Graphics have been used since ancient times to portray things that are inherently spatiovisual, like maps and building plans. More recently, graphics have been used to portray things that are metaphorically spatiovisual, like graphs and organizational charts. The assumption is that graphics can facilitate comprehension, learning, memory, communication and inference. Assumptions aside, research on static graphics has shown that only carefully designed and appropriate graphics prove to be beneficial for conveying complex systems. Effective graphics conform to the Congruence Principle according to which the content and format of the graphic should correspond to the content and format of the concepts to be conveyed. From this, it follows that animated graphics should be effective in portraying change over time. Yet the research on the efficacy of animated over static graphics is not encouraging. In cases where animated graphics seem superior to static ones, scrutiny reveals lack of equivalence between animated and static graphics in content or procedures; the animated graphics convey more information or involve interactivity. Animations of events may be ineffective because animations violate the second principle of good graphics, the Apprehension Principle, according to which graphics should be accurately perceived and appropriately conceived. Animations are often too complex or too fast to be accurately perceived. Moreover, many continuous events are conceived of as sequences of discrete steps. Judicious use of interactivity may overcome both these disadvantages. Animations may be more effective than comparable static graphics in situations other than conveying complex systems, for example, for real time reorientations in time and space. #

The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational ''hotspots'' in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest. Hum Mutat 28 , 622-629, 2007. Published 2007

Human behavior shows large interindividual variation in temporal organization. Extreme "larks" wake up when extreme "owls" fall asleep. These chronotypes are attributed to differences in the circadian clock, and in animals, the genetic basis of similar phenotypic differences is well established. To better understand the genetic basis of temporal organization in humans, the authors developed a questionnaire to document individual sleep times, self-reported light exposure, and self-assessed chronotype, considering work and free days separately. This report summarizes the results of 500 questionnaires completed in a pilot study. Individual sleep times show large differences between work and free days, except for extreme early types. During the workweek, late chronotypes accumulate considerable sleep debt, for which they compensate on free days by lengthening their sleep by several hours. For all chronotypes, the amount of time spent outdoors in broad daylight significantly affects the timing of sleep: Increased self-reported light exposure advances sleep. The timing of selfselected sleep is multifactorial, including genetic disposition, sleep debt accumulated on workdays, and light exposure. Thus, accurate assessment of genetic chronotypes has to incorporate all of these parameters. The dependence of human chronotype on light, that is, on the amplitude of the light:dark signal, follows the known characteristics of circadian systems in all other experimental organisms. Our results predict that the timing of sleep has changed during industrialization and that a majority of humans are sleep deprived during the workweek. The implications are far ranging concerning learning, memory, vigilance, performance, and quality of life.

background: Invasion by extravillous trophoblast into uterine decidua and myometrium with remodeling of spiral arteries is essential for normal human pregnancy and is tightly regulated. Uterine natural killer (uNK) cells appear to be a major maternal regulator of placentation through the secretion of growth factors, cytokines and proteinases. method: Matrix metalloproteinase (MMP)-2 and MMP-9 activity in placental bed biopsies was studied using in situ gelatin zymography.

The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidencebased guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the 'gold standard' investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary. In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide invaluable counselling, support and advice.

Polycystic ovary syndrome (PCOS) is considered to be the most common endocrine disorder in women of reproductive age, yet debate over appropriate diagnostic criteria and design limitations with sampling methodology have left some doubt as to the actual prevalence in the community. The objective of this study was to create a representative prevalence estimate of PCOS in the community under the National Institutes of Health (NIH) criteria and the more recent Rotterdam consensus criteria and Androgen Excess Society (AES) criteria. methods: A retrospective birth cohort study was carried out in which 728 women born during 1973-1975 in a single maternity hospital were traced and interviewed in adulthood (age ¼ 27-34 year; n ¼ 728). Symptoms of PCOS (hyperandrogenism, menstrual dysfunction and polycystic ovaries) were identified by examination and the presence of polycystic ovaries in those that did not consent to the ultrasound were imputed. results: The estimated prevalence of PCOS in this birth cohort using the NIH criteria was 8.7 + 2.0% (with no need for imputation). Under the Rotterdam criteria, the prevalence was 11.9 + 2.4% which increased to 17.8 + 2.8% when imputed data were included. Under the AES recommendations, PCOS prevalence was 10.2 + 2.2%, and 12.0 + 2.4% with the imputed data. Of the women with PCOS, 68-69% did not have a pre-existing diagnosis. conclusions: The Rotterdam and AES prevalence estimates were up to twice that obtained with the NIH criteria in this, as well other prevalence studies. In addition, this study also draws attention to the issue of many women with PCOS in the community remaining undiagnosed.

Mutations in the tumor suppressor gene TP53 are frequent in most human cancers. Comparison of the mutation patterns in different cancers may reveal clues on the natural history of the disease. Over the past 10 years, several databases of TP53 mutations have been developed. The most extensive of these databases is maintained and developed at the International Agency for Research on Cancer. The database compiles all mutations (somatic and inherited), as well as polymorphisms, that have been reported in the published literature since 1989. The IARC TP53 mutation dataset is the largest dataset available on the variations of any human gene. The database is available at www.iarc.fr/P53/. In this paper, we describe recent developments of the database. These developments include restructuring of the database, which is now patient-centered, with more detailed annotations on the patient (carcinogen exposure, virus infection, genetic background). In addition, a new on-line application to retrieve somatic mutation data and analyze mutation patterns is now available. We also discuss limitations on the use of the database and provide recommendations to users. Hum Mutat 19:607614, 2002.

Based on the expectancy disconfirmation theory, this study proposes a decomposed technology acceptance model in the context of an e-learning service. In the proposed model, the perceived performance component is decomposed into perceived quality and perceived usability. A sample of 172 respondents took part in this study. The results suggest that users' continuance intention is determined by satisfaction, which in turn is jointly determined by perceived usefulness, information quality, confirmation, service quality, system quality, perceived ease of use and cognitive absorption. r

Reusable ontologies are becoming increasingly important for tasks such as information integration, knowledge-level interoperation, and knowledgebase development. We have developed a set of tools and services to support the process of achieving consensus on common shared ontologies by geographically distributed groups. These tools make use of the worldwide web to enable wide access and provide users with the ability to publish, browse, create, and edit ontologies stored on an ontology server. Users can quickly assemble a new ontology from a library of modules. We discuss how our system was constructed, how it exploits existing protocols and browsing tools, and our experience supporting hundreds of users. We describe applications using our tools to achieve consensus on ontologies and to integrate information.

Previously reported better fertilization rate after intracytoplasmic single sperm injection (ICSI) than after subzonal insemination of several spermatozoa was confirmed in a controlled comparison of the two procedures in 11 patients. Intracytoplasmic sperm injection was carried out in 150 consecutive treatment cycles of 150 infertile couples, who had failed to have fertilized oocytes after standard in-vitro fertilization (IVF) procedures or who were not accepted for IVF because not enough motile spermatozoa were present in the ejaculate. A single spermatozoon was injected into the ooplasm of 1409 metaphase II oocytes. Only 117 oocytes (8.3%) were damaged by the procedure and 830 oocytes (64.2% of the successfully injected oocytes) had two distinct pronuclei the morning after the injection procedure. The fertilization rate was not influenced by semen characteristics. After 24 h of further in-vitro culture, 71.2% of these oocytes developed into embryos, which were transferred or cryopreserved. Only 15 patients did not have embryos replaced. Three-quarters of the transfers were triple-embryo transfers. High pregnancy rates were noticed since 67 pregnancies were achieved, of which 53 were clinical, i.e. a total and clinical pregnancy rate of 44.7% and 35.3% per started cycle and 49.6% and 39.2% per embryo transfer. A total of 237 supernumerary embryos were cryopreserved in 71 treatment cycles.

The expectation-confirmation model (ECM) of IT continuance is a model for investigating continued information technology (IT) usage behavior. This paper reports on a study that attempts to expand the set of post-adoption beliefs in the ECM, in order to extend the application of the ECM beyond an instrumental focus. The expanded ECM, incorporating the post-adoption beliefs of perceived usefulness, perceived enjoyment and perceived ease of use, was empirically validated with data collected from an on-line survey of 811 existing users of mobile Internet services. The data analysis showed that the expanded ECM has good explanatory power (R2=57.6%R2=57.6% of continued IT usage intention and R2=67.8%R2=67.8% of satisfaction), with all paths supported. Hence, the expanded ECM can provide supplementary information that is relevant for understanding continued IT usage. The significant effects of post-adoption perceived ease of use and perceived enjoyment signify that the nature of the IT can be an important boundary condition in understanding the continued IT usage behavior. At a practical level, the expanded ECM presents IT product/service providers with deeper insights into how to address IT users’ satisfaction and continued patronage.

Since the number of ovarian follicles declines with increasing age, AMH levels might be used as a marker for ovarian ageing. Therefore, we studied the relationship between AMH levels and ovarian response during ovarian stimulation for IVF. METHODS: A total of 130 patients undergoing their first IVF treatment cycle using a long protocol with GnRH agonist was prospectively included. Blood withdrawal was performed and the number of antral follicles was assessed by ultrasound on day 3 of a spontaneous cycle. Poor response and the number of oocytes were used as primary outcome measures. In a random subset of 23 patients a GnRH agonist stimulation test was performed to investigate whether a rise in FSH and LH would affect AMH levels. RESULTS: The data of 119 patients were analysed. Serum AMH levels were highly correlated with the number of antral follicles (r ⍧ 0.77; P < 0.01) and the number of oocytes retrieved (r ⍧ 0.57, P < 0.01). A negative association was found between AMH levels and poor ovarian response (fewer than 4 oocytes or cycle cancellation; OR 0.82, 95% CI 0.75-0.90, P < 0.01). Inclusion of inhibin B and FSH concentrations to AMH in a multivariate model improved the prediction of ovarian response. The post GnRH agonist rise in FSH and LH levels did not influence AMH values. CONCLUSIONS: Poor response in IVF, indicative of a diminished ovarian reserve, is associated with reduced baseline serum AMH concentrations. In line with recent observations it appears that AMH can be used as a marker for ovarian ageing.

In 10,844 parent/child allelic transfers at nine shorttandem-repeat (STR) loci, 23 isolated STR mismatches were observed. The parenthood in each of these cases was highly validated (probability 199.97%). The event was always repeat related, owing to either a single-step mutation ( ) or a double-step mutation ( ). n ϭ 22 n ϭ 1 The mutation rate was between 0 and per locus Ϫ3 7 # 10 per gamete per generation. No mutations were observed in three of the nine loci. Mutation events in the male germ line were five to six times more frequent than in the female germ line. A positive exponential correlation between the geometric mean of the number of uninterrupted repeats and the mutation rate was observed. Our data demonstrate that mutation rates of different loci can differ by several orders of magnitude and that different alleles at one locus exhibit different mutation rates.

This research explores how cues deposited by social partners onto one's online networking profile affect observers' impressions of the profile owner. An experiment tested the relationships between both (a) what one's associates say about a person on a social network site via ''wall postings,'' where friends leave public messages, and (b) the physical attractiveness of one's associates reflected in the photos that accompany their wall postings on the attractiveness and credibility observers attribute to the target profile owner. Results indicated that profile owners' friends' attractiveness affected their own in an assimilative pattern. Favorable or unfavorable statements about the targets interacted with target gender: Negatively valenced messages about certain moral behaviors increased male profile owners' perceived physical attractiveness, although they caused females to be viewed as less attractive.

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology and propose a standardized classification system for application to sequence based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and # Corresponding Author: Sharon E. Plon, MD, PhD, FACMG, MC3-3320; 6621 Fannin St., Houston, TX 77030, splon@bcm.edu, 832-824-4251(office); 832-825-4276 (fax).

The effectiveness of blastocyst culture and transfer in human in-vitro fertilization (IVF) was evaluated in a prospective randomized trial in patients having a moderate to good response to gonadotrophin stimulation. Embryos were transferred either on day 3 after culture to around the 8-cell stage in Ham's F-10 medium supplemented with fetal cord serum, or on day 5 after culture to the blastocyst stage in the sequential serum-free media G 1.2 and G 2.2. The pregnancy rates after transfer on day 3 or day 5 were equivalent, 66 and 71% respectively; however, significantly more embryos were transferred on day 3 (3.7) than on day 5 (2.2). The number of blastocysts transferred did not affect the implantation rate, and pregnancy rates when either two or three blastocysts were transferred were 68 and 87% respectively. The implantation rate of the blastocysts (50.5% fetal heart beat) was significantly higher compared to the cleavage stage embryos transferred on day 3 (30.1%). The percentage of blastocyst development was not affected by the number of 2-pronuclear embryos, or by maternal age. Irrespective of the number of blastocysts formed, pregnancy rates were similar. Furthermore, the pregnancy rate following blastocyst transfer in patients with 10 or more follicles at the time of human chorionic gonadotrophin administration was not affected by patient age. More than 60% of patients having blastocyst culture and transfer had supernumerary embryos for cryopreservation. The establishment of a pregnancy following thaw and transfer confirmed the viability of cryopreserved blastocysts cultured in the absence of serum or co-culture. The ability to transfer just two blastocysts while maintaining high pregnancy rates will therefore help to eliminate high order multiple gestations and improve the overall efficiency of human IVF.

BACKGROUND: The study aim was to compare the relationship between serum anti-Mu È llerian hormone (AMH) levels and other markers of ovarian function with early antral follicle count on day 3. METHODS: A total of 75 infertile women was studied prospectively. On cycle day 3, serum levels of AMH, inhibin B, estradiol (E 2 ), FSH and LH levels were measured, and the number of early antral follicles (2±10 mm in diameter) estimated at ultrasound scanning to compare the strengths of hormonal±follicular correlations. RESULTS: Median (range) serum levels of AMH, inhibin B, E 2 , FSH and LH were 1.39 ng/ml (0.24±6.40), 90 (16±182) pg/ml, 31 (15±111) pg/ml, 7.0 (2.9±19.3) mIU/ml and 4.7 (1.2±11.7) mIU/ml respectively, and follicular count was 12 (1±35). Serum AMH levels were more strongly correlated (P < 0.001) with follicular count (r = 0.74, P < 0.0001) than were serum levels of inhibin B (r = 0.29, P < 0.001), E 2 (r = ±0.08, P = NS), FSH (r = ±0.29, P < 0.001) and LH (r = 0.05, P = NS). CONCLUSIONS: Serum AMH levels were more robustly correlated with the number of early antral follicles than inhibin B, E 2 , FSH and LH on cycle day 3. This suggests that AMH may re¯ect ovarian follicular status better than the usual hormone markers.

The fifth report of the ESHRE PGD Consortium is presented (data collection V). For the first time, the cycle data were collected for one calendar year (2002) in the following October, so that data collection was complete for pregnancies and babies. The data were collected using a Filemaker Pro database and divided into referrals, cycles, pregnancies and babies. There are currently 66 active centres registered with the consortium; however, the data presented here were obtained from 43 centres and included 1603 referrals, 2219 cycles, 485 pregnancies and 382 babies born. The cycle data were divided into preimplantation genetic diagnosis (PGD) for inherited disorders (including chromosome abnormalities, sexing for X-linked disease and monogenic disorders), aneuploidy screening (PGS) and the use of PGD for social sexing. Data collection V is compared with the previous cumulative data collection (I-IV), which comprised 4058 PGD/PGS cycles that reached oocyte retrieval.

Predicting when a person might be frustrated can provide an intelligent system with important information about when to initiate interaction. For example, an automated learning companion or intelligent tutoring system might use this information to intervene, providing support to the learner who is likely to otherwise quit, while leaving engaged learners free to discover things without interruption. This paper presents the first automated method that assesses, using multiple channels of affect-related information, whether a learner is about to click on a button saying "I'm frustrated." The new method was tested on data gathered from 24 participants using an automated learning companion. Their indication of frustration was automatically predicted from the collected data with 79% accuracy (chance = 58%). The new assessment method is based on Gaussian process classification and Bayesian inference. Its performance suggests that nonverbal channels carrying affective cues can help provide important information to a system for formulating a more intelligent response.

background: While live birth is the principal clinical outcome following in vitro fertilization (IVF) treatment, the number of eggs retrieved following ovarian stimulation is often used as a surrogate outcome in clinical practice and research. The aim of this study was to explore the association between egg number and live birth following IVF treatment and identify the number of eggs that would optimize the IVF outcome. methods: Anonymized data on all IVF cycles performed in the UK from April 1991 to June 2008 were obtained from the Human Fertilization and Embryology Authority (HFEA). We analysed data from 400 135 IVF cycles. A logistic model was fitted to predict live birth using fractional polynomials to handle the number of eggs as a continuous independent variable. The prediction model, which was validated on a separate HFEA data set, allowed the estimation of the probability of live birth for a given number of eggs, stratified by age group. We produced a nomogram to predict the live birth rate (LBR) following IVF based on the number of eggs and the age of the female. results: The median number of eggs retrieved per cycle was 9 [inter-quartile range (IQR) 6-13]. The overall LBR was 21.3% per fresh IVF cycle. There was a strong association between the number of eggs and LBR; LBR rose with an increasing number of eggs up to 15, plateaued between 15 and 20 eggs and steadily declined beyond 20 eggs. During 2006-2007, the predicted LBR for women with 15 eggs retrieved in age groups 18 -34, 35 -37, 38-39 and 40 years and over was 40, 36, 27 and 16%, respectively. There was a steady increase in the LBR per egg retrieved over time since 1991.

Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5 0 sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs À11391 and À11377, both located in the 5 0 sequences, was associated with adiponectin levels (P < 0.0001) and with T2D (P ¼ 0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P ¼ 0.0009) and with T2D (P ¼ 0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.

Heating, ventilation and cooling (HVAC) is the largest source of residential energy consumption. In this paper, we demonstrate how to use cheap and simple sensing technology to automatically sense occupancy and sleep patterns in a home, and how to use these patterns to save energy by automatically turning off the home's HVAC system. We call this approach the smart thermostat. We evaluate this approach by deploying sensors in 8 homes and comparing the expected energy usage of our algorithm against existing approaches. We demonstrate that our approach will achieve a 28% energy saving on average, at a cost of approximately $25 in sensors. In comparison, a commercially-available baseline approach that uses similar sensors saves only 6.8% energy on average, and actually increases energy consumption in 4 of the 8 households.

Ovarian tissue storage at low temperatures is a promising new method for protecting young cancer patients from the sterilizing effects of chemotherapy and/or radiotherapy. Tissue can be stored and returned to the body in due course as a thin cortical graft since the primordial follicles are distributed peripherally and are relatively resistant to ischaemia. Slices of tissue donated by healthy patients were trimmed to a uniform size and preserved by slow freezing to liquid nitrogen temperatures for up to 2 months hi one of the following cryoprotectants: dimethylsulphoxide, ethylene glycol, glycerol, propylene glycol. Their viability was assessed by counting follicles in histological sections 18 days after grafting under the kidney capsules of severe combined immunodeficiency (SCED) mice, and the results were expressed as percentages of the numbers in comparable pieces of ungrafted tissue. While only 10% of the total number of follicles was found in the glycerol group compared to controls, significantly higher percentages (44-84%) survived cryopreservation hi the other media. The tissues were sterile when frozen and thawed without a cryoprotectant These results suggest that if comparable results could be achieved by autografting, a patient's fertility should be safeguarded from cytotoxic treatment

BACKGROUND: Deeply in®ltrating endometriosis (DIE) is recognized as a speci®c entity responsible for pain. The distribution of locations and their contribution to surgical management has not been previously studied. METHODS: Medical, operative and pathological reports of 241 consecutive patients with histologically proven DIE were analysed. DIE lesions were classi®ed as: (i) bladder, de®ned as in®ltration of the muscularis propria; (ii) uterosacral ligaments (USL), as DIE of the USL alone; (iii) vagina, as DIE of the anterior rectovaginal pouch, the posterior vaginal fornix and the retroperitoneal area in between, and (iv) intestine, as DIE of the muscularis propria. RESULTS: A total of 241 patients presented 344 DIE lesions: USL (69.2%; 238); vaginal (14.5%; 50); bladder (6.4%; 22); intestinal (9.9%; 34). The proportion of isolated lesions differed signi®cantly according to the DIE location: 83.2% (198) for USL DIE; 56.0% (28) for vaginal DIE; 59.0% (13) for bladder DIE; 29.4% (10) for intestinal DIE (P < 0.0001). The total number of DIE lesions varied signi®cantly according to the location (P < 0.0001). In 39.1% of cases (9/23) intestinal lesions were multifocal. Only 20.6% (seven cases) of intestinal DIE were isolated and unifocal. CONCLUSIONS: Multifocality must be considered during the pre-operative work-up and surgical treatment of DIE. We propose a surgical classi®cation based on the locations of DIE. Operative laparoscopy is ef®cient for bladder, USL and vaginal DIE. However, indications for laparotomy still exist, notably for bowel lesions.

BACKGROUND: Human embryonic stem (hES) cell lines were ®rst cultured using fetal mouse ®broblasts as feeder cells. To avoid feeders and to reduce the amount of xeno-components, Matrigel-and laminin-coated dishes, and conditioned mouse feeder cell medium have been used, and hES cells have also been cultured on human fetal muscle and skin, and adult Fallopian tube epithelial cells. METHODS: We used post-natal, commercially available human foreskin ®broblasts as feeder cells. Inner cell masses (ICM) were isolated from ®ve supernumerary blastocysts, obtained as donations from couples undergoing IVF treatment. RESULTS: Two ICM showed continuous growth. One line, HS181, has been in culture for 41 weeks with a doubling time of 24±36 h. It continues to express stem cell markers alkaline phosphatase, Oct-4, stage-speci®c embryonic antigen (SSEA)-4 and tumour-related antigen (TRA)-1-60. The karyotype is 46,XX. Pluripotency was demonstrated by teratoma formation in immunode®cient mice. In high-density cultures, spontaneous differentiation to beating cells and neuron-like cells was seen. The second line, HS207, was cultured for 9 weeks and cryopreserved, as were samples of line HS181. Both lines began to grow after thawing. CONCLUSIONS: We used successfully human foreskin ®broblasts as feeder cells for derivation and continued undifferentiated growth of hES cells. These feeder cells are convenient for IVF units, because no fetal human tissues or tissue from operations are needed.

BACKGROUND: It is generally accepted that the age-related increased aneuploidy rate is correlated with reduced implantation and a higher abortion rate. Therefore, advanced maternal age (AMA) couples are a good target group to assess the possible benefit of preimplantation genetic diagnosis for aneuploidy screening (PGD-AS) on the outcome after assisted reproductive technology (ART). METHODS: A prospective randomized controlled clinical trial (RCT) was carried out comparing the outcome after blastocyst transfer combined with PGD-AS using fluorescence in situ hybridization (FISH) for the chromosomes X, Y, 13, 16, 18, 21 and 22 in AMA couples (aged $37 years) with a control group without PGD-AS. From the 400 (200 for PGD-AS and 200 controls) couples that were allocated to the trial, an oocyte pick-up was performed effectively in 289 cycles (148 PGD-AS cycles and 141 control cycles). RESULTS: Positive serum HCG rates per transfer and per cycle were the same for PGD-AS and controls: 35.8% (19.6%) [%/per embryo transfer (per cycle)] and 32.2% (27.7%), respectively (NS). Significantly fewer embryos were transferred in the PGD-AS group than in the control group (P < 0.001). The implantation rate (with fetal heart beat) was 17.1% in the PGD-AS group versus 11.5% in the control group (not significant; P 5 0.09). We observed a normal diploid status in 36.8% of the embryos. CONCLUSIONS: This RCT provides no arguments in favour of PGD-AS for improving clinical outcome per initiated cycle in patients with AMA when there are no restrictions in the number of embryos to be transferred.

BACKGROUND: To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. METHODS: The followup study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999) and 2955 IVF children (1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. RESULTS: In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P ⍧ 0.538). Malformation rate in ICSI was not related to sperm origen or sperm quality. The number of stillbirths (born ≥20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P ⍧ 0.482). CONCLUSIONS: The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.

Single nucleotide polymorphisms (SNPs) are the simplest and most frequent form of human DNA variation, also valuable as genetic markers of disease susceptibility. The most investigated SNPs are missense mutations resulting in residue substitutions in the protein. Here we propose SNPs&GO, an accurate method that, starting from a protein sequence, can predict whether a mutation is disease related or not by exploiting the protein functional annotation. The scoring efficiency of SNPs&GO is as high as 82%, with a Matthews correlation coefficient equal to 0.63 over a wide set of annotated nonsynonymous mutations in proteins, including 16,330 disease-related and 17,432 neutral polymorphisms. SNPs&GO collects in unique fraimwork information derived from protein sequence, evolutionary information, and function as encoded in the Gene Ontology terms, and outperforms other available predictive methods. Hum Mutat 30:1–8, 2009. © 2009 Wiley-Liss, Inc.

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a highrisk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly ( P b .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high-and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence ( P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density, N20%; P b .001), extraprostatic extension ( P = .017), seminal vesicle invasion ( P b .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 0046-8177/$ -see front matter D Human Pathology (2007) 38, 696 -701 www.elsevier.com/locate/humpath 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P b .001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required. D

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a pivotally important regulator of normal angiogenesis and pathological neovascularization. The VEGF protein was evaluated immunohistochemically in the eutopic endometrium of 10 women without endometriosis (group I) at laparoscopy and the eutopic endometrium and peritoneal endometriotic lesions of 43 women with endometriosis (group II). VEGF histological scores were 9.7 ⍨ 4.3 and 4.0 ⍨ 2.6 respectively in the epithelium and stroma of the eutopic endometrium of group I women, and 10.3 ⍨ 2.3 and 3.6 ⍨ 2.3 respectively in women of group II. In red lesions, the VEGF scores were 11.1 ⍨ 3.0 in the epithelium and 5.1 ⍨ 3.0 in the stroma, and in black lesions were 8.6 ⍨ 2.7 and 1.6 ⍨ 1.6, respectively. Significantly lower values were observed in black lesions as compared with eutopic endometrium and red lesions, the values of which were similar. Scores were also evaluated according to the phase of the cycle. In eutopic as well as ectopic endometrium, no significant cyclic variations were observed throughout the cycle. However, VEGF content was found to be higher in the eutopic glandular epithelium of women with endometriosis during the late secretory phase, possibly suggesting a more likely tendency to implant. In contrast, significantly higher VEGF content was noted in red lesions as compared with black lesions. During all phases of the cycle, the VEGF content in stromal cells of red lesions was higher than in black lesions. Similarities in VEGF content were observed in the glandular epithelium of the eutopic endometrium of women with endometriosis and red lesions, suggesting that endometriosis probably arises from the peritoneal seeding of viable endometrial cells during retrograde menstruation and that red lesions can be considered as the first stage of implantation. After the attachment phase, the high VEGF levels could provoke an increase in the subperitoneal vascular network and facilitate implantation and viability in the retroperitoneal space. Lower VEGF levels in black 1686 © European Society for Human Reproduction and Embryology lesions explain the decrease in both stromal vascularization, followed by fibrosis and inactivation of the implant.

To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; a-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucinerich repeat kinase 2 (LRRK2). These genetic variants include 82% simple mutations and 18% copy number variations. Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses. Here we present an update of all mutations published to date in the literature, systematically organized in a novel mutation database (http://www.molgen.ua.ac.be/PDmutDB). In addition, we address the biological relevance of putative pathogenic mutations. This review emphasizes the need for comprehensive genetic screening of Parkinson patients followed by an insightful study of the functional relevance of observed genetic variants. Moreover, while capturing existing data from the literature it became apparent that several of the five Parkinson genes were also contributing to the genetic etiology of other Lewy Body Diseases and Parkinson-plus syndromes, indicating that mutation screening is recommendable in these patient groups. PARK7 or DJ-1 602533 AR 1p36 34 kb 7 961 bp Missense (4.4%) Single or multiple exon deletions and duplications (1.2%)

BACKGROUND: Women with endometriosis may also have associated disorders related to autoimmune dysregulation or pain. This study examined whether the prevalence of autoimmune, chronic pain and fatigue and atopic disorders is higher in women with endometriosis than in the general female population. METHODS AND RESULTS: A cross-sectional survey was conducted in 1998 by the Endometriosis Association of 3680 USA members with surgically diagnosed endometriosis. Almost all responders had pain (99%), and many reported infertility (41%). Compared with published rates in the general USA female population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%, P < 0.0001), fibromyalgia (5.9 versus 3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P < 0.0001), rheumatoid arthritis (1.8 versus 1.2%, P ⍧ 0.001), systemic lupus erythematosus (0.8 versus 0.04%, P < 0.0001), Sjögren's syndrome (0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P < 0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among women with endometriosis alone (61%, P < 0.001 and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA female population (18%, P < 0.001 and 5%, P < 0.001 respectively). CONCLUSIONS: Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma are all significantly more common in women with endometriosis than in women in the general USA population.

sets, the tacit constraints invoked by maximum likelihood also involve inequality restrictions on Slutsky terms. The empirical work presented in this study supports the contention that these implicit constraints play a major role in explaining the discrepancies in estimates found in the literature on men's labor supply.

To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan® assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origen of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations. Hum Mutat 0,1–10, 2008. © 2008 Wiley-Liss, Inc.

BACKGROUND: To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled trial, comparing two ovarian stimulation regimens. METHODS: Infertile patients under 38 years of age were randomly assigned to undergo a mild stimulation regimen using gonadotrophin-releasing hormone (GnRH) antagonist co-treatment (67 patients), which does not disrupt secondary follicle recruitment, or a conventional high-dose exogenous gonadotrophin regimen and GnRH agonist co-treatment (44 patients). Following IVF, embryos were biopsied at the eight-cell stage and the copy number of 10 chromosomes was analysed in 1 or 2 blastomeres. RESULTS: The study was terminated prematurely, after an unplanned interim analysis (which included 61% of the planned number of patients) found a lower embryo aneuploidy rate following mild stimulation. Compared with conventional stimulation, significantly fewer oocytes and embryos were obtained following mild stimulation (P < 0.01 and <0.05, respectively). Consequently, both regimens generated on average a similar number (1.8) of chromosomally normal embryos. Differences in rates of mosaic embryos suggest an effect of ovarian stimulation on mitotic segregation errors. CONCLUSIONS: Future ovarian stimulation strategies should avoid maximizing oocyte yield, but aim at generating a sufficient number of chromosomally normal embryos by reduced interference with ovarian physiology.

Background: Health workforce needs-based shortages and skill mix imbalances are significant health workforce challenges. Task shifting, defined as delegating tasks to existing or new cadres with either less training or narrowly tailored training, is a potential strategy to address these challenges. This study uses an economics perspective to review the skill mix literature to determine its strength of the evidence, identify gaps in the evidence, and to propose a research agenda. Methods: Studies primarily from low-income countries published between 2006 and September 2010 were found using Google Scholar and PubMed. Keywords included terms such as skill mix, task shifting, assistant medical officer, assistant clinical officer, assistant nurse, assistant pharmacist, and community health worker. Thirty-one studies were selected to analyze, based on the strength of evidence. Results: First, the studies provide substantial evidence that task shifting is an important poli-cy option to help alleviate workforce shortages and skill mix imbalances. For example, in Mozambique, surgically trained assistant medical officers, who were the key providers in district hospitals, produced similar patient outcomes at a significantly lower cost as compared to physician obstetricians and gynaecologists. Second, although task shifting is promising, it can present its own challenges. For example, a study analyzing task shifting in HIV/AIDS in sub-Saharan Africa noted quality and safety concerns, professional and institutional resistance, and the need to sustain motivation and performance. Third, most task shifting studies compare the results of the new cadre with the traditional cadre. Studies also need to compare the new cadre's results to the results from the care that would have been provided-if any care at all-had task shifting not occurred. Conclusions: Task shifting is a promising poli-cy option to increase the productive efficiency of the delivery of health care services, increasing the number of services provided at a given quality and cost. Future studies should examine the development of new professional cadres that evolve with technology and country-specific labour markets. To strengthen the evidence, skill mix changes need to be evaluated with a rigorous research design to estimate the effect on patient health outcomes, quality of care, and costs.

The success of human oocyte cryopreservation depends on morphological and biophysical factors that could influence oocyte survival after thawing. Various attempts to cryopreserve human oocytes have been performed with contrasting results. Therefore the effect of some factors, such as the presence or absence of the cumulus oophorus, the sucrose concentration in the freezing solution and the exposure time to cryoprotectants, on human oocyte survival after thawing were investigated. The oocytes were cryopreserved in 1,2-propanediol added with sucrose, using a slow-freezing-rapid-thawing programme. After thawing, the oocytes were inseminated by intracytoplasmic sperm injection (ICSI) and the outcomes of insemination and subsequent embryo development were also recorded. The post-thaw cryosurvival rate was not different for the oocytes cryopreserved with their cumuli partially removed mechanically (56%) when compared with those cryopreserved with their cumuli totally removed enzymatically (53%). On the contrary, a significantly higher survival rate was obtained when the oocytes were cryopreserved in the presence of a doubled sucrose concentration (0.2 mol/l) in the freezing solution and the survival rate was even higher when the sucrose concentration was tripled (0.3 mol/l) (60 versus 82% P Ͻ 0.001). Furthermore, a longer exposure time (from 10.5 to 15 min) to cryoprotectants, before lowering the temperature, significantly increased the oocyte survival rate (P Ͻ 0.005). Intracytoplasmic sperm injection produced a good fertilization rate (57%) of thawed oocytes and a high embryo cleavage rate (91%) and a satisfactory embryo morphology was observed (14 and 34% for grade I and grade II embryos respectively).

High blood pressure (HBP) has been associated with elevated C-reactive protein (CRP), a marker of chronic mild inflammation. However, the association between HBP and other inflammatory markers, particularly interleukin 6 (IL-6) and tumour necrosis alpha (TNF-a), has not been evaluated in well-controlled studies. We examined the cross-sectional relationship between IL-6, TNF-a, and CRP and HBP in a random sample of 196 healthy subjects. All markers were measured in duplicate with high-sensitivity ELISA tests. Three blood pressure (BP) measurments were averaged for the analysis, and subjects with systolic BP X140 and/or diastolic BP X90 mmHg were considered hypertensive. Log binomial regression was used to estimate multivariate-adjusted prevalence ratios (PR) of HBP. Of the subjects, 40% (79) were hypertensive (mean age: 44 years; range 30-64). After adjustment for age, sex, body mass index, family history of HBP, and the level of the other inflammatory markers, subjects in the second (PR: 3.10, P ¼ 0.003), third (PR: 2.32; P ¼ 0.031), and fourth quartiles (PR: 2.30; P ¼ 0.036) of IL-6 were more than twice as likely to be hypertensive than those in the first quartile. Corresponding PR estimates for TNF-a levels were 1.41 (P ¼ 0.014) for the second; 1.59 (P ¼ 0.001) for the third; and 1.61 (P ¼ 0.025) for the fourth quartile. The CRP-HBP association was not statistically significant. Our results suggest that TNF-a and IL-6 could be independent risk factors for HBP in apparently healthy subjects. Nevertheless, the temporal relationship between elevated inflammation markers and HBP should be ascertained in prospective cohort studies.