Ergebnis der selektiven Verpaarung beim Entlebucher Sennenhund zur Reduktion der ureteralen Ektopie

Outcome of selective mating in the Entlebucher Mountain Dog for reduction of ureteral ectopia The Entlebucher Mountain Dog is predisposed to ureteral ectopia and associated diseases of the urinary tract as well as the kidneys, which can have severe to lethal consequences. Due to the clustered occurrence of clinical signs in 11 % of Entlebucher Mountain dogs in the absence of a genetic test for ureteral ectopia, screening was introduced in 2008 to allow phenotype-based breeding selection. The ureteral orifices of the dogs are visualized by ultrasound and existing urinary retention or urinary incontinence is documented. The diagnostic findings were evaluated centrally with assignment to one of five phenotypes depending on the localization of the ureteral orifices and the renal and ureteral shape. Breeding approval and mating restrictions are the responsibility of the respective breeding associations and predominantly Entlebucher Mountain Dogs with extravesical ectopic ureters and/or clinical signs were excluded from breeding. The effect of phenotype-based selective mating on the incidence of ureteral ectopia and its clinical signs, as well as possible factors influencing the expression of the phenotype, were determined in the birth cohorts after the introduction of screening. Analysis of the data set of 1456 phenotyped Entlebucher Mountain Dogs showed, that at 11 % versus 5 %, males were more frequently assigned to the extravesical phenotype than females. The effect of phenotype-based breeding selection was examined in a subpopulation consisting of phenotyped parents and their offspring (n = 876). The prevalence of the extravesical phenotype decreased from 24 % in the 2005 to 2007 birth cohorts to 1,4 % in the 2015 to 2017 birth cohorts. Since 2015 almost no Entlebucher Mountain Dogs with incontinence, hydroureter or hydronephrosis have been recorded. It was feared that the additional selection measures to control ureteral ectopia in the small Entlebucher Mountain Dog population would intensify the inbreeding increase. However, this has so far remained absent. Therefore, as long as no genetic test is available, it is recommended to continue phenotype-based breeding selection with exclusion of dogs with extravesical ureteral ectopia and/or hydroureter/hydronephrosis/urinary incontinence, while keeping an eye on the development of the inbreeding coefficient. Keywords: Ectopic ureter, Dog, Inbreeding, Phenotype, Breeding selection Deutsch Ergebnis der selektiven Verpaarung beim Entlebucher Sennenhund zur Reduktion der ureteralen Ektopie Der Entlebucher Sennenhund ist prädisponiert für die ureterale Ektopie und damit für assoziierte Erkrankungen der Harnwege sowie der Nieren, was schwerwiegende bis letale Folgen haben kann. Aufgrund des gehäuften Auftretens klinischer Symptome bei 11 % der Entlebucher Sennenhunde wurde in Ermangelung eines Gentests auf ureterale Ektopie 2008 ein Screening eingeführt, um eine Phänotyp-basierte Zuchtselektion zu ermöglichen. Die Uretermündungen der Hunde werden in der Regel mittels Ultraschall lokalisiert und bestehender Harnrückstau oder Harninkontinenz wird dokumentiert. Die Befundung erfolgte zentral mit einer Zuordnung zu einem von fünf Phänotypen in Abhängigkeit von der Lokalisation der Uretermündungen sowie der Nieren – und Ureterengestalt. Die Zuchtzulassung und Verpaarungsbeschränkungen obliegen den jeweiligen Zuchtverbänden, wobei überwiegend Entlebucher Sennenhunde mit extravesikal ektopischen Ureteren und/oder klinischen Symptomen von der Zucht ausgeschlossen wurden. Die Auswirkung der Phänotyp-basierten selektiven Verpaarung auf das Auftreten der ureteralen Ektopie und deren klinischen Symptome sowie mögliche Einflussfaktoren auf die Ausprägung des Phänotyps wurden in den Geburtsjahren nach Einführung des Screenings ermittelt. Die Analyse des Datensatzes mit 1456 phänotypisierten Entlebucher Sennenhunden zeigte, dass mit 11 % versus 5 % Rüden häufiger als Hündinnen dem extravesikalen Phänotyp zugeteilt wurden. Die Auswirkung der Phänotyp-basierten Zuchtselektion wurde an einer Teilpopulation, bestehend aus phänotypisierten Elterntieren und ihren Nachkommen (n = 876), untersucht. Die Prävalenz des extravesikalen Phänotyps nahm von 24 % bei den Geburtsjahren 2005 bis 2007 auf 1,4 % bei den Geburtsjahren 2015 bis 2017 ab. Seit 2015 wurden nahezu keine Entlebucher Sennenhunde mehr mit Inkontinenz, Hydroureter oder Hydronephrose erfasst. Befürchtet wurde, dass die zusätzlichen Selektionsmassnahmen zur Bekämpfung der ureteralen Ektopie in der kleinen Entlebucher Sennenhundepopulation den Inzuchtanstieg verstärken würde. Dies blieb bisher jedoch aus. Daher wird, solange kein genetischer Test zur Verfügung steht, empfohlen, die Phänotyp-basierte Zuchtselektion mit Ausschluss von Hunden mit extravesikaler ureteraler Ektopie und/oder Hydroureter/Hydronephrose/Harninkontinenz vorerst weiterzuführen und gleichzeitig die Entwicklung des Inzuchtkoeffizienten im Auge zu behalten. Schlüsselwörter: Ektopischer Ureter, Hund, Inzucht, Phänotyp, Zuchtselektion Français Résultat de l’accouplement sélectif chez le bouvier de l’Entlebuch pour réduire l’ectopie urétérale Le Bouvier de l’Entlebuch est prédisposé à l’ectopie urétérale et aux maladies associées des voies urinaires ainsi que des reins, ce qui peut entraîner des conséquences fatales. En raison de l’apparition de signes cliniques chez 11 % des chiens et en l’absence d’un test génétique pour l’ectopie urétérale, un dépistage a été introduit en 2008 pour permettre une sélection d’élevage basée sur le phénotype. Les orifices urétraux des chiens ont été visualisés par échographie et la rétention ou l’incontinence urinaire existante documentée. Les résultats du diagnostic ont été évalués de manière centralisée avec attribution à l’un des cinq phénotypes en fonction de la localisation des orifices urétéraux ainsi que de la forme des reins et des uretères. L’approbation pour la reproduction et les restrictions d’accouplement relèvent de la responsabilité des associations d’élevage respectives et les bouviers de l’Entlebuch présentant des uretères ectopiques extravésicaux et/ou des signes cliniques ont majoritairement été exclus de la reproduction. L’effet de cet accouplement sélectif basé sur le phénotype sur l’incidence de l’ectopie urétérale et de ses signes cliniques ainsi que les facteurs possibles influençant l’expression du phénotype ont été déterminés dans les cohortes de naissance après l’introduction du dépistage. L’analyse de l’ensemble des données de 1456 Bouviers de l’Entlebuch phénotypés a montré que, à 11 % contre 5 %, les mâles étaient plus fréquemment affectés au phénotype extravésical que les femelles. L’effet de la sélection d’élevage basée sur le phénotype a été examiné dans une sous-population composée de parents phénotypés et de leur progéniture (n = 876). La prévalence du phénotype extravésical est passée de 24 % dans les cohortes de naissance de 2005 à 2007 à 1,4 % dans les cohortes de naissance de 2015 à 2017. Depuis 2015, presque aucun bouvier d’Entlebuch présentant une incontinence, un hydrouretère ou une hydronéphrose n’a été enregistré. Une possible augmentation de la consanguinité due aux mesures de sélection supplémentaires visant à contrôler l’ectopie urétérale ne s’est pas produite. Par conséquent, tant qu’aucun test génétique n’est disponible, il est recommandé de poursuivre la sélection d’élevage basée sur le phénotype avec exclusion des chiens présentant une ectopie urétérale extravésicale et/ou une hydrouretère/hydronéphrose/incontinence urinaire, tout en surveillant l’évolution du coefficient de consanguinité. Mots-clés: auretère ectopique, chien, consanguinité, phénotype, sélection d’élevage Italiano Risultato dell'accoppiamento selettivo nel cane da montagna Entlebuch per ridurre l'ectopia ureterale Il bovaro dell’Entlebuch è predisposto all’ectopia ureterale e quindi alle malattie che sono correlate al tratto urinario e renale con possibili conseguenze letali. A causa della frequente comparsa di segni clinici nell’11 % dei cani e in assenza di un test genetico per l’ectopia ureterale, nel 2008 è stato introdotto uno screening per consentire la selezione fenotipica dei riproduttori. Gli orifizi ureterali dei cani sono solitamente localizzato tramite ecografia e viene documentata la presenza di ritenzione o incontinenza urinaria. I risultati sono stati valutati in modo centralizzato e si è assegnato il risultato a uno dei cinque fenotipi a seconda della localizzazione degli orifizi ureterali e della forma dei reni e degli ureteri. L’autorizzazione all’allevamento e le restrizioni all’accoppiamento sono di competenza delle rispettive associazioni di allevatori e i bovari dell’Entlebuch con ureteri ectopici extravescicali e/o con segni clinici sono stati prevalentemente esclusi dalla riproduzione. L’effetto dell’accoppiamento selettivo, basato sul fenotipo per rapporto all’incidenza dell’ectopia ureterale e dei suoi segni clinici, nonché dei possibili fattori che influenzano l’espressione del fenotipo, è stato determinato nelle coorti di nascita dopo l’introduzione dello screening. L’analisi del set di dati di 1456 bovari dell’Entlebuch fenotipizzati ha dimostrato che, con una percentuale dell’11 % rispetto al 5 %, i maschi erano più frequentemente assegnati al fenotipo extravescicale rispetto alle femmine. L’effetto della selezione riproduttiva basata sul fenotipo è stato esaminato in una subpopolazione composta da genitori fenotipizzati e dalla loro discendenza (n = 876). La prevalenza del fenotipo extravescicale è diminuita dal 24 % nelle coorti di nascita dal 2005 al 2007 all’1,4 % nelle coorti di nascita dal 2015 al 2017. Dal 2015 non sono stati registrati quasi più bovari dell’Entlebuch con incontinenza, idrouretere o idronefrosi. Non si è riscontrato un possibile aumento della consanguineità dovuto alle misure di selezione aggiuntive per controllare l’ectopia ureterale. Pertanto, finché non è disponibile un test genetico, si raccomanda di continuare la selezione fenotipica con l’esclusione dei cani con ectopia ureterale extravescicale e/o idrouretere/idronefrosi/incontinenza urinaria, facendo particolare attenzione all’andamento del coefficiente di consanguineità. Parole chiavi: Uretere ectopico, cane, consanguineità, fenotipo, selezione riproduttiv

A Case Report of Sandhoff Disease

Sandhoff disease is a rare and severe lysosomal storage disorder representing 7% of GM2 gangliosidoses. Bilateral thalamic involvement has been suggested as a diagnostic marker of Sandhoff disease. A case of an 18-month-old infant admitted for psychomotor regression and drug resistant myoclonic epilepsy is presented. Cerebral CT scan showed bilateral and symmetrical thalamic hyperdensity. MRI revealed that the thalamus was hyperintense on T1-weighted images and hypointense on T2-weighted images with a hypersignal T2 of the white matter. Enzymatic assays objectified a deficiency of both hexosaminidases A and B confirming the diagnosis of Sandhoff disease

Early prediction of response to radiotherapy and androgen-deprivation therapy in prostate cancer by repeated functional MRI: a preclinical study

<p>Abstract</p> <p>Background</p> <p>In modern cancer medicine, morphological magnetic resonance imaging (MRI) is routinely used in diagnostics, treatment planning and assessment of therapeutic efficacy. During the past decade, functional imaging techniques like diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI have increasingly been included into imaging protocols, allowing extraction of intratumoral information of underlying vascular, molecular and physiological mechanisms, not available in morphological images. Separately, pre-treatment and early changes in functional parameters obtained from DWMRI and DCEMRI have shown potential in predicting therapy response. We hypothesized that the combination of several functional parameters increased the predictive power.</p> <p>Methods</p> <p>We challenged this hypothesis by using an artificial neural network (ANN) approach, exploiting nonlinear relationships between individual variables, which is particularly suitable in treatment response prediction involving complex cancer data. A clinical scenario was elicited by using 32 mice with human prostate carcinoma xenografts receiving combinations of androgen-deprivation therapy and/or radiotherapy. Pre-radiation and on days 1 and 9 following radiation three repeated DWMRI and DCEMRI acquisitions enabled derivation of the apparent diffusion coefficient (ADC) and the vascular biomarker <it>K</it>^trans, which together with tumor volumes and the established biomarker prostate-specific antigen (PSA), were used as inputs to a back propagation neural network, independently and combined, in order to explore their feasibility of predicting individual treatment response measured as 30 days post-RT tumor volumes.</p> <p>Results</p> <p>ADC, volumes and PSA as inputs to the model revealed a correlation coefficient of 0.54 (p < 0.001) between predicted and measured treatment response, while <it>K</it>^trans, volumes and PSA gave a correlation coefficient of 0.66 (p < 0.001). The combination of all parameters (ADC, <it>K</it>^trans, volumes, PSA) successfully predicted treatment response with a correlation coefficient of 0.85 (p < 0.001).</p> <p>Conclusions</p> <p>We have in a preclinical investigation showed that the combination of early changes in several functional MRI parameters provides additional information about therapy response. If such an approach could be clinically validated, it may become a tool to help identifying non-responding patients early in treatment, allowing these patients to be considered for alternative treatment strategies, and, thus, providing a contribution to the development of individualized cancer therapy.</p

Invasive carcinomas of the male breast: a morphologic study of the distribution of histologic subtypes and metastatic patterns in 778 cases

The current investigation was conducted to evaluate the proportional distribution of the various histologic subtypes (including newly recognized variants) of male breast carcinomas, to determine whether any histologic subtypes occur with a frequency that is markedly discordant with the expected frequencies from published data on parallel female breast tumors. We also aimed to document the distribution of malignancies metastatic to the breast. Seven hundred fifty-nine archived cases of primary invasive carcinoma involving the male breast were retrieved and subcategorized into histologic subtypes according to contemporary criteria. Six hundred forty-three (84.7%) tumors were pure infiltrating ductal carcinoma (IDC) not otherwise specified. The most common of the remainder included papillary carcinoma with invasion in the form of IDC (n = 34), mixed IDC and mucinous carcinoma (n = 26), and pure mucinous carcinoma (n = 21). In 19 cases, metastases from other sites involved the breast, most commonly (58%) cutaneous melanoma. Invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes that is comparable to those of the female breast, with some expected variation. Compared with published experience on their female counterparts, there is a two-fold increase in the frequency of invasive papillary carcinoma in the male breast. Finally, the most common tumor metastatic to the male breast in this series was cutaneous melanoma

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy.

A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water:fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water:fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water:fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment

How Are ‘Barack Obama’ and ‘President Elect’ Differentially Stored in the Brain? An ERP Investigation on the Processing of Proper and Common Noun Pairs

BACKGROUND:One of the most debated issues in the cognitive neuroscience of language is whether distinct semantic domains are differentially represented in the brain. Clinical studies described several anomic dissociations with no clear neuroanatomical correlate. Neuroimaging studies have shown that memory retrieval is more demanding for proper than common nouns in that the former are purely arbitrary referential expressions. In this study a semantic relatedness paradigm was devised to investigate neural processing of proper and common nouns. METHODOLOGY/PRINCIPAL FINDINGS:780 words (arranged in pairs of Italian nouns/adjectives and the first/last names of well known persons) were presented. Half pairs were semantically related ("Woody Allen" or "social security"), while the others were not ("Sigmund Parodi" or "judicial cream"). All items were balanced for length, frequency, familiarity and semantic relatedness. Participants were to decide about the semantic relatedness of the two items in a pair. RTs and N400 data suggest that the task was more demanding for common nouns. The LORETA neural generators for the related-unrelated contrast (for proper names) included the left fusiform gyrus, right medial temporal gyrus, limbic and parahippocampal regions, inferior parietal and inferior frontal areas, which are thought to be involved in the conjoined processing a familiar face with the relevant episodic information. Person name was more emotional and sensory vivid than common noun semantic access. CONCLUSIONS/SIGNIFICANCE:When memory retrieval is not required, proper name access (conspecifics knowledge) is not more demanding. The neural generators of N400 to unrelated items (unknown persons and things) did not differ as a function of lexical class, thus suggesting that proper and common nouns are not treated differently as belonging to different grammatical classes

Can cognitive enhancers reduce the risk of falls in older people with Mild Cognitive Impairment? A protocol for a randomised controlled double blind trial

<p>Abstract</p> <p>Background</p> <p>Older adults with cognitive problems have a higher risk of falls, at least twice that of cognitively normal older adults. The consequences of falls in this population are very serious: fallers with cognitive problems suffer more injuries due to falls and are approximately five times more likely to be admitted to institutional care. Although the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. Since cognitive enhancers, such as cholinesterase inhibitors, improve attention and executive function, we hypothesise that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.</p> <p>Method/Design</p> <p>Double blinded randomized controlled trial with 6 months follow-up in 140 older individuals with Mild Cognitive Impairment (MCI). Participants will be randomized to the intervention group, receiving donepezil, and to the control group, receiving placebo. A block randomization by four and stratification based on fall history will be performed. Primary outcomes are improvements in gait velocity and reduction in gait variability. Secondary outcomes are changes in the balance confidence, balance sway, attention, executive function, and number of falls.</p> <p>Discussion</p> <p>By characterizing and understanding the effects of cognitive enhancers on fall risk in older adults with cognitive impairments, we will be able to pave the way for a new approach to fall prevention in this population. This RCT study will provide, for the first time, information regarding the effect of a medication designed to augment cognitive functioning have on the risk of falls in older adults with Mild Cognitive Impairment. We expect a significant reduction in the risk of falls in this vulnerable population as a function of the reduced gait variability achieved by treatment with cognitive enhancers. This study may contribute to a new approach to prevent and treat fall risk in seniors in early stages of dementia.</p> <p>Trial Registration</p> <p>The protocol for this study is registered with the Clinical Trials Registry, identifier number: NCT00934531 <url>http://www.clinicaltrials.gov</url></p