bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Antireflux Technique: Mucosal Flap Barrier
Authors: Dayanc Murat , Tahmaz Lutfu , Bedir Selahattin , Avci Ali
Published: March 2007

Introduction: In this study, our aim was to evaluate the effectiveness of the mucosal flap barrier (MFB) upon the incompetent ureteral orifice of an experimentally produced rabbit reflux model. The rabbit reflux model was done in the first stage of the study. This method is a new and original procedure which is different from Bischoff’s and Witherington’s osteoplasty techniques. Materials and Methods: We performed the mucosal flap procedure in eight 2–2.5 kg male New Zealand rabbits with experimentally produced refluxing ureters. The first stage of our study was to create refluxing ureters. Due to the upward and inward ‘J’ fishhook course of the intravesical ureter of rabbits, we performed two deep 12- and 4-o’clock incisions by suturing the edges of the intravesical ureter apart with catgut sutures. Additionally, to stop the tilting action of the trigonum during micturition, we performed two parallel incisions between the ureteral meatus. These parallel incisions were the authors’ modifications for the rabbit reflux model and which gives long-lasting reflux for the rabbit. We checked the reflux at the end of the 3rd month and performed our new MFB antireflux procedure. This mucosal flap made a cover on the incompetent ureteral orifice. This technique is completely different from the osteoplasty techniques described by Bischoff and Witherington. Results: Four months after the MFB application, we performed intravenous urography, cystometry and cinefluorography. There was no obstruction or reflux. Two rabbits were sacrificed at the 4th month. Both flaps were fully intact without any fixation at the medial side causing obstruction. At present, 3 rabbits are still alive. We did cinefluorography and cystometry at the 15th month and there was no obstruction or reflux. We are trying to keep them alive till the end of their natural lifespan. Conclusions: During the formation of the rabbit reflux model, we observed that spontaneous reflux even at high intravesical pressures did not have high percentages as previously mentioned in the literature. But it is possible and enough to produce an experimental reflux model by using meatotomy and interureteric incisions. Moreover, in rabbits with vesicoureteral regurgitation produced by ureteral meatotomy and interureteral incisions, reflux can be eliminated the MFB procedure. This method is an easy procedure for small bladders or dilated ureters after any kind of open reimplantation applications and it could be used by pneumovesical applications in the future.
Upregulation of Heme Oxygenase and Collagen Type III in the Rat Bladder after Partial Bladder Outlet Obstruction
Authors: Inaba Mitsuhiko , Ukimura Osamu , Yaoi Takeshi , Kawauchi Akihiro , Fushiki Shinji , Miki Tsuneharu
Published: March 2007

The objective of the study was to evaluate possible changes of the gene expression and localization of the enzymes, heme oxygenase and nitric oxide synthase (NOS), with reference to increase of collagen type III in response to the partial obstruction of the bladder. Following initial obstruction, whole rat bladders were removed for real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Real-time RT-PCR demonstrated significantly enhanced expression of HO (p < 0.01) and collagen type III (p < 0.001) gene on postoperative day 14. Enhanced expression of NOS gene was seen only on postoperative day 4 (p < 0.01). Immunohistochemistry revealed that immunoreactivity to HO-1 had much in common in neural cells and fibers, although immunoreactivity to HO-2 and iNOS was relatively weak. This study suggested gene expression of HO, especially HO-1, was more dramatically changed than NOS, and was upregulated simultaneously with increase of collagen type III after obstruction. HO systems could be involved in the pathogenesis of bladder dysfunction related to increase of collagen type III after obstruction.
Cutaneonephrobronchial Fistula: An Unusual Presentation of an Inadequately Treated Perinephric Abscess
Authors: Saw N.K. , Yakubu A. , Woodhead P.M.
Published: March 2007

We report a case of cutaneonephrobronchial fistula secondary to an inadequately treated perinephric abscess associated with a staghorn calculus. The patient, a 72-year-old lady, was initially treated for a superficial flank abscess by incision and drainage. She returned 4 months later with a persistent discharging flank sinus, at which time the above complex pathology was diagnosed. We review similar cases in the literature and discuss pathophysiology and current management of perinephric abscesses.
Vesicular Release of Prolactin from Preformed Prolactin Granules Is Stimulated by Soluble Factor(s) from the Anterior Pituitary of Lactating Rats
Authors: Huerta-Ocampo Icnelia , Fiordelisio Tatiana , Díaz Nestor , Navarro Nilda , Castilla Alejandra , Cárabez Alfonso , Aguilar Manuel B. , Morales Teresa , Hernández-Cruz Arturo , Mena Flavio
Published: March 2007

This study demonstrates that conditioned media (CM) from the anterior pituitary gland (AP) of lactating rats contains soluble factors that promote in vitro prolactin (PRL) release from the pituitary glands of male rats. CM-induced PRL release was confirmed by polyacrylamide gel electrophoresis, ELISA and bioassay. In cultured AP cells challenged with CM, increased intracellular staining with the dye FM1-43 was observed, suggesting vesicular PRL release and subsequent endocytosis. The percentage and hormone content of PRL-containing cells but not of growth hormone-containing cells increased in cultured male AP cells when exposed to CM. When the release of PRL, prelabeled with [3H] leucine for 30 min to 24 h was examined, no stimulatory effect of CM was observed, suggesting that released PRL originates from hormone synthesized more than 24 h earlier. Accordingly, the PRL content of mature granules from male pituitary tissues decreased after CM treatment. These findings were confirmed by electron microscopy immunogold PRL labeling. Treatment with inhibitors of protein synthesis or vesicle trafficking between the endoplasmic reticulum and the Golgi complex did not prevent the stimulatory effect of CM on PRL release. However, blockage of traffic to the plasma membrane completely abolished the effect of CM. These results suggest that CM from the AP of lactators contains soluble factor(s) capable of inducing rapid vesicular release of PRL in the male AP, which originates from preformed, mature granules by mechanisms independent of protein synthesis.
Rap1/B-Raf Signaling Is Activated in Neuroendocrine Tumors of the Digestive Tract and Raf Kinase Inhibition Constitutes a Putative Therapeutic Target
Authors: Karhoff Dorothee , Sauer Susanne , Schrader Jörg , Arnold Rudolf , Fendrich Volker , Bartsch Detlef K. , Hörsch Dieter
Published: March 2007

Objective: Molecular pathogenesis of digestive neuroendocrine tumors (dNETs) is largely unknown. Recently, the serine-threonine kinase B-Raf was identified as an oncogene in endocrine cancer such as thyroid carcinoma. In endocrine cells, the small G-protein Rap1 stimulates mitogen-activated protein kinase (MAPK) signaling by activating B-Raf. We examined the expression of Rap1 and B-Raf in dNETs and their contribution to MAPK signaling in neuroendocrine cell lines. In addition, we explored the effect of suppressing B-Raf kinase by the recently developed inhibitor BAY43-9006 (Sorafinib) on growth, apoptosis and MAPK activation neuroendocrine cell lines. Methods and Results: Expression of Rap1 and B-Raf in dNETs (19 insulinomas, 15 carcinoid tumors and 10 gastrinomas) was examined by immunohistochemistry, which revealed that Rap1 and B-Raf were highly prevalent in the majority of dNETs. Overexpression of Rap1 and B-Raf activated MAPK extracellular dependent kinase (ERK) ERK-2 and ERK-dependent transcription factor Elk-1 in neuroendocrine cell lines Bon and INS-1. Suppression of B-Raf by BAY43-9006 inhibited growth and induced apoptosis in Bon and INS-1 cells. In addition, BAY43-9006 suppressed phosphorylation of MAPK ERK1/2 and its upstream kinase MEK1/2 in Bon and INS-1 cells. Conclusion: These results indicate that Rap1-B-Raf signaling may contribute to pathogenesis of dNETs and provides a molecular target for treatment of dNETs.
Relation between Corticotropin-Releasing Hormone Neuron Number in the Hypothalamic Paraventricular Nucleus and Depressive State in Alzheimer’s Disease
Authors: Meynen Gerben , Unmehopa Unga A. , Hofman Michel A. , Swaab Dick F. , Hoogendijk Witte J.G.
Published: March 2007

Background/Aims: Depression occurs in 20–50% of the Alzheimer disease (AD) patients. It is not known whether depression in AD shares its pathophysiology with depressive disorder. Previously we found a fourfold increase of corticotropin-releasing hormone (CRH)-immunoreactive (IR) neurons in the hypothalamic paraventricular nucleus in depression. The objective of the present study was to find out whether in depression in AD the same phenomenon of an increased number of CRH-IR neurons could be observed. Methods: Post-mortem brain tissue was obtained from a cohort of 23 AD patients prospectively studied using the Cornell Scale for Depression in Dementia to measure depressive symptoms. The number of CRH-IR neurons was determined using immunocytochemistry and the Image Pro Plus analysis program. Results: A significant positive correlation was found between the Cornell scores and the number of CRH-IR neurons (p = 0.039) in AD patients. Conclusion: These results suggest that depressive disorder and depression in AD share, at least partly, their pathophysiology.
Intentionality as a Link between the Neuropsychology and the Symptoms of Schizophrenia
Authors: Kaiser Stefan , Weisbrod Matthias
Published: March 2007

Cognitive deficits are an important feature of schizophrenia, particularly in the areas of working memory and executive function. However, their relationship to other clinical dimensions of the illness has remained elusive. We suggest that a phenomenological exploration of disordered intentionality in schizophrenia symptoms might provide us with a framework for understanding the role of cognitive deficits. We propose an understanding of intentionality as having a layered structure, which facilitates a mapping onto neuropsychological concepts. A disturbance of basic intentional processes can explain some of the ‘positive’ symptoms of schizophrenia. We focus on the temporal aspect of intentionality, which will be related to recent conceptions of prefrontal cortical function as the temporal organization of thought and behavior. A compensation of these basic disturbances leads to a ‘minimization of change’, which can explain some of the ‘negative’ symptoms. The compensatory strategies are thought to rely on the higher-order executive functions of the prefrontal cortex. These are also disturbed in schizophrenia, which often renders the process of compensation ineffective, leading to a fragmentation of thought and behavior. Thus the concept of intentionality might help us relate different aspects of prefrontal dysfunction to specific schizophrenic symptom clusters.
The Temporal Structure of Intentionality and Its Disturbance in Schizophrenia
Authors: Fuchs Thomas
Published: March 2007

Working memory, attention and executive control functions are central areas of neuropsychological research in schizophrenia. These concepts implicitly refer to the basic temporal structure of mental life as an integration of past, present and future. From a phenomenological point of view, they may be paralleled to the structure of internal time consciousness as analyzed by Husserl, consisting of a retentional, presentational and protentional function. These synthetic functions, operating at the most basic layer of consciousness, are capable of integrating the sequence of single moments into an ‘intentional arc’, enabling us to direct ourselves towards objects and goals in a meaningful way. On this background, basic symptoms of schizophrenia such as formal thought disorder, loss of automatic performances and disturbances of self-awareness may be conceived as caused by a weakening and dissolution of the intentional arc. A failure of the continuous intertwining of succeeding moments, and especially of the protentional function, leads to a loss of the tacit or operative intentionality that carries the acts of perceiving, thinking and acting. The loss of tacit, implicit functions undermines the common-sensical understanding of reality and has to be compensated by the deliberate, hyperreflexive reconstruction of everyday performances. Phenomenological analyses may thus establish a link between experimental research on single mental dysfunctions on the one hand and the higher level of the patient’s subjective experience on the other.
Interaction of Lipophilic Moisturizers on Stratum Corneum Lipid Domains in vitro and in vivo
Authors: Caussin J. , Gooris G.S. , Groenink H.W.W. , Wiechers J.W. , Bouwstra J.A.
Published: March 2007

Dry skin symptoms such as scaling and itching are often treated with lipophilic moisturizers. The aim of this study was to investigate the effect of lipophilic moisturizers on the stratum corneum (SC) ultra-structure and lipid organization. Lipophilic moisturizers were applied on the forearms of 4 healthy volunteers for 3 h. Subsequently, the application sites were tape stripped, and selected tape strips prepared for Freeze Fracture Electron Microscopy (FFEM), a method to visualize the SC intercellular lipid parallel to the skin surface. To investigate the effect of lipid moisturizers on the lipid lamellae, isolated SC was pretreated with the lipophilic moisturizers for 24 h prior to performing small angle X-ray diffraction (SAXD) measurements. Additionally, the lipid organization of mixtures prepared with ceramides, cholesterol, free fatty acids and lipophilic moisturizer in a 2:1:1:1 molar ratio were studied using SAXD. The FFEM data (in vivo) as well as the SAXD data (in vitro) show that the lipophilic moisturizers do not change the lipid lamellar organization in the SC. Addition of 20% m/m lipophilic moisturizer to the ceramide:cholesterol:free fatty acids mixture did not inhibit the formation of the long periodicity phase, the characteristic lamellar phase in the SC, even though there was clear evidence that two of the three moisturizers were at least partially incorporated in the long periodicity phase. Concluding, all findings suggest that the lipophilic moisturizers investigated in this study do not drastically change the lamellar organization of the SC intracellular lipid matrix, but that the moisturizers form separate domains in the SC, as was visualized by FFEM.
Kinetic Characteristics of Acidic and Alkaline Ceramidase in Human Epidermis
Authors: Houben E. , Uchida Y. , Nieuwenhuizen W.F. , De Paepe K. , Vanhaecke T. , Holleran W.M. , Rogiers V.
Published: March 2007

It has recently become evident that at least five ceramidase (CDase) isoforms are present in human epidermis, and that specifically acidic CDase (aCDase) and alkaline CDase (alkCDase) activities increase during keratinocyte differentiation, and thus might play a pivotal role(s) in permeability barrier function. Prior to investigating their possible roles in the epidermal barrier function, it is necessary to characterize basic kinetic parameters for these enzymes, as well as to determine the effects of the established CDase inhibitors and their activities. In this study, assays for both aCDase and alkCDase activities in fully differentiated human epidermis were optimized using a radiolabeled substrate. These studies revealed that aCDase activity is substantially higher than alkCDase activity, and that both isoenzymes are inhibited by a CDase inhibitor N-oleylethanolamine. These findings were also confirmed using an in situ enzyme assay.
Follicular Penetration of Topically Applied Caffeine via a Shampoo Formulation
Authors: Otberg N. , Teichmann A. , Rasuljev U. , Sinkgraven R. , Sterry W. , Lademann J.
Published: March 2007

Aims: Follicular drug delivery is the prerequisite for an effective treatment of androgenetic alopecia or other reasons of premature hair loss. Methods: The follicular penetration of caffeine, applied topically in a shampoo formulation for 2 min, was measured with highly sensitive surface ionization in combination with mass spectroscopy, a selective method for the detection of very small quantities of transcutaneously absorbed substances in the blood. An experimental protocol, developed to selectively block the follicular pathway within the test area, was used. Based on this principle, a clear distinction between interfollicular and follicular penetration of topically applied caffeine was feasible. Results: After 2 min, caffeine penetrated via the hair follicles and stratum corneum. Conclusion: It was found that the penetration via hair follicles was faster and higher compared with the interfollicular route and that hair follicles are the only pathway for fast caffeine absorption during the first 20 min after application.
Final Height in Children with Idiopathic Growth Hormone Deficiency Treated with a Fixed Dose of Recombinant Growth Hormone
Authors: Rachmiel Marianna , Rota Vanessa , Atenafu Eshetu , Daneman Denis , Hamilton Jill
Published: March 2007

There is no consensus regarding the optimal dosing of recombinant human growth hormone (rhGH) for children with growth hormone deficiency (GHD). Our objective was to evaluate the final adult height (FAH) in children with idiopathic GHD treated with a fixed rhGH dose of 0.18 mg/kg/week. We reviewed all charts of patients with idiopathic GHD treated with rhGH since 1985 who reached FAH. Ninety-six patients were treated for an average of 5.4 years. The mean age was 11.9 years, the mean height –2.87 standard deviation score (SDS) and the mean FAH was –1.04 SDS. Females had a lower predicted adult height than males at the initiation of therapy (–2.0 vs. –1.01 SDS; p = 0.0087) but a higher FAH – predicted adult height (1.08 vs. 0.04 SDS; p = 0.0026). In multiple regression analysis, the FAH SDS was positively related to the midparental height SDS, the height SDS at GH initiation and growth velocity during the first year of therapy, and negatively correlated with peak GH and bone age at initiation (r2 = 0.51; p < 0.005). Treatment of children with idiopathic GHD with a fixed dose of 0.18 mg/kg/week rhGH is sufficient to reach FAH within 2 SDS of the normal population range (84%) with an average FAH within –0.5 SDS of midparental height.
Cytokine-Release Patterns in Elderly Patients with Systemic Inflammatory Response Syndrome
Authors: Marti Luis , Cervera Carlos , Filella Xavier , Marin Jose Luis , Almela Manuel , Moreno Asunción
Published: March 2007

Background: Information is scarce about the inflammatory responses to infection in elderly patients. Objective: To investigate the inflammatory pattern in elderly patients with systemic inflammatory response syndrome (SIRS). Methods: We assessed the value of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and C-reactive protein (CRP) in elderly patients with SIRS at the time of consultation in the emergency room and on the fourth day of hospitalization. Results: Of 100 patients with SIRS, 92 had a clinical suspicion of infection and 46 were microbiologically confirmed. Basal TNF-α and IL-6 levels were higher in patients with bacteremia (p < 0.001 and p = 0.017, respectively). Basal levels of TNF-α (p < 0.001) and fourth-day levels of CRP (p = 0.004), TNF-α (p < 0.001) and IL-6 (p = 0.002) had a positive correlation with the length of hospitalization. Higher IL-6 levels on the fourth day showed a correlation with mortality (p = 0.016), while the other cytokines and CRP did not show this association. Conclusion: Febrile elderly patients showed an inflammatory response pattern to infection equivalent to that reported in younger patients. Despite some limitations of our study, among febrile elderly patients, pro-inflammatory cytokine levels can be good markers for evaluating the prognosis of infections.
Prevalence of Balkan Endemic Nephropathy Has Not Changed Since 1971 in the Kolubara Region in Serbia
Authors: Bukvić Danica , Marić Ivko , Arsenović Aleksandra , Janković Slavenka , Djukanović Ljubica
Published: March 2007

Background/Aims: Thirty-one years after the first cross-sectional study, the population of Vreoci, a Balkan endemic nephropathy (BEN) village, was reinvestigated in order to determine the current prevalence of BEN and the clinical and laboratory characteristics of BEN family members with detected signs of kidney disease. Methods: A total of 2,009 inhabitants (82% of the adult population) of the village were examined. Danilovic’s criteria were used for diagnosis and classification of BEN. Results: The prevalence of BEN (1.70%) was similar to that in 1971 (1.67%). Diagnosis of BEN was established in 19 BEN family members, suspected BEN in 23, proteinuria in 29, while 16 healthy members were examined as controls. Urine protein, alpha1-microglobulin levels and frequency of glucosuria were significantly higher and kidney length significantly smaller in the three patient groups than in healthy persons. Serum urea and creatinine levels were significantly higher, but creatinine clearance was lower in BEN and BEN suspected patients than in the other two groups. Conclusion: The prevalence of BEN remains stable over time in Vreoci village. Manifested disease was found in both BEN and BEN suspected patients. In persons with proteinuria but not enough criteria for BEN, tubular disorders and hypertension were frequently found.
Treatment of Lupus Nephritis with Cyclosporine – An Outcome Analysis
Authors: Rihova Zuzana , Vankova Zdenka , Maixnerova Dita , Dostal Ctibor , Jancova Eva , Honsova Eva , Merta Miroslav , Rysava Romana , Tesař Vladimir
Published: March 2007

Background: The optimal therapy for lupus nephritis (LN), including the role of cyclosporine (CsA), still lacks scientifically valid clinical experience. We evaluated the efficacy of CsA in the induction and maintenance treatment of patients with biopsy-proven LN. Patients and Methods: A total of 31 patients (25 women, 6 men, mean age 29.5 years) were enrolled in the study. The majority had proliferative LN. The mean follow-up was 85.6 ± 24.7 months. Results: CsA was used as first-line treatment in 38.7% of patients and as second-line treatment in 61.3% of patients. Complete remission was achieved in 93.5% of patients. The relapse rate was 45.2%. The mean disease-free interval was 33 months. At the end of follow-up, a total of 67.9% of the patients were in remission. The treatment led to significant improvement in proteinuria (p = 0.001) and stabilization of renal function. Conclusion: CsA might be an appropriate and a less toxic alternative drug for LN both as a first-choice and rescue therapy.
Dexamethasone Treatment and ICAM-1 Deficiency Impair VEGF-Induced Angiogenesis in Adult Brain
Authors: Kasselman Lora J. , Kintner Jennifer , Sideris Alexandra , Pasnikowski Elizabeth , Krellman Jason W. , Shah Sagar , Rudge John S. , Yancopoulos George D. , Wiegand Stanley J. , Croll Susan D.
Published: March 2007

Background: Infusion of exogenous vascular endothelial growth factor (VEGF) into adult brain at doses above 60 ng/day induces dramatic angiogenesis accompanied by vascular leak and inflammation. Blood vessels formed by this treatment are dilated and tortuous, exhibiting a pathological morphology. Pathological VEGF-induced angiogenesis is preceded by vascular leak and inflammation, which have been proposed to mediate subsequent angiogenesis. Methods: To test this hypothesis, we infused VEGF into the brains of adult rats to induce pathological angiogenesis. Some of these rats were treated with dexamethasone, a potent anti-inflammatory glucocorticoid, to inhibit inflammation and edema. Results: We demonstrate that inhibition of inflammation by treatment with dexamethasone significantly attenuated VEGF-induced pathological angiogenesis. To present converging evidence that inflammation may be important in this angiogenic process, we also demonstrate that mice genetically deficient in the inflammatory mediator intercellular adhesion molecule-1 have attenuated VEGF-induced angiogenesis. These same mice showed normal amounts of physiological angiogenesis in response to enriched environments, however, suggesting that a generalized reduction in vascular plasticity could not account for their poor angiogenic response to VEGF. Conclusions: Taken together, the data from these experiments suggest that the inflammation which occurs before or during VEGF-induced pathological brain angiogenesis plays a contributory role in the pathological angiogenic process.
Membrane Cholesterol Depletion with β-Cyclodextrin Impairs Pressure-Induced Contraction and Calcium Signalling in Isolated Skeletal Muscle Arterioles
Authors: Potocnik Simon J. , Jenkins Nicole , Murphy Timothy V. , Hill Michael A.
Published: March 2007

Objective: Given evidence for clustering of signalling molecules and ion channels in cholesterol-rich membrane domains, the involvement of such structures in arteriolar smooth muscle mechanotransduction was examined. Method: To determine the contribution of smooth muscle cholesterol-rich membrane domains to the myogenic response, isolated arterioles were exposed to the cholesterol-depleting agent β-cyclodextrin (1–10 mM) in the absence and presence of excess exogenous cholesterol. Results: β-Cyclodextrin significantly impaired pressure-induced vasoconstriction, while excess cholesterol attenuated this effect. Impaired myogenic constriction was evident in de-endothelialized vessels, indicating an action at the level of smooth muscle. β-Cyclodextrin treatment uncoupled increases in intracellular Ca2+ from myogenic constriction and depleted intracellular Ca2+ stores consistent with a loss of connectivity between plasma membrane and sarcoplasmic reticulum signalling. However, β-cyclodextrin-treated arterioles showed unaltered constrictor responses to KCl and phenylephrine. Electron microscopy verified that β-cyclodextrin caused a decrease in caveolae, while confirmation of smooth muscle containing caveolae was obtained by immunostaining for caveolin-1. Viability of β-cyclodextrin-treated arterioles was confirmed by agonist sensitivity and propidium iodide nuclear staining. Conclusion: The data suggest that smooth muscle cholesterol-rich membrane domains contribute to the myogenic response. Further studies are required to determine whether this relates to specific mechanosensory events or generalized alterations in membrane function.
Association of Extracellular Cleavage of E-Cadherin Mediated by MMP-7 with HGF-Induced in vitro Invasion in Human Stomach Cancer Cells
Authors: Lee K.H. , Choi E.Y. , Hyun M.S. , Jang B.I. , Kim T.N. , Kim S.W. , Song S.K. , Kim J.H. , Kim J.-R.
Published: March 2007

Background: Proteolytic shedding of the ectodomain of a variety of transmembrane proteins, including cell-to-cell adhesion molecules, has been observed in solid cancers. We have investigated whether extracellular cleavage of E-cadherin mediated by matrix metalloproteinase-7 (MMP-7) is involved in hepatocyte growth factor (HGF) induced in vitro invasion in stomach cancer cells. Methods: The effects of HGF on the expression of E-cadherin/β-catenin and MMP-7 at both the protein and mRNA levels were assessed in stomach cancer cells, NUGC-3 and MKN-28, and in cells in which the expression of MMP-7 was downregulated by transfection with a MMP-7 short hairpin RNA plasmid. Results: Treatment with HGF increased the extracellular cleavage of E-cadherin and the release of MMP-7 and reduced the level of E-cadherin in a dose- and time-dependent manner. HGF treatment repressed the phosphorylation of β-catenin in a Triton-soluble fraction, but enhanced this phosphorylation in a Triton-insoluble fraction. The association of E-cadherin with β-catenin was decreased by HGF treatment in the Triton-soluble fraction. In addition, treatment of MMP-7 short hairpin RNA transfected NUGC-3 cells with HGF resulted in no extracellular cleavage of E-cadherin and also decreased the in vitro cell invasion. Conclusions: These results suggest that incubation with HGF mediated the release of MMP-7, resulting in extracellular cleavage of E-cadherin from stomach cancer cells. This might be a key mechanism in HGF-induced in vitro invasion and metastasis.
Podocyte Injury and Glomerulosclerosis in Hyperhomocysteinemic Rats
Authors: Yi Fan , dos Santos Elisabete A. , Xia Min , Chen Qi-Zheng , Li Pin-Lan , Li Ningjun
Published: March 2007

Background/Aims: We previously reported that increase in plasma homocysteine (Hcys) levels by a 6-week methionine treatment produced remarkable glomerular injury. However, the mechanism by which hyperhomocysteinemia (hHcys) produces glomerular injury remains unknown. The present study was to observe when glomerular injury happens during hHcys and to explore the possible role of podocyte injury in the progression of glomerulosclerosis associated with hHcys. Methods: Uninephrectomized Sprague-Dawley rats treated with methionine were used to examine the time course of glomerular injury induced by hHcys. Results: Creatinine clearance was not different until rats were treated with methionine for 6 weeks, although plasma Hcys levels significantly increased at the 1st week of methionine treatment. However, urinary albumin excretion increased at the 2nd week of methionine treatment. Morphological examinations showed that mesangial expansion occurred at the 2nd week and podocyte effacement was also observed as processed glomerular damage during hHcys. Immunofluorescence analyses demonstrated that podocin and nephrin expressions were reduced, while α-actinin-4 increased during hHcys. Conclusions: Increased plasma Hcys level is an important pathogenic factor resulting in glomerular injury even in the very early time of hHcys. These pathogenic effects of Hcys are associated with podocyte injury and changed expression and distribution of podocyte-associated proteins.
Expiratory Flow Limitation in Patients with Pleural Effusion
Authors: Spyratos D. , Sichletidis L. , Manika K. , Kontakiotis T. , Chloros D. , Patakas D.
Published: March 2007

Background: Expiratory flow limitation (EFL) is one of the main mechanisms contributing to dyspnea in patients with chronic obstructive pulmonary disease but has not been explored in patients with pleural effusion. Objectives: It was the aim of this study to determine whether patients with pleural effusion exhibit EFL and to investigate the effect of therapeutic thoracentesis on EFL. Patients and Methods: The study was performed on 21 patients with pleural effusion who were subjected to thoracentesis and measurement of pleural pressure (PP). Spirometry and estimation of flow limitation by the negative expiratory pressure technique were performed before and after thoracentesis. Results: Statistically significant differences were observed in all spirometric parameters. No correlation between the increase in lung volumes and flows and any of the aspirated fluid parameters was observed. Before thoracentesis, 14 out of 21 patients were flow limited, compared with 7 patients after thoracentesis (χ2 = 6.151, p = 0.013). Mean values of flow limitation before and after thoracentesis differed significantly. The decrease in flow limitation did not correlate with the increase in the spirometric parameters, the aspirated fluid volume or PP decrease. Conclusions: In the majority of patients with pleural effusion, flow limitation improves after thoracentesis. Flow limitation may be a contributing factor to the sensation of dyspnea in these patients.
The BTB-Kelch Protein KLEIP Controls Endothelial Migration and Sprouting Angiogenesis
Authors: Nacak Tanju G. , Alajati Abdullah , Leptien Kerstin , Fulda Christine , Weber Holger , Miki Toru , Czepluch Frauke S. , Waltenberger Johannes , Wieland Thomas , Augustin Hellmut G. , Kroll Jens
Published: March 2007

Sprouting and invasive migration of endothelial cells are important steps of the angiogenic cascade. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating intracellular signal transduction cascades, which regulate endothelial cell morphology and function. BTB-kelch proteins are intracellular proteins that control cellular architecture and cellular functions. The BTB-kelch protein KLEIP has been characterized as an actin-binding protein that interacts with the nucleotide exchange factor ECT2. We report that KLEIP is preferentially expressed in endothelial cells, suggesting that it may play a critical role in controlling the functions of migrating, proliferating, and invading endothelial cells during angiogenesis. KLEIP mRNA level in endothelial cells is strongly regulated by hypoxia which is controlled by hypoxia-inducible factor-1α. Functional analysis of KLEIP in endothelial cells revealed that it acts as an essential downstream regulator of VEGF- and basic fibroblast growth factor-induced migration and in-gel sprouting angiogenesis. Yet, it is not involved in controlling VEGF- or basic fibroblast growth factor-mediated proliferative responses. The depletion of KLEIP in endothelial cells blunted the VEGF-induced activation of the monomeric GTPase RhoA but did not alter the VEGF-stimulated activation of extracellular signal-regulated kinase 1/2. Moreover, VEGF induced a physical association of KLEIP with the guanine nucleotide-exchange factor ECT2, the depletion of which also blunted VEGF-induced sprouting. We conclude that the BTB-kelch protein KLEIP is a novel regulator of endothelial function during angiogenesis that controls the VEGF-induced activation of Rho GTPases.
Inhibition of Endogenous Mst1 Prevents Apoptosis and Cardiac Dysfunction Without Affecting Cardiac Hypertrophy After Myocardial Infarction
Authors: Odashima Mari , Usui Soichiro , Takagi Hiromitsu , Hong Chull , Liu Jing , Yokota Mitsuhiro , Sadoshima Junichi
Published: March 2007

Mammalian sterile 20–like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%,
P
<0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg,
P
<0.05) and lung weight/body weight (9.8 versus 12.2
P
<0.05) were significantly smaller in Tg-DN-Mst1 than in NTg. The number of TUNEL-positive myocytes (0.17 versus 0.28%,
P
<0.05) and amount of interstitial fibrosis (5.0 versus 7.1%,
P
<0.05) in the remodeling area were significantly less in Tg-DN-Mst1 than in NTg. Upregulation of matrix metalloproteinase 2 and proinflammatory cytokines was significantly attenuated in Tg-DN-Mst1. These results indicate that endogenous Mst1 plays an important role in mediating cardiac dilation, apoptosis, fibrosis, and cardiac dysfunction, but not cardiac hypertrophy, after MI. Inhibition of Mst1 improves cardiac function without attenuating cardiac hypertrophy. Thus, Mst1 may be an important target of heart failure treatment.
Clinical Impact of NXY-059 Demonstrated in the SAINT I Trial
Authors: Saver Jeffrey L.
Published: March 2007

Background and Purpose—

The SAINT I trial demonstrated that the neuroprotective agent NXY-059 improves the distribution of acute stroke patient outcomes on the modified Rankin Scale (mRS) of global disability. Standard dichotomized number-needed-to-treat (NNT) analyses for the magnitude of treatment benefit range widely, from 22.7 to infinity, and each capture only a portion of the observed beneficial shift in outcomes. Derivation of an NNT value reflecting the treatment’s benefit over the entire range of the mRS is required to describe the clinical import of the trial results.

Methods—

The minimum and maximum possible NNTs for benefit over the range of mRS global disability outcomes were calculated by completing a joint distribution outcome table for a model population of 1000 patients, shifting responders by the greatest and smallest possible increments, respectively. The biologically most plausible NNT within this range was derived by having 10 neurologist and emergency-physician acute stroke-care experts independently specify the joint distribution of outcomes in model samples of 1000 patients assigned to placebo and active therapy.

Results—

The minimum possible NNT for benefit incorporating all mRS state transitions is 7.9 and the maximum is 16.7. The biologically most plausible NNT for 1 additional patient to have a better outcome by 1 or more grades on the mRS outcomes is 9.8 (95% CI, 8.7 to 10.9).

Conclusions—

Considering improvements in global disability over the entire outcome range, the SAINT I trial results indicate that for every 100 patients treated, ≈10 will benefit and none be harmed as a result of treatment.
A Single Infusion of Zoledronate Prevents Bone Loss After Stroke
Authors: Poole Kenneth E.S. , Loveridge Nigel , Rose Collette M. , Warburton Elizabeth A. , Reeve Jonathan
Published: March 2007

Background and Purpose—Stroke is a major risk factor for hip fracture. Patients with intermediate rather than severe or mild stroke deficits at the time of hospital discharge have the most fractures. This proof-of-concept study evaluated the efficacy of a single infusion of zoledronate, an intravenous bisphosphonate, in preserving hip bone density after stroke.

Methods—In a 1-year randomized, double-blind, placebo-controlled, clinical trial, 27 newly hemiplegic patients (6 females, 21 males) with acute stroke were assigned to receive 4 mg of the intravenous zoledronate (n=14) or placebo (n=13) within 35 days. Strict inclusion criteria were followed-up to ensure recruited patients were likely to have residual functional impairment. Both groups received calcium and vitamin D supplementation. The primary outcome measure was the change in bone mineral density (BMD; Lunar Prodigy) at the hemiplegic hip during the year of investigation.

Results—The treatment was generally well tolerated. Mean total hip BMD was unchanged in the hemiplegic hip of the zoledronate group (mean 0.0% change), whereas in the placebo group the total hip BMD changed by −5.5%, with the greatest bone loss observed in the trochanteric subregion (mean, −8.1%). On the unaffected side the mean change in total hip BMD was +1.0% with zoledronate versus a mean change of −2.7% without. Repeated measures ANOVA confirmed the significance of the differences between groups at both hips (hemiplegic,P<0.001; unaffected,P=0.002).

Conclusions—Stroke patients were protected from the deleterious effects of hemiplegia on hip bone density for at least 1 year after a single infusion of zoledronate.
Atrial Fibrillation, Stroke, and Cognition
Authors: Rastas Sari , Verkkoniemi Auli , Polvikoski Tuomo , Juva Kati , Niinistö Leena , Mattila Kimmo , Länsimies Esko , Pirttilä Tuula , Sulkava Raimo
Published: March 2007

Background and Purpose—

The aim of this study was to investigate the association between atrial fibrillation (AF), stroke, dementia, and their correlation with brain pathology in subjects aged 85 years or older.

Methods—

This is a prospective 9-year follow-up population based study in Vantaa, a town in Southern Finland; 553 subjects (92% of the total population) aged 85 years or older were clinically examined by a neurologist. The presence of AF was collected from the medical records or examined by ECG or ambulatory ECG. Neuropathological examination was conducted in more than half of the clinically examined subjects.

Results—

AF was significantly associated with stroke at baseline; 32% of patients with AF had clinical evidence of stroke compared with 16.7% of those without such evidence (
P
<0.001). Dementia at baseline was significantly associated with age, clinical stroke, and the presence of apolipoprotein E ε4 allele, but not with sex, education, or vascular risk factors. Multiple regression analysis including neuropathological results showed that dementia was significantly associated with education (OR, 0.89; 95% CI, 0.80 to 0.98;
P
=0.019), the β-amyloid load in the brain (OR, 1.26; 95% CI, 1.13 to 1.39;
P
<0.001) and with the vascular pathology (OR, 2.03; 95% CI, 1.14 to 3.62;
P
=0.016), but not with sex, age at death, apolipoprotein E ε4 allele, or vascular risk factors.

Conclusions—

AF is a significant and preventable risk factor for stroke but not for dementia in the very old. The etiology of dementia syndrome in the very old is multifactorial. Both Alzheimer disease pathology and vascular pathology, particularly multiple small infarcts, contribute to cognitive decline.
A Novel, Self-Expanding, Nitinol Stent in Medically Refractory Intracranial Atherosclerotic Stenoses
Authors: Bose Arani , Hartmann Marius , Henkes Hans , Liu Hon Man , Teng Michael M.H. , Szikora Istvan , Berlis Ansgar , Reul Jurgen , Yu Simon C.H. , Forsting Michael , Lui Matt , Lim Winston , Sit Siu Po
Published: March 2007

Background and Purpose—

The purpose of this study was to assess the safety and performance of the Wingspan stent system and Gateway percutaneous transluminal angioplasty balloon catheter in the treatment of high-grade, intracranial atherosclerotic lesions in patients who had failed medical therapy.

Methods—

In this prospective, multicenter, single-arm study, medically refractory patients with a modified Rankin score ≤3 and recurrent symptoms attributable to angiographically demonstrated intracranial stenosis ≥50% in a vessel 2.5 to 4.5 mm in diameter were enrolled. Intracranial lesions were predilated with an undersized Gateway balloon catheter to 80% of the native vessel diameter, followed by deployment of the self-expanding Wingspan stent to facilitate further remodeling of the atherosclerotic plaque and to maintain vessel patency. Neurologic examinations and angiograms were performed at 6 months after the procedure.

Results—

Among the 45 patients enrolled, the degree of stenosis was reduced from a baseline of 74.9±9.8% to 31.9±13.6% after stenting and 28±23.2% at the 6-month follow-up. The 30-day composite ipsilateral stroke/death rate was 4.5% (2/44); at the 6-month follow-up, the ipsilateral stroke/death rate was 7.0%, the rate for all strokes was 9.7%, and all-cause mortality was 2.3%. Physician-reported follow-up in 43 patients (average of 13 months) conducted outside the study protocol (not adjudicated by the clinical event committee) reported 1 additional ipsilateral stroke.

Conclusions—

In medically refractory patients with high-grade intracranial atherosclerotic stenoses, a new treatment paradigm involving predilation with an undersized Gateway percutaneous transluminal angioplasty balloon catheter and placement of a self-expanding Wingspan stent system appears to be safe, may facilitate remodeling, and may contribute to favorable angiographic outcomes.
Radiological Findings, Clinical Course, and Outcome in Asymptomatic Moyamoya Disease
Authors: Kuroda Satoshi , Hashimoto Nobuo , Yoshimoto Takashi , Iwasaki Yoshinobu
Published: March 2007

Background and Purpose—

Although the development of a noninvasive MR examination has increased the opportunity to identify asymptomatic patients with moyamoya disease who have experienced no stroke episodes, their clinical features are still unclear. This was the first multicenter, nation-wide survey focused on asymptomatic moyamoya disease in Japan and was designed to clarify their clinical features.

Methods—

A clinical database of asymptomatic patients with moyamoya disease was collected from 12 participating hospitals in Japan between 2003 and 2006. In total, 40 patients were enrolled in this historical prospective cohort study. Of these, 6 underwent surgical revascularization, including superficial temporal artery to middle cerebral artery anastomosis and/or pial synangiosis. Their demographic and radiological findings as well as outcome were evaluated.

Results—

On initial evaluation, cerebral infarction and disturbed cerebral hemodynamics were detected in ≈20% and 40% of the involved hemispheres, respectively. Angiographical stage was more advanced in more elderly patients. Of 34 nonsurgically treated patients, 7 experienced transient ischemic attack (n=3), ischemic stroke (n=1), or intracranial bleeding (n=3) during follow-up periods (mean, 43.7 months). The annual risk for any stroke was 3.2%. Disease progression was associated with ischemic events or silent infarction in 4 of 5 patients. No cerebrovascular event occurred in the 6 patients who underwent surgical revascularization.

Conclusions—

The findings revealed that asymptomatic moyamoya disease is not a silent disorder and may potentially cause ischemic or hemorrhagic stroke. Asymptomatic patients with moyamoya disease should be carefully followed-up to further clarify their outcome and to establish the management guideline for them.
Reduced Medication Access
Authors: Levine Deborah A. , Kiefe Catarina I. , Howard George , Howard Virginia J. , Williams O. Dale , Allison Jeroan J.
Published: March 2007

Background and Purpose—

Medication access is crucial to secondary stroke prevention. We assessed medication access and associated barriers to care across region and time in a national sample of US stroke survivors.

Methods—

Among all 5840 black or white stroke survivors aged ≥45 years responding to the National Health Interview Survey years 1997 to 2004, we examined inability to afford medications within the last 12 months across region (Northeast, Midwest, West, South) and time. With logistic regression, we adjusted associations between medication inaffordability and region and time for age, sex, race, neurological disability, comorbidity, health status, insurance, income and out-of-pocket medical expenses.

Results—

In 2004, ≈76 000 US stroke survivors were unable to afford medications. Lower medication affordability was reported among stroke survivors who were <65 years old, black, female, had high comorbidity or low health status. Compared with stroke survivors able to afford medications, those unable more frequently reported lack of transportation (15% versus 3%;
P
<0.001), no health insurance (16% versus 3%;
P
<0.001), no usual place of care (6% versus 2%;
P
=0.001), income <$20 000 (66% versus 40%;
P
<0.001) and out-of-pocket medical expenses ≥$2000 (35% versus 25%;
P
<0.001). From 1997 to 2004, inability to afford medications increased significantly from 8.1% to 12.7% (P
trend
=0.01) overall and increased in all US regions except the Northeast.

Conclusions—

We identified a vulnerable stroke survivor population with reduced medication access and increased barriers to medical care. Membership in this population has grown substantially from 1997 to 2004, potentially leading to increased recurrent stroke incidence.