bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Ca2+-activated K+channels in duodenal mucosal ion transport and bicarbonate secretion
Authors: Dong Hui , Smith Anders , Hovaida Marjan , Chow Jimmy Y.
Published: June 2006

Stimulation of muscarinic receptors in the duodenal mucosa raises cytosolic free Ca2+concentration ([Ca2+]cyt), thereby regulating duodenal epithelial ion transport. However, little is known about the downstream molecular targets that account for this Ca2+-mediated biological action. Ca2+-activated K+(KCa) channels are candidates, but the expression and function of duodenal KCachannels are poorly understood. Therefore, we determined whether KCachannels are expressed in the duodenal mucosa and investigated their involvement in Ca2+-mediated duodenal epithelial ion transport. Two selective blockers of intermediate-conductance Ca2+-activated K+(IKCa) channels, clotrimazole (30 μM) and 1-[(2-chlorophenyl)diphenylmethyl]-1 H-pyrazole (TRAM-34; 10 μM), significantly inhibited carbachol (CCh)-induced duodenal short-circuit current ( Isc) and duodenal mucosal bicarbonate secretion (DMBS) in mice but did not affect responses to forskolin and heat-stable enterotoxin of Escherichia coli. Tetraethylammonium, 4-aminopyridine, and BaCl2failed to inhibit CCh-induced Iscand DMBS. A-23187 (10 μM), a Ca2+ionophore, and 1-ethyl-2-benzimidazolinone (1-EBIO; 1 mM), a selective opener of KCachannels, increased both Iscand DMBS. The effect of 1-EBIO was more pronounced with serosal than mucosal addition. Again, both clotrimazole and TRAM-34 significantly reduced A23187- or 1-EBIO-induced Iscand DMBS. Moreover, clotrimazole (20 mg/kg ip) significantly attenuated acid-stimulated DMBS of mice in vivo. Finally, the molecular identity of IKCachannels was verified as KCNN4 (SK4) in freshly isolated murine duodenal mucosae by RT-PCR and Western blotting. Together, our results suggest that the IKCachannel is one of the downstream molecular targets for [Ca2+]cytto mediate duodenal epithelial ion transport.
Sympathetic neural responses to increased osmolality in humans
Authors: Farquhar William B. , Wenner Megan M. , Delaney Erin P. , Prettyman Allen V. , Stillabower Michael E.
Published: June 2006

The purpose of this study was to examine the relationship between osmolality and efferent sympathetic outflow in humans. We hypothesized that increased plasma osmolality would be associated with increases in directly measured sympathetic outflow. Muscle sympathetic outflow was successfully recorded in eight healthy subjects during a 60-min intravenous hypertonic saline infusion (HSI; 3% NaCl) on one day and during a 60-min intravenous isotonic saline (ISO) infusion (0.9% NaCl) on a different day. The HSI provides an osmotic and volume stimulus, whereas the ISO infusion provides a volume-only stimulus. Muscle sympathetic nerve activity was quantified using the technique of peroneal microneurography. Plasma osmolality increased during the HSI but not during the ISO infusion (ANOVA, P < 0.05). Sympathetic outflow differed between the trials (ANOVA, P < 0.05); during the HSI burst, frequency initially increased from 14.6 ± 2.5 to 18.1 ± 1.9 bursts/min; during the ISO infusion, burst frequency initially declined from 14.7 ± 2.5 to 12.0 ± 2.1 bursts/min. Plasma norepinephrine concentration was greater at the end of the HSI compared with the end of the ISO infusion (HSI: 297 ± 64 vs. ISO: 202 ± 49 pg/ml; ANOVA, P < 0.05). We conclude that HSI-induced increases in plasma osmolality are associated with increases in sympathetic activity in humans.
Hormonal and environmental regulation of epithelial calcium channel in gill of rainbow trout (Oncorhynchus mykiss)
Authors: Shahsavarani Arash , Perry Steve F.
Published: June 2006

We indirectly tested the idea that the epithelial Ca2+channel (ECaC) of the trout gill is regulated in an appropriate manner to adjust rates of Ca2+uptake. This was accomplished by assessing the levels of gill ECaC mRNA and protein in fish exposed to treatments known to increase or decrease Ca2+uptake capacity. Exposure of trout to soft water ([Ca2+] = 20–30 nmol/l) for 5 days (a treatment known to increase Ca2+uptake capacity) caused a significant increase in ECaC mRNA levels and an increase in ECaC protein expression. The inducement of hypercalcemia by infusing fish with CaCl2(a treatment known to reduce Ca2+uptake) was associated with a significant decrease in ECaC mRNA levels, yet protein levels were unaltered. ECaC mRNA and protein expression were increased in fish treated with the hypercalcemic hormone cortisol. Finally, exposure of trout to 48 h of hypercapnia (∼7.5 mmHg, a treatment known to increase Ca2+uptake capacity) elicited an ∼100-fold increase in the levels of ECaC mRNA and a significant increase in protein expression. Immunocytochemical analysis of the gills from hypercapnic fish suggested a marked increase in the apical expression of ECaC on pavement cells and a subpopulation of mitochondria-rich cells. The results of this study provide evidence that Ca2+uptake rates are, in part, regulated by the numbers of apical membrane Ca2+channels that, in turn, modulate the inward flux of Ca2+into gill epithelial cells.
Parathyroid hormone-related protein regulates intestinal calcium transport in sea bream (Sparus auratus)
Authors: Fuentes Juan , Figueiredo Joana , Power Deborah M. , Canário Adelino V. M.
Published: June 2006

Parathyroid hormone-related protein (PTHrP) is a factor associated with normal development and physiology of the nervous, cardiovascular, immune, reproductive, and musculoskeletal systems in higher vertebrates. It also stimulates whole body calcium uptake in sea bream ( Sparus auratus) larvae with an estimated 60% coming from intestinal uptake in seawater. The present study investigated the role of PTHrP in the intestinal calcium transport in the sea bream in vitro. Unidirectional mucosal-to-serosal and serosal-to-mucosal45Ca fluxes were measured in vitro in duodenum, hindgut, and rectum mounted in Ussing chambers. In symmetric conditions with the same saline, bathing apical and basolateral sides of the preparation addition of piscine PTHrP 1–34 (6 nM) to the serosal surface resulted in an increase in mucosal to serosal calcium fluxes in duodenum and hindgut and a reduction in serosal to mucosal in the rectum, indicating that different mechanisms are responsive to PTHrP along the intestine. In control asymmetric conditions, with serosal normal and mucosal bathed with a saline similar in composition to the intestinal fluid, there was a net increase in calcium uptake in all regions. The addition of 6 nM PTHrP 1–34 increased net calcium uptake two- to threefold in all regions. The stimulatory effect of PTHrP on net intestinal calcium absorption is consistent with a hypercalcemic role for the hormone. The results support the view that PTHrP, alone or in conjunction with recently identified PTH-like peptides, counteracts in vivo the hypocalcemic effects of stanniocalcin.
Lesions in the cerebellar fastigial nucleus have a small effect on the hyperpnea needed to meet the gas exchange requirements of submaximal exercise
Authors: Martino P. F. , Davis S. , Opansky C. , Krause K. , Bonis J. M. , Czerniak S. G. , Pan L. G. , Qian B. , Forster H. V.
Published: June 2006

The purpose of this study was to test the hypothesis that an intact cerebellar fastigial nucleus (CFN) is necessary for the hyperpnea to meet the gas exchange needs of submaximal exercise. Bilateral stainless steel microtubules were implanted in the cerebellum inside ( n = 12) or outside ( n = 2) the CFN for injection (0.5 to 10 μl) of the neurotoxin ibotenic acid. All goats had difficulty maintaining normal posture and walking for up to 1 mo after the implantation of the microtubules and again for hours or days after the neurotoxin was injected. Postmortem histology indicated there were 55% fewer living neurons ( P < 0.001, n = 9, 3,720 ± 553 vs. 1,670 ± 192) in the CFN of the experimental goats compared with a control group of goats. As is typical for goats before implantation of the microtubules, the decrease in arterial Pco2 from rest during mild and moderate treadmill exercise was 2.0 ± 0.39 and 3.5 ± 0.45 Torr, respectively. Implantation of the microtubules did not significantly change this exercise hyperventilation. However, neurotoxic lesioning with 10 μl ibotenic acid significantly ( P < 0.05) attenuated the decrease in arterial Pco2 by 1.3 and 2.8 Torr at the first and second workload, respectively. The modest attenuation of the exercise hypocapnia at both workloads in CFN-lesioned goats suggests that the CFN is part of the control system that enables the ventilatory response to meet the gas exchange requirements of submaximal exercise.
Interleukin 5 Plays an Essential Role in Elicitation of Contact Sensitivity through Dual Effects on Eosinophils and B-1 Cells
Authors: Itakura Atsuko , Kikuchi Yuji , Kouro Taku , Ikutani Masashi , Takaki Satoshi , Askenase Philip W. , Takatsu Kiyoshi
Published: June 2006

Background: Elicitation of contact sensitivity (CS) depends on B-1-cell-derived antigen-specific immunoglobulin M (IgM) antibodies that recruit CS effector T cells into the local tissue, which is followed by infiltration of antigen-nonspecific mononuclear cells and polymorphonuclear cells, such as neutrophils and eosinophils. In this study, we investigated the role of interleukin (IL)-5, which has broad effects on both eosinophils and B-1 cells, in elicitation of CS. Methods: IL-5 receptor α-chain-deficient (IL-5Rα–/–) mice and IL-5Rα+/+ mice were contact sensitized with oxazolone hapten. Four days later, mice were challenged with the same hapten, and ear swelling responses were measured at 24 h after challenge. Eosinophil infiltration into the local tissue was determined by examination of skin histology and eosinophil peroxidase activity. To investigate the role of IL-5 in B-1 cell activation, the number of oxazolone-specific IgM-producing cells in the spleen was determined by enzyme-linked immunospot assay. Results: Ear swelling responses in IL-5Rα–/– mice were about half of those in IL-5Rα+/+ mice, and nearly no eosinophil infiltration was observed in IL-5Rα–/– mouse skin. Eosinophil peroxidase activity in the sensitized and challenged IL-5Rα–/– mice was about 11 times less than that in immunized IL-5Rα+/+ mice. Contact sensitization significantly increased in numbers of oxazolne-specific IgM-producing cells in IL-5Rα+/+ mouse spleen, but not in IL-5Rα–/– mouse spleen. Conclusion: We conclude that IL-5-dependent activation of eosinophils and B-1 cells is necessary for induction and elicitation of CS. These findings provide a new insight into complicated mechanisms of CS elicitation and suggest a novel role of IL-5 in the regulation of immune responses.
Differential Effects of Salbutamol and Montelukast on Eosinophil Adhesion and Superoxide Anion Generation
Authors: Kushiya Mariko , Saito Keiko , Kikuchi Izumi , Kobayashi Takehito , Hagiwara Koichi , Kanazawa Minoru , Nagata Makoto
Published: June 2006

Background: β2-Agonists, a representative class of bronchodilators used for asthma, have been shown to modulate some functions of eosinophils, including cell adhesion. Similarly, a leukotriene receptor antagonist (LTRA) may be beneficial in controlling inflammation in asthma, as cysteinyl leukotrienes (cysLTs) can cause accumulation or activation of eosinophils. Recent evidence suggests that the addition of an LTRA, but not a long-acting β2-agonist, to inhaled corticosteroid additionally reduces the number of eosinophils in sputum and blood from patients with asthma. The present study examined whether a β2-agonist and an LTRA differentially modify eosinophil adhesion and activation induced by cysLTs and other activators. Methods: Eosinophils were isolated from blood of healthy donors and then incubated in the presence or absence of salbutamol (albuterol) or montelukast. Eosinophils were then exposed to leukotriene D4 (LTD4) or another activator, and the generation of superoxide anion (O2–) was evaluated by cytochrome C reduction assay. Eosinophil adhesion was examined by an eosinophil peroxidase assay. Results: Montelukast, but not salbutamol (both at 1 µM), inhibited LTD4-induced (100 nM) eosinophil adhesion to recombinant human intercellular adhesion molecule 1. Both drugs similarly and partially inhibited the 100 pM interleukin-5-induced adhesive response of eosinophils to recombinant human intercellular adhesion molecule 1. Montelukast, but not salbutamol, blocked LTD4-induced eosinophil O2– generation of eosinophils. Finally, neither salbutamol nor montelukast modified phorbol myristate acetate (1 ng/ml)-induced O2– generation from eosinophils. Conclusion: These results confirm that LTD4 directly induces activation of eosinophils via the cysLT1 receptor. Furthermore, the results suggest that a β2-agonist has no effect on eosinophil adhesion and activation induced by cysLTs. These results explain the differential effects of an LTRA and a β2-agonist in the treatment of eosinophilic inflammation in asthma.
CpG Oligodeoxynucleotide Prolongs Eosinophil Survival through Activation of Contaminating B Cells and Plasmacytoid Dendritic Cells in vitro
Authors: Matsumoto Kenji , Terakawa Maki , Fukuda Shuhei , Kato Atsushi , Toki Shinji , Shinohara Miwa , Wakiguchi Hiroshi , Saito Hirohisa
Published: June 2006

Background: In our previous study, oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODNs) significantly prolonged eosinophil survival without inducing active release of eosinophil-derived neurotoxin or interleukin 8. In addition, this survival-promoting activity was nuclear factor-ĸB dependent. However, some eosinophil preparations from different donors hardly responded to CpG ODNs at all. To clarify why CpG ODN-induced nuclear factor-kB activation in eosinophils does not cause eosinophil-derived neurotoxin or interleukin 8 release and why the survival-promoting activity of CpG ODNs was not found in some eosinophil preparations, we determined the effect of extensive removal of contaminating B cells and plasmacytoid dendritic cells from human eosinophil preparations. Methods: Eosinophils were purified from the peripheral blood of healthy or slightly allergic donors by gradient sedimentation and negative selection with anti-CD16 alone or a combination of anti-CD16, anti-CD19 and anti-blood dendritic cell antigen 4 (BDCA4) immunomagnetic beads. Eosinophil survival was measured with FITC-conjugated annexin V and propidium iodide by FACS after incubation with synthetic CpG 2006(CpG-B), CpG 2216 (CpG-A) or their GpC control ODNs for 24 h. Results: The addition of anti-CD19 and anti-BDCA4 immunomagnetic beads reduced the number of contaminating CD19+ cells and CD123+ BDCA2+ cells in eosinophil preparations. CpG 2006 and CpG 2216, but not their GpC control ODNs, significantly prolonged survival of eosinophils purified with anti-CD16 immunomagnetic beads alone but not eosinophils purified with a combination of anti-CD16, anti-CD19 and anti-BDCA4 beads. Conclusions: These results strongly suggest that contaminating B cells or plasmacytoid dendritic cells in eosinophil preparations critically regulate CpG ODN-mediated prolongation of eosinophil survival and that CpG ODNs do not activate eosinophils directly.
Epidemiology and Outcome of Severe Hepatitis A Infection in Children in Kuwait
Authors: Husain Entesar , Al-Tawfiq Jaffar A. , Husain Khalid
Published: June 2006

Objective: To describe the epidemiology, clinical features and outcome of hepatitis A virus (HAV) infection in children in Kuwait. Subjects and Method: The medical records of 350 patients (age 0–16 years) admitted to the Infectious Diseases Hospital, Kuwait, between January 2000 and December 2002, with hepatitis A infection were reviewed. Results: The mean age was 8.6 ± 3.8 years and 47% of patients were between 7 and 12 years old. Kuwaiti children comprised 44% of admitted patients. The largest proportion of children with hepatitis A (34%) were from the northern part of the country. HAV infection was prevalent throughout the year with a peak during the months of August to October. Of the Kuwaiti children, 31% reported a history of contact with jaundiced patients, while 52% of the non-Kuwaiti children had a history of recent travel prior to their illness. Patients had symptoms for a mean of 6 ± 3.6 days prior to presentation. The mean length of hospitalization was 5.8 ± 2.9 days. The rate of complications of HAV infection was 6% and only one child required admission to the intensive care unit for fulminant hepatitis. None of the patients had permanent sequelae. Conclusions: HAV infection is a significant cause of morbidity for children in Kuwait. The disease is mostly prevalent in preschool and school age children. Despite the excellent outcome of all patients, a considerable number of patients tend to have a complicated course and prolonged hospitalization. In view of these data, hepatitis A vaccine should be considered as a part of routine childhood immunization in Kuwait.
Antioxidative and Neuroprotective Activities of Extracts from the Fruit Hull of Mangosteen (Garcinia mangostana Linn.)
Authors: Weecharangsan Wanlop , Opanasopit Praneet , Sukma Monrudee , Ngawhirunpat Tanasait , Sotanaphun Uthai , Siripong Pongpan
Published: June 2006

Objective: The aim of this study was to investigate the antioxidative and neuroprotective activities of various extracts from the fruit hull of mangosteen (Garcinia mangostana Linn., GM). Materials and Methods: Four extracts: water, 50% ethanol, 95% ethanol and ethyl acetate, were used. The antioxidative activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl free-radical scavenging assay at extract concentrations of 1, 10, 50 and 100 µg/ml. Based on the free radical scavenging activity of the extracts, two (water and 50% ethanol) were selected for their protective activity in NG108-15 neuroblastoma cells against H2O2-induced oxidative stress and for cell viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: All extracts exhibited antioxidative activity. The water and 50% ethanol extracts showed high free-radical scavenging activity with IC50 values of 34.98 ± 2.24 and 30.76 ± 1.66 µg/ml, respectively. Both water and 50% ethanol extracts exhibited neuroprotective activity on NG108-15 cells. The highest activity was observed at the concentration of 50 µg/ml for both the water and 50% ethanol extracts. For cytotoxicity test, none of the extracts was toxic to the cells except at the high concentration of 100 µg/ml. Conclusions: These results suggest that the water and 50% ethanol extracts from the fruit hull of GM may be potent neuroprotectants.
Single-Agent Irinotecan for Recurrent/Metastatic Colorectal Cancer: A Retrospective Analysis
Authors: Sanli Ulus A. , Karabulut Bulent , Uslu Ruchan , Korkut Mustafa , Goker Erdem
Published: June 2006

Objective: To evaluate the efficacy, toxicity and factors affecting the survival rate of patients treated with irinotecan. Subjects and Methods: Data from the medical records of 74 patients who had recurrent/metastatic colorectal cancer treated with single-agent irinotecan were analyzed. Results: The mean age for all the patients was 56 years (range 19–77). Forty-one (55%) and 33 (45%) patients had recurrent and/or metastatic colon cancer, respectively. All the patients were treated with irinotecan 350 mg/m2 every 21 days. Grade 3–4 emesis, grade 3–4 diarrhea, grade 3–4 neutropenia and severe early cholinergic events developed in 7, 15, 7 and 1.3% of patients, respectively. One patient died due to acute renal failure. The overall response rate was 14% (complete response 5%, partial response 9%); 61% had stable response while another 25% had progressive disease. Patients with multiple metastatic foci, patients ≤50 years of age and patients with peritonitis carcinomatosa were shown to have worse outcomes than others. The median duration of response was 16.7 months. The median progression-free survival and overall survival were 4 and 14 months, respectively. Conclusion: The data show that irinotecan was useful in the treatment of recurrent/metastatic colorectal cancer with acceptable toxicity.
Closed and Open Grade I and II Tibial Shaft Fractures Treated by Reamed Intramedullary Nailing
Authors: Djahangiri Ali , Garofalo Raffaele , Chevalley François , Leyvraz Pierre-François , Wettstein Michael , Borens Olivier , Schizas Constantin , Mouhsine Elyazid
Published: June 2006

Objective: To evaluate the results of closed and open grade I and II tibial shaft fractures treated by reamed nail and unreamed nailing. Subjects and Methods: Between 1997 and 2000, 119 patients with tibial shaft fractures were treated with reamed tibial nails. Postoperatively 96 patients (70 closed and 26 grade I and II open fractures) were followed clinically and radiologically for up to 18 months. The nail was inserted either by patellar tendon splitting or by nonsplitting technique. The nail was inserted after overreaming by 1.5 mm. Postoperatively, patients with isolated tibial fracture were mobilized by permitting partial weight bearing on the injured leg for 6 weeks. Patients with associated ankle fractures were allowed to walk with a Sarmiento cast. Results: Postoperatively, 6 (6.3%) patients developed a compartment syndrome after surgery. In 48 (50%) cases, dynamization of the nail was carried out after a mean period of 12 weeks for delayed union. Overall, a 90.6% union was obtained at a mean of 24 weeks without difference between closed or open fractures. Two (2.1%) patients with an open grade II fracture developed a deep infection requiring treatment. A 9.4% rate of malunion was observed. Eight (8.3%) patients developed screw failure without clinical consequences. At the last follow-up, 52% of patients with patellar tendon splitting had anterior knee pain, compared to those (14%) who did not have tendon splitting. Conclusion: Reamed intramedullary nail is a suitable implant in treating closed as well as grade I and II open tibial shaft fractures.
Acute Pyelonephritis Associated with Transudative Pleural Effusion in a Middle-Aged Woman without Urinary Tract Obstruction
Authors: Wang I-Kuan , Chuang Feng-Rong , Chang Hung-Yu , Lin Chun-Liang , Yang Cheng-Ta
Published: June 2006

Objective: To describe a case of acute pyelonephritis associated with pleural effusion. Clinical Presentation and Intervention: A 39-year-old female non-smoker who had Escherichia coli bacteremia due to acute pyelonephritis, developed bilateral transudative pleural effusions during hospitalization. She was successfully treated with intravenous antibiotic therapy. Follow-up chest radiographs revealed complete resolution of the bilateral pleural effusions. Conclusion: Though quite rare, pleural effusion is a potential complication of acute pyelonephritis. The exact pathogenesis of transudative pleural effusion is unknown, but the effusion may resolve spontaneously when infection is adequately controlled.
Serum Homocysteine and Long-Term Risk of Myocardial Infarction and Sudden Death in Patients with Coronary Heart Disease
Authors: Haim Moti , Tanne David , Goldbourt Uri , Doolman Ram , Boyko Valentina , Brunner Daniel , Sela Ben-Ami , Behar Solomon
Published: June 2006

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 µmol/l increment was associated with a 25% higher risk.
Nitric Oxide Levels in Disruptive Behavioral Disorder
Authors: Varol Tas Fatma , Guvenir Taner , Tas Gultekin , Cakaloz Burcu , Ormen Murat
Published: June 2006

There are various evidences of the role of nitric oxide (NO) in several neuropsychiatric disorders. However, there is no clinical study which investigated the role of NO in disruptive behavioral disorders (DBD). The aim of this study is to investigate the relation between NO levels and DBD. NO levels were measured in serum from 45 patients diagnosed as having DBD (30 patients with a diagnosis of attention deficit and hyperactivity disorder [ADHD] and 15 with ADHD + oppositional defiant disorder [ODD]) and 51 healthy control subjects. It is statistically significant that the pure ADHD group’s blood NO levels are lower than those of both the ADHD + ODD and control groups. There was no significant difference between the ADHD + ODD group and the controls. The difference of the NO levels in DBD may indicate the effect of NO in the etiology of this disorder spectrum.
Stratum Corneum: An Ideal Osmometer?
Authors: Pirot Fabrice , Falson Françoise , Pailler-Mattéi Cyril , Maibach Howard I.
Published: June 2006

Water and osmolyte homeostasis is an essential biological function. Remarkably devoid of aquaporin (i.e., water channel protein) expression, the stratumcorneumavoids a substantial transepidermal water loss, compulsory for the adaptation to terrestrial life. In spite of its heterogeneity, the stratum corneumexhibits a homogeneous water transport, whereas highly osmotic endogenous materials control its water-holding capacity and skin’s physical properties (e.g., stiffness, firmness, flexibility) under various conditions. However, the contingent interplay between water homeostasis of the stratum corneumand an exogenous osmotic stress has been not reported, although constituting a cornerstone of skin physiology. Here, we show that an osmotic shock reinforces the endogenous stratum corneumosmolality proportionally to the osmotic pressure exerted against it and, therefore, reduces the magnitude of outward water transfer and net evaporation. The strengthening of endogenous osmolality enhanced the water-holding capacity of the stratum corneum with respect to chemical potentials. This property was found for organic osmolytes, but questioned for mineral electrolytes characterized by minimal stratum corneumpermeability. Besides, straightforward experiments performed using a built-in house osmometer, a so-called ‘corneosmometer’, have confirmed water transfer through the stratum corneumsubmitted to a gradient of osmotic pressure. Thus, the ambivalent function of the stratum corneum, which firstly behaves as an ideal osmometer and secondly adapts its own osmolality to an exogenous gradient of osmotic pressure, has been clearly demonstrated. This duality influences the water-holding capacity of the stratum corneum, by regulating the water transfer proportionally to an initial osmotic stress, and, finally, conditions the further capacity of the stratum corneumto facilitate or impede skin hydration.
Peroxisome Proliferator-Activated Receptor-γ Polymorphism, Body Mass and Prostate Cancer Risk: Evidence for Gene-Environment Interaction
Authors: Zmuda Joseph M. , Modugno Francesmary , Weissfeld Joel L. , Cauley Jane A. , Trump Donald L. , Moffett Susan P. , Ferrell Robert E.
Published: June 2006

Background: Peroxisome proliferator-activated receptor (PPAR)-γ has been implicated in prostate cancer. In the present case-control study, we tested if a common Pro12Ala polymorphism in PPAR-γ is associated with the risk of prostate cancer. Methods: Ninety-one adult Caucasians with prostate cancer were recruited between 1994 and 1998. Blood samples were also obtained from 237 community-based Caucasian men without prostate cancer. Results: Twenty-six percent of cases and 19% of controls carried at least one Ala allele (p = 0.16). There was a significant interaction between the PPAR-γ polymorphism and body mass index (BMI) in age-adjusted analyses (p < 0.05). Among the subgroup of men with BMI above 27.2 kg/m2 (median in controls), carriers of the Ala allele had over 2-fold greater risk of prostate cancer compared to those with the Pro12Pro genotype (odds ratio, OR: 2.77; 95% confidence interval, CI: 1.25–6.16). No association was observed between the PPAR-γ genotype and prostate cancer among men with BMI below the median (OR: 0.68; 95% CI: 0.23–1.97). Conclusions: Our results suggest a novel gene-environment interaction between the PPAR-γ Pro12Ala polymorphism and body mass in prostate cancer. Further research, particularly prospective studies, is needed to confirm these findings and to clarify the underlying mechanisms involved.
Respiratory Diseases and Helicobacter pylori Infection: Is There a Link?
Authors: Roussos Anastasios , Philippou Nikiforos , Mantzaris Gerassimos J. , Gourgoulianis Konstantinos I.
Published: June 2006

Recent studies suggest an epidemiological association between Helicobacter pylori infection and several extragastroduodenal pathologies, including cardiovascular, rheumatic, skin and liver diseases. The observed associations might be explained by a role of H. pylori infection in the pathogenesis of certain extradigestive disorders, as a variety of inflammatory mediators are activated by H. pylori infection. The present review summarizes the current literature, including our own studies, concerning the association between respiratory diseases and H. pylori infection. A small number of epidemiological and serologic case-control studies suggest that patients with chronic obstructive pulmonary disease have an increased seroprevalence of H. pylori. A frequent coexistence of bronchiectasis and H. pylori infection has also been found. Moreover, recent studies have shown an increased prevalence of H. pylori infection in patients with pulmonary tuberculosis and in those with lung cancer. On the other hand, bronchial asthma does not seem to be related to H. pylori infection. At present, there is no definite proof of a causal relationship between H. pylori and respiratory diseases. The primary evidence rests on case-control studies, concerning relatively small numbers of patients. Future studies should be large enough for moderate-sized effects to be assessed or registered reliably. The activation of inflammatory mediators by H. pylori infection might be the pathogenetic mechanism underlying the observed associations. Therefore, the role of genetic predisposition of the infected host, the presence of strain-specific virulence factors and the serum concentration of proinflammatory markers in H. pylori-infected patients with respiratory diseases need further evaluation.
IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis
Authors: Yamaoka-Tojo Minako , Tojo Taiki , Kim Ha Won , Hilenski Lula , Patrushev Nikolay A. , Zhang Lynn , Fukai Tohru , Ushio-Fukai Masuko
Published: June 2006

Objective—

Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating reactive oxygen species (ROS) production primarily through the VEGF receptor-2 (VEGFR2). One of the initial responses in established vessels to stimulate angiogenesis is loss of vascular endothelial (VE)-cadherin–based cell–cell adhesions; however, little is known about the underlying mechanisms. IQGAP1 is a novel VEGFR2 binding protein, and it interacts directly with actin, cadherin, and β-catenin, thereby regulating cell motility and morphogenesis.

Methods and Results—

Confocal microscopy analysis shows that IQGAP1 colocalizes with VE-cadherin at cell–cell contacts in unstimulated human endothelial cells (ECs). VEGF stimulation reduces staining of IQGAP1 and VE-cadherin at the adherens junction without affecting interaction of these proteins. Knockdown of IQGAP1 using siRNA inhibits localization of VE-cadherin at cell–cell contacts, VEGF-stimulated recruitment of VEGFR2 to the VE-cadherin/β-catenin complex, ROS-dependent tyrosine phosphorylation of VE-cadherin, which is required for loss of cell–cell contacts and capillary tube formation. IQGAP1 expression is increased in a mouse hindlimb ischemia model of angiogenesis.

Conclusions—

IQGAP1 is required for establishment of cell–cell contacts in quiescent ECs. To induce angiogenesis, it may function to link VEGFR2 to the VE-cadherin containing adherens junctions, thereby promoting VEGF-stimulated, ROS-dependent tyrosine phosphorylation of VE-cadherin and loss of cell–cell contacts.
A Novel β-Oxa Polyunsaturated Fatty Acid Downregulates the Activation of the IκB Kinase/Nuclear Factor κB Pathway, Inhibits Expression of Endothelial Cell Adhesion Molecules, and Depresses Inflammation
Authors: Ferrante Antonio , Robinson Brenton S. , Singh Harmeet , Jersmann Hubertus P.A. , Ferrante Judith V. , Huang Zhi H. , Trout Neil A. , Pitt Michael J. , Rathjen Deborah A. , Easton Christopher J. , Poulos Alf , Prager Rolf H. , Lee Frank S. , Hii Charles S.T.
Published: June 2006

Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the β-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, β-oxa-23:4n-6, unlike natural PUFAs, lacked ability to stimulate oxygen radical production in neutrophils but caused marked inhibition of agonist-induced upregulation of leukocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC) and E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. In addition, β-oxa-23:4n-6 inhibited acute and chronic inflammatory responses in mice as well as the upregulation of adhesion molecule expression in arterial endothelium. This action of β-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas β-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IκB kinase/nuclear factor κB pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.
eNOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes
Authors: Elrod John W. , Duranski Mark R. , Langston Will , Greer James J.M. , Tao Ling , Dugas Tammy R. , Kevil Christopher G. , Champion Hunter C. , Lefer David J.
Published: June 2006

Previous studies indicate that endothelial nitric oxide synthase (eNOS) function is impaired in diabetes as a result of increased vascular generation of reactive oxygen species. We hypothesized that eNOS gene therapy would augment NO· bioavailability and protect against hepatic ischemia-reperfusion (I-R) injury in type 2 diabetes mellitus. We developed a transgenic (Tg) diabetic mouse in which eNOS is systemically overexpressed. We also examined the effects of hepatic eNOS adenovirus therapy in diabetic mice. Diabetic (db/db) and nondiabetic mice were subjected to hepatic I-R injury. In nondiabetic mice, genetic overexpression of eNOS (both eNOS-Tg and eNOS adenovirus) resulted in hepatoprotection. In contrast, hepatic I-R injury was significantly increased in the db/db eNOS-Tg mouse, as serum alanine aminotransaminase (ALT) levels were increased by 3.3-fold compared with diabetic controls. Similarly, eNOS adenovirus treatment resulted in a 3.2-fold increase in serum ALT levels as compared with diabetic controls. We determined that hepatic eNOS was dysfunctional in the db/db mouse and increased genetic expression of eNOS resulted in greater production of peroxynitrite. Treatment with the eNOS cofactor tetrahydrobiopterin (BH
4
) or the BH
4
precursor sepiapterin resulted in a significant decrease in serum ALT levels following I-R injury. We present clear examples of the protective and injurious nature of NO· therapy in I-R. Our data indicate that eNOS exists in an “uncoupled” state in the setting of diabetes and that “recoupling” of the eNOS enzyme with cofactor therapy is beneficial.
Characterization of Fluoromisonidazole Binding in Stroke
Authors: Spratt Neil J. , Ackerman Uwe , Tochon-Danguy Henri J. , Donnan Geoffrey A. , Howells David W.
Published: June 2006

Background and Purpose—

[
18
F]fluoromisonidazole (FMISO) positron emission tomography has been used to image hypoxia early after human stroke. To further study the role of hypoxia in stroke and the binding characteristics of FMISO, we aimed to develop [
3
H]FMISO autoradiography in an animal stroke model. We hypothesized that [
3
H]FMISO binding is prolonged, allowing correlation with 24-hour histology, and that there is no FMISO binding after effective reperfusion.

Methods—

Temporary middle cerebral artery (MCA) occlusion was performed in rats, followed by [
3
H]FMISO administration. Tissue preparation for autoradiography and histology (from the same sections) was performed 2.5 hours after MCA occlusion (MCAo; replicating [
18
F]FMISO studies). Then, otherwise identical cohorts with tissue preparation at 2.5 or 24 hours were prepared. For reperfusion studies, animals had 1-hour MCAo, with [
3
H]FMISO administered 1 hour after reperfusion.

Results—

[
3
H]FMISO autoradiography provided a high-resolution image of hypoxia throughout the ischemic territory. Delaying animal death from 2.5 to 24 hours allowed histological changes of stroke to develop, without significantly altering either relative intensity (1.88±0.06 and 2.02±0.11, respectively) or volume (25±6 mm
3
and 28±5 mm
3
, respectively) of hypoxic binding. [
3
H]FMISO binding did not occur after effective reperfusion, despite histological injury from the preceding MCAo.

Conclusions—

[
3
H]FMISO autoradiography of hypoxia in experimental stroke offers several advantages. Bound FMISO is retained in tissues long term, enabling direct correlation with 24-hour histology. It is not bound after effective reperfusion. Therefore, positive [
18
F]FMISO positron emission tomography studies in stroke patients are indicative of ongoing tissue hypoxia, not merely recent tissue injury.
Cerebral Vasodilatation to Exogenous NO Is a Measure of Fitness for Life at Altitude
Authors: Appenzeller Otto , Claydon Victoria E. , Gulli Giosué , Qualls Clifford , Slessarev Marat , Zenebe Guta , Gebremedhin Amha , Hainsworth Roger
Published: June 2006

Background and Purpose—

Andean highlanders, unlike Ethiopians, develop chronic mountain sickness (CMS), a maladaptation to their native land. Ambient hypoxia induces NO-mediated vasodilatation. Fitness for life at altitude might be revealed by cerebrovascular responses to NO.

Methods—

Nine altitude-native men were examined at 3622 and 794 m in Ethiopia and compared with 9 altitude-native Andean men tested at 4338 and 150 m in Peru. We assessed CMS scores, hematocrits, end-tidal pressure of carbon dioxide (P
ET
co
2
), oxygen saturations, and cerebral blood flow velocity (CBV). We evaluated fitness for life at altitude from the cerebrovascular response to an exogenous NO donor.

Results—

At high altitude, CMS scores and hematocrits were higher in Andeans, and they had lower oxygen saturations. Ethiopians had higher P
ET
co
2
at all study sites. At low altitude, saturations were similar in both groups. Responsiveness of the cerebral circulation to NO was minimal in Ethiopians at low altitude, whereas Andeans had a large response. In contrast, at high altitude, Ethiopians showed large responses, and Peruvians had minimal responses.

Conclusions—

By our measure, high altitude-native Peruvians were well-adapted lowlanders, whereas Ethiopian highlanders were well adapted to altitude life. Environmental pressures were sufficient for human adaptation to chronic hypoxia in Africa but not South America. The mechanisms underlying these differences are unknown, although studies of neurovascular diseases suggest that this may be related to a NO receptor polymorphism.
Intracerebral Hemorrhage Elicits Aberration in Cardiomyocyte Contractile Function and Intracellular Ca
2+
Transients
Authors: Fang Cindy X. , Wu Shan , Ren Jun
Published: June 2006

Background and Purpose—

The sequelae of intracerebral hemorrhage involve multiple organ damage including electrocardiographic alteration, although the mechanism(s) behind myocardial dysfunction is unknown. The aim of this study was to examine the impact of intracerebral hemorrhage on cardiomyocyte contractile function, intracellular Ca
2+
handling, Ca
2+
cycling proteins, I kappa B beta protein (IκB) phosphorylation, hypoxia-inducible factor 1α (HIF-1α), and nitrosative damage within 48 hours of injury.

Methods—

Mechanical and intracellular Ca
2+
properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR
90
), fura-2 fluorescence intensity (FFI), and intracellular Ca
2+
decay.

Results—

Myocytes from intracerebral hemorrhage rats exhibited depressed PS, ±dL/dt, prolonged TPS and TR
90
, as well as declined baseline FFI and slowed intracellular Ca
2+
decay between 12 and 24 hours after injury. Most of these aberrations returned to normal levels 48 hours after hemorrhage with the exception of −dL/dt and TR
90
. Myocytes from 24-hour posthemorrhage rats exhibited a stepper negative staircase in PS with increased stimulus frequency. Cardiac expression of sarco(endo)plasmic reticulum Ca
2+
-ATPase 2a and phospholamban was enhanced, whereas that of Na
+
-Ca
2+
exchanger and voltage-dependent K
+
channel was decreased. IκB phosphorylation, HIF-1α, inducible NO synthase, and 3-nitrotyrosine were enhanced 12 hours after injury.

Conclusions—

These data demonstrated that intracerebral hemorrhage initiates cardiomyocyte contractile and intracellular Ca
2+
dysregulation possibly related to altered expression of Ca
2+
cycling proteins, nitrosative damage, and myocardial phosphorylation of IκB.
Body
Authors: Turner Bryan S.
Published: June 2006

Contemporary academic interest in the human body is a response to fundamental changes in the relationship between body, economy, technology and society. Scientific advances, particularly new reproductive technologies and therapeutic cloning techniques, have given the human body a problematic status. Ageing, disease and death no longer appear to be immutable facts about the human condition. The emergence of the body as a topic of research in the humanities and social sciences is also a response to the women's and gay liberation movements, and environmentalism, animal rights, anti-globalism, religious fundamentalism and conservative politics. Further, the human body is now central to economic growth in various biotechnology industries, in which disease itself has become a productive factor in the global economy and the body a code or system of information from which profits can be extracted through patents. In modern social theory, the body has been studied in the contexts of advertising and consumerism, in ethical debates about cloning, in research on HIV/AIDS, in postmodern reflections on cybernetics, cyberbodies and cyberpunk, and in the analysis of the global trade in human organs. The body is a central feature of contemporary politics, because its ambiguities, vulnerability and plasticity have been amplified by new genetic technologies.
Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells
Authors: Qiu Lin , Lai Raymond , Lin Quan , Lau Esther , Thomazy David M. , Calame Daniel , Ford Richard J. , Kwak Larry W. , Kirken Robert A. , Amin Hesham M.
Published: June 2006

The aberrant fusion protein NPM-ALK plays an important pathogenetic role in ALK+ anaplastic large-cell lymphoma (ALCL). We previously demonstrated that Jak3 potentiates the activity of NPM-ALK. Jak3 activation is restricted to interleukins that recruit the common γ chain (γc) receptor, including IL-9. NPM-ALK was previously shown to promote widespread lymphomas in IL-9 transgenic mice by unknown mechanisms. We hypothesized that IL-9 plays an important role in ALK+ ALCL via Jak3 activation. Our studies demonstrate the expression of IL-9Rα and IL-9 in 3 ALK+ ALCL-cell lines and 75% and 83% of primary tumors, respectively. IL-9 was detected in serum-free culture medium harvested from ALK+ ALCL-cell lines, supporting autocrine release of IL-9. Treatment of these cells with an anti–IL-9–neutralizing antibody decreased pJak3 and its kinase activity, along with pStat3 and ALK kinase activity. These effects were associated with decreased cell proliferation and colony formation in soft agar and cell-cycle arrest. Evidence suggests that cell-cycle arrest can be attributed to up-regulation of p21 and down-regulation of Pim-1. Our results illustrate that IL-9/Jak3 signaling plays a significant role in the pathogenesis of ALK+ ALCL and that it represents a potential therapeutic target for treating patients with ALK+ ALCL.
TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells
Authors: Oram Shane W , Liu Xing Xing , Lee Tin-Lap , Chan Wai-Yee , Lau Yun-Fai Chris
Published: June 2006

Background

TSPY is a repeated gene mapped to the critical region harboring the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on this male-specific chromosome. Elevated levels of TSPY have been observed in gonadoblastoma specimens and a variety of other tumor tissues, including testicular germ cell tumors, prostate cancer, melanoma, and liver cancer. TSPY contains a SET/NAP domain that is present in a family of cyclin B and/or histone binding proteins represented by the oncoprotein SET and the nucleosome assembly protein 1 (NAP1), involved in cell cycle regulation and replication.

Methods

To determine a possible cellular function for TSPY, we manipulated the TSPY expression in HeLa and NIH3T3 cells using the Tet-off system. Cell proliferation, colony formation assays and tumor growth in nude mice were utilized to determine the TSPY effects on cell growth and tumorigenesis. Cell cycle analysis and cell synchronization techniques were used to determine cell cycle profiles. Microarray and RT-PCR were used to investigate gene expression in TSPY expressing cells.

Results

Our findings suggest that TSPY expression increases cell proliferation in vitro and tumorigenesis in vivo. Ectopic expression of TSPY results in a smaller population of the host cells in the G2/M phase of the cell cycle. Using cell synchronization techniques, we show that TSPY is capable of mediating a rapid transition of the cells through the G2/M phase. Microarray analysis demonstrates that numerous genes involved in the cell cycle and apoptosis are affected by TSPY expression in the HeLa cells.

Conclusion

These data, taken together, have provided important insights on the probable functions of TSPY in cell cycle progression, cell proliferation, and tumorigenesis.