bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic and Therapeutic Approach to Hypothalamic Amenorrhea
Authors: GENAZZANI ALESSANDRO D. , RICCHIERI FEDERICA , LANZONI CHIARA , STRUCCHI CLAUDIA , JASONNI VALERIO M.
Published: February 2007

Abstract:  Hypothalamic amenorrhea (HA) is a secondary amenorrhea with no evidence of endocrine/systemic causal factors, mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressant conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be exclude any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressant situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This article tries to give insights into diagnosis and putative therapeutic strategies.
Causes of Intrauterine Growth Restriction and the Postnatal Development of the Metabolic Syndrome
Authors: VALSAMAKIS GEORGE , KANAKA‐GANTENBEIN CHRISTINA , MALAMITSI‐PUCHNER ARIADNE , MASTORAKOS GEORGE
Published: February 2007

Abstract:  The term intrauterine growth restriction (IUGR) is assigned to newborns with a birth weight and/or birth length below the 10th percentile for their gestational age and whose abdominal circumference is below the 2.5th percentile with pathologic restriction of fetal growth. IUGR is usually due to maternal, fetal, or placental factors. However, many IUGR cases have unknown underlying cause. Recent studies focus on new factors that can influence fetal development and birth outcome like the timing and the type of fetal nutrition, maternal psychosocial stress and personality variables, 11β‐hydroxysteroid dehydrogenase type 2 placental activity, the activity of the neuroendocrine system that mediates the effects of psychosocial stress, and the role of proinflammatory cytokines and of oxidative stress. Data have shown that IUGR is associated with a late life increased prevalence of metabolic syndrome, a condition associating obesity with hypertension, type 2 diabetes mellitus (DM2), and cardiovascular disease. Recent data demonstrated that the diabetes‐associated mortality appears to be disproportionately concentrated among individuals of abnormal birth weight.
Premature Adrenarche Leads to Polycystic Ovary Syndrome?
Authors: KOUSTA ELENI
Published: February 2007

Abstract:  Premature adrenarche is characterized by an early increase in adrenal androgen production that results in the development of pubic hair before the age of 8 years in girls and 9 years in boys, with or without axillary hair, and with no other signs of sexual development. Premature adrenarche has no adverse effects on the onset and progression of gonadarche and final height. However, it can no longer be considered a benign condition as it has been associated with hyperinsulinemia, dyslipidemia, and obesity already in the prepubertal period and polycystic ovary syndrome (PCOS) at adolescence. Furthermore, a possible association between premature adrenarche and metabolic and endocrine abnormalities with low birth weight has been postulated. PCOS, as recently redefined, is the most common endocrine disorder to affect women of reproductive age and has been associated with increased risk for type 2 diabetes and increased prevalence of cardiovascular risk factors at an earlier age than expected. Premature adrenarche and PCOS share similar metabolic disturbances. It may be that metabolic abnormalities start very early in life during the prenatal or prepubertal period and premature adrenarche may be a forerunner of PCOS and the metabolic syndrome in some girls. Large long‐term epidemiological studies are needed to allow clear association of the two conditions and assessment of the risk of disease in later life.
Polycystic Ovary Syndrome
Authors: PASQUALI RENATO , GAMBINERI ALESSANDRA
Published: February 2007

Abstract:  Polycystic ovary syndrome (PCOS), one of the most common causes of ovulatory infertility, affects 4–7% of women. Although it was considered that PCOS may have some genetic component and that clinical features of this disorder may change throughout a life span, starting from adolescence to postmenopausal age, no effort has been made to define differences in the phenotype and clinical presentation according to age. Indeed, it has been widely recognized in the last decade that several features of metabolic syndrome (MS), particularly insulin resistance and hyperinsulinemia, are inconsistently present in the majority of women with PCOS. This represents an important factor in the evaluation of PCOS throughout life, which implies that PCOS by itself may not be a hyperandrogenic disorder exclusively related to young and fertile‐aged women, but may also have some health implications later in life. In young women with PCOS, hyperandrogenism, menses irregularities, and insulin resistance may occur together, emphasizing the pathophysiological role of excess androgen and insulin on PCOS. Hyperandrogenism and infertility represent the major complaints of PCOS in adult fertile age. In addition, obesity and MS may affect more than half these women. Later in life, it becomes clear that the association of obesity (particularly the abdominal phenotype) and PCOS renders affected women more susceptible to develop type 2 diabetes mellitus (T2DM), with some difference in the prevalence rates among countries, suggesting that environmental factors are important in determining individual susceptibility. Little is known about ovarian morphology and androgen production in women with PCOS after menopause. Some studies found that morphological ultrasonographic features consistent with polycystic ovaries are very common in postmenopausal women, and that these features are associated with higher than normal testosterone levels and metabolic alterations. There is an obvious need for further research in this area. Identification of major complaints and features of PCOS during the different ages of an affected woman may help, in fact, to plan individual therapeutic strategies, and, possibly, prevent long‐term chronic metabolic diseases.
Laparoscopic Management of Hydrosalpinx
Authors: BONTIS JOHN N. , THEODORIDIS THEODOROS D.
Published: February 2007

Abstract:  Hydrosalpinx is a common cause of female infertility. Lower implantation and pregnancy rates have been reported in women with hydrosalpinges. How hydrosalpinx exerts its negative effect on the implantation process is not clearly understood. Mechanical factors, toxicity of the hydrosalpingeal fluid, and receptivity dysfunction may explain the impaired IVF outcome in the presence of hydrosalpinx. Laparoscopic surgery has a place in the diagnosis and management of hydrosalpinx. Analysis of the results of laparoscopic management of hydrosalpinx underscores the positive role of laparoscopy in fertility outcomes in women with this pathological tubal disease. Laparoscopic salpingectomy should be offered in those women who have bilateral disease or in cases where hydrosalpinges are large enough to be visible on ultrasound. Further randomized trials are required to assess other surgical treatment options for hydrosalpinx, such as laparoscopic salpingostomy, laparoscopic or hysteroscopic tubal occlusion, and drainage of hydrosalpinx before or during oocyte retrieval.
Laparoscopic Management of the Adnexal Mass
Authors: PADOS GEORGE , TSOLAKIDIS DIMITRIS , BONTIS JOHN
Published: February 2007

Abstract:  In the past few years the contribution of operative laparoscopy in all fields of gynecological surgery has been revolutionary. Nowadays laparoscopic management of adnexal masses is the most frequently performed laparoscopic intervention. Laparoscopy in comparison to laparotomy has the advantages of lower morbidity, shorter length of hospital stay, decreased postoperative pain, lesser de novo adhesion formation, better cosmetic results, faster recovery, and reduced overall cost of care. However, careful preoperative evaluation is important for the appropriate and successful use of laparoscopy for removal of adnexal masses and the advantages of the laparoscopic approach should, in no way, compromise the clinical outcome in women with malignancy. Patient's age, history, findings of physical examination, and the results of serum markers in combination with the imaging assessment, such as Doppler sonograpy, CT, or MRI, should be considered to reach the diagnosis preoperatively. However, only pathology of the adnexal mass can provide the definitive diagnosis. The specific characteristics of the adnexal masses in childhood, adolescent, reproductive, and postmenopausal age represent the essential parameters that will determine the therapeutic strategy to be followed. Furthermore, the clinician has to determine whether an adnexal mass requires surgery or expectant management as well as to estimate the possibility of malignancy.
Oocyte Maturation in Assisted Reproductive Techniques
Authors: LOUTRADIS DIMITRIS , KIAPEKOU ERASMIA , ZAPANTI EVANGELIA , ANTSAKLIS ARISTIDIS
Published: February 2007

Abstract:  Human oocyte maturation is a long process during which nuclear maturation occurs resulting in germinal vesicle breakdown (transition from prophase I to metaphase II) and extrusion of the first polar body. During oocyte maturation, in parallel with nuclear maturation, a number of events take place in the oocyte cytoplasm that assist fertilization and early embryonic development. So far several attempts have been made to mature human oocytes in vitro. The main patient group to which in vitro maturation (IVM) has been applied is polycystic ovarian syndrome. In a concise review we present the techniques used for the IVM of oocytes and the role of hormones and growth factors in IVM and subsequent fertilization and early embryonic development.
Fertility Drugs and Gynecologic Cancer
Authors: KANAKAS NIKOS , MANTZAVINOS THEMIS
Published: February 2007

Abstract:  Fertility drugs (FD) are spreading worldwide fast and therefore many studies have reviewed the possible association between the use of these drugs and cancer. Since the drugs used for ovulation induction during in vitro fertilization (IVF) like hCG, hMG, rFSH increase the levels of gonadal hormones, concerns have grown regarding the risk of developing cancer in breast, ovary, endometrium, and other target organs. In this review, we discuss a number of different studies published in recent years that show no association between the use of these drugs and most cancers.
Preimplantation Genetic Diagnosis
Authors: MAROULIS GEORGE B. , KOUTLAKI NIKOLETTA
Published: February 2007

Abstract:  Preimplantion genetic diagnosis (PGD) is now used for identification of gene and chromosomal defects in embryos. In this article we describe its use primarily for identification of chromosomal defects in women with recurrent abortions, repeated in vitro fertilization (IVF) failure, and advanced maternal age. In all these situations there is increase in chromosomal defects. The identification of normal embryos and the elimination of abnormal embryos are argued to be helpful in increasing implantation and pregnancy rates in these women.
Intrauterine Growth Restriction, Brain‐Sparing Effect, and Neurotrophins
Authors: MALAMITSI‐PUCHNER ARIADNE , NIKOLAOU K.E. , PUCHNER K‐P.
Published: February 2007

Abstract:  Intrauterine growth restriction (IUGR) is failure of the fetus to achieve his or her intrinsic growth potential, due to anatomical/functional diseases or disorders in the feto–placental–maternal unit. Growth restriction successfully balances reduced oxygen delivery and consumption; however, chronic hypoxia is responsible for fetal blood flow redistribution to cardinal organs (brain, myocardium, and adrenal glands), the so‐called brain‐sparing effect. The neurotrophin family comprises four structurally related molecules: the nerve growth factor (NGF), the brain‐derived neurotrophic factor (BDNF), the neurotrophin‐3 (NT‐3), and the neurotrophin‐4 (NT‐4). By exerting neuroprotection, neurotrophins are critical for pre‐ and postnatal brain development. Based on the assumption that the brain‐sparing effect might be activated in full‐term IUGR infants, we hypothesized that circulating neurotrophin levels should not differ between IUGR and appropriate for gestational age (AGA) infants. Indeed, we found that in both groups, circulating NT‐3, NT‐4, and BDNF levels do not differ, and this finding could possibly be attributed to the activation of the brain‐sparing effect. In contrast, NGF levels were higher in the AGA compared to the IUGR group. However, only NGF levels positively correlated with the customized centile and the birth weight of the infants, and both of them were lower in the IUGR group.
Doppler Assessment of the Intrauterine Growth‐Restricted Fetus
Authors: BOTSIS D. , VRACHNIS N. , CHRISTODOULAKOS G.
Published: February 2007

Abstract:  The evaluation of fetal well‐being by Doppler velocimetry in cases of intrauterine growth restriction (IUGR) is of great importance as it is very useful in detecting those IUGR fetuses that are at high risk because of hypoxemia. Several Doppler studies initially on fetal arteries and recently on the fetal venous system provide valuable information for the clinicians concerning the optimal time to deliver. Doppler sonography in combination with the other biophysical methods such as cardiotocogram and biophysical profile score should be used in everyday practice for the monitoring and appropriate management of the growth‐restricted fetuses. The purpose of this review is to describe the current approaches in Doppler assessment of IUGR fetal circulation.
Pitfalls of the WHIs
Authors: MASTORAKOS GEORGE , SAKKAS EVANGELOS GR. , XYDAKIS ANTONIOS M. , CREATSAS GEORGE
Published: February 2007

Abstract:  Recently, the use of hormone replacement therapy (HRT) at menopause has become a matter of debate. Its utility has been questioned after the publication of the results of the Women's Health Initiative (WHI) studies. This trial was divided in two arms of which the first examined the use of combined HRT (continuous estrogens plus progestins) and the second the use of estrogens alone in menopausal women. The first arm was terminated prematurely at 5.2 years because the number of cases of coronary heart disease (CHD), strokes, venous thromboembolic disease, and breast cancer were more in women receiving HRT than in women receiving placebo, if the nominal confidence intervals (CIs) were taken into account. However, in the same study the authors made clear that the adjusted CIs should be taken into account instead of the nominal ones. These latter ones caused the ending of the trial. Moreover, WHI was criticized for its conclusions as far as cardiovascular disease is concerned because of serious defects regarding design of the trial. If the adjusted CIs were taken into account then the increase in adverse events was significant only for deep vein thrombosis. The second arm demonstrated that the use of estrogens was not correlated to an increase of neither breast cancer incidence nor cardiovascular disease. A closer look at the results of the WHI trial reveals that the use of HRT for 5 years should not be considered deleterious for the appearance of breast cancer, cardiovascular diseases, strokes, and pulmonary embolisms. We suggest that HRT should be given early in menopause. The regimen should be individualized for each patient. More intense follow‐up should be offered to women with a positive family history of breast cancer, diagnosed coronary disease, and to women with a predisposition to deep venous thrombosis.
Hormone Replacement Therapy and Cardioprotection
Authors: ROSANO GIUSEPPE M.C. , VITALE CRISTIANA , FINI MASSIMO
Published: February 2007

Abstract:  The incidence of cardiovascular diseases (CVDs) increases after menopause and at any age postmenopausal women have a significantly higher incidence of CVD compared to premenopausal women. Several epidemiological findings suggest the causative pathogenetic role of ovarian hormone deficiency in the development of CVD in women. Ovarian hormones have several potential protective effects on the cardiovascular system and despite several observational studies have shown the beneficial effect of estrogens and estrogen/progestin associations on CVD, at the present, after the findings of randomized studies, the effect of hormone replacement therapy (HRT) in the prevention of CVD is still under debate. The randomized studies (Heart and Estrogen/Progestin Replacement Study [HERS] and Women's Health Initiative [WHI]) found largely concordant results with the observational studies except for the divergent findings about coronary heart disease (CHD). The discrepancy between the two arms of the WHI study suggests that two factors, time to initiation of HRT since menopause and estrogen/progestin associations, are of pivotal importance to explain the widely divergent findings on the cardiovascular effects of observational studies and randomized clinical studies. Basic science and animal studies together with clinical investigations and the results of clinical studies are concordant in suggesting that a long time since menopause is associated with a reduced protective effect of estrogens while the unfavorable effects upon coagulation remain unaltered. In early postmenopausal women, like the ones included in the observational studies, ovarian hormone replacement may be cardioprotective because of the responsiveness of the endothelium to estrogens that also buffer the detrimental effects upon coagulation. In late postmenopausal women ovarian hormones have either a null effect or even a detrimental effect because of the predominance of the procoagulant or plaque‐destabilizing effects over the vasoprotective effects. Therefore, HRT has beneficial cardiovascular effects in younger women while it may have detrimental effect on coagulative balance and vascular inflammation and has little effect on cardiovascular functions in older women.
Bone Remodeling
Authors: HADJIDAKIS DIMITRIOS J. , ANDROULAKIS IOANNIS I.
Published: February 2007

Abstract:  The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. The remodeling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced. Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone (PTH), calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Factors such as insulin‐like growth factors (IGFs), prostaglandins, tumor growth factor‐beta (TGF‐β), bone morphogenetic proteins (BMP), and cytokines are involved as well. As far as local regulation of bone remodeling is concerned, a large number of cytokines and growth factors that affect bone cell functions have been recently identified. Furthermore, through the RANK/receptor activator of NF‐kappa B ligand (RANKL)/osteoprotegerin (OPG) system the processes of bone resorption and formation are tightly coupled allowing a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity.
Bisphosphonates
Authors: LAMBRINOUDAKI IRENE , CHRISTODOULAKOS GEORGE , BOTSIS DIMITRIOS
Published: February 2007

Abstract:  Bisphosphonates belong to a class of compounds similar to pyrophosphate. In these compounds the oxygen atom of the pyrophosphate is replaced by a carbon atom resulting in a P‐C‐P bond. They exert a potent inhibitory effect on osteoclasts and are therefore potent antiresorptive agents. They reduce bone turnover, increase bone mineral density, and decrease fracture risk both at the lumbar spine and the hip. Bisphosphonates have a high affinity for bone surfaces, where they accumulate, mainly at sites of bone remodeling. Due to their selectivity in action, they are usually not associated with systemic side effects. Their main unwanted effect is upper gastrointestinal irritation. Alendronate and risedronate are the two most widely used compounds in the treatment of postmenopausal osteoporosis. They are administered orally either daily or once weekly. Ibandronate is a highly potent newer third‐generation bisphosphonate administered once monthly with similar efficacy with respect to bone mineral density and fracture risk. Zoledronate, another potent third‐generation bisphosphonate, currently approved for the treatment of malignancy‐associated hypercalcemia, is currently undergoing phase III trials for the treatment of postmenopausal osteoporosis as an intravenous (i.v.) infusion once annually.
Strontium Ranelate
Authors: TOURNIS S. , ECONOMOPOULOS D. , LYRITIS G.P.
Published: February 2007

Abstract:  Strontium ranelate (SR) is a novel antiosteoporotic agent, electively concentrated in positions of active bone formation, and especially onto the crystal surface that allows permanent exchanges with extracellular fluid. Although the mechanism(s) of action is still under rigorous research, SR appears to reduce bone resorption by decreasing osteoclast differentiation and activity and to stimulate bone formation by increasing replication of preosteoblast cells, leading to increased matrix synthesis. In the placebo‐controlled, phase III trial spinal osteoporosis therapeutic intervention (SOTI) (no = 1442; mean age 69 years), there was a 41% decrease over 3 years in the number of patients with new vertebral fractures in the SR (2 g/day) group versus placebo (P < 0.001), already detected after 12 months (49% lower risk, P < 0.001). The phase III treatment of peripheral osteoporosis (TROPOS) study assessed the efficacy of SR (2 g/day) in preventing nonvertebral fractures in postmenopausal osteoporosis (no = 4932; mean age 77 years). SR reduced nonvertebral fracture risk by 16% versus placebo (P= 0.04) and hip fracture risk by 36% (P= 0.031) in osteoporotic patients older than 74 years. Thus SR is an effective and safe treatment for vertebral and hip osteoporosis with a unique mode of action.
Maternal Age and the Duration of the Second Stage of Labor
Authors: PAPADIAS K. , CHRISTOPOULOS P. , DELIGEOROGLOU E. , VITORATOS N. , MAKRAKIS E. , KALTAPANIDOU P. , TSOUKAS A. , CREATSAS G.
Published: February 2007

Abstract:  The purpose of this study was to investigate the relationship between parity, maternal age at delivery, gestational age, and duration of the second stage of labor. In this article a retrospective analysis of deliveries during the period from 2000 to 2005 in our Institution was made. We recorded 208 pregnant women under the age of 20 years, 6,115 between 20 and 40 years, and 188 over the age of 40 years considering parity, duration of second stage of labor, birth weight, and gestation age. The correlation of the above parameters was statistically analyzed. In primigravidas, under the age of 20 years, the second stage of labor was significantly shorter compared to women aged over 40 years, and significantly shorter compared to women between the age of 20 and 40 years. Gestational age at delivery was significantly shorter in women aged over 40 years compared to those under the age of 20 years as well as to those between 20 and 40 years of age. Age was positively correlated to the duration of the second stage of labor and negatively correlated to the gestation age at delivery. In multigravidas, age was negatively correlated to the gestational age at delivery. In primigravidas, maternal age was positively correlated with the duration of the second stage of labor. On the contrary, gestational age at delivery was negatively correlated with maternal age. In multigravidas, a negative correlation between maternal age and gestational age at delivery was statistically significant.
Insulin‐Like Growth Factor–1 Isoform mRNA Expression in Women with Endometriosis
Authors: MILINGOS DIMITRIOS , KATOPODIS HARALAMPOS , MILINGOS SPYROS , PROTOPAPAS ATHANASIOS , CREATSAS GEORGE , MICHALAS STELIOS , ANTSAKLIS ARIS , KOUTSILIERIS MICHAEL
Published: February 2007

Abstract:  Pathogenesis of endometriosis involves growth factors, which are synthesized locally. Insulin‐like growth factor‐1 (IGF‐1) prevents apoptosis and has mitogenic action on endometrial cells. The IGF‐1 gene undergoes alternative splicing and results in three isoforms (IGF‐1Ea, IGF‐1Eb, and IGF‐1Ec or MGF). We analyzed the mRNA expression of IGF‐1 isoforms in tissue samples of eutopic endometrium and endometriotic cyst obtained during laparoscopy from women with endometriosis. We documented that all three IGF‐1 isoforms are expressed in both eutopic endometrium and ovarian endometrioma. Furthermore, we documented a significant decrease in all IGF‐1 isoform expression in endometriotic cyst compared to endometrium of women with endometriosis. The reduction may correlate with the disease status and presence of fibrotic inactive tissue found in late stages of the disease.
The Use of Simulation in Emergency Medicine: A Research Agenda
Authors: Bond William F. , Lammers Richard L. , Spillane Linda L. , Smith‐Coggins Rebecca , Fernandez Rosemarie , Reznek Martin A. , Vozenilek John A. , Gordon James A.
Published: February 2007

Medical simulation is a rapidly expanding area within medical education. In 2005, the Society for Academic Emergency Medicine Simulation Task Force was created to ensure that the Society and its members had adequate access to information and resources regarding this new and important topic. One of the objectives of the task force was to create a research agenda for the use of simulation in emergency medical education. The authors present here the consensus document from the task force regarding suggested areas for research. These include opportunities to study reflective experiential learning, behavioral and team training, procedural simulation, computer screen–based simulation, the use of simulation for evaluation and testing, and special topics in emergency medicine. The challenges of research in the field of simulation are discussed, including the impact of simulation on patient safety. Outcomes‐based research and multicenter efforts will serve to advance simulation techniques and encourage their adoption.
What Is the Most Cost-Effective Population-Based Cancer Screening Program for Chinese Women?
Authors: Woo Pauline P.S. , Kim Jane J. , Leung Gabriel M.
Published: February 2007

Purpose

To develop a policy-relevant generalized cost-effectiveness (CE) model of population-based cancer screening for Chinese women.

Methods

Disability-adjusted life-years (DALYs) averted and associated screening and treatment costs under population-based screening using cervical cytology (cervical cancer), mammography (breast cancer), and fecal occult blood testing (FOBT), sigmoidoscopy, FOBT plus sigmoidoscopy, or colonoscopy (colorectal cancer) were estimated, from which average and incremental CE ratios were generated. Probabilistic sensitivity analysis was undertaken to assess stochasticity, parameter uncertainty, and model assumptions.

Results

Cervical, breast, and colorectal cancers were together responsible for 13,556 DALYs (in a 1:4:3 ratio, respectively) in Hong Kong's 3.4 million female population annually. All status quo strategies were dominated, thus confirming the suboptimal efficiency of opportunistic screening. Current patterns of screening averted 471 DALYs every year, which could potentially be more than doubled to 1,161 DALYs under the same screening and treatment budgetary threshold of US $50 million with 100% Pap coverage every 4 years and 30% coverage of colonoscopy every 10 years. With higher budgetary caps, biennial mammographic screening starting at age 50 years can be introduced.

Conclusion

Our findings have informed how best to achieve allocative efficiency in deploying scarce cancer care dollars but must be coupled with better integrated care planning, improved intersectoral coordination, increased resources, and stronger political will to realize the potential health and economic gains as demonstrated.
Randomized Controlled Trial of a Prompt List to Help Advanced Cancer Patients and Their Caregivers to Ask Questions About Prognosis and End-of-Life Care
Authors: Clayton Josephine M. , Butow Phyllis N. , Tattersall Martin H.N. , Devine Rhonda J. , Simpson Judy M. , Aggarwal Ghauri , Clark Katherine J. , Currow David C. , Elliott Louise M. , Lacey Judith , Lee Philip G. , Noel Michael A.
Published: February 2007

Purpose

To determine whether provision of a question prompt list (QPL) influences advanced cancer patients’/caregivers’ questions and discussion of topics relevant to end-of-life care during consultations with a palliative care (PC) physician.

Patients and Methods

This randomized controlled trial included patients randomly assigned to standard consultation or provision of QPL before consultation, with endorsement of the QPL by the physician during the consultation. Consecutive eligible patients with advanced cancer referred to 15 PC physicians from nine Australian PC services were invited to participate. Consultations were audiotaped, transcribed, and analyzed by blinded coders; patients completed questionnaires before, within 24 hours, and 3 weeks after the consultation.

Results

A total of 174 patients participated (92 QPL, 82 control). Compared with controls, QPL patients and caregivers asked twice as many questions (for patients, ratio, 2.3; 95% CI, 1.7 to 3.2; P < .0001), and patients discussed 23% more issues covered by the QPL (95% CI, 11% to 37%; P < .0001). QPL patients asked more prognostic questions (ratio, 2.3; 95% CI, 1.3 to 4.0; P = .004) and discussed more prognostic (ratio, 1.43; 95% CI, 1.1 to 1.8, P = .003) and end-of-life issues (30% v 10%; P = .001). Fewer QPL patients had unmet information needs about the future (χ21 = 4.14; P = .04), which was the area of greatest unmet information need. QPL consultations (average, 38 minutes) were longer (P = .002) than controls (average, 31 minutes). No differences between groups were observed in anxiety or patient/physician satisfaction.

Conclusion

Providing a QPL and physician endorsement of its use assists terminally ill cancer patients and their caregivers to ask questions and promotes discussion about prognosis and end-of-life issues, without creating patient anxiety or impairing satisfaction.
Clinical and Molecular Characteristics of Malignant Transformation of Low-Grade Glioma in Children
Authors: Broniscer Alberto , Baker Suzanne J. , West Alina N. , Fraser Melissa M. , Proko Erika , Kocak Mehmet , Dalton James , Zambetti Gerard P. , Ellison David W. , Kun Larry E. , Gajjar Amar , Gilbertson Richard J. , Fuller Christine E.
Published: February 2007

Purpose

To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children.

Patients and Methods

The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval.

Results

Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient.

Conclusion

The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.
Cyclin D1 Guanine/Adenine 870 Polymorphism With Altered Protein Expression Is Associated With Genomic Instability and Aggressive Clinical Biology of Esophageal Adenocarcinoma
Authors: Izzo Julie G. , Wu Tsung-Teh , Wu Xifeng , Ensor Joe , Luthra Rajyalakshmi , Pan Jennifer , Correa Arlene , Swisher Stephen G. , Chao Clifford K.S. , Hittelman Walter N. , Ajani Jaffer A.
Published: February 2007

Purpose

Altered cyclin D1 (CD1), a cell cycle regulator, may play an important role in imparting aggressive nature to esophageal adenocarcinoma (EAC). CD1 gene single nucleotide polymorphism G/A870 results in two alternatively spliced transcripts, CD1a and CD1b. CD1b, preferentially encoded by the A870 allele, is putatively oncogenic. We hypothesized that CD1 A870 allele would be associated with higher CD1 protein expression, and increased genomic instability during EAC evolution, leading to more aggressive phenotype.

Patients and Methods

One hundred twenty-four archival specimens of EAC, and 39 associated Barrett's esophagus (BE) specimens were examined for CD1 genotype, CD1 protein expression, and chromosome 9 polysomy (representing genomic instability). We correlated CD1 genotypes with CD1 protein expression, genomic instability, age at diagnosis of EAC, and overall survival (OS).

Results

The A870 allele was associated with higher levels of CD1 protein expression in EAC (P = .032); in BE (P = .01) where it was associated with concomitant increased chromosome 9 polysomy (P = .002); and with a younger age at diagnosis (P < .001) and poor OS (P = .0003) of EAC patients.

Conclusion

Our data suggest that CD1 A870 background may be imparting aggressive phenotype to EAC. It provides a molecular basis to explain the clinical biology associated with CD1 polymorphism whereas aberrant nuclear accumulation of CD1 protein enhances the acquisition of genomic instability (ie, clonal diversity), thus leading to early age of EAC diagnosis and poor OS. CD1 genotyping with other biomarkers may help create a biomarker-based prognostic model for EAC and CD1 may also serve as a therapeutic target.
Development of Anti-PRL (Prolactin) Autoantibodies by Homologous PRL in Rats: A Model for Macroprolactinemia
Authors: Hattori Naoki , Nakayama Yasuhisa , Kitagawa Kaori , Li Tiesong , Inagaki Chiyoko
Published: February 2007

Macroprolactinemia is hyperprolactinemia in humans mainly due to anti-PRL (prolactin) autoantibodies and is a pitfall for the differential diagnosis of hyperprolactinemia. Despite its high prevalence, the pathogenesis remains unclear. In this study, we examined whether anti-PRL autoantibodies develop via immunization with homologous rat pituitary PRL in rats to elucidate what mechanisms are involved and whether they cause hyperprolactinemia with low PRL bioactivity, as seen in human macroprolactinemia. Anti-PRL antibodies were developed in 19 of 20 rats immunized with homologous rat pituitary PRL and 29 of 30 rats with heterogeneous bovine or porcine pituitary PRL but did not develop in 25 control rats. In rats with anti-PRL antibodies, the basal serum PRL levels were elevated, and a provocative test for PRL secretion using dopamine D2 receptor antagonist (metoclopramide) showed a normal rising response with a slower clearance of PRL because of the accumulation of macroprolactin in blood. Antibodies developed by porcine or rat pituitary PRL reduced the bioactivity of rat serum PRL, and gonadal functions in these rats were normal despite hyperprolactinemia. Anti-PRL antibodies were stable and persisted for at least 5 wk after the final injection of PRL. These findings suggest that pituitary PRL, even if homologous, has antigenicity, leading to the development of anti-PRL autoantibodies. We successfully produced an animal model of human macroprolactinemia, with which we can explain the mechanisms of its clinical characteristics, i.e. asymptomatic hyperprolactinemia.
Synergistic Expression of Angiotensin-Converting Enzyme (ACE) and ACE2 in Human Renal Tissue and Confounding Effects of Hypertension on the ACE to ACE2 Ratio
Authors: Wakahara Shigeyuki , Konoshita Tadashi , Mizuno Shinichi , Motomura Makoto , Aoyama Chikako , Makino Yasukazu , Kato Norihiro , Koni Ichiro , Miyamori Isamu
Published: February 2007

Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.
Activation of a Membrane-Associated Androgen Receptor Promotes Cell Death in Primary Cortical Astrocytes
Authors: Gatson Joshua W. , Singh Meharvan
Published: February 2007

In the central nervous system, androgens can exert either protective or damage-promoting effects. For example, testosterone protects neurons against β-amyloid toxicity, whereas in other studies, testosterone exacerbated stroke-induced lesion size. The mechanism underlying this duality of androgens is still unclear. Recently, our laboratory reported that androgens elicit opposite effects on the ERK/MAPK and Akt signaling pathways, depending on whether a membrane androgen receptor (AR) or intracellular AR was activated. By extension, we hypothesized that androgens may affect cell viability differently depending on which receptor is activated. Here, we found that dihydrotestosterone (DHT) protected primary cortical astrocytes from the metabolic and oxidative insult associated with iodoacetic acid-induced toxicity, whereas DHT-BSA, a cell impermeable analog of DHT that preferentially targets the membrane AR, suppressed Akt signaling, increased caspase 3/7 activity, and enhanced iodoacetic acid-induced cell death. Interestingly, DHT-BSA also blocked the protective effects of DHT and estradiol. Collectively, these data support the existence of two, potentially competing, pathways for androgens in a given cell or tissue that may provide insight into the controversy of whether androgen therapy is beneficial or detrimental.
The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11β-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue
Authors: Marcolongo Paola , Piccirella Simona , Senesi Silvia , Wunderlich Livius , Gerin Isabelle , Mandl József , Fulceri Rosella , Bánhegyi Gábor , Benedetti Angelo
Published: February 2007

11β-Hydroxysteroid dehydrogenase type 1, expressed mainly in the endoplasmic reticulum of adipocytes and hepatocytes, plays an important role in the prereceptorial activation of glucocorticoids. In liver endoplasmic reticulum-derived microsomal vesicles, nicotinamide adenine dinucleotide phosphate reduced supply to the enzyme is guaranteed by a tight functional connection with hexose-6-phosphate dehydrogenase and the glucose-6-phosphate transporter (G6PT). In adipose tissue, the proteins and their activities supporting the action of 11β-hydroxysteroid dehydrogenase type 1 have not been explored yet. Here we report the occurrence of the hexose-6-phosphate dehydrogenase in rat epididymal fat, as detected at the level of mRNA, protein, and activity. In the isolated microsomes, the activity was evident only on the permeabilization of the membrane because of the poor permeability to the cofactor nicotinamide adenine dineucleotide phosphate (NADP+), which is consistent with the intralumenal compartmentation of both the enzyme and a pool of pyridine nucleotides. In fat cells, the access of the substrate, glucose-6-phosphate to the intralumenal hexose-6-phosphate dehydrogenase appeared to be mediated by the liver-type G6PT. In fact, the G6PT expression was revealed at the level of mRNA and protein. Accordingly, the transport of glucose-6-phosphate was demonstrated in microsomal vesicles, and it was inhibited by S3483, a prototypic inhibitor of G6PT. Furthermore, isolated adipocytes produced cortisol on addition of cortisone, and the production was markedly inhibited by S3483. The results show that adipocytes are equipped with a functional G6PT-hexose-6-phosphate dehydrogenase-11β-hydroxysteroid dehydrogenase type 1 system and indicate that all three components are potential pharmacological targets for modulating local glucocorticoid activation.
Disabled-2 Is Expressed in Adrenal Zona Glomerulosa and Is Involved in Aldosterone Secretion
Authors: Romero Damian G. , Yanes Licy L. , de Rodriguez Angela F. , Plonczynski Maria W. , Welsh Bronwyn L. , Reckelhoff Jane F. , Gomez-Sanchez Elise P. , Gomez-Sanchez Celso E.
Published: February 2007

The differentiation of the adrenal cortex into functionally specific zones is probably due to differential temporal gene expression during fetal growth, development, and adulthood. In our search for adrenal zona glomerulosa-specific genes, we found that Disabled-2 (Dab2) is expressed in the zona glomerulosa of the rat adrenal gland using a combination of laser capture microdissection, mRNA amplification, cDNA microarray hybridization, and real-time RT-PCR. Dab2 is an alternative spliced mitogen-regulated phosphoprotein with features of an adaptor protein and functions in signal transduction, endocytosis, and tissue morphogenesis during embryonic development. We performed further studies to analyze adrenal Dab2 localization, regulation, and role in aldosterone secretion. We found that Dab2 is expressed in the zona glomerulosa and zona intermedia of the rat adrenal cortex. Low-salt diet treatment increased Dab2-long isoform expression at the mRNA and protein level in the rat adrenal gland, whereas high-salt diet treatment did not cause any significant modification. Angiotensin II infusion caused a transient increase in both Dab2 isoform mRNAs in the rat adrenal gland. Dab2 overexpression in H295R human adrenocortical cells caused an increase in aldosterone synthase expression and up-regulated aldosterone secretion under angiotensin II-stimulated conditions. In conclusion, Dab2 is an adrenal gland zona glomerulosa- and intermedia-expressed gene that is regulated by aldosterone secretagogues such as low-salt diet or angiotensin II and is involved in aldosterone synthase expression and aldosterone secretion. Dab2 may therefore be a modulator of aldosterone secretion and be involved in mineralocorticoid secretion abnormalities.
Protein Expression Patterns Associated with Progression of Chronic Obstructive Pulmonary Disease in Bronchoalveolar Lavage of Smokers
Authors: Plymoth Amelie , Löfdahl Claes-Göran , Ekberg-Jansson Ann , Dahlbäck Magnus , Broberg Per , Foster Martyn , Fehniger Thomas E , Marko-Varga György
Published: February 2007

Background: We modeled the expression of proteins in baseline bronchoalveolar lavage (BAL) samples from asymptomatic 60-year-old lifelong current smokers or healthy never-smokers, who were reevaluated after 6 to 7 years to record clinical outcome.

Methods: Applying a technology toolbox consisting of replicate 2-dimensional gel separations, image annotation, and mass spectrometry identification, we catalogued a global set of proteins that were differentially expressed in individuals by presence, absence, and intensity scores.

Results: By use of multivariate analysis, we selected a subset of proteins that accurately separated smokers from never-smokers based on composite scoring. Follow-up after 6 to 7 years identified a group of individuals who had progressed to chronic obstructive pulmonary disease (COPD), Global Initiative for Chronic Obstructive Lung Disease stage 2. The baseline BAL samples of these eventual COPD patients shared a distinct protein expression profile that could be identified using partial least-squares discriminant analysis. This pattern was not observed in BAL samples of asymptomatic smokers free of COPD at 6- to 7-year follow-up.

Conclusions: Our model suggests that certain patterns of protein expression occurring in the airways of long-term smokers may be detected in smokers susceptible to a progression of COPD disease, before disease is clinically evident.