High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

OBJECTIVE: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score. MATERIALS AND METHODS: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis. RESULTS: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores. CONCLUSIONS: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

[Ischemic Stroke].

CASE: A patient with a history of chronic atrial fibrillation was diagnosed with sudden onset of right hemiparalysis in the hospital. The patient had been normal two hours prior and was referred to the cerebral vascular center. Images: Head CT images showed early ischemic changes in the left frontal lobe, insula, and temporal lobe(Alberta Stroke Program Early CT Score[ASPECTS]: 6 points). A hyperdense internal carotid artery(ICA)sign was found at the top of the left internal carotid artery. MRI DWI-ASPECTS was performed at 6 points. The MRA showed loss of the left internal carotid, anterior cerebral, and middle cerebral arteries. T2*WIs showed a susceptibility vessel sign(SVS)at the top of the left ICA and FLAIR vessel hyperintensity(FVH)in the left ICA to the middle cerebral artery. DIAGNOSIS: The patient was diagnosed with acute cerebral embolism with clinical-DWI mismatch and treated with endovascular therapy. COMMENTARY: Early CT signs are important in determining cerebral ischemic lesions, and hyperdense ICA/MCA signs are useful in identifying occluded vessels. Early ischemic changes can be seen more easily on MRI-DWI, and the location of the occluded vessel can be estimated by evaluating MRA, SVS, and FVH together.

Identifying causative medications for agranulocytosis: A case report of an older adult with cerebral infarction.

Key Clinical Message: Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative drug among four suspect drugs administered during emergency treatment. Abstract: We present the case of a 93-year-old man who was admitted for the treatment of cerebrovascular events. The patient was initially prescribed dual antiplatelet therapy with aspirin and clopidogrel along with lansoprazole, Hange-koboku-toh, and elobixibat. On day 36 after admission, the patient was found to have developed agranulocytosis. To improve his cerebrovascular prognosis, we first discontinued medications other than the anticoagulant medicines and initiated filgrastim. We discontinued clopidogrel 9 days after the discontinuation of the other medicines considering his low white blood cell count. One day after the discontinuation of clopidogrel, the agranulocytosis was alleviated. Considering the time course, clopidogrel, lansoprazole, Hange-koboku-toh, and elobixibat were suspected as the culprit medicines. This case highlights the considerable challenges encountered in clinical practice when attempting to identify the drugs responsible for agranulocytosis, particularly in patients on intensive medication therapy.

Evaluating the Potential Pathology and Short-Term Outcomes of Cryptogenic Stroke Using the Etiological Classification System.

AIM: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system. METHODS: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge. RESULTS: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P =0.012), body mass index (OR, 0.93 [0.88-0.99]; P =0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P＜0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01-1.08]; P =0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P =0.009), and S＋C score (OR, 1.26 [1.03-1.56]; P =0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3. CONCLUSIONS: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

The brainstem is at high risk for recurrent noncardioembolic cerebral infarction in association with diabetes mellitus: a hospital-based study.

The goals of the study were to investigate the importance of brainstem infarction (BSI) in recurrent noncardioembolic ischemic stroke and to examine the relevant clinical background. Data were retrospectively reviewed for 655 consecutive patients with acute noncardioembolic infarction who were admitted to our hospital from January 2004 to August 2010. The patients were divided into first-stroke (n = 592) and recurrent-stroke (n = 63) groups. Acute infarcted lesions were explored on MRI, and clinical background factors including age, sex, smoking, atrial fibrillation, coronary heart disease, hypertension, hyperlipidemia and diabetes mellitus (DM) were assessed. The frequency of BSI in the recurrent-stroke group was significantly higher than that in first-stroke patients (30.2 vs. 14.9%, p = 0.0033). No other clinical background factors differed between the two groups. Only the frequency of DM differed significantly among four subgroups formed based on stroke recurrence and BSI (p < 0.0001): DM was present in 63.2% of recurrent-stroke patients with BSI, 54.5% of first-stroke patients with BSI, 27.4% of first-stroke patients without BSI, and 20.5% of recurrent-stroke patients without BSI. We conclude that the brainstem is at high risk for recurrent cerebral infarction in patients with DM.

Occurrence and clinicotopographical correlates of brainstem infarction in patients with diabetes mellitus.

BACKGROUND: The goal of the study was to clarify the association between diabetes mellitus (DM) and brainstem infarctions (BSIs) and to investigate the clinicotopographic characteristics of BSIs in patients with diabetes. METHODS: Data were retrospectively reviewed for 1026 consecutive patients admitted to our hospital because of acute cerebral infarctions from January 2004 to August 2010. Acute symptomatic BSIs were explored on radiologic images and classified into multiple infarctions with BSIs, multifocal BSIs, and monofocal BSIs. Isolated BSIs were further classified based on the vertical distribution into midbrain, pontine, and medullary infarctions, and on the horizontal distribution into anterior-dominant, posterior-dominant, and anterior/posterior BSIs. Neurologic symptoms of BSIs and clinical background were compared between DM and non-DM patients. RESULTS: The prevalence of BSIs was 2.6-fold higher (P < .0001) in DM patients. Logistic regression analysis including age, sex, smoking, previous stroke, atrial fibrillation, other cardiac diseases, hypertension, hyperlipidemia, and DM showed that DM was independently associated with BSIs (odds ratio [OR] 2.814; 95% confidence interval [CI] 1.936-4.090; P < .0001). Compared with non-DM patients, DM patients showed more frequent monofocal BSIs (P < .0001) and multifocal BSIs (P = .0296). Monofocal BSIs (n = 114) more frequently involved the pons (P < .0001) and medulla (P = .0212). Anterior-dominant BSIs (P < .0001) were more common in DM patients than in non-DM patients. Symptoms of BSIs included more frequent motor paresis (P = .0180) and less frequent diplopia (P = .0298) in DM patients than in non-DM patients. CONCLUSIONS: DM is important in the development of BSIs, and the associated clinical characteristics include more frequent motor paresis and less frequent diplopia.

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19-15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35-7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

Atrial Septal Aneurysm may Cause In-Hospital Recurrence of Cryptogenic Stroke.

AIMS: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke. METHODS: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed. RESULTS: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061). CONCLUSIONS: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

Utility of Coaxial Angioplasty-thrombectomy for Acute Tandem Occlusion of Intracranial and Extracranial Arteries.

Objective: We report a novel technique for acute occlusion of both intracranial and extracranial arteries (tandem lesions [TL]). Case Presentation: A 67-year-old male was transferred to our hospital because of right hemiparesis and aphasia. MRA revealed occlusion of the left cervical internal carotid artery (ICA) and middle cerebral artery (MCA). A balloon guide catheter (BGC) was advanced into the left common carotid artery (CCA). A microcatheter was advanced over a microwire through the intracranial thrombus. A stent retriever (SR) was deployed from the MCA to the ICA through the microcatheter. Next, with the SR anchored to the thrombus, the microcatheter was withdrawn. The extracranial percutaneous transluminal angioplasty (PTA) balloon was coaxially advanced over the SR's delivery wire and angioplasty was performed. Then, an aspiration catheter was coaxially advanced to the proximal aspect of the intracranial thrombus over the delivery wire by pump aspiration. We removed the SR and the aspiration catheter as a single unit into the BGC, resulting in sufficient recanalization. The puncture to recanalization time was 29 minutes. Conclusion: This technique can lead to faster recanalization in cases of TL.

Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke.

BACKGROUND: Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. METHODS: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs. RESULTS: A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18-2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03-2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11-2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16-2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37-3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12-2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83-33.9, p = 0.006) was related to lobar CMBs. CONCLUSIONS: CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.

Large aortic arch plaques correlate with CHADS2 and CHA2DS2-VASc scores in cryptogenic stroke.

BACKGROUND AND AIMS: Current trends have suggested covert atrial fibrillation as a mechanism of cryptogenic stroke. However, etiological heterogeneity regarding the underlying embolic sources remains a critical issue in cryptogenic stroke. METHODS: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) is a multicenter observational registry of cryptogenic stroke patients admitted to participating hospitals, who underwent transesophageal echocardiography between April 2014 and December 2016. We obtained baseline characteristics, radiological and laboratory data, and echocardiographic findings, especially for embolic sources demonstrated on transesophageal echocardiography, and conducted comparisons according to CHADS2 and CHA2DS2-VASc scores (0-1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/(UMIN000032957). RESULTS: The study comprised 677 patients (age, 68.7 ±â€¯12.8 years; 455 males; median National Institutes of Health Stroke Scale score, 2) with cryptogenic stroke. On multiple logistic regression analysis, large aortic arch plaque ≥4 mm (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.51-3.36; p < 0.001), with ulcerative or mobile components (OR, 2.37; 95%CI, 1.38-4.06; p = 0.002), was associated with CHADS2 score ≥2. Large aortic arch plaque ≥4 mm (OR, 3.88; 95%CI, 2.07-7.27; p < 0.001) and ulcerative or mobile components (OR, 3.25; 95%CI, 1.44-7.34; p = 0.005) were linked to CHA2DS2-VASc score ≥2. CONCLUSIONS: The CHALLENGE ESUS/CS registry is a large TEE registry, and clarifies potential embolic etiologies of cryptogenic stroke using TEE. Large aortic arch plaques were associated with high CHADS2 and CHA2DS2-VASc scores, and represented important embolic sources in cryptogenic stroke.

[Syndrome of inappropriate secretion of anti-diuretic hormone associated with limbic encephalitis due to herpes simplex virus infection--a case report].

We report a case of syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) associated with limbic encephalitis. A 79-year-old woman was admitted with a complaint of fever, disturbance of consciousness and generalized seizure. Her conscious level was E1V2M4 by Glasgow coma scale. Physical examination showed generalized seizure, neck stiffness, hyperreflexia and flaccid paralysis in her all extremities, and pathological reflexes. Blood analysis revealed hyponatremia, decrease of plasma osmolarity, spared secretion of urine sodium and increase of ADH, leading to the diagnosis of SIADH. Cerebrosponal fluid examination showed mild pleocytosis, elevated protein, and normal glucose level. Although herpes simplex virus (HSV) DNA was not detected by the polymerase chain reaction method, titers of anti-HSV IgG antibody elevated chronologically. Brain MRI revealed abnormal T2 and FLAIR high intensities in the cingulate gyrus and hippocampus bilaterally. An EEG revealed periodic synchronous discharges predominantly in the frontal areas. Based on the clinical course, laboratory data, MRI and EEG findings, we diagnosed as SIADH associated with acute limbic encephalitis caused by HSV infection. After the fluid restriction and sodium supply, plasma sodium was normalized. Administration of acyclovir and steroid was not so effective, however her condition improved gradually. Several cases of SIADH associated with limbic encephalitis have been reported; however, the pathophysiology is to be clarified. We thought that in the presented case, SIADH was caused by disturbance of the hormonal control at the hypothalamus on the pituitary gland due to the spreading of inflammation from limbic system to these areas.

Simultaneous determination of selegiline and desmethylselegiline in human body fluids by headspace solid-phase microextraction and gas chromatography-mass spectrometry.

A method for the simultaneous determination of selegiline and its metabolite, desmethylselegiline, in human whole blood and urine is presented. The method, which combines a fiber-based headspace solid-phase microextraction (SPME) technique with gas chromatography-mass spectrometry (GC-MS), required optimization of various parameters (e.g., salt additives, extraction temperatures, extraction times and the extraction properties of the SPME fiber coatings). Pargyline was used as the internal standard. Extraction efficiencies for both selegiline and desmethylselegiline were 2.0-3.4% for whole blood, and 8.0-13.2% for urine. The regression equations for selegiline and desmethylselegiline extracted from whole blood were linear (r(2)=0.996 and 0.995) within the concentration ranges 0.1-10 and 0.2-20 ng/ml, respectively. For urine, the regression equations for selegiline and desmethylselegiline were linear (r(2)=0.999 and 0.998) within the concentration ranges 0.05-5.0 and 0.1-10 ng/ml, respectively. The limit of detection for selegiline and desmethylselegiline was 0.01-0.05 ng/ml for both samples. The lower and upper limits of quantification for each compound were 0.05-0.2 and 5-20 ng/ml, respectively. Intra- and inter-day coefficients of variation for selegiline and desmethylselegiline in both samples were not greater than 8.7 and 11.7%, respectively. The determination of selegiline and desmethylselegiline concentrations in Parkinson's disease patients undergoing continuous selegiline treatment is presented and is shown to validate the present methodology.

Analysis of phenothiazines in human body fluids using disk solid-phase extraction and liquid chromatography.

Seven phenothiazine derivatives, perazine, perphenazine, prochlorperazine, propericiazine, thioproperazine, trifluoperazine, and flupentixol, have been found to be extractable from human plasma and urine samples using disk solid-phase extraction (SPE) with an Empore C18 cartridge. Human plasma and urine (1 mL each) containing the 7 phenothiazine derivatives were mixed with 2 mL of 0.1M NaOH and 7 mL distilled water and then poured into the disk SPE cartridges. The drugs were eluted with 1 mL chloroform- acetonitrile (8 + 2) and determined by liquid chromatography with ammonium formate/formic acid-acetonitrile gradient elution. The detection was performed by ultraviolet absorption at 250 nm. The separation of the 7 phenothiazine derivatives from each other and from impurities was generally satisfactory using a SymmetryShield RP8 column (150 x 2.1 mm id, 3.5 microm particle size). The recoveries of the 7 phenothiazine derivatives spiked into plasma and urine samples were 64.0-89.9% and 65.1-92.1%, respectively. Regression equations for the 7 phenothiazine derivatives showed excellent linearity, with detection limits of 0.021-0.30 microg/mL for plasma and 0.017-0.30 microg/mL for urine. The within-day and day-to-day coefficients of variation for both samples were commonly below 9.0 and 14.9%, respectively.

[A case report of acute neuromyopathy induced by concomitant use of colchicine and bezafibrate].

We report a patient of acute neuromyopathy induced by concomitant use of colchicine and bezafibrate. A 75-year-old man with chronic renal failure and hyperlipidemia treated with bezafibrate (400 mg/day) for 1.5 years had developed watery diarrhea followed by acute tetraparesis, 14 days after the administration of colchicine for recurrent gout. Neurological examination showed proximal muscle weakness with myalgia, distal mild numbness (dysesthesia) of four limbs and generalized decreased or absent reflexies. The findings including elevated serum muscle enzymes, myogenic patterns with widespread myotonic discharge on the electromyography and delayed latency of F-wave on nerve conduction study indicated that the patient's clinical features were consistent with neuromyopathy. Soon after both colchicine and bezafibrate were stopped, the patient's symptoms resolved rapidly, therefore we made a diagnosis of drug-induced neuromyopathy, although rhabdomyolysis with Guillain-Barré syndrome was initially suspected. Recently, there had been reported acute and severe neuromuscular disorder induced by combination therapy with colchicine and anti-hyperlipidemic drugs, and there were clinical similarities between the cases of these reports and our case. Co-administration of colchicine with bezafibrate might accelerate the onset of neuromyopathy in connection with chronic renal failure in this case. Extreme caution is warranted when the patient with renal insufficiency concomitant use of colchicine and bezafibrate.

Dilative arterial remodeling of the brain with different effects on the anterior and posterior circulation: an MRI study.

OBJECTIVE: The goal of the study was to investigate factors associated with dilation of the internal carotid artery (ICA) and basilar artery (BA), which reflect the anterior and posterior circulation respectively, and to examine if these arteries are affected differently by specific factors. METHODS: The diameters of ICA and BA were measured using T2-weighted magnetic resonance (MR) images at the level of the brainstem in 304 outpatients, with the maximal width of the flow void taken as the diameter for each artery. The association between the diameters and clinical data including hemoglobin A1c (HbA1c) and estimated glomerular filtration rate (eGFR) was investigated. The same analysis was performed for the BA/ICA ratio. RESULTS: Multiple regression analysis adjusted for confounding factors including gender and age showed that a lower eGFR was independently associated with dilation of both the ICA (beta coefficient -0.148, P=0.0135) and the BA (beta -0.219, P=0.0007). HbA1C was independently associated with a greater BA/ICA ratio (beta -0.183, P=0.0015) but eGFR did not show this association. Diabetes mellitus was significantly more frequent (P=0.0353) in patients with a BA/ICA ratio higher than the mean, compared to those with a lower BA/ICA ratio. CONCLUSION: Kidney dysfunction was shown to be a dilative factor for the anterior and posterior circulation as reflected by the ICA and BA diameters, respectively. The association of the BA/ICA ratio with HbA1c suggests that diabetes mellitus may affect each circulation differently.

Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.

Ten antihistamine drugs, diphenhydramine, orphenadrine, chlorpheniramine, diphenylpyraline, triprolidine, promethazine, homochlorcyclizine, cyproheptadine, cloperastine and clemastine, have been found to be extractable from human plasma samples using MonoTip C18 tips, inside which C18- bonded monolithic silica gel was fixed. Human plasma (0.1 mL) containing the ten antihistamines was mixed with 0.4 mL of distilled water and 25 microL of a 1 M potassium phosphate buffer (pH 8.0). After centrifugation of the mixture, the supernatant fraction was extracted to the C18 phase of the tip by 25 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C18 phase were then eluted with methanol by five repeated aspirating/dispensing cycles. The eluate was injected into a gas chromatography (GC) injector without evaporation and reconstitution steps, and was detected by a mass spectrometer with selected ion monitoring in the positive-ion electron impact mode. The separation of the ten drugs from each other and from impurities was generally satisfactory using a DB-1MS column (30 m x 0.32 mm i.d., film thickness 0.25 microm). The recoveries of the ten antihistamines spiked into plasma were 73.8-105%. The regression equations for the ten antihistamines showed excellent linearity with detection limits of 0.02-5.0 ng/0.1 mL. The within-day and day-to-day coefficients of variation for plasma were not greater than 9.9%. The data obtained from determination of diphenhydramine and chlorpheniramine in human plasma after oral administration of the drugs are also presented.