bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrogen desorption kinetics from H‐Si (111) surfaces studied by optical sum frequency generation and second harmonic generation
Authors: Sattar Md. Abdus , Hien Khuat Thi Thu , Miyauchi Yoshihiro , Mizutani Goro , Rutt Harvey N.
Published: July 2016

We have studied hydrogen desorption from a flat H‐Si (111)1 × 1 surface at 711 K by observing sum frequency generation (SFG) and second harmonic generation (SHG) spectra. Flat H‐Si (111) surfaces were prepared by dosing hydrogen molecules in an ultra‐high vacuum chamber with a base pressure of 〜10−8 Pa. Combining the SFG and SHG methods, the desorption order has been clarified over the whole hydrogen coverage range from 1 monolayer (ML) to 0 ML. The hydrogen desorption was assigned as second order in the high coverage range of 1 ML–0.18 ML by using SFG spectroscopy and as first order in the coverage range of 0.18 ML–0.0 ML by using SHG spectroscopy. Copyright © 2016 John Wiley & Sons, Ltd.
Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats
Authors: Varayoud Jorgelina , Durando Milena , Ramos Jorge G. , Milesi María M. , Ingaramo Paola I. , Muñoz‐de‐Toro Mónica , Luque Enrique H.
Published: July 2016

Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate‐based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10−5 g E2/kg/day (uterotrophic dose; UE2), 2.10−7 g E2/kg/day (nonuterotrophic dose; NUE2), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty‐four hours after the last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen‐responsive genes were evaluated (estrogen receptors, ERα and ERβ; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERα mRNA was downregulated by all GBH doses and E2 groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5‐, GBH50‐, and UE2‐treated rats showed downregulated ERα protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERβ (GBH0.5–50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE2 group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen‐sensitive genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1191–1201, 2017.
Effects of depuration on histopathological changes in tilapia (Oreochromis niloticus) after exposure to cylindrospermopsin
Authors: Guzmán‐Guillén Remedios , Prieto Ortega Ana I. , Moreno Isabel M. , Ríos Victoria , Moyano Rosario , Blanco Alfonso , Vasconcelos Vitor , Cameán Ana M.
Published: July 2016

Cylindrospermopsin (CYN) is a highly water‐soluble cytotoxin produced by several species of freshwater cyanobacteria and it is considered the second most studied cyanotoxin worldwide. CYN acts as a potent protein and glutathione synthesis inhibitor, as well as inducing genotoxicity, oxidative stress and histopathological alterations. Studies concerning the depuration of cyanobacterial toxins in aquatic organisms, especially in fish, are of great interest for fish economy and public health, but are scarce in the case of CYN. This is the first study reporting the ability of depuration (3 − 7 days) in reversing or ameliorating the histopathological lesions induced in liver, kidney, heart, intestines, and gills of tilapia (Oreochromis niloticus) due to exposure by immersion to repeated doses of a CYN‐containing culture of A. ovalisporum for 14 days. The main histopathological changes induced by CYN were glucogenic degeneration and loss of the normal hepatic cord‐structure (liver), hyperemia, dilated Bowman's capsule and cellular tumefaction (kidney), myofibrolysis, hemorrhages and edema (heart), necrosis and partial loss of microvilli (gastrointestinal tract), and hyperemia and inflammatory cells infiltrates (gills). After 3 days of depuration, gills were totally recovered, while the liver, kidney, and gastrointestinal tract required 7 days, and longer depuration periods may be needed for a full recovery of the heart. In addition, the morphometric study indicated that depuration managed to reverse the affectation in the hepatocytes nuclear diameters and cross sections of the proximal and distal convoluted tubules induced in CYN‐exposed fish. In general, these results validate depuration as an effective practice for detoxification of fish contaminated with CYN. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1318–1332, 2017.
‘Resilience’ – a characteristic clinicians now need to acquire
Authors: Kirby Roger
Published: July 2016

Recently, the Chairman of the General Medical Council (GMC), Professor Sir Terence Stephenson, commented that each and every doctor can expect to be the subject of a complaint and investigated at some stage in his or her career by the GMC, and that rather than be downhearted about this, doctors need to develop ‘resilience’ in the face of criticism or an investigation…
‘Mind maps’: helping from pedagogy to packing
Authors: Dickinson Ian
Published: July 2016

A straw poll at the recent Royal Society of Medicine Winter Meeting in Saalbach, Austria, showed that only a handful of delegates were aware of ‘mind maps’ – surprising given that an internet search will find millions of mind map images and articles. In this article the author describes the basic concept of mind maps and how they can be used by healthcare professionals in their work.
Angina, nitrates and erectile dysfunction
Authors: Hackett Geoffrey
Published: July 2016

A common vascular pathology means that many patients with coronary artery disease (CAD) also suffer from erectile dysfunction (ED). The use of oral nitrates in these patients excludes them from the help that a PDE5 inhibitor (PDE5I) could offer. Using a case history, Geoffrey Hackett describes how, with some medicines optimisation, this problem can be resolved.
Scoring Systems Used to Predict Bladder Dysfunction After Laparoscopic Rectal Cancer Surgery
Authors: Kim Hyung Ook , Cho Young Sam , Kim Hungdai , Lee Sung Ryol , Jung Kyung Uk , Chun Ho‐Kyung
Published: July 2016

Background

Postoperative bladder dysfunction often occurs after rectal cancer surgery, necessitating long‐term urinary catheter drainage. The aim of this study was to evaluate the feasibility of early catheter removal and to propose scoring systems that may predict urinary dysfunction after laparoscopic rectal cancer surgery.

Methods

A total of 110 patients who underwent elective laparoscopic rectal cancer surgery were included in this prospective observational study. The urinary catheter was removed on the first postoperative day.

Results

The overall incidence of bladder dysfunction was 29.1 % (32/110). The incidence of bladder dysfunction was significantly higher in patients with an age of 65 years or older, male gender, and anastomosis levels from the anal verge of 6 cm or below (P = 0.03, 0.002, and 0.03, respectively). By setting a cut‐off of two of the risk factors, this simple scoring system can predict postoperative bladder dysfunction with sensitivity of 96.9 %, specificity of 50.0 %, and accuracy of 63.6 %. A scoring system based on regression coefficients was also conducted according to the following formula: bladder dysfunction predicting score = 18 (1 for male or 0 for female) +0.5 (age, years) −2 (anastomosis level, cm). With this method, a cut‐off value of 35+ points predicts postoperative bladder dysfunction with a sensitivity of 81.3 %, specificity of 71.8 %, and accuracy of 74.5 %.

Conclusions

Bladder dysfunction after laparoscopic rectal cancer surgery following early catheter removal occurred in 29.1 % of patients. Two scoring systems using three risk factors (age, male gender, and anastomosis level) may predict postoperative bladder dysfunction.
Insufficient Lymph Node Sampling in Patients with Colorectal Cancer Perforation is Associated with an Adverse Oncological Outcome
Authors: Sugawara Kotaro , Kawaguchi Yoshikuni , Nomura Yukihiro , Koike Daisuke , Nagai Motoki , Tanaka Nobutaka
Published: July 2016

Background

The impact of lymph node (LN) dissection on long‐term outcomes for patients with colorectal cancer (CRC) perforation remains unclear. We aim to investigate factors associated with poor prognosis and recurrence in patients with CRC, with special reference to cancer perforation and LN dissection.

Methods

The subjects comprised 550 patients who underwent colorectal surgery for CRC at Stage II or III (TNM classification) between February 2006 and November 2013. Short‐ and long‐term outcomes of patients with or without CRC perforation were evaluated. We also sought risk factors on poor prognosis, focusing on LN dissection in patients with CRC perforation.

Results

A total of 508 underwent surgery for CRC without perforation (the non‐perforation group) and 39 for CRC with perforation (the perforation group). Both overall survival and recurrence‐free survival rates were significantly lower in the perforation group than in the non‐perforation group (overall survival, P = 0.009; recurrence‐free survival, P < 0.001). The relapse rates at the peritoneum (P = 0.002), lung (P = 0.007) and LNs (P = 0.021) were significantly higher in the perforation group than in the non‐perforation group. Multivariable Cox proportional hazards model revealed that CRC perforation (hazard ratio [HR] 2.55, 95 % confidential interval [CI] 1.16–4.98, P = 0.022), LN dissection <12 (HR 1.83, 95 % CI 1.07–3.13, P = 0.027), and Stage III (HR 1.79, 95 % CI 1.06–3.08, P = 0.031) were significant and independent risk factors for poor prognosis.

Conclusions

Conducting <12 LN dissections independently increased the risk of reduction in overall survival for patients with CRC perforation. Thus, radical LN dissections should be performed to improve patients’ survival rates, when patients’ general and surgical conditions allow.
Employees’ Company Reputation-related Social Media Competence: Scale Development and Validation
Authors: Walsh Gianfranco , Schaarschmidt Mario , von Kortzfleisch Harald
Published: July 2016

Cases in which employees’ uses of social media harm their company's reputation highlight the need for a measure to evaluate employees’ company reputation-related social media competence (RSMC). Drawing on reputation and human capital theory and data from four occupationally diverse samples of employees, this study develops and validates a new, multidimensional measure of RSMC, or an employee's ability to use social media without causing harm to the employer's reputation. Exploratory factor analyses, first- and second-order confirmatory factor analyses, and structural equation modeling all provide strong evidence of the convergent, discriminant, known-group, and nomological validities of the proposed RSMC scale. The higher-order RSMC construct also relates to job demands and resources and to two behavioral outcomes: bad mouthing and positive word of mouth. The RSMC scale also exhibits test–retest reliability and ecological validity. Thus, the new scale offers both research directions and managerial implications.
Law and Society in the Evolution of Malaysia’s Islamic Capital Market Regulation
Authors: CHEN Vivien
Published: July 2016

The strong growth of Islamic capital markets internationally has seen the corresponding development of regulatory frameworks incorporating sharia law. Malaysia has been at the forefront of Islamic capital market regulatory development, merging corporate law drawn from its common-law heritage with sharia principles. This article examines the interaction of law with political economy and sociocultural influences in Malaysia which has underpinned the evolution of hybrid Islamic capital market regulation. It analyses the evolution of Malaysian Islamic capital market regulation against theories of legal origin and legal evolution. The analysis suggests that the sharia and common-law components of Islamic capital market regulation have evolved along two separate and seemingly inconsistent trajectories. While the secular corporate law component continues to evolve in tandem with its common-law tradition, development of the sharia component represents a distinct shift away from common-law traditions.
Validation of the new Vancouver Chest Pain Rule in Asian chest pain patients presenting at the emergency department
Authors: Ong Marcus Eng Hock , Hao Ying , Yap Susan , Pek Pin Pin , Chua Terrance Siang Jin , Ng Faith Suan Peng , Lim Swee Han
Published: July 2016

Objectives

The new Vancouver Chest Pain (VCP) Rule recommends early discharge for chest pain patients who are at low risk of developing acute coronary syndrome (ACS), and thus can be discharged within 2 hours of arrival at the emergency department (ED). This study aimed to assess the performance of the new VCP Rule for Asian patients presenting with chest pain at the ED.

Methods

This prospective cohort study involved patients attended to at the ED of a large urban centre. Patients of at least 25 years old, presenting with stable chest pain and a non-diagnostic ECG, and with no history of active coronary artery disease were included in the study. The main outcome measures were cardiac events, angioplasty, or coronary artery bypass within 30 days of enrolment.

Results

The study included 1690 patients from 27 August 2000 to 1 May 2002, with 661 patients fulfilling the VCP criteria. Of those for early discharge, 24 had cardiac events and 13 had angioplasty or bypass at 30 days, compared to 91 and 41, respectively, for those unsuitable for discharge. This gave the rule a sensitivity of 78.1% for cardiac events, including angioplasty and bypass. Specificity was 41.0%, and negative predictive value (NPV) was 94.4%.

Conclusion

We found the new VCP Rule to have moderate sensitivity and poor specificity for adverse cardiac events in our population. With an NPV of less than 100%, this means that a small proportion of patients sent home with early discharge would still have adverse cardiac events.
Examination of a historic collection of isolated cranial and appendicular hadrosaurid material from the lower Kirtland Formation of the San Juan Basin, New Mexico
Authors: Wosik Mateusz , Guenther Merrilee F.
Published: July 2016

The Field Museum of Natural History collection contains several isolated hadrosaurid specimens collected by Charles H. Sternberg from the lower Kirtland Formation of the San Juan Basin, New Mexico, that have been previously overlooked. Cranial elements described herein consist of a dentary and three jugals while appendicular material is limited to two humeri and two pubes. Many of the specimens preserve taxonomically informative characters that show strong affinities with Kritosaurini but are distinct from Kritosaurus navajovius (Brown, 1910) suggesting that the saurolophine-dominated San Juan Basin diversity is greater than currently recognized. Future examination of currently unprepared material will add to our developing understanding of the ambiguous hadrosaurid diversity of the San Juan Basin.
Making Visible the First Women in Astronomy in Australia: The Measurers and Computers Employed for the Astrographic Catalogue
Authors: Stevenson T.
Published: July 2016

In Australia a significant number of women were employed to measure and compute the position of stars for the Astrographic Catalogue at Adelaide, Sydney, Melbourne and Perth Observatories. New archival research has provided evidence that the first women employed in astronomy in Australia were engaged due to this project.

This paper focuses on Mary Emma Greayer, who was employed as a computer at Adelaide Observatory from 1890, and Charlotte Emily Fforde Peel, employed as a star measurer, computer and astrographic assistant at Melbourne Observatory from 1898. The measurement bureaux at Melbourne, Perth and Sydney Observatories are examined within the context of women working on the Astrographic Catalogue in other observatories during the late nineteenth century.

Evidence is presented that individuals, such as Greayer and Peel, were vital to the completion of the Astrographic Catalogue and other astronomical work. Furthermore, it is argued that this evidence points to women having a broader role and greater agency within observatories in Australia and in astronomy than has previously been acknowledged.
Characteristics of Adaptation Period for Extrauterine Life of Neonates from Multiple Pregnancies
Authors: Mikulska M. , Wolnicka B.
Published: July 2016

Multiple pregnancies pose numerous threats both for foetuses and neonates. The following disorders are encountered among the most important perinatal disturbances: EPH – gestosis, immature labour and premature rupture of foetal membranes. Also during the labour, particularly the second one and the following ones, various lesions that may cause increased incidence of diseases and mortality in this group of neonates [5, 6, 10, 18, 21, 22, 25]. Complications encountered in neonates from multiple pregnancies, resulting both from abnormal conditions of intrauterine development and from perinatal pathology, require still wider studies, particularly within the context of intensified obstetrical care of women with multiple pregnancies [7, 11, 13, 16, 24].

In the years 1996-1998, out of 3883 neonates born in the Chair of Obstetrics and Gynaecology of the Silesian Medical Academy, 152 (3,9%) came from multiple pregnancies. This period included one case of quadruplets, eight cases of triplets and 62 twin pregnancies. Pregnant women were directed to our Chair within the program of multidisciplinary care of women with complicated pregnancies and they also came from the Department of Pathology of Pregnancy in our Chair. In 18 women, treated for infertility, the pregnancy was accomplished as a result of application of various techniques of assisted procreation. In one case – 4 foetuses were indicated, in five cases – three foetuses and in 12 cases – two foetuses.
Long-Term Follow-Up Study of Somatic Development in Prematurely Born Twins after Life-Threatening Episodes
Authors: Chlebna-Sokół D. , Ligenza I. , Haładaj K.
Published: July 2016

The study comprised 14 pairs of twins. All the children were prematurely born between the 27 and the 33 weeks of pregnancy with birth weight 600-1900 g. Somatic development was assessed on the basis of the body weight, length/height measurements taken in the 6thand 12thmonths of the corrected age and in the 24thmonth of the calendar age. Body mass index was also calculated as weight in kilograms divided by the square of the height in meters. The obtained results were compared with the regional norms for children from Lodz. Moreover, in each child individual measurements and body mass index were normalized as compared to the arithmetic mean and the standard deviation for the established age norm. The percentage of children with body mass deficiency and decreased body length/height was relatively high. Individual assessment of somatic development, taking into account the normalized values enable observation of the direction of changes within the range of somatic features in individual children. Retardation of somatic development of prematurely born twins should be first of all associated with their very low birth weight. Severe complications of prematurity affect physical development of the children examined by us, especially in the first two years of life.
From Genetic Research into Clinical Practice
Authors: Dallapiccola B. , Torrente I. , Mingarelli R. , Novelli G.
Published: July 2016

The present genome era is characterized by speedy progress and prompt transfer of results into clinical practice. This creates the need for rapid disclosure of results and renewal of laboratory's protocols. Molecular cytogenetics has provided and increased ability to identify chromosomes, correlate chromosome structure with gene location, find out cryptic aberrations, and detect specific DNA sequences. These advances have allowed the confident discovery of a number of contiguous gene syndromes. The positional cloning and positional candidate strategies have greatly expedited the search process of disease genes, and become relevant methods for genes' discovery. Understanding the molecular basis of diseases has shown an unpredicted wide genetic heterogeneity, which has splitted single disorders into many clinically similar conditions, and added complexity to the nosology of human diseases. The opposite process, allelism, where clinical diversity results from allelic mutations, has lumped together many distinct disorders, by showing that different clinical entities are not necessarily due to mutations in different genes. Dynamic mutations have provided the molecular understanding of interindividual and intrafamilial variability including anticipation, in a number of diseases. The discovery of distinct correlations between the molecular pattern and disease severity is providing a unique opportunity for using molecular results to assess the clinical outcome. Diagnostic, presymptomatic and predictive molecular testing are becoming widely used and provide enormous opportunities for improving the lot of our patients.
Case of Gastroschisis of the Surviving Fetus in Monochorionic Twin Pregnancy
Authors: Malinowski W. , Biskup I.
Published: July 2016

The authors describe the case of gastroschisis and Dandy-Walker syndrome of the surviving fetus after the intra-uterine co-twin demise in a monochorionic twin pregnancy.
Prevalence and Correlates of Susceptibility to Motion Sickness
Authors: Sharma Krishan
Published: July 2016

Data on susceptibility to motion sickness were collected on a sample of 535 individuals divided into eight groups. The prevalence of motion sickness among Tibetans and Northeast Indians (28%) was slightly higher than Northwest Indians (26%). Generally speaking, females (27.3%) were more susceptible than males (16.8%). Among different groups, the highest incidence of susceptibility to motion sickness (SMS) was recorded in schizophrenic patients (30%), while the lowest in rowers (zero percent). Ears and eyes are the most potent receptors of provocative motion that causes sickness. Individuals with greater spatial and motor control, reflected in sports like rowing, athletics and professions like armed and paramilitary forces, were less susceptible to motion sickness.

The SMS was significantly higher in individuals who suffered from spatial disorientation (35.05%), migraine (26.31%), gastrointestinal disorders (26.82%) and those who were more sensitive to unpleasant odours (24.64%) and preferred sweet flavours (24.48%) than their counterparts. These correlates have been utilized to explain the genesis of sickness using threshold model. Genetic and environmental pathways are strongly advocated. Past episodes of motion sickness acted as a strong psychological attribute in determining further episodes. The roadway buses and trucks proved more effective passive transportation types that caused sickness. The voluntary stabilization of the head and neck movements and gaze control proved very effective natural measures adopted by 38% subjects to avoid or limit motion sickness. About 50% of susceptible individuals became less susceptible or fully acclimatized to motion sickness due to habituation. The mean age at acclimatization was 21.98 ± 5.93 years.
The Assessment of the Umbilical Blood Flow of the Surviving Twin after the Intrauterine Death of the Other Twin
Authors: Malinowski W. , Dec W. , Biskup I.
Published: July 2016

This paper summarizes our experience with Doppler velocimetry in survivors of intrauterine co-twin demise. In the first trimester, ten dichorionic deaths occurred; none of the survivors developed flow disorders. During the second trimester, there were three intrauterine demises, two of them were monochorionic and the survivors developed flow disorders: one presented transitory venous flow aberration, the other one an impaired development of diastolic flow. In the third trimester, two intrauterine deaths occurred. One case of twin to twin transfusion syndrome (TTTS) was complicated by the donor's death and the recipient showed a loss of diastolic flow. The second one happened during a dichorionic twin pregnancy. The survivor presented high systolic/diastolic daily ratio (S/D = 7.8).
Prader-Willi and Angelman Syndromes and the Implications of Genomic Imprinting in Their Etiology
Authors: Cassidy S.B.
Published: July 2016

The unfolding of the genetic story of Prader-Willi and Angelman syndromes provided the first recognition of human genomic imprinting. These disorders, which are clinically very distinct, are related through their genomic proximity and the inverse direction of the imprinting which affects them. Both are interesting disorders in themselves, especially in that both have distinctive behavioral patterns among their clinical features that may teach us much about normal human behavior.

Prader-Willi syndrome (PWS) is a complex multi-system condition whose major features include infantile hypotonia with decreased arousal, poor suck and failure-to-thrive; characteristic dysmorphic facial features; hypopigmentation; childhood onset of obesity due to lack of satiety; hypogonadotropic hypogonadism with genital hypoplasia and delayed and incomplete puberty; short stature for genetic background; developmental delay and usually mild mental retardation; and a characteristic behavioral disturbance with temper tantrums and obsessive-compulsive behavior. PWS occurs in about 1/15,000 people. Since its first description in 1956, it has been apparent that many of these features arise from insufficient function of the hypothalamus, and recent identification of neurosecretory growth hormone insufficiency and temperature and sleep regulation abnormalities support this. However, no visible gross or microscopic abnormalities of the hypothalamus are seen on neuropathology. The finding of a chromosome 15q 11-13 deletion in a proportion of patients with PWS by Ledbetter and colleagues in 1981 was the first window to the exciting genetic discoveries of the past decade, including recognition (initially by Butler and Palmer) that the deletion is always on the paternally-derived chromosome 15 in PWS, and the finding by Nicholls and coworkers that the vast majority of the remainder of patients had normal chromosomes but had maternal uniparental disomy (UPD). Nearly all patients with clinically typical PWS have either 15q deletion (about 75%) or maternal UPD (about 25%). This is the first human disorder that was recognized to result from uniparental disomy, and lead to many insights into imprinting.
Tuberous Sclerosis: Between Genetic and Physical Analysis
Authors: Halley D.J.J.
Published: July 2016

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder with extensive clinical variability. Present estimates of the prevalence of TSC suggest that it may exceed 1:6,000. New mutations are frequent, as about 2/3 of all cases are apparently sporadic. Locus heterogeneity has been established, with one gene on chromosome 9q34 (TSC1) and the other on chromosome 16p13.3 (TSC2). The majority of TSC2 mutations are propably subtle alterations. In some cases, somatic and germline mosaicism might be explanations for intrafamilial phenotypic variation and apparent non penetrance. A role of the predicted protein product tuberin in growth suppression would be in agreement with allelic losses observed in tumors of TSC patients. Studies on tuberin using antibodies raised against various parts of the protein can be expected to provide insight into its normal and impaired function.
Dosage and Imprinting Effects in Abnormalities of Human Chromosome 15
Authors: Ledbetter D.H. , Christian S.L. , Kubota T. , Mutirangura A. , Sutcliffe J.S. , Nakao M. , Beaudet A.L.
Published: July 2016

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by paternal deficiency (PWS) or maternal deficiency (AS) of gene(s) in 15qll.2-ql3. We have constructed a 3.5 Mb yeast artificial chromosome (YAC) contig of the PWS/AS region and cosmid contigs of selected YACs at D15S13, SNRPN, S10, and S113. Cosmid clones have been used for fluorescence in situ hybridization (FISH) detection of deletions in PWS and AS patients. In addition, a total of 28 short tandem repeat polymorphisms (STRs) have been mapped to specific YACs in the contig, providing a highly informative set of markers for detection of deletion or uniparental disomy (UPD) in PWS and AS patients. Use of the 3 most informative markers in this region (S542, S128, and ASSCA-1) plus 3 markers distal on 15q (S123, S125, and S131) provide an efficient diagnostic strategy for UPD15.

A combination of FISH and STR analysis has identified small deletions in one sporadic and one familial case of PWS (family O). Both deletions involve all or part of the SNRPN gene but do not extend telomeric to PAR-5 or PAR-1, two novel transcripts expressed exclusively from the paternal chromosome. However, expression of SNRPN, PAR-5, and PAR-1 is lost in both cases, implying the presence of an imprinting control region near SNRPN. The smallest deletion in family O is estimated at approximately 30-40 kb in size and involves a newly identified CpG island at the 5′ end of SNRPN which is methylated on the maternal chromosome. This small deletion in two PWS affected siblings was present in the father and the paternal grandmother, both of whom were phenotypically normal.
X Chromosome Inactivation and Imprinting
Authors: Lyon M.F.
Published: July 2016

In contrast to the random inactivation of either maternal or paternal X-chromosome in the somatic cells of eutherian mammals, in marsupials the paternal X-chromosome is preferentially inactivated in all cells. Similar exclusively paternal X-inactivation occurs in two extraembryonic cell lineages of mice and rats. Thus, genetic imprinting is an important feature of X-inactivation. In embryonic development the initiation of X-inactivation is thought to occur through the X-inactivation centre, located on the X-Chromosome, and thus imprinting probably acts through this centre. A candidate gene for a role in the inactivation centre is Xist (X inactive specific transcript) which is expressed only from the inactive X-Chromosome. The expression of Xist in the mouse embryo is appropriate for it to be a cause rather than a consequence of inactivation. It appears before inactivation, and only the paternal allele is expressed in the extraembryonic lineages. In the germ cells also changes in X-chromosome activity are accompanied by changes in Xist expression. Studies of methylation of the Xist gene have shown that in male tissues where Xist is not active it is fully methylated, whereas in the female the allele on the active X-chromosome only is methylated. In male germ cells, where Xist is expressed, it is demethylated and the demethylation persists in mature spermatozoa. Thus a methylation difference in germ cells could possibly be the imprint. In androgenotes, with paternally derived chromosomes, Xist is expressed at the 4-cell stage, whereas in gynogenotes and parthenogenotes expression does not appear until the blastocyst stage. Thus, Xist expression shows imprinting. When expression appears in parthenogenotes it is random, suggesting that the imprint has been lost. The Xist gene has no open reading frame and is thought to act through mRNA but its function is unknown.
Multiple Imprinted Genes Associated with Prader-Willi Syndrome and Location of an Imprinting Control Element
Authors: Nicholls R.D. , Jong M.T.C. , Glenn C.C. , Gabriel J. , Rogan P.K. , Driscoll D.J. , Saitoh S.
Published: July 2016

Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.
Fragile X Syndrome in Humans and Mice
Authors: Oostra B. A.
Published: July 2016

Fragile X syndrome is the most common cause of interited mental retardation in humans, with a frequency of approximately 1 in 1200 males and 1 in 2500 females [1]. It is second only to Down syndrome as a genetic cause of mental retardation, which has an overall frequency of 1 in 600. These frequency estimates suggest that fragile X syndrome accounts for approximately 3% of mental retardation in males, and perhaps as much as 20% in males with IQs between 30 and 55 [2]. The disease derives its name from the observation of a fragile site at Xq27.3 in cultured lymphocytes, fibroblasts and amniocytes [3].

The phenotype of the fragile X syndrome is mental retardation, usually with an IQ in the 4-70 range [4] and a number of dysmorphic features: long face, everted ears and large testicles [for review see ref. 5] (Fig. 1). Not every patient shows all the physical symptoms, which are generally more apparent after childhood. Macroorchidism is a common feature of fragile X syndrome in more than 90% of postpuberal males. Some patients show hyperactivity and attention deficits as well as avoidance behaviour similar to autism. Affected females generally have a less severe clinical presentation, and their IQ scores are generally higher, with typically borderline IQs or mild mental retardation.

No gross pathological abnormalities have been described in the brains of fragile X patients. Only a few post-mortem brain studies of fragile X males have been described and the information is very limited, presenting only non-specific findings such as brain atrophy, ventricular dilatation and pyramidal neurons with abnormal dendritic spines. It has been shown that the volume of the hippocampus was enlarged compared to controls [6], while a significantly decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle was found [7]. Using magnetic resonance imaging it was shown that fragile X patients have an increased volume of the caudate nucleus [8]. The caudate volume is correlated with IQ and methylation status of the FMR1 gene.
Clinical Use of Molecular Genetic Studies in Retinoblastoma
Authors: Passarge E.
Published: July 2016

With a population incidence of about 1 in 15.000 retinoblastoma is the most frequent intraocular tumor in infancy and early childhood. It occurs in a hereditary form due to a germline mutation in about 40% of patients (30% de novo mutation and 10% transmission from an affected parent) and in a non-hereditary form due to a somatic mutation. The retinoblastoma gene is located on chromosome 13q14. This large gene of about 180 kb, consists of 27 exons of rather different sizes and encodes a 4.7 kb transcript with important function in cell cycle regulation. Individuals with bilateral, multifocal tumors are assumed to carry a germline mutation, whereas unilateral and unifocal tumors are generally due to the somatic form. Both copies of the RB1 gene must be in inactivated before a tumor develops. In about half of patients with the germline mutation the second event inactivating the second allele can be shown by loss of heterozygosity in tumor tissues compared to surrounding somatic tissues.

Knowledge of the RB1 gene locus affords an opportunity to specify the type of mutation in many patients and arrive at a definitive molecular diagnosis. This is the basis for clinical evaluation and genetic counseling. The types of mutation are large scale deletions, small deletions and insertions, and base substitutions. There is no hot-spot for mutations.

During the last several years we have studied more than 200 patients in search for large scale and small deletions and insertions, and missense mutations. Using intragenic polymorphic DNA markers we were able to identify the mutant haplotype in all familial cases. Direct DNA analysis identified a mutation in about 25% of patients. The distribution of lesions will be described in relation to the clinical situation.
A Bird's Eye View of Human Sex Determination
Authors: Polani P.E.
Published: July 2016

In the beginning the dogma was that sex determination in man followed the Drosophila pattern in which XO is male, XXY female, and the Y chromosome has no direct influence on the determination of sex. On the grounds of specific anomalies with which they presented, females with Turner Syndrome were sex chromatin tested and found to be chromatin negative [1]. This result, confirmed in 1956 by the male frequency of red-green colour blindness in these subjects which indicated that they carried only one X chromosome in spite of their female phenotype, suggested that therefore they might be XO, and, so, hinted that sex determination in man might not follow the then accepted pattern [2]. In 1959 chromosome studies confirmed that XOs were female [3] and showed that subjects with the symmetrical XXY sex-chromosome anomaly were with Klinefelter syndrome [4]. In the same year, by showing that XOs were females also in mice [5] it became accepted that the Y chromosome was the determiner of the formation of the testis in the mammalian embryo, and so was the key element in primary sexual differentation. It would seem appropriate to call this formal model of chromosomal sex determination the Malandrium pattern [6].

In 1966 Jacobs and Ross [7], from work on males with Y chromosome deletions narrowed down the testis determining function of the Y chromosome to its short arm. Then, in 1975, Wachtel and collaborators [8] were the first to formulate a hypothesis on the sex determining gene, or, more precisely on the nature of its product. They suggested that this developmental role might be played by the H-Y antigen, a weak histocompatibility antigen which had been known to be involved in the rejection of male skin grafted onto otherwise histocompatible female mice. The idea had run into technical difficulties and a major problem was related to the significance that should be attached to the results of two different ways for demonstrating the antigen, namely the cell-mediated cytotoxicity test or the serological test. Efforts were made to keep the H-Y hypothesis alive, largely because there was a certain elegance about it [9, 10]. However eventually XX male mice, lacking H-Y by either test, spelt the end of the candidature of H-Y as the testis determining mechanism [11, 12].
The Genetics of Retinoblastoma, Revisited
Authors: Sapienza G. , Naumova A.K.
Published: July 2016

The fact that all individuals are not identical in their risk for certain cancers has been known for many years. The factors responsible for the increased risk observed in certain individuals, families, or populations may be either environmental or genetic. The genetic risk factors identified to date generally result in a greatly increased relative risk – on the order of ten to one hundred thousand-fold in the case of familial retinoblastoma, for example. The major reason for the identification of genetic factors that result in such large increases in relative risk is that the transmission of such genes in families results in an easily identifiable pattern of inheritance and the concommitant ability to locate the gene resulting in increased risk by genetic linkage analysis. From our study of sporadic and familial retinoblastoma, we have identified a genetic factor whose action appears to result in a more modest increase in relative risk – on the order of one-hundred to one-thousand-fold. We believe that a locus that is responsible for this increase in relative risk lies on the human X-chromosome. Our data indicate that aberrant alleles at this locus not only appear to increase an individual's risk for a number of cancers, but also participate in the process of genome imprinting.

The epidemiological and genetic arguments in favor of the involvement of an X-linked “imprintor, mutator” gene in the generation of new, heritable, RB-1 mutations are given in detail in Naumova and Sapienza (1994). The pertinent data may be summarized as follows:

1. there is a significant excess-of-males among patients with bilateral sporadic but not unilateral sporadic retinoblastoma;

2. there is preferential retention of paternally-derived RB-1 alleles in bilateral, but not unilateral, sporadic retinoblastoma;

3. sex ratio bias in favor of males is observed among the offspring of male founders but not female founders of retinoblastoma pedigrees (i.e. the male founders fail to transmit their X-chromosomes with the expected frequency;

4. transmission ratio distortion in favor of affected individuals is observed among the offspring of male founders but not female founders, and

5. the affected male offspring of these male founders have families in which offspring are distributed equally among affected and unaffected boys and girls, as expected for an autosomal dominant trait, i.e. sex-ratio and transmission-ratio distortion are observed only among the offspring of male founders of retinoblastoma pedigrees.
Uniparental Disomy and Genomic Imprinting in Humans
Authors: Schinzel A.
Published: July 2016

Uniparental disomy (UPD), the inheritance of both homologues from one chromosome from the same parent, was first proposed in 1980 by Erik Engel [1] to be a potential cause of congenital developmental defects in hymans. First hints from the premolecular era towards its existence came from instances where a pericentric inversion was present on one homologue in a parent and on both in one offspring [2] and where there was transmission of an interhomologous Robertsonian translocation (of chromosome 22) from a healthy mother to healthy offspring [3-4]. In mice, UPD was experimentally produced by crossing two mice lines with different Robertsonian translocations both involving the same chromosome [for 2 review see ref. 5].

Through this approach, it was possible to define imprinted regions, chromosomes and chromosomal segments for which either maternal or paternal or both types of uniparental disomy led to phenotypic abnormalities. The latter are explained by genomic imprinting, the differential silencing of a gene or genes from one of the parents (the mother or the father) during any stage of embryogenesis or later in life. If, for example, the maternal homologue of a given gene is imprinted (and hence only the paternal allele is active), maternal UPD would lead to loss of the active allele and thus might cause consequences due to loss of function.
Combined Molecular and Cytogenetic Analysis for the Rapid Diagnosis of Fragile X Syndrome
Authors: Mastellone C. Bussani , Uzielli M.L. Giovannucci , Grasso M. , Chiurazzi P. , Neri G. , Wang Q.
Published: July 2016

The fragile X mutation is the result of an abnormal expansion of a CGG repeat sequence in the FMR-1 gene.

Molecular techniques enable the detection of the mutation and also of the exact length of this DNA sequence, allowing the classification of the tested subjects as normal, carrier or affected.

We propose a protocol of analysis that combines a method of non-radioactive PCR, Southern blotting and cytogenetic testing.

This protocol can be used for screening programme of selected groups of mentally retarded individuals and for prevention studies in families at risk.
The Mouse Xist Gene: a Model for Studying the Gametic Imprinting Phenomenon
Authors: Zuccotti M. , Monk M.
Published: July 2016

In mammals, normal embryonic development requires differential genomic imprinting of male and female gametes [1, 2]. Many investigations have been directed towards the understanding of the molecular mechanisms of imprinting and the timing of establishment of the imprint during gametogenesis and its erasure during development.

Methylation is the focus of many of these studies as it has been known for some time that this epigenetic modification of the DNA correlates with the status of gene activity. So far, five imprinted genes, expressed from only one of the parental alleles, have been found to be differentially methylated in somatic tissue: mouse Igf2 [3] and Xist [4] and human SNRPN [5, 6] expressed from the paternal allele; mouse Igf2r [7] and H19 [8, 9] expressed from the maternal allele. However, so far, a gametic methylation imprint has been detected for only two of these genes: in an intron region of mouse Igf2r [7], and in the promoter region [10] and the first exon [11] of the Xist (X-inactivation-specific transcript [12, 13] gene.

The data accumulated for the Xist gene, during different phases of gametogenesis and development, provides the most comprehensive story about the role of methylation as a primary gametic imprint, and on the timing of its establishment during gametogenesis and erasure during development. Methylation studies have now been performed during oogenesis and spermatogenesis [Norris et al., 1994; 11] and in mature gametes and during early stages of development [10, 11]. In addition, expression of the gene has been described during gametogenesis [14-16] and throughout early development [4-17].
AreABLandBCRImprinted?
Authors: Fink M. , Argyriou-Tirita A. , Haas O.A.
Published: July 2016

An increasing number of clinical observations and genetic experiments have shown that some parts of the genome behave differently depending on whether they are of paternal or maternal origin. This phenomenon is known as “genomic imprinting” and has been defined as “a reversible process whereby a gamete-specific modification in the parental generation can sometimes lead to functional differences between maternal and paternal genomes in diploid cells of the offspring” [1]. The accumulating evidence for its important role in cancer predisposition syndromes as well as for the pathogenesis of certain types of sporadic tumors prompted us to investigate whether imprinting may also be instrumental in selecting particular parental chromosome regions involved in balanced rearrangements, such as the leukemia-specific translocation t(9;22) [2]. Several reports have analyzed the expression, the methylation and the replication patterns of the two genes, ABL and BCR, on chromosomes 9 and 22, respectively, which are affected by this translocation [3-6]. Although not directly comparable, the results of these studies seem to invalidate our cytogenetic observations. We therefore review this controversial issue and provide some possible explanations for the contradictory results.