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In the Netherlands, child abuse affects about 100.000 children resulting in at least 17 child fatalities a year. General practitioners' (GPs) health care position is of vital importance for recognising and managing child abuse. In this Clinical Lesson, using three illustrating cases, we discuss how GPs' suspicion of child abuse may arise including the role of gut feelings, and what the mandatory national guideline on child abuse means for the follow-up. We also clarify the role of the Dutch Child Abuse Counselling and Reporting Centre (CACRC) in the process. A first lesson is that any doubts about child abuse should lead to action because diagnostic failure has serious consequences for vulnerable children. A second lesson is that asking CACRC for anonymous advice how to deal with a situation may certainly have added value. Finally, we advise CACRC to invest in building a relationship of trust with the collaborating partners.

Aim: We examined how gut feelings of child health care physicians' (CHCPs) contribute to the development of a suspicion of child abuse, how they act upon this suspicion and what barriers they experience in their management. To gain insight into the youth health care chain, we compared the diagnostic reasoning and management regarding this issue by CHCPs and family physicians (FPs)., Methods: Three focus groups, 20 CHCPs, thematic content analysis., Results: A gut feeling acted as an early alert to look for the triggering cue(s), by observing more closely and asking relevant questions. CHCPs struggled to distinguish whether the situation involved child abuse or a lack of parenting skills, and how to communicate their concerns with parents. They tried to motivate parents to improve the situation, avoiding the term child abuse and considered involving the Child Abuse Counselling and Reporting Centre (CACRC) a measure of last resort only., Conclusion: As with FPs, gut feelings support CHCPs in becoming attentive to child abuse and to situations which can lead to child abuse. The next step, discussing their suspicion with the parents, is a difficult one, and the CACRC might actually help to make this step easier., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: Patients with advanced lung cancer experience high physical symptom burden with substantial psychological distress. Depressive and anxiety symptoms are common and associated with worse quality of life (QoL). Early palliative care (EPC) addresses the complex supportive care needs improving QoL and mood. The mechanisms of EPC are uncertain. We examined whether and how coping strategy, a primary component of EPC, influenced QoL in these patients., Materials and Methods: We conducted a multicenter cross-sectional study of patients with advanced lung cancer. A total of 125 patients completed assessments of QoL (QLQ-C15-PAL), depressive and anxiety symptoms (HADS), and coping (brief COPE questionnaire). The data were analyzed by descriptive statistics. To determine whether and how coping strategy influences QoL, correlations and logistic regressions were performed., Results: Positive reframing correlates significantly with global QoL (r = 0.25, P < .01), emotional well-being (r = 0.33, P < .01), pain (r = -0.30, P < .01), fatigue (r = -0.22, P < .01), loss of appetite (r = -0.22, P < .01) and nausea (r = -0.24, P < .01). Self-blame correlates significantly with worse emotional well-being (r = -0.19, P < .05) and insomnia (r = 0.19, P < .05). Using a 4-step logistic regression model, it was found that anxiety and depressive symptoms fully mediated the relationship between positive reframing and QoL., Conclusions: Patients with advanced lung cancer using positive reframing as coping strategy, experience higher QoL. The mechanism behind it seems that positive reframing goes along with less anxiety and depressive symptoms leading to a better QoL. Self-blame leads to more insomnia and worse emotional well-being. Providing skills to cope effectively could impact QoL in these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor it, despite the fact that little is known about the ultrasound appearance due to the novelty of the illness. The aim of this manuscript is to characterise the lung ultrasonographic appearance of critically ill patients with SARS-CoV-2 pneumonia, with particular emphasis on its relationship with the time course of the illness and clinical parameters., Methods: Adult patients from the intensive care unit of two academic hospitals who tested positive for SARS-CoV-2 were included. Images were analysed using internationally recognised techniques which included assessment of the pleura, number of B-lines, pathology in the PLAPS (posterolateral alveolar and/or pleural syndrome) point, bedside lung ultrasound in emergency profiles, and the lung ultrasound score. The primary outcomes were frequencies, percentages and differences in lung ultrasound findings overall and between short (≤14 days) and long (>14 days) durations of symptoms and their correlation with clinical parameters., Results: In this pilot observational study, 61 patients were included with 76 examinations available for analysis. 26% of patients had no anterior lung abnormalities, while the most prevalent pathological ultrasound findings were thickening of the pleura (42%), ≥3 B-lines per view (38%) and presence of PLAPS (74%). Patients with "long" duration of symptoms presented more frequently with a thickened and irregular pleura (32 (21%) versus 11 (9%)), C-profile (18 (47%) versus 8 (25%)) and pleural effusion (14 (19%) versus 3 (5%)), compared to patients with short duration of symptoms. Lung ultrasound findings did not correlate with arterial oxygen tension/inspiratory oxygen fraction ratio, fluid balance or dynamic compliance., Conclusion: SARS-CoV-2 results in significant, but not specific, ultrasound changes, with decreased lung sliding, thickening of the pleura and a B-profile being the most commonly observed. With time, a thickened and irregular pleura, C-profile and pleural effusion become more common findings. When screening patients, a comprehensive ultrasound protocol might be necessary., Competing Interests: Conflict of interest: M.E. Haaksma has nothing to disclose. Conflict of interest: M.L.A. Heldeweg has nothing to disclose. Conflict of interest: J.E. Lopez Matta has nothing to disclose. Conflict of interest: J.M. Smit has nothing to disclose. Conflict of interest: J.D. van Trigt has nothing to disclose. Conflict of interest: J.S. Nooitgedacht has nothing to disclose. Conflict of interest: C.V. Elzo Kraemer has nothing to disclose. Conflict of interest: M. van de Wiel has nothing to disclose. Conflict of interest: A.R.J. Girbes has nothing to disclose. Conflict of interest: L. Heunks has nothing to disclose. Conflict of interest: D.J. van Westerloo has nothing to disclose. Conflict of interest: P.R. Tuinman has nothing to disclose., (Copyright ©ERS 2020.)

Background: Child abuse is widespread, occurs in all cultures and communities, remains undiscovered in 90% of cases and has serious long-term effects. Physicians generally underidentify and underreport child abuse. To understand this low reporting rate and how the suspicion of child abuse arises, we examined GPs' experiences. Research questions: How does the suspicion of child abuse arise in GPs' diagnostic reasoning? How do they act upon their suspicion and which barriers do they encounter in their management? Methods: Twenty-six GPs participated in four focus groups. We used purposive sampling to include GPs with different levels of experience. We performed a thematic content analysis. Results: Suspicion of child abuse arose from common triggers and a gut feeling that 'something is wrong here'. GPs acted upon their suspicion by gathering more data, through history taking and physical examination. They often found it difficult to decide whether a child was abused, because parents, despite good intentions, may simply lack parenting skills and have different values. Clear signs of sexual abuse and physical violence were institutionally reported by GPs, whereas in less clear-cut cases they followed them up and built a supporting network of professionals around the family. Conclusions: A low child abuse reporting rate by GPs to CACRC does not mean a low detection rate. In trying to improve a child's situation, GPs make use of patients' trust in their doctor by involving other professionals. Awareness of the role of gut feelings in developing a suspicion may increase early detection and preventive actions.Key pointsPhysicians generally underidentify and underreport child abuse.Suspicion of child abuse arose from common triggers and a gut feeling that 'something is wrong here'.GPs acted upon their suspicion by gathering more data, through history taking and physical examination.GPs found it difficult to decide whether a child was abused, because parents, despite good intentions, may lack parenting skills.

Self-perceived word-finding difficulties are common in aging individuals as well as in Alzheimer's Disease (AD). Language and speech deficits are difficult to objectify with neuropsychological assessments. We therefore aimed to investigate whether amyloid, an early AD pathological hallmark, is associated with speech-derived semantic complexity. We included 63 individuals with subjective cognitive decline (age 64 ± 8, MMSE 29 ± 1), with amyloid status (positron emission tomography [PET] scans n = 59, or Aβ 1-42 cerebrospinal fluid [CSF] n = 4). Spontaneous speech was recorded using three open-ended tasks (description of cookie theft picture, abstract painting and a regular Sunday), transcribed verbatim and subsequently, linguistic parameters were extracted using T-scan computational software, including specific words (content words, frequent, concrete and abstract nouns, and fillers), lexical complexity (lemma frequency, Type-Token-Ratio) and syntactic complexity (Developmental Level scale). Nineteen individuals (30%) had high levels of amyloid burden, and there were no differences between groups on conventional neuropsychological tests. Using multinomial regression with linguistic parameters (in tertiles), we found that high amyloid burden is associated with fewer concrete nouns (OR middle (95%CI): 7.6 (1.4-41.2), OR lowest : 6.7 (1.2-37.1)) and content words (OR lowest : 6.3 (1.0-38.1). In addition, we found an interaction for education between high amyloid burden and more abstract nouns. In conclusion, high amyloid burden was modestly associated with fewer specific words, but not with syntactic complexity, lexical complexity or conventional neuropsychological tests, suggesting that subtle spontaneous speech deficits might occur in preclinical AD., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of gut feelings in diagnostic reasoning is recognized by most GPs throughout Europe, and probably throughout the world. Studies on this topic have emerged from different countries but there is the risk that authors will use different terms for similar concepts. The European Expert Group on Cognitive and Interactive Processes in Diagnosis and Management in General Practice, COGITA for short, was founded in 2008 to conduct cross-border research in the area of non-analytical diagnostic reasoning. Academic GPs, PhD students, psychologists, linguists and students meet once a year to share their experiences, exchange results and initiate new studies on the topic. A milestone in their research is this publication of a short glossary of diagnostic reasoning terms relating to the gut feelings research topic. It was constructed by the COGITA group members following a literature review, which aimed to define salient terms used in their publications. They described the terms, cross-reviewed the wording and reached consensus within the group. Two sections were created: (1) a diagnostic reasoning section that describes concepts such as analytical and non-analytical reasoning, clinical mind lines, and intuition, and (2) a research methods section describing concepts such as linguistic validity and saturation. The glossary, including relevant literature, has been published on the website http://www.gutfeelingsingeneralpractice.eu . In the future, the glossary will be modified if necessary and completed by members of the COGITA group. [Box: see text].

The management of locally advanced breast cancer (LABC) remains a major clinical issue, despite progress achieved in diagnosis and therapy. Preoperative or neoadjuvant therapy has gained interest since breast cancer has been regarded as a systemic disease. Comparing adjuvant versus neoadjuvant treatment, the neoadjuvant approach offers the advantage of downstaging the disease and testing the efficacy of therapy administered to patients. A large number of clinical trials have attempted to define the optimal neoadjuvant treatment, but little attention has been paid to the sequence of chemotherapy. Moreover, the integration of antibodies against Human Epidermal Receptor-2 (HER-2) and other biological therapies that may improve the long-term control of breast cancer patients, have a special clinical interest. In this review, we will discuss these topics attempting to answer the questions why, when and which regimen to use for patients with LABC. Especially, the introduction of the platina derivatives in neoadjuvant trials with their exceptional high pathological complete response rates are challenging to rethink the optimal treatment options in early and locally advanced breast cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia., Design: Data collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al 's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions., Results: Based on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al 's definition and 40% according to Evans et al 's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between patients with and without cachexia is more significant using the diagnostic criteria of Evans et al . The focus of Fearon et al on weight loss and sarcopenia over-rates the assignment of patients to the cachectic group and OS rates have less prognostic value., Conclusion: This study presents a correlation with prognosis in favour of Evans et al ' definition as a tool for cachexia diagnosis. This means that weight loss and BMI decline are both key factors in patients with cancer leading to cachexia but less decisive as stated by Fearon et al . Instead, extra factors gain importance in order to predict survival, such as chronic inflammation, anaemia, protein depletion, reduced food intake, fatigue, decreased muscle strength and lean tissue depletion., Trial Registration Number: B300201112334., Competing Interests: Conflicts of Interest: None declared.

Metastatic cancer was previously treated with distinctive lines of chemotherapy regimens upon disease progression or toxicity, yet the choices of therapy are actually interrelated, with the selection of a first-line regimen in part determining the choices available for subsequent treatment. Lately the therapeutic approach based on separate lines of treatment, tends to be replaced from a perspective strategical approach, that of the "continuum of care". This strategy targets to an improved overall survival, improved of quality of life and minimization of toxicity through upfront design of treatment selection and sequencing, exposure to all available drugs and minimization of unnecessary treatment. Anti-VEGF treatment has a well-documented role in this approach. Bevacizumab should be included in upfront treatment regimens for all mCRC patients independently of RAS status, unless contraindicated. Upfront bevacizumab could be combined with all available regimens since the optimal choice of backbone chemotherapy is yet to be defined. In RAS wild-type population, when metastasectomy is the target, an anti-EGFR combination is also a valid approach. Maintenance with bevacizumab and fluoropyrimidines should be considered upon intolerance of induction treatment and/or disease stabilization; maintenance with bevacizumab monotherapy should be avoided. In highly selected patients, complete treatment cessation could be also an option. Continuation with bevacizumab upon first progression and switch of the "backbone" chemotherapy is a validated approach. Patients progressing after first-line oxaliplatin regimen including bevacizumab combinations could be treated with an aflibercept-irinotecan combination. When no more options are available, regorafenib monotherapy should be the following choice. Combinations of anti-VEGF and anti-EGFR treatment have no place in this approach and are not indicated.

Osteoclasts and macrophages share progenitors that must receive decisive lineage signals driving them into their respective differentiation routes. Macrophage colony stimulation factor M-CSF is a common factor; bone is likely the stimulus for osteoclast differentiation. To elucidate the effect of both, shared mouse bone marrow precursor myeloid blast was pre-cultured with M-CSF on plastic and on bone. M-CSF priming prior to stimulation with M-CSF and osteoclast differentiation factor RANKL resulted in a complete loss of osteoclastogenic potential without bone. Such M-CSF primed cells expressed the receptor RANK, but lacked the crucial osteoclastogenic transcription factor NFATc1. This coincided with a steeply decreased expression of osteoclast genes TRACP and DC-STAMP, but an increased expression of the macrophage markers F4/80 and CD11b. Compellingly, M-CSF priming on bone accelerated the osteoclastogenic potential: M-CSF primed cells that had received only one day M-CSF and RANKL and were grown on bone already expressed an array of genes that are associated with osteoclast differentiation and these cells differentiated into osteoclasts within 2 days. Osteoclastogenesis-insensitive precursors grown in the absence of bone regained their osteoclastogenic potential when transferred to bone. This implies that adhesion to bone dictates the fate of osteoclast precursors. Common macrophage-osteoclast precursors may become insensitive to differentiate into osteoclasts and regain osteoclastogenesis when bound to bone or when in the vicinity of bone., (© 2014 Wiley Periodicals, Inc.)

Correctly predicting the course of a patient's pattern of symptoms, even if no diagnosis has (yet) been established, is a core task of the general practitioner (GP). This is a complex task requiring extensive knowledge and experience, as the presentation of diseases in primary care regularly deviates from what doctors learn at medical school. In addition, knowledge among GPs about clinical pictures requiring immediate action is not always sufficient. Finally, GPs' context and experiential knowledge are decreasing due to changes in the organization of care. In the authors' opinion, postgraduate courses for GPs insufficiently address these issues. Postgraduate courses should teach them about serious diseases that must not be missed, about uncommon presentations of common diseases and about the role of gut feelings in diagnostic thinking and the way to act on these feelings. GPs should be obliged to devote part of their compulsory postgraduate training to these subjects.

Over the last few decades, a suite of numerical models has been developed for studying river history and evolution that is almost as diverse as the subject of river history itself. A distinction can be made between landscape evolution models (LEMs), alluvial architecture models, meander models, cellular models and computational fluid dynamics models. Although these models share some similarities, there also are notable differences between them, which make them more or less suitable for simulating particular aspects of river history and evolution. LEMs embrace entire drainage basins at the price of detail; alluvial architecture models simulate sedimentary facies but oversimplify flow characteristics; and computational fluid dynamics models have to assume a fixed channel form. While all these models have helped us to predict erosion and depositional processes as well as fluvial landscape evolution, some areas of prediction are likely to remain limited and short-term owing to the often nonlinear response of fluvial systems. Nevertheless, progress in model algorithms, computing and field data capture will lead to greater integration between these approaches and thus the ability to interpret river history more comprehensively., (This journal is © 2012 The Royal Society)

Background: Colorectal cancer develops in a multi-step manner from normal epithelium, through a pre-malignant lesion (so-called adenoma), into a malignant lesion (carcinoma), which invades surrounding tissues and eventually can spread systemically (metastasis). It is estimated that only about 5% of adenomas do progress to a carcinoma., Aim: The present study aimed to unravel the biology of adenoma to carcinoma progression by mRNA expression profiling, and to identify candidate biomarkers for adenomas that are truly at high risk of progression., Methods: Genome-wide mRNA expression profiles were obtained from a series of 37 colorectal adenomas and 31 colorectal carcinomas using oligonucleotide microarrays. Differentially expressed genes were validated in an independent colorectal gene expression data set. Gene Set Enrichment Analysis (GSEA) was used to identify altered expression of sets of genes associated with specific biological processes, in order to better understand the biology of colorectal adenoma to carcinoma progression., Results: mRNA expression of 248 genes was significantly different, of which 96 were upregulated and 152 downregulated in carcinomas compared to adenomas. Classification of adenomas and carcinomas using the expression of these genes showed to be very accurate, also when tested in an independent expression data set. Gene-sets associated with ageing (which is related to senescence) and chromosomal instability were upregulated, and a gene-set associated with fatty acid metabolism was downregulated in carcinomas compared to adenomas. Moreover, gene-sets associated with chromosomal location revealed chromosome 4q22 loss and chromosome 20q gain of gene-set expression as being relevant in this progression. CONCLUDING REMARK: These data are consistent with the notion that adenomas and carcinomas are distinct biological entities. Disruption of specific biological processes like senescence (ageing), maintenance of chromosomal instability and altered metabolism, are key factors in the progression from adenoma to carcinoma.

Background: General practitioners (GPs) are often faced with complicated, vague problems in situations of uncertainty that they have to solve at short notice. In such situations, gut feelings seem to play a substantial role in their diagnostic process. Qualitative research distinguished a sense of alarm and a sense of reassurance. However, not every GP trusted their gut feelings, since a scientific explanation is lacking., Objective: This paper explains how gut feelings arise and function in GPs' diagnostic reasoning., Approach: The paper reviews literature from medical, psychological and neuroscientific perspectives., Conclusions: Gut feelings in general practice are based on the interaction between patient information and a GP's knowledge and experience. This is visualized in a knowledge-based model of GPs' diagnostic reasoning emphasizing that this complex task combines analytical and non-analytical cognitive processes. The model integrates the two well-known diagnostic reasoning tracks of medical decision-making and medical problem-solving, and adds gut feelings as a third track. Analytical and non-analytical diagnostic reasoning interacts continuously, and GPs use elements of all three tracks, depending on the task and the situation. In this dual process theory, gut feelings emerge as a consequence of non-analytical processing of the available information and knowledge, either reassuring GPs or alerting them that something is wrong and action is required. The role of affect as a heuristic within the physician's knowledge network explains how gut feelings may help GPs to navigate in a mostly efficient way in the often complex and uncertain diagnostic situations of general practice. Emotion research and neuroscientific data support the unmistakable role of affect in the process of making decisions and explain the bodily sensation of gut feelings.The implications for health care practice and medical education are discussed.

The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89%) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17%) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes., (Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Introduction: Concerns have been growing about the effects of the working environment on junior doctors and the learning opportunities available to them. In order to identify problems and opportunities for improvement, we explored junior doctors' opinions about the transition from student to practitioner., Method: Seventeen recent graduates in four focus groups discussed the transition., Data Analysis: Related comments were combined in the report of the discussions, which was approved by the participants., Results: The transition was perceived as a major change, particularly the increased responsibility and workload and contacts with other health care workers and patients. Preparation during undergraduate training was adequate as regards knowledge, communication, history taking and physical examination skills but not for pharmacological knowledge and patient management skills. Problems were connected with practical procedures and feelings of uncertainty. There was little formal education. Proposals to ease the transition were earlier patient contacts, more involvement in patient management and growing responsibility during clerkships., Discussion: Although the sample was small, the uniform opinion in all groups supports the validity of the findings. Junior doctors felt confident with regard to knowledge and skills, but experienced difficulties with patient management, practical matters and their role on the team. Contrary to the idea of an educational continuum, formal learning appeared to be very limited in the hospital environment., Conclusions: Preparation for medical practice may benefit from active involvement of clerks in patient management decisions and a gradual increase in responsibilities. An effective medical education continuum would require more attention for house officers' learning.

In spite of numerous curricular innovations, the problems medical students encounter in making the transition from theoretical training to clinical training remain unresolved and the problem has received scant attention in the literature. We performed a qualitative study to explore students' perceptions and attitudes regarding this transition in undergraduate medical training. Twenty fifth-year students of the Maastricht Medical School participated in focus group discussions about the transition from the preclinical phase to the clinical phase of the curriculum. All focus group discussions were videotaped, literally transcribed and qualitatively analysed using content analysis. The results suggest that students have difficulty in bridging the gap between the theoretical and clinical phase of the curriculum. The problems they experience arise largely from professional socialisation processes. However, students also find it difficult to apply theoretical knowledge in clinical practice. Students find contacts with real patients highly motivating. In the clinical phase their learning changes from passive acquisition of knowledge to more active learning.Since the problem-based learning approach is supposed to enhance application of basic science concepts to clinical problems, it is surprising that students experience difficulties in applying their knowledge in practice. To facilitate the transition from theory to practice in the Maastricht Medical School some curricular changes could be introduced, such as early patient contacts to motivate students and help them learn usable knowledge. Furthermore, the advantages of a problem-based preclinical curriculum to student learning should be fully exploited. Finally, the assessment system must be congruent with the educational programme, because examinations have a powerful effect on student learning.

We present five patients with the clinical diagnosis of Fountain's syndrome, an autosomal recessive entity with mental retardation, deafness, skeletal abnormalities and coarse face with full lips as cardinal features and review all cases reported so far. We report two new isolated cases, and present follow-up data on three previously reported patients. The clinical features of all these patients are presented to further delineate the clinical picture and the natural course of this rare syndrome. We propose that epilepsy, short stature, large head circumference, broad, plump hands and the remarkable behavior are important accessory findings of this syndrome. The clinical features of this syndrome become more evident with advancing age.

Proopomelanocortin (POMC) is the precursor protein for a number of peptide hormones and neuropeptides, and the POMC gene is transcriptionally very active in the pars intermedia of the pituitary of the amphibian Xenopus laevis (Xenopus). We analysed the expression of this gene during Xenopus embryogenesis, in order to examine whether it can function as a (novel) neural marker. We investigated the spatio-temporal distribution of POMC mRNA, using a single-stranded probe that corresponds to the 3' untranslated region of Xenopus POMC gene B mRNA. Gene transcripts were first detected at stage 25 of development via RNase protection assays. In situ hybridization analysis performed at stage 46 showed clearly that these transcripts are localised in a region representing the future pars intermedia of the pituitary. Experiments using Xenopus explants indicate that the POMC gene can be used successfully as an indirect marker in studies on neural induction: in the absence of interactions with mesoderm, ectoderm fails to express the POMC gene, whereas POMC transcripts are readily detectable in conjugates of ectoderm and mesoderm. Artificial application of two different signals, which are likely to be relevant for neural differentiation (namely retinoic acid and the activation of protein kinase C via phorbol ester), was not effective in evoking POMC gene expression in cultured ectoderm explants. However, retinoic acid treatment of conjugates of Xenopus ectoderm and mesoderm successfully prevented POMC expression. We conclude that POMC gene expression can be used as an indirect marker for anterior neural differentiation in Xenopus.

In a series of 467 patients treated for mammary carcinoma 96 (20%) had a family history for this tumour. Sixty-eight (71%) had at least one first degree, 28 (29%) a second or third degree family member. Only the mean age of the second degree relative group differed significantly from that of the non-familial group. The size of the primary tumour at first presentation did not differ significantly in the familial and non-familial group, as the estimated survival. So patients with a family history for mammary carcinoma did not present themselves in an earlier stage of disease. Because of the higher risk of developing this type of tumour in female relatives we have to instruct this potential patient group more explicitly.