bluuebunny/crossref_metadata_2025 huggingface dataset:
An Initial Assessment of the Optical Properties of Human Laryngeal Tissue
Authors: Mahlstedt Kathrin , Netz Uwe , Schädel Daniela , Eberle Hans-Georg , Gross Manfred
Published: April 2003

The optical properties of human laryngeal tissue have been examined over the whole wavelength range from 400 to 2,200 nm to facilitate the development of new laser applications. Tissue samples were taken from healthy vocal fold and from vocal fold of patients with papillomatosis and with chronic, nonspecific laryngitis. The transmission and scattering properties of the tissue samples were recorded with a computer-guided integrating-sphere system. From the measured data the optical properties were calculated by means of the inverse Monte Carlo simulation. In the 500- to 600-nm range papilloma tissues had a considerably higher absorption than healthy vocal fold. When applying the optical tissue properties as a possible influencing factor of the effectiveness of laser systems, laser applications at this wavelength range may be useful in the ablation of papilloma tissue.
Coincident Warthin’s Tumor and Intraparotid Dermatopathic Lymphadenopathy
Authors: Naroditsky I. , Misselevich I. , Fradis M. , Lunz M. , Boss J.H.
Published: April 2003

A 52-year-old patient underwent excision of a parotid lump which was fond to consist of a Warthin’s tumor coexistent with a lymph node involved in dermatopathic lymphadenopathy. A preoperative fine-needle aspiration specimen contained brown pigment-granule-laden macrophages within the background of many lymphocytes. Failure to correctly diagnose the parotid tumor was likely due to a sampling error.
Cytokine Production and Antibodies against Heat Shock Protein 60 in Cardiomyopathies of Different Origins
Authors: Mándi Yvette , Hőgye Márta , Talha Elyas M. , Skolák Eszter , Csanády Miklós
Published: April 2003

Objective: There is growing evidence that proinflammatory cytokines play an important role in a variety of cardiac pathophysiological conditions. The purpose of this study was to determine the circulating tumour necrosis factor (TNF) and interleukin-6 (IL-6) levels in patients with dilated cardiomyopathy (DCM) (n = 40) or ischaemic heart disease (IHD) (n = 38) in comparison with the corresponding data from patients with hypertrophic cardiomyopathy (HCM) (n = 10) or valvular aorta stenosis (AS) (n = 10) and from healthy blood donors (n = 20). Methods: To investigate the possible sources of cytokines, the in vitro cytokine-inducing capacity of the patients’ peripheral blood leucocytes was also measured. The TNF and IL-6 expression levels in the myocardium were investigated from biopsy specimens. The study of the immunological background of the cardiomyopathies was supplemented with screening of anti-heat shock protein 60 (Hsp60) antibodies in the sera of the patients. Results: Elevated levels of circulating TNF (25–150 U/ml) and IL-6 (50–500 pg/ml) were found in 85% of the patients in the DCM and IHD groups, whereas only the IL-6 level was elevated (125–500 pg/ml) in the HCM patients. The in vitro TNF-α production was higher than in the normal controls only in the DCM group. The ventricular tissue of the DCM patients expressed TNF-α and IL-6. In vitro experiments were performed to examine the production of TNF and IL-6 by cultured rat cardiac myocytes (H9C2) under hypoxic conditions. Even a short hypoxic treatment resulted in cytokine production between 4 and 72 h following reoxygenization. Considerable amounts of anti-Hsp60 antibodies were found in 80% of the IHD patients and in 65% of the DCM patients. The in vitro cytokine production of leucocytes and the frequency of anti-Hsp60 positivity in patients with HCM or AS was not significantly different from those in the normal blood donors. Conclusions: These results demonstrate that TNF-α and IL-6 are of pathophysiological importance in some but not all types of cardiomyopathies, and the sources of cytokine production may differ. The mechanism of the development of primary DCM is still unknown; the high in vitro production of proinflammatory cytokines in the leucocytes of patients with DCM, the presence of TNF and IL-6 in their cardiac tissue and the high prevalence of anti-Hsp60 antibodies in their sera suggest a strong immunological background in the pathophysiology of the disease.
Laser Microdissection and Microsatellite Analyses of Breast Cancer Reveal a High Degree of Tumor Heterogeneity
Authors: Wild Peter , Knuechel Ruth , Dietmaier Wolfgang , Hofstaedter Ferdinand , Hartmann Arndt
Published: April 2003

Carcinomas with productive fibrosis are the most common forms of breast cancer. Analysis of tumor-specific genomic alterations can be compromised by the presence of normal cells, demanding microdissection of small tumor areas to detect loss of heterozygosity (LOH) and microsatellite instability (MSI). The aim of this study was to evaluate the importance of precise laser microdissection for microsatellite analyses and investigation of tumor heterogeneity in breast cancer. 39 primary breast tumor samples were analyzed for MSI and LOH by PCR followed by polyacrylamide gel electrophoresis and silver staining using 15 microsatellite markers. Different tumor areas were processed separately in 30 patients. Both intraductal and invasive breast cancer regions were investigated in 11 patients. The following results were obtained: (1) accurate microdissection revealed MSI in 3 or more of the investigated markers (≧20%) in 33% of the patients, a higher frequency than reported previously; (2) laser microdissection was 43% more sensitive in detection of LOH compared to manual microdissection due to a reduction of contamination by normal cells, and (3) 29 of 30 investigated tumors showed heterogeneity of genetic alterations in different tumor regions. Laser-based microdissection is a valuable tool in genetic analysis of desmoplastic tumors and allows an accurate determination of genetic alterations in histologically different tumor regions.
Investigations into the Molecular Effects of Single Nucleotide Polymorphism
Authors: Lohrer Horst D. , Tangen Uwe
Published: April 2003

Objectives: DNA sequences are very rich in short repeats and their pattern can be altered by point mutations. We wanted to investigate the effect of single nucleotide polymorphism (SNP) on the pattern of short DNA repeats and its biological consequences. Methods: Analysis of the pattern of short DNA repeats of the Thy-1 sequence with and without SNP. Searching for DNA-binding factors in any region of significance. Results: Comparing the pattern of short repeats in the Thy-1 gene sequences of Turkish patients with ataxia telangiectasia (AT) with the ‘wild type’ sequence from the DNA database, we identified a missing 8-bp repeat element due to an SNP in position 1271 (intron II) in AT-DNA sequences. Only the mutated sequence had the potential for the formation of a stem loop in DNA or pre-mRNA. In super-shift experiments we found that DNA oligomers covering the area of this SNP formed a complex with proteins amongst which we identified the proliferating cell nuclear antigen (PCNA) protein. Conclusion: SNPs have the potential to alter DNA or pre-mRNA conformation. Although no SNP-depeding formation of the DNA-protein complex was evident, future investigations could reveal differential molecular mechanisms of cellular regulation.
Expression of Lymphotoxin-α by Keratinocytes: A Further Mediator for the Lichenoid Reaction
Authors: Middel Peter , Lippert Undine , Hummel Klaus Matthias , Bertsch Hans Peter , Artuc Metin , Schweyer Stefan , Radzun Heinz-Joachim
Published: April 2003

Objective: Lichen planus (LP) represents a disease in which autoimmune mechanisms mediated by Th1 T cells are involved. Lymphotoxin-α (LT-α) represents a Th1 cytokine with proinflammatory activities in LP, as has recently been demonstrated for interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Methods: Expression of LT-α mRNA was investigated by RT-PCR and nonradioactive in situ hybridization. Double staining methods were applied to characterize the phenotype of cells expressing LT-α. Cell stimulation experiments were performed on the transformed squamous cell line HaCaT. Results: In contrast to normal skin, LT-α-specific RT-PCR products were found in all cases of LP. Cells in the inflammatory infiltrate expressing LT-α were identified as mainly T cells and mast cells, as shown by in situ hybridization. Furthermore, predominant LT-α mRNA expression could be observed in lesional keratinocytes adjacent to the band-like inflammatory infiltrate. In cell stimulation experiments, it could be shown that IFN-γ induces LT-α and TNF-α mRNA in the human squamous cell line HaCaT, concomitant with upregulation of MHC class II and intercellular adhesion molecule-1, which could also be observed on lesional keratinocytes in LP. Conclusions: In LP, LT-α mRNA is predominantly expressed by lesional keratinocytes and to a lesser extent by inflammatory cells. Induction of LT-α in keratinocytes is closely related to the expression of TNF-α and MHC class II. The loci of TNF-α and LT-α map to MHC class III on chromosome 6, which is closely linked to the MHC class II gene locus. Our results suggest that stimulation of keratinocytes with IFN-γ results in the upregulation of proinflammatory cytokines such as LT-α and TNF-α as well as MHC class II, which map to the same gene region of immunoregulatory genes on chromosome 6 and may be involved in the induction and maintenance of the disease.
Imaging of Aortic Atherosclerotic Lesions by 125I-LDL, 125I-Oxidized-LDL, 125I-HDL and 125I-BSA
Authors: Shaish Aviv , Keren Gad , Chouraqui Pierre , Levkovitz Hana , Harats Dror
Published: April 2003

Objective: The aim of the present study was to compare the accumulation of 125I-labeled low-density lipoproteins (LDL), oxidized LDL (oxLDL), HDL and BSA in advanced atherosclerotic lesions of apoE-deficient mice. Methods:125I-lipoproteins or 125I-BSA were injected into the tail vein of apoE-deficient mice. Blood clearance of 125I-lipoproteins and 125I-BSA and their accumulation in atherosclerotic lesions were assayed. Results: Blood clearance of 125I-LDL and 125I-HDL was moderate, and approximately 30% of the injected lipoproteins were present in plasma 24 h following injection. oxLDL was removed much faster from plasma, and less than 10% of 125I-oxLDL was present in the circulation 30 min after 125I-oxLDL injection. The clearance of 125I-BSA from the circulation was slower than the lipoprotein clearance. The highest accumulation of LDL, oxLDL, HDL and BSA was detected in atherosclerotic lesions in the aortic arch and abdominal aorta, while lower accumulation was detected in the less atherosclerotic descending thoracic aorta. Conclusion: Our findings demonstrate that both 125I-HDL and 125I-BSA as well as 125I-LDL are accumulated in atherosclerotic plaques and that they can be used for the detection of atherosclerotic lesions.
Complete Visual Recovery in Osteopetrosis by Early Optic Nerve Decompression
Authors: Hwang Jeong-Min , Kim In-One , Wang Kyu-Chang
Published: April 2003

Visual loss with optic atrophy is common in osteopetrosis. The efficacy of optic nerve decompression in patients with osteopetrosis is still controversial. The purpose of this study is to report that visual deterioration in osteopetrosis can be completely reversed by early optic nerve decompression. An 8-year-old female patient with osteopetrosis was found to have reduced visual acuity on routine ophthalmologic examination. Extensive optic nerve decompression was performed. It not only included unroofing the optic canal, but also drilling away bone on both sidewalls of the optic nerve. Both optic nerves were decompressed during the same surgical procedure. Progressive loss of vision associated with osteopetrosis can be prevented by optic nerve decompression in the early stage of visual deterioration. When managing patients with osteopetrosis, the importance of careful and regular assessment of visual function should be stressed.
Hydrocephalic Children Presenting to a Malaysian Community-Based University Hospital over an 8-Year Period
Authors: Abdullah J. , Naing N.N.
Published: April 2003

There are few local statistics on the incidence of hydrocephalus and the outcome of hydrocephalic shunts in the South East Asian region. We report a retrospective study on 285 hydrocephalic patients who underwent shunting procedures between 1990 and 1998 at the University Hospital Science Malaysia, a regional referral center. Multiple logistic regression analysis was applied to predict determinants of outcome in relation to the timing of diagnosis, other congenital abnormalities associated with the hydrocephalus, timing of surgery and cortical thickness from CT scan. The relationship of shunt infection was correlated to the age of the patient and surgical procedure. The predictors for developmental outcome reported by this study were age at diagnosis, type of brain abnormalities and gender. Time of operation and cortical thickness did not contribute to the outcome.
Antley-Bixler Syndrome, Description of Two New Cases and Review of the Literature
Authors: Lee H.-J. , Cho D.-Y. , Tsai F.-J. , Shen W.-C.
Published: April 2003

Objective: Antley-Bixler syndrome (ABS) is a rare disorder characterized by multiple malformations of cartilage and bone including multisynostotic osteodysgenesis, midface hypoplasia, choanal atresia or stenosis, femoral bowing, neonatal fractures and multiple joint contractures and, occasionally, urogenital, gastrointestinal or cardiac defects. Since the first report in 1975, at least 34 cases (including this report) have been described. We present 2 cases of congenital hydrocephalus, suggesting the cause of craniosynostosis and midface hypoplasia is associated with ABS. Clinical Presentation: The first case was a 1-day-old female with Arnold-Chiari malformation, multiple cranial synostosis, obstructive hydrocephalus and radioulnahumeral synostosis. Ventriculoperitoneal (V-P) shunting was performed when she was 7 days old. She died 42 days later due to cardiopulmonary failure. The second case was a 2-month-old female with bilateral coronal synostosis, obstructive hydrocephalus and brachycephaly. V-P shunting was done soon after her admission, and bilateral lateral canthal advancement with the floating forehead procedure was performed 1 month later. She is still alive with good development. Discussion: The main anomalies of the ABS can be divided into 4 categories: craniofacial, skeletal, extremity and urogenital anomalies. They may be the result of mutation in the fibroblast growth factor receptor 2 (Ser351Cys) gene, which was confirmed in our case 2. Craniosynostosis combined with hydrocephalus created congenital increased intracranial pressure (IICP). Early V-P shunt implantation and surgical release of the closed suture and lateral canthal advancement should be done as soon as possible, ideally when the patient is younger than 3 months. Conclusion: Early correction of craniosynostosis was feasible and safe for one of our patients. We offer our experience in the treatment of hydrocephalus and correction of craniosynostosis to relieve IICP.
Impaired Motor Learning in Children with Hydrocephalus
Authors: Ding Yuchuan , Lai Qin , McAllister II James P. , Canady Alexa I.
Published: April 2003

Hydrocephalic (n = 19) and normal (n = 20) children in two age groups (averaged at 10 and 14 years old) were asked to learn 5 predetermined timing rhythm interval tasks (including timing duration and relative timing pattern) by pressing keys on a computer keyboard. In the acquisition phase, visual and auditory goal timing intervals, as well as visualized feedback were presented to all participants before and after their key presses, respectively. A retention test without the auditory information and visualized feedback was administered 1 day later. By using the computerized timing test, we demonstrated in this study that the hydrocephalic group had significantly (ANOVA analysis) increased relative timing errors; this function depends on the formation of an internal model or a motor program related to long-term memory disorders. These findings could lead to the formulation of training procedures with simplified movements that may help hydrocephalic children improve their motor skill learning.
Permanent Low-Activity 125I Seed Placement for the Treatment of Pediatric Brain Tumors: Preliminary Experience
Authors: Rostomily Robert C. , Halligan John , Geyer Russ , Stelzer Keith , Lindsley Karen , Berger Mitchel S.
Published: April 2003

Although external beam radiation therapy is effective in the treatment of many pediatric brain neoplasms its use in this patient population has been associated with the development of significant cognitive and endocrine dysfunction and is severely limited as an option in previously irradiated patients. Therefore, we have adopted a strategy for management of residual microscopic disease by implantation of low-activity 125I seeds in the tumor bed at the time of surgery. Six patients aged 2–14 years with recurrent tumors including two supratentorial primitive neuroectodermal tumors (n = 2), one medulloblastoma, one malignant ependymoma (n = 1), glioblastoma (n = 1) and one pleomorphic xanthoastrocytoma were implanted at the time of reoperation. A total of 11–126 seeds were implanted resulting in total doses of 16–21.8 Gy (after theoretical infinite time) at a depth of 5 mm from the implanted resection bed. Five patients had prior external beam radiation while the other patient (2 years old at initial diagnosis) progressed after surgery and chemotherapy. Two patients had lasting local tumor control. One patient is alive at 390 weeks of follow-up and another who died of distant failure at 366 weeks had no recurrence on MRI at 333 weeks’ follow-up. Only 2 patients had first local failures. These results suggest that the use of permanent low-activity 125I seeds as an adjunct to surgery can provide good local tumor control and is a suitable treatment option for pediatric patients.
Endoscope-Assisted Microsurgery for Treatment of a Suprasellar Craniopharyngioma Presenting Precocious Puberty
Authors: Cheng Wen-Yu , Chang Cheng-Siu , Shen Chiung-Chyi , Wang Yeou-Chih , Sun Ming-Hsi , Hsieh Pin-Pen
Published: April 2003

Being the most common childhood tumor to involve the hypothalamus and pituitary gland, craniopharyngioma, a histologically benign tumor, is usually related to growth retardation and hypogonadism. The presentation of precocious puberty is very rare for a hypothalamic craniopharyngioma. Here, we report such a case. The female patient had presented with symptoms of menarche and breast development since she was 6 years old. Hormonal therapy with a gonadotropin-releasing hormone analogue was instituted to cease precocious puberty but was unsuccessful. Magnetic resonance imaging of the sella showed a 1-cm tumor in the hypothalamic area. Through a pterional approach, the tumor was removed en bloc with endoscope-assisted microsurgery. After the operation, our patient’s symptoms improved, so the hormone therapy was discontinued. This extremely unique association of craniopharyngioma and precocious puberty, the causes and mechanisms involved along with the advantages of endoscope-assisted microsurgery are discussed.
Lobar and Multilobar Resections for Medically Intractable Pediatric Epilepsy
Authors: Leiphart James W. , Peacock Warwick J. , Mathern Gary W.
Published: April 2003

Pediatric epilepsy surgery patients are different than adult epilepsy surgery patients by having a higher proportion of extratemporal than temporal lobe lesions, and by having cortical dysplasia as the most frequent pathology. We analyzed 111 pediatric epilepsy patients who received lobar or multilobar resections at the University of California, Los Angeles, between the years 1986 and 2000 to determine if there were differences in seizure outcome by lobe of resection and tissue pathology. Results showed that temporal lobe resection patients had lower pre- and postoperative seizure frequencies compared with extratemporal single lobe resection patients (p < 0.05). Furthermore, single lobe resection patients from any brain region had lower pre- and postoperative seizure frequencies compared with multilobar resection patients (p < 0.05), an effect which was due to the better seizure outcomes in temporal lobe resection cases. Patients with mass lesions had the best postoperative seizure control, followed by cortical dysplasia patients and other pathologies (p < 0.05). In all patient groups, there was a significant reduction in pre- to postoperative seizure frequencies (p < 0.0001). These results indicate that postsurgery seizure outcomes in pediatric epilepsy surgery patients vary by lesion location and pathology, with the best outcomes in temporal lobe patients with mass lesions. However, surgical resections of epileptogenic lesions, regardless of lobe, were associated with significant postoperative improvements in seizure frequency.
Modulatory Effect of Protein Kinase C Activator on Contractility of Rat Vas deferens
Authors: Huang Yu , Pai Raymond K. , Lau C.W. , Chan F.L. , Chen Z.Y. , Yao X.Q.
Published: April 2003

The modulatory effect of the protein kinase C activator was examined on contraction of rat isolated vas deferens induced by constrictive agonists, noradrenaline (NA), ATP, BaCl2 and high K+. Phorbol 12,13-diacetate (PDA, 1 µmol/l) induced a transient extracellular Ca2+-dependent contraction while the inactive analogue, 4α-phorbol (1 µmol/l) had no effect. PDA significantly enhanced the peak amplitude of the contractile response to NA (0.1–10 µmol/l), ATP (100 µmol/l), Ba2+ (3 mmol/l) or high K+ (30 mmol/l). Staurosporine at 30 nmol/l reduced the enhancing effect of PDA on the agonist-induced contraction. NA (10 µmol/l) produced a phasic contraction followed by a sustained contraction, while ATP induced monophasic contraction. Pretreatment with nifedipine (10 nmol/l) had no effect on the phasic contraction induced by NA, but it significantly reduced ATP- or high K+-induced contraction. Staurosporine (30 nmol/l) alone attenuated the peak contractile response induced by NA or ATP but not by Ba2+. NA produced a transient contraction in Ca2+-free Krebs solution, and PDA (1 µmol/l) markedly enhanced this effect. These novel data indicate that activation of a protein kinase C-dependent mechanism not only affects contraction mediated by Ca2+ influx through voltage-sensitive Ca2+ channels, but also promotes intracellular Ca2+ release or intracellular Ca2+-mediated contractile mechanism in rat vas deferens.
Gastric Emptying in Diabetic Gastroparetic Dogs: Effects of SK-951,a Novel Prokinetic Agent
Authors: Takeda Motohiro , Mizutani Yuka , Yamano Masaya , Tsukamoto Katsura , Suzuki Tsunemasa
Published: April 2003

We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.
Increased Dilator Response to Heptanol and Octanol in Aorta from DOCA-Salt-Hypertensive Rats
Authors: Leite Romulo , Webb R. Clinton
Published: April 2003

This study tests the hypothesis that contractile responses in aortae of hypertensive rats are more dependent on gap junctional communication compared to those from normotensive rats. The experimental approach was pharmacological, using inhibitors of gap junctional activity (heptanol and octanol). Two models of experimental hypertension were characterized: (1) mineralocorticoid (DOCA)-hypertensive rats and (2) stroke-prone spontaneous hypertensive rats (SHRSP). Vessels from DOCA-hypertensive rats showed a greater relaxation to heptanol and octanol, particularly when precontracted with phenylephrine, compared to sham-operated animals. Octanol-induced relaxation in aortic segments from SHRSP did not differ from normotensive values regardless of the agonist used to cause contraction. These results suggest that in DOCA hypertension, gap junctional communication and voltage-operated calcium channels are differentially regulated, which could explain in part the changes in vascular reactivity observed in mineralocorticoid hypertension.
Effects of a Novel Hepatoprotective Drug, ZNC-2381, on Fas-Induced Hepatocellular Caspase-3 Activity and Apoptosis in Mice
Authors: Segawa Yoshihide , Tsuzuike Naoki , Itokazu Yoshihiko , Omata Takeshi , Inoue Naonori , Nagasawa Masaaki , Nishioka Hiroyasu , Nakano Yoshihisa , Kobayashi Tadashi , Kanda Takashi
Published: April 2003

We examined the effects of ZNC-2381 (1-(4-aminophenyl)methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b] pyridine-2-one), a new oral hepatoprotective agent, on hepatocellular caspase-3 activity and apoptosis induced by anti-mouse Fas antibody (anti-Fas ab) in mice. Oral ZNC-2381, administered at doses of 10, 30 and 100 mg/kg 1 h before inducing hepatic injury with anti-Fas ab, dose-dependently inhibited the increase in serum alanine aminotransferase (s-ALT) activity 8 h after injection of anti-Fas ab. Increases in DNA fragmentation (nucleosome assay) and caspase-3 activity in the liver 2 h after injection of anti-Fas ab were also inhibited by ZNC-2381 in a dose-dependent manner. As shown by histopathological examination, ZNC-2381 dose-dependently inhibited the appearance of TUNEL-positive apoptotic cells in the liver. Moreover, in studies in vitro, ZNC-2381 (1– 100 µmol/l) concentration-dependently inhibited increases in DNA fragmentation and caspase-3 activity caused by anti-Fas ab in isolated mouse hepatocytes. N- Acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-cho), a caspase-3-specific inhibitor, inhibited hepatocellular apoptosis caused by anti-Fas ab both in vivo and in vitro, as well as the increase in s-ALT activity in vivo. These results demonstrate that orally administered ZNC-2381 inhibits hepatocellular apoptosis induced by anti-Fas ab and presents the progression of hepatic injury. We propose that the mechanism of action of ZNC-2381 may involve blockade of the signal transduction pathway (caspase-3) of apoptosis mediated by anti-Fas ab.
Pharmacological Properties of Excitation-Contraction Mechanisms in Isolated Mouse Left Atria
Authors: Nishimaru Kazuhide , Makuta Ryuji , Tanaka Yoshio , Tanaka Hikaru , Shigenobu Koki
Published: April 2003

Effects of 4-aminopyridine (4-AP), nicardipine and ryanodine on the action potential and contractile force were examined in isolated mouse left atria. The mouse left atria had an action potential with an extremely short duration and two phases of repolarization; action potential duration at 50% repolarization was 6.7 ± 0.4 ms (n = 15). The action potential duration, as well as contractile force, was increased by 4-AP (at 100 µmol/l and 1 mmol/l). Nicardipine (3 µmol/l), which is known to greatly reduce the contractile force in atria of most other experimental animal species, had no significant effect on the action potential and decreased contractile force by only 40% in mouse atria. Ryanodine (10 nmol/l) decreased the contractile force by 90% of basal value. At 100 nmol/l, ryanodine slightly affected the action potential configuration, which could be explained by indirect effects through inhibition of Ca2+ release from the sarcoplasmic reticulum. The extremely short action potential duration and the highly sarcoplasmic reticulum-dependent contraction of the mouse atria appear to underlie its unique response to agonists.
Effect of SR59230A on Atypical β-Adrenoceptor Mediating Relaxation in the Guinea Pig Gastric Fundus
Authors: Horinouchi Takahiro , Yamamoto Yoshihisa , Koike Katsuo
Published: April 2003

The purpose of the present study was to clarify whether atypical β-adrenoceptors which presented in the guinea pig gastric fundus are β3-adrenoceptors or putative β4-adrenoceptors. In the presence of both the selective β1-adrenoceptor antagonist atenolol (10–4 mol/l) and the selective β2-adrenoceptor antagonist butoxamine (10–4 mol/l), the selective β3-adrenoceptor antagonist SR59230A caused a concentration-dependent rightward shift of the concentration-response curve to catecholamines (isoprenaline, noradrenaline and adrenaline) and β3-adrenoceptor agonists (BRL37344 and CGP12177A) in the guinea pig gastric fundus. Schild plot analyses of SR59230A against these agonists gave pA2 values of 7.35 ± 0.03 (isoprenaline), 7.26 ± 0.04 (noradrenaline), 7.26 ± 0.05 (adrenaline), 7.79 ± 0.03 (BRL37344) and 6.74 ± 0.03 (CGP12177A), respectively, and all Schild slopes were not significantly different from unity. These results suggest that atypical β-adrenoceptors mediating relaxant responses of these agonists in the guinea pig gastric fundus are β3-adrenoceptors rather than putative β4-adrenoceptors.
Activity of N-(Phenethyl)phenylethanolamines at β1 and β2 Adrenoceptors: Structural Modifications Can Result in Selectivity for Either Subtype
Authors: Urtishak Karen , McCafferty Gerald , Zaratin Paola , Scheideler Mark , Grugni Mario , Artico Marco , Hieble J. Paul
Published: April 2003

A series of phenylethanolamines bearing a 2-[1-phenylpropyl] substituent on the nitrogen atom was evaluated in vitro for activity at β1- and β2-adrenoceptors. As previously observed, the presence of 3,4-dihydroxy substitution on phenylethanolamine is required for potent activation of both subtypes, whereas the 3,5-dihydroxy analog showed selectivity for the β2-subtype. Replacement by a carboxyl group of the 4-hydroxyl group on the aralkyl nitrogen substituent produced only a small reduction in β1 potency (5-fold), whereas β2 potency was reduced by more than 100-fold. Hence this structural class includes agonists having either a β1, nonselective β1/β2 or β2 selectivity profile.
Lack of Reinforcing Effect of the Benzodiazepine and Tricyclic Antidepressant Combination of Diazepam and Dothiepin
Authors: Oittinen Henna , Rameis Heinz , Saria Alois , Zernig Gerald
Published: April 2003

Fixed combinations of a tricyclic antidepressant (TCA) with a benzodiazepine (BZD) for the treatment of depressive syndromes enjoy remarkable acceptance among patients and prescribing physicians. In order to investigate if the widespread use of one such fixed TCA-BZD combination might be due to its high positive reinforcing effect, we tested each drug alone and in combination in an operant conditioning paradigm (fixed ratio 1 time-out 150 s) of intravenous self-administration in rats and compared their reinforcing effects to that of cocaine. Diazepam proved to be of only moderate reinforcing strength. Dothiepin alone was ineffective as a reinforcer but essentially abolished the reinforcing effect of diazepam when given in combination with it. These data indicate that the widespread acceptance of the fixed diazepam-dothiepin combination by the therapeutic community is not due to an increase in the positive reinforcing effect of diazepam by dothiepin but that, in contrast, addition of dothiepin might even decrease diazepam’s moderately positive reinforcing effect.
Effects of the Calcium Release Inhibitor Dantrolene and the Ca2+-ATPase Inhibitor Thapsigargin on Spinal Nociception in Rats
Authors: Álvarez-Vega Marco , Baamonde Ana , Hidalgo Agustín , Menéndez Luis
Published: April 2003

The effects produced by the intrathecal administration of dantrolene and thapsigargin, measured in several analgesic tests in the rat are described. Dantrolene decreases the release of calcium from intracellular stores and thapsigargin is able to inhibit the reticular Ca2+-ATPase, avoiding intracellular calcium storage. Dantrolene (30–300 nmol/rat) and thapsigargin (3–30 nmol/rat) reduced the nociceptive behavior (biting, scratching, licking; BSL) produced by the NK1 receptor agonist septide (0.5 µg), without affecting the BSL induced by AMPA (2 µg) or NMDA (4 µg). Also, both drugs elicited analgesia in the tail-flick test but not in the formalin test. The antinociceptive effects induced by thapsigargin were more intense and long-lasting than those produced by dantrolene. These results seem to indicate that the intracellular modulation of calcium homeostasis could be an interesting target in order to induce spinal analgesia.
Encapsulation in Cationic Liposomes Enhances Antitumour Efficacy and Reduces the Toxicity of Etoposide, a Topo-Isomerase II Inhibitor
Authors: Sengupta S. , Tyagi P. , Chandra S. , Kochupillai V. , Gupta S.K.
Published: April 2003

Etoposide exerts its antineoplastic effect by forming a ternary complex with topo-isomerase II and DNA, leading to DNA breaks and cell death. However, it causes myelosuppression and its lipophilicity poses a major limitation during administration. Liposomes have been reported to increase the efficacy and reduce the toxicity of antineoplastic agents. Recent evidence suggests that cationic liposomes bind efficiently to tumours. The present study was thus designed to encapsulate etoposide in cationic liposomes and to evaluate its antitumour efficacy and systemic toxicity in comparison with a conventional parenteral formulation. Etoposide encapsulated in liposomes was synthesised by thin film hydration followed by an extrusion method. Fibrosarcoma was induced in mice by subcutaneous administration of 20-methylcholanthrene. Chemotherapy was started when the tumour reached 200 mm3 in volume. Liposomal etoposide (10 mg/m2/day for 5 days) significantly delayed tumour growth as compared to non-liposomal etoposide. The median time of death was calculated to be 19.5, 26.25 and 56 days in vehicle-treated controls, non-liposomal-etoposide- and liposomal-etoposide-treated groups, respectively. A transient reduction in body weight was seen in both the liposomal- and non-liposomal-etoposide-treated groups. The maximum tolerated dose was however significantly higher in the group treated with liposomal etoposide, which also exhibited a lesser degree of myelosuppression than the animals treated with non-liposomal etoposide. The present findings suggest that cationic liposomes could be considered as potential for delivery of etoposide to tumours.
Diabetes-Induced Changes in Retinal NAD-Redox Status
Authors: Obrosova Irina G. , Stevens Martin J. , Lang Hans-Jochen
Published: April 2003

Diabetes-induced changes in retinal metabolism and function have been linked to increased aldose reductase activity, hypoxia or ‘pseudohypoxia’ (increase in NADH/NAD+ attributed to increased sorbitol dehydrogenase activity). To address this controversy, we evaluated the effects of two vasoactive compounds, α1-adrenoceptor antagonist prazosin and antioxidant DL-α-lipoic acid, as well as sorbitol dehydrogenase inhibitor (SDI-157) and aldose reductase inhibitor (sorbinil) on retinal free mitochondrial and cytosolic NAD+/NADH ratios in streptozotocin-diabetic rats. Diabetes-induced decrease in mitochondrial and cytosolic NAD+/NADH ratios was completely or partially corrected by prazosin and DL-α-lipoic acid (despite the fact that prazosin did not affect and DL-α-lipoic acid even further increased sorbitol pathway activity) as well as by sorbinil, whereas SDI-157 was totally ineffective. Hypoxia-like metabolic changes in the diabetic retina originate from aldose reductase, but not sorbitol dehydrogenase activity.
The Effect of Lactate on Sex Differences in Rat Renal Tubular Energy-Dependent Transport of the Organic Cation Amantadine
Authors: Bobby Bradley , Sitar Daniel S.
Published: April 2003

The purpose of this study was to determine if the inhibitory effect of lactate on the tubular transport of amantadine would extend to a demonstrable sex difference between male and female rats. Enriched fractions of renal proximal and distal tubules were incubated with [3H]-amantadine in the presence and absence of racemic lactate. Lactate buffer unmasked a sex difference in proximal tubular transport capacity. Compared to bicarbonate, lactate also decreased the affinity for amantadine uptake by both proximal and distal tubule fragments in both male and female rats. No difference occurred between male and female rats in terms of the inhibitory constant (Ki) for lactate. These data suggest that female rats have decreased amantadine transport efficiency and potentially increased susceptibility to amantadine toxicity due to transport inhibition by lactate. Our data may help to explain the mechanism for increased amantadine toxicity observed in elderly female patients.
Effect of Nitric Oxide on Strophanthidin-Induced Ventricular Tachycardia
Authors: Chen Yi-Jen , Tsai Chin-Feng , Chiou Chuen-Wang , Chan Paul , Chen Shih-Ann
Published: April 2003

Nitric oxide (NO) has been demonstrated to have several effects on the heart. Through the stimulation of guanylate cyclase, NO increases cyclic GMP and decreases intracellular calcium. The purpose of this study was to evaluate the effects of NO on ventricular arrhythmia induced by strophanthidin in guinea pigs and dogs. In experiment 1, after strophanthidin-induced ventricular tachycardia, guinea pigs received different doses of L-arginine (0, 25, 50, 100, 200, and 400 mg/kg; n = 10 for each dose), 200 mg/kg L-arginine combined with 100 mg/kg NG-nitro-L-arginine methylester (L-NAME, n = 10), or 200 mg/kg D-arginine (n = 10). In experiment 2, after strophanthidin-induced ventricular tachycardia, dogs (n = 7) received 200 mg/kg L-arginine. By 12-lead ECG, monophasic action potentials in left and right ventricles were recorded throughout the study. In experiment 1, guinea pigs which received 200 mg/kg or 400 mg/kg L-arginine had greater incidences of ventricular tachycardia termination (60 and 80%, respectively) than those which received 0, 25, 50, and 100 mg/kg L-arginine (0, 0, 20, and 30%, respectively), those which received L-arginine with L-NAME (0%), and those which received D-arginine (0%). In experiment 2, 5 (71%) of the dogs had successful termination of ventricular tachycardia. These findings suggest that L-arginine was effective in treating strophanthidin-induced ventricular tachycardia in vivo and that the underlying mechanism is through a NO pathway.
The in vitro Inhibitory Effect of Tannin Derivatives on 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase on Vero Cells
Authors: Chang Jun-Jen , Chen Tso-Hsiao , Chan Paul , Chen Yi-Jen , Hsu Feng-Lin , Lo Ming-Yu , Lin Jung-Yaw
Published: April 2003

Coronary heart disease is still the major cause of death in industrialized countries. Multiple primary or secondary interventional trials to lower serum cholesterol in humans have resulted in significant reduction of coronary events and death, one of the major reasons attributed to developing a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor such as pravastatin. Developing new inhibitors of cholesterol synthesis is still common in the pharmaceutical industry. Tannin comprises a large group of natural polyphenolic compounds possessing antioxidant effects. The methods for analysis of specific inhibitors of mevalonate biosynthesis have already been well established by using Vero cells, a cell line obtained from kidneys of African green monkeys. Tannin derivatives isolated from different traditional Chinese herbs were dissolved in DMSO and incubated with Vero cells with or without the addition of 1 mmol/l mevalonate or 5 mmol/l sodium acetate for 24 h in order to observe cell growth. Pravastatin, a specific HMG-CoA reductase inhibitor, was used as positive control which could inhibit Vero cells growth effectively and cell growth inhibition was reversible after adding 1 mmol/l mevalonate. More than 50 tannin derivatives were used for the study, but only two compounds – proanthrocyanidin A-2 (belonging to the flavan-3-ol group) and 1,2,3,6-tetra-O-galloyl-β-D-glucose (belonging to the gallotannin group) – showed significant growth inhibition of Vero cells. This study showed that some isolated tannin derivatives from traditional herbs were effective HMG-CoA reductase inhibitors which might be developed into new hypocholesterolemic agents.
Effects of Taurine on Cerulein-Induced Acute Pancreatitis in the Rat
Authors: Ahn Byung Ok , Kim Kwang Hee , Lee Goo , Lee Hong Sik , Kim Chang Duck , Kim Young Sik , Son Mi Won , Kim Won Bae , Oh Tae Young , Hyun Jin Hai
Published: April 2003

Taurine, or 2-aminoethane sulfonic acid, is an intracellular amino acid and has been suggested to have a function in protecting biological systems from oxidative tissue damage. The aim of this study was to determine the effect of taurine against cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by administering three subcutaneous injections of cerulein (40 µg/kg body weight) at 1-hour intervals, while taurine was administered intravenously at graded doses (30, 100, or 300 mg/kg, respectively) following the first cerulein injection. The severities of pancreatitis and lung injury were determined by measuring biochemical parameters, tissue myeloperoxidase (MPO), and histological changes. To clarify the mechanism of taurine, serum IL-1β and TNF-α levels and tissue concentrations of malondialdehyde (MDA) were evaluated. In cerulein-induced acute edematous pancreatitis, treatment with taurine significantly decreased hyperamylasemia, tissue MPO, pancreatic edema, and the extent of pancreatic and pulmonary injury. Taurine decreased MDA concentration in the pancreas and lung, but not the serum cytokine concentration. We would conclude that taurine has beneficial effects in cerulein-induced acute pancreatitis and lung injuries by preventing the production of oxygen free radicals.
Honokiol and Magnolol Selectively Interact with GABAA Receptor Subtypes in vitro
Authors: Ai Jinglu , Wang Xiaomei , Nielsen Mogens
Published: April 2003

Honokiol and magnolol have been identified as modulators of the GABAA receptors in vitro. Our previous study suggested a possible selectivity of honokiol and magnolol on GABAA receptor subtypes. This possibility was examined in the current study by 3H-muscimol and 3H-flunitrazepam binding assays on various rat brain membrane preparations and human recombinant GABAA receptor subunit combinations expressed by the Sf-9/baculovirus system. Generally, honokiol and magnolol have a similar enhancing effect on 3H-muscimol binding to various membrane preparations in nonsaturation binding assays. Honokiol and magnolol preferentially increased 3H-muscimol binding to hippocampus compared to cortex and cerebellum (with a maximum enhancement of 400% of control). As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on α2 subunit containing combinations (with a maximum enhancement of 400–450% of control). This action was independent of the γ subunit. In saturation binding assays, magnolol affected either the number of binding sites (ca. 4-fold on α2 containing combinations) or the binding affinity (on α1 containing combinations) of 3H-muscimol binding to various GABAA receptor subunit combinations. In contrast, honokiol increased only binding sites on α2β3γ2s and α2β3 combinations, but both the number of binding sites and the binding affinity on α1β2γ2S and α1β2 combinations. These results indicate that honokiol and magnolol have some selectivity on different GABAA receptor subtypes. The property of interacting with GABAA receptors and their selectivity could be responsible for the reported in vivo effects of these two compounds.
The Pharmacological Effect of Omeprazole on Water Gastric Emptying: A Study Based on an Impedance Measure
Authors: Chang Full-Young , Lu Ching-Liang , Chen Chih-Yen , Lee Shou-Dong , Tsai Dong-Shing , Fu Shih-En
Published: April 2003

The present study was performed to validate the accuracy of a self-designed applied-potential tomograph (APT) in measuring the cross area of a studied object and to assess the effect of omeprazole premedication on water gastric emptying (GE), based on APT. Twelve electrodes were evenly placed in a circular array around the studied subjects. Ten electrodes in a rotated order recorded the electrical current injected into paired electrodes. Based on tomography, averaged signals of changed resistivity were constructed to display the area of interest and GE curve. Six beakers of various diameters were respectively placed into a cylindrical perspex tank which was filled with saline to measure their cross areas via computer-generated diagrams of APT. One hour after either omeprazole (20 mg) or placebo premedication, 15 healthy males were ordered to consume 500 ml of test water to assess emptying for 40 min. Within 3 days, a similar procedure was repeated using the counterpart premedication. The true cross areas of the 6 beakers are 2.01, 15.9, 18.8, 30.19, 38.48 and 63.61 cm2, whereas those obtained by APT were 7.9 ± 2.9, 16.7 ± 3.3, 22.4 ± 4.9, 28 ± 4.8, 48.7 ± 7.6 and 67 ± 6.1 cm2, respectively (r = 0.98, p < 0.001). Valid emptying data were obtained in 73.3 and 86.6% of subjects, following placebo and omeprazole, respectively (not significant). The half emptying times were 12.7 ± 5.1 min for the placebo-treated group and 10.5 ± 3.6 min for the omeprazole-treated group, respectively (p < 0.05). The areas under the emptying curve were 1,611.5 ± 357.6 and 1,317.3 ± 316.7 arbitrary units, respectively (p < 0.01). In conclusion, our APT system is accurate for large-area measurements; acid inhibition before APT measurement does not increase the success rate but enhances water emptying. The interpretation of impedance-obtained GE should consider the acid-inhibitory effect.
Effects of Peroxynitrite on the Reactivity of Diabetic Rat Aorta
Authors: Zobalı Fulya , Çakıcı İclal , Karasu Çimen
Published: April 2003

Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of either oxidizing or nitrating various biological substrates. We compared the vasodilatory effect of exogenous peroxynitrite with the effects of decomposed peroxynitrite or sodium nitrite in precontracted aorta isolated from streptozotocin-induced diabetic and age-matched control rats. Peroxynitrite (10 nmol/l to 300 µmol/l) produced a concentration-dependent relaxation in aortic rings with or without endothelium. Relaxation was also observed with a higher concentration of its decomposition product or sodium nitrite, although these relaxations were considerably slower and with reduced sensitivity. Endothelium-containing rings were less sensitive to the vasorelaxant effect of peroxynitrite than the endothelium-denuded rings in control (pD2 was 5.19 ± 0.06 in rings with endothelium and 5.86 ± 0.03 in rings without endothelium, p < 0.01) but not in diabetic aorta (pD2 was 5.97 ± 0.05 in rings with endothelium and 6.12 ± 0.06 in rings without endothelium, p > 0.05). The maximum relaxation to peroxynitrite also increased in diabetics, but did not change by removal of the endothelium either in diabetic or control rings. Diabetes did not alter the relaxations elicited by both decomposed peroxynitrite and sodium nitrite. Peroxynitrite-induced relaxation was not inhibited by diethylenetriaminepentaacetic acid, an inhibitor of hydroxyl radical formation. Pretreatment with peroxynitrite (1 µmol/l, 15 min) significantly suppressed the phenylephrine-induced tone and acetylcholine-stimulated endothelium-dependent relaxation, both effects were more pronounced in diabetic than in control aorta. The increased responsiveness of diabetic vessels to exogenous peroxynitrite seems to be related to depressed basal NO bioavailability and may be considered as a compensatory way against activated contractile mechanisms of diabetic vascular smooth muscle.