bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking Alu evolution in New World primates
Authors: Ray David A , Batzer Mark A
Published: October 2005

Background

Alu elements are Short INterspersed Elements (SINEs) in primate genomes that have proven useful as markers for studying genome evolution, population biology and phylogenetics. Most of these applications, however, have been limited to humans and their nearest relatives, chimpanzees. In an effort to expand our understanding of Alu sequence evolution and to increase the applicability of these markers to non-human primate biology, we have analyzed available Alu sequences for loci specific to platyrrhine (New World) primates.

Results

Branching patterns along an Alu sequence phylogeny indicate three major classes of platyrrhine-specific Alu sequences. Sequence comparisons further reveal at least three New World monkey-specific subfamilies; Alu Ta7, Alu Ta10, and Alu Ta15. Two of these subfamilies appear to be derived from a gene conversion event that has produced a recently active fusion of Alu Sc- and Alu Sp-type elements. This is a novel mode of origin for new Alu subfamilies.

Conclusion

The use of Alu elements as genetic markers in studies of genome evolution, phylogenetics, and population biology has been very productive when applied to humans. The characterization of these three new Alu subfamilies not only increases our understanding of Alu sequence evolution in primates, but also opens the door to the application of these genetic markers outside the hominid lineage.
The distribution of SNPs in human gene regulatory regions
Authors: Guo Yongjian , Jamison D Curtis
Published: October 2005

Background

As a result of high-throughput genotyping methods, millions of human genetic variants have been reported in recent years. To efficiently identify those with significant biological functions, a practical strategy is to concentrate on variants located in important sequence regions such as gene regulatory regions.

Results

Analysis of the most common type of variant, single nucleotide polymorphisms (SNPs), shows that in gene promoter regions more SNPs occur in close proximity to transcriptional start sites than in regions further upstream, and a disproportionate number of those SNPs represent nucleotide transversions. Additionally, the number of SNPs found in the predicted transcription factor binding sites is higher than in non-binding site sequences.

Conclusion

Current information about transcription factor binding site sequence patterns may not be exhaustive, and SNPs may be actively involved in influencing gene expression by affecting the transcription factor binding sites.
Sequence diversity within the HA-1 gene as detected by melting temperature assay without oligonucleotide probes
Authors: Graziano Claudio , Giorgi Massimo , Malentacchi Cecilia , Mattiuz Pier Luigi , Porfirio Berardino
Published: October 2005

Background

The minor histocompatibility antigens (mHags) are self-peptides derived from common cellular proteins and presented by MHC class I and II molecules. Disparities in mHags are a potential risk for the development of graft-versus-host disease (GvHD) in the recipients of bone marrow from HLA-identical donors. Two alleles have been identified in the mHag HA-1. The correlation between mismatches of the mHag HA-1 and GvHD has been suggested and methods to facilitate large-scale testing were afterwards developed.

Methods

We used sequence specific primer (SSP) PCR and direct sequencing to detect HA-1 gene polymorphisms in a sample of 131 unrelated Italian subjects. We then set up a novel melting temperature (Tm) assay that may help identification of HA-1 alleles without oligonucleotide probes.

Results

We report the frequencies of HA-1 alleles in the Italian population and the presence of an intronic 5 base-pair deletion associated with the immunogeneic allele HA-1H. We also detected novel variable sites with respect to the consensus sequence of HA-1 locus. Even though recombination/gene conversion events are documented, there is considerable linkage disequilibrium in the data. The gametic associations between HA-1R/H alleles and the intronic 5-bp ins/del polymorphism prompted us to try the Tm analysis with SYBR® Green I. We show that the addition of dimethylsulfoxide (DMSO) during the assay yields distinct patterns when amplicons from HA-1H homozygotes, HA-1R homozygotes, and heterozygotes are analysed.

Conclusion

The possibility to use SYBR® Green I to detect Tm differences between allelic variants is attractive but requires great caution. We succeeded in allele discrimination of the HA-1 locus using a relatively short (101 bp) amplicon, only in the presence of DMSO. We believe that, at least in certain assets, Tm assays may benefit by the addition of DMSO or other agents affecting DNA strand conformation and stability.
Prevalence of abnormal findings on brain magnetic resonance (MR) examinations in adult participants of brain docking
Authors: Tsushima Yoshito , Taketomi-Takahashi Ayako , Endo Keigo
Published: October 2005

Background

To determine the prevalence of abnormal findings on brain magnetic resonance (MR) examinations in adult participants of brain docking in order to assess its usefulness.

Methods

We analyzed screening brain MR examinations for 1113 adults (age, 52.6+/-8.5 years; range, 22–84; 761 male and 352 female) performed during 6-year period from April 1998 to March 2004. All participants voluntarily sought a brain MR examination at their own expense. All subjects were studied using the same 1.0-T MR scanner, on axial T1-weighted spin echo (SE) images, proton-density-weighted and T2-weighted fast SE images, and intracranial MR angiography (MRA). All abnormal findings were classified into three basic categories: (1) findings with no referral necessary; (2) findings not requiring further evaluation, but which needed to be reported to the referring physician; (3) findings requiring further evaluation.

Results

Participants with abnormal MR findings requiring further evaluation accounted for 1.3 %, but five of seven suspected intracranial aneurysms were not confirmed by other imaging modalities (false positive). No malignant tumors or other life-threatening pathology was detected, and only three participants (0.27 %) with abnormalities underwent surgical treatment. No participant groups were identified from our data as being high risk for MR abnormal findings requiring further evaluation.

Conclusion

Brain-docking participants had a variety of abnormalities on brain MR examinations, but only a small percentage of these findings required further evaluation. The usefulness of the brain docking with MRI and MRA has yet to be proven, and at this time we cannot approve this screening procedure.
Citalopram associated with acute angle-closure glaucoma: case report
Authors: Croos Robert , Thirumalai Srinivasa , Hassan Sabit , Davis Jane Da Roza
Published: October 2005

Background

Acute angle-closure glaucoma is a rare complication in patients receiving anti-depressant treatment. In the following case, we report the development of acute angle closure glaucoma in a patient who overdosed on Citalopram, an antidepressant, and discuss the possible etiological mechanisms for the condition.

Case presentation

We report a 54 year old, Caucasian lady, with depression and alcohol dependence syndrome, who developed acute angle-closure glaucoma after an overdose of Citalopram, along with alcohol. She was treated with medications and had bilateral Yag laser iridotomies to correct the glaucoma and has made complete recovery. In this case, the underlying cause for glaucoma appears to be related to the ingestion of Citalopram.

Conclusion

The patho-physiological basis for acute angle closure glaucoma in relation to antidepressant medications remains unclear. The authors suggest Citalopram may have a direct action on the Iris or Ciliary body muscle through serotonergic or anti-cholinergic mechanisms or both. This case highlights the importance of the awareness of the underlying risks, which may predispose an individual to develop acute angle-closure glaucoma, and reminds the clinicians the significance of history taking and examination of the eye before and after starting anti-depressants. This area needs to be further researched.
Chronic koro-like symptoms – two case reports
Authors: Kar Nilamadhab
Published: October 2005

Background

Koro is a culture bound syndrome, which has been reported usually from Asian countries. It has been described as an acute, brief lasting illness, which often occurs in epidemics. There is no description in literature of a chronic form of this syndrome.

Case presentation

Two sporadic cases with koro-like symptoms from East India are presented where the illness had a chronic course with durations spanning more than ten years. In contrast to acute, good prognosis, psycho-education responsive form that is usually seen in epidemics; the chronic form, appeared to be associated with greater morbidity and poorer response to interventions.

Conclusion

There is a possibility of a chronic form of koro syndrome.
Is relatively young age within a school year a risk factor for mental health problems and poor school performance? A population-based cross-sectional study of adolescents in Oslo, Norway
Authors: Lien Lars , Tambs Kristian , Oppedal Brit , Heyerdahl Sonja , Bjertness Espen
Published: October 2005

Background

Several studies have shown that children who are relatively young within a school year are at greater risk for poorer school performance compared with their older peers. One study also reported that relative age within a school year is an independent risk factor for emotional and behavioral problems. The objective of this study was to test the hypothesis that relatively younger adolescents in the multiethnic population of Oslo have poorer school performance and more mental health problems than their relatively older classmates within the same school year.

Methods

This population-based cross-sectional study included all 10th-grade pupils enrolled in 2000 and 2001 in the city of Oslo. The participation rate was 88%. Of the 6,752 pupils in the study sample, 25% had a non-Norwegian background. Mental health problems were quantified using the abbreviated versions of Symptom Check List-25 (SCL-10) and the Strength and Difficulties Questionnaire (SDQ). Information on school performances and mental health problems were self-reported. We controlled for confounding factors including parental educational level, social support, gender, and ethnicity.

Results

The youngest one-third of pupils had significantly lower average school grades than the middle one-third and oldest one-third of their classmates (p < 0.001). Of the mental health problems identified in the questionnaires, the groups differed only on peer problems; the youngest one-third reported significantly more problems than the middle and oldest groups (p < 0.05). Age within a school year and gender showed significant interactions with total SDQ score, SDQ peer problems score, SDQ pro social score, and SCL-10 score. After stratifying for gender, the peer problem scores differed significantly between age groups only among boys. The SCL-10 score was significant, but only in girls and in the opposite direction to that expected, with the oldest pupils having significantly higher scores than the other two groups (p < 0.05).

Conclusion

In adolescents from a multicultural city in Norway, relative age within a school year significantly influenced academic performance. In contrast to data from Great Britain, relative age within a school year was not an important risk factor for mental health problems in adolescents in Oslo.
Work ethics and general work attitudes in adolescents are related to quality of life, sense of coherence and subjective health – a Swedish questionnaire study
Authors: Axelsson Lars , Andersson Ingemar , Håkansson Anders , Ejlertsson Göran
Published: October 2005

Background

Working life is an important arena in most people's lives, and the working line concept is important for the development of welfare in a society. For young people, the period before permanent establishment in working life has become longer during the last two decades. Knowledge about attitudes towards work can help us to understand young people's transition to the labour market. Adolescents are the future workforce, so it seems especially important to notice their attitudes towards work, including attitudes towards the welfare system. The aim of this study was to describe and analyse upper secondary school students' work attitudes, and to explore factors related to these attitudes.

Methods

The sample consisted of 606 upper secondary school students. They all received a questionnaire including questions about quality of life (QOL), sense of coherence (SOC), subjective health and attitudes towards work. The response rate was 91%. A factor analysis established two dimensions of work attitudes. Multivariate analyses were carried out by means of logistic regression models.

Results

Work ethics (WE) and general work attitudes (GWA) were found to be two separate dimensions of attitudes towards work. Concerning WE the picture was similar regardless of gender or study programme. Males in theoretical programmes appeared to have more unfavourable GWA than others. Multivariate analyses revealed that good QOL, high SOC and good health were significantly related to positive WE, and high SOC was positively related to GWA. Being female was positively connected to WE and GWA, while studying on a practical programme was positively related to GWA only. Among those who received good parental support, GWA seemed more favourable.

Conclusion

Assuming that attitudes towards work are important to the working line concept, this study points out positive factors of importance for the future welfare of the society. Individual factors such as female gender, good QOL, high SOC and good health as well as support from both parents, positive experience of school and work contacts related positively to attitudes towards work. Further planning and supportive work have to take these factors into account.
Conventional liquid-based techniques versus Cytyc Thinprep® processing of urinary samples: a qualitative approach
Authors: Piaton Eric , Faÿnel Jacqueline , Hutin Karine , Ranchin Marie-Claude , Cottier Michèle
Published: October 2005

Background

The aim of our study was to objectively compare Cytyc Thinprep® and other methods of obtaining thin layer cytologic preparations (cytocentrifugation, direct smearing and Millipore® filtration) in urine cytopathology.

Methods

Thinprep slides were compared to direct smears in 79 cases. Cytocentrifugation carried out with the Thermo Shandon Cytospin® 4 was compared to Thinprep in 106 cases, and comparison with Millipore filtration followed by blotting was obtained in 22 cases. Quality was assessed by scoring cellularity, fixation, red blood cells, leukocytes and nuclear abnormalities.

Results

The data show that 1) smearing allows good overall results to be obtained, 2) Cytocentrifugation with reusable TPX® chambers should be avoided, 3) Cytocentrifugation using disposable chambers (Cytofunnels® or Megafunnel® chambers) gives excellent results equalling or surpassing Thinprep and 4) Millipore filtration should be avoided, owing to its poor global quality. Despite differences in quality, the techniques studied have no impact on the diagnostic accuracy as evaluated by the rate of abnormalities.

Conclusion

We conclude that conventional methods such as cytocentrifugation remain the most appropriate ones for current treatment of urinary samples. Cytyc Thinprep processing, owing to its cost, could be used essentially for cytology-based molecular studies.
Validity of a self-administered food frequency questionnaire (FFQ) and its generalizability to the estimation of dietary folate intake in Japan
Authors: Ishihara Junko , Yamamoto Seiichiro , Iso Hiroyasu , Inoue Manami , Tsugane Shoichiro ,   the JPHC FFQ Validation Study Group
Published: October 2005

Background

In an epidemiological study, it is essential to test the validity of the food frequency questionnaire (FFQ) for its ability to estimate dietary intake. The objectives of our study were to 1) validate a FFQ for estimating folate intake, and to identify the foods that contribute to inter-individual variation of folate intake in the Japanese population.

Methods

Validity of the FFQ was evaluated using 28-day weighed dietary records (DRs) as gold standard in the two groups independently. In the group for which the FFQ was developed, validity was evaluated by Spearman's correlation coefficients (CCs), and linear regression analysis was used to identify foods with large inter-individual variation. The cumulative mean intake of these foods was compared with total intake estimated by the DR. The external validity of the FFQ and intake from foods on the same list were evaluated in the other group to verify generalizability. Subjects were a subsample from the Japan Public Health Center-based prospective Study who volunteered to participate in the FFQ validation study.

Results

CCs for the internal validity of the FFQ were 0.49 for men and 0.29 and women, while CCs for external validity were 0.33 for men and 0.42 for women. CCs for cumulative folate intake from 33 foods selected by regression analysis were also applicable to an external population.

Conclusion

Our FFQ was valid for and generalizable to the estimation of folate intake. Foods identified as predictors of inter-individual variation in folate intake were also generalizable in Japanese populations. The FFQ with 138 foods was valid for the estimation of folate intake, while that with 33 foods might be useful for estimating inter-individual variation and ranking of individual folate intake.
Ethnic variation in validity of classification of overweight and obesity using self-reported weight and height in American women and men: the Third National Health and Nutrition Examination Survey
Authors: Gillum RF , Sempos Christopher T
Published: October 2005

Background

Few data have been published on the validity of classification of overweight and obesity based on self-reported weight in representative samples of Hispanic as compared to other American populations despite the wide use of such data.

Objective

To test the null hypothesis that ethnicity is unrelated to bias of mean body mass index (BMI) and to sensitivity of overweight or obesity (BMI >= 25 kg/m2) derived from self-reported (SR) versus measured weight and height using measured BMI as the gold standard.

Design

Cross-sectional survey of a large national sample, the Third National Health and Nutrition Examination Survey (NHANES III) conducted in 1988–1994.

Participants

American men and women aged 20 years and over (n = 15,025).

Measurements

SR height, weight, cigarette smoking, health status, and socio-demographic variables from home interview and measured weight and height.

Results

In women and Mexican American (MA) men SR BMI underestimated true prevalence rates of overweight or obesity. For other men, no consistent difference was seen. Sensitivity of SR was similar in non-Hispanic European Americans (EA) and non-Hispanic African Americans (AA) but much lower in MA. Prevalence of obesity (BMI >= 30 kg/m2) is consistently underestimated by self-report, the gap being greater for MA than for other women, but similar for MA and other men. The mean difference between self-reported and measured BMI was greater in MA (men -0.37, women -0.76 kg/m2) than in non-Hispanic EA (men -0.22, women -0.62 kg/m2). In a regression model with the difference between self-reported and measured BMI as the dependent variable, MA ethnicity was a significant (p < 0.01) predictor of the difference in men and in women. The effect of MA ethnicity could not be explained by socio-demographic variables, smoking or health status.

Conclusion

Under-estimation of the prevalence of overweight or obesity based on height and weight self-reported at interview varied significantly among ethnic groups independent of other variables.
Activity of peroxisomal enzymes, and levels of polyamines in LPA-transgenic mice on two different diets
Authors: Eliassen Knut A , Brodal Bjørn P , Svindland Aud , Osmundsen Harald , Rønning Helle , Djurovic Srdjan , Berg Kåre
Published: October 2005

Background

In man, elevated levels of plasma lipoprotein (a)(Lp(a)) is a cardiovascular risk factor, and oxidized phospholipids are believed to play a role as modulators of inflammatory processes such as atherosclerosis. Polyamines are potent antioxidants and anti-inflammatory agents. It was therefore of interest to examine polyamines and their metabolism in LPA transgenic mice.

Concentration of the polyamines putrescine, spermidine and spermine as well as the activity of peroxisomal polyamine oxidase and two other peroxisomal enzymes, acyl-CoA oxidase and catalase were measured. The mice were fed either a standard diet or a diet high in fat and cholesterol (HFHC). Some of the mice in each feeding group were in addition given aminoguanidine (AG), a specific inhibitor of diamine oxidase, which catalyses degradation of putrescine, and also inhibits non-enzymatic glycosylation of protein which is implicated in the aetiology of atherosclerosis in diabetic patients. Non-transgenic mice were used as controls.

Results

Intestinal peroxisomal polyamine oxidase activity was significantly higher in LPA transgenic mice than in the non-transgenic mice, while intestinal peroxisomal catalase activity was significantly lower. Hepatic β-oxidation increased in Lp(a) transgenic mice fed the HFHC diet, but not in those on standard diet.

Hepatic spermidine concentration was increased in all mice fed the HFHC diet compared to those fed a standard diet, while spermine concentration was decreased. With exception of the group fed only standard diet, transgenic mice showed a lower degree of hepatic steatosis than non-transgenic mice. AG had no significant effect on hepatic steatosis.

Conclusion

The present results indicate a connection between peroxisomal enzyme activity and the presence of the human LPA gene in the murine genome. The effect may be a result of changes in oxidative processes in lipid metabolism rather than resulting from a direct effect of the LPA construct on the peroximal gene expression.
Malignant schwannoma of the upper mediastinum originating from the vagus nerve
Authors: Shoji Fumihiro , Maruyama Riichiroh , Okamoto Tatsuro , Wataya Hiroshi , Nishiyama Kenichi , Ichinose Yukito
Published: October 2005

Background

Malignant schwannoma of the upper mediastinum originating from the vagus nerve is extremely rare.

Case presentation

A 46-year-old female was admitted for a left cervical mass which was associated with both hoarseness and Horner's syndrome. Chest computed tomography showed a mass extending from the left upper mediastinum to the left supraclavicular area. A fine needle aspiration cytological examination suggested primary lung cancer stage IIIB large cell carcinoma. After administering induction chemo-radiotherapy, a complete surgical resection was performed. The tumor was found to involve both the left vagus nerve and the left sympathetic nerve. Histological examination of the resected specimen revealed the tumor to be malignant schwannoma.

Conclusion

Despite incorrect preoperative diagnosis, the multimodality treatment administered in this case, including induction chemo-radiotherapy and surgery, proved to be effective.
Human Lsg1 defines a family of essential GTPases that correlates with the evolution of compartmentalization
Authors: Reynaud Emmanuel G , Andrade Miguel A , Bonneau Fabien , Ly Thi Bach Nga , Knop Michael , Scheffzek Klaus , Pepperkok Rainer
Published: October 2005

Background

Compartmentalization is a key feature of eukaryotic cells, but its evolution remains poorly understood. GTPases are the oldest enzymes that use nucleotides as substrates and they participate in a wide range of cellular processes. Therefore, they are ideal tools for comparative genomic studies aimed at understanding how aspects of biological complexity such as cellular compartmentalization evolved.

Results

We describe the identification and characterization of a unique family of circularly permuted GTPases represented by the human orthologue of yeast Lsg1p. We placed the members of this family in the phylogenetic context of the YlqF Related GTPase (YRG) family, which are present in Eukarya, Bacteria and Archea and include the stem cell regulator Nucleostemin. To extend the computational analysis, we showed that hLsg1 is an essential GTPase predominantly located in the endoplasmic reticulum and, in some cells, in Cajal bodies in the nucleus. Comparison of localization and siRNA datasets suggests that all members of the family are essential GTPases that have increased in number as the compartmentalization of the eukaryotic cell and the ribosome biogenesis pathway have evolved.

Conclusion

We propose a scenario, consistent with our data, for the evolution of this family: cytoplasmic components were first acquired, followed by nuclear components, and finally the mitochondrial and chloroplast elements were derived from different bacterial species, in parallel with the formation of the nucleolus and the specialization of nuclear components.
A network approach for researching partnerships in health
Authors: Lewis Jenny M
Published: October 2005

Background

The last decade has witnessed a significant move towards new modes of governing that are based on coordination and collaboration. In particular, local level partnerships have been widely introduced around the world. There are few comprehensive approaches for researching the effects of these partnerships. The aim of this paper is to outline a network approach that combines structure and agency based explanations to research partnerships in health. Network research based on two Primary Care Partnerships (PCPs) in Victoria is used to demonstrate the utility of this approach. The paper examines multiple types of ties between people (structure), and the use and value of relationships to partners (agency), using interviews with the people involved in two PCPs – one in metropolitan Melbourne and one in a rural area.

Results

Network maps of ties based on work, strategic information and policy advice, show that there are many strong connections in both PCPs. Not surprisingly, PCP staff are central and highly connected. Of more interest are the ties that are dependent on these dedicated partnership staff, as they reveal which actors become weakly linked or disconnected without them. Network measures indicate that work ties are the most dispersed and strategic information ties are the most concentrated around fewer people. Divisions of general practice are weakly linked, while local government officials and Department of Human Services (DHS) regional staff appear to play important bridging roles. Finally, the relationships between partners have changed and improved, and most of those interviewed value their new or improved links with partners.

Conclusion

Improving service coordination and health promotion planning requires engaging people and building strong relationships. Mapping ties is a useful means for assessing the strengths and weaknesses of partnerships, and network analysis indicates concentration and dispersion, the importance of particular individuals, and the points at which they will fragment. A narrative approach adds an assessment of whether the partnerships are being used and valued. The approach outlined here, which examines structure and agency as separate but related explanations, has much to offer in examining partnerships.
Dihydrotestosterone Inhibits Insulin-Stimulated Cyclin D2 Messenger Ribonucleic Acid Expression in Rat Ovarian Granulosa Cells by Reducing the Phosphorylation of Insulin Receptor Substrate-1
Authors: Kayampilly Pradeep P. , Menon K. M. J.
Published: October 2005

The effect of 5α-dihydrotestosterone (DHT) on insulin-stimulated granulosa cell proliferation was examined using cyclin D2 mRNA as a marker. Granulosa cells from 3-d estradiol-treated immature rats showed a concentration-dependent increase in cyclin D2 mRNA expression in response to insulin. Exposure to DHT reduced the insulin-stimulated cyclin D2 mRNA expression. Inhibition of the two insulin-signaling pathways, ERK and phosphatidylinositol 3 kinase (PI3 kinase), by using specific inhibitors, also reduced this insulin-stimulated response. These results suggest that both ERK and PI3 kinase signaling are involved in insulin stimulated granulosa cell proliferation. DHT exposure resulted in reduced insulin-stimulated ERK phosphorylation. DHT treatment also reduced the insulin mediated insulin receptor substrate-1 and Raf-1 phosphorylation, the upstream molecules of ERK in insulin signaling pathway. Additionally, inhibition of insulin stimulated PI3 kinase activation reduced ERK phosphorylation. The present study therefore shows that the inhibitory effect of DHT on insulin-stimulated granulosa cell proliferation occurs early in the signaling pathway at the level of insulin receptor substrate-1 phosphorylation, leading to reduced ERK phosphorylation and subsequent inhibition of cyclin D2 mRNA expression.
Differential Effects of Estradiol, Progesterone, and Testosterone on Vaginal Structural Integrity
Authors: Pessina Monica A. , Hoyt Richard F. , Goldstein Irwin , Traish Abdulmaged M.
Published: October 2005

Ovarian steroids are known to be important in maintaining vaginal tissue, and evidence is mounting that imbalances in the hormonal milieu contribute to vaginal pathophysiology. To date, limited data are available on the effects of hormone deprivation and replacement on vaginal tissue morphology and vaginal innervation. The goal of this study was to assess the dynamic changes in vaginal tissue structure in response to sex steroid hormone deprivation and administration. Female Sprague-Dawley rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. Histological techniques, including stereological analysis and immunohistochemistry for localization of neuronal markers, were used. Ovariectomy produced a significant decrease in epithelial height that was restored with estradiol replacement. Interestingly, a subphysiological dose of estradiol resulted in hyperplasia of the vaginal epithelium and nonvascular smooth muscle. Neither testosterone nor progesterone had a significant effect on epithelial height or muscularis thickness. However, testosterone treatment resulted in a significant increase in small adrenergic nerve fibers. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. This study demonstrates that estradiol and testosterone have differential effects on vaginal tissue parameters and that ovarian hormones are critical for the maintenance of genital tissue structure. Present observations also suggest that combined replacement regimens may be required for an optimal physiological response.
Differential Effects of Central Leptin, Insulin, or Glucose Administration during Fasting on the Hypothalamic-Pituitary-Thyroid Axis and Feeding-Related Neurons in the Arcuate Nucleus
Authors: Fekete Csaba , Singru Praful S. , Sanchez Edith , Sarkar Sumit , Christoffolete Marcelo A. , Riberio Rogerio S. , Rand William M. , Emerson Charles H. , Bianco Antonio C. , Lechan Ronald M.
Published: October 2005

The reductions in circulating levels of leptin, insulin, and glucose with fasting serve as important homeostasis signals to neurons of the hypothalamic arcuate nucleus that synthesize neuropeptide Y (NPY)/agouti-related protein (AGRP) and α-MSH/cocaine and amphetamine-regulated transcript. Because the central administration of leptin is capable of preventing the inhibitory effects of fasting on TRH mRNA in hypophysiotropic neurons primarily through effects on the arcuate nucleus, we determined whether the continuous administration of 30 mU/d insulin or 648 μg/d glucose into the cerebrospinal fluid by osmotic minipump might also have similar effects on the hypothalamic-pituitary-thyroid axis. As anticipated, the intracerebroventricular infusion of leptin reduced fasting-induced elevations in NPY and AGRP mRNA and increased proopiomelanocortin and cocaine and amphetamine-regulated transcript mRNA in the arcuate nucleus. In addition, leptin prevented fasting-induced reduction in pro-TRH mRNA levels in the paraventricular nucleus and in circulating thyroid hormone levels. In contrast, whereas insulin increased proopiomelanocortin mRNA and both insulin and glucose reduced NPY mRNA in arcuate nucleus neurons, neither prevented the fasting-induced suppression in hypophysiotropic TRH mRNA or circulating thyroid hormone levels. We conclude that insulin and glucose only partially replicate the central effects of leptin and may not be essential components of the hypothalamic-pituitary-thyroid regulatory system during fasting.
Effects of Central Infusion of Ghrelin on Food Intake and Plasma Levels of Growth Hormone, Luteinizing Hormone, Prolactin, and Cortisol Secretion in Sheep
Authors: Iqbal Javed , Kurose Yohei , Canny Benedict , Clarke Iain J.
Published: October 2005

Ghrelin is an endogenous ligand for the GH secretagogue/ghrelin receptor (GHS-R) and stimulates feeding behavior and GH levels in rodents and humans. A preprandial increase in plasma ghrelin levels is seen in sheep on programmed feeding, followed by a postprandial rise in plasma GH levels, but effects on food intake and endocrine function are not defined in this ruminant species. We administered ghrelin to female sheep in various modes and measured effects on voluntary food intake (VFI) and plasma levels of GH, LH, prolactin, and cortisol. Whether administered intracerebroventricularly or iv, ghrelin consistently failed to stimulate VFI. On the other hand, ghrelin invariably increased plasma GH levels and α,β-diaminopropanoic acid-octanoyl3 human ghrelin was more potent than ovine ghrelin. Bolus injection of ghrelin into the third cerebral ventricle reduced plasma LH levels but did not affect levels of prolactin or cortisol. These findings suggested that the preprandial rise in plasma ghrelin that is seen in sheep on programmed feeding does not influence VFI but is likely to be important in the postprandial rise in GH levels. Thus, ghrelin does not appear to be a significant regulator of ingestive behavior in this species of ruminant but acts centrally to indirectly regulate GH and LH secretion.
Cyclic Guanosine 5′-Monophosphate-Dependent Protein Kinase II Is Induced by Luteinizing Hormone and Progesterone Receptor-Dependent Mechanisms in Granulosa Cells and Cumulus Oocyte Complexes of Ovulating Follicles
Authors: Sriraman Venkataraman , Rudd Michael D. , Lohmann Suzanne M. , Mulders Sabine M. , Richards JoAnne S.
Published: October 2005

Cyclic GMP (cGMP)-dependent protein kinase II (Prkg2, cGK II) was identified as a potential target of the progesterone receptor (Nr3c3) in the mouse ovary based on microarray analyses. To document this further, the expression patterns of cGK II and other components of the cGMP signaling pathway were analyzed during follicular development and ovulation using the pregnant mare serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG)-primed immature mice. Levels of cGK II mRNA were low in ovaries of immature mice, increased 4-fold in response to pregnant mare serum gonadotropin and 5-fold more within 12 h after hCG, the time of ovulation. In situ hybridization localized cGK II mRNA to granulosa cells and cumulus oocyte complexes of periovulatory follicles. In progesterone receptor (PR) null mice, cGK II mRNA was reduced significantly at 12 h after hCG in contrast to heterozygous littermates. In primary granulosa cell cultures, cGK II mRNA was induced by phorbol 12-myristate 13-acetate enhanced by adenoviral expression of PR-A and blocked by RU486 and trilostane. PR-A in the absence of phorbol 12-myristate 13-acetate was insufficient to induce cGK II. Expression of cGK I (Prkg1) was restricted to the residual tissue and not regulated by hormones. Guanylate cyclase-A (Npr1; GC-A) mRNA expression increased 6-fold by 4 h after hCG treatment in contrast to pregnant mare serum gonadotropin alone and was localized to granulosa cells of preovulatory follicles. Collectively, these data show for the first time that cGK II (not cGK I) and GC-A are selectively induced in granulosa cells of preovulatory follicles by LH- and PR-dependent mechanisms, thereby providing a pathway for cGMP function during ovulation.
Drug delivery to tumours: recent strategies
Authors: Reddy L Harivardhan
Published: October 2005

Despite several advancements in chemotherapy, the real therapy of cancer still remains a challenge. The development of new anti-cancer drugs for the treatment of cancer has not kept pace with the progress in cancer therapy, because of the nonspecific drug distribution resulting in low tumour concentrations and systemic toxicity. The main hindrance for the distribution of anti-cancer agents to the tumour site is the highly disorganized tumour vasculature, high blood viscosity in the tumour, and high interstitial pressure within the tumour tissue. Recently, several approaches such as drug modifications and development of new carrier systems for anti-cancer agents have been attempted to enhance their tumour reach. Approaches such as drug delivery through enhanced permeability and retention (EPR) effect have resulted in a significant improvement in concentration in tumours, while approaches such as drug-carrier implants and microparticles have resulted in improvement in local chemotherapy of cancer. This review discusses different strategies employed for the delivery of anti-cancer agents to tumours, such as through EPR effect, local chemotherapeutic approaches using drug delivery systems, and special strategies such as receptor-mediated delivery, pH-based carriers, application of ultrasound and delivery to resistant tumour cells and brain using nanoparticles.
Effect of the molecular weight of poly(ethylene glycol) used as emulsifier on α-chymotrypsin stability upon encapsulation in PLGA microspheres
Authors: Castellanos Ingrid J , Flores Giselle , Griebenow Kai
Published: October 2005

Poly(ethylene glycol) (PEG) was used as emulsifier to prepare α-chymotrypsin-loaded poly(lactic-coglycolic) acid (PLGA) microspheres by a solid-in-oil-in-water (s/o/w) technique. The effect of the molecular weight of PEG on protein stability was assessed by the determination of the amount of insoluble aggregates, the activity loss and the magnitude of structural perturbations. In addition, the effect of the molecular weight of PEG on the encapsulation efficiency, microsphere characteristics and release kinetics was investigated. X-ray photoelectron spectroscopy (XPS) was employed to characterize the surface chemistry of the microspheres. Microspheres were prepared using PEG with molecular weight of 6000, 8000, 10000, 12000 and 20000. The results indicate that PEG 20000 was the most effective emulsifier when producing α-chymotrypsin-loaded microspheres with respect to protein stability. The aggregate formation was decreased from 18% to 3%; the protein inactivation and the encapsulation-induced structural perturbations were largely prevented. XPS confirmed that PEG was largely located on the surface of microspheres. The molecular weight of PEG affected the microspheres' characteristics and release kinetics. Microspheres prepared with PEG 20000 showed improved encapsulation efficiency (80%) and a continuous release (for 50 days) with the lowest amount of initial release. It is demonstrated that the selection of the optimum molecular weight of PEG when used as emulsifier in the preparation of microspheres is a critical factor in the development of sustained-release formulations for the delivery of proteins.
Transport characteristics of rutin deca (H-) sulfonate sodium across Caco-2 cell monolayers
Authors: He Ying , Zeng Su
Published: October 2005

The aim of this study was to explore potential transport mechanisms of rutin deca (H-) sulfonate sodium (RDS) across Caco-2 cell monolayers. As an in-vitro model of human intestinal epithelial membrane, Caco-2 cells were utilized to evaluate the transepithelial transport characteristics of this hydrophilic macromolecular compound. Bi-directional transport study of RDS demonstrated that the apparent permeability (Papp) in the secretory direction was 1.4∼4.5-fold greater than the corresponding absorptive Papp at concentrations in the range 50.0∼2000 μm. The transport of RDS was shown to be concentration, temperature and pH dependent. In the presence of ciclosporin and verapamil, potent inhibitors of P-glycoprotein (P-gp)/MRP2, the absorptive transport was enhanced and secretory efflux was diminished. RDS significantly reduced the efflux ratio of the P-gp substrate rhodamine-123 in a fashion indicative of P-gp activity suppression, while rhodamine-123 competitively inhibited the polarized transport of the compound. In conclusion, the results indicated that RDS was likely a substrate of P-gp. Several efflux transporters, including P-gp, participated in the absorption and efflux of RDS and they might play significant roles in limiting the oral absorption of the compound. These observations offered important information for the pharmacokinetics of RDS.
Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase
Authors: Fujino Hideki , Saito Tsuyoshi , Ogawa Shin-ichiro , Kojima Junji
Published: October 2005

The purpose of this study was to gain a better understanding of the transport mechanism of pitavastatin, a novel synthetic HMG-CoA reductase inhibitor. Experiments were performed using oocytes of Xenopus laevis expressing several solute carrier (SLC) transporters and recombinant membrane vesicles expressing several human ABC transporters. The acid form of pitavastatin was shown to be a substrate for human OATP1, OATP2, OATP8, OAT3 and NTCP, and for rat Oatp1 and Oatp4 with relatively low Km values. In contrast, these SLC transporters were not involved in the uptake of the lactone form. A significant stimulatory effect was exhibited by pitavastatin lactone, while the acid form did not exhibit ATPase hydrolysis of P-glycoprotein. In the case of breast cancer resistant protein (BCRP), the acid form of pitavastatin is a substrate, whereas the lactone form is not. Taking these results into consideration, several SLC and ABC transporters were identified as critical to the distribution and excretion of pitavastatin in the body. This study showed, for the first time, that acid and lactone forms of pitavastatin differ in substrate activity towards uptake and efflux transporters. These results will potentially contribute to the differences in the pharmacokinetic profiles of pitavastatin.
Protective effect of taurine on myocardial antioxidant status in isoprenaline-induced myocardial infarction in rats
Authors: Shiny K S , Kumar S Hari Senthil , Farvin K H Sabeena , Anandan R , Devadasan K
Published: October 2005

We have examined the protective effect of taurine on the myocardial antioxidant defense system in isoprenaline (isoproterenol)-induced myocardial infarction in rats, an animal model of myocardial infarction in man. Levels of diagnostic marker enzymes in plasma, lipid peroxides and reduced glutathione, and the activity of glutathione-dependent antioxidant enzymes and antiperoxidative enzymes in the heart tissue were determined. Intraperitoneal administration of taurine significantly prevented the isoprenaline-induced increases in the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine phosphokinase in the plasma of rats. Taurine exerted an antioxidant effect against isoprenaline-induced myocardial infarction by preventing the accumulation of lipid peroxides and by maintaining the level of reduced glutathione and the activity of glutathione peroxidase, glutathione-S-transferase, catalase and superoxide dismutase at near normality. The results indicated that the cardioprotective potential of taurine was probably due to the increase of the activity of the free radical enzymes, or to a counteraction of free radicals by its antioxidant nature, or to a strengthening of myocardial membrane by its membrane stabilizing property.
Design and synthesis of long-chain arylpiperazines with mixed affinity for serotonin transporter (SERT) and 5-HT1A receptor
Authors: Perrone Roberto , Berardi Francesco , Colabufo Nicola A , Lacivita Enza , Larizza Carmela , Leopoldo Marcello , Tortorella Vincenzo
Published: October 2005

A new generation of antidepressant agents could be represented by compounds with mixed activity as serotonin transporter (SERT) inhibitors and 5-HT1A receptor antagonists. We report here on the synthesis and evaluation of SERT and 5-HT1A receptor affinity of long-chain arylpiperazines obtained either by modifying 6-nitroquipazine into a long-chain arylpiperazine or by inserting a modified 6-nitroquipazine moiety or other structures endowed with SERT affinity into a long-chain arylpiperazine with 5-HT1A affinity. Among the compounds studied, 2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-(6-nitro-2-quinolyl)ethylamine (21) and 1-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-propanone (24) showed good affinity values for SERT and 5-HT1A receptors (SERT: Ki (inhibition constant) = 71.8 and 62.8 nm; 5-HT1A Ki = 14.2 and 0.82 nm, respectively).
Renal effects induced by the lectin from Vatairea macrocarpa seeds
Authors: Monteiro Ana M O , Havt Alexandre , Barbosa Paulo S F , Soares Taís F , Evangelista Janaína S A M , Alencar Nylane M N , Monteiro Helena S A , Martins Alice M C , de Menezes Dalgimar B , Fonteles Manassés C , Teixeira Edson H , Pinto Vicente P T , Nascimento Kyria S , Cavada Benildo S
Published: October 2005

Lectins are glycoproteins that interact reversibly and specifically with carbohydrates. The renal effects of the galactose-binding lectin from the seeds of Vatairea macrocarpa were investigated. Isolated kidneys from Wistar rats (240–280 g) were perfused with Krebs-Henseleit solution containing 6% bovine serum albumin. The V. macrocarpa lectin (10 μg mL−1) increased the perfusion pressure, renal vascular resistance, urinary flow and glomerular filtration rate. However, V. macrocarpa lectin did not change the percentage sodium, potassium or chloride tubular transport. Pretreatment with lectin-galactose complex significantly blocked the increase in perfusion pressure, renal vascular resistance, urinary flow and glomerular filtration rate. The control group showed a small amount of a proteinaceous material in the urinary space, although no alteration in the renal tubules was detected. The administration of galactose alone did not modify the functional parameters of the kidney. Kidneys perfused with V. macrocarpa lectin showed moderate deposits of a proteinaceous material in the tubules and urinary space. Those pre-treated with lectin-galactose complex had only small amount of a proteinaceous material in the urinary space. No abnormalities were seen in renal tubules. The results suggest that lectin from V. macrocarpa seeds has important effects on the carbohydrate-binding sites of the renal system, given the reversal of renal effects with the use of that specific inhibitor.