bluuebunny/crossref_metadata_2025 huggingface dataset:
Can We Modulate the Clinical Course of Inflammatory Bowel Diseases by Our Current Treatment Strategies?
Authors: Cosnes Jacques
Published: November 2009

Ulcerative colitis and Crohn’s disease are chronic disabling lifelong diseases which may be disturbed by severe flares and anatomical complications requiring surgery. Until the very last years there was no clear indication that treatment was able to modify the long-term natural history of the disease. In particular, there are no data demonstrating a clear improvement through the period 1950–2003 in disease activity, occurrence of complications and need for surgery, in spite of an increased use of immunosuppressants since the 1990s. However, in inflammatory bowel disease, both thiopurines and methotrexate are very efficient in about one half of the patients, and in responders, may heal the mucosa and decrease the need for surgery. The early use of immunosuppressants in selected patients may have an impact on occurrence of severe flares and complications, and need for surgery. Moreover, anti-TNF now used for 10 years in Crohn’s disease and for 5 years in ulcerative colitis demonstrated in two thirds of the patients a remarkable anatomic effect, healing the mucosa, closing fistulae and preventing strictures. Infliximab does prevent endoscopic recurrence following ileal resection for Crohn’s disease. Actually, because irreversible anatomical damage may develop during the first years of disease, there is a need to classify early in the course of the disease patients who will benefit from anti-TNF and classical immunosuppressants, respectively. There is the need in the next few years to better define these subgroups and to compare different strategies within each group through randomized interventional studies.
Primary Sclerosing Cholangitis: A Clinical Case
Authors: Gubergrits Natalya B.
Published: November 2009

The basic hypotheses of pathogenesis of primary sclerosing cholangitis (PSC) are discussed, i.e. genetically conditioned pathology, autoimmune pathology, the result of inflammatory reaction in bile ducts, and cholangiopathy. A clinical case of monozygotic twins with association of PSC and non-specific ulcerative colitis (NUC) is presented. The first twin had a severe course of PSC and a mild course of NUC; he died due to bacterial complications of cholangitis. The second twin, patient B, had an opposite situation, a severe course of NUC, while PSC was suspected only after determination of cholestasis biochemical markers. As soon as cholestasis was revealed, patient B was administered Ursofalk and Budenofalk (in 2001). He received Salofalk as a basic therapy for NUC. Repeated liver biopsy in 2005 showed no progression of PSC, but minimal biochemical signs of cholestasis were present in 2009. It is therefore necessary to study the first-degree relatives of patients with PSC.
Medical Management of Crohn’s Disease: Treatment Algorithms 2009
Authors: Hanauer Stephen B.
Published: November 2009

There has been a continual evolution of therapy for Crohn’s disease (CD) over the past decade since the introduction of biological therapies targeting tumor necrosis factor-α. Conventional agents continue to be safe and effective for patients with mild to moderately active CD and, in population series, less than half of the patients with CD require corticosteroid therapy. In contrast, patients presenting at young ages, those with extensive disease, deep ulcerations, transmural complications or extraintestinal complications that require corticosteroid therapy have a poor prognosis. Introduction of immunosuppressives late in the course or for patients with steroid-dependent or steroid-refractory disease have not changed the ‘natural history’ of CD or the need for eventual surgical resections. There is increasing evidence that early intervention with immunosuppressives or biologic agents at the same time as corticosteroids, or biologic agents targeting tumor necrosis factor or adhesion molecules, can have rapid and prolonged benefits, including steroid sparing, reductions in hospitalizations and, perhaps, reductions in the need for surgery. Treatment should be optimized according to the patient status and response with whichever level of therapy is introduced and maintained.
Diagnostic and Treatment Algorithms of Ulcerative Colitis in Ukraine
Authors: Skrypnyk I.N.
Published: November 2009

Questions concerning the diagnosis and treatment of ulcerative colitis (UC) in Ukraine are described. In recent years, there has been considerable progress in conservative therapy and new drugs have been developed that provide persistent remission of the inflammatory process after long-term application in many cases. The results of our own investigation on the efficiency of rebamipide in the complex treatment of UC patients are presented. Optimization of treatment with substitution of mesalazine in tablet or granule form, especially with an additional rebamipide prescription and a once-daily administration of budesonide, leads to an increased effectiveness of treatment and improvement of quality of life in UC patients. In the future, development of new approaches in the pharmacotherapy of UC will use medications as a basic therapy with the purpose of achieving high-quality and effective ‘convalescence of mucous membrane’, including cytoprotectors, bilious acids, endogenous substances, stabilization of membranes, antihyp-oxants and correction of microbiocenosis disorders.
Laparoscopic Management of Inflammatory Bowel Disease
Authors: Rosenthal Raul J. , Bashankaev Badma , Wexner Steven D.
Published: November 2009

The goal of the surgical management of Crohn’s disease is to improve quality of life. Surgical management is generally reserved for patients who developed complications of the disease or who are unresponsive to or develop complications from aggressive medical therapy. Friable mesentery, inflammatory phlegmons, fistulas, abscesses, and adhesions from previous surgeries pose a surgical challenge to the laparoscopic approach. The laparoscopic approach to terminal ileal Crohn’s disease is feasible and safe even in cases complicated by fistulas with previous abdominal surgery or recurrent disease. This approach is associated with an increased operative time compared to laparotomy, however, offers significant advantages over open ileocolic resection in terms of pulmonary function, length of hospital stay, duration of postoperative ileus, cosmesis, postoperative small bowel obstruction, and early postoperative complications. Laparoscopy is also associated with decreased overall hospitalization costs and improved patient satisfaction. Therefore, the laparoscopic approach for patients with Crohn’s disease should be considered as the preferred operative approach.
Malignant Transformation in Inflammatory Bowel Disease – Surveillance Guide
Authors: Stallmach Andreas , Bielecki Christiane , Schmidt Carsten
Published: November 2009

Nowadays, it is considered as an established fact that patients with long-standing ulcerative colitis (UC) are at an increased risk of developing colorectal cancer (CRC). Although data for CRC risk in Crohn’s disease (CD) are not as extensive, it has been suggested that the risks are comparable to UC. Current strategies for the prevention and early detection of cancer in this high-risk population are grounded in the concept of an inflammation-neoplasia-carcinoma sequence. To reduce CRC mortality in inflammatory bowel disease, colonoscopic surveillance with random and targeted biopsies were recommended to detect early neoplasia. The introduction of novel endoscopic techniques such as chromoendoscopy, narrow band imaging or confocal endomicroscopy to facilitate targeted biopsy has become increasingly associated with enhanced neoplasia detection. However, there is only indirect evidence that such surveillance strategies are likely to be effective at reducing the risk of death from inflammatory bowel disease-associated CRC. Further, new data revealed that surveillance strategies largely based upon disease duration delayed or missed a substantial number of patients with early CRC. Therefore, actual surveillance guidelines seem to be insufficient and need to be restructured.
Cortisol and 3,4-Methylenedioxymethamphetamine: Neurohormonal Aspects of Bioenergetic Stress in Ecstasy Users
Authors: Parrott A.C.
Published: November 2009

Aims: 3,4-Methylenedioxymethamphetamine (MDMA) can affect both neurotransmitter and neurohormonal activity. This review will debate the role of the metabolic activation hormone cortisol for the psychobiological effects of ecstasy/MDMA. Methods: The empirical literature on cortisol release following acute MDMA administration and cortisol functioning in drug-free recreational ecstasy/MDMA users will be reviewed. This will be followed by an overview of cortisol as a bioenergetic stress neurohormone, and a debate on how it could be modulating the acute and chronic psychobiological effects of MDMA. Results: Cortisol release is increased by stimulatory factors, including physical activity, thermal stress and stimulant drugs. In laboratory studies MDMA leads to an acute cortisol increase of around 150% in sedentary humans. In MDMA-using dance clubbers, the cortisol levels are increased by around 800%, possibly due to the combined factors of stimulant drug, physical exertion and psychosocial stimulation. Regular ecstasy/MDMA users also demonstrate changes in baseline cortisol levels and cortisol reactivity, with compromised hypothalamic-pituitary-adrenal activity. Nonpharmacological research has shown how cortisol is important for psychological aspects such as memory, cognition, sleep, impulsivity, depression and neuronal damage. These same functions are often impaired in recreational ecstasy/MDMA users, and cortisol may be an important modulatory co-factor. Conclusions: The energizing hormone cortisol is involved in the psychobiology of MDMA, probably via its effects on energy metabolism. Acute cortisol release may potentiate the stimulating effects of MDMA in dance clubbers. Chronically, cortisol may contribute to the variance in functional and structural consequences of repeated ecstasy usage.
Investigating the Role of Serotonin in Visual Orientation Processing Using an ‘Ecstasy’ (MDMA)-Based Research Model
Authors: Dickson Clare , Bruno Raimondo , Brown John
Published: November 2009

Aims/Objectives:A growing body of evidence suggests that regular ‘ecstasy’ (3,4-methylenedioxymethamphetamine) use causes lasting changes to central serotonergic functioning in humans, including in the occipital lobe. Serotonin may play a role in visual orientation processing, mediated in the occipital lobe, via lateral inhibition. The tilt aftereffect is an illusion apparent following adaptation to stimuli angled 5–50° from vertical and thought to be affected by lateral inhibition between occipital neurons. A recent study identified an enhanced tilt aftereffect among ecstasy users, but only in a subset that were recently abstinent from amphetamines. The current study examined the effects of ecstasy use, cannabis use and their interacting effect on the magnitude of the tilt aftereffect among participants with no recent history of amphetamine consumption. Materials and Methods: Eleven ecstasy users, 15 cannabis users, 15 ecstasy plus cannabis users and 15 drug-naïve controls were compared on the magnitude of the tilt aftereffect elicited following adaptation to stimuli angled 15, 30, 40 or 60° from vertical. Results:At a 40° adaptation condition, ecstasy users had a greater magnitude of the tilt aftereffect compared to those that had not taken the drug. Additionally, the extent of ecstasy use was positively associated with the magnitude of the tilt aftereffect generated following 15, 30 and 40° adaptation conditions, but not at 60°. Conclusions:Given that lateral inhibition mediates the tilt aftereffect following adaptation to 5–50°, the findings of a relationship between ecstasy use and tilt magnitude at the 15–40° but not 60° adaptation conditions support a role for serotonin in visual orientation processing via lateral inhibition.
Corneal and Aqueous Humor Concentrations of Amphotericin B Using Three Different Routes of Administration in a Rabbit Model
Authors: Qu Linghui , Li Liangmao , Xie Hanping
Published: November 2009

Background:Little is known about the ocular penetration following intrastromal or intracameral injection of amphotericin B (AMB), the current drug of choice in fungal keratitis. Concentrations of AMB were investigated in the cornea and aqueous humor of rabbits after using one of three different routes of administration: topical 0.25% AMB eye drops and intrastromal and intracameral injection of AMB (10 µg). Methods: Forty-five healthy rabbits were randomly divided into 3 groups. The eyes of group A and group B received a 0.1-ml intrastromal and intracameral injection, respectively, containing 10 µg AMB. Group C received topical 0.25% AMB (corneal epithelium debrided, every 5 min for 30 min). Cornea and aqueous humor concentrations of AMB after 30 min, 6 h, 1, 3 and 7 days were analyzed by high-performance liquid chromatography. Results: After a single injection, effective drug levels were achieved in corneas in group A, maintained for 7 days, exceeding the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) for a wide spectrum of fungi and molds. There were significant differences (p < 0.001) compared with group B and group C. Effective drug levels were achieved in the aqueous humor in group B at 30 min after a single injection, exceeding MIC90, but drug levels decreased abruptly within 1 day. There were significant differences (p < 0.004) compared with group A and group C, and a considerable amount of AMB was detected in corneas and aqueous in group C within 1 day. Conclusion: High drug levels can be reached that cover the MICs of most fungi in the rabbit cornea and aqueous humor after intrastromal and intracameral injection, respectively. Penetration of topical AMB greatly increased after epithelial abrasion.
Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats
Authors: Liao Jie , Soltani Zohreh , Ebenezer Philip , Isidro-Carrión Angel A. , Zhang Rubin , Asghar Arshad , Aguilar Erwin , Francis Joseph , Hu Xuejiao , Ferder León , Reisin Efrain
Published: November 2009

Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)α/γ agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 µmol/kg/day) was given for 8 weeks in the treatment group (OZR-T). Metabolic parameters, 24-hour urine albumin excretion, and tail blood pressure were measured. Glomerular filtration rate by inulin clearance, abdominal fat and renal histology were determined at the end of the study. In comparison with the OZR and OZR-T groups, the LZR control animals’ parameters were significantly more favorable in all measures. Tesaglitazar treatment in OZR significantly reduced nonfasting glucose, C-reactive protein levels and improved dyslipidemia. Body weight, blood pressure and urine albumin excretion were lower, but the adjusted glomerular filtration rate higher, in the OZR-T group than in the OZR controls. Glomerular area, mesangial expansion and tubulointerstitial changes were ameliorated, and the glomerular expression of desmin was markedly more decreased in the OZR-T group than in the OZR controls. Therefore, the PPARα/γ agonist tesaglitazar significantly improved metabolic abnormalities and renal function, decreased blood pressure, and protected against glomerular and interstitial damage in OZR.
Prevalence and Risk Factors of Somatic and Autonomic Neuropathy in Prediabetic and Diabetic Patients
Authors: Hsu Wei-Chih , Yen Amy Ming-Fang , Liou Horng-Huei , Wang Han-Cheng , Chen Tony Hsiu-Hsi
Published: November 2009

Aims/Hypothesis: To investigate the prevalence and correlates of somatic and autonomic neuropathies concurrently in prediabetic and diabetic subjects in the general population. Subjects and Methods: Nerve conduction and heart rate variability studies were used for detecting both types of diabetic neuropathy. Of 1,576 inhabitants, 143 persons were identified as prediabetic or having diabetic mellitus. One hundred and thirty-three persons completed a nerve conduction test and 118 persons a valid heart rate variability test. Significant correlates responsible for diabetic neuropathies were also collected. Results: The prevalence rates of definite, probable and no somatic neuropathy were 9.0% (12/133), 20.3% (27/133) and 70.7% (94/133), respectively. The corresponding figures for autonomic neuropathy were 14.4% (17/118), 54.2% (64/118) and 31.4% (37/118). The prevalence rate for the presence of both neuropathies was 16.9%. In a univariate analysis, age, renal insufficiency, HbA1c and fasting glucose level were significantly associated with somatic neuropathy whereas only systolic blood pressure was statistically significantly associated with autonomic neuropathy. In a multivariate analysis, systolic blood pressure and fasting glucose level were positively associated with somatic neuropathy and systolic blood pressure remained statistically significant for autonomic neuropathy. Conclusions: The prevalence of autonomic neuropathy is twofold compared with somatic neuropathy. Concurrence of the two kinds of neuropathy was approximately half of sole somatic neuropathy and a quarter of sole autonomic neuropathy. Systolic blood pressure and fasting glucose level were related to somatic neuropathy whereas only systolic blood pressure was correlated with autonomic neuropathy.
Effectiveness of Different Modalities of Psychotherapeutic Treatment for Patients with Cluster C Personality Disorders: Results of a Large Prospective Multicentre Study
Authors: Bartak Anna , Spreeuwenberg Marieke D. , Andrea Helene , Holleman Lot , Rijnierse Piet , Rossum Bert V. , Hamers Elisabeth F.M. , Meerman Anke M.M.A. , Aerts Janneke , Busschbach Jan J.V. , Verheul Roel , Stijnen Theo , Emmelkamp Paul M.G.
Published: November 2009

Background: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C personality disorders. The aim of this multicentre study was to compare the effectiveness of 5 treatment modalities for patients with cluster C personality disorders in terms of psychiatric symptoms, psychosocial functioning, and quality of life. The following treatment modalities were compared: long-term outpatient (more than 6 months), short-term day hospital (up to 6 months), long-term day hospital, short-term inpatient, and long-term inpatient psychotherapy. Methods: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 371 patients with a DSM-IV-TR axis-II cluster C diagnosis. Patients were assigned to 5 different modalities of psychotherapeutic treatment, and effectiveness was assessed at 12 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. Results: Patients in all treatment groups had improved on all outcomes 12 months after baseline. Patients receiving short-term inpatient treatment showed more improvement than patients receiving other treatment modalities. Conclusions: Psychotherapeutic treatment, especially in the short-term inpatient modality, is an effective treatment for patients with cluster C personality disorders.
Group Psychotherapy of Dysfunctional Fear of Progression in Patients with Chronic Arthritis or Cancer
Authors: Herschbach Peter , Berg Petra , Waadt Sabine , Duran Gabriele , Engst-Hastreiter Ursula , Henrich Gerhard , Book Katrin , Dinkel Andreas
Published: November 2009

Background: This study investigated the effectiveness of brief psychotherapeutic group interventions in reducing dysfunctional fear of disease progression (FoP). The interventions comprised either cognitive-behavioral group therapy or supportive-experiential group therapy. We tested whether these generic interventions would prove effective in different illness types. Methods: Chronic arthritis in- patients (n = 174) and cancer in-patients (n = 174), respectively, were randomized to receive one of the two interventions. The patients provided data before intervention, at discharge, and at 3 and 12 months of follow-up. FoP was the primary outcome, secondary outcomes were anxiety, depression and quality of life. A treatment-as-usual control group provided data on the primary outcome. Results: Patients with chronic arthritis indicated higher levels of FoP than cancer patients. The results revealed that, compared with no specialized intervention, both group therapies were effective in reducing dysfunctional FoP, but only among cancer patients. The effect sizes were 0.54 (cognitive-behavioral therapy) and 0.50 (supportive experiential therapy). The interventions were not differently effective in reducing the secondary outcomes. Conclusions: Dysfunctional FoP can be effectively targeted with brief group interventions. Psychotherapeutic interventions for reducing FoP should focus on specific illness characteristics.
Neurally Adjusted Ventilatory Assist and Pressure Support Ventilation in Small Species and the Impact of Instrumental Dead Space
Authors: Campoccia Jalde Francesca , Almadhoob Abdul Raoof , Beck Jennifer , Slutsky Arthur S. , Dunn Michael S. , Sinderby Christer
Published: November 2009

Background: Neurally adjusted ventilatory assist (NAVA) is a pneumatically-independent mode of mechanical ventilation controlled by diaphragm electrical activity (EAdi), and has not yet been implemented in very small species. Objectives: The aims of the study were to evaluate the feasibility of applying NAVA in very small species and to compare this to pressure support ventilation (PSV) in terms of ventilatory efficiency and breathing pattern, and evaluate the impact of instrumental dead space on breathing pattern during both modes. Methods: Nine healthy rats (mean weight 385 ± 4 g) were studied while breathing on PSV or NAVA, at baseline or with added dead space. Results: A clear difference in breathing pattern between NAVA and PSV was observed during both baseline and dead space, where PSV – despite similar EAdi and tidal volume as during NAVA – caused shortened inspiratory time (p < 0.05) and increased the respiratory rate (p < 0.05). A higher minute ventilation (p < 0.05) in order to reach the same arterial CO2 was observed. Ineffective inspiratory efforts occurred only during PSV and decreased with the dead space. Conclusion: This study demonstrates, in a small group of animals, that NAVA can deliver assist in very small species with a higher efficiency than PSV in terms of eliminating CO2 for a given minute ventilation.
Genotype-Phenotype Correlation for DFNA22: Characterization of Non-Syndromic, Autosomal Dominant, Progressive Sensorineural Hearing Loss due to MYO6 Mutations
Authors: Topsakal Vedat , Hilgert Nele , van Dinther Joost , Tranebjærg Lisbeth , Rendtorff Nanna D. , Zarowski Andrzej , Offeciers Erwin , Van Camp Guy , van de Heyning Paul
Published: November 2009

Clinical and audiological examination was done in 2 Belgian families with autosomal dominant sensorineural hearing loss (SNHL) linked to DFNA22. Nineteen subjects in family 1 had mild to moderate SNHL starting in the third decade. The hearing loss was characterized by a flat audiogram affecting all tested frequencies with statistically significant progression. In family 2 eleven subjects were affected with mild to moderate SNHL starting in the second decade. Most of them showed a flat audiogram, but some had mid-frequency hearing loss. Significant progression of thresholds was present at 4 and 8 kHz. For all hitherto known DFNA22 families the audiological and clinical characteristics were correlated with the molecular data. This study describes the phenotype of 2 Belgian families with SNHL linked to DFNA22, both with a pathogenic change in the deafness gene MYO6. The phenotypes of all hitherto reported DFNA22 families with mutations in the MYO6 gene have been studied and compared. It seems that genetic defects that spare the motor domain of the myosin VI protein have a milder phenotype.
Long-Term Survival after Hospitalization for Community-Acquired and Healthcare-Associated Pneumonia
Authors: Cecere Laura M. , Rubenfeld Gordon D. , Park David R. , Root Richard K. , Goss Christopher H.
Published: November 2009

Background: Elderly patients surviving community-acquired pneumonia (CAP) have subsequent increased mortality. However, little is known regarding long-term survival in younger adults or those with healthcare-associated pneumonia (HCAP). Objectives: To identify factors associated with mortality and compare long-term survival in patients hospitalized with HCAP to that of patients with CAP. Methods: We determined survival after discharge as of December 2002 in a patient cohort admitted with pneumonia between June 1994 and May 1996. We used the Cox proportional hazard model to estimate differences in survival after controlling for confounders. Results: Of the 522 patients hospitalized with pneumonia, 457 survived to discharge. One hundred sixty-four patients (36%, 95% confidence interval, CI, 31–40%) were admitted with HCAP, while 293 (64%, 95% CI 60–69%) were admitted with CAP. Of the 181 deaths in the follow-up period, 70 occurred in patients under age 65 years admitted with HCAP (53% death rate, 95% CI 44–62%). Nineteen of these deaths (27%, 95% CI 17–39%) occurred in the absence of HIV infection. In patients under the age of 65 whose only risk factor for HCAP was treatment for pneumonia or hospitalization in the previous 90 days, 4 of 13 patients (31%, 95% CI 9–61%) died. Twenty percent (95% CI 15–26%) of patients under age 65 years admitted with CAP died during the follow-up. Conclusions: Admission for HCAP, and to a lesser degree CAP, is associated with increased long-term mortality even in young patients. Future studies are warranted to identify interventions to improve survival in this population.
Stress and Psychopathology in Latin-American Immigrants: The Role of Coping Strategies
Authors: Patiño Camila , Kirchner Teresa
Published: November 2009

Introduction: Increased migration into Spain requires the development of preventive strategies that help both immigrants and the host society to deal with the associated risk factors and thus avoid the emergence of psychopathology. Objective: To determine the level of psychopathology in Latin-American immigrants who reside in Barcelona and its relationship to the coping strategies used to mitigate the effects of the stress linked to migration. Method: The sample comprised 210 Latin-American immigrants over the age of 18. Sampling was based on consecutive cases, and participants were contacted through an NGO. Results: Employment is the stressor that most affects immigrants. Psychopathological symptoms are common among the immigrant population, and there is a relationship between the use of avoidance coping strategies and greater symptomatology. The longer immigrants have been in the host country, the less they make use of approach strategies. Conclusions: The migratory process produces high levels of stress that are linked to psychopathology. Being subjected to a prolonged stressor has a destabilizing effect on both mental and physical health and can lead to a deterioration in social relationships due to more intense feelings of anger and frustration. Coping strategies appear to be more widely used among immigrants than in the indigenous population, and this may indicate the high levels of stress to which the former are subject and the attempts they make to deal with it. The limitations of the study include the source of data collection and the fact that most of the instruments used have not been validated in the participants’ countries of origin.
Thrombin Peptide TP508 Stimulates Rapid Nitric Oxide Production in Human Endothelial Cells
Authors: Olszewska-Pazdrak Barbara , Hart-VanTassell Audrey , Carney Darrell H.
Published: November 2009

TP508, a 23-amino-acid peptide representing a portion of human thrombin, promotes tissue revascularization and repair. The molecular mechanisms of TP508 action, however, remain unclear. Nitric oxide (NO) plays a crucial role in regulation of angiogenesis and wound healing. We, therefore, investigated TP508 effects on NO production in human endothelial cells. TP508 stimulated a rapid, dose-dependent, 2- to 4-fold increase in NO production. TP508 induced NO release as early as 5 min. Continued exposure to TP508 for 1–24 h increased NO concentrations over controls by 100.5 ± 9.6 and 463.3 ± 24.2 nM, respectively. These levels of NO release were similar to those produced in response to vascular endothelial growth factor (VEGF). TP508- and VEGF-induced NO production was decreased by inhibitors of PI-3K (LY294002) and Src (PP2). TP508 stimulated early transient phosphorylation of Src and Akt. In contrast to VEGF, TP508 stimulation of NO release was inhibited by PKC inhibitor (Go6976) and was independent of intracellular calcium mobilization. These results demonstrate that TP508 and VEGF stimulate NO production to similar levels but through distinct pathways. This study provides new insights into the initial molecular mechanisms by which TP508 may stimulate diverse cellular effects leading to tissue revascularization and wound healing.
Endoscopic Lung Volume Reduction
Authors: Herth Felix J.F. , Gompelmann Daniela , Ernst Armin , Eberhardt Ralf
Published: November 2009

Chronic obstructive pulmonary disease (COPD) is a category of diseases characterized by chronic airflow obstruction and hyperinflation. The GOLD committee and the American Thoracic Society/European Respiratory Society have published detailed, evidence-based reviews of management approaches, providing stepped-care algorithms for pharmacologic and nonpharmacologic therapy. Over the past several decades, much effort was spent in designing additional nonpharmacologic approaches to ameliorate symptoms in these patients. Three endoscopic lung volume reduction principles have shown promise and reached later-stage clinical trials in patients with heterogeneous emphysematous diseases. These include so-called blocking devices (valves), nonblocking devices (coils) and irreversible nonblocking techniques (bronchoscopic thermal vapor ablation, polymeric lung volume reduction) designed to collapse and remodel hyperinflated lung. For homogeneous diseases the formation of airway bypass tracts designed to facilitate emptying of damaged lung regions with long expiratory times is being investigated.
Impact of Low Glucose Degradation Product Bicarbonate/Lactate-Buffered Dialysis Solution on the Epithelial-Mesenchymal Transition of Peritoneum
Authors: Oh Eun-Joo , Ryu Hye-Myung , Choi Soon-Youn , Yook Ju-Min , Kim Chan-Duck , Park Sun-Hee , Chung Ho-Young , Kim In-San , Yu Min-A , Kang Duk-Hee , Kim Yong-Lim
Published: November 2009

Background: Epithelial-mesenchymal transition (EMT) is important in the development of peritoneal fibrosis. Glucose degradation products (GDPs) may induce EMT in human peritoneal mesothelial cells (HPMCs). Methods: The effects of individual GDPs and GDPs derived from peritoneal dialysis fluid (PDF) in both HPMCs and peritoneal membranes were evaluated. EMT was assessed with α-smooth muscle actin (α-SMA) and E-cadherin. Results: In vitro, α-SMA protein and mRNA levels increased in the presence of the GDPs (formaldehyde, glyoxal, methylglyoxal, and 3-deoxyglucosone), and E-cadherin decreased. Changes in the EMT markers were most prominent after exposure to 3-deoxyglucosone. Changes in both α-SMA and E-cadherin protein levels were less with low (L)-GDP bicarbonate/lactate-buffered PDF compared to high (H)-GDP PDF. In the rat model after 8 weeks’ PDF infusion, the α-SMA/E-cadherin mRNA ratio increased in the H-GDP group compared with the L-GDP group (p < 0.05). The peritoneum in the H-GDP group tended to be thicker (p = 0.052) and had more blood vessels than that in the L-GDP group (p < 0.05). Tissue staining for TGF-β1 decreased in the L-GDP group. Dual-stained cytokeratin and α-SMA-positive myofibroblasts in the submesothelial layer were more prominent in the H-GDP group. Conclusion: GDPs found in PDF induce EMT of HPMCs, which is associated with peritoneal fibrosis and vascularization. Conversely, L-GDP PDF reduces EMT and peritoneal fibrosis.
Aldosterone Promotes Fibronectin Synthesis in Rat Mesangial Cells via ERK1/2-Stimulated Na+-H+ Exchanger Isoform 1
Authors: Zhang Minmin , Chen Jing , Lai Lingyun , You Li , Lin Shanyan , Hao Chuanming , Gu Yong
Published: November 2009

Background: Aldosterone plays an important role in fibrosis. Recent studies showed that Na+-H+ exchanger isoform 1 (NHE1) is involved in mineralocorticoid-induced organ fibrosis. In this study, we examined the role of NHE1 in aldosterone-induced fibronectin accumulation in rat mesangial cells and the signaling pathway involved. Methods: We detected the expression of mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase 2 in rat glomeruli by immunochemistry and Western blot. Then the eukaryotic vectors of shRNA with insert targeting on NHE1 were successfully constructed and transfected into rat mesangial cells. The mRNA was quantified by real-time PCR. We measured the protein abundance of NHE1, ERK1/2 and phosphor-ERK1/2 by Western blot and the level of fibronectin by ELISA. Results: First we demonstrated the local action of aldosterone on rat glomeruli in vivo. Then, after exposure to aldosterone, the NHE1 protein abundance was found increased in rat mesangial cells. Aldosterone treatment markedly increased the fibronectin level, which can be reduced by PD98059, spironolactone and shRNA-NHE1. PD98059 substantially reduced the aldosterone-induced NHE1 expression, while the knocking down of NHE1 did not alter aldosterone-stimulated phospho-ERK1/2 stimulation. Conclusion: The present study suggests that NHE1 may play an important role in aldosterone-mediated fibronectin accumulation in rat mesangial cells via the ERK1/2 pathway.
In vivo Percutaneous Penetration of Corticoids in Man and Unresolved Problems in Their Efficacy
Authors: Maibach Howard I.
Published: November 2009

This paper reviews the percutaneous penetration of corticosteroids in vivo in man utilizing urinary excretion of 14C-hydrocortisone as the experimental method. In general corticosteroids are only minimally absorbed from most areas of glabrous skin. Increasing the amount that penetrates – by use of occlusion – and increasing concentration provides the most practical method currently available for increasing efficacy in treatment-resistant dermatoses. Some practical research problems relevant to topical corticoid efficacy are discussed.
Bioavailability of Topical Steroids
Authors: Barry B.W.
Published: November 2009

This paper reviews our modification of the vasoconstrictor (blanching) assay for topical corticosteroids using human volunteers, which we have improved and extended so that it may be used as a useful screening test for clinical efficacy besides being employed to determine the bioavailability of steroids from topical bases. Work is reported on the blanching activities of (1) 14 novel steroids in ethanol, (2) hydrocortisone 17-butyrate in eight topical vehicles, (3) betamethasone 17-benzoate in foam, ointment, cream and gel bases, and (4) 61 commercial formulations used in Great Britain. Pharmacokinetic/pharmacodynamic relationships are discussed as aids to optimizing topical steroid treatment.
Methods for the Assessment of Skin Atrophogenicity of Topical Corticosteroids
Authors: Marks R.
Published: November 2009

A review is given of the methods used to estimate the atrophogenicity of corticosteroids after topical use. An experiment was performed in human volunteers in which measurement of mean epidermal thickness showed that the adverse effect of betamethasone 17-valerate exceeded that of placebo, hydrocortisone 17-butyrate ranking in between. To evaluate the atrophy caused by corticosteroid on dermis the radiological technique of Black was further modified and adapted. With this method clobetasol proprionate proved to give significantly more atrophy compared with a placebo. The atrophy disappeared 2 months after treatment was stopped.
Objective Measurement of Topically Applied Corticosteroids
Authors: Király K. , Soós Gy.
Published: November 2009

The vasoconstriction caused by four topical corticosteroid preparations was compared according to subjective ranking and according to measurement by a tristimulus colourimeter (Momcolor®). The measured results agreed well with visual evaluation. The colourimeter was proved to be measuring the degree of vasoconstriction. Among the preparations examined, the vasoconstriction effected by hydrocortisone 17-butyrate cream (Locoid®) and by betamethasone dipropionate ointment (Diprosone®) was stronger than that exerted by triamcinolone acetonide (Ftorocort®) and fluocinolone acetonide (Flucinar®). With the aid of colourimetric measurement of the vasoconstriction, differences could be demonstrated between clinically effective topical corticosteroid preparations. An open question remains, what the predictive significance is of the objectively measured vasoconstriction test, for clinical practice.
Mechanism of Local Skin Atrophy Caused by Intradermally Injected Corticosteroids
Authors: Fülöp É.
Published: November 2009

Different hydrocortisone microcrystal suspensions applied intradermally in rabbits caused skin atrophy. This could be ascribed to secondary tissue degeneration as was ascertained histologically. The degree of degeneration was related to the concentration of the suspension, size of the microcrystals and frequency of the intervals between the injections. The ground substance of the connective tissue changes and is characterized by a basophilic granular mass, homogenized collagen fibers and degeneration of the elastic fibers. The patho-mechanism of local skin atrophy not only differs from connective tissue degeneration caused by systemic corticosteroid treatment but also from the degeneration caused by topical treatment.
Perioral Dermatitis and Rosacea-Like Dermatitis: Clinical Features and Treatment
Authors: Urabe H. , Kōda H.
Published: November 2009

Nine cases of perioral dermatitis and 16 cases of rosacea-like dermatitis have been treated for the last 3 years at our clinic. These cases were all females whose ages ranged from 18 to 61 years with a mean of 45 years. All had been under treatment with fluorinated steroids for a period of from 3 months to 10 years, about 3 years on the average. Tetracyclines were beneficial as remedies for these conditions, bringing about healing or remission in approximately 3 months. About 1 year was required for the recovery from atrophy of the skin and telangiectasia. Hydrocortisone 17-butyrate was more useful as a topical medication than hydrocortisone acetate but gave rise to withdrawal rebound eruptions in some cases.
Topical Corticosteroid Therapy and Its Effect on the Hypothalamic-Pituitary-Adrenal Axis
Authors: Munro D.D.
Published: November 2009

All clinically effective topical corticosteroids have the potential for suppressing the pituitary-adrenal axis if large amounts are applied under occlusion on extensive areas. Recovery of the axis function occurs rapidly. In children, however, the risk of chronic suppression of the adrenal axis function with impairment of growth after topical treatment with potent steroids is a real one. Potent steroids in children should, therefore, only be used on refractory areas with carefully controlled quantities.
Topical and Systemic Effects of Hydrocortisone 17-Butyrate
Authors: Wieriks J. , Hespe W. , Jaitly K.D. , van Kan B.L.
Published: November 2009

In a series of hydrocortisone 17-esters, hydrocortisone 17-butyrate (HC-17B) has almost optimal lipophilicity resulting in a topical effect comparable to that of the fluorinated corticosteroids as measured in the McKenzie test on the human skin. In rats its systemic effects are weak, being in the order of those of hydrocortisone. In man systemic effects have been demonstrated, but no exact comparative data are available. Important factors controlling the intensity of systemic effects are: rate of liberation into plasma from the depot in the horny layer, rate of metabolic degradation, and rate of plasma clearance. In rats the main factor seems to be rapid clearance from plasma (t1/2 = 0.5 h) by selective concentration in the liver and, to a lesser extent, in the kidneys. Rapid hydrolysis by esterases in plasma and liver plays an additional role. In man hydrolysis by esterases appears to be rather slow; the rate of clearance from plasma is still unknown, whereas the absorption from the intact skin into the blood seems to be very slow (t1/2 = 25 h).
Effect of Hydrocortisone 17-Butyrate on the Percutaneous Absorption of Antibiotics
Authors: Simon N. , Dobozy A.
Published: November 2009

Absorption of antibiotics from combined preparations containing oxytetracycline, chlortetracycline, doxycycline or gentamicin and hydrocortisone 17-butyrate into the skin of rats was examined. The penetration of antibiotics from the ointment into the skin was inhibited by 0.2% hydrocortisone 17-butyrate to a significant degree. It is suggested that this effect of hydrocortisone 17-butyrate is the consequence of its vasoconstrictor action.
Intelligibility of Tonic Accents
Authors: Efremova I.B. , Fintoft K. , Ormestad H.
Published: November 2009

A psycho-physical test with 95 observers was used for investigations of tonic accents in East Norwegian spoken language. Fractions of different lengths from the beginning of the stressed syllable of the same verb, but with different accents, were presented to the listeners, who were asked to decide which accent they heard. The accents were correctly identified to a degree of about 90% with very short word fractions, before the end of the stressed syllable. The most important identifying parameters seem to be the fundamental frequency and its variation.
Fibulin-2 and Fibulin-5 Cooperatively Function to Form the Internal Elastic Lamina and Protect From Vascular Injury
Authors: Chapman Shelby L. , Sicot F.-X. , Davis Elaine C. , Huang Jianbin , Sasaki Takako , Chu Mon-Li , Yanagisawa Hiromi
Published: November 2009

Objective—

Recent findings on the role of fibulin-5 (Fbln5) have provided substantial progress in understanding the molecular mechanism of elastic fiber assembly in vitro. However, little is known about differential roles of fibulins in the elastogenesis of blood vessels. Here, we generated double knockout mice for
Fbln5
and
Fbln2
(termed
DKO
) and examined the role of fibulins-2 and -5 in development and injury response of the blood vessel wall.

Methods and Results—

Fibulin-2 is distinctly located in the subendothelial matrix, whereas fibulin-5 is observed throughout the vessel wall. All of the elastic laminae, including the internal elastic lamina (IEL), were severely disorganized in
DKO
mice, which was not observed in single knockout mice for
Fbln2
or
Fbln5
. Furthermore,
DKO
vessels displayed upregulation of vascular adhesion molecules, tissue factor expression, and thrombus formation with marked dilation and thinning of the vessel wall after carotid artery ligation-injury.

Conclusions—

Fibulin-2 and fibulin-5 cooperatively function to form the IEL during postnatal development by directing the assembly of elastic fibers, and are responsible for maintenance of the adult vessel wall after injury. The
DKO
mouse will serve as a unique animal model to test the effect of vessel integrity during various pathological insults.
CCL5 Promotes Macrophage Recruitment and Survival in Human Adipose Tissue
Authors: Keophiphath Mayoura , Rouault Christine , Divoux Adeline , Clément Karine , Lacasa Danièle
Published: November 2009

Objectives—

To examine the role of adipose-produced chemokine, chemokine ligand (CCL) 5, on the recruitment and survival of macrophages in human white adipose tissue (WAT).

Methods and Results—

CCL5 levels measured by enzyme immunoassay in serum and by real-time polymerase chain reaction in WAT were higher in obese compared to lean subjects. CCL5, but not CCL2, secretion was higher in visceral compared to subcutaneous WAT. CCL5 mRNA expression was positively correlated with the inflammatory macrophage markers as CD11b, tumor necrosis factor-α, and IL-6 in visceral WAT (n=24 obese subjects), and was higher in macrophages than other WAT cells. We found that CCL5 triggered adhesion and transmigration of blood monocytes to/through endothelial cells of human WAT. Whereas in obese WAT apoptotic macrophages were located around necrotic adipocytes, we demonstrated that CCL5, but not CCL2, protected macrophages from free cholesterol-induced apoptosis via activation of the Akt/Erk pathways.

Conclusions—

CCL5 could participate in the inflammation of obese WAT by recruiting blood monocytes and exerting antiapoptotic properties on WAT macrophages. This specific role of CCL5 on macrophage survival with maintenance of their lipid scavenging function should be taken into account for future therapeutic strategies in obesity-related diseases.
Resident Intimal Dendritic Cells Accumulate Lipid and Contribute to the Initiation of Atherosclerosis
Authors: Paulson Kim E. , Zhu Su-Ning , Chen Mian , Nurmohamed Sabrina , Jongstra-Bilen Jenny , Cybulsky Myron I.
Published: November 2009

Rationale
:

Atherosclerosis is an inflammatory disease in which leukocytes and oxidatively modified lipids accumulate in the arterial intima. Previously, we showed that dendritic cells (DCs) accumulate preferentially in regions predisposed to atherosclerosis in the normal murine aortic intima. The function of these cells in atherogenesis is unknown.

Objective
:

Our goal was to determine the role of resident intimal DCs in the initiation of atherosclerosis.

Methods and Results
:

En face immunostaining of nascent atherosclerotic lesions in low-density lipoprotein receptor–deficient (
Ldlr
−/−
) mice fed a cholesterol-rich diet for 5 or 10 days demonstrated that foam cells expressed DC markers CD11c, 33D1, and major histocompatibility complex class II. Transmission electron microscopy revealed that the majority of intimal lipid was intracellular. The role of resident intimal DCs in lesion formation was verified by their conditional depletion using transgenic mice expressing the simian diphtheria toxin receptor in CD11c
+
cells. A single injection of diphtheria toxin depleted intimal CD11c
+
DCs by >98% within 24 hours, with 25% and 75% recovery at 1 and 3 weeks, respectively. When bred onto the
Ldlr
−/−
background, intimal DC depletion with diphtheria toxin during 5 days of lesion formation reduced the intimal lipid area by 55% relative to undepleted controls. Transmission electron microscopy revealed few foam cells in DC-depleted mice and abundant accumulation of subendothelial extracellular lipid.

Conclusions
:

Induction of hypercholesterolemia in mice triggers rapid ingestion of lipid by resident intimal DCs, which initiate nascent foam cell lesion formation.