bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Functional Study on CysLT<sub>1</sub> Receptors in Human Eosinophils
Authors: Ohshima Nobuharu , Nagase Hiroyuki , Koshino Takeshi , Miyamasu Misato , Yamaguchi Masao , Hirai Koichi , Yamamoto Kazuhiko , Fujisawa Takao , Nakagawa Naoki , Kishikawa Katsuya , Morita Yutaka 
Published: April 2003

<i>Background:</i> The cysteinyl leukotrienes (CysLTs) mediate their biological actions through two receptors: CysLT<sub>1</sub> receptor and CysLT<sub>2</sub> receptor. <i>Objective:</i> This study was undertaken to examine the direct effects of CysLTs on eosinophils, such as chemotaxis and degranulation, focusing on CysLT<sub>1</sub>. <i>Methods:</i> Eosinophils were isolated from venous blood from normal volunteers who had no history of allergy (purity >99%). They were subjected to reverse transcription-PCR analysis and flow-cytometric analysis for CysLT<sub>1</sub>. Binding assays were performed with [<sup>3</sup>H]LTD<sub>4</sub>. Purified eosinophils loaded with Fura-2 acetoxymethyl ester were stimulated with CysLTs, and Ca<sup>2+</sup> influx was measured. Eosinophil migration in response to CysLTs was measured using a 96-well multiwell Boyden chamber. Eosinophils were treated with LTD<sub>4</sub> at 10<sup>–6</sup><i>M</i> for 60 min followed by incubation for 4 h at 37°C in the presence or absence of IL-5 and eosinophil-derived neurotoxin (EDN) release was evaluated. <i>Results:</i> The expression of the mRNA and protein of CysLT<sub>1</sub> on eosinophils and [<sup>3</sup>H]LTD<sub>4</sub>-specific binding to eosinophils were observed. Neither Th1 cytokine (IFN-γ) nor Th2 cytokines (IL-4 or IL-5) affected CysLT<sub>1</sub> expression in eosinophils. CysLTs induced an increase in intracellular free Ca<sup>2+</sup> in eosinophils via CysLT<sub>1</sub>, as suggested by the efficient inhibition by a CysLT<sub>1</sub> antagonist, pranlukast, in addition to the rank order of potency being LTD<sub>4</sub>, LTC<sub>4</sub> and LTE<sub>4</sub>. LTD<sub>4</sub> stimulated eosinophils to migrate at 10<sup>–6</sup><i>M</i> via CysLT<sub>1</sub>. LTE<sub>4</sub> also induced significant eosinophil migration at 10<sup>–6</sup><i>M</i>. LTD<sub>4</sub> enhanced EDN release induced by IL-5 via CysLT<sub>1</sub>. <i>Conclusion:</i> CysLTs induce migration and enhance degranulation in eosinophils via CysLT<sub>1</sub>. Accordingly, interaction of CysLTs and CysLT<sub>1</sub> on eosinophils has the potential to play a prominent role in the pathophysiology of asthma.
Alteration of Locus coeruleus Neuronal Activity by Interleukin-1 and the Involvement of Endogenous Corticotropin-Releasing Hormone
Authors: Borsody Mark K. , Weiss Jay M. 
Published: April 2003

Activity of the locus coeruleus (LC), which is the source of most of the norepinephrine in the brain, may participate in effects of the cytokine interleukin (IL)-1. This report describes the influence of IL-1β on the electrophysiological single-unit activity of LC neurons. When microinjected into the LC, human recombinant IL-1β (50 pg to 5 ng) increased the activity of LC neurons, predominantly by increasing ‘burst’ firing, which occurs in response to a sensory stimulus. At the higher doses and/or with longer time delays after injection, the spontaneous depolarization rate was also increased. This excitation (1) did not occur if IL-1β was microinjected nearby but outside of the LC and (2) could be reversed by administration of IL-1 receptor antagonist (IL-1RA). In contrast to excitatory effects, microinjection of a very low dose of IL-1β (5 pg) into the LC inhibited LC activity, and this change could also be blocked by IL-1RA. In view of earlier findings that (1) LC electrophysiological activity could be inhibited by microinjection of corticotropin-releasing hormone (CRH) into the LC region and (2) IL-1β in the brain stimulates the release of CRH, the hypothesis was tested that the inhibition of LC activity produced by the low dose of IL-1 was mediated by CRH. Microinfusion of the CRH receptor antagonist α-helical CRH(9–41) blocked the inhibition of LC activity otherwise produced by 5 pg of IL-1β, thus indicating that IL-1β also influences the activity of LC neurons via CRH. Finally, microinjection of IL-1RA alone was found to decrease LC activity, raising the possibility that LC neurons are under the influence of tonic excitation by IL-1 in the brain. In summary, the findings described here show that the activity of LC neurons can be influenced by IL-1β through stimulation of IL-1β receptors. The potential involvement of IL-1β in stress responses by means of this cytokine influencing the activity of LC neurons is discussed.
Cytokine Release Pathway in Mononuclear Cells Stimulated in vitro by Dialysis Membranes
Authors: Menegatti Elisa , Rossi Daniela , Chiara Marica , Alpa Mirella , Sena Luigi M. , Roccatello Dario 
Published: April 2003

<i>Background:</i> Among the possible variables associated with cytokine activation in hemodialysis, filter membrane has been reported to be a major factor and monocytes adherent to the membrane have been suggested as a possible source for cytokine synthesis. <i>Methods:</i> In order to exclude variables other than the direct cell-to-membrane interaction, suspensions of peripheral blood monocytes isolated from donors’ blood were incubated for 180 min at 37°C in Petri dishes coated with cuprophan (Cu) or polyacrylonitrile (AN69S) or polysulfone (PS). Total RNA was purified, reverse transcribed in cDNA and amplified by polymerase chain reaction (PCR) primed with specific oligomers for determining IL-1β and TNF-α gene expression. For Western blot analysis, cell homogenates and supernatants were electrophoresed and transferred to a polyvinylidene difluoride membrane and the membrane was then incubated with polyclonal antibodies specific for the detection of IL-1β and TNF-α. <i>Results:</i> Semi-quantitation of targets for PCR (using the technique of limiting dilutions and referring to actin and glyceraldehyde-3-phosphate dehydrogenase as noninducible molecule) revealed a comparable increase at 180 min (p < 0.05) in IL-1β and TNF-α mRNA in monocytes incubated with polyacrylonitrile, PS and Cu membranes. In 2 of 10 experiments pro-IL-1β was detected in monocytes interacting with Cu, PS and AN69S membrane. However, the extent of extracellular release of mature protein was greater for Cu. <i>Conclusion:</i> Some dissociation between transcriptional and translational events was detected in experiments using donors’ blood in vitro. More specifically, synthetic membranes (both polyacrylonitrile and PS) were found to be as active as Cu in inducing IL-1β and TNF-α mRNA expression, but less effective in promoting the extracellular release of proinflammatory cytokine products.
Doxorubicin-Docetaxel Sequential Schedule: Results of Front-Line Treatment in Advanced Breast Cancer
Authors: Palmeri S. , Leonardi V. , Tamburo De Bella M. , Morabito A. , Vaglica M. , Accurso V. , Ferraù F. , Failla G. , Agostara B. , Massidda B. , Valenza R. , Fanelli M. , Gasparini G. 
Published: April 2003

<i>Objective:</i> We conducted a multi-institutional phase II study to evaluate the tolerability and activity of a sequential schedule of treatment with doxorubicin and docetaxel in chemotherapy-naive women with advanced breast cancer. <i>Methods:</i> A total of 73 patients with PS (ECOG) 0–2, aged <70 years and adequate bone marrow, renal, liver and cardiac functions were included in the study (13 stage III B and 60 stage IV). The schedule of administration was doxorubicin 50 mg/m<sup>2</sup> by intravenous (i.v.) 30 min injection on day 1 followed the day after by docetaxel 75 mg/m<sup>2</sup>, by i.v. 60 min infusion. Cycles were repeated every 28 days. <i>Results:</i> Overall, the median number of administered cycles was 6 (range 1–14). The most common toxicity was hematological, with 56.2% of the patients who experienced grade 3–4 neutropenia. However, febrile neutropenia occurred only in 2.8% of the cases. The median cumulative dose of doxorubicin was 350 mg/m<sup>2</sup> (range 50–700 mg/m<sup>2</sup>). Eleven patients (15.4%) were documented to have >10% but <20% decrease in the left ventricular ejection fraction. No case of congestive heart failure was recorded. No patient experienced treatment-related death. Among the 68 evaluable patients, the overall objective response rate was 73.5% (95% confidence limits: 63–84%): 10 patients (14.7%) obtained a complete remission and 40 (58.8%) had a partial response. Only 10 patients (14.7%) experienced progressive disease. The median duration of response was 10 months (2–54+). <i>Conclusion:</i> This sequential treatment with doxorubicin and docetaxel is an effective, feasible and a well-tolerated regimen. The main toxicity was neutropenia. The lack of cardiotoxicity is an important advantage of such a doxorubicin-docetaxel combination and it justifies phase III comparative studies with other anthracyclines/taxanes containing schedules in both advanced and early-stage breast cancer.
Dominant Negative Mutants of Filamin A Block Cell Surface Expression of the D2 Dopamine Receptor
Authors: Lin Ridwan , Canfield Victor , Levenson Robert 
Published: April 2003

Protein interaction screens have revealed an interaction between the D2 dopamine receptor and the actin cross-linking protein filamin A. However, the physiological significance of this interaction has not been explained. To better understand the role of filamin A in D2 receptor-mediated signaling, we examined the effect of disrupting filamin A/D2 receptor interaction. Overexpression of a truncated form of filamin A (repeat units 18–19 containing the D2, but not the actin, binding domain) caused a marked reduction in both the number and half-life of cell surface D2 receptors. These results suggest that disruption of the linkage between D2 receptors and the actin cytoskeleton destabilizes plasma membrane-associated D2 receptors. Several missense mutations within repeat unit 19 of filamin A were identified that abrogate filamin A/D2 receptor interaction. Introduction of mutant and wild-type filamin A into filamin A-deficient M2 cells demonstrated that wild-type filamin A, but not the filamin A-binding mutants, was able to promote cell-surface expression of D2 receptors. Together, these studies provide evidence that filamin A/D2 receptor interaction is required for the proper targeting or stabilization of D2 dopamine receptors at the plasma membrane.
Severe Hypoxia Inhibits Prostaglandin I<sub>2</sub> Biosynthesis and Vasodilatory Responses Induced by Ionophore A23187 in the Isolated Rabbit Ear
Authors: Juránek Ivo , Bauer Viktor , Donnerer Josef , Lembeck Fred , Peskar Bernhard A. 
Published: April 2003

The present study was designed to test the hypothesis that lack of oxygen in severely hypoxic tissue may inhibit arachidonic acid oxygenation and thereby result in an inhibition of eicosanoid synthesis. Hypoxia was induced in the isolated rabbit ear, and arachidonate metabolism and peripheral resistance of the preparation were monitored simultaneously. Severe hypoxia completely inhibited the biosynthesis of prostaglandin I<sub>2</sub> induced by ionophore A23187 and converted the vasodilatory response observed under normoxia into vasoconstriction. The cyclooxygenase 1 inhibitor SC560 (1 µmol/l) effectively inhibited the normoxic prostaglandin I<sub>2</sub> biosynthesis, while the cyclooxygenase 2 inhibitor DFU (1 µmol/l) did not. Neither SC560 nor DFU affected normoxic vasodilatory responses, indicating no involvement of prostanoids. The nitric oxide (synthase inhibitor Nω-nitro-<i>L</i>-arginine methyl ester (100 µmol/l) converted the vasodilation into vasoconstriction, similar to what was observed under hypoxia, suggesting that the hypoxia-mediated conversion might occur due to the inhibition of nitric oxide.
Frequency and Nature of Spontaneous Age-Related Eye Lesions Observed in a 2-Year Inhalation Toxicity Study in Rats
Authors: Wegener A. , Kaegler M. , Stinn W. 
Published: April 2003

A group of 160 Wistar rats (both sexes) from a larger chronic inhalation toxicity study was monitored at baseline and after 1 and 2 years with a photo-slitlamp microscope and a direct ophthalmoscope to record spontaneous age-related eye lesions and treatment-related eye lesions over a period of 24 months. A second group from the same study was monitored at the start and after 5 months of a 6-month posttreatment period immediately following the inhalation period. Rats were nose-only exposed for 6 h/day, 7 days/week, for 2 years to low (3 µg/l) or high (10 µg/l) total particulate matter concentrations of room-aged cigarette sidestream smoke (RASS) or diesel engine exhaust (DEE). Control animals were exposed to filtered fresh air. All ophthalmological examinations were performed in mydriasis, and relevant observations were documented on color slide film. At baseline, all animals with eye lesions were excluded from the study. After 1 year, only minor lesions were found: retrolental opacities (14%) and a few cases of corneal dryness with reddish lid margins. After 2 years, 23% of the animals had unilateral or bilateral retrolental opacities, but the most frequent eye lesions were posterior subcapsular cataracts (PSC, 32%). Water clefts and spokes were found in 11% of the lenses and mature cataracts in 6%. All other eye lesions observed were much less frequent. There were a few cases of glaucoma, corneal dryness and stromal neovascularization. The frequency and type of lesion in animals monitored from the start of the posttreatment period was comparable to what was seen after 2 years. Toward the end of this period the frequency of mature cataracts went up to 9% and that of (secondary) glaucomas to 5%. None of the eye lesions observed showed any association in frequency or severity of expression to the treatment, either RASS or DEE, or to the sex of the animals. In comparison to the (limited) literature data available, far fewer corneal lesions were found in this study, but PSCs and mature cataracts were more frequent. Strain differences may influence these parameters. This study provided valuable information on the nature and frequency of spontaneous age-related eye lesions (0–56%, depending on the tissue) in long-term toxicity studies in Wistar rats.
Deferoxamine Attenuates Iron-Induced Oxidative Stress and Prevents Mitochondrial Aggregation and α-Synuclein Translocation in SK-N-SH Cells in Culture
Authors: Sangchot P. , Sharma S. , Chetsawang B. , Porter J. , Govitrapong P. , Ebadi M. 
Published: April 2003

One of the defining characteristics of neurodegenerative diseases, including Parkinson’s disease, is an abnormal accumulation of iron in the affected brain areas. By using SK-N-SH, a dopaminergic cell line, we have found that iron (100–250 µ<i>M</i> FeSO<sub>4</sub>) decreased cell viability, increased lipid peroxidation, and the said effects were blocked by deferoxamine (DFO: 10 µ<i>M</i>). Furthermore, DFO, in the absence of iron, enhanced the level of adenosine triphosphate (ATP), but caused chromatin condensation and cell death. Morphological studies revealed that iron (50–100 µ<i>M</i>) altered mitochondrial morphology, disrupted nuclear membrane, and translocated α-synuclein from perinuclear region into the disrupted nucleus. The results of these studies suggest that DFO is able to block and attenuate iron-mediated oxidative stress. However, in the absence of excess iron, DFO itself may have deleterious effects on the morphology and hence integrity of dopaminergic neurons.
Multicenter Phase I Study of Irinotecan plus Raltitrexed in Patients with 5-Fluorouracil-Refractory Advanced Colorectal Cancer
Authors: Aparicio Jorge , de las Peñas Ramón , Vicent José María , Garcerá Salvador , Llorca Cristina , Maestu Inmaculada , Yuste Ana L. , Farrés Jordi 
Published: April 2003

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m<sup>2</sup> as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m<sup>2</sup> as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m<sup>2</sup>) and raltitrexed (3 mg/m<sup>2</sup>) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.
Open Eye Injuries in the Pediatric Population in Kuwait
Authors: Behbehani Abdul M. , Lotfy Nashaat , Ezzdean Hania , Albader Salem , Kamel Mostafa , Abul Nadia 
Published: April 2003

<i>Objective:</i> To report the epidemiological characteristics of pediatric open globe injuries and to discuss treatment, management and outcomes of such injuries. <i>Materials and Method:</i> The hospital records and operative notes of 95 patients 16 years old and younger who were treated for open eye injury at Ibn Sina Hospital, Kuwait between September 1995 and January 1999 were reviewed. The average age of patients was 6.6 years. Patients were divided into three groups according to their final visual acuity (FVA): group 1, FVA of 20/40 or better; group 2, 20/40–20/200, and group 3, 20/400 or worse. The FVA of each group was compared to initial visual acuity (IVA), wound entry site, injury-to-presentation interval, injury-to-surgery interval, time of surgery, duration of surgery, associated injuries and medical treatment. <i>Results:</i> Injury was most common in children 3–6 years old. Most injuries occurred during play at home (46%), between the months of July and November (58%), and evening time (42%). The most common causes were glass, pencil, stick, soft drink bottle, metal bar, and stone. The cornea was the most common entry site (59 cases). Seventy-three patients presented on the day of injury, and 38 of them had surgical repair that same day. The follow-up period ranged from 2 weeks to 58 months. Thirty-eight patients (40%) had an FVA of 20/40 or better (group 1), 23 (24%) between 20/40 and 20/200 (group 2), 12 (13%) 20/400 or worse (group 3), and 22 (23%) had no record of FVA. The difference between IVA and FVA of wound entry site was statistically significant (p < 0.005). Differences due to injury-to-presentation interval, injury-to-surgery interval, time of surgery, duration of surgery, associated injuries, and the use of systemic antibiotics were found not to be statistically significant (p > 0.2). <i>Conclusion:</i> The prevalence of open globe injury among the pediatric population in Kuwait was high. Most injuries were due to household objects and occurred at home in the evening during the summer and autumn. IVA and anatomical location of the wound impacted on final outcome.
Principal Components Representation of the Two-Dimensional Coronal Tongue Surface
Authors: Slud Eric , Stone Maureen , Smith Paul J. , Goldstein Jr. Moise 
Published: April 2003

Abstract
This paper uses principal components (PC) analysis to represent coronal tongue contours for the 11 vowels of English in two consonant contexts (/s/, /l/), based upon five replicated measurements in three sessions for each of 6 subjects. Curves from multiple sessions and speakers were overlaid before analysis onto a common (x, y) coordinate system by extensive preprocessing of the curves including: extension (padding) or truncation within session, translation, and truncation to a common x range. Four PCs plus a mean level allow accurate representation of coronal tongue curves, but PC shapes depend strongly on the degree of padding or truncation. The PCs successfully reduced the dimensionality of the curves and reflected vowel height, consonant context, and physiological features.
Fibrinogen and the Amount of Leukoaraiosis in Patients with Symptomatic Small-Vessel Disease
Authors: Martí-Fàbregas Joan , Valencia Carlos , Pujol Jesús , García-Sánchez Carmen , Martí-Vilalta Josep-Lluis 
Published: April 2003

We investigated whether there is a direct correlation between plasma fibrinogen levels and the amount of leukoaraiosis (LA) in patients with symptomatic small-vessel disease. The study included 28 patients: 12 with a first-ever lacunar infarction (LI) and 16 with Binswanger’s disease (BD). The mean age was 71 years (SD 8.6), and 21 were men. For each patient, we recorded demographic data, vascular risk factors and the results of blood chemistry analysis including fibrinogen (g/l), hematocrit (decimal fraction) and total serum proteins (g/l). A cerebral MR scan was performed in each patient and an LA score was obtained by an investigator blind to clinical data, using a semiquantified scale in six areas of each cerebral hemisphere (0–4 points in each area, total scoring range 0–48 points). <i>Results:</i> The mean (SD) for the LA score was 18.9 (10.7) and for plasma fibrinogen 3.97 (1.1). Pearson’s and Spearman’s correlation coefficients between fibrinogen and LA score were 0.43 (p = 0.02) and 0.49 (p = 0.007), respectively. Multiple-regression analysis between groups (LI or BD) and fibrinogen versus LA score showed the strongest association for the BD group (p = 0.014) and a direct relation with fibrinogen (p = 0.018). No statistically significant association was found between LA score and age, sex, any vascular risk factor, hematocrit or total serum protein. <i>Conclusion:</i> There is a significant correlation between plasma fibrinogen levels and the amount of LA in patients with symptomatic cerebral small-vessel disease. This result suggests that fibrinogen may be involved in the pathophysiology of LA in these patients.