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Autonomic dysfunctions including impaired baroreflex sensitivity (BRS) can develop after acute ischemic stroke (AIS) and may predispose patients to subsequent cardiovascular adverse events and serve as potential indicators of long-term mortality. This study aimed to determine the potential short-term prognostic significance of BRS after AIS. All patients admitted to Kaohsiung Veterans General Hospital within 72 h after onset of first-ever AIS between April 2008 and December 2012 were enrolled. Autonomic evaluation with continuous 10-minute monitoring of beat-to-beat hemodynamic and intracranial parameters was performed within 1 week after stroke by using the Task Force Monitor and transcranial Doppler. The 176 enrolled AIS patients were divided into high-BRS and low-BRS groups. All but two enrolled patients (who died within 3 months after stroke) attended scheduled follow-ups. The high-BRS group had significantly lower National Institutes of Health Stroke Scale (NIHSS) scores at 1 and 2 weeks after stroke and at discharge, lower modified Rankin scale (mRS) scores 1, 3, 6, and 12 months after stroke, and lower rates of complications and stroke recurrence compared to the low-BRS group. This study provides novel evidence of the utility of BRS to independently predict outcomes after AIS. Furthermore, modifying BRS may hold potential in future applications as a novel therapeutic strategy for acute stroke.

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Aim To evaluate the association of cognitive impairment, depressive mood and sarcopenia among older men living in the veterans retirement community in southern Taiwan Methods This cross-sectional study recruited 353 men aged 65 years and older. In addition to demographic characteristics, all participants were measured for gait speed, handgrip strength and muscle mass by using bioelectrical impedance analysis (BIA). The diagnosis of sarcopenia was made according to the European Working Group on Sarcopenia in Older People criteria. Slow walking speed was defined as ≤0.8 meter/second. Low muscle strength was defined as the handgrip strength less than 22.5 kg which was adjusted according to Taiwanese norms. A height-adjusted muscle mass of 8.87 kg/m2 from a previous Taiwanese study was defined as low muscle mass. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE), and the Geriatric Depression Scale-15 (GDS-15) was used for screening of depressive symptoms. Results Among the 353 participants (mean age 82.7 ± 5.3 years), 30.9% (109/353) were classified as sarcopenic. Multivariate logistic regression showed that sarcopenia was independently associated with cognitive impairment (adjusted OR 3.03, 95% CI 1.63–5.65, P

Background Asians have higher frequency of intracranial arterial stenosis. The present study aimed to compare the clinical features and outcomes of ischemic stroke patients with and without middle cerebral artery (MCA) stenosis, assessed by transcranial sonography (TCS), based on the Taiwan Stroke Registry (TSR). Methods Patients with acute ischemic stroke or transient ischemic attack registered in the TSR, and received both carotid duplex and TCS assessment were categorized into those with stenosis (≥50%) and without (

PurposeTo evaluate the postacute care (PAC) needs of elderly patients in a tertiary teaching hospital.MethodsAll elderly veterans admitted to a tertiary medical center were screened for their needs for PAC services from May 1 to October 31, 2009. Case managers evaluated the inclusion/non-inclusion criteria while visiting patients before their discharge. Comprehensive geriatric assessment (CGA) was performed before their transfer, if they agreed to receive the PAC service in addition to the complete medical history review.ResultsOverall, 409 elderly patients (96.8% male; mean age = 80.4 ± 5.4 years) meeting the inclusion/exclusion criteria were screened, and 103 (25.2%) had PAC service needs. All patients diagnosed with central nervous system and musculoskeletal conditions displayed a significant decrease (93.1 ± 10.8 to 43.6 ± 33.3, p

Nutritional status is important in stroke care, but little is known regarding to the prognostic role of nutritional status on long-term functional outcomes among stroke survivors. The main purpose of this study was to evaluate to the prognostic role of nutritional status on long-term functional outcomes among stroke survivors. Data of acute stroke registry in Kaohsiung Veterans General Hospital were retrieved for analysis. Overall, 483 patients (mean age = 70.7 ± 10.3 years) with first-ever stroke were found. Among them, 95 patients (19.7%) were malnourished at admission, 310 (mean age = 70.4 ± 10.1 years, 63.5% males) survived for 6 months, and 244 (78.7%) had good functional outcomes. Subjects with poor functional outcomes were older (74.7 ± 8.9 vs. 69.0 ± 10.1 years, p < 0.001), more likely to be malnourished (56.2% vs. 26.6%, p < 0.001), to develop pneumonia upon admission (23.3% vs. 12.7%, p = 0.027), had a longer hospital stay (23.5 ± 13.9 vs. 12.5 ± 8.2 days, p < 0.001), had a higher National Institutes of Health Stroke Scale (NIHSS) score (12.9 ± 9.3 vs. 4.9 ± 4.3, p < 0.001), poorer stroke recovery (NIHSS improvement: 6.9% vs. 27.4%, p = 0.005), and poorer functional improvement (Barthel index = BI improvement in the first month: 31.4% vs. 138%, p < 0.001). Older age (odds ratio = OR) = 1.07, 95% confidence interval (CI = 1.03-1.11, p

Background— Stroke is a leading cause of death around the world. Improving the quality of stroke care is a global priority, despite the diverse healthcare economies across nations. The American Heart Association/American Stroke Association Get With the Guidelines-Stroke program (GWTG-Stroke) has improved the quality of stroke care in 790 US academic and community hospitals, with broad implications for the rest of the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry, with 30 599 stroke admissions between 2006 and 2008, was used to assess the applicability of GWTG-Stroke in Taiwan, which spends ≈1/10 of what the United States does in medical costs per new or recurrent stroke. Methods and Results— Taiwan Stroke Registry, sponsored by the Taiwan Department of Health, engages 39 academic and community hospitals and covers the entire country with 4 steps of quality control to ensure the reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applicable to assess Taiwan Stroke Registry quality of stroke care. Demographic and outcome figures are comparable between GWTG-Stroke and Taiwan Stroke Registry. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards, while 3 other indicators (intravenous tissue plasminogen activator, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Preliminary analysis shows that compliance with selected GWTG-Stroke guidelines is associated with better outcomes. Conclusions— Results suggest that GWTG-Stroke performance measures, with modification for ethnic factors, can become global standards across national and economic boundaries for assessing and improving quality of stroke care and outcomes. GWTG-Stroke can be incorporated into ongoing stroke registries across nations.

Neuropathological hallmarks of Alzheimer's disease are extracellular senile plaques and intracellular neurofibrillary lesions. The neurofibrillary lesions mainly consist of the hyperphosphorylated microtubule-associated protein Tau predominantly expressed in the axon of CNS neurons. Hyperphosphorylation of Tau negatively affects its binding to tubulin and decreases the capacity to promote microtubule assembly. Among a number of proline-directed kinases capable of phosphorylating paired helical filament-Tau, glycogen synthase kinase 3beta (GSK3beta) was first identified as a Tau protein kinase I and has been demonstrated to phosphorylate Tau both in vivo and in vitro. However, the phosphorylation mechanism of Tau by GSK3beta remained unclear. In this study, we show that the T231 is the primary phosphorylation site for GSK3beta and the Tau227-237 (AVVRTPPKSPS) derived from Tau containing T231P232 motif is identified as the GSK3beta binding site with high affinity of a Kd value 0.82 +/- 0.16 mumol/L. Our results suggest that direct binding and phosphorylation of T231P232 motif by GSK3beta induces conformational change of Tau and consequentially alters the inhibitory activity of its N-terminus that allows the phosphorylation of C-terminus of Tau by GSK3beta. Furthermore, hyperphosphorylation reduces Tau's ability to promote tubulin assembly and to form bundles in N18 cells. T231A mutant completely abolishes Tau phosphorylation by GSK3beta and retains the ability to promote tubulin polymerization and bundle formation. Taken together, these results suggest that phosphorylation of T231 by GSK3beta may play an important role in Tau's hyperphosphorylation and functional regulation.

The differences in the intracellular Ca2+ responses to hormones in platelets from systemic lupus erythematosus (SLE) patients compared to normal humans have not been explored. This study examined the Ca2+ signaling and density of platelets in normal, inactive and active SLE patients. The platelet number per µl in inactive and normal groups did not differ, whereas the number in active SLE patients was smaller than the other two groups by 60%. The intracellular free Ca2+ levels ([Ca2+]i) in response to stimulation of four endogenous Ca2+ mobilizing hormones, 100 µM arachidonic acid (AA), 10 µM ADP, 10 nM platelet activation factor (PAF) and 1 µM thrombin, were investigated using the Ca2+-sensitive fluorescent dye, fura-2. The AA-induced [Ca2+]i rises in normal and inactive groups were similar. In contrast, the AA-induced [Ca2+]i rises in the active SLE group were significantly smaller than in the normal and inactive groups. The defect in the AA-induced [Ca2+]i rises in active SLE groups appears to be caused by defective Ca2+ influx and Ca2+ releasing pathways because the AA-induced responses were not altered by removal of extracellular Ca2+, whereas the AA-induced responses in normal and inactive SLE groups were reduced by removal of extracellular Ca2+, and the AA-induced Ca2+ release was smaller in the active SLE group. PAF, ADP and thrombin all induced [Ca2+]i rises in the three groups, but no significant differences were found among the three groups. Together, the results indicate that cell density and Ca2+ signaling in platelets from active SLE patients are altered in response to particular stimulators. In these regards, platelets from inactive SLE patients appear to be similar to those from normal humans.

Posterior reversible encephalopathy syndrome (PRES) is a potentially devastating neurologic syndrome, but timely treatment may lead to complete reversal of the disease course. We reviewed 12 cases of PRES and describe the clinical history and imaging findings, including conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and calculated apparent diffusion coefficient (ADC) maps, used to establish the diagnosis of PRES. Three male and nine female patients aged between 11 and 70 years (mean, 37 years) with clinical and imaging findings consistent with PRES were enrolled in the study. All patients had undergone conventional MRI and 10 had undergone additional DWI studies. Ten patients had follow-up MRI studies. DWI was performed using a 1.5T system with a single-shot spin-echo echo-planar pulse sequence. Initial and follow-up neuroimaging and clinical history were reviewed. Lesions were almost always present over the posterior circulation, mainly the parieto-occipital region, affecting primarily the white matter. The anterior circulation region, brainstem, cerebellum, deep cerebral white matter, and thalamus were also involved in five cases. Conventional MRI revealed hyperintensity on T2- weighted and fluid-attenuated inversion recovery images. DWI showed isointensity and increased signal intensity on ADC values in all cases, indicating vasogenic edema. Clinical and MRI follow-up showed that the symptoms and radiologic abnormalities could be reversed after appropriate treatment of the causes of PRES in most patients (9 of 10). In one patient, the ADC value was lower on follow-up images, indicating cytotoxic edema with ischemic infarct. DWI was a useful complement to MRI in the diagnosis of PRES.

In human neuroblastoma IMR32 cells, the effect of the anti-depressant maprotiline on baseline intracellular Ca 2+ concentrations ([Ca 2+ ] i ) was explored by using the Ca 2+ -sensitive probe fura-2. Maprotiline at concentrations greater than 100 μM caused a rapid rise in [Ca 2+ ] i in a concentration-dependent manner (EC 50 = 200 μM). Maprotiline-induced [Ca 2+ ] i rise was reduced by 50% by removal of extracellular Ca 2+ . Maprotiline-induced [Ca 2+ ] i rises were inhibited by half by nifedipine, but was unaffected by verapamil or diiltiazem. In Ca 2+ -free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2+ -ATPase, caused a monophasic [Ca 2+ ] i rise, after which the increasing effect of maprotiline on [Ca 2+ ] i was abolished. U73122, an inhibitor of phospholipase C, did not affect maprotiline-induced [Ca 2+ ] i rises. These findings suggest that in human neuroblastoma cells, maprotiline increases [Ca 2+ ] i by stimulating extracellular Ca 2+ influx and also by causing intracellular Ca 2+ release from the endoplasmic reticulum via a phospholiase C-independent manner.

Information concerning acute myocardial infarctions (AMI) after heroin injection is limited. Only one report has described the association between heroin injections and AMI in a young woman. AMI after heroin injection in a patient with a normal coronary angiogram has not been reported. We report a 38-year-old man who developed AMI after heroin injection. He is probably the first case of AMI with normal coronary artery angiograms associated with heroin abuse. The heroin-induced toxic effect and/or coronary spasm are highly suspected to be the causes of the infarction episode.

The effects of quercetin, a natural polyphenolic compound, on voltage-dependent L-type Ca 2 + current (I C a ,L) in rat pituitary GH 3 cells were investigated with the aid of the whole-cell voltage-camp technique. Quercetin (0.5-200 pM) stimulated I C a , l l. in a concentration-dependent manner. The current-voltage (/-V) relationship of I C a , L was slightly shifted to more negative potentials in the presence of quercetin. The EC 5 0 value of the quercetin-induced stimulation of I C a , L was about 7 μM. The presence of quercetin (5 μM) shifted the steady state inactivation curve of I C a , L to a more negative potential by approximately -10 mV. Although quercetin might increase intracellular cyclic AMP, sp-cAMPS did not affect I C a , L . In addition, neither flavone nor wortmannin had any effect on the amplitude of I C a , L , while epicatechin and genistein slightly suppressed it. Quercetin (50 μM) decreased the amplitude of tetrodotoxin-sensitive Na current in GH 3 cells. Under current-clamp configuration, quercetin could increase the firing frequency of actions potentials. Conversely, in NG108-15 neuronal cells, quercetin suppressed the amplitude of I C a , L . The quercetin-induced inhibition of ICa,L was abolished in NG108-15 cells preincubated with t-butyl hydroperoxide (1 mM). Quercetin-mediated stimulation of I C a , L in GH 3 cells was presumably not associated with the level of intracellular cyclic AMP, or with the activity of tyrosine or phosphoinositide 3-kinases. Therefore, the effects of quercetin on ion currents may, at least in part, contribute to the underlying mechanisms through which it affects neuronal or neuroendocrine function.

Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for hepatic CYP2E1 activity. However, little is known about the mechanism of chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus investigated its effects on ion currents in GH(3) lactotrophs. Chlorzoxazone reversibly increased Ca(2+)-activated K(+) current (I(K(Ca))) in a concentration-dependent manner with an EC(50) value of 30 microM. The chlorzoxazone-stimulated I(K(Ca)) was inhibited by iberitoxin (200 nM) or clotrimazole (10 microM), but not by glibenclamide (10 microM) or apamin (200 nM). Chlorzoxazone (30 microM) suppressed voltage-dependent L-type Ca(2+) current. In the inside-out configuration, chlorzoxazone applied to the intracellular side of the patch did not modify single-channel conductance of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels, but did increase channel activity by increasing mean open time and decreasing mean closed time. Chlorzoxazone also caused a left shift in the activation curve of BK(Ca) channels. However, Ca(2+)-sensitivity of these channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30 microM), 2-amino-5-chlorobenzoxazole (30 microM) or chlormezanone (30 microM) enhanced BK(Ca) channel activity, while 6-hydroxychlorzoxazone (30 microM) slightly increased it; however, chlorphenesin carbamate (30 microM) had no effect on it. Under the current-clamp condition, chlorzoxazone (10 microM) reduced the firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone (30 microM) also stimulated BK(Ca) channel activity. The stimulatory effects of chlorzoxazone on these channels may be responsible for the underlying mechanism of chlorzoxazone actions on neurons and neuroendocrine cells.

The effect of nordihydroguaiaretic acid (NDGA) on Ca(2+) signaling in C6 glioma cells has been investigated. NDGA (5-100 microM) increased [Ca(2+)]i concentration-dependently. The [Ca(2+)]i increase comprised an initial rise and an elevated phase over a time period of 4 min. Removal of extracellular Ca(2+) reduced NDGA-induced [Ca(2+)]i signals by 52+/-2%. After incubation of cells with NDGA in Ca(2+)-free medium for 4 min, addition of 3 mM CaCl2 induced a concentration-dependent increase in [Ca(2+)]i. NDGA (100 microM)-induced [Ca(2+)]i increases in Ca(2+)-containing medium was not changed by pretreatment with 10 microM nifedipine or verapamil. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (1 microM) abolished 100 microM NDGA-induced [Ca(2+)]i increases. Inhibition of phospholipase C with 2 microM U73122 had little effect on 100 microM NDGA-induced Ca(2+) release. Several other lipoxygenase inhibitors had no effect on basal [Ca(2+)]i. Collectively, the results suggest that NDGA increased [Ca(2+)]i in glioma cells in a lipoxygenase-independent manner, by releasing Ca(2+) from the endoplasmic reticulum in a manner independent of phospholipase C activity and by causing Ca(2+) influx.

Background Discharge disposition planning is vital for poststroke patients. We investigated clinical factors associated with discharging patients to nursing homes, using the Taiwan Stroke Registry data collected from 39 major hospitals. Methods We randomly assigned 21,575 stroke inpatients registered from 2006 to 2008 into derivation and validation groups at a 3-to-1 ratio. We used the derivation group to develop a prediction model by measuring cumulative risk scores associated with potential predictors: age, sex, hypertension, diabetes mellitus, heart diseases, stroke history, snoring, main caregivers, stroke types, and National Institutes of Health Stroke Scale (NIHSS). Probability of nursing home care and odds ratio (OR) of nursing home care relative to home care by cumulative risk scores were measured for the prediction. The area under the receiver operating characteristic curve (AUROC) was used to assess the model discrimination against the validation group. Results Except for hypertension, all remaining potential predictors were significant independent predictors associated with stroke patient disposition to nursing home care after discharge from hospitals. The risk sharply increased with age and NIHSS. Patients with a cumulative risk score of 15 or more had an OR of 86.4 for the nursing home disposition. The AUROC plots showed similar areas under curves for the derivation group (.86, 95% confidence interval [CI], .85-.87) and for the validation group (.84, 95% CI, .83-.86). Conclusions The cumulative risk score is an easy-to-estimate tool for preparing stroke patients and their family for disposition on discharge.

The effects of five lignans (epi-aschantin, epi-magnolin, epi-yangambin, deoxypodophyllotoxin, yatein) isolated from Hernandia nymphaeifolia (Presl.) Kubitzki (Hernandiaceae) on intracellular Ca2+ levels ([Ca2+]i) in human neutrophils were investigated by using fura-2 as a fluorescent probe. In both Ca2+-containing and Ca2+-free media, the lignans (50-100 microM) did not alter basal [Ca2+]i but inhibited the [Ca2+]i increase induced by platelet activating factor (PAF, 10 microM), leukotriene B4 (LTB4, 0.2 microM), and thapsigargin (1 microM) to different extents. In Ca2+-free medium, after depleting stores of Ca2+ with PAF, LTB4 or thapsigargin, addition of 3 mM Ca2+ induced Ca2+ influx. Each of the lignans (50-100 microM) caused 39-89% inhibition of PAF-induced Ca2+ influx; whereas only epi-aschantin was able to inhibit LTB4- and thapsigargin-induced Ca2+ influx by 54-79%. Together, the results suggest that in human neutrophils, these lignans did not alter basal [Ca2+]i but inhibited Ca2+ movement induced by Ca2+ mobilizing agents.

The effect of oleamide, a sleep-inducing endogenous lipid in animal models, on intracellular free levels of Ca(2+) ([Ca(2+)](i)) in non-excitable and excitable cells was examined by using fura-2 as a fluorescent dye. [Ca(2+)](i) in pheochromocytoma cells, renal tubular cells, osteoblast-like cells, and bladder cancer cells were increased on stimulation of 50 microM oleamide. The response in human bladder cancer cells (T24) was the greatest and was further explored. Oleamide (10-100 microM) increased [Ca(2+)](i) in a concentration-dependent fashion with an EC(50) of 50 microM. The [Ca(2+)](i) signal comprised an initial rise and a sustained plateau and was reduced by removing extracellular Ca(2+) by 85 +/- 5%. After pre-treatment with 10-100 microM oleamide in Ca(2+)-free medium, addition of 3 mM Ca(2+) increased [Ca(2+)](i) in a manner dependent on the concentration of oleamide. The [Ca(2+)](i) increase induced by 50 microM oleamide was reduced by 100 microM La(3+) by 40%, but was not altered by 10 microM nifedipine, 10 microM verapamil, and 50 microM Ni(2+). In Ca(2+)-free medium, pre-treatment with thapsigargin (1 microM), an endoplasmic reticulum Ca(2+) pump inhibitor, abolished 50 microM oleamide-induced [Ca(2+)](i) increases; conversely, pretreatment with 50 microM oleamide reduced 1 microM thapsigargin-induced [Ca(2+)](i) increases by 50 +/- 3%. Suppression of the activity of phospholipase C with 2 microM U73122 failed to alter 50 microM oleamide-induced Ca(2+) release. Linoleamide (10-100 microM), another sleep-inducing lipid with a structure similar to that of oleamide, also induced an increase in [Ca(2+)](i). Together, it was shown that oleamide induced significant [Ca(2+)](i) increases in cells by a phospholipase C-independent release of Ca(2+) from thapsigargin-sensitive stores and by inducing Ca(2+) entry.

The effects of ceramide on ion currents in rat pituitary GH(3) cells were investigated. Hyperpolarization-elicited K(+) currents present in GH(3) cells were studied to determine the effect of ceramide and other related compounds on the inwardly rectifying K(+) current (I(K(IR))). Ceramide (C(2)-ceramide) suppressed the amplitude of I(K(IR)) in a concentration-dependent manner, with an IC(50) value of 5 microM. Ceramide caused a rightward shift in the midpoint for the activation curve of I(K(IR)). Pretreatment with PD-98059 (30 microM) or U-0126 (30 microM) did not prevent ceramide-mediated inhibition of I(K(IR)). However, the magnitude of ceramide-induced inhibition of I(K(IR)) was attenuated in GH(3) cells preincubated with dithiothreitol (10 microM). TNF alpha (100 ng/g) also suppressed I(K(IR)). In the inside-out configuration, application of ceramide (30 microM) to the bath slightly suppressed the activity of large conductance Ca(2+)-activated K(+) channels. Under the current clamp mode, ceramide (10 microM) increased the firing of action potentials. Cells that exhibited an irregular firing pattern were converted to those displaying a regular firing pattern after application of ceramide (10 microM). Ceramide also suppressed I(K(IR)) in neuroblastoma IMR-32 cells. Therefore, ceramide can produce a depressant effect on I(K(IR)). The blockade of this current by ceramide may affect cell function.

The effect of histamine on intracellular free Ca2+ levels ([Ca2+](i)) in MG63 human osteosarcoma cells was explored using fura-2 as a Ca2+ dye. Histamine increased ([Ca2+](i)) in a concentration-dependent fashion with an EC(50) value of 0.5 microM. Extracellular Ca2+ removal inhibited the ([Ca2+](i)) signals. Histamine failed to increase ([Ca2+](i)) in Ca2+-free medium after cells were pretreated with thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). Addition of Ca2+ induced concentration-dependent ([Ca2+](i)) increases after preincubation with histamine in Ca2+-free medium. Histamine-induced intracellular Ca2+ release was abolished by inhibiting phospholipase C with 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). The ([Ca2+](i)) increase induced by histamine in Ca2+ medium was abolished by cimetidine, but was not altered by pyrilamine, nifedipine, verapamil, and La(3+). Together, this study shows that histamine increased in ([Ca2+](i)) in osteosarcoma cells by stimulating H2 histamine receptors. The Ca2+ signal was caused by Ca2+ release from the endoplasmic reticulum in a phospholipase C-dependent manner. The Ca2+ release was accompanied by Ca(2+) influx.

The effect of the antidepressant fluoxetine on Ca 2+ signaling in cultured cells was largely unknown. The effect of various concentrations of fluoxetine on [Ca 2+] i in populations of bladder female transitional cancer (BFTC) cells was evaluated by using fura-2 as a Ca 2+ probe. Fluoxetine increased [Ca 2+] i concentration dependently (20–100 μ M) with an EC 50 value of 30 μ M. The response was inhibited by 50–60% on extracellular Ca 2+ removal. In Ca 2+ -free medium, pretreatment with 1 μ M thapsigargin (an inhibitor of the endoplasmic reticulum Ca 2+ pump) abolished 50 μ M fluoxetine-induced Ca 2+ release; whereas pretreatment with fluoxetine did not alter the thapsigargin-induced Ca 2+ response. Addition of 3 mM Ca 2+ increased [Ca 2+] i after pretreatment with 50 μ M fluoxetine in Ca 2+ -free medium, suggestive of fluoxetine-induced capacitative Ca 2+ entry. Suppression of inositol 1,4,5-trisphosphate formation by 2 μ M U73122 (a phospholipase C inhibitor) did not affect 50 μ M fluoxetine-induced Ca 2+ release. Collectively, this study shows that fluoxetine increased [Ca 2+] i in bladder cancer cells in a concentration-dependent fashion, by releasing Ca 2+ from thapsigargin-sensitive Ca 2+ stores in an IP 3 -independent manner, and by inducing Ca 2+ influx from extracellular medium.

The effect of fendiline, an anti-anginal drug, on cytosolic free Ca(2+) levels ([Ca(2+)](i)) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca(2+) indicator. Fendiline at concentrations between 1 and 200 microM increased [Ca(2+)](i) in a concentration-dependent manner and the signal saturated at 100 microM. The Ca(2+) signal was inhibited by 65+/-5% by Ca(2+) removal and by 38+/-5% by 10 microM nifedipine, but was unchanged by 10 microM La(3+) or verapamil. In Ca(2+)-free medium, pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+) store inhibited fendiline-induced intracellular Ca(2+) release. The Ca(2+) release induced by 50 microM fendiline appeared to be independent of IP(3) because the [Ca(2+)](i) increase was unaltered by inhibiting phospholipase C with 2 microM U73122. Collectively, the results suggest that in MG63 cells fendiline caused an increase in [Ca(2+)](i) by inducing Ca(2+) influx and Ca(2+) release in an IP(3)-independent manner.

The effect of oleamide, a sleep-inducing endogenous lipid in animal models, on intracellular free levels of Ca2+ ([Ca2+]i) in Madin-Darby renal tubular cells was examined using fura-2 as a fluorescent dye. Oleamide (5–50 μM) increased [Ca2+]i in a concentration-dependent fashion with an EC50 value of 20 μM. The [Ca2+]i signal comprised an initial rise and an elevated phase and was reduced by removing extracellular Ca2+ by 50%. After pretreatment with 5–50 μM oleamide in Ca2+-free medium, addition of 3 mM Ca2+ increased [Ca2+]i in a manner dependent on the concentration of oleamide. In Ca2+-free medium, pretreatment with thapsigargin (1 μM), an endoplasmic reticulum Ca2+ pump inhibitor, abolished [Ca2+]i increases induced by 20 μM oleamide; conversely, pretreatment with 20 μM oleamide reduced 1 μM thapsigargin-induced [Ca2+]i increases by 50%. Suppression of the activity of phospholipase C with 2 μM U73122 abolished 20 μM oleamide-induced Ca2+ release. Collectively, these data demonstrate that oleamide induced significant [Ca2+]i increases in renal tubular cells by a phospholipase C-dependent release of Ca2+ from thapsigargin-sensitive stores and by inducing Ca2+ entry via store-operated Ca2+ entry. Drug Dev. Res. 54:40–44, 2001. © 2001 Wiley-Liss, Inc.

To evaluate the association of cognitive impairment, depressive mood and sarcopenia among older men living in the veterans retirement community in southern TaiwanThis cross-sectional study recruited 353 men aged 65 years and older. In addition to demographic characteristics, all participants were measured for gait speed, handgrip strength and muscle mass by using bioelectrical impedance analysis (BIA). The diagnosis of sarcopenia was made according to the European Working Group on Sarcopenia in Older People criteria. Slow walking speed was defined as ≤ 0.8 meter/second. Low muscle strength was defined as the handgrip strength less than 22.5 kg which was adjusted according to Taiwanese norms. A height-adjusted muscle mass of 8.87 kg/m2 from a previous Taiwanese study was defined as low muscle mass. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE), and the Geriatric Depression Scale-15 (GDS-15) was used for screening of depressive symptoms.Among the 353 participants (mean age 82.7 ± 5.3 years), 30.9% (109/353) were classified as sarcopenic. Multivariate logistic regression showed that sarcopenia was independently associated with cognitive impairment (adjusted OR 3.03, 95% CI 1.63-5.65, P0.001) and depressive symptoms (adjusted OR 2.25, 95% CI 1.03-4.89, P = 0.04).Sarcopenia was significantly associated with cognitive impairment and depressive symptoms among otherwise healthy older men living in the veterans retirement community. Further outcome study is required to explore the interrelationship of cognition, depressive symptoms and sarcopenia in older adults.

To emphasize the importance of early recognition and emergent surgery for spontaneous spinal epidural hematoma (SSEH).A 61-year-old female presented with sudden onset of severe neck and back pain after finishing worshiping Buddha followed by quadriparesis, sensory deficits below C4 level and sphincter dysfunction. MR imaging demonstrated acute extensive epidural hematoma of cervico-thoracic spinal segments (C2-T7). Idiopathic SSEH was diagnosed and emergent decompressive laminectomy with hematoma evacuation was performed within 12 hours of symptoms onset. Good functional and neurological outcomes were obtained.SSEH is a rare but disabling or even fatal entity. Early diagnosis and prompt surgery improve the neurological and functional outcome but still remain a clinical challenge. Relevant physicians should pay attention to the typical symptoms of the rare entity and SSEH should be one of differential diagnoses.

We reviewed the medical records and imaging studies on the in-hospital patients to investigate the clinical and etiological patterns in hemorrhagic stroke in young patients. We evaluated 210 patients (131 males and 79 females) aged 15-45 years who had traumatic hemorrhagic stroke between April 1, 1986, and November 30, 1992. Nontraumatic intracerebral hemorrhage was diagnosed in 170 patients (80.9%). The main causes of nontraumatic intracerebral hemorrhage were hypertension, ruptured arteriovenous malformation, and blood dyscrasia. A cause was not found in 42 patients (24.7%). Subarachnoid hemorrhage was found in 40 patients (19.1%). The main causes were ruptured aneurysms and arteriovenous malformations. The overall in-hospital survival of young patients with hemorrhagic stroke was 64.7%. Young adults with nontraumatic intracerebral and subarachnoid hemorrhage are a heterogeneous group. Hypertension accounts for about one-third of intracerebral hemorrhage and is an important preventable cause of hemorrhagic stroke in young adults in Taiwan.

Elderly people with dementia are at increased risk of falls and intervention trials to prevent falls have failed to demonstrate clinical effectiveness in this population. This study evaluates the role of urinary incontinence as a fall risk factor in older patients with dementia, with the aim of developing relevant intervention strategies.Elderly patients with dementia visiting our center were recruited. All subjects underwent a Comprehensive Geriatric Assessment (CGA), and patients were divided into two groups (fall and non-fall) according to their history of falls in the past year. Components of the CGA, including physical function, mental function, depressive symptoms, incontinence, and nutritional status, were evaluated according to fall history.Overall, 159 patients with dementia (mean age 77.3 ± 9.0 years, 59.1% male) participated. Fifty-four patients (34.0%) had experienced falls in the past year. Among all subjects, 50.3% were diagnosed with mild dementia, 37.7% with moderate dementia, and 12.0% with severe dementia according to an established Clinical Dementia Rating scale. Subjects in the fall group displayed poorer physical function, balance, depressive mood, nutritional status, urinary incontinence, and had an increased prevalence of polypharmacy. However, multivariate analysis revealed urinary incontinence as the only independent risk factor for falls (OR = 4.9 ± 2.2, 95% CI: 2.0-12.0, P0.001).Urinary incontinence is a previously unidentified risk factor for falls among elderly dementia patients. An interventional study with the focus of urinary incontinence could improve the effectiveness of fall prevention among these patients.

This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged ≥ 16 years ( N = 251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a ≥ 50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.

Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-beta(42) levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Abeta(42) levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=-0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients.

Objective: To compare the effectiveness of the Minimum Data Set-based Depression Rating Scale (MDS-DRS) and Geriatric Depression Scale (GDS) in screening depression among older institutionalized Chinese men living in Taiwan. Method: MDS Nursing Home 2.1 Chinese version, Mini-Mental State Examination (MMSE), and short form Geriatric Depression Scale (GDS-15) were used among elderly residents in Banciao Veterans Home. Screening results of MDS-DRS and GDS-15, and relationship between 16 MDS Mood and Anxiety symptoms and depression were evaluated. Results: The prevalence of depression defined by MDS-DRS and GDS were 0.2% and 8.7%, respectively. Multiple logistic regression disclosed that E1a (OR: 12.9, 95% CI: 2.8-58.8, p = 0.001), E1k (OR: 15.6, 95% CI: 5.6-43.5, p < 0.001), and E1l (OR: 22.2, 95% CI: 6.1-83.3, p < 0.001) were all independent associative factors for GDS-defined depression but only explained 51.9% of all depressive subjects. Conclusions: The effectiveness of MDS-DRS is limited, and a new MDS-based depression screening instrument is needed.

To describe a patient with lithium intoxication presenting as acute parkinsonism, adverse metabolic effects and nephrogenic diabetes insipidus (DI).We report a case of a 67-year-old woman with a bipolar affective disorder who was treated with lithium for 10 years. Under concomitant renal insufficiency and urinary tract infarction, she experienced progressive hand tremor, bradykinesia, and unsteady gait. Laboratory results revealed hypercalcemia and hypermagnesiemia. A high serum lithium level (3.6 mEq/L) was found; thus lithium was discontinued. She was found to have a high serum level of intact parathyroid hormone: 135.0 pg/ml and a suspicious parathyroid adenoma. Polyuria with hypernatremia was also noted. A water deprivation test confirmed nephrogenic diabetes insipitces. After correction of electrolyte imbalance and reduction of lithium level, her consciousness recovered. Her parkinsonian features were responsive to levodopa 400 mg/day in 2 divided doses. One month later, apart from the residual extrapyramidal symptoms and mania, her condition was otherwise stationary.Tremor is the most frequent movement disorder associated with lithium therapy, while severe parkinsonism has been rarely reported. It should be kept in mind in differential diagnosis of acute parkinsonism especially in elder patients who receive a chronic lithium carbonate therapy.

Elevated plasma homocysteine levels are associated with an increased risk of deep vein thrombosis. Herein we report a case of familial hyperhomocysteinemia-related cerebral venous sinus thrombosis and pulmonary embolism in a 21-year-old man who presented with severe headache over bilateral frontal areas. Neurological examination revealed no evidence of focal neurological deficit. Chest CT showed pulmonary thromboembolism in bilateral basal lung fields and brain MRI disclosed right transverse and sigmoid venous sinus thrombosis. Routine immunological tests, coagulation factors and occult tumor screening were normal, as were vitamin B12 and folate levels. The DIC profile was negative, The only risk factor we were able to identify was an elevated serum homocysteine level, namely 46.23 microM/L. Hyperhomocysteinemia was also noted in the patient's asymptomatic elder brother (68.0 microM/L) and, to a lesser extent, in his parents (father 12.5 microM/L; mother 11.7 microM/L). In conclusion, the cause of cerebral venous thrombosis and pulmonary embolism in this young patient was most likely related to familial hyperhomocysteinemia, with the thromboembolic events precipitated by a preceding systemic infection. After anticoagulation therapy; the patient recovered completely without any residual neurological deficit.

Primary intracerebral hemorrhage (ICH) occurs more commonly in Taiwan than in other western countries. Recurrence of primary ICH after a first episode is not rare. The purpose of this study is to investigate the incidence, risk factors, and prognosis of recurrent primary ICH.From the stroke registration data of Kaohsiung Veterans General Hospital (KSVGH), all patients admitted between Jan. 1999 and Dec. 2003 with the discharge diagnosis of ICH were identified. The hospital records and images of each ICH patient were carefully reviewed and the diagnosis was confirmed by one of the investigators. For those patients admitted in this study period with the diagnosis of acute primary ICH who also had past medical history of ICH, the record and image of the past admission were also obtained for review, either from KSVGH or other hospitals. Patients with ICH due to secondary causes were excluded.585 patients with primary ICH were reviewed. Among them, 34 (5.8%) patients were found to have recurrent primary ICH. The medical records of these 34 patients were obtained for further analysis. Cerebral amyloid angiopathy was diagnosed in 4 (11.7%) patients. Mean ages at the onset of the first and second hemorrhages were 64 +/- 13 and 66 +/- 13 years, respectively. The mean interval between first and second hemorrhages was 33 months (from 1 month to 10 years). The most common location of first-second bleeding was basal ganglion-basal ganglion. The mortality rate in this group was 23.5%. Fifteen (38.2%) patients became totally dependent or vegetative after the second ICH.Recurrent primary ICH is not uncommon. The main location of recurrent bleeding was basal ganglion. This may implicate hypertension as the main cause of ICH. Hypertension is an important risk factor of recurrent primary ICH. Amyloid angiopathy is another cause of recurrent primary ICH. The prognosis after the second hemorrhage is worse, while the mortality and morbidity after first ever primary ICH were 15.6% and 17.9%, respectively.

Neuropathological hallmarks of Alzheimer's disease are extracellular senile plaques and intracellular neurofibrillary lesions. The neurofibrillary lesions mainly consist of the hyperphosphorylated microtubule-associated protein Tau predominantly expressed in the axon of CNS neurons. Hyperphosphorylation of Tau negatively affects its binding to tubulin and decreases the capacity to promote microtubule assembly. Among a number of proline-directed kinases capable of phosphorylating paired helical filament-Tau, glycogen synthase kinase 3beta (GSK3beta) was first identified as a Tau protein kinase I and has been demonstrated to phosphorylate Tau both in vivo and in vitro. However, the phosphorylation mechanism of Tau by GSK3beta remained unclear. In this study, we show that the T231 is the primary phosphorylation site for GSK3beta and the Tau227-237 (AVVRTPPKSPS) derived from Tau containing T231P232 motif is identified as the GSK3beta binding site with high affinity of a Kd value 0.82 +/- 0.16 mumol/L. Our results suggest that direct binding and phosphorylation of T231P232 motif by GSK3beta induces conformational change of Tau and consequentially alters the inhibitory activity of its N-terminus that allows the phosphorylation of C-terminus of Tau by GSK3beta. Furthermore, hyperphosphorylation reduces Tau's ability to promote tubulin assembly and to form bundles in N18 cells. T231A mutant completely abolishes Tau phosphorylation by GSK3beta and retains the ability to promote tubulin polymerization and bundle formation. Taken together, these results suggest that phosphorylation of T231 by GSK3beta may play an important role in Tau's hyperphosphorylation and functional regulation.

Background/Purpose MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome is often associated with A3243G point mutation of mitochondrial DNA (mtDNA). We previously described a MELAS family characterized by harboring an additional ∼260 bp tandem duplication in the D-loop and a novel C3093G point mutation in the 16S rRNA gene of mtDNA in the proband. We studied the clinical progression and fluctuation of mtDNA mutations in this Taiwanese MELAS family. Methods We followed up the clinical course in all members of this family (1 proband, her mother and 3 sons) for 12 years. Mutations of mtDNA in serial muscle biopsies of the proband and blood samples and hair follicles taken at different time points from the members of this family were analyzed. Results The proband developed repeated stroke-like episodes, chronic intestinal pseudo-obstruction, polyneuropathy, progressive renal failure and dilated cardiomyopathy with heart failure. During the follow-up period, the mother and one of the siblings of the proband developed stroke-like episodes at age 62 and 12, respectively. There was no significant difference in the proportions of mtDNA with A3243G mutation among five serial muscle biopsies of the proband. In one carrier (I-2), the proportion of A3243G mutated mtDNA in blood cells was slightly increased with disease progression. Conclusion This study underlines the importance of early detection of extraneuromuscular symptoms in the members of a family with MELAS syndrome by adequate follow-up. The age of onset of stroke-like episode in MELAS syndrome may be as late as 62 years. We suggest that the manifestations of MELAS syndrome in this family might be associated with the additional ∼260 bp tandem duplication in the D-loop region and the coexistence of C3093G mutation in the 16S rRNA gene with the A3243G mutation of mtDNA.

We report on the case of a 60-year-old man who suffered from hiccup, dysphagia and unsteady gait for three months. He was diagnosed with intracranial dural arteriovenous fistula in medulla with retrograde perimedullary vein drainage. He developed quadriplegia, persistent shock status and symptomatic bradycardia immediately after a conventional cerebral angiography study. After excluding cardiogenic, hypovolemic, anaphylactic and septic shock, central vasomotor failure caused by venous thrombosis of the lesion was considered. The patient's central vasomotor failure recovered after continuous dopamine infusion treatment for 42 days. We concluded that venous hypertension with venous thrombosis in rostral ventrolateral medulla (RVLM), a major vasomotor center in the brainstem, was the lesion site. In our case, vasomotor dysfunction caused by an RVLM lesion related to venous thrombosis is considered as causative.

The behavioral and psychological symptoms of dementia (BPSD) often present major problems for patients and their caregivers. In the past, neurologists paid less attention to such symptoms than to the cognitive symptoms of dementia. This prospective study investigated the prevalence of psychiatric morbidity in a neurology-based memory clinic and the stress of caregivers. Our patients with dementia were found to have a high prevalence of BPSD. The most frequent were anxiety, apathy, and delusion; the most distressing to caregivers were agitation, anxiety, delusion, and sleep disturbance. Using Clinical Dementia Rating (CDR), we compared BPSD between patients with mild dementia and those with moderate dementia. Only hallucinations and agitation were different significantly. Moderate dementia patients experienced these symptoms more frequently. The high prevalence of these symptoms might be explained by the fact that the cognitive symptoms were neglected or no enough information were received by many family members of patients with dementia until their own life quality was interfered and then they began to seek medical help. These symptoms and their effect of caregiver distress can be effectively reduced by pharmacologic and nonpharmacoloic managements, caregiver-focused training and education. They can be better approached by assessing neuropsychiatric symptoms regularly, educating the general population better, and treating these patients earlier.

A 69-year-old woman developed deep coma and brain stem areflexia after subarachnoid hemorrhage. Due to unstable vital signs, she was not a candidate for an apnea test. Computed tomographic angiography revealed absence of intracranial circulation, and brain death was diagnosed.

Theoretically, sensory nerve action potential (SNAP) of the superficial peroneal nerve (SPN) should be preserved when L5 roots are damaged. Previous study indicated that SNAP of SPN was lost or reduced in amplitude in patiens with L5 radiculopathy. To address this issue, this study compared results of SPN sensory conduction studies between healthy subjects and patients with L5 radiculopathy.Ninety-four healthy subjects were enrolled and assigned to two age groups: group I (or = 60 years, n=61) and group II (60 years, n=33). Forty-one patients with unilateral L5 radiculopathy were enrolled by our electrodiagnostic laboratory between July 2000 and July 2003 and assigned to two age groups: 60 years or below (n=19) and above 60 years (n=22).SPN response was found to be abnormal in only 1.6% of group I healthy subjects, but absent or abnormal SPN response was noted in 21.1% of patients with L5 radiculopathy of the same age group (p=0.01). However, a greater proportion of (27.3%) our healthy subjects above 60 years had abnormal SPN responses. This proportion was similar to that of patients with L5 radiculopathy and abnormal SPN response (31.8%) (p=0.72).SPN sensory responses are reliably obtained in most healthy subjects under 60 years of age. Absence of SNAP or reduced SNAP amplitude of SPN on the side of their lesions did not necessarily exclude the diagnosis of L5 radiculopathy in the patients under 60 years of age.

Brain abscesses and brain tumors may have similar clinical presentations. For example, only 50% brain abscess patients have fever, which could be masked by corticosteroid therapy. Also, the differential diagnosis of brain abscesses versus cystic or necrotic tumors may be difficult based on computed tomography (CT) or magnetic resonance (MR) imaging findings. However, the strategies of management for abscess and neoplasm are very different, and it is especially imperative to have a correct diagnosis before any surgical intervention of cystic brain lesions. The MR special techniques, e.g. diffusion-weighted imaging (DWI) and proton (1H) MR spectroscopy, are useful as additional diagnostic modalities for differentiating brain abscesses from cystic or necrotic brain tumors. DWI shows high signal intensity in most cases of pyogenic abscesses and low signal intensity in most cases of cystic or necrotic tumors. MR spectroscopy shows characteristic metabolites in pyogenic abscesses, distinct from those in cystic or necrotic tumors.

Cerebral amyloid angiopathy (CAA) contributes to sporadic lobar intracerebral hemorrhage in older patients, especially those who are more than 70 years old. In clinical practice, a diagnosis of CAA refers to the Boston Criteria, which requires that "definitive" cases be confirmed by pathologic evidence at autopsy. A "Probable" case, means that there is clinical support and that pathologic evidence is available by biopsy from the craniotomy for patients with severe lobar intracerebral hemorrhage. Cerebral amyloid that is deposited in cortical vessels is revealed by apple-green birefringence under polarized light using Congo-red stain. Rebleeding after a first primary intracerebral hemorrhage is common. This paper describes five cases of aged patients with lobar cerebral hemorrhage and craniotomy with hematoma evacuation and biopsy. Pathological results all showed amyloid angiopathy. Various outcomes are discussed, and the literature is reviewed. Findings show that although patients with CAA were at high risk of recurrent hemorrhage after surgery, the mortality rate was relatively low despite the severity of lobar intracerebral hemorrhage.

1. The effect of maprotiline, an antidepressant, on human prostate cells is unclear. In the present study, the effect of maprotiline on [Ca 2 + ] i and growth in PC3 human prostate cancer cells was measured using the fluorescent dyes fura-2 and tetrazolium, respectively. 2. Maprotiline caused a rapid, concentration-dependent increase in [Ca 2 + ] i (EC 5 0 = 200 μmol/L). The maprotiline-induced [Ca 2 + ] i increase was reduced by removal of extracellular Ca 2 + or pretreatment with nicardipine. 3. The maprotiline-induced Mn 2 + influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca 2 + influx. 4. In Ca 2 + -free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2 + -ATPase, caused a monophasic [Ca 2 + ] i increase, after which the effects of maprotiline of increasing [Ca 2 + ] i were abolished. In addition, pretreatment with maprotiline reduced a major portion of the thapsigargin-induced increase in [Ca 2 + ] i . 5. U73122, an inhibitor of phospholipase C, abolished the ATP (but not maprotiline)-induced increase in [Ca 2 + ] i . 6. Overnight incubation with 1-10 μmol/L maprotiline did not alter cell proliferation, although incubation with 30-50 μmol/L maprotiline decreased cell proliferation. 7, These findings suggest that maprotiline rapidly increases [Ca 2 + ] i in human prostate cancer cells by stimulating both extracellular Ca 2 + influx and intracellular Ca 2 + release and that it may modulate cell proliferation in a concentration-dependent manner.

The differences in the intracellular Ca(2+) responses to hormones in platelets from systemic lupus erythematosus (SLE) patients compared to normal humans have not been explored. This study examined the Ca(2+) signaling and density of platelets in normal, inactive and active SLE patients. The platelet number per mul in inactive and normal groups did not differ, whereas the number in active SLE patients was smaller than the other two groups by 60%. The intracellular free Ca(2+) levels ([Ca(2+)](i)) in response to stimulation of four endogenous Ca(2+) mobilizing hormones, 100 microM arachidonic acid (AA), 10 microM ADP, 10 nM platelet activation factor (PAF) and 1 microM thrombin, were investigated using the Ca(2+)-sensitive fluorescent dye, fura-2. The AA-induced [Ca(2+)](i) rises in normal and inactive groups were similar. In contrast, the AA-induced [Ca(2+)](i) rises in the active SLE group were significantly smaller than in the normal and inactive groups. The defect in the AA-induced [Ca(2+)](i) rises in active SLE groups appears to be caused by defective Ca(2+) influx and Ca(2+) releasing pathways because the AA-induced responses were not altered by removal of extracellular Ca(2+), whereas the AA-induced responses in normal and inactive SLE groups were reduced by removal of extracellular Ca(2+), and the AA-induced Ca(2+) release was smaller in the active SLE group. PAF, ADP and thrombin all induced [Ca(2+)](i) rises in the three groups, but no significant differences were found among the three groups. Together, the results indicate that cell density and Ca(2+) signaling in platelets from active SLE patients are altered in response to particular stimulators. In these regards, platelets from inactive SLE patients appear to be similar to those from normal humans.

In Madin-Darby canine kidney (MDCK) cells, the effect of maprotiline, an antidepressant, on intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured using fura-2. Maprotiline (2.5 microM) caused a rapid rise of [Ca(2+)](i) in a concentration-dependent manner (EC(50) 200 microM). Maprotiline-induced [Ca(2+)](i) rise was reduced by removal of extracellular Ca(2+) or by addition of La(3+), but was not altered by voltage-gated Ca(2+)-channel blockers. Maprotiline-induced Mn(2+) influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca(2+) influx. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca(2+)](i) rise, after which the increasing effect of maprotiline on [Ca(2+)](i) was nearly abolished; also, pretreatment with maprotiline reduced a portion of thapsigargin-induced [Ca(2+)](i) rise. U73122, an inhibitor of phospholipase C, abolished [Ca(2+)](i) rise induced by ATP (but not by maprotiline). Overnight incubation with 1-10 microM maprotiline enhanced cell viability, but 20-50 microM maprotiline decreased it. These findings suggest that maprotiline rapidly increases [Ca(2+)](i) in renal tubular cells by stimulating both extracellular Ca(2+) influx and intracellular Ca(2+) release, and may modulate cell proliferation in a concentration-dependent manner.