bluuebunny/crossref_metadata_2025 huggingface dataset:
Follicle-Stimulating Hormone Receptor Gene Mutations Are Not Evident in Greek Women with Premature Ovarian Failure and Poor Responders
Authors: Loutradis Dimitris , Patsoula Eleni , Stefanidis Konstantinos , Drakakis Peter , Antonakis Georgios , Bletsa Ritsa , Antsaklis Aris , Michalas Stylianos
Published: October 2005

Background/Aims: This clinical and molecular study aimed to investigate the presence of follicle-stimulating hormone (FSH) receptor gene mutations in women with premature ovarian failure (POF) and poor responders to in vitro fertilization treatment. Methods: DNA was extracted from blood samples for subsequent polymerase chain reaction (PCR). PCR was followed by restriction fragment length polymorphism and direct sequencing. Results: No inactivating mutations reported so far were identified in exons 6, 7, and 10 in women with POF and poor responders. Conclusion: FSH receptor gene mutations are not frequent in Greek patients with POF as is the case in the rest of the world except for cases with ovarian dysgenesis in Finland.
Prevalence of Stroke and Vascular Risk Factors among First-Degree Relatives of Stroke Patients and Control Subjects
Authors: Lindgren Arne , Lövkvist Håkan , Hallström Björn , Höglund Peter , Jönsson Ann-Cathrin , Kristoffersson Ulf , Luthman Holger , Petersen Björn , Norrving Bo
Published: October 2005

Background: Genetic and environmental factors may be of importance for stroke risk. We assessed the prevalence of stroke and vascular risk factors among first-degree relatives and spouses of stroke patients and control subjects. Methods: As a part of the Lund Stroke Register study, we asked 925 consecutive patients with first-ever stroke and 286 control subjects to complete a questionnaire about all their first-degree relatives and spouses. The questionnaires addressed whether these relatives had been affected by stroke or TIA, hypertension, heart disease, diabetes mellitus, and if they were smokers. Results: A total of 606 patients and 261 control subjects returned the questionnaire, providing information on 4,972 first-degree relatives and 738 spouses. The prevalence of stroke or TIA was 12.3% among first-degree relatives of patients and 7.5% among first-degree relatives of control subjects (OR 1.74, 95% CI 1.36–2.22). Corresponding results for hypertension were 21.0 and 16.7% (OR 1.33, 95% CI 1.10–1.60). The prevalences of heart disease, diabetes mellitus and smoking did not differ significantly between first-degree relatives of patients and control subjects. Spouses of patients and control subjects had similar prevalences of stroke or TIA and vascular risk factors. Conclusions: The prevalences of stroke or TIA and hypertension are higher among first-degree relatives of stroke patients than among first-degree relatives of control subjects. This, and the lack of differences between spouses of patients and control subjects, indicates that an increased risk of stroke may in part be explained by heritability of hypertension.
Renal Functional Deterioration Is Not Affected by the Magnitude of Sodium Consumption in a Normotensive Model of Moderate Renal Failure
Authors: Weissgarten Joshua , Berman Sylvia , Efrati Shai , Rapoport Michael , Aladjem Mordechay , Modai David , Golik Ahuva , Cohen Natan , Galperin Elena , Averbukh Zhan
Published: October 2005

Background/Aims: High sodium consumption has been repeatedly reported to exert deleterious effects on severe chronic renal failure progression, mainly via glomerular mechanisms. However, the role of high sodium intake in renal function deterioration in a model of moderate chronic tubulointerstitial disease has not yet been addressed. We evaluated the effects of exaggerated dietary sodium and the resultant increase in proteinuria on renal function deterioration in experimental tubulointerstitial disease in rats. Methods: In 48 Sprague-Dawley rats, moderate renal failure (approximately 50% of normal glomerular filtration rate) was induced by administration of lithium chloride in drinking water. The animals were divided into three groups fed low (<0.2% Na+), normal (0.5% Na+), or high (8% Na+) sodium diets. Results: Animals in all groups remained normotensive with a similar course of GFR downslope and 100% survival, irrespective of sodium regimen. Rats consuming high sodium diets developed significantly greater proteinuria compared to their counterparts fed normal or low sodium chow. Conclusions: (1) Deterioration of renal function in a lithium-induced model of normotensive moderate chronic renal failure was not affected by dietary sodium. (2) Unlike in some other human or experimental renal failure models, the magnitude of proteinuria had no adverse effect on the progression of renal deterioration.
Protein Detection in Dried Blood by Surface-Enhanced Laser Desorption/Ionization-Time of Flight Mass Spectrometry (SELDI-TOF MS)
Authors: Dammann Christiane E.L. , Meyer Markus , Dammann Olaf , von Neuhoff Nils
Published: October 2005

Background: The rapid and reliable identification of biomarkers in the smallest possible amount of blood remains a challenge in biomarker epidemiological research involving preterm newborns. Objective: We wanted to explore whether the proteomics approach of ‘surface-enhanced laser desorption/ionization-time of flight mass spectrometry’ (SELDI-TOF MS) is possible and feasible in whole cord blood previously dried on filter paper. Methods: Umbilical cord blood from 7 healthy newborns was frozen as serum, whole blood (with or without additives), or dried on filter paper (with or without additives). We used the SELDI-TOF MS technique for protein detection on the ProteinChip® arrays: weak cationic exchange array (CM10), hydrophobic array (H50), and strong anion exchange array (Q10). Profiles were compared in terms of peak intensity and number of resolved peaks. Results: Dried neonatal blood, eluted from filter paper, revealed profiles similar to the profiles derived from serum at a protein range of 3–10 kDa. Among additives, heparin led to highest peak intensities for both blood and dried blood. Spectra from heparinized whole blood and heparinized dried blood from the umbilical cord of 8 different healthy newborns on three different types of ProteinChip arrays were very similar. Conclusion: We conclude that it is possible and feasible to use SELDI-TOF MS for recovery and detection of whole proteins from dried blood collected on filter paper. The method is easy to perform in large groups of newborns, minimizing the amount of blood needed for biomarker studies. The validity and reproducibility of this method needs to be studied in detail.
Effect of Disodium Cromoglycate on Airway Mucus Secretion during Antigen-Induced Late Asthmatic Responses in a Murine Model of Asthma
Authors: Koyama Harumi , Tokuyama Kenichi , Nishimura Hideko , Mizuno Takahisa , Mayuzumi Hiroo , Ohki Yasushi , Arakawa Hirokazu , Mochizuki Hiroyuki , Morikawa Akihiro
Published: October 2005

Background: Disodium cromoglycate (DSCG) is known to inhibit both immediate and late asthmatic responses (IAR and LAR). However, its effect on mucus hypersecretion is unknown. Using a murine model of asthma, we aimed to determine whether mucus secretion increased during IAR and LAR. We also studied the potency of DSCG in inhibiting mucus secretion and on airway eosinophilia. Methods: Mice were subjected to initial intraperitoneal sensitizationand airway challenge to ovalbumin (OVA) and then provokedby additional exposure to OVA. Some mice were pretreated with aerosolized DSCG (20 mg/ml) 1 h before the provocation with OVA. After serial measurements of enhanced pause (Penh), an indicator of airflow obstruction, serum samples and bronchoalveolar lavage fluids (BALF) were collected. Then, the lungs were excised and a morphometric analysis for mucus hypersecretion was performed. Results: A biphasic increase in Penh (IAR and LAR) was observed in sensitized animals after provocation with OVA. Airway eosinophilia was observed during both responses. Intraluminal mucus significantly increased during LAR, but not during IAR. DSCG significantly attenuated both IAR and LAR, and significantly inhibited the increase in intraluminal mucus during LAR, but had no effect on eosinophilia in BALF. Conclusion: Our results suggest that airway hypersecretion may be involved as a component of airflow obstruction during LAR, and that this is unlikely during IAR. DSCG may be effective in reducing excessive airway mucus caused by exposure to allergens.
Pharmacokinetics of Der p 2 Allergen and Derived Monomeric Allergoid in Allergic Volunteers
Authors: Bagnasco Marcello , Altrinetti Vania , Pesce Giampaola , Caputo Mauro , Mistrello Gianni , Falagiani Paolo , Canonica Giorgio Walter , Passalacqua Giovanni
Published: October 2005

Background: Presently, sublingual immunotherapy is widely used as an alternative to the injection route for respiratory allergy, but its pharmacokinetics in humans is poorly known, and data are available only for Par j 1 allergen. We aimed at assessing the biodistribution of iodine-123-radiolabelled Der p 2 in allergic volunteers. Methods: Purified Der p 2 and its monomeric allergoid were radiolabelled with iodine-123 and administered sublingually to 7 allergic volunteers. The subjects were allowed to swallow 6 min after administration. Dynamic (up to 10 min) and static scintigraphic images (30 min, 1, 2, 3 and 20 h) were recorded, and blood samples were obtained at different time points to measure the plasma radioactivity and to assess the presence of circulating radiolabelled species by gel chromatography. Results: The local pharmacokinetics did not differ between allergen and allergoid. Plasma radioactivity began to increase only after swallowing and peaked at 1–2 h. Both the allergen and the allergoid persisted in the mouth for several hours, and traces could be detectable up to 20 h. At radioactivity plasma peak, gel chromatography showed that a fraction of the allergoid, but not the allergen, was absorbed as an intact molecule. Conclusions: These results indicate that the pharmacokinetics of sublingual administration is independent of the allergen used and characterized by the long persistence in the mouth. The contribution of enteric absorption of the allergoid in the mechanism of action of sublingual immunotherapy remains to be defined.
Food-Additive-Induced Urticaria: A Survey of 838 Patients with Recurrent Chronic Idiopathic Urticaria
Authors: Di Lorenzo Gabriele , Pacor Maria Luisa , Mansueto Pasquale , Martinelli Nicola , Esposito-Pellitteri Maria , Lo Bianco Claudia , Ditta Vito , Leto-Barone Maria Stefania , Napoli Nicola , Di Fede Gaetana , Rini GiovamBattista , Corrocher Roberto
Published: October 2005

Background: Recurrent chronic idiopathic urticaria (RCIU) is a common skin condition that affects 0.1–3% of the population in the USA and Europe and accounts for nearly 75% of all ‘ordinary’ chronic urticaria (CU) cases. Methods: We studied 838 consecutive patients with RCIU referred to hospital between 1998 and 2003. Patients with known causes of CU were excluded. Clinical history, physical examination, and symptom diaries were evaluated during two periods, a diet-free period (1 week) and a food-additive-free diet (FAFD) period (4 weeks), respectively, and two double-blind placebo-controlled (DBPC) challenges of six food additives were administered. The first DBPC challenge included a mixture of the six food additives (DBPCmixed) given to all patients. The second DBPC challenge comprised the single food additives, administered at increasing doses (DBPCsingle) to patients with a positive DBPCmixed test and 105 patients with a negative DBPCmixed test, as a control. Results: The DBPCmixed challenge was positive in 116 patients. None of the 105 control patients had a positive DBPCsingle test. Only 31 DBPCsingle tests were positive in patients with positive DBPCmixed challenge. Twenty-four of the 116 patients showing a positive DBPCmixed challenge also had a positive DBPCsingle result. Conclusions: Our results confirmed that food additive hypersensitivity reactions occurred in few RCIU patients using DBPCsingle challenge. The combination of the results of FAFD and DBPCmixed challenge seems to be of considerable practical interest for allergists, internists and dermatologists, rather than the data of clinical history and the results of DBPCsingle challenge, in patients with RCIU.
Prenatal 2-Dimensional and 3-Dimensional Ultrasonography Diagnosis and Autoptic Findings of Isolated Ectopia Cordis
Authors: Bianca S. , Bartoloni G. , Auditore S. , Reale A. , Tetto C. , Ingegnosi C. , Pirruccello B. , Ettore G.
Published: October 2005

Ectopia cordis is a very rare congenital malformation, commonly associated with intracardiac anomalies. It is due to a defect in fusion of the anterior chest wall resulting in an extrathoracic location of the heart. We report prenatal 2-dimensional (2D) and 3D ultrasonography diagnosis and postnatal autoptic findings of an isolated ectopia cordis with tricuspid atresia. Ectopia cordis prenatal diagnosis is easily made with ultrasound by visualizing the heart outside the thoracic cavity. 3D ultrasonography may add more detailed visualization of the heart anomaly even if the 2D ultrasonography alone permits the prenatal diagnosis. Obstetrical management should include a careful search for associated anomalies, especially cardiac, and the assessment of fetal karyotype. As this is considered a sporadic anomaly, the recurrence risk is low and no genetic origin is known.
Naloxone Treatment Prevents Prenatal Stress Effects on Peritoneal Macrophage Activity in Mice Offspring
Authors: Fonseca Evelise S.M. , Sakai Monica , Carvalho-Freitas Maria Isabel R. , Palermo Neto João
Published: October 2005

The present study analyzed the effects of maternal stress (PS) and/or naloxone treatment on the activity of peritoneal macrophage in male and female Swiss mice offspring. Pregnant female rats received a daily footshock (0.2 mA) and/or a naloxone injection from gestational day 15 to 19. Experiments were performed on postnatal day 30 on male and female pups. The following results were obtained in male offspring: (1) PS decreased both the index and the percentage of phagocytosis, this decrement being reversed by naloxone treatment, and (2) naloxone alone decreased the percentage of phagocytosis. The following results were obtained in female offspring: (1) PS decreased spontaneous and phorbol myristate acetate-induced macrophage oxidative burst, this decrement being reversed by naloxone pretreatment, and (2) PS decreased both the index and percentage of the phagocytosis, this effect was prevented by naloxone treatment. These data are discussed focussing on a putative neuroimmune interaction involving opioidergic systems during the ontogeny of the central nervous and immune systems.
Individual Differences in the Expression of Tyrosine Hydroxylase mRNA in Neurosecretory Neurons of the Human Paraventricular and Supraoptic Nuclei: Positive Correlation with Vasopressin mRNA
Authors: Panayotacopoulou Maria T. , Malidelis Yiannis , van Heerikhuize Joop , Unmehopa Unga , Swaab Dick
Published: October 2005

Previous studies indicated that in the human paraventricular nucleus (PVN) and in the supraoptic nucleus (SON) tyrosine hydroxylase (TH) – the first and rate-limiting enzyme in catecholamine synthesis – is localized mainly in magnocellular neurosecretory neurons. Individual differences were observed among control subjects in number and distribution of TH-immunoreactive (IR) perikarya, indicating that antemortem factors may regulate TH expression. Since a large number of TH-IR perikarya were observed in subjects who suffered from somatic illnesses leading to prolonged osmotic or nonosmotic stimulation of vasopressin (VP) release, we suggested that TH expression is related to the activation of VP neurons. The purpose of our study was to apply (1) in situ hybridization for TH mRNA on human PVN and SON to investigate how the previously reported individual differences in TH protein expression are depicted at the transcriptional level and (2) quantitative TH immunohistochemistry and in situ hybridization for VP mRNA throughout the dorsolateral part of the SON (dl-SON) in order to elucidate whether indeed expression of TH in neurosecretory nuclei depends on activation of VP neurons. Postmortem formalin-fixed, paraffin-embedded hypothalamic sections of 16 control subjects were studied for TH protein and TH and VP mRNAs. For 6 of the above cases, the number of TH-IR neurons and the total VP mRNA levels were estimated throughout the entire dl-SON using an image analysis system. Individual variation was observed in TH mRNA expression which appears to parallel the expression of TH-protein. Using Spearman’s bivariate test, a positive correlation was found between the number of TH-IR- and TH-mRNA-expressing neurons in both PVN and SON (p < 0.01) as well as between the number of TH-IR neurons and the total VP mRNA in the dl-SON (p < 0.05). Our results show (1) that the individual variability in the number of TH-IR neurons within the neurosecretory nuclei might be due to differential expression and/or stability of TH mRNA and (2) that expression of TH-immunoreactivity in human PVN and SON depends on the activation of VP neurons.
Neostigmine, but not Metoclopramide, Abolishes Ethosuximide-Induced Functional Gastrointestinal Disturbances
Authors: Sirakov V. , Krastev A. , Kostadinova I. , Turiiski V.
Published: October 2005

Ethosuximide is a drug used for the treatment of absence seizures. Its prolonged application leads to gastrointestinal (GI) disturbances. The purpose of the present study was to determine the severity and nature of the disturbances, as well as the influence exerted upon them by neostigmine methylsulfate and metoclopramide. The drug-induced alterations, occurring in the rat GI tract, were registered by X-ray contrast examination. In vitro experiments were carried out on isolated GI smooth muscle (SM) preparations. The latter revealed that the drug hyperpolarized the SM tissues and inhibited their contractile activity. X-rays of ethosuximide-treated rats showed GI hypotonia, disturbed peristalsis and decreased evacuation activity. The inhibition of the GI functions was associated with hyperpolarization of SM and a reduction in Ca2+ influx, ensuring spontaneous contractile activity. The application of neostigmine methylsulfate significantly removed ethosuximide-induced functional GI disturbances in rats treated for 15 days with ethosuximide.
Endocrine Regulation of the Growth Plate
Authors: Nilsson Ola , Marino Rose , De Luca Francesco , Phillip Moshe , Baron Jeffrey
Published: October 2005

Longitudinal bone growth occurs at the growth plate by endochondral ossification. Within the growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. The newly formed cartilage is invaded by blood vessels and bone cells that remodel the newly formed cartilage into bone tissue. This process of longitudinal bone growth is governed by a complex network of endocrine signals, including growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin. Many of these signals regulate growth plate function, both by acting locally on growth plate chondrocytes and also indirectly by modulating other endocrine signals in the network. Some of the local effects of hormones are mediated by changes in paracrine factors that control chondrocyte proliferation and differentiation. Many human skeletal growth disorders are caused by abnormalities in the endocrine regulation of the growth plate. This review provides an overview of the endocrine signals that regulate longitudinal bone growth, their interactions, and the mechanisms by which they affect growth plate chondrogenesis.
Quality of Life in Adolescents Born Small for Gestational Age: Does Growth Hormone Make a Difference?
Authors: Bannink Ellen M.N. , van Pareren Yvonne K. , Theunissen Nicolet C.M. , Raat Hein , Mulder Paul G.M. , Hokken-Koelega Anita C.S.
Published: October 2005

Background/Aims: To evaluate quality of life (QoL) in adolescents born SGA without spontaneous catch-up growth, treated with and without long-term growth hormone (GH) therapy. Additionally, to assess whether GH treatment has a positive effect on QoL, besides improving adult height and height SDS during childhood. Methods: Two groups of adolescents born SGA without spontaneous catch-up growth participated in the QoL evaluation; a GH-treated group (n = 44, mean GH duration: 8.8 (1.7) years) and an untreated group (n = 28), both mean age 15.8 (2.1) years. QoL was measured by self-reports of the TACQOL-S, a disorder-specific questionnaire, and the CHQ, a generic questionnaire. Results: The GH group scored significantly better health status and health-related QoL on several scales of the TACQOL-S. On all TACQOL-S scales the GH group scored better QoL than the untreated group, with effect sizes of moderate to large, not all differences reaching statistical significance. The generic CHQ did not reveal significant differences in QoL between the GH group and the untreated group. Conclusions: Firstly, adolescents born SGA, with a GH-induced improved height, had in many aspects a better QoL than untreated adolescents born SGA, according to the disorder-specific questionnaire. Secondly, we advise to use, in addition to a generic questionnaire, a disorder-specific questionnaire for measuring QoL in children treated for short stature, as the generic CHQ did not reveal such differences.
Absent or Delayed Adrenarche in Pit-1/POU1F1 Deficiency
Authors: Taha Doris , Mullis Primus-E. , Ibáñez Lourdes , de Zegher Francis
Published: October 2005

Mutations of the PIT1/POU1F1 gene are responsible for a rare variant of anterior hypopituitarism, including deficiency of growth hormone, prolactin and thyrotropin. In 8 ethnically diverse POU1F1-deficient patients (4 different mutations) with normal circulating levels of cortisol and adrenocorticotropic hormone, and with spontaneous onset and progression of puberty, we observed an absence or delay of adrenarche (median circulating dehydroepiandrosterone-sulfate –6.2 SD); in each of the 4 postmenarcheal females, pubarche (i.e. appearance of pubic hair) was also absent or delayed. The absence/delay of adrenarche in POU1F1-deficient patients and the absence/delay of pubarche in POU1F1-deficient females suggest that a POU1F1-dependent factor contributes to the normal development of adrenarche and female pubarche.
Rheumatoid Factors: Good or Bad for You?
Authors: Nowak Urszula M. , Newkirk Marianna M.
Published: October 2005

Background: Rheumatoid factors (RFs) are autoantibodies associated with rheumatoid arthritis. They can be detected in normal individuals, although transiently. This dichotomy has led to questions about the origins and types of RFs. Recently it has been shown that B cells that produce RFs only do so when activated by two signals, one from engagement of the B-cell receptor and the other from recognition of a pathogen-associated molecular pattern through a Toll-like receptor (TLR). These autoantibodies thus link the innate and acquired immune responses. Objective: Through a review of the literature, an examination of the current knowledge of RF induction is presented. The focus is on a discussion of a beneficial or detrimental role for RFs in normal individuals and in those with chronic disease. Results: What makes RF ‘good’ in some cases and ‘bad’ in others may reflect the type of RF produced. Low-affinity polyreactive IgM RFs are probably beneficial as they aid in the clearance of immune complexes that are more efficiently cleared, and the RF B cell can act as an antigen-presenting cell and stimulate host defense. However, large amounts of high-affinity RFs found in patients with chronic disease may be harmful by participation in a vicious cycle of autoantibody production by stimulation of self lymphocytes, and/or deposition in blood vessels thus causing vasculitis. Conclusions: Whether RFs are beneficial or detrimental depends on the context in which they are expressed, the type and amount of RF produced, whether the response is perpetuated by TLR ligation and whether other cells are stimulated either directly or indirectly by RF-positive B cells.
Renal Redox Stress and Remodeling in Metabolic Syndrome, Type 2 Diabetes mellitus, and Diabetic Nephropathy: Paying Homage to the Podocyte
Authors: Hayden Melvin R. , Whaley-Connell Adam , Sowers James R.
Published: October 2005

Type 2 diabetes mellitus has reached epidemic proportions and diabetic nephropathy is the leading cause of end-stage renal disease. The metabolic syndrome constitutes a milieu conducive to tissue redox stress. This loss of redox homeostasis contributes to renal remodeling and parallels the concurrent increased vascular redox stress associated with the cardiometabolic syndrome. The multiple metabolic toxicities, redox stress and endothelial dysfunction combine to weave the complicated mosaic fabric of diabetic glomerulosclerosis and diabetic nephropathy. A better understanding may provide both the clinician and researcher tools to unravel this complicated disease process. Cellular remodeling of podocyte foot processes in the Ren-2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27) and the Zucker diabetic fatty model of type 2 diabetes mellitus have been observed in preliminary studies. Importantly, angiotensin II receptor blockers have been shown to abrogate these ultrastructural changes in the foot processes of the podocyte in preliminary studies. An integrated, global risk reduction, approach in therapy addressing the multiple metabolic abnormalities combined with attempts to reach therapeutic goals at an earlier stage could have a profound effect on the development and progressive nature to end-stage renal disease and ultimately renal replacement therapy.
Effects of Captopril on Cardiac and Renal Damage, and Metabolic Alterations in the Nitric Oxide-Deficient Hypertensive Rat
Authors: Khattab Mahmoud M. , Mostafa Adel , Al-Shabanah Othman
Published: October 2005

Chronic inhibition of nitric oxide (NO) synthesis is characterized by increased blood pressure accompanied with both cardiac hypertrophy as well as renal damage. We investigated whether the angiotensin-converting enzyme (ACE) inhibitor captopril can inhibit the cardiac hypertrophy and reverse the renal failure. We tested the influence of captopril on the nitrate-nitrite (NOx) in plasma and heart and kidney tissues. Oxidative stress, in terms of glutathione and thiobarbituric acid-reactive substances measured as malondialdehyde, was monitored examining their involvement in the cardioprotective and renoproptective actions. Three groups of Wistar rats were used: untreated group, and rats treated with the NO synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) and L-NAME plus captopril (10 mg/kg/day). Systolic, diastolic and mean blood pressure (BPs, BPd and BPm respectively) was measured weekly in addition to the heart rate using rat-tail plethysmography. After 3 weeks, L-NAME significantly increased BPs, BPd and BPm. Captopril treatment reversed the increments in pressure back to normal values by the fourth week. ACE inhibition by captopril reverted the L-NAME-induced hypertrophy and inhibited the enzymatic indices of cardiac damage (glutamate oxaloacetate transaminase and lactate dehydrogenase) back to normal values. Furthermore, the NO synthesis inhibition produced renal damage as indicated by significant increase in creatinine. Captopril ameliorated the raised creatinine to normal. Chronic L-NAME treatment increased serum NOx levels but concomitant treatment with captopril was without effect.
Frequencies of A(TA)7TAA, G71R, and G493R Mutations of the UGT1A1 Gene in the Malaysian Population
Authors: Yusoff Surini , van Rostenberghe Hans , Yusoff Narazah M. , Talib Norlelawati A. , Ramli Noraida , Ismail N. Zainal A.N. , Ismail W. Pauzi W. , Matsuo Masafumi , Nishio Hisahide
Published: October 2005

Background: Gilbert syndrome is caused by defects in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. These mutations differ among different populations and many of them have been found to be genetic risk factors for the development of neonatal jaundice. Objectives: The objective was to determine the frequencies of the following mutations in the UGT1A1 gene: A(TA)7TAA (the most common cause of Gilbert syndrome in Caucasians), G71R (more common in the Japanese and Taiwanese population), and G493R (described in a homozygous Malay woman with Crigler-Najjar syndrome type 2) in a group of Malaysian babies with hyperbilirubinemia and a group of normal controls. Methods: The GeneScan fragment analysis was used to detect the A(TA)7TAA variant. Mutation screening of both G71R and G493R was performed using denaturing high performance liquid chromatography. Results: Fourteen out of fifty-five neonates with hyperbilirubinemia (25%) carried the A(TA)7TAA mutation (10 heterozygous, 4 homozygous). Seven out of fifty controls (14%) carried this mutation (6 heterozygous, 1 homozygous). The allelic frequencies for hyperbilirubinemia and control patients were 16 and 8%, respectively (p = 0.20). Heterozygosity for the G71R mutation was almost equal among both groups (5.5% for hyperbilirubinemia patients and 6.0% for controls; p = 0.61). One subject (1.8%) in the hyperbilirubinemia group and none of the controls were heterozygous for the G493R mutation (p = 0.476). Conclusions: The A(TA)7TAA seems more common than the G71R and G493R mutations in the Malaysian population.
Exposure to Endotoxins during Sensitization Prevents Further Endotoxin-Induced Exacerbation of Airway Inflammation in a Mouse Model of Allergic Asthma
Authors: Delayre-Orthez Carine , Becker Julien , de Blay Frédéric , Frossard Nelly , Pons Françoise
Published: October 2005

Background: We have shown previously that lipopolysaccharides (LPS) inhibited airway inflammation in allergen-sensitized and challenged mice when administered during sensitization, while exacerbating the inflammation when given upon challenge. We have here investigated the effect of LPS administered during both sensitization and challenge on airway inflammation, as well as on the profile of the T-helper (Th) response to allergen. Methods: Mice were sensitized and challenged with ovalbumin (OVA), in the presence or absence of effective doses of LPS, namely 1 µg during sensitization and 1 ng during challenge. Inflammation was assessed by measuring cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF). The profile of the Th response was determined by quantifying OVA-specific IgE and IgG2a in serum and Th1/Th2 cytokines in the culture medium of splenocytes and in BALF. Results: Allergen-induced airway eosinophilia was increased in mice exposed to LPS during challenge only when compared with controls, whereas it was similarly reduced in animals exposed during sensitization only and during both sensitization and challenge. Mice exposed to LPS during sensitization only or during both sensitization and challenge also displayed a decrease in IgE and an increase in IgG2a, suggesting a switch in the immune response toward the Th1 profile. This was confirmed by quantification of Th1/Th2 cytokines in culture medium of splenocytes and in BALF. Conclusions: Our data demonstrate that exposure to endotoxins during sensitization prevents allergen-induced airway inflammation, as well as its exacerbation triggered by further exposure to endotoxins during challenge, while switching the immune response to allergen from a Th2 to a Th1 profile.
Arterial Stiffness Is Related to Systemic Inflammation in Essential Hypertension
Authors: Mahmud Azra , Feely John
Published: October 2005

The acute phase–reactant high-sensitivity C-reactive protein, a marker of vascular inflammation and an atherosclerotic risk factor, is related to arterial stiffness in healthy subjects and in systemic vasculitis. To explore the relationship between markers of inflammation, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein with arterial stiffness, we studied untreated patients (n=78; 56% male; 47±1 years of age; mean±SEM) with essential hypertension. After overnight fast, augmentation index and pulse wave velocity were assessed noninvasively and related to plasma levels of inflammatory markers measured by ELISA. Pulse wave velocity was significantly related to plasma high-sensitivity C-reactive protein (
r
=0.31;
P
<0.001), TNF-α, (
r
=0.30;
P
<0.001) and IL-6 (
r
=0.21;
P
<0.05). There was also a relationship between heart rate–corrected augmentation index to high-sensitivity C-reactive protein (
r
=0.37;
P
<0.001), IL-6 (
r
=0.24;
P
<0.05), and TNF-α (
r
=0.19,
P
=0.06). High-sensitivity C-reactive protein was an independent predictor of pulse wave velocity and augmentation index in a multiple stepwise regression model. High-sensitivity C-reactive protein, a marker of systemic inflammation, is independently related to pulse wave velocity, a marker of aortic stiffness, and augmentation index, a manifestation of wave reflection, in essential hypertension.
Sympathectomy or Doxazosin, But Not Propranolol, Blunt Myocardial Interstitial Fibrosis in Pressure-Overload Hypertrophy
Authors: Perlini Stefano , Palladini Giuseppina , Ferrero Ivana , Tozzi Rossana , Fallarini Silvia , Facoetti Angelica , Nano Rosanna , Clari Francesca , Busca Giuseppe , Fogari Roberto , Ferrari Alberto U.
Published: October 2005

The adaptive changes that develop in the pressure-overloaded left ventricular (LV) myocardium include cardiomyocyte hypertrophy and interstitial fibrosis. Although the former is known to depend to a sizeable extent on sympathetic (over)activity, little information exists whether the same applies to the latter, ie, whether excess catecholamine exposure contributes to the imbalance between collagen deposition by fibroblasts and degradation by matrix metalloproteases (MMPs), eventually leading to LV collagen accumulation. Sprague-Dawley rats were subjected to abdominal aortic banding (B) or sham operation (S) and treated with β-blockade (Bb, oral propranolol, 40 mg/kg per day), chemical sympathectomy (Sx, 6-hydroxydopamine, 150 mg/kg intraperitoneal twice per week) or vehicle (Vh). Ten weeks later, systolic blood pressure, LV weight, collagen abundance (computer-aided histology), zymographic matrix metalloproteinase (MMP)-2 activity and its specific tissue inhibitor concentration (TIMP-2) were measured. Both sympathectomy and β-blockade failed to attenuate the banding-induced blood pressure elevation but significantly attenuated the attendant LV hypertrophy. As expected, pressure-overload hypertrophy was associated with interstitial fibrosis (collagen: 4.37±1.23% BVh versus 1.23±0.44% SVh,
P
<0.05), which was abolished by sympathectomy (2.55±1.31%,
P
=not significant versus SSx) but left unchanged by β-blockade (4.11±1.23%,
P
<0.05 versus both SBb and BSx). β-blockade, but not sympathectomy, was also associated with an increased TIMP-2/MMP-2 ratio (
P
<0.05), indicating reduced interstitial collagenolytic activity. In separate groups of banded and sham-operated rats, treatment with the α-receptor blocker doxazosin (10 mg/kg per day) displayed similar antifibrotic and biochemical effects as sympathectomy. Thus in the course of experimental pressure overload, the sympathetic nervous system plays a major pro-fibrotic role, which is mediated via α-adrenergic but not β-adrenergic receptors.
Critical Role for CuZn-Superoxide Dismutase in Preventing Angiotensin II-Induced Endothelial Dysfunction
Authors: Didion Sean P. , Kinzenbaw Dale A. , Faraci Frank M.
Published: October 2005

The goal of the present study was to test the hypothesis that the CuZn isoform of superoxide dismutase (CuZnSOD) protects against angiotensin II (Ang II)–induced endothelial dysfunction. Vascular responses of carotid arteries from control, CuZnSOD-deficient (CuZnSOD
+/−
), and CuZnSOD transgenic mice were examined in vitro after overnight incubation with either vehicle or Ang II (1 or 10 nmol/L). In control mice, acetylcholine produced concentration-dependent relaxation that was not affected by 1 nmol/L Ang II. In contrast, relaxation to acetylcholine in arteries from CuZnSOD+/− mice was markedly and selectively attenuated after incubation with 1 nmol/L Ang II (eg, 100 μmol/L acetylcholine produced 93±6% and 44±15% relaxation in vehicle- and Ang II-treated arteries, respectively). A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to acetylcholine in arteries from control mice (eg, 100 μmol/L acetylcholine produced 96±4% and 45±7% relaxation in vehicle- and Ang II-treated vessels, respectively). In contrast, 10 nmol/L Ang II had no effect on responses to acetylcholine in carotid arteries from CuZnSOD transgenic mice (or in control mice treated with the superoxide scavenger Tiron [1 mmol/L]). Superoxide levels in control mice were higher in aorta treated with Ang II than with vehicle and were markedly reduced in CuZnSOD transgenic mice. These findings provide the first direct evidence that CuZnSOD limits Ang II-mediated impairment of endothelial function and that loss of 1 copy of the CuZnSOD gene is sufficient to enhance Ang II-induced vascular dysfunction.
Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3–Induced Myocarditis and Influences Type I Interferon Production
Authors: Fuse Koichi , Chan Grace , Liu Youan , Gudgeon Patrick , Husain Mansoor , Chen Manyin , Yeh Wen-Chen , Akira Shizuo , Liu Peter P.
Published: October 2005

Background—

Myeloid differentiation factor (MyD)-88 is a key adaptor protein that plays a major role in the innate immune pathway. How MyD88 may regulate host response in inflammatory heart disease is unknown.

Methods and Results—

We found that the cardiac protein level of MyD88 was significantly increased in the hearts of wild-type mice after exposure to Coxsackievirus B3 (CVB3). MyD88
−/−
mice showed a dramatic higher survival rate (86%) in contrast to the low survival (35%) in the MyD88
+/+
mice after CVB3 infection (
P
<0.0001). Pathological examination showed a significant decrease of cardiac and pancreatic inflammation in the MyD88
−/−
mice. Viral concentrations in the hearts were significantly decreased in the MyD88
−/−
mice. Cardiac mRNA levels for interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-18 were significantly decreased in the MyD88
−/−
mice. Similarly, serum levels of T-helper 1 cytokines were significantly decreased in the MyD88
−/−
mice. In contrast, cardiac protein levels of the activated interferon regulatory factor (IRF)-3 and IFN-β were significantly increased in the MyD88
−/−
mice but not other usual upstream signals to IRF-3. The cardiac expression of coxsackie-adenoviral receptor and p56
lck
were also significantly decreased.

Conclusions—

MyD88 appears to be a key contributor to cardiac inflammation, mediating cytokine production and T-helper-1/2 cytokine balance, increasing coxsackie-adenoviral receptor and p56
lck
expression and viral titers after CVB3 exposure. Absence of MyD88 confers host protection possibly through novel direct activation of IRF-3 and IFN-β.
Angiotensin Receptor Blockade and Exercise Capacity in Adults With Systemic Right Ventricles
Authors: Dore Annie , Houde Christine , Chan Kwan-Leung , Ducharme Anique , Khairy Paul , Juneau Martin , Marcotte François , Mercier Lise-Andrée
Published: October 2005

Background—

Pharmacological blockade of the renin-angiotensin system improves exercise tolerance in patients with left ventricular dysfunction, yet its impact on patients with systemic right ventricles (RVs) remains unknown.

Methods and Results—

A multicenter, randomized, double-blind, placebo-controlled, crossover clinical trial was performed to assess the effects of losartan on exercise capacity and neurohormonal levels in patients with systemic RVs. Of 29 patients studied (age, 30.3±10.9 years), 21 had transposition of the great arteries with a Mustard baffle, and 8 had congenitally corrected transposition of the great arteries. Baseline values were as follows: V̇
o
2
max, 29.8±5.6 mL · kg
−1
· min
−1
(73.5±12.9% predicted value); RV ejection fraction, 41.6±9.3%; N-terminal pro brain natriuretic peptide (NT-proBNP), 257.7±243.4 pg/mL (normal <125 pg/mL); and angiotensin II, 5.7±4.9 pg/mL (normal <5.0 pg/mL). Comparing losartan to placebo showed no differences in V̇
o
2
max (29.9±5.4 versus 29.4±6.2 mL · kg
−1
· min
−1
;
P
=0.43), exercise duration (632.3±123.0 versus 629.9±140.7 seconds;
P
=0.76), and NT-proBNP levels (201.2±267.8 versus 229.7±291.5 pg/mL;
P
=0.10), despite a trend toward increased angiotensin II levels (15.2±13.8 versus 8.8±12.5 pg/mL;
P
=0.08).

Conclusions—

In adults with systemic RVs, losartan did not improve exercise capacity or reduce NT-proBNP levels. Minimal baseline activation of the renin-angiotensin system may explain this lack of benefit and imply an alternative pathophysiological mechanism for the progressive ventricular dysfunction and impaired exercise capacity observed in such patients.
Clinical Features, Management, and Outcome of Children With Fetal and Postnatal Diagnoses of Isomerism Syndromes
Authors: Lim Joyce S.L. , McCrindle Brian W. , Smallhorn Jeffrey F. , Golding Fraser , Caldarone Christopher A. , Taketazu Mio , Jaeggi Edgar T.
Published: October 2005

Background—

Isomerism is associated with a complex spectrum of anomalies. There is paucity of data on prenatally detected cases.

Methods and Results—

Between January 1990 and February 2004, 83 of 166 cases (50%) had a prenatal diagnosis of left isomerism (LAI; 52 of 97) or right isomerism (RAI; 31 of 69) at our institution. The spectrum of anomalies, management, and outcomes was compared for fetal and postnatal diagnoses of LAI and RAI. RAI more often than LAI was associated with AV septal defect (90% versus 56%;
P
<0.0001), pulmonary outflow obstruction (91% versus 37%;
P
<0.0001), total anomalous pulmonary venous drainage (73% versus 13%;
P
<0.0001), and abnormal VA connections (68% versus 33%;
P
<0.0001), whereas inferior vena cava interruption (3% versus 93%;
P
<0.0001), complete AV block (0% versus 13%;
P
=0.004), aortic obstruction (6% versus 33%;
P
<0.0001), and extracardiac defects (5% versus 25%;
P
=0.006) were less common. The spectrum of lesions was comparable for fetal and postnatal cases, except for AV block (fetal, 25%; postnatal, 0%;
P
=0.0002) and AV septal defect (fetal, 67%; postnatal, 42%;
P
=0.023) in LAI. Fetal demise was due mainly to pregnancy termination (LAI, 42%; RAI, 45%). Survival of actively managed children with LAI was significantly better than for those with RAI (
P
<0.0001) but did not differ with regard to fetal versus postnatal diagnosis. Most LAI cases required no intervention or underwent successful biventricular cardiac surgery (65%), unlike RAI cases (13%;
P
<0.0001).

Conclusions—

Prenatal diagnosis did not affect overall survival despite facilitated care. The prognosis of RAI was worse compared with LAI because of more complex associated cardiac defects and the inability to perform successful surgical procedures.
Role of Nitric Oxide in Mediating In Vivo Vascular Responses to Calcitonin Gene-Related Peptide in Essential and Peripheral Circulations in the Fetus
Authors: Thakor A.S. , Giussani D.A.
Published: October 2005

Background—

The role of calcitonin gene-related peptide (CGRP) in cardiovascular regulation is gaining clinical and scientific interest. In the adult, in vivo studies have shown that CGRP-stimulated vasodilation in several vascular beds depends, at least in part, on nitric oxide (NO). However, whether CGRP acts as a vasodilator in the fetus in vivo and whether this effect is mediated via NO have been addressed only minimally. This study tested the hypothesis that CGRP has potent NO-dependent vasodilator actions in essential and peripheral vascular beds in the fetus in late gestation.

Methods and Results—

Under anesthesia, 5 fetal sheep at 0.8 gestation were instrumented with vascular catheters and Transonic flow probes around an umbilical artery and a femoral artery. Five days later, fetuses received 2- and 5-μg doses of exogenous CGRP intra-arterially in randomized order. Doses were repeated during NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for tonic production of the gas, thereby maintaining basal cardiovascular function. CGRP resulted in potent and long-lasting NO-dependent dilation in the umbilical and femoral circulations, hypotension, and a positive cardiac chronotropic effect. During NO blockade, the femoral vasodilator response to CGRP was diminished. In contrast, in the umbilical vascular bed, the dilator response was not only prevented but reversed to vasoconstriction.

Conclusions—

CGRP has potent NO-dependent vasodilator actions in fetal essential and peripheral vascular beds. CGRP-induced NO-dependent effects in the umbilical vascular bed may provide an important mechanism in the control and maintenance of umbilical blood flow during pregnancy.
Corin Gene Minor Allele Defined by 2 Missense Mutations Is Common in Blacks and Associated With High Blood Pressure and Hypertension
Authors: Dries Daniel L. , Victor Ronald G. , Rame J. Eduardo , Cooper Richard S. , Wu Xiaodong , Zhu Xiaofeng , Leonard David , Ho Su-Inn , Wu Qingyu , Post Wendy , Drazner Mark H.
Published: October 2005

Background—

The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes.

Method and Results—

This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38;
P
=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7±20.7 versus 129.4±17.4 mm Hg;
P
=0.029) and adjusted (132.5±1.6 versus 128.9±0.6 mm Hg;
P
=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06;
P
=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8±1.9 versus 121.4±0.7 mm Hg;
P
=0.03).

Conclusions—

The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.