bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Aspects of Presymptomatic Diagnosis of Spinocerebellar Ataxia Type 2 in Cuba
Authors: Paneque H.M. , Prieto A.L. , Reynaldo R.R. , Cruz M.T. , Santos F.N. , Almaguer M.L. , Velázquez P.L. , Heredero B.L.
Published: June 2007

Objective: In this paper, we present a descriptive study of the first year of implementation of the predictive genetic testing program for spinocerebellar ataxia type 2 (SCA2) in Cuba, which has been structured along the international guidelines for Huntington disease. Subjects and Methods:Medical records were retrospectively reviewed from 100 individuals who requested presymptomatic diagnosis. They had been seen between February 2001 and May 2002 at the Ataxia Clinic in the province of Holguín and had completed the protocol. The participants had psychological evaluations before testing and 1 week after being informed of the result. Results: The average age of the participants in the presymptomatic testing for SCA2 was 39.3 years, 62% were female. The main reasons for taking the test were family planning and risk assessment in their children. Family participation in the process was high and there were several additional sources of social support. Before the test, the subjects did not present high levels of anxiety or depression. On informing the patients of the test results indicators for anxiety and depression significantly decreased, and there were no significant differences according to whether the test result had been positive or negative. Catastrophic events were rare during the first week after the test. Conclusions: The results indicate a strong interest in presymptomatic diagnosis among individuals at risk for SCA2 in Holguín and a lack of significant psychological drawbacks up to 1 week after information of results.
Attitudes towards Genetic Diagnosis in Pakistan: A Survey of Medical and Legal Communities and Parents of Thalassemic Children
Authors: Gilani Ahmed I. , Jadoon Atif S. , Qaiser Rabia , Nasim Sana , Meraj Riffat , Nasir Nosheen , Naqvi Fizza F. , Latif Zafar , Memon Muhammad A. , Menezes Esme V. , Malik Imran , Memon Muhammad Z. , Kazim Syed F. , Ahmad Usman
Published: June 2007

Objectives: It was the aim of this study to assess the attitudes of doctors, medical students, lawyers, parliament members and parents of thalassemic children towards genetic diagnosis in Pakistan. Study Design: A cross-sectional descriptive survey was conducted among representative samples. Results: Five hundred and seventy doctors, 49 lawyers, 178 medical students, 89 parents of thalassemic children and 16 members of parliament (MPs) were included in the survey. The groups showed considerable difference in their attitudes towards different aspects of the issue. A large proportion (88.5%) agreed to the idea of genetic diagnostic screening, especially the parents of thalassemic patients. Premarital carrier screening was favored by 77% of the respondents. Prenatal screening was most favored by the parents of thalassemic children (94.4%). Likewise, a majority of parents of thalassemic children were in favor of abortion in case of an affected fetus. Genetic self-screening was also favored most by the parents of thalassemic patients (78.2%). Only 24% of the doctors favored making genetic screening mandatory, whereas 63% of the parents agreed to the idea. Conclusion: Attitudes regarding genetic diagnosis are markedly different among various societal groups in Pakistan. The parents of the affected children strongly favor genetic screening as does the medical community, though not as strongly as the parents. The legislative groups, particularly the MPs, are reserved in their support. Genetic diagnosis can help decrease the disease burden in the future. However, it raises a number of ethical issues, which need to be addressed. It is important to educate the population about potential benefits as well as ethical dilemmas involved so that the general public is able to make the right decisions for themselves and their families.
Genetic Counselling for Familial Conditions during Pregnancy: A Review of the Literature Published during the Years 1989–2004
Authors: Aalfs C.M. , Smets E.M.A. , Leschot N.J.
Published: June 2007

Background: Genetic counselling for familial conditions during pregnancy may have some disadvantages, such as time pressure and induced worry. However, little is known about the reasons for and consequences of this timing of genetic counselling. Objective: The objective of this study was to provide an overview of research aimed at the counselee’s reasons for seeking genetic counselling during pregnancy and the medical-technical and procedural consequences thereof. Methods: We searched the databases Medline and PsycINFO for primary research papers, reviews and case reports, published from 1989 to June 2004. Results: No papers could be retrieved which explicitly addressed our research questions. However, 34 papers, out of a total of 399 papers, covered issues with some relevance to our research questions. Limited knowledge and alertness towards genetics and a greater apparent relevance of genetic issues during pregnancy seemed to explain, at least partly, the timing of referral during pregnancy. Literature on the consequences of this timing for the quality of the genetic counselling process appeared to be scarce. These consequences, therefore, remain unclear. Conclusion: In the literature, little attention is paid to the various aspects of the timing of genetic counselling for familial conditions during pregnancy. More research on this issue is important, with a view to improving the care of pregnant women and their children.
Attitudes to Prenatal Testing and Termination of Pregnancy in Saudi Arabia
Authors: Alsulaiman Ayman , Hewison J.
Published: June 2007

Objective: To assess the attitudes of Saudi parents towards prenatal diagnosis and termination of pregnancy for a range of different genetic disorders. Methods: Two hundred Saudi parents (100 fathers and 100 mothers) completed a structured questionnaire which sought their views about each of 30 different conditions. Results: The great majority of people would consider a termination of pregnancy for at least one of the conditions studied. Mothers and fathers held similar attitudes towards prenatal diagnosis, but mothers’ attitudes towards termination of pregnancy were more favourable. Parents’ collective attitudes towards prenatal diagnosis and towards termination of pregnancy were correlated. Conclusions: Saudi parents are favourably inclined towards prenatal diagnosis, and consider termination of pregnancy to be acceptable for some conditions. New technologies provide parents with more reproductive choices but also present them with more dilemmas.
Early Diagnosis of 5α-Reductase Deficiency in Newborns
Authors: Bertelloni S. , Scaramuzzo R.T. , Parrini D. , Baldinotti F. , Tumini S. , Ghirri P.
Published: June 2007

5α-reductase-2 deficiency is a rare autosomal recessive form of 46,XY disorders of sex differentiation (DSD), caused by mutations in the steroid 5α-reductase type 2 gene (SRD5A2), presenting at birth with variable degrees of undervirilization. We report on three Italian newborns with 46,XY DSD in whom the evaluation of testosterone, dihydrotestosterone, testosterone/dihydrotestosterone (T/DHT) ratio and molecular analysis of the 5α-reductase type 2 gene was made in their first month of life. Baseline T/DHT ratio suggested 5α-reductase-2 deficiency; the diagnosis was confirmed by molecular genetics (homozygous mutation in exon 4 [G196S], heterozygous mutation in exon 1 and 5 [W35X/Y235F], heterozygous mutation plus polymorphism in exon 1 [G34W/A49T]). Proper investigation permitted early reassignment to male sex in two babies, assigned to female sex just after birth. In infancy, the T/DHT ratio, assessed by suitable assay methods and evaluated by age-appropriate reference values, seems to be able to select newborns affected by 5α-reductase-2 deficiency. Molecular analysis of the SRD5A2 gene should be warranted in newborns with abnormal ratio before sex assignment.
Combined Haploinsufficiency of SF-1 and GATA4 Does Not Reveal a Genetic Interaction in Mouse Gonadal Development
Authors: Pelusi C. , Zhao L. , Stallings N.R. , Parker K.L.
Published: June 2007

The nuclear receptor steroidogenic factor 1 (SF-1 or NR5A1) and the zinc finger protein GATA4 mediate key events in the early steps of gonadal development and sex differentiation, presumably by activating the expression of essential target genes. An important SF-1 target in male sex differentiation is the gene encoding the anti-Müllerian hormone (AMH), which induces regression of the Müllerian ducts in the developing male embryo. In cell transfection studies, there is apparent cooperation between GATA4 and SF-1 in the regulation of both human and mouse Amh promoters. We hypothesized that compound haploinsufficiency of both SF-1 and GATA4, by reducing their synergism, might cause a more severe phenotype than that seen in mice that were heterozygous for either SF-1 or Gata4 alone. Surprisingly, in adult and embryonic mice, compound haploinsufficiency of SF-1 and GATA4 caused no gonadal or reproductive abnormalities beyond those seen in SF-1+/– mice. Thus, although cooperation between SF-1 and GATA4 very likely is important for regulation of their target genes, such synergy was not revealed in our in vivo studies of gonadal development and function.
Marsupial WT1 Has a Novel Isoform and Is Expressed in Both Somatic and Germ Cells in the Developing Ovary and Testis
Authors: Pask A.J. , Paplinska J.Z. , Shaw G. , Graves J.A.M. , Renfree M.B.
Published: June 2007

The Wilms‘ tumour 1 gene is essential for the formation of the mouse and human urogenital systems. We characterised this gene and examined its expression throughout gonadal development in a marsupial, the tammar wallaby. WT1 protein was detected in the Sertoli and granulosa cells of the developing testis and ovary, respectively. There was also strong immunostaining in the germ cells of both males and females at all stages of gonadal development. In the adult gonads WT1 appears to be dynamically regulated during spermatogenesis and oogenesis. Tammar WT1 has a novel isoform in which a portion of exon 1 is removed, partially deleting the RNA recognition motif (RRM). Despite its removal, WT1 still localised to RNA rich regions of the oocyte including speckled bodies within the nucleus, in the nucleolus and the perinucleolar compartment. This suggests that the RRM is not required for WT1 co-localisation with RNA. This is also the first report of WT1 in association with the perinucleolar compartment, important for RNA metabolism. Our data suggest that WT1 has a conserved function in both the somatic and germ cell lineages of the gonads of marsupials.
Steroid Signaling System Responds Differently to Temperature and Hormone Manipulation in the Red-Eared Slider Turtle (Trachemys scripta elegans), a Reptile with Temperature-Dependent Sex Determination
Authors: Ramsey M. , Crews D.
Published: June 2007

Many reptiles, including the red-eared slider turtle (Trachemys scripta elegans), exhibit temperature-dependent sex determination (TSD). Temperature determines gonadal sex during the middle of embryogenesis, or the temperature-sensitive period (TSP), when gonadal sex is labile to both temperature and hormones – particularly estrogen. The biological actions of steroid hormones are mediated by their receptors as defined here as the classic transcriptional regulation of target genes. To elucidate estrogen action during sex determination, we examined estrogen receptor α (Esr1, hereafter referred to as ERα), estrogen receptor β (Esr2, hereafter referred to as ERβ), and androgen receptor (Ar, hereafter referred to as AR) expression in slider turtle gonads before, during and after the TSP, as well as following sex reversal via temperature or steroid hormone manipulation. ERα and AR levels spike at the female-producing temperature while ovarian sex is determined, but none of the receptors exhibited sexually dimorphic localization within the gonad prior to morphological differentiation. All three receptors respond differentially to sex-reversing treatments. When shifted to female-producing temperatures, embryos maintain ERα and AR expression while ERβ is reduced. When shifted to male-producing temperatures, medullary expression of all three receptors is reduced. Feminization via estradiol (E2) treatment at a male-producing temperature profoundly changed the expression patterns for all three receptors. ERα and ERβ redirected to the cortex in E2-created ovaries, while AR medullary expression was transiently reduced. Although warmer incubation temperature and estrogen result in the same endpoint (ovarian development), our results indicate different steroid signaling patterns between temperature- and estrogen-induced feminization.
Mapping of sox2 and sox14 in Tilapia (Oreochromis spp.)
Authors: Cnaani A. , Lee B.-Y. , Ozouf-Costaz C. , Bonillo C. , Baroiller J.F. , D’Cotta H. , Kocher T.
Published: June 2007

Sox genes encode transcription factors that are involved in a variety of embryonic developmental pathways. Sox2 and Sox14 are located on the same chromosomal arm in several mammalian and bird species and on the basis of comparative maps were suggested as candidate genes for the major sex-determining locus on tilapia LG3. We have sequenced the sox2 and sox14 genes in four tilapia species and mapped them to different chromosomes, LG17 and LG23 respectively. Although excluded as being one of the major sex-determining genes so far mapped in tilapia, sox14 did fall within a QTL region for growth, stress response, embryonic mortality and a minor effect on sex determination.
Accounting for Relatedness in Family Based Genetic Association Studies
Authors: McArdle P.F. , O’Connell J.R. , Pollin T.I. , Baumgarten M. , Shuldiner A.R. , Peyser P.A. , Mitchell B.D.
Published: June 2007

Objective: Assess the differences in point estimates, power and type 1 error rates when accounting for and ignoring family structure in genetic tests of association. Methods: We compare by simulation the performance of analytic models using variance components to account for family structure and regression models that ignore relatedness for a range of possible family based study designs (i.e., sib pairs vs. large sibships vs. nuclear families vs. extended families). Results: Our analyses indicate that effect size estimates and power are not significantly affected by ignoring family structure. Type 1 error rates increase when family structure is ignored, as density of family structures increases, and as trait heritability increases. For discrete traits with moderate levels of heritability and across many common sampling designs, type 1 error rates rise from a nominal 0.05 to 0.11. Conclusion: Ignoring family structure may be useful in screening although it comes at a cost of a increased type 1 error rate, the magnitude of which depends on trait heritability and pedigree configuration.
Changes in Neuroendocrine and Metabolic Hormones Induced by Atypical Antipsychotics in Normal-Weight Patients with Schizophrenia
Authors: Popovic Vera , Doknic Mirjana , Maric Nadja , Pekic Sandra , Damjanovic Aleksandar , Miljic Dragana , Popovic Srdjan , Miljic Natasa , Djurovic Marina , Jasovic-Gasic Miroslava , Dieguez Carlos , Casanueva Felipe F.
Published: June 2007

Context: Atypical antipsychotics (SGA) have the propensity to induce weight gain. Objective: The aim was to evaluateearly changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels. Design: We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study. Setting and Patients: Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University. Intervention: Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months. Results: At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals. Conclusions: Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.
Availability Influences Initial and Continued Ingestion of Nicotine by Adolescent Female Rats
Authors: Biondolillo K.D. , Pearce A.R.
Published: June 2007

Background: The availability of tobacco products is associated with the likelihood that adolescents will begin using tobacco. Yet the relationship between nicotine availability and voluntary consumption has not been tested experimentally in developing rats. Method: The impact of environmental availability on adolescent female rats’ initial reaction to and continued ingestion of a novel solution (nicotine or control) was compared using a standard 2-bottle free-choice method and a multiple-bottle method. Results: Manipulating the ratio of bottles containing novel solution to water directly influenced the amount of both nicotine and control solutions consumed. Although subtle differences emerged in intake patterns with prolonged exposure, overall intake patterns were remarkably similar for nicotine and control solutions. Conclusion: The intake of oral nicotine was directly influenced by the availability of nicotine solution relative to water. The results indicate that simply providing the right environment is sufficient, and perhaps necessary, to increase rats’ voluntary consumption of a nicotine solution without relying on deprivation or sweetening of the solution. That overall intake patterns were comparable for nicotine and control solutions suggests that this may be a general principle of rodent behavior rather than an effect specific to nicotine.
Perazine and Carbamazepine in Comparison to Olanzapine in Schizophrenia
Authors: Ohlmeier M.D. , Jahn K. , Wilhelm-Gössling C. , Gödecke-Koch T. , Hoffmann J. , Seifert J. , Emrich H.M. , Schneider U.
Published: June 2007

Atypical antipsychotics like olanzapine are more efficacious in treating negative symptoms and have less side effects. Nevertheless, important adverse effects of olanzapine are, for example, weight gain and hyperglycemia. Perazine in combination with carbamazepine has shown satisfying results in several single-schizophrenia patients, leading to the hypothesis of being equal or even superior to atypical antipsychotic monotherapy. The aim of the present study was to survey the hypothesis that perazine in combination with carbamazepine have an outcome and risk of side effects comparable to olanzapine. Eleven patients with DSM-IV schizophrenia received 14.0 ± 5.0 mg/day olanzapine and 12 patients received 360.0 ± 196.0 mg/day perazine in combination with 404.0 ± 229.0 mg/day carbamazepine. Symptoms and neuropsychological state were assessed 3 times (days 0, 7, 21) using the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale. The neuropsychological state was assessed by the following neuropsychological tests: Benton, d2, ZVT, VLMT and MWT-B. Data were analyzed of variance for multiple dependent variables and repeated-measures multivariate analysis of variance. Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores showed superior improvement in the group receiving olanzapine. Olanzapine offers a more favorable response in positive symptoms than does perazine in combination with carbamazepine. The effect on negative symptoms is favorable in both forms of therapy and no significant differences between the groups could be determined. In both groups, treatment was associated with improved performance in cognitive tests; however, no differences were determined in the effects of the drugs. Results suggest that olanzapine offers a better response in positive symptoms than perazine in combination with carbamazepine.
Circadian Rhythm of Hydration in Healthy Subjects and Uremic Patients Studied by Bioelectrical Impedance Analysis
Authors: Buemi Michele , Campo Susanna , Sturiale Alessio , Aloisi Carmela , Romeo Adolfo , Nostro Lorena , Crascì Eleonora , Ruello Antonella , Manfredini Roberto , Floccari Fulvio , Cosentini Vincenzo , Frisina Nicola
Published: June 2007

Background: Healthy subjects and patients after successful kidney transplantation show a circadian rhythm for glomerular filtration rate and for the glomerular transport of macromolecules. We aimed to evaluate by bioelectrical impedance analysis (BIA) whether body hydration status also follows a circadian rhythm in patients with impaired renal function. Methods: The study was conducted on 28 subjects divided into 3 groups: 8 healthy volunteers, 8 patients affected by chronic kidney disease and 12 end-stage renal disease (ESRD) patients on hemodialysis. During 24 h, 9 BIA measurements were taken in every subject every 180 min. Results: BIA findings demonstrate that normal subjects have a circadian rhythm in hydration status that reaches maximum body water content at night, between 21.00 and 23.00 h. In patients with chronic kidney disease, this rhythm, with maximum at night, is maintained. The rhythm is also present in ESRD patients, if the residual diuresis is at least 500 ml/day, while there is no rhythm when residual diuresis is <300 ml/day. Conclusions: In normal subjects, body hydration status shows a circadian rhythm, which is weakened or lost in oligoanuric patients on dialysis, but partially maintained in subjects with preterminal uremia and in hemodialyzed patients with residual diuresis >500 ml/day.
Investigation of the Ba2+-Sensitive NH4+ Transport Pathways in the Apical Cell Membrane of Primary Cultured Rabbit MTAL Cells
Authors: Jans Frank , Balut Corina , Ameloot Marcel , Wouters Patrick , Steels Paul
Published: June 2007

Background: Several apical ammonium (NH4+/NH3) transport pathways have been described in medullary thick ascending limb (MTAL) cells. The exact nature and importance of some of these pathways remain controversial. Methods: Ammonium transport in primary cultured rabbit MTAL cells was investigated by measuring intracellular pH (pHi). Results: To create physiological conditions, experiments were performed in the symmetrical presence of NH4Cl, which acidified the cells to pHi 6.89. When blockers of apical NH4+ transport were used, the cells alkalinized due to a decreased NH4+ loading. The following values (pH units) were observed: bumetanide, +0.05; verapamil, +0.04; Ba2+ and Cs+, +0.19; tertiapin, +0.09. Tetraethylammonium had no effect. Depolarizing the cells by increasing the K+ concentration alkalinized the cells by 0.16 pH units. Because NH4+ might enter through nonspecific channels, ammonium pulse experiments were performed: an NH4Cl pulse acidified controls as well as depolarized cells. In contrast, when Ba2+, Cs+ or tertiapin were present, an NH4Cl pulse alkalinized the cells. The pharmacological profile of this apical NH4+ transport pathway correlates with the renal outer medullary K+ (ROMK) channel. Indirect immunofluorescence showed the presence of the ROMK protein. Conclusion: In these MTAL cells the Ba2+-sensitive component of NH4+ transport is predominant and consists of permeation of NH4+ through an apical ROMK-related channel.
Absence of Association between Codon 129 and 219 Polymorphisms of the Prion Protein Gene and Vascular Dementia
Authors: Jeong Byung-Hoon , Na Hae-Ri , Bae Jae-Chun , Lee Kyung-Hee , Lee Yun-Jung , Kim Nam-Ho , Song Joon-Ho , Carp Richard I. , Kim Yong-Sun
Published: June 2007

Background: Polymorphisms of the prion protein gene (PRNP) are known to cause a strong susceptibility to the occurrence of prion diseases, such as Creutzfeldt-Jakob disease, and might be associated with other neurodegenerative disorders. However, an association between PRNP polymorphisms and vascular dementia (VaD) has not been reported thus far. Objective: To investigate whether the PRNP polymorphisms are associated with an increased risk for developing VaD in the Korean population. Methods: We compared the genotype, allele and haplotype frequencies of PRNP polymorphisms in 160 VaD patients with those in 236 healthy Koreans. Results and Conclusion: Codon 129 (M129V) and 219 (Q219K) polymorphisms in Korean VaD patients were found in the open reading frame of PRNP. Our study shows that there is no significant difference in the genotype, allele and haplotype frequencies of PRNP codon 129 and 219 polymorphisms between Korean VaD patients and normal controls. This was the first genetic association study of the polymorphisms of PRNP with VaD.
Structural Correlates of Apathy in Alzheimer’s Disease
Authors: Apostolova Liana G. , Akopyan Gohar G. , Partiali Negar , Steiner Calen A. , Dutton Rebecca A. , Hayashi Kiralee M. , Dinov Ivo D. , Toga Arthur W. , Cummings Jeffrey L. , Thompson Paul M.
Published: June 2007

Background: Apathy is the most common noncognitive symptom inAlzheimer’s disease (AD). The structural correlates of apathy in AD have not yet been described. Methods: We analyzed magnetic resonance imaging data of 35 AD patients with and without apathy. Results: There was a significant linear association between apathy severity and cortical gray matter atrophy in the bilateral anterior cingulate [Brodmann area (BA) 24; r = 0.39–0.42, p = 0.01] and left medial frontal cortex (BA 8 and 9; r = 0.4, p < 0.02). Left mean cingulate cortical thinning predicted the presence/absence of apathy at the trend level of significance. Conclusion: Our study demonstrates a strong association between apathy and the integrity of medial frontal regions in AD.
Prevalence of Hepatitis E Virus Antibodies in Patients with Chronic Hepatitis B and Chronic Hepatitis C
Authors: Bayram A. , Eksi F. , Mehli M. , Sözen E.
Published: June 2007

Objectives: To investigate the prevalence of hepatitis E virus (HEV) among patients with chronic hepatitis B and chronic hepatitis C, serum samples were collected between January and December 2004 from patients with chronic hepatitis B and chronic hepatitis C. Methods: There were 190 adult patients with chronic hepatitis B virus (HBV) and 174 with chronic hepatitis C virus (HCV) infection in the study group. As the control group, a cohort of 178 age- and sex-matched individuals without known liver disease was selected. Results: Anti-HEV IgG antibodies were positive in 26/190 (13.7%) of chronic HBV and 94/174 (54%) of chronic HCV patients. In the control group anti-HEV positivity was 15.7% (28/178). There was no difference in the percentage of chronic HBV patients and control group who were positive for anti-HEV antibody, but the presence of HEV infection was significantly higher in chronic HCV patients. Conclusions: Our findings suggest that HEV and HCV might share a common route of transmission in our region. We recommend that preventive measures against HEV should be undertaken in chronic HCV patients as superinfection with HEV can cause a more severe pattern of disease in chronic hepatitis patients.
Ameliorative Effect of Combination of Fenofibrate and Rosiglitazone in Pressure Overload-Induced Cardiac Hypertrophy in Rats
Authors: Rose Madhankumar , Balakumar Pitchai , Singh Manjeet
Published: June 2007

The present study has been designed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α agonist, rosiglitazone, a PPARγ agonist and the combination of both fenofibrate and rosiglitazone in partial abdominal aortic constriction (PAAC)-induced pathological cardiac hypertrophy in rats. Rats were subjected to PAAC for 4 weeks to produce pathological cardiac hypertrophy. The fenofibrate (3 mg/kg day–1, p.o.), rosiglitazone (3 mg/kg day–1, p.o.) and the combination of both fenofibrate (3 mg/kg day–1, p.o.) and rosiglitazone (3 mg/kg day–1, p.o.) were administered 3 days before PAAC and continued for 4 weeks after PAAC. The development of cardiac hypertrophy was assessed in terms of measuring ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content and LV collagen content. Further, the collagen accumulation in left ventricle was analyzed using picrosirius red staining. Moreover, the cross-sectional area (CSA) of cardiomyocytes was assessed using hematoxylin and eosin staining and measured using a NIH Scion image analyzer. The PAAC produced cardiac hypertrophy by increasing LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. However, treatment with fenofibrate and rosiglitazone either alone or in combination significantly attenuated PAAC-induced increase in LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. The combination of fenofibrate and rosiglitazone was more effective in attenuating the PAAC-induced cardiac hypertrophy than either drug alone. Thus, it may be concluded that dual activation of PPARα and PPARγ may provide synergistic benefits in preventing the development of pathological cardiac hypertrophy.
Screening Candidate Longevity Therapeutics Using Gene-Expression Arrays
Authors: Spindler Stephen R. , Mote Patricia L.
Published: June 2007

Background: We review studies showing that CR acts rapidly, even in late adulthood, to extend health- and lifespan in mice. These rapid physiological effects are closely linked to patterns of gene expression in liver and heart. Non-human primate and human studies suggest that the signal transduction pathways responsible for the lifespan and health effects of caloric restriction (CR) may also be involved in human longevity. Thus, pharmaceuticals capable of mimicking the effects of CR (and other methods of lifespan extension) may have application to human health. Objective: We show that lifespan studies are an inefficient and theoretically problematic way of screening for longevity therapeutics. We review studies suggesting that rapid changes in patterns of gene expression can be used to identify pharmaceuticals capable of mimicking some positive effects of caloric restriction. Results: We present a traditional study of the effects of melatonin, melatonin and pregnenolone, aminoguanidine, aminoguanidine and α-lipoic acid, aminoguanidine, α-lipoic acid, pregnenolone, and coenzyme-Q10 on the lifespan of mice. No treatment extended lifespan. However, because the mice die mostly of cancer, only chemopreventives active against specific cancers can be identified by such studies. The studies were also time-consuming and expensive. We discuss high-density microarray studies of the effectiveness of glucoregulatory drugs and putative cancer chemopreventatives at reproducing the hepatic gene-expression profiles of long-term and short-term CR. We describe the identification of one compound, metformin, which reproduces a subset of the gene-expression and physiological effects of CR. Conclusion: Taken together, our results suggest that gene-expression biomarkers may be superior to lifespan studies for initial screening of candidate longevity therapeutics.
Severe Postnatal Cytomegalovirus Infection in a Very Premature Infant
Authors: Takahashi Ritsuko , Tagawa Masato , Sanjo Masatoshi , Chiba Hiroo , Ito Takeshi , Yamada Masaaki , Nakae Shingi , Suzuki Akira , Nishimura Hidekazu , Naganuma Masako , Tominaga Norio , Moriuchi Masako , Moriuchi Hiroyuki
Published: June 2007

Several studies have reported that postnatally acquired cytomegalovirus (CMV) infection can cause sepsis-like syndrome in premature infants. We here report a 622-gram birth weight male infant of 23 weeks’ gestation who had sepsis-like syndrome and pneumonia. Substantial CMV loads were detected in peripheral blood cells, plasma, and urine when the patient was in crisis, but was decreased in parallel to clinical improvement without using ganciclovir. CMV DNA was not detected from his umbilical cord or Guthrie card, even by highly sensitive real-time PCR. Molecular profiles were indistinguishable between the CMV strain isolated from his urine and that from maternal breast milk, indicating postnatal acquisition of CMV through breast milk. Although he had transient hearing impairment, his neurodevelopmental outcome of 30 months of corrected age was normal. Further accumulation of clinical and virological data in postnatal CMV infection is necessary for evaluating the severity and selecting patients requiring antiviral therapy.
Formalin-Fixed Staphylococcus aureus Particles Prevent Allergic Sensitization in a Murine Model of Type I Allergy
Authors: Gisch Karina , Gehrke Nadine , Bros Matthias , Priesmeyer Christina , Knop Jürgen , Reske-Kunz Angelika B. , Sudowe Stephan
Published: June 2007

Background: Bacterial infections are supposed to act counterregulatory to the development of allergen-specific Th2 immune responses. We analyzed whether administration of extracellular Staphylococcus aureus inhibited experimental sensitization against allergens. Methods: BALB/c mice were immunized with alum-adsorbed ovalbumin (OVA) together with formalin-fixed Staphylococcus particles. OVA-specific antibody production and cytokine synthesis by spleen cells was analyzed. Airway reactivity and cellular infiltration into the airways was assessed after intranasal challenge of mice with OVA. In addition, the capacity of Staphylococcus particles to modulate cytokine production by bone marrow-derived dendritic cells was analyzedin vitro. Results: Simultaneous application of OVA and Staphylococcus particles very efficiently inhibited production of specific IgE and IgG1 as well as secretion of IL-4 and IL-5 by splenocytes, while enhancing IgG2a formation and production of IFN-γ, indicating a shift from a Th2 response towards a Th1-biased response. This effect was not dependent on the expression of protein A by Staphylococcus. An enhanced frequency or activity of regulatory T cells after administration of Staphylococcus particles was not apparent. Treatment of mice with Staphylococcus particles during the sensitization phase prevented lung inflammation (airway hyperreactivity, eosinophilia) after local challenge with OVA. Culture of bone marrow-derived dendritic cells with Staphylococcus particles induced IL-12p35 and p40 mRNA expression as well as secretion of IL-12p70, and increased production of IL-10 mRNA and protein. Conclusions: Administration of formalin-fixed Staphylococcus particles induced Th1-biased immune responses and prevented allergic sensitization.
Increased Adiponectin Secretion by Highly Purified Eicosapentaenoic Acid in Rodent Models of Obesity and Human Obese Subjects
Authors: Itoh Michiko , Suganami Takayoshi , Satoh Noriko , Tanimoto-Koyama Kanami , Yuan Xunmei , Tanaka Miyako , Kawano Hiroyuki , Yano Takashi , Aoe Seiichiro , Takeya Motohiro , Shimatsu Akira , Kuzuya Hideshi , Kamei Yasutomi , Ogawa Yoshihiro
Published: June 2007

Objectives—

Fish oil rich in
n-3
polyunsaturated fatty acids (PUFAs) or
n-3
PUFAs have been shown to reduce the incidence of coronary heart disease. Here we investigated the effect of highly purified eicosapentaenoic acid (EPA) on production of adiponectin, the only established antiatherogenic and antiinflammatory adipocytokine, in rodent models of obesity and human obese subjects.

Methods and Results—

We demonstrated that EPA increases adiponectin secretion in genetically obese
ob/ob
mice and high-fat diet–induced obese mice. In the in vitro coculture of adipocytes and macrophages, EPA reversed the coculture-induced decrease in adiponectin secretion at least in part through downregulation of tumor necrosis factor-α in macrophages. We also showed significant increase in plasma adiponectin concentrations in human obese subjects after a 3-month treatment with EPA (1.8 g daily). Multivariate regression analysis revealed that EPA treatment is the only independent determinant of plasma adiponectin concentrations.

Conclusion—

This study demonstrates that EPA increases adiponectin secretion in rodent models of obesity and human obese subjects, possibly through the improvement of the inflammatory changes in obese adipose tissue. Because EPA has reduced the risk of major coronary events in a large-scale, prospective, randomized clinical trial, this study provides important insight into its therapeutic implication in obesity-related metabolic sequelae.
A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease
Authors: Luke May M. , Kane John P. , Liu Dongming M. , Rowland Charles M. , Shiffman Dov , Cassano June , Catanese Joseph J. , Pullinger Clive R. , Leong Diane U. , Arellano Andre R. , Tong Carmen H. , Movsesyan Irina , Naya-Vigne Josephina , Noordhof Curtis , Feric Nicole T. , Malloy Mary J. , Topol Eric J. , Koschinsky Marlys L. , Devlin James J. , Ellis Stephen G.
Published: June 2007

Objectives—

The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD).

Methods and Results—

We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in
LPA
,
CALM1
,
HAP1
,
AP3B1
, and
ABCG2
) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD:
LPA
I4399M (rs3798220).
LPA
encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (
P
=0.003).

Conclusions—

The
LPA
I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.
Thrombospondins, Their Polymorphisms, and Cardiovascular Disease
Authors: Stenina Olga I. , Topol Eric J. , Plow Edward F.
Published: June 2007

The thrombospondins are a 5-member gene family that mediate cell-cell and cell-matrix interactions. The thrombospondins are either trimers or pentamers, and their functions depend on their abilities to interact with numerous extracellular ligands and cell surface receptors through the multiple domains that compose each subunit. Recent genetic studies have indicated associations of particular single nucleotide polymorphisms in 3 of the 5 thrombospondins with cardiovascular disease. This observation has stimulated efforts to understand how the thrombospondins influence cardiovascular pathology, to dissect how the individual polymorphisms alter the structure and function of the parent thrombospondin molecules, and to replicate the genetic data in different patient populations. This review seeks to summarize current information that has emerged on each of these fronts.
Increased Uridine Adenosine Tetraphosphate Concentrations in Plasma of Juvenile Hypertensives
Authors: Jankowski Vera , Meyer Andreas-Alexander , Schlattmann Peter , Gui Yu , Zheng Xi-long , Stamcou Irini , Radtke Kristina , Anh Tran Thi Nguyet , van der Giet Markus , Tölle Markus , Zidek Walter , Jankowski Joachim
Published: June 2007

Background—Uridine adenosine tetraphosphate (Up4A) was been recently characterized as a potent vasoconstrictor. Up4A occurs in plasma from healthy subjects at concentrations sufficient to cause strong vasoconstrictive effects. In this study, Up4A concentrations in plasma from juvenile hypertensives and normotensives were determined.

Methods and Results—Up4A was purified to homogeneity by preparative reverse phase high performance liquid-chromatography (HPLC), affinity chromatography HPLC, and analytic reverse phase HPLC from deproteinized plasma of juvenile hypertensives and normotensives. Mean total plasma Up4A concentration was significantly increased in juvenile hypertensives compared with juvenile normotensives (33.0±25.4 versus 3.7±0.9 nmol/L; mean±SEM, n=40 and 38, respectively;P<0.005). Accordingly, Up4A showed a significant association with juvenile hypertension (OR for ln(Up4A): 1.82; 95% CI 1.12, 2.95). Plasma Up4A concentrations correlated with left ventricular mass (Kendall-τ correlation coefficient 0.220, n=40;P<0.05) and intima media wall thickness (Kendall-τ correlation coefficient 0.296, n=40;P<0.05) in the hypertensives. Because the increased intima media thickness may be related to proliferative effects of Up4A, we studied the effects of Up4A on human vascular smooth muscle cell proliferation. The maximum proliferative effect of Up4A was 80.0±24.0% % above control (P<0.01). The proliferative effect of Up4A on smooth muscle cells is cell cycle–dependent, involving stimulation of S phase entry.

Conclusion—Circulating levels of Up4A are strongly associated with juvenile hypertension. The endothelium-derived vasoconstrictor Up4A may contribute to the early development of primary hypertension and is moreover an important risk factor of juvenile hypertension.
A Systematic Review and Meta-Analysis of Statin Therapy in Children With Familial Hypercholesterolemia
Authors: Avis H.J. , Vissers M.N. , Stein E.A. , Wijburg F.A. , Trip M.D. , Kastelein J.J.P. , Hutten B.A.
Published: June 2007

Objective—

Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH.

Methods and Results—

We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing ≥1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK ≥10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of ≥3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm).

Conclusion—

In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.
Preferential Sphingosine-1-Phosphate Enrichment and Sphingomyelin Depletion Are Key Features of Small Dense HDL3 Particles
Authors: Kontush Anatol , Therond Patrice , Zerrad Amal , Couturier Martine , Négre-Salvayre Anne , de Souza Juliana A. , Chantepie Sandrine , Chapman M. John
Published: June 2007

Objective—

The purpose of this study was to define heterogeneity in the molecular profile of lipids, including sphingomyelin and sphingosine-1-phosphate, among physicochemically-defined HDL subpopulations and potential relevance to antiatherogenic biological activities of dense HDL3.

Methods and Results—

The molecular profile of lipids (cholesteryl esters, phospholipids, sphingomyelin, and sphingosine-1-phosphate) in physicochemically-defined normolipidemic HDL subpopulations was determined by high-performance liquid chromatography and gas chromatography. As HDL particle size and molecular weight decreased with increment in density, molar lipid content diminished concomitantly. On a % basis, sphingomyelin abundance diminished in parallel with progressive increase in HDL density from HDL2b (12.8%) to HDL3c (6.2%;
P
<0.001); in contrast, sphingosine-1-phosphate was preferentially enriched in small HDL3 (40 to 50 mmol/mol HDL) versus large HDL2 (15 to 20 mmol/mol HDL;
P
<0.01). Small HDL3c was equally enriched in LpA-I particles relative to LpA-I:A-II. The sphingosine-1-phosphate/sphingomyelin ratio correlated positively with the capacities of HDL subspecies to attenuate apoptosis in endothelial cells (
r
=0.73,
P
<0.001) and to retard LDL oxidation (
r
=0.58,
P
<0.01).

Conclusions—

An elevated sphingosine-1-phosphate/sphingomyelin ratio is an integral feature of small dense HDL3, reflecting enrichment in sphingosine-1-phosphate, a key antiapoptotic molecule, and depletion of sphingomyelin, a structural lipid with negative impact on surface fluidity and LCAT activity. These findings further distinguish the structure and antiatherogenic activities of small, dense HDL.
Endothelin-1, but not Ang II, Activates MAP Kinases Through c-Src–Independent Ras-Raf–Dependent Pathways in Vascular Smooth Muscle Cells
Authors: Yogi A. , Callera G.E. , Montezano A.C.I. , Aranha A.B. , Tostes R.C. , Schiffrin E.L. , Touyz R.M.
Published: June 2007

Objective—Endothelin-1 (ET-1) and angiotensin II (Ang II) activate common signaling pathways to promote changes in vascular reactivity, remodeling, inflammation, and oxidative stress. Here we sought to determine whether upstream regulators of mitogen-activated protein kinases (MAPKs) are differentially regulated by ET-1 and Ang II focusing on the role of c-Src and the small GTPase Ras.

Methods and Results—Mesenteric vascular smooth muscle cells (VSMCs) from mice with different disruption levels in the c-Src gene (c-Src+/−and c-Src−/−) and wild-type (c-Src+/+) were used. ET-1 and Ang II induced extracellular signal-regulated kinase (ERK) 1/2, SAPK/JNK, and p38MAPK phosphorylation in c-Src+/+VSMCs. In VSMCs from c-Src+/−and c-Src−/−, Ang II effects were blunted, whereas c-Src deficiency had no effect in ET-1–induced MAPK activation. Ang II but not ET-1 induced c-Src phosphorylation in c-Src+/+VSMCs. Activation of c-Raf, an effector of Ras, was significantly increased by ET-1 and Ang II in c-Src+/+VSMCs. Ang II but not ET-1–mediated c-Raf phosphorylation was inhibited by c-Src deficiency. Knockdown of Ras by siRNA inhibited both ET-1 and Ang II–induced MAPK phosphorylation.

Conclusions—Our data indicate differential regulation of MAPKs by distinct G protein–coupled receptors. Whereas Ang II has an obligatory need for c-Src, ET-1 mediates its actions through a c-Src–independent Ras-Raf–dependent pathway for MAPK activation. These findings suggest that Ang II and ET-1 can activate similar signaling pathways through unrelated mechanisms. MAP kinases are an important point of convergence for Ang II and ET-1.