Mapping of a new locus for congenital anomalies of the kidney and urinary tract on chromosome 8q24

Congenital anomalies of the kidney and urinary tract (CAKUT) account for the majority of end-stage renal disease in children (50%). Previous studies have mapped autosomal dominant loci for CAKUT. We here report a genome-wide search for linkage in a large pedigree of Somalian descent containing eight affected individuals with a non-syndromic form of CAKUT.

Spindle cell oncocytoma of the pituitary gland with follicle-like component: organotypic differentiation to support its origin from folliculo-stellate cells

Spindle cell oncocytoma (SCO) is a rare, non-adenomatous tumor originating from the anterior pituitary gland. Composed of fusiform, mitochondrion-rich cells sharing several immunophenotypic and ultrastructural properties with folliculo-stellate cells (FSC), SCO has been proposed to represent a neoplastic counterpart of the latter. To date, however, SCO has failed to meet one criterion commonly used in histological-based taxonomy and diagnostics; that of recapitulating any of FSCs' morphologically defined developmental or physiological states. We describe a unique example of SCO wherein a conventional fascicular texture was seen coexisting with and organically merging into follicle-like arrangements. The sellar tumor of 2.7 × 2.6 × 2.5 cm was transphenoidally resected from a 55-year old female. Preoperative magnetic resonance imaging indicated an isointense, contrast enhancing mass with suprasellar extension. Histology showed multiple rudimentary to well-formed, follicle-like cavities on a classical spindle cell background; while all the participating cells exhibited an SCO immunophenotype, including positivity for S100 protein, vimentin, EMA, Bcl-2, and TTF-1, as well as staining with the antimitochondrial antibody 113-1. Conversely no expression of GFAP, follicular-epithelial cytokeratin, carcinoembryonic antigen, or anterior pituitary hormones was detected. Ultrastructurally, tumor cells facing follicular lumina displayed organelles of epithelial specialization, in particular surface microvilli and apical tight junctions. This constellation is felt to be reminiscent of FSCs' metaplastic transition to follicular epithelium, as observed during embryonic development and physiological renewal of the hormone-secreting parenchyma. Such finding is apt to being read as a supporting argument for SCO's descent from the FSC lineage.

Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians

A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.

Mitochondrial tRNA import and its consequences for mitochondrial translation

The mitochondrial genomes of most eukaryotes lack a variable number of tRNA genes. This lack is compensated for by import of a small fraction of the corresponding cytosolic tRNAs. There are two broad mechanisms for the import of tRNAs into mitochondria. In the first one, the tRNA is coimported together with a mitochondrial precursor protein along the protein import pathway. It applies to the yeast tRNA(Lys) and has been elucidated in great detail. In the second more vaguely defined mechanism, which is mainly found in plants and protozoa, tRNAs are directly imported independent of cytosolic factors. However, results in plants indicate that direct import of tRNAs may nevertheless require some components of the protein import machinery. All imported tRNAs in all systems are of the eukaryotic type but need to be functionally integrated into the mitochondrial translation system of bacterial descent. For some tRNAs, this is not trivial and requires unique evolutionary adaptations.

Observations of middle atmospheric H2O and O3 during the 2010 major sudden stratospheric warming by a network of microwave radiometers

In this study, we present middle atmospheric water vapor (H2O) and ozone (O3) measurements obtained by ground-based microwave radiometers at three European locations in Bern (47° N), Onsala (57° N) and Sodankylä (67° N) during Northern winter 2009/2010. In January 2010, a major sudden stratospheric warming (SSW) occurred in the Northern Hemisphere whose signatures are evident in the ground-based observations of H2O and O3. The observed anomalies in H2O and O3 are mostly explained by the relative location of the polar vortex with respect to the measurement locations. The SSW started on 26 January 2010 and was most pronounced by the end of January. The zonal mean temperature in the middle stratosphere (10 hPa) increased by approximately 25 Kelvin within a few days. The stratospheric vortex weakened during the SSW and shifted towards Europe. In the mesosphere, the vortex broke down, which lead to large scale mixing of polar and midlatitudinal air. After the warming, the polar vortex in the stratosphere split into two weaker vortices and in the mesosphere, a new, pole-centered vortex formed with maximum wind speed of 70 m s−1 at approximately 40° N. The shift of the stratospheric vortex towards Europe was observed in Bern as an increase in stratospheric H2O and a decrease in O3. The breakdown of the mesospheric vortex during the SSW was observed at Onsala and Sodankylä as a sudden increase in mesospheric H2O. The following large-scale descent inside the newly formed mesospheric vortex was well captured by the H2O observations in Sodankylä. In order to combine the H2O observations from the three different locations, we applied the trajectory mapping technique on our H2O observations to derive synoptic scale maps of the H2O distribution. Based on our observations and the 3-D wind field, this method allows determining the approximate development of the stratospheric and mesospheric polar vortex and demonstrates the potential of a network of ground-based instruments.

Representations of the Human/ Nonhuman Primate Divide: the Influence of Science, Fiction, and Science-Fiction on the Concept of 'Being Human'

For as far back as human history can be traced, mankind has questioned what it means to be human. One of the most common approaches throughout Western culture's intellectual tradition in attempts to answering this question has been to compare humans with or against other animals. I argue that it was not until Charles Darwin's publication of The Descent of Man and Selection in Relation to Sex (1871) that Western culture was forced to seriously consider human identity in relation to the human/ nonhuman primate line. Since no thinker prior to Charles Darwin had caused such an identity crisis in Western thought, this interdisciplinary analysis of the history of how the human/ nonhuman primate line has been understood focuses on the reciprocal relationship of popular culture and scientific representations from 1871 to the Human Genome Consortium in 2000. Focusing on the concept coined as the "Darwin-Müller debate," representations of the human/ nonhuman primate line are traced through themes of language, intelligence, and claims of variation throughout the popular texts: Descent of Man, The Jungle Books (1894), Tarzan of the Apes (1914), and Planet of the Apes (1963). Additional themes such as the nature versus nurture debate and other comparative phenotypic attributes commonly used for comparison between man and apes are also analyzed. Such popular culture representations are compared with related or influential scientific research during the respective time period of each text to shed light on the reciprocal nature of Western intellectual tradition, popular notions of the human/ nonhuman primate line, and the development of the field of primatology. Ultimately this thesis shows that the Darwin-Müller debate is indeterminable, and such a lack of resolution makes man uncomfortable. Man's unsettled response and desire for self-knowledge further facilitates a continued search for answers to human identity. As the Human Genome Project has led to the rise of new debates, and primate research has become less anthropocentric over time, the mysteries of man's future have become more concerning than the questions of our past. The human/ nonhuman primate line is reduced to a 1% difference, and new debates have begun to overshadow the Darwin-Müller debate. In conclusion, I argue that human identity is best represented through the metaphor of evolution: both have an unknown beginning, both have an indeterminable future with no definite end, and like a species under the influence of evolution, what it means to be human is a constant, indeterminable process of change.

Fatal myocardial infarction at 4.5 years in a case of homozygous familial hypercholesterolaemia

Management of homozygous familial hypercholesterolaemia is notoriously difficult. For these patients, LDL apheresis is considered the treatment of choice. Treatment initiation is advocated generally from the age of seven years onwards (Thompson et al., Atherosclerosis 198:247-255, 2008). Here, we present the case of a young girl from a large inbred family of Turkish descent with homozygous familial hypercholesterolaemia and fatal outcome at the early age of 4(1/2) years.In conclusion, this case suggests that management of homozygous familial hypercholesterolaemia may require earlier and more aggressive treatment, including LDL apheresis before the age of seven years.

Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer

Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Fetal haemoglobin levels in adult type 1 (insulin-dependent) diabetic patients

Glycated haemoglobin levels (HbA1 and HbA1c) are established parameters of long-term glycaemic control in diabetic patients. Depending on the method used, fetal haemoglobin interferes with the assays for glycated haemoglobin. If present in high amounts, fetal haemoglobin may lead to overestimation of glycated haemoglobin levels, and therefore, of average blood glucose concentration in diabetic patients. Glycated (HbA1c) and fetal haemoglobin levels were measured by high pressure liquid chromatography in 60 (30 female) adult Type 1 (insulin-dependent) diabetic patients of Swiss descent, and were compared with levels obtained from 60 normal, non-diabetic control subjects matched for age and sex. Fetal haemoglobin levels were significantly higher in the diabetic patients (0.6 +/- 0.1%, mean +/- SEM; range: 0-3.6%) than in the control subjects (0.4 +/- 0.1%, p < 0.001). Elevated fetal haemoglobin levels (> or = 0.6%) were found in 23 of 60 diabetic patients (38%) compared to 9 of 60 control subjects (15%; chi 2 = 8.35, p < 0.01). In addition, fetal haemoglobin levels in diabetic patients are weakly correlated with glycated haemoglobin (HbA1c) (r = 0.38, p < 0.01). Fetal haemoglobin results were confirmed with the alkali denaturation procedure, and by immunocytochemistry using a polyclonal rabbit anti-fetal haemoglobin antibody. A significant proportion of adult patients with Type 1 diabetes has elevated fetal haemoglobin levels. In certain patients this may lead to a substantial over-estimation of glycated haemoglobin levels, and consequently of estimated, average blood glucose levels. The reason for this increased prevalence of elevated fetal haemoglobin remains unclear, but it may be associated with poor glycaemic control.

Sexual function after sacrospinous fixation for vaginal vault prolapse: bad or mad?

BACKGROUND: The main indication for sacrospinous ligament suspension is to correct either total procidentia, a posthysterectomy vaginal vault prolapse with an associated weak cardinal uterosacral ligament complex, or a posthysterectomy enterocele. This study aimed to evaluate sexual function and anatomic outcome for patients after sacrospinous ligament suspension. METHODS: For this study, 52 patients who had undergone sacrospinous ligament fixation during the preceding 5 years were asked to complete the Female Sexual Function Index (FSFI) questionnaire. The patients were vaginally examined using the ICS POP score, and the results were compared with their preoperative status. For statistical analysis, GraphPad for Windows, version 4.0, was used. RESULTS: The 52 patients were examined during a follow-up period of 38 months. No major intraoperative complications were noted. Recurrence of symptomatic apical descent was noted in 6% of the patients and de novo prolapse in 13.5%. Only one patient was symptomatic. Three patients experienced de novo dyspareunia, which resolved in two cases after stitch removal. Sexual function was good, rating higher than three points for each of the domains including satisfaction, lubrication, desire, orgasm, and pain. CONCLUSION: Sacrospinous ligament fixation still is a valuable option for the treatment of vaginal vault prolapse. Sexual function is satisfactory, with few cases of de novo dyspareunia.

Male and female sexual function after surgical repair of female organ prolapse

INTRODUCTION: Few data are available referring to male and female sexual function after prolapse repair of symptomatic pelvic organ. AIM: Primary aim of this study is to determine the male and female sexual function before and after surgery for pelvic organ prolapse. MAIN OUTCOME MEASURES: We used the Female Sexual Function Index (FSFI) questionnaire for female patients and for their male partners the Brief Male Sexual Inventory (BMSI) as measurement of sexual function. METHODS: We included sexually active heterosexual couples that were referred to the Department of Urogynaecology because of symptomatic cystocele, rectocele or vault descent. For cystoceles, anterior repair was performed, for rectoceles posterior repair, and for vault descent sacrospinous ligament fixation. FSFI and BMSI questionnaires were distributed before and after pelvic organ surgery and 4 months after. Female clinical examination assessing the degree of prolapse was performed before and 6 weeks after surgery. RESULTS: A full data set of 70 female questionnaires and 64 male questionnaires could be evaluated. Two cases of female de novo dyspareunia occurred. In women, FSFI scores improved significantly in the domains desire, arousal, lubrication, overall satisfaction, and particularly pain. Orgasm remained unchanged. In men, interest, sexual drive, and overall satisfaction improved significantly. Erection, ejaculatory function, and orgasm remained unchanged. Despite remaining unchanged, erection, strength of erection, ejaculation, and orgasm were not considered problems anymore compared to preoperative BMSI scores. CONCLUSION: Surgery for pelvic organ prolapse improves male and female sexual function in some domains but not in all.

Dry grasslands of NW Bulgarian mountains: first insights into diversity, ecology and syntaxonomy

We present the data of the 3rdresearch expedition of the European Dry Grasslands Group (EDGG), which was conducted in 2011 in two contrasting areas in NW Bulgarian mountains. The aim was to collect plot data for comparing Bulgarian dry grasslands with those of other parts of Europe in terms of syntaxonomy and biodiversity. We sampled 15 nested-plot series (0.0001–100 m²) and 68 normal plots(10 m²) covering the full variety of dry grassland types occurring in the Vratsa area (Balkan Mts.) and the Koprivshtitsa area (Sredna Gora Mt.). In the plots all vascular plants, terricolous non-vascular plants and a set of soil and other environmental parameters were determined. By applying modified TWIN-SPAN, we distinguished 10 floristically well characterised vegetation types at the association level. After comparison with the regional and European literature, we propose to place them within three classes and five orders: Festuco-Brometea with the orders Stipo pulcherrimae-Festucetalia pallentis (xerophilous dry grasslands of base-rich rocks; alliance Saturejion montanae), Brachypodietalia pinnate (meso-xeric, basiphilous grasslands; alliances Cirsio-Brachypodion pinnate and Chyrsopogono grylli-Danthonion calycinae),Calluno-Ulicetea with the order Nardetalia stricae (lowland to montane Nardus swards; alliance Violion caninae), and Koelerio-Corynephoretea with the orders Sedo-Scleranthetalia (open communities of skeleton-rich, acidic soils; alliance unclear) and Trifolioarvensis-Festucetalia ovinae(closed, meso-xeric, acidophilous grasslands; alliance Armerio rumelicae-Potentillion). The Violion caninae with the association Festuco rubrae-Genistelletum sagittalisis reported from Bulgaria for the first time, while the two occurring Koelerio-Corynephoretea communities are described as new associations (Cetrario aculeatae-Plantaginetum radicatae, Plantagini radicatae-Agrostietum capillaris). According to DCA the main floristic gradient was largely determined by soil conditions, differentiating the Festuco-Brometea communities on soils with high pH and high humus content from the Koelerio-Corynephoretea communities on acidic, humus-poor soils, while the Calluno-Ulicetea stands are the connecting link. At 10 m² Festuco-Brometea and Calluno-Ulicetea stands were richer in species across all investigated taxa and in vascular plants than Koelerio-Corynephoretea stands; the latter were richest in lichen species, while bryophyte richness did not differ significantly among syntaxa. Among the Bulgarian classes, the species-area relationships tended to be steepest in the Festuco-Brometea (i.e. highest beta diversity), but both alpha and beta diversity clearly fell behind the Festuco-Brometea communities in the Transylvanian Plateau, Romania, located less than 500 km north of the study region. Overall, our study contributes to a more adequate placement of the Bulgarian dry grasslands in the European syntaxonomic system and provides valuable data for large-scale analyses of biodiversity patterns

Characteristics of a spina bifida population including North American Caucasian and Hispanic individuals.

BACKGROUND: Meningomyelocele (MM) is a common human birth defect. MM is a disorder of neural development caused by contributions from genes and environmental factors that result in the NTD and lead to a spectrum of physical and neurocognitive phenotypes. METHODS: A multidisciplinary approach has been taken to develop a comprehensive understanding of MM through collaborative efforts from investigators specializing in genetics, development, brain imaging, and neurocognitive outcome. Patients have been recruited from five different sites: Houston and the Texas-Mexico border area; Toronto, Canada; Los Angeles, California; and Lexington, Kentucky. Genetic risk factors for MM have been assessed by genotyping and association testing using the transmission disequilibrium test. RESULTS: A total of 509 affected child/parent trios and 309 affected child/parent duos have been enrolled to date for genetic association studies. Subsets of the patients have also been enrolled for studies assessing development, brain imaging, and neurocognitive outcomes. The study recruited two major ethnic groups, with 45.9% Hispanics of Mexican descent and 36.2% North American Caucasians of European descent. The remaining patients are African-American, South and Central American, Native American, and Asian. Studies of this group of patients have already discovered distinct corpus callosum morphology and neurocognitive deficits that associate with MM. We have identified maternal MTHFR 667T allele as a risk factor for MM. In addition, we also found that several genes for glucose transport and metabolism are potential risk factors for MM. CONCLUSIONS: The enrolled patient population provides a valuable resource for elucidating the disease characteristics and mechanisms for MM development.

Neural tube defects in Mexican-Americans living on the US-Mexico border: The effects of folic acid and dietary folate

Neural tube defects (NTDs) are malformations of the developing brain and spinal cord; the most common are anencephaly and spina bifida. Evidence from many populations suggests that 50% of NTDs can be prevented through daily consumption of folic acid. A recent study has reported that folic acid may not protect populations of Mexican descent. This finding has serious implications for women living along the US-Mexico border. Not only is risk high in these Mexican American women compared with other US women; they also differ markedly in supplemental folic acid and dietary folate consumption, and in NTD-related risks (e.g., obesity, diabetes). This case-control study investigated whether folic acid supplements and dietary folate reduces NTDs in Mexican Americans. Cases included liveborn, stillborn, electively and spontaneously aborted NTD-affected fetuses and infants occurring in the 14-county Texas-Mexico border. Controls were randomly selected from unaffected live births, frequency matched to cases by hospital and year. An in-person interview of 110 case and 113 control mothers solicited data on folic acid supplements, dietary folate, and other covariates. Consumption of folic acid-containing vitamins before conception was only 5% for both case and control women. Taking vitamins the trimester before conception had no apparent effect, after adjusting for covariates [odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.3–3.4]. Combining folate from vitamins and diet showed a 20% risk reduction for women consuming at least 400 μg of folate daily [OR = 0.8, 95% CI = 0.5–1.5]; however, this estimate is statistically indistinguishable from the null. Although consistent with an inherent ineffectiveness of supplemental folic acid, that so few women consumed multivitamins during the critical time severely limited the assessment of folic acid in this population. A reduced folate response in Mexican descent women may be due to a genetic heterogeneity for metabolizing folate. Alternatively, folate intakes may be insufficient to overcome other underlying risk factors. In conclusion, determining whether folic acid reduces NTD risk in Mexican American women requires further study in populations with higher folic acid exposures. Meanwhile, we should pursue all recommended prevention strategies to reduce risk, including motivating Mexican American women of childbearing age to take folic acid routinely. ^

Stair climbing - An insight and comparison between women with and without joint hypermobility: A descriptive study.

Generalized joint hypermobility (GJH) is a frequent entity in rheumatology with higher prevalence among women. It is associated with chronic widespread pain, joint dislocations, arthralgia, fibromyalgia and early osteoarthritis. Stair climbing is an important functional task and can induce symptoms in hypermobile persons. The aim of this study was to compare ground reaction forces (GRF) and muscle activity during stair climbing in women with and without GJH. A cross-sectional study of 67 women with normal mobility and 128 hypermobile women was performed. The hypermobile women were further divided into 56 symptomatic and 47 asymptomatic. GRFs were measured by force plates embedded in a six step staircase, as well as surface electromyography (EMG) of six leg muscles. Parameters derived from GRF and EMG were compared between groups using t-test and ANOVA. For GRF no significant differences were found. EMG showed lower activity for the quadriceps during ascent and lower activity for hamstrings and quadriceps during descent in hypermobile women. For symptomatic hypermobile women these differences were even more accentuated. The differences in EMG may point towards an altered movement pattern during stair climbing, aimed at avoiding high muscle activation. However, differences were small, since stair climbing seems to be not demanding.