis; case-control ratio was 1 : 3-4. The prevalence of PVT in the database, clinical, laboratory, instrumental parameters of the groups were evaluated. Logistic regression model was used to estimate association between variables and PVT. RESULTS: The overall prevalence of PVT was 6.2% with the highest rates among the patients with HBV infection - 16.7%, nonalcoholic steatohepatitis - 15.6%, alcohol abuse in combination with HCV infection - 11.7%. The best predictive model included variables: Child-Pugh classes B-C (coefficient of regression ß=1.853, р=0.001), ascites (ß=0.460, р=0.003), hepatocellular carcinoma without vascular invasion (ß=2.126, р=0.0001), endoscopic band ligation (ß=0.774, р=0.003), azygoportal disconnection (ß=2.734, р=0.001), portal hypertensive gastropathy (ß=0.793, р=0.017), portal vein diameter (ß=0.203, р=0.004), and local factors - ulcerative colitis flare, Clostridium difficile enterocolitis, spontaneous bacterial peritonitis, colorectal cancer, splenectomy, cholecystectomy (ß=2.075, р=0.017). The model had accuracy 85.8% (95% CI 81.7-89.4%), sensitivity - 55.1% (95% CI 43.4-66.4%), specificity - 95% (95% CI 91.6-97.3%), and AUC - 0.871 (95% CI 0.826-0.916). CONCLUSION: Child-Pugh classes B-C, severe portal hypertension, hepatocellular carcinoma without vascular invasion, and local factors were estimated as risk factors of PVT in cirrhotic patients.

Contrasts between mucormycosis and aspergillosis in oncohematological patients.

In retrospective multicenter study from years 2007-2017, we evaluated 59 oncohematological patients with mucormycosis and 541 with invasive aspergillosis (IA). Mucormycosis developed more often in children and adolescents (P = .001), as well as after the emergence of graft versus host disease (P = .0001). Patients with mucormycosis had more severe neutropenia (88% vs 82%), the median duration was 30 versus 14 days (P = .0001) and lymphocytopenia (77% vs 65%), with a median duration (25 vs 14 days, P = .001) as compared to patients with IA. The lung infection was less frequent in patients with mucormycosis than in IA patients (73% vs 97%, P = .02), but more frequent was involvement of 2 or more organs (42% vs 8%, P = .001) and involvement of paranasal sinuses (15% vs 6%, P = .04). Typical clinical features of mucormycosis were localized pain syndrome (53% vs 5%, P = .0001), hemoptysis (32% vs 6%, P = .001), pleural effusion on lung CT scan (53% vs 7%, P = .003), lesions with destruction (38% vs 8%, P = .0001), and a "reverse halo" sign (17% vs 3%). The overall 12-week survival was significantly lower in patients with mucormycosis than for IA patients (49% vs 81%, P = .0001). In both groups unfavorable prognosis factors were ≥2 organs involvement (P = .0009), and concomitant bacterial or viral infection (P = .001, P = .008, respectively). In mucormycosis patients favorable prognosis factor was remission of underlying disease (P = .006).

[Acute period in a rat model of brain trauma: immediate seizures, damage to functional neocortical zones and behavioral disturbances]. / Ostryi period pri modelirovanii cherepno-mozgovoi travmy u krys: nemedlennye sudorogi, povrezhdenie funktsional'nykh zon novoi kory i narusheniia povedeniia.

BACKGROUND: Establishing the relationship between the damage in the neocortex and the functional manifestations of these lesions is important to understand the mechanisms of acute seizures and their consequences. An analysis of immediate seizures in patients with a traumatic brain injury (TBI) in practice is difficult, however it can be performed in animal models. AIM: To compare the damage to functional neocortical areas with the semiology of immediate seizures and behavioral disturbances in the acute period after lateral fluid percussion (TBI model) in rats. MATERIAL AND METHODS: The study was performed on 48 Wistar rats. TBI was modelled using lateral fluid-percussion injury to the right sensory-motor cortex. To study the semiology of immediate seizures, video recording was performed at the moment of the injury and 5 min after it. After that, a number of behavioral tests were employed. RESULTS AND CONCLUSION: This study presents the first detailed evaluation of damage to the functional neocortical areas in the acute period of TBI using the 'unfolded maps' approach. The focus of damage in the cortex increased from 3rd to 7th day and demonstrated a complex shape, extending far beyond the area of the direct impact. TBI induced immediate seizures with a variability which cannot be explained by the involvement of certain areas of the neocortex alone, as well as behavioral disturbances suggested to reflect developing necrosis predominantly in the sensory area of the neocortex.

[Clinical Value of Algorithms of Minimization of Right Ventricular Pacing in Patients With Sick Sinus Syndrome and History of Atrial Fibrillation].

PURPOSE: to assess effectiveness of algorithms of minimization of right ventricular pacing (MRVP) for prevention of progression of atrial fibrillation (AF), lowering of frequency of hospitalizations due to cardiovascular causes, and mortality in patients with sick sinus syndrome (SSS) and history of paroxysmal AF compared with standard compared with dual-chamber pacing (DDDR). MATERIALS AND METHODS: We included in this single-center prospective study 74 consecutive patients with indications to permanent DDDR pacing because of SSS combined with documented history of paroxysmal AF. Patients were randomized in the groups of DDDR pacing (n=36) and with activated algorithms of MRVP (n=38). Pacemaker check up was made after 6 months during 1 year after device implantation. Primary composite endpoint included development of persistent AF, hospitalization due to cardiovascular causes, and all cause death. RESULTS: During follow-up there was no statistically significant difference in achievement of the primary endpoint (27.8 and 18.4% in groups of DDDR pacing and activated algorithms of MRVP respectively (relative risk 1.29% confidence interval 0.43 to 3.86; p=0.25). Rate of development of persistent AF in both groups was comparable (8.6 and 5.3% in DDDR and MRVP groups, respectively; p=0.47). Median AF burden was 6.0 (0;42) and 6.0 (0;42) min/day in DDDR and MRVP groups, respectively (p=0.67). CONCLUSION: Our study failed to demonstrate advantages of the use of algorithms of decreasing "unmotivated" right ventricular pacing over standard regimen of standard DDDR pacing in patients with SSS and history of paroxysmal AF.

[Issues of antithrombotic therapy in ACS patients with atrial fibrillation].

The review analyzed current ideas on prevalence and clinical significance of atrial fibrillation following acute coronary syndrome; described modern approaches to administration of antithrombotic therapy; and addressed available clinical studies on the treatment with warfarin and new oral anticoagulants as a part of combination antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome.