A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.

Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer.

Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other BRCA2-linked families provide support for this correlation.

Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene.

The human skin is a complex organ composed of the surface epidermis, the subjacent dermis (in which blood vessels, lymphatics and nerves are located) and the skin appendages. The latter include hair follicles, sebaceous glands (which secrete lipids that may serve as a permeability barrier, emollient or antimicrobial agent), apocrine glands (which secrete scents) and eccrine glands (which produce sweat for temperature control). Hereditary cylindromatosis (MIM 123850) is a rare autosomal dominant disease characterised by the development of multiple neoplasms originating from the skin appendages. These neoplasms have been termed cylindromas due to their characteristic microscopic architecture and are believed to exhibit apocrine or eccrine differentiation. We have carried out a genome search using two families with this disease, which has provided strong evidence for linkage of cylindromatosis to loci on chromosome 16q12-q13. Using markers close to the cylindromatosis gene, consistent loss of the wild-type allele was observed in 19 tumours from four individuals in the two families, indicating that the gene is likely to be a tumour suppressor gene.

Instability of short tandem repeats (microsatellites) in human cancers.

The allele sizes of polymorphic microsatellite repeats in DNA from human cancers were compared to normal DNA from the same patients. In 16 out of 196 paired samples (8%), we found evidence of an extra allele of a different size in the tumour which was not present in the normal DNA. Sequence analysis confirmed that the extra allele originates from the appropriate locus and that the size change is attributable to alteration in the number of repeat units. This form of instability was more common in tri- and tetranucleotide repeats than in dinucleotide repeats. In any single tumour sample only one repeat in the set examined was abnormal, the remainder showing identical patterns in normal and tumour DNA or evidence of allele loss. The pattern of instability in diverse types of cancer differs from that reported in colorectal neoplasms.

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Diphtheria in Europe.

A rising number of diphtheria cases were recorded in Europe in 2022, including in Belgium, within the newly arriving young migrant population. In October 2022, Médecins Sans Frontières (MSF) opened a temporary roadside container-clinic offering free medical consultations. Over 3 months of activity, the temporary clinic detected 147 suspected cases of cutaneous diphtheria with 8 laboratory-confirmed cases growing toxigenic Corynebacterium diphtheriae. This was followed by a mobile vaccination campaign, during which 433 individuals living rough in squats and informal shelters were vaccinated. This intervention has shown how even in Europe's capital, access to preventive and curative medical services remains difficult for those who need it the most. Appropriate access to health services, including routine vaccination, are crucial to improve the health status among migrants.

Un nombre croissant de cas de diphtérie a été enregistré en Europe en 2022, y compris en Belgique, au sein de la population de jeunes migrants nouvellement arrivés. En octobre 2022, Médecins Sans Frontières (MSF) a ouvert un conteneur-clinique temporaire en bord de route offrant des consultations médicales gratuites. En 3 mois d'activité, la clinique temporaire a détecté 147 cas suspects de diphtérie cutanée et 8 cas confirmés en laboratoire de Corynebacterium diphtheriae toxigène. Cette opération a été suivie d'une campagne de vaccination mobile, au cours de laquelle 433 personnes vivant dans la rue, dans des squats et des abris informels, ont été vaccinées. Cette intervention a montré que même dans la capitale de l'Europe, l'accès aux services médicaux préventifs et curatifs reste difficile pour ceux qui en ont le plus besoin. Un accès adéquat aux services de santé, y compris une vaccination de routine, est primordial pour améliorer l'état de santé des migrants.

Multicentric breast cancer: clonality and prognostic studies.

Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer.

Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.

A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.

An interstitial tandem duplication of 9p23-24 coexists with a mutation in the BRCA2 gene in the germ line of three brothers with breast cancer.

Germ-line mutations of the BRCA2 gene account for the majority of families with both male and female breast cancer. However, among independently ascertained families with the same mutation, cases of male breast cancer often appear to cluster in a single family or in a particular branch of one family. This suggests that the risk of male breast cancer conferred by BRCA2 mutations may be modified by other genetic or environmental factors. We report a family in which three brothers with breast cancer carry in their germ line two genetic abnormalities: an insertion A at nucleotide 2041 in exon 10 of BRCA2, which leads to premature termination of the encoded protein at codon 615, and a tandem interstitial duplication involving chromosome bands 9p23-24. We propose that the coexistence of this rare chromosomal abnormality with BRCA2 mutation may be augmenting the risk of male breast cancer conferred by the BRCA2 mutation.

Sparks creating light? Strengthening peripheral disease surveillance in the Democratic Republic of Congo.

SETTING: The Democratic Republic of Congo suffers from an amalgam of disease outbreaks and other medical emergencies. An efficient response to these relies strongly on the national surveillance system. The Pool d'Urgence Congo (PUC, Congo Emergency Team) of Médecins Sans Frontières is a project that responds to emergencies in highly remote areas through short-term vertical interventions, during which it uses the opportunity of its presence to reinforce the local surveillance system. OBJECTIVE: To investigate whether the ancillary strengthening of the peripheral surveillance system during short-term interventions leads to improved disease notification. DESIGN: A descriptive paired study measuring disease notification before and after 12 PUC interventions in 2013-2014. RESULTS: A significant increase in disease notification was observed after seven mass-vaccination campaigns and was sustained over 6 months. For the remaining five smaller-scaled interventions, no significant effects were observed. CONCLUSION: The observed improvements after even short-term interventions underline, on the one hand, how external emergency actors can positively affect the system through their punctuated actions, and, on the other hand, the dire need for investment in surveillance at peripheral level.

Contexte : La République Démocratique du Congo souffre d'un amalgame de flambées épidémiques et d'autres urgences médicales. Une réponse efficace à ces problèmes est basée sur le système national de surveillance. Le Pool d'Urgence Congo (PUC) de Médecins Sans Frontières est un projet répondant aux urgences dans les zones très reculées grâce à des interventions verticales à court terme, pendant lesquelles le projet met à profit l'opportunité de sa présence pour renforcer le système de surveillance local.Objectif : Vérifier si le renforcement complémentaire du système de surveillance périphérique pendant des interventions à court terme amène une amélioration de la notification des maladies.Schéma : Une étude descriptive par paires mesurant la notification des maladies avant et après 12 interventions PUC en 2013­2014.Résultats : Une augmentation significative de la notification des maladies a été observée après sept campagnes de vaccination de masse et elle s'est maintenue pendant 6 mois. En ce qui concerne les cinq interventions restantes à plus petite échelle, aucun effet significatif n'a été observé.Conclusion : Les améliorations observées, même après des interventions à court terme, soulignent d'un côté comment des acteurs externes de l'urgence peuvent affecter positivement le système à travers leurs actions ponctuelles et, d'un autre côté, le besoin pressant d'investir dans la surveillance au niveau périphérique.

Marco de referencia: La República Democrática del Congo adolece de una amalgama de brotes epidémicos y otras urgencias médicas y la eficiencia de la respuesta a esta situación depende en gran medida del sistema nacional de vigilancia. El proyecto 'Pool d'Urgence Congo' (PUC, en francés) de Médecins Sans Frontières responde a las situaciones de urgencia en zonas muy remotas, mediante intervenciones verticales a corto plazo, durante las cuales se aprovecha la presencia en el terreno con el fin de reforzar el sistema local de vigilancia sanitaria.Objetivo: Investigar si el fortalecimiento complementario del sistema periférico de vigilancia sanitaria durante las intervenciones de corta duración contribuye a mejorar la notificación de las enfermedades.Método: Un estudio descriptivo emparejado, en el cual se midió la notificación de las enfermedades antes y después de 12 intervenciones del PUC del 2013 al 2014.Resultados: Se observó un aumento estadísticamente significativo de la notificación de las enfermedades después de siete campañas de vacunación colectiva, el cual se mantuvo durante 6 meses. En las cinco intervenciones restantes de menor escala no se observaron efectos considerables.Conclusión: El progreso observado incluso después de intervenciones a corto plazo, por una parte, pone de manifiesto que los actores externos en situaciones de emergencia pueden inducir modificaciones positivas del sistema mediante sus actividades puntuales y, en segundo lugar, destaca la necesidad urgente de invertir en el sistema de vigilancia sanitaria a nivel periférico.

BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability.

Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a T-cell leukaemia line), which lacked detectable BAX expression. Apoptosis of DG75 cells induced by low serum or ionomycin was significantly delayed relative to similar Burkitt lymphoma cell lines with normal BAX levels. Although DG75 and Jurkat cells expressed several BAX RNA species including the prototypical BAX alpha RNA, the absence of BAX protein was due to single base deletions and additions in a polyguanine tract within the BAX open reading frame. These frameshift mutations result in premature termination of translation and have recently also been identified in some colon cancers with microsatellite instability. Although mismatch repair defects are not considered a common feature of haemopoietic malignancies, DG75 and Jurkat cells had widespread microsatellite instability and did not express detectable levels of MSH2. In Jurkat cells, lack of MSH2 expression was due to a point mutation in exon 13 of MSH2 resulting in premature termination of translation. Our results suggest that a pathway linking mismatch repair defects, BAX tumour suppressor frameshift mutations and resistance to apoptosis may be a key feature of some lymphomas and leukaemias.

Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13.

A small proportion of breast cancer is attributable to the inheritance of dominant, high penetrance susceptibility genes. One of these genes, BRCA2, has recently been localised by genetic linkage analysis to chromosome 13q12-13. This is a region known to exhibit loss of heterozygosity in 20-40% sporadic breast cancers. In this study, we have examined cancers from a family showing strong evidence of linkage to BRCA2. LOH was seen in seven out of eight informative cancers. In all cases the allele lost was the wild type allele that does not segregate with the disease in the family. The data suggest that both alleles of BRCA2 are inactivated in cancers, the pattern expected of a recessive oncogene or tumour suppressor gene.

Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22.

Several recent studies indicate that the majority of families with five or fewer cases of breast cancer and no cases of ovarian cancer are not due to BRCA1 or BRCA2. It has been proposed that a further breast cancer susceptibility gene that may account for some of these families is located on chromosome 8p12-p22. We have identified 31 site-specific breast cancer families that have a greater than 80% posterior probability of being due to genes other than BRCA1 or BRCA2. These families have been examined for linkage to 8p12-p22 using markers flanking the putative location of the gene. The overall multi-point LOD score is strongly negative across the whole 44 cM. The individual multi-point LOD score is negative in 23 families and only exceeds 0.5 in a single family (with a multi-point LOD score of 1.22). The maximum heterogeneity LOD score was 0.03 at marker D8S136 with estimated proportion linked (alpha) of 3% (95% CI 0 - 30%). These data do not lend support to the hypothesis that chromosome 8p12-p22 harbours a familial breast cancer susceptibility gene. Oncogene (2000) 19, 4170 - 4173

Reversibility and pathohistological basis of left ventricular remodeling in hibernating myocardium.

The phenomenon of left ventricular (LV) remodeling with dilatation, wall thinning, and increased muscle mass has previously been reported in pigs with 7-day myocardial hibernation. This study investigated cellular and extracellular basis and reversibility of the structural LV remodeling with hibernating myocardium. Five groups of pigs were included: Group A: 7-day myocardial hibernation with a fixed coronary stenosis; Group B: 7-day hibernation with subsequent 3-week reperfusion by release of the stenosis; Group C: control group with sham operation; Group D: 24-hour myocardial hibernation to define structural mechanism of initial wall thinning in the hibernating region without confounding factors of cell loss or hypertrophy, Group E: 4-week myocardial hibernation to exclude the possibility of spontaneous regression of LV remodeling with hibernation. LAD flow decreased by 38+/-12% (p<0.01) with a significant decrease in systolic wall thickening at 7 days of hibernation with severe coronary stenosis (Group A). End-diastolic wall thickness decreased by 19% (p<0.01) accompanied by a decrease in myocyte number across the wall (44%) and in myocyte density (24%), a significant increase in myocyte width (17%), a mild increase in interstitial tissues in hibernating region, and significant increases in LV diastolic volume and in LV mass at 7 days. After reperfusion (Group B), LV volume decreased, LV ejection fraction improved, and myocyte hypertrophy regressed with a decreased LV mass index without a significant change in interstitial tissue. LV remodeling progressed with further increases in LV volume, mass, and interstitial fibrosis in 4-week hibernation. In pigs undergoing 24 hours of myocardial hibernation (Group D), end-diastolic LV wall thickness decreased significantly in the hibernating region with a proportional decrease in the transmural myocyte number but without changes in myocyte width, myocyte density, or interstitial tissues. Therefore, progressive gross LV remodeling associated with hibernating myocardium is accompanied by increasing myocyte hypertrophy and interstitial fibrosis. In hibernating myocardial region, wall thinning is proportional to a decreased myocyte number across the LV wall, indicating slippage of myocytes as a preponderant mechanism for the wall thinning. Myocyte hypertrophy develops within 7 days in hibernating myocardium, causing an increase in LV mass. These changes are partially reversible after reperfusion.

Impact of delayed reperfusion of myocardial hibernation on myocardial ultrastructure and function and their recoveries after reperfusion in a pig model of myocardial hibernation.

UNLABELLED: This study examined the effect of delayed reperfusion of myocardial hibernation from 24 hours to 7 days on myocardial ultrastructural and functional changes and their recoveries after reperfusion. BACKGROUND: We have previously shown in pigs that after reperfusion the functional and structural alterations in short-term myocardial hibernation which was reperfused in 24 hours can recover in 7 days. The effect of delayed reperfusion of hibernating myocardium on the extent and severity of cellular and extracellular structural changes of hibernating myocardium, and their recoveries after reperfusion is not known. METHODS AND RESULTS: A severe LAD stenosis was created in 27 pigs, reducing resting flow by 30-40% immediately after placement of the stenosis and producing acute ischemia as evidenced by regional lactate production, a decrease in regional coronary venous pH, reduced regional wall thickening (from 38.5 +/- 5.1% to 10.4 +/- 8.0%) and a 33% reduction of regional oxygen consumption. The stenosis was maintained either for 24 hours in 9 pigs (group 1) with LAD flow of 0.65 +/- 0.13 ml/min/g (38% reduction), or for 7 days in 17 pigs (group 2) with LAD flow of 0.67 +/- 0.14 ml/min/g (36% reduction). There were no differences (p = NS) in the reduction of wall thickening, rate-pressure product, lactate production, or regional oxygen consumption between group 1 and group 2. Quantitative morphometric evaluation of the ultrastructure on electromicrographs revealed a greater decrease in sarcomere volume and a higher incidence of myocytes with reduced sarcomere volume in 7-day than in 24-hour hibernating regions (53 +/- 19% versus 33 +/- 14%, p < 0.05). Patchy myocardial necrosis with replacement fibrosis was common, but 6 of the 18 pigs had no myocardial necrosis or replacement fibrosis in the 7-day hibernating group, and 4 of 9 pigs had no patchy myocyte necrosis in the 24 hour hibernating group. In 6 pigs in group 1 in which the stenosis was then released and hibernating myocardium reperfused in 24 hours, regional wall thickening recovered to 30 +/- 6% (p = NS compared to baseline) after one week of reperfusion. In 12 pigs in group 2 in which the stenosis was released and hibernating myocardium reperfused in 7 days, regional wall thickening recovered slowly, from 10.1 +/- 7.2% to 18.1 +/- 8.3% at one week (n = 5) and to 28.0 +/- 3.6% at 3-4 weeks of reperfusion (n = 7, p < 0.05 compared to baseline). Similarly, the sarcomere volume or myofilament recovered significantly (p < 0.01) and was not different compared to the normal region (p = NS) in the 24-hour hibernating region of group 1, but the recovery was much slower and was incomplete at 4 weeks (p < 0.01) compared to baseline in the 7-day hibernating region of group 2. Recovery of regional wall thickening correlated with ultrstructural recovery (p < 0.01). By multivariate stepwise regression analysis, the degree of LAD flow reduction, the extent of fibrosis, and myofilament loss were independent predictors of the extent of functional recovery. CONCLUSIONS: In a porcine model of myocardial hibernation with myocardial hypoperfusion, systolic dysfunction, and metabolic adaptations, a longer period of myocardial hibernation with delayed reperfusion was associated with more severe abnormalities of myocytes. an increasing interstitial fibrosis, and more protracted myofibrillar and functional recoveries after reperfusion. The extent of functional recovery is related to the degree of coronary flow reduction, the severity of the ultrastructural changes, and the extent of interstitial fibrosis.

"Diverticula" of anterior mitral valve leaflet as a cause of subvalvular aortic stenosis.

A 77-year-old male patient presented with symptoms of shortness of breath, fatigue, chest pain on exertion and dizziness. Transthoracic echocardiography suggested the presence of a diaphragmatic type of obstruction in the subaortic area of the left ventricular outflow tract. The systolic peak gradient at rest was 34 mmHg with a mean of 23 mmHg. Cardiac catheterization demonstrated rounded radiolucencies in the left ventricular outflow tract in the form of two "pouches" that moved back and forth causing subaortic stenosis. There was also a 70% stenosis of the left anterior descending coronary artery. Left ventricular function was normal. At surgery, a transesophageal echocardiogram demonstrated two distinct pouches arising from the anterior leaflet of the mitral valve. The larger of the two originated near the free edge of the leaflet and was attached via a chord to the membranous septum traversing the subaortic area of the left ventricular outflow tract. The patient underwent a left internal mammary to left anterior descending bypass graft, excision of the larger pouch and over-sewing of the smaller pouch. The excision and repair were performed through the aortic root and aortic valve. The patient made an uncomplicated recovery and on follow up his symptoms disappeared. This case shows the excellent results that can be obtained by surgery of diverticula of the mitral valve causing intermittent subaortic stenosis, a rare pathologic entity, morphologically different from the classical diaphragmatic subaortic stenosis.

Lupus-related mitral valve disease: embolic coronary occlusion as a unique cause of myocardial infarction.

Early diagnosis and greatly improved treatment have markedly altered the clinical evolution of systemic lupus erythematosus; the pattern of cardiac involvement in lupus has also changed. To illustrate this, a young woman who died from severe mitral valve disease, including a coronary embolus from verrucous endocarditis, is presented. Mitral valve involvement in lupus is no longer limited to the small benign lesions described by Libman and Sacks.

Pigeon-breeder's lung. Extensive workup clarifies the clinical picture.

Pigeon-breeder's lung should be included in the differential diagnosis when patients present with interstitial lung disease or intermittent cough and dyspnea. No single test confirms the diagnosis. Rather, careful attention must be given to results of history taking, physical examination, pulmonary function and precipitin testing, chest radiography, and, if indicated, lung biopsy. Symptoms usually resolve when exposure to suspected antigens is avoided.