Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke.

BACKGROUND AND PURPOSE: The P2Y12 receptor, a well-known factor in the platelet activation pathway, plays a role in thrombosis as well as systemic inflammation. Clopidogrel, a prototype P2Y12 receptor antagonist, reportedly decreases inflammation and systemic infection. The aim of this study was to evaluate whether clopidogrel use decreases the risk of post-stroke infection following ischaemic stroke. METHODS: A total of 1643 patients with acute ischaemic stroke (within 7 days after onset) were included for analysis between March 2010 and December 2015. Patients were categorized into two groups (clopidogrel users versus clopidogrel non-users), and clinical characteristics and risks of post-stroke infection were compared between the two groups. The inverse probability of treatment weighting using propensity scores for baseline imbalance adjustments was applied. RESULTS: Of the included patients (mean age 67.7 years; men 60.6%), 670 (40.8%) patients were clopidogrel users and 164 (10.0%) patients had post-stroke infection. The proportion of patients with post-stroke infection was significantly lower in clopidogrel users compared to clopidogrel non-users (6.7% vs. 12.2%, P ≤ 0.001). Moreover, clopidogrel users were less likely to be admitted to the intensive care unit (13.3% vs. 35.3%, P = 0.006). A multivariate analysis with inverse probability of treatment weighting revealed that clopidogrel users exhibited a lower risk of post-stroke infection (odds ratio 0.56, 95% confidence interval 0.42-0.75) and intensive care unit admission (odds ratio 0.34, 95% confidence interval 0.22-0.53). CONCLUSIONS: The study suggested that clopidogrel users exhibit a lower risk of infection and develop less severe infections after ischaemic stroke. Further prospective studies are needed.

Stemmed DNA nanostructure for the selective delivery of therapeutics.

DNA has emerged as a biocompatible biomaterial that may be considered for various applications. Here, we report tumor cell-specific aptamer-modified DNA nanostructures for the specific recognition and delivery of therapeutic chemicals to cancer cells. Protein tyrosine kinase (PTK)7-specific DNA aptamer sequences were linked to 15 consecutive guanines. The resulting aptamer-modified product, AptG15, self-assembled into a Y-shaped structure. The presence of a G-quadruplex at AptG15 was confirmed by circular dichroism and Raman spectroscopy. The utility of AptG15 as a nanocarrier of therapeutics was tested by loading the photosensitizer, methylene blue (MB), to the G-quadruplex as a model drug. The generated MB-loaded AptG15 (MB/AptG15) showed specific and enhanced uptake to CCRF-CEM cells, which overexpress PTK7, compared with Ramos cells, which lack PTK7, or CCRF-CEM cells treated with a PTK7-specific siRNA. The therapeutic activity of MB/AptG15 was tested by triggering its photodynamic effects. Upon 660 nm light irradiation, MB/AptG15 showed greater reactive oxygen species generation and anticancer activity in PTK7-overexpressing cells compared to cells treated with MB alone, those treated with AptG15, and other comparison groups. AptG15 stemmed DNA nanostructures have significant potential for the cell-type-specific delivery of therapeutics, and possibly for the molecular imaging of target cells.

D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer.

BACKGROUND AND PURPOSE: The occurrence of stroke in cancer patients is caused by conventional vascular risk factors and cancer-specific mechanisms. However, cryptogenic stroke in patients with cancer was considered to be more related to cancer-specific hypercoagulability. In this study, we investigated the potential of the D-dimer level to serve as a predictor of early neurologic deterioration (END) in cryptogenic stroke patients with active cancer. METHODS: We recruited 109 cryptogenic stroke patients with active cancer within 72 h of symptom onset. We defined END as an increase of ≥1 point in the motor National Institutes of Health Stroke Scale (NIHSS) score or ≥2 points in the total NIHSS score within 72 h of admission. After adjusting for potential confounding factors in the multivariate analysis, we calculated the odds ratios (ORs) and confidence intervals (CIs) of D-dimer in the prediction of END. RESULTS: Among 109 patients, END events were identified in 34 (31%) patients within 72 h. END was significantly associated with systemic metastasis, multiple vascular territory lesions on the initial magnetic resonance imaging (MRI), initial NIHSS score and D-dimer levels. In the multivariate analysis, the D-dimer level (adjusted OR, 1.11; 95% CI, 1.04-1.17; P < 0.01) and initial NIHSS score (adjusted OR, 1.08; 95% CI, 1.01-1.15; P = 0.03) predicted END after adjusting for potential confounding factors. In the subgroup analysis of 72 follow-up MRIs, D-dimer level was also correlated with new territory lesions on the follow-up MRI in a dose-dependent manner. CONCLUSION: Ischemic stroke patients with active cancer and elevated D-dimer levels appear to be at increased risk for END recurrent thromboembolic stroke.

Prolonged sleep increases the risk of intracerebral haemorrhage: a nationwide case-control study.

BACKGROUND AND PURPOSE: Although abnormal sleep duration is positively associated with increased risk for cardiovascular disease and mortality, the specific impact on intracerebral haemorrhage (ICH) risk remains unclear. The relationship between sleep duration and the risk of ICH was investigated in our study. METHODS: A nationwide, multicentre matched case-control study was performed to investigate the risk factors for haemorrhagic stroke, using patients from 33 hospitals in Korea. In all, 490 patients with ICH and 980 age- and sex-matched controls were enrolled. Detailed information regarding sleep, sociodemographic factors, lifestyle and medical history before ICH onset was obtained using qualified structured questionnaires. Sleep duration was categorized and the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a conditional logistic regression with 7 h as the reference duration. RESULTS: The number of subjects with long sleep duration, more than 8 h, was significantly greater in the ICH group than in the control group (≥8 h, 30.4% vs. 22.6%, P = 0.002). After controlling for relevant confounding factors, longer sleep duration was found to be independently associated with the risk of ICH in a dose-response manner (8 h, OR 1.57, 95% CI 1.00-2.47; ≥9 h, OR 5.00, 95% CI 2.18-11.47). CONCLUSIONS: Our study suggested that long sleep duration is positively associated with an increased ICH risk in a dose-dependent manner. Further studies on the relationship linking long sleep duration with increased risk of ICH are required.

Association between metabolic syndrome and functional outcome in patients with acute ischaemic stroke.

BACKGROUND AND PURPOSE: There is a paucity of information on the role of metabolic syndrome (MetS) as a prognosticator after ischaemic stroke. We investigated the association between MetS and functional outcome in patients with acute ischaemic stroke. METHODS: We evaluated 691 consecutive patients with acute stroke who were admitted to a tertiary medical center between January 2007 and June 2011. We defined MetS as having three or more of the five cardinal cardiovascular risk factors. Unfavorable functional outcome was determined using responder analysis, in which the outcome was adjusted by the initial severity of the stroke. Multivariable logistic regression analysis was used to evaluate the relationship between MetS and unfavorable outcomes (UnFO). RESULTS: Among 691 patients, 277 patients were classified as having an UnFO. The association between MetS and UnFO remained significant after adjusting for possible confounders; the adjusted odds ratio (95% confidence interval) was 1.57 (1.13-2.19). The risk for UnFO was positively associated with the number of MetS components. CONCLUSIONS: MetS may be a potent predictor of functional outcome after ischaemic stroke.

Standard steroid treatment for autoimmune pancreatitis.

OBJECTIVE: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). METHODS: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. RESULTS: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. CONCLUSIONS: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

An impulse based sensor for medical sensing applications.

This work designs a non-coherent impulse basedtransceiver operating in a frequency range of 3.1-10.6 GHz for medical sensing applications. The transmitter consists of an ON/OFF Keying data modulator, a Gaussian pulse generator, and a variable gain amplifier to control the transmitting pulse level. The receiver consists of an LNA, a multiplier, an integrator, and a comparator. The IC is designed using 0.18 microm CMOS technology with a supply voltage of 1.8 V. The simulated pulse width is 0.2 ns and the maximum pulse rate is over 1 GHz. A heart motion detection performance was demonstrated with high precision for an overall power consumption of 40 mW. This design can also be modified to be used in wireless UWB data communications to build a complete low power wireless sensor node.

Data acquisition system using six degree-of-freedom inertia sensor and ZigBee wireless link for fall detection and prevention.

Fall detection and prevention require logged physiological activity data of a patient for a long period of time. This work develops a data acquisition system to collect motion data from multiple patients and store in a data base. A wireless sensor network is built using high precision inertia sensors and low power Zigbee wireless transceivers. Testing results prove the system function properly. Researchers and physicians can now retrieve and analyze the accurate data of the patient movement with ease.

Comparative analysis of the spatial distribution and severity of cerebral microbleeds and old lacunes.

BACKGROUND: Cerebral microbleeds, which result from microangiopathic changes following chronic hypertension, may reflect bleeding-prone microangiopathy. However, the distribution of these lesions has not been compared with that of lacunes, which represent occlusive type microangiopathy. OBJECTIVES: To compare the cerebral distribution of microbleeds and lacunes and correlate their severity. METHODS: The study population comprised 129 hypertensive patients who underwent brain magnetic resonance imaging (MRI), including gradient echo (GE) sequences. Cerebral microbleeds were counted using GE-MRI data, and lacunes were also counted by comparing T1 and T2 weighted MRI. To investigate the distributions, the number of patients with each type of lesion was compared, and the occurrence index (the total number of the specific lesions divided by the total number of patients) was examined statistically. Correlation analyses were done on the relations between the different grades of microbleeds, lacunes, and leukoaraiosis. RESULTS: Cerebral microbleeds and lacunes were found at various foci in the brain, with a preference for the cortico-subcortical region and the deep grey matter. The occurrence index of microbleeds, but not of lacunes, was significantly higher in the cortico-subcortical region than in the deep grey matter. The severity of the microbleeds was positively correlated with the severity of lacunes, and both types of lesion were closely correlated with the degree of leukoaraiosis. CONCLUSIONS: These data suggest that microbleeds and lacunes tend to occur to a similar extent in long standing hypertension, but not necessarily in the same locations.

5-hydroxytryptamine strongly inhibits fluid secretion in guinea pig pancreatic duct cells.

We studied the distribution of 5-hydroxytryptamine- (5-HT-) containing cells in the guinea pig pancreas and examined the effects of 5-HT on fluid secretion by interlobular pancreatic ducts. The 5-HT-immunoreactive cells with morphological characteristics of enterochromaffin (EC) cells were scattered throughout the duct system and were enriched in islets of Langerhans. The fluid secretory rate in the isolated interlobular ducts was measured by videomicroscopy. Basolateral applications of 5-HT strongly but reversibly reduced HCO(3)-dependent, as well as secretin- and acetylcholine- (ACh-) stimulated, fluid secretion, whereas 5-HT applied into the lumen had no such effects. Secretin-stimulated fluid secretion could be inhibited by a 5-HT(3) receptor agonist, but not by agonists of the 5-HT(1), 5-HT(2), or 5-HT(4) receptors. Under the stimulation with secretin, 5-HT decreased the intracellular pH (pH(i)) and reduced the rate of pH(i) recovery after acid loading with NH(4)(+), suggesting that 5-HT inhibits the intracellular accumulation of HCO3(-). The elevation of intraductal pressure in vivo reduced secretin-stimulated fluid secretion, an effect that could be attenuated by a 5-HT(3) receptor antagonist. Thus, 5-HT, acting through basolateral 5-HT(3) receptors, strongly inhibits spontaneous, secretin-, and ACh-stimulated fluid secretion by guinea pig pancreatic ducts. 5-HT released from pancreatic ductal EC cells on elevation of the intraductal pressure may regulate fluid secretion of neighboring duct cells in a paracrine fashion.

Insulinoma with subsequent association of Zollinger-Ellison syndrome.

We report a patient with insulinoma associated with Zollinger-Ellison syndrome. A 67-year-old woman was first admitted to our hospital for an abdominal mass. Abdominal computed tomography (CT) revealed a large pancreatic tumor, which was then diagnosed as an unresectable pancreatic adenocarcinoma. At the age of 71, she presented symptoms of hypoglycemia. Fasting blood glucose was 21 mg/dl and plasma immunoreactive insulin level was 846 microU/ ml. Plasma gastrin, glucagon, vasoactive intestinal polypeptide and somatostatin levels were all normal. At the age of 73, hypoglycemic attacks occurred more frequently and she was admitted to our hospital. Abdominal CT scan showed multiple liver metastases. Chemotherapy with 5-fluorouracil and doxorubicin was performed. Three months later, she had an emergency laparotomy because of a perforated duodenal ulcer. Plasma gastrin level was 1,960 pg/ml at that time. Gastric hypersecretion was well controlled with a proton pump inhibitor (lansoprazole) but she died of widespread cancer dissemination 8 years after her first admission. On autopsy, histologic examination revealed a mixed acinar-endocrine carcinoma of the pancreas. Immunohistochemical stains were positive for insulin, gastrin, and alpha1-antitrypsin.

The effect of calcitonin gene-related peptide on pancreatic blood flow and secretion in conscious dogs.

The effects of human alpha-calcitonin gene-related peptide (alpha-CGRP) and beta-CGRP on pancreatic arterial (PA), superior mesenteric (SMA) and left gastric arterial (LGA) blood flows were studied by ultrasound transit-time blood flow meters in five conscious dogs. Intravenous injections of alpha-CGRP and beta-CGRP (5-200 pmol/kg) induced a dose-related increase in PA flow and a dose-related decrease in its resistance. At lower doses, alpha-CGRP was more potent than beta-CGRP, but their maximal responses were similar. The blood flow responses to alpha-CGRP (200 pmol/kg) were 153% of the basal flow in LGA, 313% in PA, and 534% in SMA, while those to VIP (100 pmol/kg) were 467% in LGA, 953% in PA and 163% in SMA. Somatostatin reduced blood flow in all arteries. alpha-CGRP, but not beta-CGRP, at higher doses induced gastric contractions and pancreatic protein-rich secretion, which were blocked by atropine. These results suggest that CGRP in perivascular nerves in the pancreas may regulate pancreatic blood flow in dogs but its physiological function remains to be studied.

HCO3- salvage mechanisms in the submandibular gland acinar and duct cells.

In the present work, we characterized H(+) and HCO3- transport mechanisms in the submandibular salivary gland (SMG) ducts of wild type, NHE2-/-, NHE3-/-, and NHE2-/-;NHE3-/- double knock-out mice. The bulk of recovery from an acid load across the luminal membrane (LM) of the duct was mediated by a Na(+)-dependent HOE and ethyl-isopropyl-amiloride (EIPA)-inhibitable and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-insensitive mechanism. HCO3- increased the rate of luminal Na(+)-dependent pH(i) recovery but did not change inhibition by HOE and EIPA or the insensitivity to DIDS. Despite expression of NHE2 and NHE3 in the LM of the duct, the same activity was observed in ducts from wild type and all mutant mice. Measurements of Na(+)-dependent OH(-) and/or HCO3- cotransport (NBC) activities in SMG acinar and duct cells showed separate DIDS-sensitive/EIPA-insensitive and DIDS-insensitive/EIPA-sensitive NBC activities in both cell types. Functional and immunocytochemical localization of these activities in the perfused duct indicated that pNBC1 probably mediates the DIDS-sensitive/EIPA-insensitive transport in the basolateral membrane, and splice variants of NBC3 probably mediate the DIDS-insensitive/EIPA-sensitive NBC activity in the LM of duct and acinar cells. Notably, the acinar cell NBC3 variants transported HCO3- but not OH(-). By contrast, duct cell NBC3 transported both OH(-) and HCO3-. Accordingly, reverse transcription-polymerase chain reaction analysis revealed that both cell types expressed mRNA for pNBC1. However, the acini expressed mRNA for the NBC3 splice variants NBCn1C and NBCn1D, whereas the ducts expressed mRNA for NCBn1B. Based on these findings we propose that the luminal NBCs in the HCO3- secreting SMG acinar and duct cells function as HCO3- salvage mechanisms at the resting state. These studies emphasize the complexity but also begin to clarify the mechanism of HCO3- homeostasis in secretory epithelia.

Diffusion-weighted MR findings of central pontine and extrapontine myelinolysis.

Diffusion-weighted MR (DWI) can detect changes in water diffusion associated with cellular dysfunction, which enables the differentiation of cytotoxic edema from vasogenic edema. In this study on DWI findings in central pontine (CPM) and extrapontine myelinolysis (EPM), DWI showed high signal intensities in the bilateral pons, midbrain, and genu of the corpus callosum. The corresponding apparent diffusion coefficient values were rather low. This suggests that cytotoxic edema does in fact exist in CPM and EPM and that DWI can be useful in the rapid diagnosis and prediction of the various types of edema occurring in active demyelinating diseases.

Serotonin and pancreatic duct function.

1. 5-HT inhibits spontaneous fluid secretion as well as stimulated secretion with secretin (cAMP mediated) or ACh (Ca2+ mediated) in the isolated guinea pig pancreatic ducts. 2. The inhibitory effect of 5-HT is reversible and is dependent on the concentration in the range 0.01-0.1 microM, which is much lower than those that affect intestinal motility and secretion. 3. The 5-HT3 receptor in duct cells appears to mediate the inhibitory effect of 5-HT. 4. [Ca2+]i is unlikely to mediate the inhibitory effect of 5-HT.

Arginine vasopressin inhibits fluid secretion in guinea pig pancreatic duct cells.

The effects of arginine vasopressin (AVP) on pancreatic ductal secretion were studied in guinea pigs. In the isolated vascularly perfused pancreas, AVP reduced secretin-stimulated fluid secretion and increased the vascular resistance when the perfusion rate was held constant. In the isolated interlobular duct segments, AVP inhibited secretin-stimulated fluid secretion, indicating the direct inhibitory action of AVP on the duct cells. AVP affected neither the basal nor the secretin-induced cAMP productions, suggesting that AVP inhibits the fluid secretion at a point distal to the production of cAMP. AVP increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in the absence of extracellular Ca(2+). When [Ca(2+)](i) was elevated by the application of thapsigargin, AVP caused a rapid decrease in [Ca(2+)](i). AVP seems to activate both Ca(2+) release from intracellular stores and Ca(2+) efflux across the plasma membrane, but its relation to the inhibition of fluid secretion remains to be clarified. It is concluded that AVP directly inhibits secretin-stimulated ductal fluid secretion in the guinea pig pancreas.