Genetic diversity in the modern horse illustrated from genome-wide SNP data.

Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection.

Genome-wide analysis reveals selection for important traits in domestic horse breeds.

Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.

Is thermochemotherapy with the Synergo system a viable treatment option in patients with recurrent non-muscle-invasive bladder cancer?

OBJECTIVES To prospectively evaluate the outcome of combined microwave-induced bladder wall hyperthermia and intravesical mitomycin C instillation (thermochemotherapy) in patients with recurrent non-muscle-invasive bladder cancer. METHODS Between 2003 and 2009, 21 patients (median age 70 years, range 35-95 years) with recurrent non-muscle-invasive bladder cancer (pTaG1-2 n = 9; pTaG3 n = 3; pT1 n = 9; concurrent pTis n = 8) were prospectively enrolled. Of 21 patients, 15 (71%) had received previous intravesical instillations with bacillus Calmette-Guérin, mitomycin C and/or farmorubicin. Thermochemotherapy using the Synergo system was carried out in 11 of 21 patients (52%) with curative intent, and in 10 of 21 patients (48%) as prophylaxis against recurrence. RESULTS The median number of thermochemotherapy cycles per patient was six (range 1-12). Adverse effects were frequent and severe: urinary urgency/frequency in 11 of 21 patients (52%), pain in eight of 21 patients (38%) and gross hematuria in five of 21 patients (24%). In eight of 21 patients (38%), thermochemotherapy had to be abandoned because of the severity of the adverse effects (pain in 3/8, severe bladder spasms in 2/8, allergic reaction in 2/8, urethral perforation in 1/8). Overall, six of 21 patients (29%) remained free of tumor after a median follow up of 50 months (range 1-120), six of 21 patients (29%) had to undergo cystectomy because of multifocal recurrences or cancer progression and seven of 21 patients (33%) died (2/7 of metastatic disease, 5/7 of non-cancer related causes). CONCLUSIONS Given the high rate of severe side-effects leading to treatment discontinuation, as well as the limited tumor response, thermochemotherapy should be offered only in highly selected cases of recurrent non-muscle-invasive bladder cancer.

Treatment and outcomes of urethral recurrence of urinary bladder cancer in women after radical cystectomy and orthotopic neobladder: a series of 12 cases

INTRODUCTION The incidence, treatment, and outcome of urethral recurrence (UR) after radical cystectomy (RC) for muscle-invasive bladder cancer with orthotopic neobladder in women have rarely been addressed in the literature. PATIENTS AND METHODS A total of 12 patients (median age at recurrence: 60 years) who experienced UR after RC with an orthotopic neobladder were selected for this study from a cohort of 456 women from participating institutions. The primary clinical and pathological characteristics at RC, including the manifestation of the UR and its treatment and outcome, were reviewed. RESULTS The primary bladder tumors in the 12 patients were urothelial carcinoma in 8 patients, squamous cell carcinoma and adenocarcinoma in 1 patient each, and mixed histology in 2 patients. Three patients (25%) had lymph node-positive disease at RC. The median time from RC to the detection of UR was 8 months (range 4-55). Eight recurrences manifested with clinical symptoms and 4 were detected during follow-up or during a diagnostic work-up for clinical symptoms caused by distant metastases. Treatment modalities were surgery, chemotherapy, radiotherapy, and bacillus Calmette-Guérin urethral instillations. Nine patients died of cancer. The median survival after the diagnosis of UR was 6 months. CONCLUSIONS UR after RC with an orthotopic neobladder in females is rare. Solitary, noninvasive recurrences have a favorable prognosis when detected early. Invasive recurrences are often associated with local and distant metastases and have a poor prognosis. © 2014 S. Karger AG, Basel.

A 4,103 marker integrated physical and comparative map of the horse genome

A comprehensive second-generation whole genome radiation hybrid (RH II), cytogenetic and comparative map of the horse genome (2n = 64) has been developed using the 5000rad horse x hamster radiation hybrid panel and fluorescence in situ hybridization (FISH). The map contains 4,103 markers (3,816 RH; 1,144 FISH) assigned to all 31 pairs of autosomes and the X chromosome. The RH maps of individual chromosomes are anchored and oriented using 857 cytogenetic markers. The overall resolution of the map is one marker per 775 kilobase pairs (kb), which represents a more than five-fold improvement over the first-generation map. The RH II incorporates 920 markers shared jointly with the two recently reported meiotic maps. Consequently the two maps were aligned with the RH II maps of individual autosomes and the X chromosome. Additionally, a comparative map of the horse genome was generated by connecting 1,904 loci on the horse map with genome sequences available for eight diverse vertebrates to highlight regions of evolutionarily conserved syntenies, linkages, and chromosomal breakpoints. The integrated map thus obtained presents the most comprehensive information on the physical and comparative organization of the equine genome and will assist future assemblies of whole genome BAC fingerprint maps and the genome sequence. It will also serve as a tool to identify genes governing health, disease and performance traits in horses and assist us in understanding the evolution of the equine genome in relation to other species.

Na 1 Nachlass Max Horkheimer, 17 - Korrespondenzen u.a. mit M. Gosling (p. I 9, 1-159)

11 Briefe zwischen M. Gosling und Max Horkheimer, 1935-1938; 1 Brief von Ellen Gottschalk an 04.08.1936; 1 Brief von Brill an Max Horkheimer, 15.08.1936; 2 Briefe zwischen Louise Gottschalk und Max Horkheimer, 06.12.1937, 19.04.1937; 3 Briefe zwischen Max Gottschalk und Max Horkheimer, 1941, 23.01.1941; 2 Briefe zwischen Nemes Gottschalk und Max Horkheimer, 29.03.1939, 03.04.1939; 2 Briefe zwischen Lawrence Gould und Max Horkheimer, 12.01.1947, 04.01.1947; 4 Briefe zwischen Isaeque Graeber und Max Horkheimer, 20.07.1941, 1941; 4 Briefe zwischen Malborne W. Graham und Max Horkheimer, 17.10.1940, 1940; 1 Brief von Max Horkheimer an J. A. C. Grant, 23.10.1940; 2 Briefe zwischen dem Grant Grove Lodge Kings Canyon National Park California und Max Horkheimer, 30.09.1946, 04.10.1946; 4 Brefe zwischen Liesel Gras und Max Horkheimer, 1948, 02.04.1948; 2 Briefe zwischen Claire F. Gravel und 23.03.1942, 26.03.1942; 1 Brief und 4 Briefentwürfe von Max Horkheimer an Edward S. Greenbaum, 20.06.1940; 13 Briefe zwischen B. Groethuysen und Max Horkheimer, 1935-1937; 1 Hochzeitsanzeige von Isabelle Grossen, 26.11.1938; 1 Brief von Max Horkheimer an Isabelle Grossen, 17.12.1938; 1 Brief von Kurt Grossmann an Max Horkheimer, 29.12.1939; 3 Briefe von Eva Grosz an Max Horkheimer, 1937; 5 Briefe zwischen Franz M. Groedel und Max Horkheimer, 1939, Oktober 1939; 7 Briefe zwischen Emil Grünberg und Max Horkheimer, 1935-1940; 1 Brief von B. M. Telders an Max Horkheimer, 27.09.1938; 3 Briefe zwischen dem Academic Assistance Council London und Max Horkheimer, 1935, 29.03.1935; 1 Briefentwurft von Max Horkheimer an Karl Grünberg, 07.02.1936; 1 Brief von Juliette Favez an Max Horkheimer, 07.02.1936; 3 Briefe zwsichen Martin Grünberg und Max Horkheimer, November 1938, 18.11.1938; 3 Briefe zwischen Alfred Grünebaum und Max Horkheimer, 10.01.1939, 1939; 2 Briefe zwischen D. E. Grünebaum und Max Horkheimer, 24.11.1940, 02.12.1940; 3 Briefe zwischen Richard Güldenstein und Max Horkheimer, August 1937, 17.08.1937; 1 Brief von Daniel Guérin an Max Horkheimer, 13.07.1947; 1 Brief von Max Horkheimer an Guerro, 08.09.1936;

Economic evaluation of latent tuberculosis infection screening among health care workers in Houston

Since interferon-gamma release assays (IGRAs) were introduced in the 2000's, tuberculin skin testing (TST) and IGRAs have been used in various latent tuberculosis infection (LTBI) screening settings. IGRAs are laboratory-based tests and are considered not to be affected by previous Bacille de Calmette et Guérin (BCG) vaccination; however, they are more costly when compared directly with TST, which does not require specimen processing in a laboratory. This study aimed to examine TST and two types of IGRAs, QuantiFERON-TB Gold in Tube (QFT-GIT) and T-SPOT. TB (TSPOT), from an economic viewpoint. Firstly, a systematic literature review was conducted to identify cost related analyses of LTBI screening. Secondly, specific cost information detailing each test's items and labor was collected from an LTBI screening program of health care workers in Houston, and the cost of each test was computed. Thirdly, using the computed cost estimate of each test, cost-effectiveness analyses were conducted to compare TST and IGRAs.^ A literature search showed that a limited number of studies have been conducted, but the IGRA's economic advantages were common among studies. Cost analyses showed that IGRAs were much more costly than TST. The results were consistent with previous studies. In cost-effectiveness analyses, where test cost and consequential TB-related cost were considered, IGRAs showed variable advantages over TST depending on the targeted population. When only non BCG-vaccinated people were considered, TST was the least costly option among the three tests. On the other hand, when only BCG-vaccinated people were considered, IGRAs were less costly options. These results were mostly consistent even with varying assumption parameters.^ IGRAs can be more costly than TST, but their economic disadvantages are alleviated when the target population was BCG-vaccinated. Based on current knowledge, IGRAs may be recommended in a population where the BCG history is mixed. Additional studies are needed to better understand IGRA's reliability among low-incidence and low-risk populations in which background TB prevalence is low.^

Genetic variants within the Wnt/ B-catenin signaling pathway as indicators of bladder cancer clinical outcomes

The genetic factors that influence bladder cancer clinical outcomes are largely unknown. In this clinical outcomes study, I assessed genetic variations in the Wnt/β-catenin stem-cell pathway genes for association with recurrence and progression. A total of 230 SNPS in 40 genes from the Wnt/β-catenin pathway were genotyped in 419 histologically confirmed non-muscle invasive bladder cancer cases. Several significant associations were observed in the clinical outcomes analysis. Under the dominant model WNT8B: rs4919464 (HR: 1.55, 95% CI: 1.17-2.06, P=2.2x10-3) and WNT8B: rs3793771 (HR: 1.54, 95% CI: 1.09-1.62, P=4.6x10-3 ) were statistically significantly associated with an increase risk of recurrence while two other variants, APC2: rs11668593 (HR: 2.50, 95% CI: 1.43-4.35, P=1.2x10-3) and LRP5 : rs312778 (HR: 1.81, 95% CI: 1.23-2.65, P=2.7x10-3), were significantly associated with recurrence risk under the recessive model of inheritance. Four SNPs in the recessive model were associated with an increased risk of progression (AXIN2: rs1544427, LRP5: rs312778, AXIN1: rs370681, AXIN1: rs2301522). LRP5: rs312778 had the most significant increased risk of progression with a 2.68 (95% CI: 1.52-4.72, P=6.4x10-4)-fold increased risk. Stratification analysis based on treatment regimen (transurethral resection (TUR) and Bacillus Calmette-Guérin (BCG)) was also performed. Individuals with at least one variant in AXIN2: rs2007085 were found to have a 2.09 (95% CI: 1.24-3.52, P=5.4x10-3) -fold increased risk of recurrence in those that received TUR only, and no statistically significant effect was seen in those that received BCG. Individuals who received TUR with at least one variant in LEF1: rs10516550 were found to have a 2.26 (95% CI: 1.22-4.18, P=9.7x10-3)-fold increase risk of recurrence and no statistically significant effect was found in individuals who received BCG. Also, the recessive model of LRP6: rs2302684 in TUR only treatment was shown to have a 1.95 (95%CI: 1.18-3.21, P=8.8x10 -3)-fold increased risk of recurrence, and a suggested protective effect associated with a (HR: 0.83, 95% CI: 0.51-1.37, P=0.468) decreased risk of recurrence. Together, these findings implicate the Wnt/β-catenin stem-cell pathway as playing a role in bladder cancer clinical outcomes and have important implications for personalization of future treatment regimens. ^

El ritmo de nado, determinante de buenos resultados

Siempre me llamó la atención en mi época de nadador que mis entrenadores no me sugiriesen una forma de nadar mi prueba hasta después de haberla nadado. Entonces era cuando se me reprochaban los fallos y se me aleccionaba para cuando nadase la próxima prueba corrigiese mis errores..... Cuando volvía a nadar tropezaba de nuevo en la misma piedra... y vuelta a lo mismo. La posibilidad de terminar la carrera de Profesor de Educación Física sin haber intentado solucionar o al menos estudiar un problema, que en mi época de practicante de la natación me inquietaba, ha hecho que se plasmase esta preocupación en este trabajo f in de carrera con la pretensión de dar los últimos coletazos de mi adquisición de experiencia y conocimientos en este Instituto. El “pase”, la habilidad para cubrir una distancia específica en un grado específico de velocidad, no es algo con lo que se nace sino que necesita de mucha experiencia y práctica. La in tención de éste trabajo es analizar y buscar las posibilidades que existen de nadar las distintas pruebas del calendario olímpico de natación. El nadador debe saber cambiar de velocidad pero también saber a qué velocidad va, saber acelerar el ritmo pero sabiendo que ritmo lleva. Me decía en una ocasión Jan Freese, entrenador de natación de la Residencia Blume de Barcelona, que era muy difícil que un nadador hiciese una buena marca cuando el entrenador le preparaba exclusivamente la carrera para que ganase a sus competidores. Si se quiere lograr un registro notable para nuestro nadador es indispensable que tratemos de estudiar detenidamente la prueba para la cual éste se prepara, sugerir los pases ideales y, por supuesto, practicar el ritmo de nado, cadencia o velocidad de nado más idóneos para el logro satisfactorio de sus fines. Morehouse y Miller aluden en cuanto al ritmo de carrera que “la distribución más económica del esfuerzo al correr una distancia dada se obtiene manteniendo un ritmo constante durante toda la prueba. Esta distancia se cubre en el menor tiempo cuando toda la energía de que se dispone e s distribuida uniformemente sobre la distancia por recorrer. La aceleración es tan costosa, que los cambios de velocidad re sultan demasiado caros como para emplearlos como tácticas desorientadoras. El ritmo de nado lo define Kiputh como “la distribución de la energía para alcanzar la mayor velocidad”. Así pues, debemos tener en cuenta que el ritmo de nado de debe limitarse a predecir tiempos parciales sino también a aprender a analizar la cantidad de esfuerzo que se debe realizar. El entrenamiento del ritmo de nado, no solo da los toques finales al acondicionamiento del nadador sino que capacita al competidor para regular su propia velocidad atendiéndose a una marcha establecida, en lugar de someterse al ritmo de los competidores. No quiero suscitar polémica sobre la indistinta utilización de términos tales como “ritmo de nado”, “cadencia” y “velocidad de nado”. Estos términos serán a menudo utilizados y quiero aclarar que su verdadero significado en cuanto al empleo que les doy proviene de una única palabra inglesa: “pace”, cuya traducción literal al castellano es “paso”, “grado de celeridad”. Diversos traductores al español de diferentes obras inglesas y americanas hacen uso de etos términos en sustitución de la palabra “pace”. Por ello, y ante la ruptura de la monotonía que supone el utilizar constantemente un solo término, me he inclinado al empleo de varios que, insisto, tienen en este trabajo el significado anteriormente expuesto de “pace”.

A stationary-phase stress-response sigma factor from Mycobacterium tuberculosis.

Alternative RNA polymerase sigma factors are a common means of coordinating gene regulation in bacteria. Using PCR amplification with degenerate primers, we identified and cloned a sigma factor gene, sigF, from Mycobacterium tuberculosis. The deduced protein encoded by sigF shows significant similarity to SigF sporulation sigma factors from Streptomyces coelicolor and Bacillus subtilis and to SigB, a stress-response sigma factor, from B. subtilis. Southern blot surveys with a sigF-specific probe identified cross-hybridizing bands in other slow-growing mycobacteria, Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mycobacterium avium, but not in the rapid-growers Mycobacterium smegmatis or Mycobacterium abscessus. RNase protection assays revealed that M. tuberculosis sigF mRNA is not present during exponential-phase growth in M. bovis BCG cultures but is strongly induced during stationary phase, nitrogen depletion, and cold shock. Weak expression of M. tuberculosis sigF was also detected during late-exponential phase, oxidative stress, anaerobiasis, and alcohol shock. The specific expression of M. tuberculosis sigF during stress or stationary phase suggests that it may play a role in the ability of tubercle bacilli to adapt to host defenses and persist during human infection.