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Background: Lower survival rates for many cancer types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific manner. Hypothesizing that such changes might confer an advantage to tumor cells, we aimed at the identification of commercially available compounds to guide further mechanistic studies. We therefore screened for Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved compounds that reverse the direction of characteristic tumor nuclear size changes in PC3, HCT116, and H1299 cell lines reflecting, respectively, prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer. Results: We found distinct, largely nonoverlapping sets of compounds that rectify nuclear size changes for each tumor cell line. Several classes of compounds including, e.g., serotonin uptake inhibitors, cyclo-oxygenase inhibitors, β-adrenergic receptor agonists, and Na +/K + ATPase inhibitors, displayed coherent nuclear size phenotypes focused on a particular cell line or across cell lines and treatment conditions. Several compounds from classes far afield from current chemotherapy regimens were also identified. Seven nuclear size-rectifying compounds selected for further investigation all inhibited cell migration and/or invasion. Conclusions: Our study provides (a) proof of concept that nuclear size might be a valuable target to reduce cell migration/invasion in cancer treatment and (b) the most thorough collection of tool compounds to date reversing nuclear size changes specific to individual cancer-type cell lines. Although these compounds still need to be tested in primary cancer cells, the cell line-specific nuclear size and migration/invasion responses to particular drug classes suggest that cancer type-specific nuclear size rectifiers may help reduce metastatic spread.

Computer-aided design and manufacturing of custom-made elastomer implants leads from a CT scan to fill in with precision, a congenital chest wall congenital deformity, both bone (pectus excavatum) and muscle (Poland Syndrome), resulting in a natural repositioning of the breasts. We report our 25 years' experience in 301 women (234 Pectus+64 Poland). Parietal correction must always be done in first intention. It is common to have to carry out a second stage in women with an additional mammaplasty especially in the presence of insufficient glandular volume or a fairly frequently associated tuberous breast.

OBJECTIVE: Cervical esophagogastric anastomosis (CEA) is a common procedure used to restore the continuity of the digestive tract following curative or palliative surgery for esophageal cancer. At the HCPA, we carry out CEA procedures in two steps: first, we carry out a lateral cervical esophagostomy and position the esophageal substitute in the neck; second, after one week, the esophageal remnant is sutured to the esophageal substitute. The choice of esophageal substitute is made according to gastric pull-up (GP) or greater curvature gastric tube (GCGT), depending on the possibility of resection of the lesion. The objective of this paper is to describe the early results (up to 30 days) of delayed cervical esophagogastric anastomosis after resection or esophageal bypass procedures due to esophageal neoplasia. MATERIAL AND METHODS: Fifty-nine patients fulfilled the criteria for inclusion in our study, out of which there were 49 male and 55 white patients; the age average was of 51.5 years. Twenty-two patients were submitted to gastric pull-up. The risk factors for postoperative complications were similar for both groups. Tumor staging was the only difference between the two groups in preoperative examination; this difference was expected according to the criteria used for choosing the procedure. RESULTS: Seven patients (31.8%) of the GP group and in 9 patients (34.3%) from the GCGT group (RR 1.3; CI 95%: 0.5-3.0, P = 0.54) presented leakage. Two patients (9.1%) from the GP group and 1 (2.7%) from the GCGT group died (RR 3.4; CI 95%: 0.3-34.9, P = 0.54). One patient (4.5%) from the GP group and 7 (18.9%) patients from the GCGT group (RR 0.2; CI 95%: 0.1-1.8, P = 0.23) presented infections. There were no differences between the groups regarding occurrence of leakage, short-term postoperative death (until 30 days after surgery), and infections. CONCLUSIONS: Our results are similar to those of other services of reference for the treatment of esophageal cancer. In this study, we did not find any differences between the GP and GCGT groups regarding short-term postoperative complications., OBJETIVO: A anastomose esofagogástrica cervical é um procedimento utilizado para restaurar a continuidade do trato digestivo após cirurgias curativas ou paliativas para o câncer esofágico. O Grupo de Cirurgia do Esôfago, Estômago e Intestino Delgado do Hospital de Clínicas de Porto Alegre realiza o procedimento em 2 tempos cirúrgicos. No primeiro tempo, realiza-se uma esofagostomia cervical lateral e posiciona-se o substituto esofágico no pescoço. O segundo tempo é realizado uma semana após, com a sutura do esôfago remanescente no substituto elevado ao pescoço. Este substituto é escolhido entre os procedimentos de levantamento gástrico (LG) e tubo gástrico de grande curvatura (TGC), conforme a possibilidade ou não de ressecção da lesão esofágica. O objetivo do presente trabalho é de descrever os resultados precoces (até 30 dias) obtidos com a realização de anastomose esôfago-gástrica cervical retardada (postergada) após procedimento cirúrgico de ressecção ou bypass esofágico por neoplasia de esôfago. MATERIAIS E MÉTODOS: Cinqüenta e nove pacientes preencheram os critérios de inclusão, sendo 49 homens, 55 brancos, com uma média de idade de 51,5 anos. Vinte e dois pacientes realizaram cirurgia de levantamento gástrico. Os fatores de risco conhecidos para complicações pós-operatórias foram similares entre os dois grupos. A única diferença entre os grupos na avaliação pré-operatória foi o estágio do tumor, o que era esperado, tendo em vista os critérios usados para a escolha do procedimento. RESULTADOS: A fístula cervical foi detectada em sete pacientes (31,8%) do grupo LG e em nove pacientes (34,3%) do grupo TGC (RR 1,3; IC 95%: 0,5-3,0, P = 0.54). Dois pacientes (9,1%) do grupo LG e um paciente (2,7%) do grupo TGC foram a óbito (RR 3,4; IC 95%: 0,3-34,9, P = 0,54). As complicações infecciosas ocorreram em um paciente (4,5%) do grupo LG e 7 pacientes (18,9%) do grupo TGC (RR 0,2; IC 95%: 0,1-1,8, P = 0,23). Não houve diferenças entre os grupos, levando em conta a ocorrência de fístula cervical no pós-operatório, mortalidade hospitalar precoce (30 dias após a cirurgia) e infecções. CONCLUSÕES: Os dados apresentados nesta série são semelhantes a outros serviços de referência para o tratamento do câncer de esôfago, e nessa série não houve diferença entre os LG e TGC em relação às complicações no pós-operatório precoce.

INTRODUCTION: The correction of groin hernias using a transperitoneal videolaparoscopic method with a polypropylene mesh is becoming increasingly common. This could lead to an increased incidence of adhesion formation.MATERIALS AND METHODS: The incidence of adhesions induced by mesh placement and by reperitonization was observed in 40 male adult Wistar rats, randomlyallocated to four groups of 10 rats (Group A = no mesh, no reperitonization; B = no mesh, reperitonization; C = mesh, no reperitonization; D = mesh and reperitonization). After opening the abdominal cavity, the iliac fossa was identified and a peritoneal opening, measuring about 2 by 2 cm, was done on the parietal wall. In the rats in which a polypropylene prosthesis was used, a piece of Marlex mesh, measuring about 1.5 by 1.5 cm was placed on the peritoneal opening. A simple suture was performed in the animals submitted to reperitonization, using a 5.0 monofilamentar polypropylene thread on a cardiovascular (atraumatic) needle. The animals were killed 15 days after the operation. Macroscopic analysis was done by an investigator blinded to intervention group. Fisher’s exact test and the c2 test were used for statistical analysis of the results. A P < 0.05 was considered as significant.RESULTS: Adhesions were significantly more common in the groups in which the prosthesis was placed (59% vs. 95%; P = 0.01), as well as in the groups in whichreperitonization was performed (58% vs. 100%; P = 0.03).CONCLUSIONS: The results suggest that polypropylene mesh placement and reperitonization are each independent factors that have a role in inducing the formationof adhesions., INTRODUÇÃO: A correção de hérnias na virilha através de um método videolaparoscópico transperitoneal está se tornando cada vez mais comum. Contudo,este método poderia levar a um aumento na incidência de formação de aderências.MATERIAIS E MÉTODOS: A incidência de aderências induzidas pela colocação de retícula e pela reperitonização foram observadas em 40 ratos Wistar adultos, machos, divididos aleatoriamente em quatro grupos com 10 ratos cada um (Grupo A = sem retícula, sem reperitonização; B = sem retícula, com reperitonização; C = com retícula, sem reperitonização; D = retícula e reperitonização). Após a abertura da cavidade abdominal, a fossa ilíaca foi identificada e fez-se uma abertura de aproximadamente 2 x 2 cm na parede parietal. Nos ratos em que uma prótese de polipropileno foi utilizada, uma retícula Marlex com 1,5 x 1,5 cm foi colocada sobre a abertura peritoneal. Nos outros animais, a reperitonização foi feita com sutura simples, utilizando-se fio de polipropileno monofilamentar 5.0 com uma agulha cardiovascular (atraumática). Os animais foram sacrificados 15 dias depois da operação. A análise macroscópica foi realizada por um investigador cego quanto ao grupo de origem dos animais. A análise estatística utilizou o teste exato de Fisher e o c2. Um P < 0,05 foi considerado significativo.RESULTADOS: As aderências foram significativamente mais comuns nos grupos nos quais a prótese foi utilizada (59% vs. 95%; P = 0,01), assim como nos gruposnos quais foi feita a reperitonização (58% vs. 100%; P = 0,03). CONCLUSÕES: Os resultados sugerem que a retícula de polipropileno e a reperitonização são fatores independentes entre si quanto à indução de formaçãode aderências.

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes find its pathomechanism were unavailing, so we here engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in 7 genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling, and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism, and myogenic signaling pathways. This pathway approach revealed a clear EDMD signature that can both be used as the basis for establishing a biomarker panel specific to EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into three distinct categories that appear to correlate with clinical presentation may be developed into prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.

After cochlear implantation, auditory and speech training is usually necessary. Up until now, this has been performed on an out- or inpatient basis in direct contact with a therapist. Due to technical advances but also particularly because of an increasing use of digital media and a desire for mobility and independence, the demand for digital training programs is increasing in the field of hearing rehabilitation.In a first step, the most important elements of auditory training were determined on the basis of commonly used auditory and speech processing models, and the core features of a computer-based teletherapeutic hearing platform were defined. This process considered motivational elements and adaptive mechanisms as regularly used in educational and speech and language therapy. In a second step, an initial prototype of the "train2hear" teletherapeutic hearing platform was developed by an interdisciplinary research team.The core of the train2hear platform is an initial analysis according to the International Classification of Functioning, Disability, and Health (ICF), on the basis of which an individual training plan is designed. Various adaptive mechanisms enable the level of difficulty to be continually adapted to the individual user's learning progress. A videoconference tool enables contact between the patient and the therapist.The train2hear platform represents a first prototype of a computer-based auditory rehabilitation program in German. Further evaluation and development in a clinical study are needed to determine the feasibility and efficacy of the platform.EINLEITUNG: Nach einer Cochleaimplantation (CI) ist i.d.R. ein Hör- und Sprachtraining erforderlich, das bislang entweder ambulant oder stationär im direkten Kontakt mit einem Therapeuten erfolgt. Bedingt durch technische Weiterentwicklungen, aber vor allem durch die zunehmende Nutzung digitaler Medien und dem Wunsch nach Mobilität und Selbständigkeit steigt der Bedarf an digitalen Trainingsprogrammen auch im Rahmen der Hörrehabilitation.In einem ersten Schritt wurden entsprechend den gängigen Hör- und Sprachverarbeitungsmodellen die wichtigsten Elemente eines Hörtrainings definiert und die Kernbausteine für eine computerbasierte teletherapeutische Hörplattform bestimmt. Dabei wurden lerntherapeutisch orientierte Elemente der Motivationsförderung sowie Mechanismen der Adaptivität, wie sie im Rahmen der logopädischen Therapie eingesetzt werden, berücksichtigt. In einem zweiten Schritt erfolgte die Entwicklung eines ersten Prototyps der teletherapeutischen Hörplattform „train2hear“ im Rahmen eines interdisziplinären Forschungsprojektes.Kernbaustein des vorgestellten „train2hear“ Hörtrainings ist eine an die „International Classification of Functioning, Disability, and Health“ (ICF) angelehnte Eingangsanalyse, aufgrund derer ein individueller Trainingsplan erstellt wird. Verschiedene Adaptivitätsmechanismen dienen dazu, den Schwierigkeitsgrad kontinuierlich an den individuellen Lernfortschritt des Nutzers anzupassen. Ein teletherapeutisches Videotool ermöglicht den Austausch mit dem Therapeuten vor Ort.Die vorgestellte Plattform „train2hear“ stellt einen ersten deutschsprachigen Prototyp einer computerbasierten Hörrehabilitation dar. Dieser muss nun im Rahmen einer klinischen Studie im Hinblick auf die Anwendbarkeit und Effektivität evaluiert und weiterentwickelt werden.

Die Digitalisierung ist mittlerweile im Alltag, auch der Alteren, angekommen. Die Horrehabilitation nach Cochleaimplantation (CI) findet in Deutschland jedoch meist noch vor Ort in spezialisierten Zentren statt. In den vergangenen Jahren erschienen zahlreiche computerbasierte Hortrainingsprogramme (CBAT) v. a. fur Horgerate-, aber auch einzelne fur CI-Trager. Die vorliegende Arbeit soll einen Uberblick uber derzeit verfugbare CBAT sowie ihre Wirksamkeit geben. Englisch- und deutschsprachige CBAT fur erwachsene CI-Trager wurden in einer auf Google basierten Suche und in Programmen im App Store und Play Store recherchiert und im Hinblick auf Therapieinhalte und die Programmgestaltung analysiert. Anschliesend erfolgte eine systematische Literaturrecherche von 2000 bis 2019 zu Studien uber CBAT fur erwachsene CI-Trager in den Datenbanken PubMed, LIVIVO und Google Scholar. Meist sind die vorliegenden CBAT als zusatzliches Therapieangebot zur bestehenden face-to-face Therapie konzipiert. Die Programminhalte unterscheiden sich vor allem hinsichtlich der Aufgabenkomplexitat und -quantitat, der grafischen Gestaltung, der zeitlichen Vorgabe und des Endgerates. Im Gegensatz zu den deutschsprachigen weisen die englischen Programme zum Teil bereits gute Adaptivitats- und Feedbackkonzepte auf. Wissenschaftliche Untersuchungen zur Effektivitat liegen uberwiegend zu den englischsprachigen und meist nur zu einzelnen Therapiemodulen vor. Allen Untersuchungen gemeinsam ist eine kurzzeitige Verbesserung auditiver Teilfunktionen nach dem Training. Die Studienqualitat ist jedoch bislang als gering einzustufen, Follow-up-Untersuchungen finden sich nur in zwei Fallen. CBAT konnten eine Moglichkeit der Horrehabilitation von CI-Patienten sein. Derzeit fehlt es im deutschsprachigen Raum jedoch noch an Trainingsplattformen, die als Alternative zur Therapie vor Ort konzipiert sind. Auch liegen keine groseren Wirksamkeitsstudien zu Kurz-, Langzeit- sowie Transfereffekten vor.

Tissue-specific patterns of radial genome organization contribute to genome regulation and can be established by nuclear envelope proteins. Studies in this area often use cancer cell lines, and it is unclear how well such systems recapitulate genome organization of primary cells or animal tissues; so, we sought to investigate radial genome organization in primary liver tissue hepatocytes. Here, we have used a NET47/Tm7sf2–/– liver model to show that manipulating one of these nuclear membrane proteins is sufficient to alter tissue-specific gene positioning and expression. Dam-LaminB1 global profiling in primary liver cells shows that nearly all the genes under such positional regulation are related to/important for liver function. Interestingly, Tm7sf2 is a paralog of the HP1-binding nuclear membrane protein LBR that, like Tm7sf2, also has an enzymatic function in sterol reduction. Fmo3 gene/locus radial mislocalization could be rescued with human wild-type, but not TM7SF2 mutants lacking the sterol reductase function. One central pathway affected is the cholesterol synthesis pathway. Within this pathway, both Cyp51 and Msmo1 are under Tm7sf2 positional and expression regulation. Other consequences of the loss of Tm7sf2 included weight gain, insulin sensitivity, and reduced levels of active Akt kinase indicating additional pathways under its regulation, several of which are highlighted by mispositioning genes. This study emphasizes the importance for tissue-specific radial genome organization in tissue function and the value of studying genome organization in animal tissues and primary cells over cell lines.

Loss of Nemp leads to softening of the germline nuclear envelope and loss of fertility., Human genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in NEMP1 (nuclear envelope membrane protein 1) with early menopause; however, it is unclear whether NEMP1 has any role in fertility. We show that whole-animal loss of NEMP1 homologs in Drosophila, Caenorhabditis elegans, zebrafish, and mice leads to sterility or early loss of fertility. Loss of Nemp leads to nuclear shaping defects, most prominently in the germ line. Biochemical, biophysical, and genetic studies reveal that NEMP proteins support the mechanical stiffness of the germline nuclear envelope via formation of a NEMP-EMERIN complex. These data indicate that the germline nuclear envelope has specialized mechanical properties and that NEMP proteins play essential and conserved roles in fertility.

Digitalization has become a part of everyday life and digital applications offer an opportunity to promote health. In Germany, hearing rehabilitation after cochlear implantation (CI) typically takes place in specialized audiology centers. However, a variety of new auditory training programs have been developed and although most are for hearing aid users, some are suitable for CI patients. The purpose of this study is to give an overview of CBAT schedules and their effectiveness.Currently available English and German CBAT programs for adult CI users identified in searches of Google, Google App Store, and Google Play Store were analyzed. A systematic literature search on studies dealing with CBAT in adult CI recipients from 2000 to 2019 was performed in PubMed, LIVIVO, and Google Scholar.German and English CBAT for adult hearing aid and CI users are generally intended to complement face-to-face therapies. The content of the programs differs primarily in terms of complexity and quantity of tasks, graphic design, allowed time and the device used. In contrast to the nine available German programs, some of the English CBAT include advanced concepts of adaptivity and feedback. Studies on the effectiveness of CBAT have mainly been conducted for the English versions and generally analyze only individual therapeutic subfunctions. All investigations show a short-term improvement of the auditory subfunction shortly after training. Unfortunately, the quality of the studies is low and follow-up results are only available in two cases.CBAT programs might be an effective option for auditory rehabilitation in CI patients. However, suitable German-language programs conceived as an alternative to face-to-face training and studies on longterm effects of CBAT are still lacking.HINTERGRUND: Die Digitalisierung ist mittlerweile im Alltag, auch der Älteren, angekommen. Die Hörrehabilitation nach Cochleaimplantation (CI) findet in Deutschland jedoch meist noch vor Ort in spezialisierten Zentren statt. In den vergangenen Jahren erschienen zahlreiche computerbasierte Hörtrainingsprogramme (CBAT) v. a. für Hörgeräte-, aber auch einzelne für CI-Träger. Die vorliegende Arbeit soll einen Überblick über derzeit verfügbare CBAT sowie ihre Wirksamkeit geben.Englisch- und deutschsprachige CBAT für erwachsene CI-Träger wurden in einer auf Google basierten Suche und in Programmen im App Store und Play Store recherchiert und im Hinblick auf Therapieinhalte und die Programmgestaltung analysiert. Anschließend erfolgte eine systematische Literaturrecherche von 2000 bis 2019 zu Studien über CBAT für erwachsene CI-Träger in den Datenbanken PubMed, LIVIVO und Google Scholar.Meist sind die vorliegenden CBAT als zusätzliches Therapieangebot zur bestehenden face-to-face Therapie konzipiert. Die Programminhalte unterscheiden sich vor allem hinsichtlich der Aufgabenkomplexität und -quantität, der grafischen Gestaltung, der zeitlichen Vorgabe und des Endgerätes. Im Gegensatz zu den deutschsprachigen weisen die englischen Programme zum Teil bereits gute Adaptivitäts- und Feedbackkonzepte auf. Wissenschaftliche Untersuchungen zur Effektivität liegen überwiegend zu den englischsprachigen und meist nur zu einzelnen Therapiemodulen vor. Allen Untersuchungen gemeinsam ist eine kurzzeitige Verbesserung auditiver Teilfunktionen nach dem Training. Die Studienqualität ist jedoch bislang als gering einzustufen, Follow-up-Untersuchungen finden sich nur in zwei Fällen.CBAT könnten eine Möglichkeit der Hörrehabilitation von CI-Patienten sein. Derzeit fehlt es im deutschsprachigen Raum jedoch noch an Trainingsplattformen, die als Alternative zur Therapie vor Ort konzipiert sind. Auch liegen keine größeren Wirksamkeitsstudien zu Kurz-, Langzeit- sowie Transfereffekten vor.

Interdigitated, screen-printed platinum microelectrodes are used for non-Faradaic impedance spectroscopy detection of viable Saccharomyces cerevisiae . The time dependence of the complex impedance of both living and heat-inactivated yeast cells immersed in plain medium or immobilized in agar is measured between 0.01 Hz and 1 MHz for 300 min. To understand the processes probed by the impedance measurement, an equivalent electrical circuit, containing a constant phase element, a charge transfer resistance and a suspension resistance, is established and analyzed. For both heat-inactivated and living yeast cells in plain medium, the suspension resistance increases over time caused by sedimentation of the yeast cells into the stray field of the electrodes. The measured increase is found to be larger for living cells than for heat-inactivated ones. The time dependence of the double-layer capacitance is rather dominated by the metabolic activity of living cells, but a possible impact of cell sedimentation cannot be completely neglected. In experiments carried out with cells immobilized in agar, cell sedimentation is suppressed, and thus, the time evolution of the double-layer capacitance is solely caused by metabolic active cells. Therefore, the time-dependent change of the double-layer capacitance can be used to directly monitor the viability of Saccharomyces cerevisiae in situ , since inactivated cells do not contribute to the signal generation in this case.

Nuclear size normally scales with the size of the cell, but in cancer this ‘karyoplasmic ratio’ is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types.

Lower survival rates for many cancer types correlate with increases or decreases in nuclear size/scaling in a tumor-type/tissue-specific manner. Postulating that nuclear size changes confer a fitness advantage on tumor cells, we screened for FDA/EMA-approved compounds that reverse tumor nuclear size changes in cell lines from three such tumor types: prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer. We found distinct, largely non-overlapping sets of compounds that either rectify or exacerbate nuclear size changes for each tumor type. Nuclear size phenotypes across cell lines clustered particular classes of compounds including serotonin uptake inhibitors, cyclo-oxygenase inhibitors, beta-adrenergic receptor agonists, monoamine oxidase inhibitors, and Na+/K+ATPase inhibitors. Nearly all compounds selected for further investigation inhibited cell migration and/or invasion, suggesting that targeting nuclear size control pathways in chemotherapy regimens could improve patient survival.

Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation. Methods: A primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates — other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype. Findings: Twenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation. Interpretation: Our multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases. Funding: The Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)”. Keywords: Emery-Dreifuss muscular dystrophy, Nuclear envelope, Nuclear envelope transmembrane protein, primer library, Orphan disease