bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study
Authors: Ray Arghya , Cowan-Jacob Sandra W. , Manley Paul W. , Mestan Jürgen , Griffin James D.
Published: February 2007

Patients with advanced stages of chronic myeloid leukemia (CML) often manifest imatinib mesylate resistance associated with point mutations in BCR-ABL. AMN107 is a new higher-potency inhibitor of BCR-ABL. To identify mutations in BCR-ABL that could result in resistance to AMN107, a cDNA library of BCR-ABL mutants was introduced into Ba/F3 cells followed by selection in AMN107 (0.125-0.5 μM). A total of 86 individual, drug-resistant colonies were recovered, and the SH3, SH2, and kinase domains of BCR-ABL were sequenced. A total of 46 colonies had single point mutations in BCR-ABL, with a total of 17 different mutations, all within the kinase domain. The other 40 colonies had multiple point mutations and were not analyzed further. Each of the 17 single point mutants were reconstructed by site-directed mutagenesis of native BCR-ABL and found to be approximately 2.5- to 800-fold more resistant to AMN107 than native BCR-ABL. The mutations included 6 known imatinib mesylate–resistant mutations, including T315I, which showed complete resistance to AMN107. Interestingly, most AMN107-resistant mutants were also resistant to imatinib mesylate. These results may predict some of the resistance mutations that will be detected in clinical trials with this kinase inhibitor.
HIV-1–specific CTLs effectively suppress replication of HIV-1 in HIV-1–infected macrophages
Authors: Fujiwara Mamoru , Takiguchi Masafumi
Published: February 2007

Both CD4+ T cells and macrophages are major reservoirs of HIV-1. Previous study showed that HIV-1–specific cytolytic T lymphocytes (CTLs) hardly recognize HIV-1–infected CD4+ T cells because of Nef-mediated HLA class I down-regulation, suggesting that HIV-1 escapes from HIV-1–specific CTLs and continues to replicate in HIV-1–infected donors. On the other hand, the CTL recognition of HIV-1–infected macrophages and the effect of Nef-mediated HLA class I down-regulation on this recognition still remain unclear. We show a strong HIV-1 antigen presentation by HIV-1–infected macrophages. HIV-1–specific CTLs had strong abilities to suppress HIV-1R5 virus replication in HIV-1–infected macrophages and to kill HIV-1R5–infected macrophages. Nef-mediated HLA class I down-regulation minimally influenced the recognition of HIV-1–infected macrophages by HIV-1–specific CTLs. In addition, HIV-1–infected macrophages had a stronger ability to stimulate the proliferation of HIV-1–specific CTLs than HIV-1–infected CD4+ T cells. Thus, the effect of Nef-mediated HLA class I down-regulation was less critical with respect to the recognition by HIV-1–specific CTLs of HIV-infected macrophages than that of HIV-1–infected CD4+ T cells. These findings support the idea that the strong HIV-1 antigen presentation by HIV-1–infected macrophages is one of the mechanisms mediating effective induction of HIV-1–specific CTLs in the acute and early chronic phases of HIV-1 infection.
CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms
Authors: Zhan Fenghuang , Colla Simona , Wu Xiaosong , Chen Bangzheng , Stewart James P. , Kuehl W. Michael , Barlogie Bart , Shaughnessy John D.
Published: February 2007

Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27Kip1. Overexpression of CKS1B or SKP2 contributes to increased p27Kip1 turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27Kip1, cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27Kip1 (p27T187A) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27T187A induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27Kip1, CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.
Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas
Authors: Pantelias Anastasia , Pagel John M. , Hedin Nathan , Saganic Laura , Wilbur Shani , Hamlin Donald K. , Wilbur D. Scott , Lin Yukang , Stone Diane , Axworthy Don , Gopal Ajay K. , Press Oliver W.
Published: February 2007

Pretargeted radioimmunotherapy (PRIT) using streptavidin (SA)–conjugated antibodies (Abs), followed by clearing agent and radiolabeled biotin is a promising method that can increase the effectiveness of RIT, while decreasing the toxicities associated with directly labeled Abs. Although CD20 has been the traditional target antigen for RIT of non-Hodgkin lymphoma (NHL), studies targeting HLA DR and CD22 have yielded promising results. Targeting all 3 antigens at once may further augment the effect of PRIT. This study compares the targeting of Ramos, Raji, and FL-18 lymphoma xenografts with either anti-CD20 Ab/SA (1F5/SA), anti-HLA DR Ab/SA (Lym-1/SA), anti-CD22 Ab/SA (HD39/SA), or all 3 conjugates in combination, followed 24 hours later by a biotin-N-acetyl-galactosamine clearing agent, and 3 hours after that by 111In-DOTA-biotin. The Ab/SA conjugate yielding the best tumor uptake and tumor-to–normal organ ratios of radioactivity varied depending on the target antigen expression on the cell line used, with 1F5/SA and Lym-1/SA yielding the most promising results overall. Also, the best tumor-to–normal organ ratios of absorbed radioactivity were obtained using single conjugates optimized for target tumor antigen expression rather than the combination therapy. This study highlights the importance of screening the antigenic expression on lymphomas to select the optimal reagent for PRIT.
Hybrid elementary flux analysis/nonparametric modeling: application for bioprocess control
Authors: Teixeira Ana P , Alves Carlos , Alves Paula M , Carrondo Manuel JT , Oliveira Rui
Published: February 2007

Background

The progress in the "-omic" sciences has allowed a deeper knowledge on many biological systems with industrial interest. This knowledge is still rarely used for advanced bioprocess monitoring and control at the bioreactor level. In this work, a bioprocess control method is presented, which is designed on the basis of the metabolic network of the organism under consideration. The bioprocess dynamics are formulated using hybrid rigorous/data driven systems and its inherent structure is defined by the metabolism elementary modes.

Results

The metabolic network of the system under study is decomposed into elementary modes (EMs), which are the simplest paths able to operate coherently in steady-state. A reduced reaction mechanism in the form of simplified reactions connecting substrates with end-products is obtained. A dynamical hybrid system integrating material balance equations, EMs reactions stoichiometry and kinetics was formulated. EMs kinetics were defined as the product of two terms: a mechanistic/empirical known term and an unknown term that must be identified from data, in a process optimisation perspective. This approach allows the quantification of fluxes carried by individual elementary modes which is of great help to identify dominant pathways as a function of environmental conditions. The methodology was employed to analyse experimental data of recombinant Baby Hamster Kidney (BHK-21A) cultures producing a recombinant fusion glycoprotein. The identified EMs kinetics demonstrated typical glucose and glutamine metabolic responses during cell growth and IgG1-IL2 synthesis. Finally, an online optimisation study was conducted in which the optimal feeding strategies of glucose and glutamine were calculated after re-estimation of model parameters at each sampling time. An improvement in the final product concentration was obtained as a result of this online optimisation.

Conclusion

The main contribution of this work is a novel bioreactor optimal control method that uses detailed information concerning the metabolism of the underlying biological system. Moreover, the method allows the identification of structural modifications in metabolism over batch time.
Context based mixture model for cell phase identification in automated fluorescence microscopy
Authors: Wang Meng , Zhou Xiaobo , King Randy W , Wong Stephen TC
Published: February 2007

Background

Automated identification of cell cycle phases of individual live cells in a large population captured via automated fluorescence microscopy technique is important for cancer drug discovery and cell cycle studies. Time-lapse fluorescence microscopy images provide an important method to study the cell cycle process under different conditions of perturbation. Existing methods are limited in dealing with such time-lapse data sets while manual analysis is not feasible. This paper presents statistical data analysis and statistical pattern recognition to perform this task.

Results

The data is generated from Hela H2B GFP cells imaged during a 2-day period with images acquired 15 minutes apart using an automated time-lapse fluorescence microscopy. The patterns are described with four kinds of features, including twelve general features, Haralick texture features, Zernike moment features, and wavelet features. To generate a new set of features with more discriminate power, the commonly used feature reduction techniques are used, which include Principle Component Analysis (PCA), Linear Discriminant Analysis (LDA), Maximum Margin Criterion (MMC), Stepwise Discriminate Analysis based Feature Selection (SDAFS), and Genetic Algorithm based Feature Selection (GAFS). Then, we propose a Context Based Mixture Model (CBMM) for dealing with the time-series cell sequence information and compare it to other traditional classifiers: Support Vector Machine (SVM), Neural Network (NN), and K-Nearest Neighbor (KNN). Being a standard practice in machine learning, we systematically compare the performance of a number of common feature reduction techniques and classifiers to select an optimal combination of a feature reduction technique and a classifier. A cellular database containing 100 manually labelled subsequence is built for evaluating the performance of the classifiers. The generalization error is estimated using the cross validation technique. The experimental results show that CBMM outperforms all other classifies in identifying prophase and has the best overall performance.

Conclusion

The application of feature reduction techniques can improve the prediction accuracy significantly. CBMM can effectively utilize the contextual information and has the best overall performance when combined with any of the previously mentioned feature reduction techniques.
Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease
Authors: Mukherjee Odity , Kauwe John SK , Mayo Kevin , Morris John C , Goate Alison M
Published: February 2007

Background

Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort.

Results

In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD.

Conclusion

In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD.
Characterization of an Oct1 orthologue in the channel catfish, Ictalurus punctatus: A negative regulator of immunoglobulin gene transcription?
Authors: Lennard Mara L , Hikima Jun-ichi , Ross David A , Kruiswijk Corine P , Wilson Melanie R , Miller Norman W , Warr Gregory W
Published: February 2007

Background

The enhancer (Eμ3') of the immunoglobulin heavy chain locus (IGH) of the channel catfish (Ictalurus punctatus) has been well characterized. The functional core region consists of two variant Oct transcription factor binding octamer motifs and one E-protein binding μE5 site. An orthologue to the Oct2 transcription factor has previously been cloned in catfish and is a functionally active transcription factor. This study was undertaken to clone and characterize the Oct1 transcription factor, which has also been shown to be important in driving immunoglobulin gene transcription in mammals.

Results

An orthologue of Oct1, a POU family transcription factor, was cloned from a catfish macrophage cDNA library. The inferred amino acid sequence of the catfish Oct1, when aligned with other vertebrate Oct1 sequences, revealed clear conservation of structure, with the POU specific subdomain of catfish Oct1 showing 96% identity to that of mouse Oct1. Expression of Oct1 was observed in clonal T and B cell lines and in all tissues examined. Catfish Oct1, when transfected into both mammalian (mouse) and catfish B cell lines, unexpectedly failed to drive transcription from three different octamer-containing reporter constructs. These contained a trimer of octamer motifs, a fishVHpromoter, and the core region of the catfish Eμ3'IGHenhancer, respectively. This failure of catfish Oct1 to drive transcription was not rescued by human BOB.1, a co-activator of Oct transcription factors that stimulates transcription driven by catfish Oct2. When co-transfected with catfish Oct2, Oct1 reduced Oct2 driven transcriptional activation. Electrophoretic mobility shift assays showed that catfish Oct1 (native or expressedin vitro) bound both consensus and variant octamer motifs. Putative N- and C-terminal activation domains of Oct1, when fused to a Gal4 DNA binding domain and co-transfected with Gal4-dependent reporter constructs were transcriptionally inactive, which may be due in part to a lack of residues associated with activation domain function.

Conclusion

An orthologue to mammalian Oct1 has been found in the catfish. It is similar to mammalian Oct1 in structure and expression. However, these results indicate that the physiological functions of catfish Oct1 differ from those of mammalian Oct1 and include negative regulation of transcription.
ESTs from a wild Arachis species for gene discovery and marker development
Authors: Proite Karina , Leal-Bertioli Soraya CM , Bertioli David J , Moretzsohn Márcio C , da Silva Felipe R , Martins Natalia F , Guimarães Patrícia M
Published: February 2007

Background

Due to its origin, peanut has a very narrow genetic background. Wild relatives can be a source of genetic variability for cultivated peanut. In this study, the transcriptome of the wild speciesArachis stenospermaaccession V10309 was analyzed.

Results

ESTs were produced from four cDNA libraries of RNAs extracted from leaves and roots ofA. stenosperma. Randomly selected cDNA clones were sequenced to generate 8,785 ESTs, of which 6,264 (71.3%) had high quality, with 3,500 clusters: 963 contigs and 2537 singlets. Only 55.9% matched homologous sequences of known genes. ESTs were classified into 23 different categories according to putative protein functions. Numerous sequences related to disease resistance, drought tolerance and human health were identified. Two hundred and six microsatellites were found and markers have been developed for 188 of these. The microsatellite profile was analyzed and compared to other transcribed and genomic sequence data.

Conclusion

This is, to date, the first report on the analysis of transcriptome of a wild relative of peanut. The ESTs produced in this study are a valuable resource for gene discovery, the characterization of new wild alleles, and for marker development. The ESTs were released in the [GenBank:EH041934 to EH048197].
Gastroparesis secondary to a demyelinating disease: a case series
Authors: Reddymasu Savio C , Bonino John , McCallum Richard W
Published: February 2007

Background

Gastroparesis has a number of etiologies. The main ones are secondary to a complication from diabetes mellitus, related to post vagotomy or post gastric surgical resections, or idiopathic when the etiology is unclear. Gastroparesis secondary to a demyelinating disease of the brain is unusual.

Case presentation

A 22-year-old woman was referred for acute onset of intractable nausea and vomiting. She also had cerebellar deficits, dysphagia and paresthesias. Magnetic resonance imaging (MRI) of the brain revealed an isolated area of demyelination in the medullary region. Another 24-year-old woman had a similar presentation with right hemiplegia and MRI of the brain revealed a distal medullary region. Both these patients had an abnormal gastric emptying test. Gastroparesis and neurological deficits improved with intravenous corticosteroids. While the former patient has had no further recurrences, the latter patient developed multiple sclerosis within three months of presentation.

Conclusion

A demyelinating disease is a rare cause gastropareis, but should be suspected when symptoms of gastroparesis are associated with neurological deficits. MRI might help in the diagnosis and intravenous coriticosteroids can address the underlying disease process and improve gastric emptying, especially when used early during the course of the disease.
Cultural competence in mental health care: a review of model evaluations
Authors: Bhui Kamaldeep , Warfa Nasir , Edonya Patricia , McKenzie Kwame , Bhugra Dinesh
Published: February 2007

Background

Cultural competency is now a core requirement for mental health professionals working with culturally diverse patient groups. Cultural competency training may improve the quality of mental health care for ethnic groups.

Methods

A systematic review that included evaluated models of professional education or service delivery.

Results

Of 109 potential papers, only 9 included an evaluation of the model to improve the cultural competency practice and service delivery. All 9 studies were located in North America. Cultural competency included modification of clinical practice and organizational performance. Few studies published their teaching and learning methods. Only three studies used quantitative outcomes. One of these showed a change in attitudes and skills of staff following training. The cultural consultation model showed evidence of significant satisfaction by clinicians using the service. No studies investigated service user experiences and outcomes.

Conclusion

There is limited evidence on the effectiveness of cultural competency training and service delivery. Further work is required to evaluate improvement in service users' experiences and outcomes.
Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity
Authors: Stillfried Gillian E , Saunders Darren N , Ranson Marie
Published: February 2007

Introduction

The regulation of extracellular proteolytic activity via the plasminogen activation system is complex, involving numerous activators, inhibitors, and receptors. Previous studies on monocytic and colon cell lines suggest that plasmin pre-treatment can increase plasminogen binding, allowing the active enzyme to generate binding sites for its precursor. Other studies have shown the importance of pre-formed receptors such as annexin II heterotetramer. However, few studies have used techniques that exclusively characterise cell-surface events and these mechanisms have not been investigated at the breast cancer cell surface.

Methods

We have studied plasminogen binding to MCF-7 in which urokinase plasminogen activator receptor (uPAR) levels were upregulated by PMA (12-O-tetradecanoylphorbol-13-acetate) stimulation, allowing flexible and transient modulation of cell-surface uPA. Similar experiments were also performed using MDA-MB-231 cells, which overexpress uPAR/uPA endogenously. Using techniques that preserve cell integrity, we characterise the role of uPA as both a plasminogen receptor and activator and quantify the relative contribution of pre-formed and cryptic plasminogen receptors to plasminogen binding.

Results

Cell-surface plasminogen binding was significantly enhanced in the presence of elevated levels of uPA in an activity-dependent manner and was greatly attenuated in the presence of the plasmin inhibitor aprotinin. Pre-formed receptors were also found to contribute to increased plasminogen binding after PMA stimulation and to co-localise with uPA/uPAR and plasminogen. Nevertheless, a relatively modest increase in plasminogen-binding capacity coupled with an increase in uPA led to a dramatic increase in the proteolytic capacity of these cells.

Conclusion

We show that the majority of lysine-dependent plasminogen binding to breast cancer cells is ultimately regulated by plasmin activity and is dependent on the presence of significant levels of active uPA. The existence of a proteolytic positive feedback loop in plasminogen activation has profound implications for the ability of breast cancer cells expressing high amounts of uPA to accumulate a large proteolytic capacity at the cell surface, thereby conferring invasive potential.
Women's Health and the Metabolic Syndrome
Authors: MITRAKOU ASIMINA
Published: February 2007

Abstract:  The metabolic syndrome is a cluster of cardiovascular risk factors that identifies individuals at a relatively high, long‐term risk for atherosclerosis, cardiovascular disease, and type 2 diabetes. Insulin resistance and central obesity are the main risk conditions underlying the metabolic syndrome. As obesity rates increase worldwide especially in women, accompanying rising frequency of insulin resistance, dyslipidemia, diabetes, and hypertension contribute to increasing rates of cardiovascular morbidity and mortality. According to the latest NCEP/ATPIII definition of the metabolic syndrome almost 25% (from 6.7 up to 43.5% according to age) of the United States and European adult population appear to have the syndrome and in the recent years it has been more prevalent in men than in women. Prevalence is increasing and the increase seems to be steeper in women. The contribution of the different components of the syndrome differs between genders. Age, endocrine dysfunction (especially loss of ovarian estrogens) as well as genetic factors modify the response to underlying factors. Physical inactivity, which diminishes by age, is more prevalent in women than in men. Treatment goals are to prevent cardiovascular disease by both altering the risk factors that are components of the syndrome and more importantly applying lifestyle modifications with caloric restriction and exercise.
From Menarche to Regular Menstruation
Authors: MESSINIS IOANNIS E.
Published: February 2007

Abstract:  Marked changes in hormone secretion occur from childhood to adulthood. Prior to puberty gonadotropin‐releasing hormone (GnRH) secretion is markedly suppressed. At the onset of puberty, the hypothalamic gonadostat is derepressed and the amplitude of GnRH pulses increases. Follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) levels increase gradually during puberty stimulating follicle maturation and estrogen production in the ovaries. Only the negative feedback mechanism is powerful before puberty, while the positive feedback mechanism becomes active for the first time in late puberty. As a result, normal cyclicity is usually established at that time. During normal menstrual cycle, steroidal and nonsteroidal hormones mediate the effect of the ovaries on the hypothalamic‐pituitary system. Estradiol and progesterone are important regulators of FSH and LH secretion, while inhibins play a role in the control of FSH secretion. Gonadotropin surge attenuating factor (GnSAF) is a nonsteroidal ovarian substance that controls the amplitude of the midcycle LH surge by antagonizing the sensitizing effect of estradiol on the pituitary.
A Behind‐the‐Scenes Look at the Safety Assessment of Feminine Hygiene Pads
Authors: FARAGE MIRANDA A.
Published: February 2007

Abstract:  Forms of menstrual protection have evolved with time. Today's disposable feminine hygiene products, notably sanitary pads, include a wide range of designs and features to meet women's needs for reliable, discreet, and comfortable protection. Manufacturers support substantive research and testing programs to ensure the safety of these products. The premarket safety assessment of feminine hygiene pads is a systematic, stepwise process that includes toxicological evaluation of the raw materials, the conduct of prospective, controlled clinical trials to assess product safety‐in‐use, and, in some cases, independent scientific review. A broad clinical database, developed over the past 20 years, substantiates that modern, feminine hygiene pads are not associated with significant gynecological, dermatological, or microbiological effects. Postmarket surveillance provides reassurance that the products are acceptable to consumers worldwide.
Use of Cognitive Behavior Therapy for Functional Hypothalamic Amenorrhea
Authors: BERGA SARAH L. , LOUCKS TAMMY L.
Published: February 2007

Abstract:  Behaviors that chronically activate the hypothalamic‐pituitary‐adrenal (HPA) axis and/or suppress the hypothalamic‐pituitary‐thyroidal (HPT) axis disrupt the hypothalamic‐pituitary‐gonadal axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of hypothalamic hypogonadism are more than an isolated disruption of gonadotropin‐releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional hypothalamic amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only or primarily an alteration in the hypothalamic‐pituitary‐gonadal axis. Potential health consequences of functional hypothalamic amenorrhea, often termed stress‐induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes, such as cognitive behavior therapy (CBT), have the potential to permit resumption of full ovarian function along with recovery of the adrenal, thyroidal, and other neuroendocrine aberrations. Full endocrine recovery potentially offers better individual, maternal, and child health.
Ovarian and Adrenal Hyperandrogenism
Authors: CARMINA ENRICO
Published: February 2007

Abstract:  Because in normal women androgens are secreted in almost equal quantities by both adrenals and ovaries, for many years many studies have tried to distinguish the source of androgen excess. However, in the last 10–15 years, the diagnoses of ovarian or adrenal hyperandrogenism have almost disappeared. This is due to the lack of specificity of dynamic tests as well as to the emphasis given on clinical information and ovarian sonography for the diagnosis of hyperandrogenic syndromes. However, determination of the source of increased androgens may still be useful for improving the classification and the understanding of androgen excess disorders. The aim of this review is to examine the source of androgen excess in the three more common androgen excess disorders: polycystic ovary syndrome (PCOS), idiopathic hyperandrogenism; and nonclassic 21‐hydroxylase deficiency (NCAH). The ovary is the main androgen source in PCOS and idiopathic hyperandrogenism while adrenal androgen secretion is prevalent in NCAH. However, androgen secretion from more than one source is common in all main forms of hyperandrogenism as is the case in 70–80% of patients with NCAH, in 35% of women with PCOS, and in 50% of patients with idiopathic hyperandrogenism. Secondary PCOS is the main cause of ovarian androgen excess in nonclassic 21‐hydroxylase deficiency while adrenal hyperandrogenism in PCOS and idiopathic hyperandrogenism is probably the consequence of multiple factors including hyperinsulinemia, altered cortisol metabolism, and increased ovarian steroid production. The clinical image is not generally affected by the source of androgen excess. However, hyperandrogenic patients with increased dehydroepiandrosterone sulfate (DHEAS) tend to have lower body weight and insulin levels and a better metabolic profile.
Indices of Low‐Grade Inflammation in Polycystic Ovary Syndrome
Authors: DIAMANTI‐KANDARAKIS EVANTHIA , PATERAKIS THOMAS , KANDARAKIS HELEN A.
Published: February 2007

Abstract:  Polycystic ovary syndrome (PCOS) is probably the most common endocrinopathy of reproductive age. PCOS represents a disorder that not only enhances the risk for type 2 diabetes (T2D) but is also associated with an increased number of cardiovascular risk factors known to facilitate atherogenesis. On the other hand, inflammation is thought to play an important role in the progression and development of complications of atherosclerosis. Evidence of low‐grade chronic inflammation in PCOS is indicated by the presence of elevated C‐reactive protein (CRP) levels, inflammatory cytokines (i.e., IL‐6 and IL‐18), and increased leucocyte count. CRP, a nonspecific marker of inflammation, has been proven to be one of the strongest predictors of the risk of cardiovascular events in patients with or without cardiovascular disease. The levels of the adhesion molecules (AM), sIVAM‐1, sVCAM‐1, and sE‐selectin in serum reflect low‐grade chronic inflammation of the endothelium and independently predict coronary heart disease (CHD) and T2D. In a recent study in a large number of PCOS women we demonstrated elevated levels of sIVAM‐1 and sE‐selectin and we further substantiated the existence of a low‐grade chronic inflammatory process in PCOS. However, it remains to be assessed with long‐term studies whether the early presence of markers of chronic inflammation in young women with this syndrome has clinical significance.
The Retroperitoneal Approach in Minimally Invasive Pelvic Surgery
Authors: DUBUISSON JEAN‐BERNARD , DE DYCKER YANNICK , YARON MICHAL
Published: February 2007

Abstract:  The retroperitoneal approach is a minimally invasive surgery than can be performed through direct access or through indirect access, with abdominal penetration.
The choice of indirect transabdominal approach is appropriate when additional abdominal surgery is indicated (radical hysterectomy, pelviabdominal exploration).
The advantages of the direct retroperitoneal access are the absence of risk of creating intra‐abdominal adhesions associated with those of intraperitoneal operative laparoscopy.
Prevention and Management of Ovarian Hyperstimulation Syndrome
Authors: VLAHOS NIKOS F. , GREGORIOU ODYSSEAS
Published: February 2007

Abstract:  The Ovarian Hyperstimulation Syndrome (OHSS) represents one of the biggest nightmares of all physicians involved in Assisted Reproductive Technologies (ART). Every year, several hundreds of women are hospitalized and to date several deaths have been reported. The pivotal event in the development of OHSS is the disruption of capillary integrity that results in leakage of intravascular fluid and proteins into third space. On the molecular level, human chorionic godadotropin (HCG) either exogenous or endogenous, functions as the triggering point for the production of vascular endothelial growth factor (VEGF) that is the main mediator to increase permeability on the vascular bed. Spontaneous OHSS has also been reported, either due to inappropriate activation of a mutant FSH receptor or due to very high levels of HCG during pregnancy. The available evidence on the several preventive and therapeutic approaches with special attention to level 1 evidence when available is also presented. OHSS is a self‐resolving condition and the main role of the physician is to correct and maintain the intravascular volume, to support renal function and respiration and prevent thrombotic events. An algorithm on the management of OHSS on an outpatient basis and in the hospital is based on the previous mentioned principles.
Recent Developments in the Detection of Fetal Single Gene Differences in Maternal Plasma and the Role of Size Fractionation
Authors: LI YING , HAHN SINUHE , HOLZGREVE WOLFGANG
Published: February 2007

Abstract:  The presence of cell‐free fetal DNA in maternal plasma allowed noninvasive prenatal diagnosis of fetal loci completely absent from the maternal genome, such as SRY gene and RhD gene. However, the detection of fetal point mutations is hindered by the predominance of maternal DNA sequences. Recent studies have shown that cell‐free fetal DNA exists in maternal plasma in small fragments. Thus, cell‐free fetal DNA can be enriched by size fractionation, which improves detection of fetal gene mutations. Furthermore, it has been shown that Matrix Assisted Laser Desorption Ionization Time‐of‐Flight (MALDI‐TOF) mass spectrometry also permits the detection of fetal SNPs from maternal plasma. These two new developments are discussed.
“Reproductive” Corticotropin‐Releasing Hormone
Authors: VITORATOS NIKOLAOS , PAPATHEODOROU DIMITRIOS C. , KALANTARIDOU SOPHIA N. , MASTORAKOS GEORGE
Published: February 2007

Abstract:  Corticotropin‐releasing hormone (CRH), a 41 amino acid peptide, is an important regulatory molecule synthesized by neurons of the parvocellular and magnocellular hypothalamic paraventricular nuclei. It acts as the major physiologic corticotropin (ACTH) secretagogue. The CRH gene is located in humans on chromosome 8. The CRH hormone family has at least four ligands, two receptors (CRH‐R1 and CRH‐R2), and a binding protein (CRHbp). CRH is the principal regulator of the hypothalamic‐pituitary‐adrenal axis. Furthermore, CRH has been identified in most female reproductive tissues including the uterus, the placenta, and the ovary. CRH produced in the endometrium may participate in decidualization, implantation, and early maternal tolerance to semiallograft embryo. Placental CRH may participate in the physiology of pregnancy, in late pregnancy complications such as preterm labor and preeclampsia, and also in the onset of parturition. Ovarian CRH is involved in follicular maturation, ovulation, and luteolysis. Increased levels of unbound placental CRH may be responsible for the hypercortisolism of the second half of pregnancy. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period. This may explain the depressive states frequently observed in the postpartum period.
Hormone Replacement Therapy in Breast Cancer Survivors
Authors: XYDAKIS ANTONIOS M. , SAKKAS EVANGELOS GR. , MASTORAKOS GEORGE
Published: February 2007

Abstract:  It is well known that women with breast cancer who undergo therapies beyond the surgical intervention (adjuvant chemotherapy, hormone therapy, or both) often suffer from the lack of estrogen, manifesting as climacteric symptoms in either treated premenopausal or postmenopausal women. Although HRT (hormone replacement therapy) is traditionally viewed as a contraindication in women with a history of breast cancer, more women are willing to receive HRT for symptom relief. No observational or retrospective study in breast cancer survivors (whether in pre‐ or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use. Nevertheless, because these studies are retrospective and different in terms of lymph node status, estrogen receptor (ER) status, and type of HRT used, firm conclusions on potential HRT use cannot be safely drawn. The few prospective studies appear controversial possibly due to differences in the studies' design. A potential scheme for possible HRT use in selected breast cancer survivors with severe climacteric symptoms is suggested. The duration of HRT use is debatable because there is insufficient evidence at present. However, the available data suggest that 3‐year and possibly 5‐year HRT use may be safe. In summary, while HRT cannot currently be recommended as first‐line therapy, it may still be of benefit in the management of selected early stage breast cancer survivors with refractory climacteric symptoms after a well‐informed decision and an individualized risk benefit discussion.
Potential Biological Functions Emerging from the Different Estrogen Receptors
Authors: CARPENTER KAREN D. , KORACH KENNETH S.
Published: February 2007

Abstract:  Technological advances and new tools have brought about tremendous advances in elucidating the roles of estradiol and the estrogen receptors (ERs) in biological processes, especially within the female reproductive system. Development and analysis of multiple genetic models have provided insight into the particular functions of each of the ERs. This article reviews the insights into ER biology in female reproduction gained from the development and use of new types of experimental models.
The Cardiovascular Effects of Selective Estrogen Receptor Modulators
Authors: CHRISTODOULAKOS G.E. , LAMBRINOUDAKI I.V. , BOTSIS D.C.
Published: February 2007

Abstract: Coronary artery disease (CAD) is the main contributor of mortality among postmenopausal women. Menopause‐associated estrogen deficiency has both metabolic and vascular consequences that increase the risk for CAD. Hormone therapy (HT) has been reported to have a beneficial effect on metabolic and vascular factors influencing the incidence of CAD. Although observational studies have reported that HT reduces significantly the risk for CAD, randomized clinical trials (WHI, HERS, ERA) have questioned the efficacy of HT in primary and secondary CAD prevention despite confirming the lipid‐lowering effect of HT. In the aftermath of the WHI, increased interest has been given to the action of selective estrogen receptor modulators (SERMs) and their effect on the cardiovascular system. The chemical structure of SERMs, either triphenylethilyn (tamoxifen) or benzothiophene (raloxifene) derivatives, differs from that of estrogens. SERMs are nonsteroidal molecules that bind, with high affinity, to the ER. SERMs induce conformational changes to the ligand‐binding domain of the ER that modulate the ability of the ER to interact with coregulator proteins. The relative balance of coregulators within a cell determines the transcriptional activity of the receptor–ligand complex. SERMs therefore may express an estrogen‐agonist or estrogen‐antagonist effect depending on the tissue targeted. SERMs express variable effects on the metabolic and vascular factors influencing the incidence of CAD. SERMs have been reported to modulate favorably the lipid–lipoprotein profile. Toremifene expresses the most beneficial effect followed by tamoxifene and raloxifene, while ospexifene and HMR‐3339 have the least effect and may even increase triglycerides. Raloxifene and tamoxifene decrease serum homocysteine levels and C‐reactive proteins (CRP), which are both markers of CAD risk. Raloxifene has been reported to increase the nitric oxide (NO)–endothelin (ET)‐1 ratio and, thus, contribute to proper endothelial function and vasodilation. Toremifene has no effect on the NO–ET‐1 ratio. Finally, raloxifene decreases the vascular cell adhesion molecules and the inflammatory cytokines TNF‐α and IL‐6. Of the SERMs, raloxifene has had the most extensive evaluation regarding the effect on the vascular wall of endothelium. Although not confirmed by large clinical trials, raloxifene has been reported to have an effect on the cohesion of the intercellular junction (VE‐cadherin) and the synthesis—degradation of extracellular matrix (MMP‐2). The Multiple Outcomes Raloxifene Evaluation (MORE) study has reported that raloxifene may have a cardioprotective effect when administered to postmenopausal women at high risk for CAD disease.
Poor Responders in IVF
Authors: BAKA STAVROULA , MAKRAKIS EVANGELOS , TZANAKAKI DESPOINA , KONIDARIS SOCRATES , HASSIAKOS DIMITRIS , MOUSTAKARIAS THEODOROS , CREATSAS GEORGE
Published: February 2007

Abstract:  Management of women with a poor response to controlled ovarian hyperstimulation during IVF remains a frustrating challenge. The present study included 96 cycles from an equal number of women with a poor ovarian response and successful oocyte retrieval. Poor response was defined by the presence of at least one of the following characteristics: three or fewer oocytes on retrieval, serum estradiol level less than 500 pg/mL on the day of hCG administration, and serum FSH levels less than 20 IU/L. The same patients had a previous cycle cancelled because of a poor ovarian response whereas in the second cycle they preferred to continue the treatment despite the poor prognosis. We obtained 241 oocytes in the 96 IVF cycles. The fertilization rate was 60.2%. Three oocytes per cycle were retrieved in 56 cycles (58.3%), two oocytes per cycle in 33 cycles (34.4%), and one oocyte per cycle in 7 cycles (7.3%). In 19 cycles (19.8%) no fertilization was achieved. An embryo transfer was finally performed in 74 out of 96 cycles. Pregnancy rate was 12.5% per cycle and 16.2% per transfer. Among the 12 pregnancies achieved, 7 were in the 3‐oocyte cycles and 5 in the 2‐oocyte cycles. No pregnancies were achieved in the 1‐oocyte cycles. Our data demonstrate that continuation of therapy in poor responders undergoing IVF can be an option despite the low pregnancy rates. The prognosis of these patients is not affected by a poor response in the first cycle and for some of them the outcome can be favorable.
The Varying Patterns of Neurotrophin Changes in the Perinatal Period
Authors: NIKOLAOU K.E. , MALAMITSI‐PUCHNER A. , BOUTSIKOU T. , ECONOMOU E. , BOUTSIKOU M. , PUCHNER K‐P. , BAKA S. , HASSIAKOS D.
Published: February 2007

Abstract:  Neurotrophins (NTs), nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), NT‐3, and NT‐4 are of major importance in prenatal and postnatal brain development, due to their neuroprotective action. Developmental changes alter the neuronal responsiveness to certain NTs, which subsequently are variously expressed, to properly balance their action. The following study aimed at examining the pattern of perinatal changes of the four NTs—NGF, BDNF, NT‐3, and NT‐4 in 30 appropriate for gestational age (AGA) full‐term fetuses and neonates by determining their circulating levels at characteristic time points. This study show a gradual decrease of circulating levels of the NTs, NT‐3 and NT‐4 from umbilical cord (UC) to neonates day 4 (N4), while circulating levels of NGF and BDNF present the opposite pattern: an increase from UC to N4. These patterns of perinatal changes differ according to their impact on the process of neuronal development and their reaction to perinatal stress. NT3 and NT4 have been documented to act at early stages of neuronal development and to decrease after hypoxia‐ischemia, while NGF and BDNF to increase. Further studies should investigate these patterns in premature or full‐term infants, presenting various pathological conditions in the perinatal period.
Effect of Prolactin in the Absence of hCG on Maturation, Fertilization, and Embryonic Development of in Vitro Matured Mouse Oocytes
Authors: KIAPEKOU ERASMIA , ZAPANTI EVANGELIA , MASTORAKOS GEORGE , BERETSOS PANAGIOTIS , BLETSA RITSA , DRAKAKIS PETER , LOUTRADIS DIMITRIS , ANTSAKLIS ARISTIDIS
Published: February 2007

Abstract:  Oocyte maturation is a complex process involving both the progression of meiotic cycle and the reprogramming of cytoplasmic events. The aim of this study was to investigate the effects of prolactin (PRL) in the in vitro maturation (IVM) of preantral mouse oocytes, in the absence of human chorionic gonadotrophin (hCG). Mouse preantral follicles were collected from female mice without prior hormonal ovarian stimulation and were cultured in the presence of varying concentrations of PRL (20, 100, 200, and 300 ng/mL) for 12 days. A group of in vitro matured oocytes were assessed for polar body (PB) formation, while the rest were fertilized and embryonic development was recorded. The maturation of preantral mouse follicles, as well as their fertilization and cleavage rates, observed when the culture medium was supplemented with middle‐ and high‐range doses of PRL was beneficially affected. This effect was considerably high, although the culture media lacked hCG, a hormone extensively used in modern ovulation induction regiments, as well as in IVM media.
Greek Experience in the Use of Thermachoice™ for Treating Heavy Menstrual Bleeding
Authors: PASCHOPOULOS MINAS , LAVASIDIS LAZAROS G. , VREKOUSSIS THOMAS , POLYZOS NIKOLAOS P. , DALKALITSIS NIKOLAOS , STAMATOPOULOS PANAGIOTIS , GRIGORIOU ODYSSEAS , VLACHOS GEORGE , SKOLARIKOS PANAGIOTIS , ADONAKIS GEORGE , GOUMENOU ANASTASIA , LIALIOS GEORGE , MAROULIS GEORGE , PARASKEVAIDIS EVANGELOS
Published: February 2007

Abstract:  Heavy menstrual bleeding (HMB) occurs in a considerable percentage of the general population and is one of the main causes due to which a patient is referred to health services. Despite the efforts for pharmaceutical interventions, the symptom usually persists, therefore operative techniques are needed to control the bleeding. Today, apart from the choice of hysterectomy, other less aggressive techniques have been invented. The first results of the Greek Study Group on Gynecological Endoscopy regarding the use of the Thermachoice™ device are hereby presented. One hundred patients suffering HMB were treated with the Thermachoice™ device following a standard protocol designed by the Study Group. The follow‐up meetings with the patients were held at 3, 6, 12, 24, and 36 months. It seems that the overall effectiveness rate (96%) is satisfactory and it is similar to the overall effectiveness rate reported in other relevant studies upon the Thermachoice™ device.