bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the Nuchal Index Increased in Fetuses with Congenital Structural Heart Defects?
Authors: Dahlgren Leanne S. , Duncan Walter J. , Farquarhson Duncan F. , Sandor George S. , Skoll M. Amanda , Tessier Francine , Lim Kenneth I.
Published: December 2005

Objectives: To determine if the Nuchal index (NIx) is increased in euploid fetuses with structural congenital heart defects (CHD). Methods: Euploid fetuses with CHD between 18 and 24 weeks gestation were identified. The next fetus meeting the same criteria with a normal fetal echocardiogram were selected as a control. The NIx [(mean nuchal thickness /mean biparietal diameter) × 100] and cardiac axis (CA; degrees) were calculated for each fetus. Standard descriptive tests and two-tailed t test were used. Results: The NIx in the abnormal (n = 20) and control (n = 20) groups were 9.10 (2.35) and 7.54 (p = 0.04) and CA was 55.8° and 48.6° (p = 0.02), respectively. Conclusions: The NIx and CA were significantly different in fetuses with CHD. A prospective study to confirm these findings and determine clinical utility is warranted.
Three-Dimensional Cephalometric Evaluation of Maxillary Growth following in utero Repair of Cleft Lip and Alveolar-Like Defects in the Mid-Gestational Sheep Model
Authors: Papadopoulos Moschos A. , Papadopulos Nikolaos A. , Jannowitz Christina , Boettcher Peter , Henke Julia , Stolla Rudolf , Zeilhofer Hans-Florian , Kovacs Laszlo , Biemer Edgar
Published: December 2005

Objective: To evaluate maxillary growth following in utero repair of surgically created cleft lip and alveolar (CLA)-like defects by means of three-dimensional (3D) computer tomographic (CT) cephalometric analysis in the mid-gestational sheep model. Methods: In 12 sheep fetuses a unilateral CLA-like defect was created in utero (untreated control group: 4 fetuses). Four different bone grafts were used for the alveolar defect closure. After euthanasia, CT scans of the skulls of the fetuses, 3D reconstructions, and a 3D-CT cephalometric analysis were performed. Results: The comparisons between the operated and nonoperated skull sides as well as of the maxillary asymmetry among the experimental groups revealed no statistically significant differences of the 12 variables used. Conclusions: None of the surgical approaches used for the in utero correction of CLA-like defects seem to affect significantly postsurgical maxillary growth; however, when bone graft healing takes place, a tendency for almost normal maxillary growth can be observed.
Prenatal Exclusion/Confirmation of Fanconi Anemia via Flow Cytometry: A Pilot Study
Authors: Bechtold Astrid , Friedl Richard , Kalb Reinhard , Gottwald Benni , Neveling Kornelia , Gavvovidis Ioannis , Herterich Sabine , Schindler Detlev , Hoehn Holger
Published: December 2005

Objective: To explore the potential of flow cytometry in the prenatal exclusion or confirmation of Fanconi anemia (FA). Methods: Indications for prenatal diagnosis were (1) FA-negative family history, but suspicious ultrasound findings such as radial ray aplasia, (2) FA-positive family history, but without knowledge of the affected gene and/or mutation. Amniotic fluid (AF) cell cultures and umbilical cord (UC) blood cultures were assayed for typical cell cycle changes (G2-phase accumulations) without and with mitomycin C (MMC) treatments using single- and dual-parameter (BrdU-Hoechst) flow cytometry. Results: Single-parameter flow cytometry correctly identified 2 positive and 9 negative cases on the basis of MMC sensitivity of cultivated AF cells. Likewise, 8 negative and 2 positive cases were correctly predicted using bivariate flow cytometry of 72-hour UC blood cultures. In contrast, bivariate flow cytometry applied to AF cells grown in the presence of bromodeoxyuridine (BrdU) yielded false-positive and false-negative results.Conclusions: Single-parameter flow cytometry of AF cell cultures and bivariate flow cytometry of UC cell cultures have the potential to correctly predict the affected status in cases at risk for FA, whereas bivariate flow cytometry proved unreliable when applied to BrdU-substituted AF cell cultures. Cases with a low a priori risk (e.g. sonographic finding of radial ray abnormalities and negative family history) would benefit most from flow cytometry as a rapid and economical prenatal screening procedure.
Prenatal Diagnosis of Trisomy 21 with Fetal Cells in Maternal Blood Using Comparative Genomic Hybridization
Authors: Yang Young Ho , Yang Eun Suk , Kwon Ja Young , Kim In Kyu , Park Yong Won
Published: December 2005

Objective: This study was undertaken to determine the clinical use of comparative genomic hybridization (CGH) for detection of fetal trisomy 21 from fetal ceIls (nucleated red blood cells; nRBCs) isolated from maternal peripheral venous blood. Methods: Maternal peripheral venous blood samples were collected in sterile tubes containing heparin. After triple density gradient centrifugation, magnetic activated cell sorting using CD45 and CD71 was used to isolate the fetal nRBCs. Fetal nRBCs were successfully isolated from maternal peripheral blood in all cases. After laser-microdissecting fetal nRBCs, degenerate oligonucleotide-primed polymerase chain reaction, and nick translation, DNA size was suitable for hybridization. Results: By CGH analysis, we diagnosed one normal male, one normal female, and one trisomy 21 male fetus. These results were confirmed by amniocentesis. Conclusions: Prenatal diagnosis from fetal cells in maternal peripheral blood by CGH shows clinical promise as an alternative or as a supplement to fluorescence in situ hybridization with chromosome-specific probes but further studies are warranted.
Higher Median Levels of Free β-hCG and PAPP-A in the First Trimester of Pregnancy in a Chinese Ethnic Group
Authors: Leung Tak Yeung , Spencer Kevin , Leung Tse Ngong , Fung Tak Yuen , Lau Tze Kin
Published: December 2005

Objective: To study the effect of ethnic Chinese on the medians of free β-hCG and PAPP-A in the first trimester of pregnancy. Methods: The data of 943 women undergoing first trimester combined screening for fetal Down syndrome were analysed to derive the Chinese-specific medians. The calculated risk of Down syndrome based on these Chinese-specific medians was compared with that based on the original algorithm of the Fetal Medicine Foundation (FMF). Results: The maternal serum levels of multiples of median of free β-hCG and PAPP-A were significantly higher among the Chinese than among the Caucasians. The weight-adjusted gestation-specific medians were developed. Without adjustment for ethnicity, the original FMF algorithm underestimated the risk of Down syndrome by a median of 1%. Adjustment by ethnicity increased the false-positive rate by 10% (from 5.3 to 5.9%). Conclusion: Ethnic Chinese have a significantly higher maternal serum level of free β-hCG and PAPP-A in the first trimester, which could not be explained by differences in maternal weight. Adjustment for ethnicity may be necessary for these biochemical markers in a first trimester screening program.
Gender-Related Differences in Fetal Heart Rate during First Trimester
Authors: McKenna D.S. , Ventolini G. , Neiger R. , Downing C.
Published: December 2005

Objective: Many expecting parents wish to ascertain fetal gender early in pregnancy. Our goal was to determine whether fetal heart rate (FHR) of males and females during the first trimester is significantly different. Materials and Methods: From November 1997 to February 2003 we enrolled pregnant women with singleton gestations who underwent obstetric sonography at less than 14 weeks of gestational age. Indications for the sonographic study included first-trimester bleeding, uncertain gestational dating, poor obstetrical history, and aneuploidy screening by nuchal translucency. The sonographic studies were performed by a single sonographer and reviewed by the first author. The FHR was determined by m-mode. All subjects underwent second-trimester sonography at 18.0–24.0 weeks’ gestation by the same team, and fetal gender was recorded. Multiple gestations, miscarriages and pregnancies with uncertain fetal gender were excluded. Sonographically assigned fetal gender was confirmed at delivery. Results: Of the 966 first-trimester studies performed, 477 met the inclusion criteria. Of these, 244 (51%) were female and 233 (49%) were males. There were no statistical differences in mean maternal age, gravidity, parity, and mean gestational age at the time of the first study (9.0 ± 2.3 weeks for female fetuses and 9.0 ± 2.3 weeks for males, p = 0.7). The average female FHR was 151.7 ± 22.7 bpm and male FHR was154.9 ± 22.8 bpm (p = 0.13). Discussion: Contrary to beliefs commonly held by many pregnant women and their families, there are no significant differences between male and female FHR during the first trimester.
Elevated Interferon-Alpha in Fetal Blood in the Prenatal Diagnosis of Aicardi-Goutières Syndrome
Authors: Desanges Carole , Lebon Pierre , Bauman Clarisse , Vuillard Edith , Garel Catherine , Cordesse Alain , Oury Jean François , Crow Yanick , Luton Dominique
Published: December 2005

A case of Aicardi-Goutières syndrome is described in a family with index cases. The diagnosis was made prenatally based on high fetal blood concentration of interferon alpha. The biological measurement could be of interest for further diagnosis of other cases.
Examination of Maternal Plasma Erythropoietin and Activin A Concentrations with Regard to Circulatory Erythroblast Levels in Normal and Preeclamptic Pregnancies
Authors: Troeger Carolyn , Holzgreve Wolfgang , Ladewig Ariane , Zhong Xiao Yan , Hahn Sinuhe
Published: December 2005

Objectives: Preeclampsia has been shown to be associated with an increased number of fetal and maternal erythroblasts in the maternal circulation, suggesting that preeclampsia involves increased leakage of fetal cells across the placental barrier, as well as increased erythropoiesis. We examined the relationship between circulatory erythroblast levels with maternal plasma concentrations of erythropoietin and activin A. Methods: In a case-control study, we examined 15 pregnancies affected by preeclampsia and 10 matched controls. Erythroblasts were enriched from maternal blood samples by magnetic cell sorting, enumerated and correlated with corresponding plasma activin A and erythropoietin concentrations. Results: The proportion of erythroblast was elevated in preeclampsia (0.8 vs. 0.1%, p = 0.023). Erythropoietin and activin A concentrations were significantly elevated in preeclampsia (100.4 vs. 44.5 pg/ml, p = 0.023, and 7.4 vs. 1.85 ng/ml, p = 0.029, respectively). Circulatory erythroblast numbers were found to correlate with plasma activin A concentrations (r = 0.76, p = 0.01) in cases with preeclampsia. No such relationship existed for erythropoietin. Conclusions: Our data suggest that increased concentrations of activin A promote enhanced levels of erythropoiesis in preeclampsia. As the placenta is one of the major sources of activin A in pregnancy, this increase in activin A-dependent erythropoiesis in preeclampsia may be a reflection of an underlying placental hypoxic condition.
Common Pitfalls in the Conduct of Clinical Research
Authors: Zlowodzki Michael , Jönsson Anders , Bhandari Mohit
Published: December 2005

Recently, paradigm shift from expert opinion towards evidence-based medicine has occurred encouraging physicians to base their treatment decisions on the best available research evidence. In the hierarchy of evidence randomized clinical trials (level 1 evidence) are considered of the highest quality (least biased) while non-randomized studies represent lower levels (levels 2–4). Several pitfalls in the design and conduct of clinical research include: lack of randomization, lack of concealment, lack of blinding, and errors in hypothesis testing (type I and II errors). A basic understanding of these principles of research will empower both investigators and readers when applying the results of research to clinical practice.
Pyo-Pneumothorax in Patients with Active Pulmonary Tuberculosis: An Analysis of 17 Cases without Intrapleural Fibrinolytic Treatment
Authors: Kartaloglu Z. , Okutan O. , Işitmangil T. , Kunter E. , Sebit S. , Apaydin M. , Ilvan A.
Published: December 2005

Objective: To review the medical records of patients with active pulmonary tuberculosis (TB) and pyo-pneumothorax (PPT). Subjects and Methods: Medical records of 17 patients (14 male, 3 female, mean age 23.8 years, range 20–52) with PPT and active pulmonary tuberculosis at Gulhane Military Medical Academia Haydarpasa Training Hospital, Istanbul, Turkey, were reviewed from January 1998 to December 2002. The patients were treated with chest tube drainage and chemotherapy. Intrapleural fibrinolytic agents or irrigation was not performed. Results: Pleural fluid samples were available in 14 patients and the mean levels of LDH, protein and glucose in the pleural fluid were 1,767 ± 944 U/l, 5.2 ± 1.4 g/dl and 31.7 ± 22.6 mg/dl, respectively. Mycobacterium tuberculosis was detected in the pleural effusion of 3 patients. The duration of chest tube drainage was longer in cases who underwent open drainage (p = 0.014). At the end of the treatment period 10 patients developed pleural thickening, 4 of them underwent decortication and pneumonectomy was also done in 1 patient. The development of pleural thickening was related to the level of pleural fluid glucose (p = 0.04). Conclusion: This study shows that while taking care of patients with pulmonary TB the physician must be aware of the complication of PPT and that adequate chemotherapy and drainage must be duly performed.
Antibacterial Resistance and Molecular Typing of Methicillin-Resistant Staphylococcus aureus in a Kuwaiti General Hospital
Authors: Udo E.E. , Al-Sweih N. , Mohanakrishnan S. , West P.W.J.
Published: December 2005

Objective: To investigate antibiotic resistance and genetic relatedness of methicillin-resistant Staphylococcus aureus (MRSA) isolated in a general hospital in Kuwait over a period from 1996 to 1998 and 2001. Material and Methods: The isolates were characterized by antibacterial susceptibility testing, coagulase serotyping, coagulase gene polymorphism (coag-RFLP) and pulsed-field gel electrophoresis (PFGE). Results: The MRSA isolates were highly resistant to gentamicin, kanamycin, ciprofloxacin, tetracycline, fusidic acid and mupirocin. The prevalence of gentamicin, kanamycin, streptomycin, tetracycline and erythromycin resistance remained high (80–96%) throughout the study period, but the prevalence of resistance to ciprofloxacin, fusidic acid and mupirocin steadily increased. The already high mupirocin resistance level increased from 12.5 in 1996, to 85.7% in 2001, and the fusidic acid resistance varied between 70.8 and 85.7%. In contrast, chloramphenicol and trimethoprim resistance declined from 25 and 29% in 1996 to 4.7 and 14.2% in 2001, respectively. The majority (91.5%) of the isolates were coagulase serotype 4. AluI restriction endonuclease analysis of amplified coagulase gene generated four coag-RFLP patterns: 92% of them were coag-RFLP type 1, while types 2, 3 and 4 were 3.5, 4.6 and 1.1% respectively. PFGE differentiated them into seven pulsotypes (PFGE types 1–7). The PFGE type 1 pulsotype constituted 90.2% of the isolates. Isolates with the type A coag-RFLP also had the type1 PFGE pulsotypes. Conclusion: The concordant results of PFGE and coag-RFLP demonstrated the presence of a persistent MRSA clone in the hospital during the study period.
Acute Septic Arthritis due to Streptococcus sanguis
Authors: Papaioannides Demetrios , Boniatsi Loukia , Korantzopoulos Panagiotis , Sinapidis Demetrios , Giotis Christos
Published: December 2005

Objective: To present a case of acute septic arthritis due to Streptococcussanguis, a member of the viridans group streptococci. Clinical Presentation and Intervention: A 73-year-old woman presented with fever and increasing swelling and pain of the right knee several weeks after she had been treated for severe periodontal disease. Arthrocentesis yielded purulent synovial fluid. S. sanguis was isolated in synovial fluid cultures, and the patient was treated with intravenous cefotaxime for 3 weeks and repeated aspiration of the knee joint with gradual resolution of fever, joint swelling and effusion. Conclusion: Although S. sanguis is believed to be a rare cause of septic arthritis in native joints, it should be considered in the differential diagnosis of this disorder, especially in patients with recent treatment of severe dental caries and periodontal disease.
A Successful Case of Sural Nerve Cable Grafting after a Gunshot Wound to the Knees
Authors: Khanna Achal , Mahajani Ravi , Proudman Timothy
Published: December 2005

Objective: To describe a successful case of sural nerve cable grafting to the leg following a gunshot injury. Clinical Presentation and Intervention: A 28-year-old man was shot at close range, sustaining extensive damage to the left popliteal fossa. Initial exploratory operation revealed a pierced sciatic nerve proximal to its bifurcation into the tibial and common peroneal branches. The 60% division 3.5-cm common peroneal deficit and the complete transection of the tibial division were repaired using an ipsilateral sural cable nerve graft that was not reversed. Initial re-assessment in the clinic setting revealed a denervation atrophy of all 3 leg compartments and paraesthesia below the left knee sparing the sural nerve. After 3 months, the patient had a significant improvement in both power and sensation which was felt to be due to a resolution of a neuropraxic component to the nerve injury. Re-assessment at 9 months and later at 14 months revealed an almost full recovery, suggestive of the success of the nerve grafting procedure. Conclusion: This report shows that, given favourable conditions, a good result is possible following use of cable nerve grafting to treat nerve damage from gunshot.
Can Statins Be Considered as a Tertiary Level Agent in Patients with Failure of Conventional Oral Hypoglycemic Agents?
Authors: Prabhakar Vijay , Krishna Kishore P.V. , Balaji Madhuri , Balaji V. , Seshaiah V.
Published: December 2005

Background: The effect of statins in diabetic dyslipidemia has been proven in terms of lipid lowering and mortality benefit in diabetic patients. Although experimental evidence supports the beneficial effect of statins in insulin resistance, their role in clinical practice has not been studied. In this study, the effect of rosuvastatin on fasting blood glucose (FBG) and its correlation with lipid lowering was analyzed ad hoc. Objective: This open-label, prospective rosuvastatin safety and efficacy (ROSE) study was conducted to assess the safety and efficacy of rosuvastatin in the treatment of diabetic dyslipidemia. Method: Male and female diabetic patients aged 18–75 years, with low-density lipoprotein cholesterol (LDL-C) levels greater than or equal to 2.5 mmol/l were enrolled. Rosuvastatin 10 mg once daily was administered for 8 weeks. The primary endpoint was a change in LDL-C from baseline. Secondary endpoints included a change from baseline in total cholesterol, high-density lipoprotein cholesterol and triglycerides. Liver enzymes, creatine kinase, creatinine and FBG were the safety laboratory parameters assessed. The correlation between reduction in FBG and lipid parameters was calculated using Pearson’s correlation coefficient. Results: Forty-one patients were screened and 34 were enrolled. Four were lost to follow-up and not included in efficacy analysis. Thirty patients completed 8 weeks of treatment and were analyzed for efficacy. Their mean LDL-C was significantly reduced from 4.1 mmol/l at baseline to 2.1 mmol/l (p < 0.0001) after 8 weeks of treatment. Total cholesterol, high-density lipoprotein cholesterol and triglycerides also showed a significant decrease from baseline. The mean FBG was reduced from 11.1 to 5.1 mmol/l (p < 0.0001) after 8 weeks. The decrease in lipid parameters correlated with the decrease in FBG (r = 0.083; p < 0.001). Clinically, no patient complained of any adverse event during the study period. Conclusion: Rosuvastatin significantly lowered FBG in addition to its cholesterol-lowering effect. This action could be attributed to an independent action by rosuvastatin or else be brought about indirectly by lowering lipids. Statins can be considered as a tertiary level agent when conventional oral hypoglycemic agents have failed. However, large-scale trials are necessary before application in clinical practice.
Comparison of Ticlopidine and Aspirin versus Clopidogrel and Aspirin after Percutaneous Coronary Interventions in High-Risk Patients
Authors: Di Pasquale Pietro , Cannizzaro Sergio , Scalzo Sebastiano , Giambanco Francesco , Tricoli Giuseppe , Fasullo Sergio , Paterna Salvatore
Published: December 2005

Background: Studies have shown that ticlopidine and clopidogrel in association with aspirin reduce the short- and long-term incidence of major adverse coronary events in patients undergoing stent implantation. Furthermore, clopidogrel seems to show a better side-effect profile than ticlopidine, and recent evidence supports its efficacy in long-term prevention in high-risk patients. Methods: From May 2002 to December 2003, 428 consecutive patients with 1st coronary event underwent a percutaneous coronary intervention (PCI) for non-ST elevation myocardial infarction. All patients received a glycoprotein IIb/IIIa inhibitor and were randomized in double-blind fashion to ticlopidine (500 mg/day) + aspirin or clopidogrel (75 mg/day) + aspirin before PCI. After 48– 72 h, PCI with stent implantation was performed and the treatment was continued for 6 months. Two groups were obtained. The clopidogrel group contained 214 patients (146 M/68 F), mean age 61.3 ± 11.8 years, and the ticlopidine group contained 214 patients (150 M/64 F), mean age 60.7 ± 10.5 years. A protocol that included clinical follow-up at 1, 3 and 6 months was used. Results: Both groups were comparable in baseline characteristics. We observed 14 cases of non-cardiac side effects in the clopidogrel group in the first 30 days after discharge. The ticlopidine group showed 20 non-cardiac side effects (not significant). None of the patients died during the follow-up. Both groups were similar in number of diseased vessels and number of stents. During follow-up (180 days), 48 patients from the clopidogrel group and 44 from the ticlopidine group showed reocclusion in vessels treated with percutaneous transluminal coronary angioplasty (p value not significant). In addition, we observed that reocclusion was mostly evidenced in the first 90 days (44 from the clopidogrel and 40 from the ticlopidine group). In the remaining time (90 days), we observed only 4 cases of reocclusion from the clopidogrel and 4 cases from the ticlopidine group. Conclusion: Our data suggest that ticlopidine or clopidogrel associated with aspirin determine similar effects.
Scientific Basis of Cardio-Pulmonary Resuscitation, an Evidence-Based Review
Authors: von Planta Martin
Published: December 2005

Cardiac arrest claims many lives too early. Cardiopulmonary resuscitation (CPR) is the treatment of choice in this dire situation where seconds count. Thus, a solid knowledge based on scientific data helps to guide the correct therapeutic armamentarium. Diagnostic workup, physical, electrical or pharmacological interventions are described and – where possible – classified according to published evidence. Special circumstances and ethical considerations are outlined and potentially harmful measures are summarized. Robust science should improve CPR for the majority of the patients.
Inhibition of the Renin-Angiotensin System and Atrial Fibrillation in Heart Failure
Authors: Palardy Maryse , Ducharme Anique
Published: December 2005

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered clinically in patients with congestive heart failure (CHF) and has been associated with increased morbidity and possibly mortality. Small retrospective studies have shown a preventive effect on AF development with the use of agents interfering with the renin-angiotensin system (RAS). Method and Results:We carried out a systematic search of the literature in the English language in order to elucidate the potential mechanism underlying this added beneficial effect of RAS inhibitors in CHF. The concepts of ionic, electrical and structural remodelling of the atrium induced by AF are discussed. Conclusion: Inhibition of RAS could prevent AF development in patients with CHF.
Nicorandil – Review of Pharmacological Properties and Clinical Applications
Authors: Schmid Jean-Paul , Schroeder Verena
Published: December 2005

Nicorandil is a drug which has been developed as an anti-anginal medication. Its structure is characterized by a dual mechanism of action. The nicotinamide moiety acts as an opener of ATP-sensitive potassium channels, whereas the NO2 group explains its nitrate-like properties. The nitric oxide-like action leads to a dilatation of the large coronary arteries, whereas its potassium channel opening action is responsible for the dilatation of coronary resistance vessels. Nicorandil has also been found to dilate veins, enabling it to decrease both preload and afterload and to increase coronary blood flow. The ATP-sensitive potassium channel opening mimics preconditioning in the absence of ischemia and may therefore exert cytoprotective effects. These have been thought to be the reason for a reduction in major coronary events and all cardiovascular events of nicorandil in addition to a specific anti-anginal medication in the Impact Of Nicorandil in Angina study. This review summarizes the pharmacologic properties of nicorandil and assesses its actual place in different cardiovascular disease states.
Identification of Differentially Expressed Genes between Fetal and Adult Mouse Kidney: Candidate Gene in Kidney Development
Authors: Guinobert Isabelle , Viltard Mélanie , Piquemal David , Elalouf Jean-Marc , Marti Jacques , Lelièvre-Pégorier Martine
Published: December 2005

Background: The kidney development involves a wide variety of developmental processes requiring a lot of genes expressed in a sequential manner. The aim of the present study is to identify new genes involved in these processes. Methods: To obtain a view of the mouse embryonic kidney transcriptome we used the SADE method, which allows large-scale quantitative gene expression measurements. Results: 7,689 tags were sequenced from our library. Among the 4,507 unique transcripts yielded, 64% correspond to known genes, 22% ESTs, 12% unidentified genes. 472 genes were differentially expressed as compared to published adult kidney library. Among these, we identified several candidate genes and focused on a particular one: thymosin β4 (Tβ4), an actin-sequestering protein more highly expressed in fetal kidney. First we studied the in vivo expression patterns of Tβ4 transcript during kidney development. Tβ4 increases throughout the kidney development and remains high during active nephrogenesis. Moreover, the spatial distribution of Tβ4 mRNA was analysed and reveals that during active nephrogenesis (i.e., 18 dpc) Tβ4 is localised in differentiating glomeruli. In adult kidney, Tβ4 remains expressed in podocytes and collecting ducts. Conclusion: Our results provide the first demonstration of Tβ4 production in vivo by embryonic kidney and further show that Tβ4 is implicated in kidney organogenesis.
Hepatocyte Growth Factor Gene Therapy Slows Down the Progression of Diabetic Nephropathy in db/db Mice
Authors: Kagawa Tomoyo , Takemura Genzou , Kosai Ken-ichiro , Murata Ichijiro , Ohno Takamasa , Takahashi Tomoyuki , Esaki Masayasu , Maruyama Rumi , Fujiwara Takako , Ohashi Hiroshige , Fujiwara Hisayoshi
Published: December 2005

Background: Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy. Methods: Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks. Results: The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 ± 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 ± 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-β1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice. Conclusions: The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.
Polymorphism in the Cholesterol 24S-Hydroxylase Gene (CYP46A1) Associated with the APOEυ3 Allele Increases the Risk of Alzheimer’s Disease and of Mild Cognitive Impairment Progressing to Alzheimer’s Disease
Authors: Fernández del Pozo Valentina , Álvarez Álvarez Maite , Fernández Martínez Manuel , Galdós Alcelay Luis , Gómez Busto Fernando , Peña Jose A. , Alfonso-Sánchez Miguel A. , Zarranz Imirizaldu Juan José , de Pancorbo Marian M.
Published: December 2005

Background: Late-onset Alzheimer’s disease (LOAD) is associated with changes in certain proteins, such as ApoE and Cyp46A1, of the elimination route for cerebral cholesterol. The main lipoprotein involved in its transport is ApoE whose υ4 allele is the least efficient. However, the presence or absence of this allele does not determine the development of LOAD, which implies the existence of other susceptibility factors associated with the disease, such as the CYP46A1 gene that encodes the enzyme cholesterol 24S-hydroxylase. Objective: To find new data to contribute to the evaluation of whether the presence of the T allele in the polymorphic site rs754203 of the CYP46A1 gene leads to a greater risk of developing mild cognitive impairment (MCI) and LOAD. Furthermore, given the link between APOE and CYP46A1, we proceeded to relate both genotypes in each of the patient groups studied. Methods: We studied MCI and LOAD patients and also carried out an analysis of those MCI patients who progressed from a mild cognitive deterioration to a clinically evident Alzheimer’s disease during the study. Results: The frequency of the CYP46A1-T allele in the LOAD patients with APOEυ3 alleles is significantly higher with respect to the control group; the same occurs in the group made up of LOAD patients together with the MCI patients who progressed to LOAD. The risk of developing LOAD when this allelic combination exists is 2.262 times higher (95% CI 1.337–4.202). However, having the CYP46A1-T allele does not increase the risk of suffering from LOAD in carriers of the APOEυ4 allele, probably because the transport of cholesterol is already affected in such patients and possibly masks the effect of the CYP46A1-T allele. Conclusions: The CYP46A1-T allele increases the risk of suffering from LOAD in persons carrying the APOEυ3 allele.
The Efficacy of Omega–3 Fatty Acids on Cognitive Function in Aging and Dementia: A Systematic Review
Authors: Issa Amalia M. , Mojica Walter A. , Morton Sally C. , Traina Shana , Newberry Sydne J. , Hilton Lara G. , Garland Rena H. , MacLean Catherine H.
Published: December 2005

We systematically reviewed the published literature on the effects of omega–3 fatty acids on measures of cognitive function in normal aging, incidence and treatment of dementia. Computerized databases were searched for published literature to identify potentially relevant studies with the intent to conduct a meta-analysis. We screened 5,865 titles, reviewed 497 studies of which 49 underwent a detailed review, and found 5 studies that pertained to our objectives. We included controlled clinical trials and observational studies, including prospective cohort, case-control, and case series designs; we excluded case reports. We had no language restrictions. We abstracted data on the effects of omega–3 fatty acids and on study design, relevant outcomes, study population, source, type, amount, and duration of omega–3 fatty acid consumption, and parameters of methodological quality. A single cohort study has assessed the effects of omega–3 fatty acids on cognitive function with normal aging and found no association for fish or total omega–3 consumption. In four studies that assessed the effects of omega–3 fatty acids on incidence and treatment of dementia, a trend in favor of omega–3 fatty acids (fish and total omega–3 consumption) toward reducing risk of dementia and improving cognitive function was reported. The available data are insufficient to draw strong conclusions about the effects of omega–3 fatty acids on cognitive function in normal aging or on the incidence or treatment of dementia. However, limited evidence suggests a possible association between omega–3 fatty acids and reduced risk of dementia.
Trypanocidal Activity of Methylene Blue
Authors: Boda Caroline , Enanga Bertin , Courtioux Bertrand , Breton J.-Christian , Bouteille Bernard
Published: December 2005

Human African trypanosomiasis remains a difficult health problem to treat because of the few compounds available nowadays and their toxicity. The disease also affects animals and is therefore responsible for economic difficulties and zoonotic risks. There is an urgent need to develop new drugs for treatment of African trypanosomiasis. Methylene blue is a safe and easy-to-use drug employed in human therapy. It is also known to have antimalarial activity. In this study, methylene blue trypanocidal activity was found in vitro but it failed to cure trypanosome infection in mice when administered at 300 mg/kg p.o.or at 200 mg/kg i.p. Differences between in vitro and in vivo activities are discussed, and further in-depth studies are warranted.
S100A6 and CacyBP/SIP – Two Proteins Discovered in Ehrlich Ascites Tumor Cells That Are Potentially Involved in the Degradation of β-Catenin
Authors: Filipek Anna
Published: December 2005

S100A6 is a low-molecular-weight calcium-binding protein belonging to the S100 family. Originally, S100A6 was purified from Ehrlich ascites tumor cells, but later, it was found in fibroblasts, epithelial cells and in tumor cells with high metastatic activity. When Ca2+-dependent interaction of S100A6 with target proteins was studied in Ehrlich ascites tumor cells, a novel protein, now called CacyBP/SIP, was discovered. Later, it was found that CacyBP/SIP interacted with Siah-1 and Skp1 and that it was involved in the ubiquitination and degradation of an oncogen, namely β-catenin. Thus, this review describes the discovery and characterization of S100A6 and Cacy BP/SIP, the function of these two proteins in ubiquitination and degradation processes and their possible role in tumorigenesis.
Genetic strain differences in platelet aggregation of laboratory mice
Authors: Ito Hideki , Kimura Yukio , Sudo Toshiki
Published: December 2005

To investigate the physiological role of novel genes and proteins in platelet activation, various knockout mice have been produced. A number of standard inbred mouse strains each possessing genetically unique characters such as high tumor generation, hyperglycemia or hyperlipidemia, have been bred. In breeding knockout mice for investigation of specific physiological functions, appropriate selection of parental or backcross strains is necessary. Thus, examination of strain-specific platelet characteristics is important. In the present study, platelet aggregation responses of 13 laboratory mouse strains, 129/Sv, A, AKR, BALB/c, C3H/He, C57BL/6J, CBA, DBA/1, DBA/2, ddY, FVB, ICR, and NZW, and the diabetic strain C57BL/KsJ db/db, were compared. Marked strain differences were observed inADP- and collagen-induced platelet aggregation. The highest responses with both were seen in AKR/J and NZW/N, whereas the lowest were seen in DBA/2 and DBA/1.There was a 5-fold difference in the platelet aggregation threshold index (PATI) for ADP-induced PRP aggregation between AKR/J (0.6 µM) and DBA/2 (3.0 µM). With whole blood aggregation, the highest response was seen in AKR, whereas the lowest was seen in DBA/2 and DBA/1. The present study demonstrated that there is considerable strain difference in platelet aggregation among laboratory mice, which should be taken into account in backcrossing knockout strains.
Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder
Authors: Schroeder Verena , Meili Esther , Cung Trinh , Schmutz Peter , Kohler Hans
Published: December 2005

In 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 del G, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.
Thrombomodulin plays an important role in arterial remodeling and neointima formation in mouse carotid ligation model
Authors: Li Yi-Heng , Liu Shu-Lin , Shi Guey-Yueh , Tseng Guan-Hsiung , Liu Ping-Yen , Wu Hua-Lin
Published: December 2005

Thrombomodulin (TM) is a cell membrane-bound glycoprotein that functions as a thrombin cofactor in the activation of protein C. Its protein structure includes a N-terminal lectin-like domain (D1), 6 epidermal growth factor repeats (D2), a serine-threonine-rich region (D3), a transmembrane domain (D4) and a short cytoplasmic tail (D5). Recent studies have demonstrated the direct effect ofTM on cellular proliferation, adhesion and inflammation. In the study, we investigated the role of TM in vascular remodeling and neointima formation in a mouse carotid ligation model. TM expressions on the endothelium, neointima and media were examined in the ligated carotid artery by immunohistochemistry and quantitative real-time reverse transcription PCR. Endothelial TM expression decreased after ligation and appeared later in the media and neointima, which is quite similar to the appearance of TM in the human atherosclerotic process. Recombinant TMD123 was prepared. It was effective for thrombin-dependent protein C activation and the inhibition of leukocyte adhesion to the vessel wall after carotid ligation. RecombinantTMD123 and saline was administered immediately before and after carotid ligation. The TM-treated arteries demonstrated significantly less arterial dilatation (30279±12605 vs 73789±15073 µm2, p<0.05) in response to less neointima formation (14179±6538 vs 42227±8754 µm2, p<0.05) at 4 weeks after ligation. Our data indicated that there was a compensatory increase inTM expression in the media and neointima in relation to the reduced endothelial TM after carotid ligation. Early recombinant TM treatment in mice undergoing carotid ligation altered vascular remodeling and decreased the severity of neointima formation.
EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes.
Authors: Schmidt Roland , Redecke Vanessa , Breitfeld Yoshi , Wantia Nina , Miethke Thomas , Massberg Steffen , Fischel Sina , Neumann Franz-Josef , Schömig Albert , May Andreas
Published: December 2005

Chlamydia (C.) pneumoniae are thought to infect monocytes and use them as vectors into the vessel wall, where they may accelerate atherosclerosis. We investigated the effects of C. pneumoniae on monocytic matrix metalloproteinase (MMP) activation with focus on the role of the extracellular matrix metalloproteinase inducer EMMPRIN. Human monocytes or monocytic MonoMac6 cells were infected with C. pneumoniae. Infection enhanced mRNA-and surface expression of EMMPRIN and Membrane-type-1 Matrix Metalloproteinase (MT1-MMP), plus the secretion of MMP-7, MMP-9 and the urokinase receptor (uPAR). Chlamydial heat shock protein 60 was identified to be partially responsible for EMMPRIN and MMP-9 induction, while C. trachomatis-infection had no stimulatory effect, indicatinga C. pneumoniae-specific activation pathway. Suppression of EMMPRIN by gene silencing almost completely hindered the induction of MT1-MMP and MMP-9 by C. pneumoniae, suggesting a predominant regulatory role for EMMPRIN. Moreover, C. pneumoniae-infected monocytes exhibited increased MMP-and plasmin-dependent migration through “matrigel”. Additionally, incubation of SMCs with supernatants of C. pneumoniae-infected monocytes induced MMP-2 activation, which was inhibited by IL1-Receptor antagonist or anti-IL-6-mAb, indicating paracrine intercellular activation pathways. In conclusion,C. pneumoniae induce MMP activity directly in monocytes through an EMMPRINdependent pathway and indirectly in SMCs via monocytederived cytokines.
Signaling through PI3Kγ: a common platform for leukocyte, platelet and cardiovascular stress sensing
Authors: Lembo Giuseppe , Montrucchio Giuseppe , Rommel Christian , Costa Carlotta , Barberis Laura , Hirsch Emilio
Published: December 2005

The concerted activation of leukocytes and vessels shapes multiple physiological and pathological responses. A large number of these processes shares a common signal transduction platform involving the activation of plasma membrane bound G protein-coupled receptors (GPCRs). This event is usually amplified by the production of different intra-cellular second messenger molecules. Among these mediators, the phosphorylated lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) produced by phosphoinositide 3-kinase γ (PI3Kγ) has recently emerged as a crucial signal in both vascular and white blood cells. The generation of mice lacking PI3Kγ showed that the GPCR/PI3Kγ/PIP3 signaling pathway controls diverse immune modulatory and vascular functions like respiratory burst, cell recruitment, mast cell reactivity, platelet aggregation, endothelial activation as well as smooth muscle contractility. The relative specificity of these events suggests that blocking PI3Kγ function might turn out beneficial for diseases like inflammation, allergy, thrombosis, and major cardiovascular disorders like hypertension, thus offering a wide range of therapeutic opportunities.
Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator
Authors: Zhang Li , Zhang Zheng , Liu Xianshuang , Hozeska Ann , Stagliano Nancy , Riordan William , Lu Mei , Chopp Michael
Published: December 2005

Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib,a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis,inflammatory responses,and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-κB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-κB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.
Chemotaxis: moving forward and holding on to the past
Authors: Bagorda Anna , Mihaylov Vassil , Parent Carole
Published: December 2005

The ability of cells to sense external chemical cues and respond by directionally migrating towards them is a fundamental process called chemotaxis. This phenomenon is essential for many biological responses in the human body, including the invasion of neutrophils to sites of inflammation. Remarkably, many of the molecular mechanisms involved in controlling neutrophils chemotaxis arose millions of years ago in the simple eukaryotic organism Dictyostelium discoideum. Both neutrophils and Dictyostelium use G protein-coupled signaling cascades to mediate chemotactic responses, which are responsible for transducing external cues into highly organized cytoskeletal rearrangements that ultimately lead to directed migration. By using the genetically and biochemically tractable organism Dictyostelium as a model system, it has been possible to decipher many of the signal transduction events that are involved in chemotaxis.
Plasma von Willebrand factor, thrombosis, and the endothelium: The first 30 years
Authors: Blann Andrew
Published: December 2005

“It is quite useless to argue the questions concerning the development of intimal scleroses if we study and discuss the late stages of the disease alone. If we wish to gain insight into the complex question of arterio-sclerosis we must attempt to follow the lesion from its earliest beginning” (Klotz and Manning, J Path Bact 1911: 16; 211–20).

Over thirty years ago Boneu and colleagues publisheda report of raised levels of plasma vonWillebrand factor (vWf) in patients with arteritis, diabetes and sepsis. They concluded that raised levels of this molecule indicate endothelial damage, and may possibly be a contributory factor in thrombosis in arterial disease. The former aspect of this conclusion is now accepted, and numerous studies on the risk factors for atherosclerosis provide mechanisms for this damage. Other studies have demonstrated raised levels in cancer and in connective tissue disease. Numerous long-term follow-up studies have also demonstrated that increased vWf predicts major cardiovascular end points. However, the link between these studies, and the latter aspect of Boneu’s conclusion, that raised vWf contributes to thrombosis is,although attractive, nevertheless unproven. Despite this, vWf remains the most important plasma marker of endothelial damage/dysfunction and as such attracts clinical attention.