Platelets are anuclear cells that are essential for blood clotting. They are produced by large polyploid precursor cells called megakaryocytes. Previous genome-wide association studies in nearly ...70,000 individuals indicated that single nucleotide variants (SNVs) in the gene encoding the actin cytoskeletal regulator tropomyosin 4 (TPM4) exert an effect on the count and volume of platelets. Platelet number and volume are independent risk factors for heart attack and stroke. Here, we have identified 2 unrelated families in the BRIDGE Bleeding and Platelet Disorders (BPD) collection who carry a TPM4 variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia, a disorder characterized by low platelet count. N-Ethyl-N-nitrosourea- induced (ENU-induced) missense mutations in Tpm4 or targeted inactivation of the Tpm4 locus led to gene dosage- dependent macrothrombocytopenia in mice. All other blood cell counts in Tpm4-deficient mice were normal. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and had a mild effect on platelet function. Together, our findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder.
A genome-wide scan in nearly 70,000 individuals showed that the common SNP rs8109288 in the first intron of the human TPM4 gene exerts an effect on the volume and count of platelets (Gieger et al. ...Nature 2011). We isolated a mouse line with an ENU-induced missense mutation in Tpm4. Mice carrying this mutation exhibited dose-dependent macrothrombocytopenia, while other blood cell counts were normal. Bone marrow transplant experiments demonstrated that the phenotype is intrinsic to hematopoietic cells. Notably, Tpm4 insufficiency did not affect the life span or in vitro function of mutant platelets, and there was no evidence of an increased propensity to bleeding. Megakaryocyte numbers in the bone marrow were increased, although maturation as measured by ploidy appeared normal. Mutant megakaryocytes displayed altered morphology indicating fragmentation, and markedly decreased proplatelet formation in vitro.
Based on Gieger et al., we examined the functional requirement for TPM4 in human megakaryocytes. We found that the localisation of TPM4 in proplatelet-forming megakaryocytes was extremely similar to the localisation in their mouse counterparts, suggesting an identical role. Furthermore, knock down of TPM4by shRNA in human megakaryocytes did not affect maturation as measured by CD41 and CD42 expression, but significantly reduced the number of proplatelet-forming cells. The occasional megakaryocyte that did form proplatelets did not exhibit the typical “beads-on-a-string” phenotype. Typically, one large bulb at the end of a protrusion or a string with no clearly distinguishable beads was observed.
We therefore performed a look-up in the BRIDGE consortium database, which enrolled 542 cases with inherited bleeding and platelet disorders of unknown aetiology in the NIHR BioResource for exome sequencing. Calling of variants revealed single nucleotide variants with consequences in TPM4which were absent from ~30,000 control haplotypes, in three BRIDGE cases. Two cases with a stop codon at residue 105 and R91H variant presented with macrothrombocytopenia and mild bleeding symptoms with platelet counts of 103 and 128 x10e9/L and volumes of 15.10 and 14.00 fl, respectively. The remaining case with variant D20N (not conserved, genomic evolutionary rate profiling score of 2.68 compared to 4.62 for the other variants) had a count in the normal range (232 x10e9/L) and a reduced platelet volume of 7.20 fl.
Together, these results provide compelling evidence that Tropomyosin 4 is a crucial regulator of platelet production in mice and humans, being specifically required for the terminal stages of platelet formation. Our studies demonstrate that the common intronic variant exerts a subtle effect, whilst two extremely rare variants have a more robust effect on platelet formation leading to counts and volumes at the tails of the population distribution. The lack of concordance between mice and humans with regard to bleeding may be explained by strong modifiers at loci other than TPM4.
No relevant conflicts of interest to declare.
The Ontario Maternal Serum Screening (MSS) Program was introduced by the Ontario Ministry of Health as a province-wide pilot project in 1993. The objective of this study was to determine the ...influence of practice location on Ontario health care providers' use of and opinions regarding MSS, access to follow-up services and recommendations about the program.
A questionnaire was mailed to a random sample of 2000 family physicians, all 565 obstetricians and all 62 registered midwives in Ontario between November 1994 and March 1995.
Among providers who were eligible (those providing antenatal care or attending births) the response rates were 91.4% (778/851), 76.0% (273/359) and 78.0% (46/59) respectively. Fewer respondents in the Northwest region (71.4%) and in rural areas (81.9%) stated that they routinely offer MSS to all pregnant women in their practices compared with respondents in other regions (84.4%-91.5%) and urban centres (90.1%). Fewer respondents in the northern regions (Northeast 49.2%, Northwest 25.0%) than in the Central East region (includes Toronto) (76.6%) felt that follow-up services were readily available. Respondents in the northern regions had less favourable opinions of MSS than those in the other regions in terms of its complexity, cost, the time involved in counselling and the high false-positive rate. More respondents in the Central East region (64.6%) and in urban centres (52.9%) recommended not changing the MSS program than did those in the Northwest (7.1%) and rural areas (39.8%). After provider characteristics were controlled for in a logistic regression analysis, practice location was not the most important factor. Instead, the model showed that respondents who cared for 50 or more pregnant women in the previous year were more likely to offer MSS routinely (OR 2.00, 95% CI 1.21-3.27) and that those who felt that patient characteristics affect the offering of MSS (OR 0.42, 95% CI 0.26-0.67) or that follow-up services were not readily available (OR 0.33, 95% CI 0.20-0.55) were less likely to offer it.
Health care providers in northern and rural Ontario were less likely to offer MSS routinely than those in other regions and were more likely to recommend changing or eliminating the program. Providers' concerns about the social and cultural sensitivity of MSS and the availability of follow-up services affected use.
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. This disease is unusual among the polyglutamine ...diseases in that it involves lower motor and sensory neurons, with relative sparing of other brain structures. We describe the development of transgenic mice, created with a truncated, highly expanded androgen receptor driven by the neurofilament light chain promoter, which develop many of the motor symptoms of SBMA. In addition, transgenic mice created with the prion protein promoter develop widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. Thus, in these experiments, the distribution of neurologic symptoms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice described here develop neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We have shown these inclusions to be ubiquitinated and to sequester molecular chaperones, components of the 26S proteasome and the transcriptional activator CREB-binding protein. Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting that the neurologic phenotypes observed in these mice were the result of neuronal dysfunction rather than neuronal degeneration. These mice will provide a useful resource for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseases.
To describe Ontario emergency physicians' knowledge of colleagues' sexual involvement with patients and former patients, their own personal experience of such involvement, and their attitudes toward ...postvisit relationships.
Mailed survey.
Ontario.
Emergency physicians practising in Ontario.
Of 974 eligible mailed surveys, 599 (61.5%) were returned. Of these respondents, 52 (8.7%) reported being aware of a colleague in emergency practice who had been sexually involved with a patient or former patient. When describing their own behaviour, 37 respondents (6.2%) reported sexual involvement with a former patient. However, of this group, only 9 (25.0%) had met the patient in an emergency department. Thus, of the total number of respondents, only 1.5% (9/599) reported sexual involvement arising out of an emergency department visit. Most respondents (82.4%) agreed that it is inappropriate behaviour to ask a patient for a date after an emergency assessment and before the patient's departure, and 66.4% felt that it is inappropriate to contact the patient after discharge. However, only 10.6% believed it to be unacceptable to request a social meeting after encountering a patient previously cared for in the emergency department in a nonprofessional setting. Most respondents (96.5%) did not believe that sexual involvement could ever be therapeutic for the patient. However, only 66% felt that it was always an abuse of power and 62.4% supported zero tolerance of all sexual involvement between physicians and patients.
Vague regulatory guidelines currently in place have failed to dispel confusion regarding what is acceptable social behaviour for physicians providing emergency care. Our results support the need for clarification, and suggest a basis for guidelines that would be acceptable to the emergency medical community: that an emergency visit should not form the basis for the initiation of personal or sexual relationships, yet neither should it preclude their development in nonmedical settings.
To discover whether family physicians who go through residency training and The College of Family Physicians of Canada's (CFPC) certification process are more responsive than other physicians to ...woman abuse, whether they perceive and approach such abuse more appropriately, and whether they seek out more education on the subject.
A national survey using a pretested 43-item mailed questionnaire to examine perceptions of and approaches to detection and management of woman abuse.
Canadian family and general practice.
A cross-sectional sample of 1574 family physicians and general practitioners, of whom 963 (61%) volunteers responded.
Demographic variables, perceptions of abuse, methods of diagnosing and managing woman abuse.
Most respondents agreed they could not diagnose and treat woman abuse effectively, regardless of certification status. They indicated they were detecting only 33% of cases. Certificants of CFPC, in particular residency-trained certificants, were more likely to think that they should be diagnosing woman abuse than noncertificants; they were also more likely to help victims by referring them to specialists and other agencies. Certificants were also more likely to think they should be treating these patients themselves, and that they were not adequately trained to do so. Although most respondents thought they needed more education, certificants were more likely to know of relevant courses, to have attended such courses, and to have read books or articles on the topic.
Being a certificant is not associated with perceived skills in diagnosing and treating woman abuse, but is associated with an increased awareness of the problem. Certificants know that education on woman abuse is available.
To examine whether male and female family physicians practise maternity care differently, particularly regarding the maternal serum screening (MSS) program.
Mailed survey fielded between October 1994 ...and March 1995.
Ontario family practices.
Random sample of 2000 members of the College of Family Physicians of Canada who care for pregnant women. More than 90% of eligible physicians responded.
Attitudes toward, knowledge about, and behaviour toward MSS.
Women physicians were more likely than men to practise part time, in groups, and in larger communities. Men physicians were more likely to perform deliveries; women were more likely to do shared care. Despite a shorter work week, on average, female physicians cared for more pregnant women than male physicians did. Among those providing intrapartum care, women performed more deliveries, on average, than men. Women physicians were more likely than men to offer MSS to all pregnant patients. Although average time spent discussing MSS before the test was similar, women physicians had better knowledge of when best to do the test and its true-positive rate. All differences reported were statistically significant (P < or = 0.001).
Among family physicians caring for pregnant women, women physicians cared for more pregnant women than men did. Both spent similar time discussing MSS with their patients before offering screening, but more women physicians offered MSS to all their patients and were more knowledgeable about MSS than men physicians.
This volume pulls together research on several aspects of the self. One set of chapters deals with the importance of building a self based on authenticity and "Who I really am."; a second group deals ...with the ways in which we defend views of the self as positive and powerful; a third group is concerned with multiple aspects of self regulation. Each of the chapters is a well-written, non-technical description of an important, currently active research program.
Abraham Tesser , Research Professor Emeritus at the University of Georgia, is a former Editor of the Journal of Personality and Social Psychology and a former President of the Society for Personality and Social Psychology. Recognition of his research on self-evaluation and on thought and ruminative processes includes the Donald T. Campbell Award from the Society for Personality and Social Psychology and the Career Award from the International Society for Self and Identity.
After completing her Ph.D. at UCLA, Joanne Wood has held faculty positions at SUNY-Stony Brook and at the University of Waterloo. She has served as an associate editor of Personality and Social Psychology Bulletin and on the editorial boards for Journal of Personality and Social Psychology , Journal of Experimental Social Psychology, Personality and Social Psychology Bulletin, and Self and Identity. Wood's publications concern affect regulation, social comparison, and mechanisms underlying the maintenance of self-esteem.
Diederik Stapel , Professor at the University of Groningen, is a former Associate Editor of the British Journal of Social Psychology and has served on the editorial boards of Self and Identity, European Journal of Social Psychology, and Personality and Social Psychology Bulletin . For his research on knowledge accessibility effects he earned the Jos Jaspars Award of the European Association of Experimental Social Psychology. Stapel's publications concern person perception, unconscious emotional responses, and social comparison.
"Much has been written on the self in modern psychology, but rarely are so many fresh perspectives found between the covers of a single volume. Tesser, Wood, and Stapel have organized some of the field's excellent thinkers and writers and produced a book that tackles enduring issues in new ways: How malleable is the self? What about one's identity is genuine? How tied up is the self in considerations of conscious experience? Under what conditions is the self defensive to the point of delusion? In the spirit of Narcissus, we all love to reflect on the self, and this volume will help students and investigators do so in intriguing new ways." - Peter Salovey, Yale University
"In the last 20 years, research on the self has grown from street musician to corporate status. Abe Tesser and his colleagues are partly responsible for this explosion of interest. Now, with the publication of their most recent edited volume on the self, Tesser, Wood, and Stapel bring a structure to this increasingly complex research domain. The eleven chapters reflect three often-conflicting assumptions of the self -- self-as-good (Carl Rogers), self-as-bad (Freud), and self-as-self-regulating-blank-slate (Locke). The editors have assembled a phenomenal group of researchers in social psychology who are superb scientists and writers. This is an excellent book." - James W. Pennebaker, University of Texas at Austin
About the Editors
Contributors
Introduction: Building, defending and regulating the self: An overview
Abraham Tesser, Joanne V. Wood and Diederik A. Stapel
I. Building the self: The Ideal, the authentic and the open self
Chapter 1: The Michelangelo Phenomenon in Close Relationships
Caryl E. Rusbult, Madoka Kumashiro, Shevaun L. Stocker, and Scott T. Wolf
Chapter 2: From Thought and Experience to Behavior and Interpersonal Relationships: A Multicomponent Conceptualization of Authenticity
Michael H. Kernis and Brian M. Goldman
Chapter 3: Transportation into Narrative Worlds: Implications for the Self
Melanie C. Green
Chapter 4: Conflict and Habit: A Social Cognitive neuroscience Approach to the Self
Matthew D. Lieberman and Naomi I. Eisenberger
II. Defending the self
Chapter 5: Ideal Agency: The Perception of Self as an Origin of Action
Jesse Preston and Daniel M. Wegner
Chapter 6: Reflections in Troubled Waters: Narcissism and the Vicissitudes of an Interpersonally Contextualized Self
Frederick Rhodewalt and Carolyn C. Morf
Chapter 7: Nagging Doubts and a Glimmer of Hope: The Role of Implicit Self-Esteem in Self-Image Maintenance
Steven J. Spencer, Christian H. Jordan, Christine E.R. Logel, and Mark P. Zanna
III. Regulating the self
Chapter 8: Approach Avoidance Motivation and Self-Concept Evaluation
Andrew J. Elliot and Rachel R. Mapes
Chapter 9: Self Conscious Emotion and Self-Regulation
Dacher Keltner and Jennifer S. Beer
Chapter 10: On the Hidden Benefits of State Orientation: Can People Prosper without Efficient Affect Regulation Skills?
Sander L. Koole, Julius Kuhl, Nils Jostmann, and Kathleen D. Vohs
Chapter 11: The Roles of the Self in Priming-to-Behavior Effects.
S. Christian Wheeler, Kenneth G. DeMarree, and Richard E. Petty
Author Index
Subject Index
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