bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Lasting Pigmentation More than Its Intensity Is a Reliable Indicator of Skin Sun Resistance
Authors: Procaccini Enrico M. , Napolitano Alessandra , Panzella Lucia , Prizio Emilia , Monfrecola Giuseppe
Published: September 2007

Background: The currently adopted method for predicting sun sensitivity is Fitzpatrick’s classification which however is based on self-reported burning tendency and tanning ability. Objective: Determination of the individual UV susceptibility based on non-subjective parameters. Method: Minimal erythema dose (MED), intensity and duration of pigmentation on days 5, 9 and 16 following 1 MED and the levels of the melanin marker pyrrole-2,3,5-tricarboxylic acid (PTCA) were analysed in non-red-haired subjects (50, aged 20–46 years). Results: Phenotype groups or phototypes showed a good correlation with PTCA yields and the persistence of pigmentation on day 16, but not with MED values. MED values did not show a significant correlation with PTCA yields. On the other hand, high values on day 16 were exhibited only by subjects having PTCA values higher than 200 ng/mg. Conclusions: Measurement persistence of pigmentation on day 16 represents a non-invasive and easy-to-perform method to evaluate photoprotection in those individuals escaping straightforward classification based on phenotype or anamnesis.
A Retrospective Analysis of Thalidomide Therapy in Non-HIV-Related Kaposi’s Sarcoma
Authors: Ben M’barek Lilia , Fardet Laurence , Mebazaa Amel , Thervet Eric , Biet Israel , Kérob Delphine , Morel Patrice , Lebbe Céleste
Published: September 2007

Background: Thalidomide has antiangiogenic and immunomodulatory properties and has recently been used in the management of human malignancies. Several studies have suggested its interest for treating AIDS-related Kaposi’s sarcoma. Objectives: This study aimed to assess the efficacy and toxicity of thalidomide, an antiangiogenic agent, for the treatment of non-HIV-related Kaposi’s sarcoma. Methods: Eleven patients were included in this retrospective study conducted in the Department of Dermatology of Saint Louis, Paris, between 2000 and 2003. Among them, 2 were immunosuppressed (1 renal transplant recipient and 1 patient with microscopic polyangiitis treated by oral steroids) with stable immunosuppressive regimens during the past 6 months. The median daily thalidomide dosage was 100 mg and the median duration of drug treatment was 16 weeks. Results: Three patients achieved a partial response and 4 had a stable disease. Although no grade 3 or 4 was observed, 3 (27%) out of 11 patients prematurely discontinued thalidomide because of grade 1 sensory neuropathy (paresthesia) and vertigo. Conclusions: Our results show a true although modest interest of thalidomide in non-HIV-related Kaposi’s sarcoma and prompt us to evaluate less toxic thalidomide analogues for this indication.
Upper Respiratory Tract Infection in Household Contacts of Acne Patients
Authors: Bowe Whitney P. , Hoffstad Ole , Margolis David J.
Published: September 2007

Background: Antibiotic use in acne patients has been associated with an increased risk of upper respiratory tract infection (URTI). Methods: This was a retrospective cohort study using the General Practice Research Database of the United Kingdom. All study subjects were identified as sharing a residence with a patient with a diagnosis of acne. Outcome of interest was a URTI. Results: We identified 98,094 contacts of acne patients. A contact of an acne patient who had a URTI was about 43% more likely to develop a URTI than a contact of an acne patient who did not have a URTI (OR = 1.43 CI = 1.33–1.52, p < 0.001). Exposure to an acne patient using antibiotics did not independently increase a contact’s risk of URTI (OR = 0.94, CI = 0.89–1.00, p = 0.063). Conclusions: Although acne patients on antibiotics are about 2 times more likely to develop URTIs, their household contacts do not appear to be at an increased risk of URTI.
Angiolymphoid Hyperplasia with Eosinophilia Successfully Treated with Imiquimod
Authors: Gencoglan Gulsum , Karaca Semsettin , Ertekin Banu
Published: September 2007

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare disorder characterized by vascular proliferation, eosinophilia in peripheral blood samples and lymphocytosis. The etiology is unknown; this rare condition is generally seen in women. It often presents as multiple, grouped red nodules in the periauricular region, scalp line and neck. Numerous therapeutic approaches have been tried for ALHE including destructive techniques such as electrodesiccation, cryotherapy, surgical excision, radiotherapy or laser (argon, CO2, pulse dye). We present an ALHE case that was treated successfully by using topical imiquimod cream.
Generalized Lichen Nitidus with Involvement of the Palms following Interferon α Treatment
Authors: Scheler Marina , Proelss Julia , Bräuninger Wolfgang , Bieber Thomas , Wenzel Joerg
Published: September 2007

Lichen nitidus is an uncommon dermatosis of unknown etiology. Here we present the case of a generalized lichen nitidus with involvement of the palms in a patient with hepatitis C after systemic treatment with interferon α and ribavirin. Furthermore in our patient we could show a strong lesional expression of MxA, a protein specifically induced by type I interferon. It is tempting to speculate that interferon α may be involved in the pathogenesis of lichen nitidus.
Infliximab for the Treatment of Disseminated Pyoderma Gangrenosum Associated with Ulcerative Colitis
Authors: Juillerat Pascal , Christen-Zäch Stephanie , Troillet François-Xavier , Gallot-Lavallée Suzanne , Pannizzon Renato G. , Michetti Pierre
Published: September 2007

We report the case of a 19-year-old woman who developed an acute disseminated pyoderma gangrenosum (PG) during a severe flare of ulcerative colitis (UC). She was successfully treated with a 3-dose regimen of the anti-tumor-necrosis-factor-α antibody infliximab. The literature on the effectiveness of this biological agent was reviewed, including 8 other cases of UC-associated PG and 77 cases of Crohn’s-disease-associated PG. This case report and the review of the literature demonstrate that infliximab can be successfully used to treat patients with PG associated with inflammatory bowel diseases.
Epidermolysis Bullosa Acquisita following Bullous Pemphigoid, Successfully Treated with the Anti-CD20 Monoclonal Antibody Rituximab
Authors: Wallet-Faber N. , Franck N. , Batteux F. , Mateus C. , Gilbert D. , Carlotti A. , Avril M.F. , Dupin N.
Published: September 2007

Epidermolysis bullosa acquisita is a rare autoimmune subepidermal blistering disease, often resisting current treatments, especially systemic corticosteroids. We report a patient having a bullous pemphigoid who relapsed with clinical and immunological features of inflammatory epidermolysis bullosa acquisita. An anti-CD20 monoclonal antibody (rituximab) was proposed because of resistance to high-dose steroids and other immunosuppressive agents. The disease dramatically improved within a few weeks following rituximab infusion allowing the decrease in steroid therapy. Our case illustrates also the possible evolution from bullous pemphigoid to epidermolysis bullosa acquisita that should be suspected when clinical atypia occurs or in case of corticosteroid resistance.
Cost-Effectiveness Model of Topical Treatment of Mild to Moderate Psoriasis Vulgaris in Germany
Authors: Augustin M. , Peeters P. , Radtke M. , Moehling U. , Lapp C.
Published: September 2007

Background: Psoriasis vulgaris requires lifelong treatment associated with considerable health cost. Studies showed that a combination of a steroid and a vitamin D3 analogue is more effective than both compounds in monotherapy. Objective: To determine the cost-effectiveness of a fix calcipotriol/betamethasone combination (Daivobet®/Dovobet®/Taclonex®) compared to a morning/evening non-fix calcipotriol/betamethasone combination in psoriasis treatment. Methods: A Markov model (discrete-time stochastic process based on transitions between health states) with 2 treatment arms (Daivobet/Dovobet/Taclonex vs. non-fix calcipotriol/betamethasone) over a 48-week time period was developed. The effectiveness criterion was the number of days with clearance or marked improvement. Clinical and health resource utilisation data were derived from randomised studies. Results: Treatment with Daivobet/Dovobet/Taclonex showed a higher cost-effectiveness compared to the non-fix combination, even when assuming a maximum compliance for the twice daily non-fix combination and varying the effectiveness of Daivobet/Dovobet/Taclonex by 10%. Conclusion: Psoriasis treatment with a fix calcipotriol/betamethasone combination is more cost-effective than a non-fix morning/evening combination.
Influence of Subinhibitory Concentrations of Protein-Synthesis-Inhibiting Antibiotics on Production and Release of the Pneumococcal Virulence Factor Pneumolysin in vitro
Authors: Spreer Annette , von Rüden Christian , Mitchell Timothy J. , Eiffert Helmut , Nau Roland
Published: September 2007

Objective: Pneumolysin is an important virulence factor of Streptococcus pneumoniae with cytotoxic and proinflammatory activities released during growth and autolysis. At concentrations above the minimal inhibitory concentration, the protein-synthesis-inhibiting antibiotics erythromycin, clindamycin and rifampicin inhibit the production and/or release of virulence factors in various bacterial species. We investigated the influence of subinhibitory concentrations of these antibiotics on production and release of pneumolysin by S. pneumoniae strain D39. Methods: The pneumococcal strain D39 was grown in broth and treated with antibiotics at a concentration of 1/32 of the respective minimal inhibitory concentration. Cytoplasmic and extracellular pneumolysin was measured by quantitative immunoblotting with recombinant pneumolysin as standard. Results: The subinhibitory antibiotic concentrations evaluated did not affect bacterial growth. During logarithmic growth, production of pneumolysin was decreased by clindamycin, erythromycin and rifampicin by approximately 50% compared with untreated controls. The release of pneumolysin was decreased to a similar extent. Conclusion: A decrease in pneumolysin production by 50% probably has a moderate biological effect. We do not advocate the use of subinhibitory concentrations of antibiotics to modulate the expression of virulence factors during pneumococcal disease, particularly with regard to the risk of development of antibiotic resistance.
Prediction of Response to Pegylated Interferon and Ribavirin in Hepatitis C by Polymorphisms in the Viral Core Protein and Very Early Dynamics of Viremia
Authors: Akuta Norio , Suzuki Fumitaka , Kawamura Yusuke , Yatsuji Hiromi , Sezaki Hitomi , Suzuki Yoshiyuki , Hosaka Tetsuya , Kobayashi Masahiro , Kobayashi Mariko , Arase Yasuji , Ikeda Kenji , Miyakawa Yuzo , Kumada Hiromitsu
Published: September 2007

Objective: To evaluate power of amino acid polymorphisms in core protein of hepatitis C virus (HCV) for predicting sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin, when they were combined with virological response. Methods: Peg-IFN/ribavirin was given to 118 patients infected with HCV genotype 1b in high viral loads. Amino acid polymorphisms (Arg70 vs. Gln70 and Leu91 vs. Met91) in combination with on-treatment virological responses were correlated with SVR. Results: End-of-treatment response (ETR) was achieved in 71% and SVR in 47% of the 118 patients. In multivariate analysis, Arg70 and Leu91, and higher ribavirin dose were independently associated with ETR. In patients with Gln70 and/or Met91, SVR was more frequent in those with than without prompt virological response (PVR) for a decrease in viral load ≧1.0 log by 48 h. Specificity in predicting patients without ETR and SVR, in combination with core polymorphisms, was not different between PVR and early virological response at 12 weeks. Conclusion: Core polymorphisms combined with PVR would be useful in promptly identifying the patients who will not respond to Peg-IFN/ribavirin, thereby avoiding unrewarding side effects and high costs.
Platelet-Derived Growth Factor Reorganizes the Actin Cytoskeleton through 3-Phosphoinositide-Dependent and 3-Phosphoinositide-Independent Mechanisms in Human Mesangial Cells
Authors: Harper Lisa , Kashiwagi Yasuyo , Pusey Charles D. , Hendry Bruce M. , Domin Jan
Published: September 2007

Background: Platelet-derived growth factor (PDGF) is a potent activator of mesangial cell proliferation and migration. Although phosphoinositide 3-kinase (PI3K) enzymes are important downstream targets of the PDGF receptor, the contribution made by their 3-phosphoinositide products in the reorganization of actin cytoskeleton and focal adhesions has been questioned. Methods and Results: Pharmacological inhibition of the PI3K activity blocks PDGF-induced migration of human primary mesangial cells using an in vitro scrape wound healing assay. Acute (<10 min) inhibition of the PI3K activity did not alter the effect of PDGF on either stress fibre dissolution or reorganization of focal adhesions. However, at later times (>30 min), PDGF-stimulated responses were inhibited. In contrast, PDGF-stimulated membrane ruffling remained insensitive to PI3K inhibitors throughout. Inhibition of protein kinase C and Erk also attenuated PDGF-stimulated mesangial cell migration; however, neither signaling pathway was responsible for the initial effects on filamentous actin and focal adhesions. Conclusions: We propose that following PDGF stimulation of mesangial cells, reorganization of the actin cytoskeleton occurs in a biphasic manner. The mechanism responsible for mesangial cell migration that occurs immediately following PDGF stimulation may serve to ‘prime’ for the subsequent 3-phosphoinositide-, protein-kinase-C-, and Erk-dependent migration.
Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia
Authors: Del Vecchio Giovanni Carlo , Nigro Antonia , Giordano Paola , Schettini Federico , Altomare Maria , Pietrapertosa Anna , De Mattia Domenico
Published: September 2007

A hypercoagulable state has been described in thalassemia patients, partly due to a deficiency of inhibitors, protein C (PC) in particular. Since a potential role of a new hemostatic factor named protein Z (PZ) has been reported in hypercoagulability, we evaluated plasma PZ and PC levels in thalassemia and their possible relation to the hypercoagulable state. Sixty subjects with thalassemia major and 10 with thalassemia intermedia (TI) followed at our Department were enrolled in the study. An age-matched control group of healthy subjects was considered. PZ, thrombin-antithrombin complexes, PC concentration (PC:Ag) and activity (PC:Act) were measured. PZ, PC:Ag and PC:Act were significantly lower in thalassemia major and thalassemia intermedia subjects than in 30 healthy controls (p < 0.001), while thrombin-antithrombin complex levels were significantly increased (p < 0.001) and related to PC levels but not to PZ levels (p < 0.05). PZ and PC levels are reduced in thalassemia but only PC has an effect on the thalassemia hypercoagulable state.
Quantitative Analysis of Pursuit Ocular Movements in Parkinson’s Disease by Using a Video-Based Eye Tracking System
Authors: Marino Silvia , Sessa Edoardo , Di Lorenzo Giuseppe , Lanzafame Pietro , Scullica Gabriella , Bramanti Alessia , La Rosa Francesco , Iannizzotto Giancarlo , Bramanti Placido , Di Bella Paolo
Published: September 2007

The purpose of this study is to assess the efficacy and the tolerability of a new vision-based non-intrusive eye tracker in a population composed of normal controls and in patients affected by nonadvanced Parkinson’s disease (PD). PD patients characteristically have difficulty in sustaining repetitive motor actions. Previous studies showed a progressive bradykinesia and hypokinesia of pursuit ocular movements (POM) in advanced PD. We found that the values of POM were lower in PD patients than in normal controls (p < 0.001). In PD patients, the values correlated closely with Hoehn and Yahr stage and Unified Parkinson Disease Rating Scale motor subscore (p < 0.001, for both). Our data suggest that deficit in POM occurs also in nonadvanced PD patients and it is closely correlated with clinical scores. Thus, this vision-based system can be considered a new method to provide, noninvasively, measures of POM dysfunctions and can be used as reliable indices of disease severity in PD patients.
Fluctuation in Spontaneous Recovery of Left Visual Neglect: A 1-Year Follow-Up
Authors: Jehkonen M. , Laihosalo M. , Koivisto A.-M. , Dastidar P. , Ahonen J.-P.
Published: September 2007

Spontaneous recovery and possible fluctuation in left visual neglect, and its relation to stroke severity, basic activities of daily living (ADL) and extended ADL were examined at 10 days, at 3, 6, and 12 months after onset. Twenty-one of 56 right hemisphere stroke patients had visual neglect. Three visual neglect recovery groups were identified: continuous, fluctuating and poor recovery. We concentrated on the comparison of the continuous and the fluctuating recovery groups. At the acute phase the fluctuating recovery group had larger infarcts, more severe neglect and stroke, and a lower level of basic ADL compared to the continuous recovery group. In the continuous recovery group stable recovery was detected up to 6 months, whereas in the fluctuating recovery group recovery was incoherent in neglect and in extended ADL. A minimum follow-up period of 6 months including the evaluation of extended ADL is recommended for neglect patients due to possible fluctuation in visual neglect.
Motor and Nonmotor Symptom Follow-Up in Parkinsonian Patients after Deep Brain Stimulation of the Subthalamic Nucleus
Authors: Zibetti M. , Torre E. , Cinquepalmi A. , Rosso M. , Ducati A. , Bergamasco B. , Lanotte M. , Lopiano L.
Published: September 2007

Objective: To evaluate motor and nonmotor symptoms in patients with Parkinson’s disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). Methods: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson’s Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. Results: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. Conclusions: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson’s disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.
The Kinetic Change of the Serum Angiogenin Level in Patients with Acute Cerebral Infarction
Authors: Huang Li , Guo Huailian , Cheng Min , Zhao Yafeng , Jin Xin
Published: September 2007

Serum angiogenin (ANG) levels were measured with ELISA in 30 cerebral infarction patients at different time points (within 48 h and on days 3, 7 and 14 after onset of cerebral infarction) and in 20 control subjects. Serum ANG levels in patients were 415.1 ± 76.8, 410.6 ± 82.1, 443.6 ± 91.1 and 395.3 ± 83.9 ng/ml within 48 h and on days 3, 7 and 14 after cerebral infarction, respectively. Serum ANG level in control group was 334.9 ± 93.9 ng/ml. Serum ANG levels were significantly higher in patients with cerebral infarction within 48 h and on days 3 and 7 than in the control group (p < 0.05). Serum ANG level decreased on day 14. Serum ANG levels were significantly higher in patients with large infarction than in those with moderate and small infarction at each time point (p < 0.05). Our observations that serum ANG levels increase significantly in patients with cerebral infarction and the increase in ANG levels correlates with the infarct size suggest that ANG might be involved in the pathophysiologic process of ischemic brain damage.
CXCL11 (Interferon-Inducible T-Cell Alpha Chemoattractant) and Interleukin-18 in Relapsing-Remitting Multiple Sclerosis Patients Treated with Methylprednisolone
Authors: Szczuciński Adam , Kalinowska Alicja , Losy Jacek
Published: September 2007

Background/Aims: Chemokines may play a role in the pathogenesis of multiple sclerosis (MS), facilitating the trafficking of immune cells across the blood-brain barrier. Interferon-inducible T-cell α-chemoattractant (CXCL11) recruits activated Th1 cells to sites of inflammation. In this study, we wanted to estimate the levels of CXCL11 chemokine and interleukin-18 (IL-18), a proinflammatory cytokine, in sera of relapsing-remitting MS (RRMS) patients, both before and after methylprednisolone (MP) treatment, and to compare the results with those in the control group. Materials and Methods: Serum CXCL11 and IL-18 concentrations were measured by the ELISA method in 30 RRMS patients during relapse both before and after MP treatment, and in 20 healthy blood donors. Results: We found significantly increased CXCL11 and IL-18 serum levels in RRMS patients as compared with controls. Additionally, no influence of MP therapy on the serum levels of CXCL11 and IL-18 was observed. Conclusion: We suggest that CXCR3 receptor ligand, CXCL11, may be involved in MS pathogenesis.
Delayed Evacuatory Function due to Specific Smooth Muscle Reactivity in the Gastrointestinal Tracts of Tacrine-Treated Rats
Authors: Krustev A. , Sirakov V. , Turiiski V. , Getova D. , Velkova K. , Prissadova N.
Published: September 2007

Most of the side effects induced by tacrine are associated with the gastrointestinal (GI) tract. The aim of the study was to analyze the nature of radiographically registered, tacrine-induced changes in evacuatory function, as well as to find a possible correlation with the immediate in vitro action of the drug on smooth muscles from the GI tracts of rats. The tacrine dose we used reliably delayed GI passage: contrast matter was not fully evacuated, predominantly from the stomach and cecum. The delay resulted from changes in tone and peristaltic activity, specific for the various regions of the tract. These changes were associated with a superposing of the responses due to the anticholinesterase and noncholinergic action of tacrine.
Nectin and Nectin-Like Molecules: Biology and Pathology
Authors: Miyoshi Jun , Takai Yoshimi
Published: September 2007

Nectins and nectin-like molecules (Necls) are structurally related transmembrane proteins primarily involved in cell adhesion. Nectins and afadin, the adaptor or anchoring protein, stabilize the epithelium and endothelium and establish apical-basal polarity of epithelial cells, independently or in cooperation with other cell adhesion molecules. Necls facilitate cell–cell communication implicated in cell movement and proliferation, immune responses, and cancer cell phenotypes. Necls interact with nectins and specific ligands at cell–cell contacts, whereas Necls associate with integrin αvβ3 and growth factor receptors on the same cell surface. Besides their roles in cell adhesion, nectins regulate the activities of Rho family small G proteins which play critical roles in maintaining the apical junctions of epithelial cells through reorganization of the actin cytoskeleton. Since mice lacking the Rho GDP-dissociation inhibitor (GDI)α show massive proteinuria and degeneration of renal epithelial cells, nectins and other cell adhesion molecules may play roles in the structural and functional aspects of renal diseases. Here we summarize our knowledge of nectins and Necls and discuss cell adhesion biology in the kidney.
Effects of Pyridoxamine in Combined Phase 2 Studies of Patients with Type 1 and Type 2 Diabetes and Overt Nephropathy
Authors: Williams Mark E. , Bolton W. Kline , Khalifah Raja G. , Degenhardt Thorsten P. , Schotzinger Robert J. , McGill Janet B.
Published: September 2007

Background/Aims: Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation. Methods: The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr) ≤2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was ≤2.0 for PYR-205 and ≧2.0 but ≤3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg pyridoxamine twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily. Results: Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in deaths (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, pyridoxamine significantly reduced the change from baseline in serum creatinine (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr ≧1.3 mg/dl, type 2 diabetes), a treatment effect was observed on the rise in serum creatinine (p = 0.007). No differences in urinary albumin excretion were seen. Urinary TGF-β1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs. Conclusion: These data provide a foundation for further evaluation of this AGE inhibitor in DN.
Beneficial Effects of Complement Inhibition With Soluble Complement Receptor 1 (TP10) During Cardiac Surgery
Authors: Lazar Harold L. , Keilani Taha , Fitzgerald Carmel A. , Shapira Oz M. , Hunter Curtis T. , Shemin Richard J. , Marsh Henry C. , Ryan Una S. ,   the TP10 Cardiac Surgery Study Group
Published: September 2007

Background—

TP10, a potent inhibitor of complement activation during cardiopulmonary bypass (CPB) has been shown to significantly reduce the incidence of death and myocardial infarction (MI) in high-risk male patients undergoing cardiac surgery. However, the effect of TP10 in females was undefined because of the limited number of females studied. To examine the possibility of a gender effect, this phase 2 multi-center trial was undertaken to determine whether TP10 would also limit ischemic damage in a larger sample size of high-risk females undergoing cardiac surgery on cardiopulmonary bypass (CPB).

Methods and Results—

This prospective, double-blind, placebo-controlled, multi-center trial involved 297 high-risk (urgent surgery, CABG + Valve, reoperations, ejection fraction <30%) female patients randomized to receive a 5 mg/kg dose of TP10 (n=150) or placebo (n=147) as a 30-minute intravenous infusion before surgery. The primary end point was the incidence of death or MI at 28 days after surgery. Complement activation was assessed by levels of CH50 and SC5b-9 during and after CPB. TP10 was well tolerated and there were no differences in the safety profiles of the 2 groups. Although TP10 effectively suppressed complement activation (at 2 hours after CPB CH50 (mean+SD % change from baseline) 50±17% placebo versus 4±14% TP10;
P
=0.0001; SC5b-9 (ng/mL) 917±1067 placebo versus 204±79 TP10;
P
=0.0001), there was no difference in the primary end point between the groups (17% placebo versus 21% TP10;
P
=0.2550).

Conclusions—

The benefits of TP10 appear to be gender-related. and mechanisms other than complement activation may be responsible for myocardial injury in high-risk female patients during cardiac surgery on CPB.
Functional Anatomy of Aortic Regurgitation
Authors: le Polain de Waroux Jean-Benoît , Pouleur Anne-Catherine , Goffinet Céline , Vancraeynest David , Van Dyck Michel , Robert Annie , Gerber Bernhard L. , Pasquet Agnès , Khoury Gébrine El , Vanoverschelde Jean-Louis J.
Published: September 2007

Background—

For patients with aortic regurgitation (AR), aortic valve sparing or repair surgery is an attractive alternative to valve replacement. In this setting, accurate preoperative delineation of aortic valve pathology and potential repairability is of paramount importance. The aim of the present study was to assess the diagnostic value of preoperative transesophageal echocardiography (TEE) in defining the mechanisms of AR, as identified by surgical inspection, and in predicting repairability, by using the final surgical approach as reference.

Methods and Results—

One hundred and sixty-three consecutive patients (117 males, mean age: 58±14 years) undergoing AR surgery were included. Mechanisms of AR were categorized by TEE and surgical inspection as follows: type 1, aortic dilatation; type 2, cusp prolapse; and type 3, restrictive cusp motion or endocarditis. At surgery, mechanisms of AR were type 1 in 41 patients, type 2 in 62, and type 3 in 60. Agreement between TEE and surgical inspection was 93% (κ=0.90). Valve sparing or repair was performed in 125 patients and valve replacement in 38 patients. TEE correctly predicted the final surgical approach in 108/125 (86%) patients undergoing repair and in 35/38 (93%) patients undergoing replacement. The gross anatomic classification of AR lesions by TEE was determinant of valve repairability and postoperative outcome (4-year freedom from > grade 2 AR, reoperation, or death,
P
=0.04).

Conclusions—

TEE provides a highly accurate anatomic assessment of all types of AR lesions. In addition, the functional anatomy of AR defined by TEE is strongly and independently predictive of valve repairability and postoperative outcome.
Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes
Authors: Boodhwani Munir , Sodha Neel R. , Mieno Shigetoshi , Xu Shu-Hua , Feng Jun , Ramlawi Basel , Clements Richard T. , Sellke Frank W.
Published: September 2007

Background—

Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved.

Methods and Results—

Diabetes was induced in male Yucatan miniswine using a pancreatic β-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173±14 versus 234±23 cells/hpf,
P
=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4±0.9-fold increase,
P
<0.001), and endostatin (2.9±0.4-fold increase,
P
=0.03) were significantly elevated in the diabetic myocardium.

Conclusions—

Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.
Iron-Oxide Labeling and Outcome of Transplanted Mesenchymal Stem Cells in the Infarcted Myocardium
Authors: Amsalem Yoram , Mardor Yael , Feinberg Micha S. , Landa Natalie , Miller Liron , Daniels Dianne , Ocherashvilli Aharon , Holbova Radka , Yosef Orna , Barbash Israel M. , Leor Jonathan
Published: September 2007

Background—

Cell labeling with superparamagnetic iron oxide (SPIO) nanoparticles enables noninvasive MRI and tracking of transplanted stem cells. We sought to determine whether mesenchymal stem cell (MSC) outcome is affected by SPIO labeling in a rat model of myocardial infarction.

Methods and Results—

Rat MSCs were labeled with SPIO (ferumoxides; Endorem; Guerbet, Villepinte, France). By trypan-blue exclusion assay, almost 100% of the cells remained viable after labeling. Seven days after MI, rats were randomized to injections of 2×10
6
SPIO-labeled MSCs, 2×10
6
unlabeled MSCs, or saline. Labeled cells were visualized in the infarcted myocardium as large black spots by serial MRI studies throughout the 4-week follow-up. The presence of labeled cells was confirmed by iron staining and real-time polymerase chain reaction on postmortem specimens. At 4 weeks after transplantation, the site of cell injection was infiltrated by inflammatory cells. Costaining for iron and ED1 (resident macrophage marker) showed that the iron-positive cells were cardiac macrophages. By real-time polymerase chain reaction, the Y-chromosome-specific SRY DNA of MSCs from male donors was not detected in infarcted hearts of female recipients. Serial echocardiography studies at baseline and 4 weeks after cell transplantation showed that both unlabeled and labeled MSCs attenuated progressive left ventricular dilatation and dysfunction compared with controls.

Conclusions—

At 4 weeks after transplantation of SPIO-labeled MSCs, the transplanted cells are not present in the scar and the enhanced MRI signals arise from cardiac macrophages that engulfed the SPIO nanoparticles. However, both labeled and unlabeled cells attenuate left ventricular dilatation and dysfunction after myocardial infarction.
Effects of Aprotinin on Gene Expression and Protein Synthesis After Ischemia and Reperfusion in Rats
Authors: Buerke Michael , Pruefer Diethard , Sankat Dennis , Carter Justin M. , Buerke Ute , Russ Martin , Schlitt Axel , Friedrich Ivar , Börgermann Jochen , Vahl Christian F. , Werdan Karl
Published: September 2007

Background—Reperfusion injury of ischemic myocardium has been attributed to neutrophil infiltration, inflammatory activation and cardiac necrosis/apoptosis. Serine protease inhibition with aprotinin is cardioprotective, but the mechanism is unknown.

Methods and Results—We studied aprotinin in a rat model of myocardial ischemia for 20 minutes and reperfusion for 20 minutes, 8 hours or 24 hours. Aprotinin (20 000 IU/kg) given 5 minutes before reperfusion significantly reduced leukocyte accumulation (P<0.01), myocardial injury (determined by CK depletion,P<0.01) and myocyte apoptosis (P<0.05) compared with vehicle treated rats. Differential gene expression analysis showed myocardial ischemia plus reperfusion increased expression of proinflammatory genes like P-selectin, E-selectin, intercellular adhesion molecule, tumor necrosis factor-α, tumor necrosis factor-α receptor, interleukin-6, monocyte chemoattractant protein-1, p53, and Fas (CD59). Aprotinin before reperfusion suppressed expression of these inflammatory genes. Finally, differential protein expression analysis demonstrated increased intercellular adhesion molecule-1, tumor necrosis factor-α, and p53 after myocardial ischemia plus reperfusion, and this effect was diminished by aprotinin.

Conclusions—We demonstrated myocardial ischemia plus reperfusion induced leukocyte accumulation, inflammation, gene expression, protein expression and finally tissue injury and showed aprotinin limiting reperfusion injury through each of these stages, even after 24 hours of reperfusion. This effect seems partly attributable to suppression of proinflammatory genes and leukocyte accumulation. This work casts further light on the complex signaling of ischemia and reperfusion.
Surgical Revascularization Is Associated With Improved Long-Term Outcomes Compared With Percutaneous Stenting in Most Subgroups of Patients With Multivessel Coronary Artery Disease
Authors: Bair Tami L. , Muhlestein Joseph B. , May Heidi T. , Meredith Kent G. , Horne Benjamin D. , Pearson Robert R. , Li Qunyu , Jensen Kurt R. , Anderson Jeffrey L. , Lappé Donald L.
Published: September 2007

Background—

Coronary artery bypass surgery (CABG) and percutaneous coronary intervention with stenting (PCI-S) are both safe and effective approaches for revascularization in patients with multivessel coronary artery disease. However, conflicting information exists when comparing the efficacy of the two methods. In this study, we examined the outcomes of major adverse cardiovascular events and death for subgroups of typical “real-world” patients undergoing coronary revascularization in the modern era.

Methods and Results—

Patients were included if they were revascularized by CABG or PCI-S, had ≥5 years of follow-up, and had ≥2-vessel disease. Patients were followed for an average of 7.0±3.2 years for incidence of death and major adverse cardiovascular events (death, myocardial infarction, or repeat revascularization). Multivariate regression models were used to correct for standard cardiac risk factors including age, sex, hyperlipidemia, diabetes mellitus, family history of coronary artery disease, smoking, hypertension, heart failure, and renal failure. Subgroup analyses were also performed, stratified by age, sex, diabetes, ejection fraction, and history of PCI-S, CABG, or myocardial infarction. A total of 6369 patients (CABG 4581; PCI-S 1788) were included. Age averaged 66±10.9 years, 76% were male, and 26% were diabetic. Multivariate risk favored CABG over PCI-S for both death (hazard ratio 0.85;
P
=0.001) and major adverse cardiovascular events (hazard ratio 0.51;
P
<0.0001). A similar advantage with CABG was also found in most substrata, including diabetes.

Conclusions—

In this large observational study of patients undergoing revascularization for multivessel coronary artery disease, a long-term benefit was found, in relationship to both death and major adverse cardiovascular events, for CABG over PCI-S regardless of diabetic status or other stratifications.
Composite Aortic Valve Graft Replacement
Authors: Kalkat Maninder S. , Edwards Maria-Benedicta , Taylor Keith M. , Bonser Robert S.
Published: September 2007

Background—

Composite aortic valve and root replacement (CVG) is a complex surgical procedure, but excellent center-specific outcomes are reported. We sought to report outcomes in a national cohort.

Methods and Results—

The United Kingdom Heart Valve Registry was interrogated for 1962 first-time CVG (and 37 102 aortic valve replacements [AVR] as a reference group) procedures from 1986 to 2004. We analyzed 30-day mortality, long-term survival (97.2% complete follow-up), and examined available risk factors for mortality using univariate and multivariate logistic regression analysis and causes of death. CVG patients were younger, received larger valve sizes and were more likely to be emergent than AVR patients. Overall 30-day mortality was 10.7% (CVG) and 3.6% (AVR). For CVG, multivariate analysis identified advanced age (>70 years), concomitant coronary artery surgery, impaired left ventricular function, urgent or emergency status, prosthetic valve size ≤23 mm and hospital activity volume ≤8 procedures per annum as significant factors for 30-day mortality. Kaplan-Meier, 1-year, 5-year, 10-year and 20-year survival were 85.2%, 77.1%, 70% and 59.3%, respectively. The conditional (post–30-day) survival was similar to the AVR cohort.

Conclusions—

These Registry data provide a unique national insight into CVG outcomes. After a higher initial mortality risk, CVG has equivalent conditional longer-term survival to AVR.
Prenatally Fabricated Autologous Human Living Heart Valves Based on Amniotic Fluid–Derived Progenitor Cells as Single Cell Source
Authors: Schmidt Dörthe , Achermann Josef , Odermatt Bernhard , Breymann Christian , Mol Anita , Genoni Michele , Zund Gregor , Hoerstrup Simon P.
Published: September 2007

Background—

A novel concept providing prenatally tissue engineered human autologous heart valves based on routinely obtained fetal amniotic fluid progenitors as single cell source is introduced.

Methods and Results—

Fetal human amniotic progenitors were isolated from routinely sampled amniotic fluid and sorted using CD133 magnetic beads. After expansion and differentiation, cell phenotypes of CD133− and CD133+ cells were analyzed by immunohistochemistry and flowcytometry. After characterization, CD133− derived cells were seeded onto heart valve leaflet scaffolds (n=18) fabricated from rapidly biodegradable polymers, conditioned in a pulse duplicator system, and subsequently coated with CD133+ derived cells. After in vitro maturation, opening and closing behavior of leaflets was investigated. Neo-tissues were analyzed by histology, immunohistochemistry, and scanning electron microscopy (SEM). Extracellular matrix (ECM) elements and cell numbers were quantified biochemically. Mechanical properties were assessed by tensile testing. CD133− derived cells demonstrated characteristics of mesenchymal progenitors expressing CD44 and CD105. Differentiated CD133+ cells showed features of functional endothelial cells by eNOS and CD141 expression. Engineered heart valve leaflets demonstrated endothelialized tissue formation with production of ECM elements (GAG 80%, HYP 5%, cell number 100% of native values). SEM showed intact endothelial surfaces. Opening and closing behavior was sufficient under half of systemic conditions.

Conclusions—

The use of amniotic fluid as single cell source is a promising low-risk approach enabling the prenatal fabrication of heart valves ready to use at birth. These living replacements with the potential of growth, remodeling, and regeneration may realize the early repair of congenital malformations.
Patterns of Weight Change Preceding Hospitalization for Heart Failure
Authors: Chaudhry Sarwat I. , Wang Yongfei , Concato John , Gill Thomas M. , Krumholz Harlan M.
Published: September 2007

Background—

Weight gain is used by disease-management programs as a marker of heart failure decompensation, but little information is available to quantify the relationship between weight change in patients with heart failure and the risk for imminent hospitalization.

Methods and Results—

We conducted a nested case-control study among patients with heart failure referred to a home monitoring system by managed care organizations. We matched 134 case patients with heart failure hospitalization to 134 control patients without heart failure hospitalization on the basis of age, sex, duration of home monitoring, heart failure severity, and baseline body weight. Compared with control patients, case patients experienced gradual weight gain beginning ≈30 days before hospitalization; changes in daily weight between case and control patients were statistically significant (
P
<0.001). Within the week before hospitalization, when weight patterns in case and control patients began to diverge more substantially, mean increases of more than 2 and up to 5 pounds, more than 5 and up to 10 pounds, and more than 10 pounds (relative to time of enrollment in the monitoring system) were associated with matched adjusted odds ratios for heart failure hospitalization of 2.77 (95% confidence interval 1.13 to 6.80), 4.46 (95% confidence interval 1.45 to 13.75), and 7.65 (95% confidence interval 2.22 to 26.39), respectively, compared with mean increases of 2 pounds or less.

Conclusions—

Increases in body weight are associated with hospitalization for heart failure and begin at least 1 week before admission. Daily information about patients’ body weight identifies a high-risk period during which interventions to avert decompensated heart failure that necessitates hospitalization may be beneficial.
Effects of Random Allocation to Vitamin E Supplementation on the Occurrence of Venous Thromboembolism
Authors: Glynn Robert J. , Ridker Paul M , Goldhaber Samuel Z. , Zee Robert Y.L. , Buring Julie E.
Published: September 2007

Background—

Supplementation with vitamin E may antagonize vitamin K in healthy adults, but it is unclear whether intake of vitamin E decreases the risk of venous thromboembolism (VTE).

Methods and Results—

The Women’s Health Study randomized 39 876 women ≥45 years of age to receive 600 IU of natural source vitamin E or placebo on alternate days. Before randomization, 26 779 participants gave blood samples, which were used to determine factor V Leiden, G20210A prothrombin, and 677C>T MTHFR polymorphisms. Documented VTE (including deep vein thrombosis or pulmonary embolism) and unprovoked VTE (no recent surgery, trauma, or cancer diagnosis) were prospectively evaluated, secondary end points of the trial. During a median follow-up period of 10.2 years, VTE occurred in 482 women: 213 in the vitamin E group and 269 in the placebo group, a significant 21% hazard reduction (relative hazard, 0.79; 95% CI, 0.66 to 0.94;
P
=0.010). For unprovoked VTE, the hazard reduction was 27% (relative hazard, 0.73; 95% CI, 0.57 to 0.94;
P
=0.016). In subgroup analyses, the 3% of participants who reported VTE before randomization had a 44% hazard reduction (relative hazard, 0.56; 95% CI, 0.31 to 1.00;
P
=0.048), whereas women without prior VTE had an 18% hazard reduction (relative hazard 0.82; 95% CI, 0.68 to 0.99;
P
=0.040). Women with either factor V Leiden or the prothrombin mutation had a 49% hazard reduction associated with vitamin E treatment (relative hazard, 0.51; 95% CI, 0.30 to 0.87;
P
=0.014).

Conclusions—

These data suggest that supplementation with vitamin E may reduce the risk of VTE in women, and those with a prior history or genetic predisposition may particularly benefit.
Quantitative Assessment of the Effect of Angiotensinogen Gene Polymorphisms on the Risk of Coronary Heart Disease
Authors: Xu Ming-Qing , Ye Zheng , Hu Frank B. , He Lin
Published: September 2007

Background—

Angiotensinogen, a key protein in the renin-angiotensin system, plays an important role in cardiovascular hemostasis. Many studies have examined the association between polymorphisms in the angiotensinogen gene and risk of coronary heart disease (CHD), but the results have been inconsistent.

Methods and Results—

We performed a meta-analysis of 43 associations studies on 2 angiotensinogen polymorphisms (M235T and T174M) and risk of CHD published before March 2007, including a total of 13 478 CHD cases and 17 024 controls. We also explored potential sources of heterogeneity. In a combined analysis, the summary per-allele odds ratio for CHD of the M235T polymorphism was 1.11 (95% confidence interval, 1.03 to 1.19). However, when the analyses were restricted to 4 larger studies (n >500 cases), the summary per-allele odds ratio was 0.99 (95% confidence interval, 0.94 to 1.04). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 174M variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 1.07 (95% confidence interval, 0.93 to 1.22).

Conclusions—

This meta-analysis suggested an overall weak association between the M235T polymorphism and CHD risk. However, the association was not observed in several larger studies, suggesting a publication bias. Additional very large-scale studies are warranted to provide conclusive evidence on the effects of the angiotensinogen gene and other genes within the renin-angiotensin system on risk of CHD.