Autosomal-Recessive Posterior Microphthalmos Is Caused by Mutations in PRSS56, a Gene Encoding a Trypsin-Like Serine Protease.

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

Esophageal leaks repaired by a muscle onlay approach in the presence of mediastinal sepsis.

BACKGROUND: Nineteen patients were evaluated after closure of intrathoracic esophageal leaks by a pediculated muscle flap onlay repair in the presence of mediastinal and systemic sepsis. METHODS: Intrathoracic esophageal leaks with mediastinitis and systemic sepsis occurred after delayed spontaneous perforations (n = 7) or surgical and endoscopic interventions (n = 12). Six patients presented with fulminant anastomotic leaks. Seven patients had previous attempts to close the leak by surgery (n = 4) or stenting (2) or both (n = 1). The debrided defects measured up to 2 x 12 cm or involved three quarters of the anastomotic circumference and were closed either by a full thickness diaphragmatic flap (n = 13) or a pediculated intrathoracically transposed extrathoracic muscle flap (n = 6). All patients had postoperative contrast esophagography between days 7 and 10 and an endoscopic evaluation 4 to 6 months after surgery. RESULTS: There was no 30-day mortality. During follow-up (4 to 42 months), 16 patients (84%) revealed functional and morphological restoration of the esophagointestinal integrity without further interventions. One patient required serial dilatations for a stricture, and 1 underwent temporary stenting for a persistent fistula; both patients had normal control endoscopy during follow-up. A third patient requiring permanent stenting for stenosis died from gastrointestinal bleeding due to stent erosion during follow-up. CONCLUSIONS: Intrathoracic esophageal leaks may be closed efficiently by a muscle flap onlay approach in the presence of mediastinitis and where a primary repair seems risky. The same holds true for fulminant intrathoracic anastomotic leaks after esophagectomy or other surgical interventions at the gastroesophageal junction.

Detection of respiratory viruses by real-time polymerase chain reaction in outpatients with acute respiratory infection

Viruses are the major contributors to the morbidity and mortality of upper and lower acute respiratory infections (ARIs) for all age groups. The aim of this study was to determine the frequencies for a large range of respiratory viruses using a sensitive molecular detection technique in specimens from outpatients of all ages with ARIs. Nasopharyngeal aspirates were obtained from 162 individuals between August 2007-August 2009. Twenty-three pathogenic respiratory agents, 18 respiratory viruses and five bacteria were investigated using multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) and indirect immunofluorescence assay (IIF). Through IIF, 33 (20.4%) specimens with respiratory virus were recognised, with influenza virus representing over half of the positive samples. Through a multiplex real-time RT-PCR assay, 88 (54.3%) positive samples were detected; the most prevalent respiratory viral pathogens were influenza, human rhinovirus and respiratory syncytial virus (RSV). Six cases of viral co-detection were observed, mainly involving RSV. The use of multiplex real-time RT-PCR increased the viral detection by 33.9% and revealed a larger number of respiratory viruses implicated in ARI cases, including the most recently described respiratory viruses [human bocavirus, human metapneumovirus, influenza A (H1N1) pdm09 virus, human coronavirus (HCoV) NL63 and HCoV HKU1].

Time resolved construction of a bimodal laccolith (Torres del Paine, Patagonia)

Granitic and mafic magma pulses were sequentially accreted in the spectacularly exposed shallow crustal Torres del Paine laccolith, in southern Patagonia. This 12.5 Ma pluton forms a composite intrusion with a subvertical feeding system in the west and a laccolith in the east. A key unknown in the formation of sill complexes is how individual magma pulses are assembled over time and the geometry and localization of their feeding system. High resolution zircon CA-ID-TIMS U-Pb dating shows that the laccolith grew first by under-accretion of granitic sills over 90 +/- 30 ka, linked to a `sheet-like' feeding system, followed by underplating of mafic sills after similar to 20 ka of quiescence. In the mafic sills complex, individual sills were injected by over-accretion during 41 +/- 11 ka. Our data show that successive granitic and mafic magmas emplacement generated a volume of similar to 88 km(3) in 162 +/- 11 ka. (C) 2012 Elsevier B.V. All rights reserved.

Profile of European radiotherapy departments contributing to the EORTC Radiation Oncology Group (ROG) in the 21st century.

PURPOSE: Since 1982, the Radiation Oncology Group of the EORTC (EORTC ROG) has pursued an extensive Quality Assurance (QA) program involving all centres actively participating in its clinical research. The first step is the evaluation of the structure and of the human, technical and organisational resources of the centres, to assess their ability to comply with the current requirements for high-tech radiotherapy (RT). MATERIALS AND METHODS: A facility questionnaire (FQ) was developed in 1989 and adapted over the years to match the evolution of RT techniques. We report on the contents of the current FQ that was completed online by 98 active EORTC ROG member institutions from 19 countries, between December 2005 and October 2007. RESULTS: Similar to the data collected previously, large variations in equipment, staffing and workload between centres remain. Currently only 15 centres still use a Cobalt unit. All centres perform 3D Conformal RT, 79% of them can perform IMRT and 54% are able to deliver stereotactic RT. An external reference dosimetry audit (ERDA) was performed in 88% of the centres for photons and in 73% for electrons, but it was recent (<2 years) in only 74% and 60%, respectively. CONCLUSION: The use of the FQ helps maintain the minimum quality requirements within the EORTC ROG network: recommendations are made on the basis of the analysis of its results. The present analysis shows that modern RT techniques are widely implemented in the clinic but also that ERDA should be performed more frequently. Repeated assessment using the FQ is warranted to document the future evolution of the EORTC ROG institutions.

Cytogenetic and molecular relationships between Zarudny's rock shrew (Crocidura zarudnyi; Mammalia : Soricomorpha) and Eurasian taxa

We karyotyped and sequenced 1,140 base pairs of the mitochondrial DNA cytochrome b of a specimen of Zarudny's rock shrew (Crocidura zarudnyi) from Baluchestan, southeastern Iran, to clarify its cytogenetic and molecular relationships with other Eurasian species of Crocidura. According to the karyotype (2N = 40, FN = 50), Zarudny's rock shrew belongs to the group of the lesser white-toothed shrew (C. suaveolens), which is different from other known crocidurine karyotypes, considering the combination of the diploid and fundamental number of chromosomes. Molecular results revealed that C. zarudnyi is included in a monophyletic clade with the C. suaveolens group, where it is a sister taxon to the others (mean Kimura 2-parameter distance = 9.7%).

Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias.

Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

Linkage disequilibrium between a melanin-based colour polymorphism and tail length in the barn owl

A linkage disequilibrium between sexually selected and life history traits can be explained by three mutually non-exclusive mechanisms. Genes coding for two traits may be located close on the same chromosome, genes responsible for variation in one of the trait may pleiotropically alter the other, and non-random pairing with respect to two traits may generate a non-physical linkage disequilibrium between their genes. Knowledge of which of these three mechanisms is responsible for a covariation between two traits is of interest to understand why differently ornamented individuals differ in several phenotypic aspects. In Switzerland, barn owls Tyto alba mate randomly with respect to a colour polymorphism generating a large range of variants between reddish-brown and white, males being lighter coloured than females. Several studies have shown that plumage coloration is not neutral with respect to some life history components. To test whether coloration is genetically associated with body size, partial cross-fostering experiments were performed by exchanging some hatchlings between nests. These experiments showed that darker biological fathers produce longer-tailed offspring. This sex-specific pattern is consistent with the hypothesis of non-physical linkage disequilibrium. In line with this hypothesis, darker coloured males were mated with longer-tailed females, whereas female coloration was not associated with tail length of their mate. The finding that dark nestlings had a longer tail than their pale siblings also supports the physical linkage and pleiotropy hypotheses. Therefore, non-random pairing can generate or strengthen a genetic covariation between a secondary sexual character and a morphological trait.

Life-history evolution and the polyphenic regulation of somatic maintenance and survival.

Here we discuss life-history evolution from the perspective of adaptive phenotypic plasticity, with a focus on polyphenisms for somatic maintenance and survival. Polyphenisms are adaptive discrete alternative phenotypes that develop in response to changes in the environment. We suggest that dauer larval diapause and its associated adult phenotypes in the nematode (Caenorhabditis elegans), reproductive dormancy in the fruit fly (Drosophila melanogaster) and other insects, and the worker castes of the honey bee (Apis mellifera) are examples of what may be viewed as the polyphenic regulation of somatic maintenance and survival. In these and other cases, the same genotype can--depending upon its environment--express either of two alternative sets of life-history phenotypes that differ markedly with respect to somatic maintenance, survival ability, and thus life span. This plastic modulation of somatic maintenance and survival has traditionally been underappreciated by researchers working on aging and life history. We review the current evidence for such adaptive life-history switches and their molecular regulation and suggest that they are caused by temporally and/or spatially varying, stressful environments that impose diversifying selection, thereby favoring the evolution of plasticity of somatic maintenance and survival under strong regulatory control. By considering somatic maintenance and survivorship from the perspective of adaptive life-history switches, we may gain novel insights into the mechanisms and evolution of aging.

Avaliação de progênies de meios-irmãos da população de milho CMS-453 no Nordeste brasileiro

Três ciclos de seleção entre e dentro de progênies de meios-irmãos foram realizados na população de milho Zea mays L. CMS-453, de alta qualidade protéica, no período de 1995 a 1997, no Nordeste brasileiro, visando à obtenção de um material mais produtivo, melhor adaptado, portador de caracteres agronômicos desejáveis, com altos teores de triptofano e lisina na proteína, para divulgação na região. As 196 progênies de cada ciclo foram avaliadas em látice 14 x 14, com duas repetições, e realizaram-se as recombinações das progênies selecionadas, dentro do mesmo ano agrícola, de modo a se obter um ciclo/ano. As magnitudes das estimativas dos parâmetros genéticos decresceram do ciclo original para o ciclo I de seleção, registrando-se um acréscimo do ciclo I para o ciclo II. Os altos valores dessas magnitudes, associados às altas médias de produtividade das progênies e aos ganhos médio esperado e obtido com a seleção entre e dentro de progênies, por ciclo de seleção de 11,62% e 3,0% respectivamente, evidenciam o grande potencial da população em responder à seleção, o que permitirá a obtenção de um material mais produtivo e melhor adaptado às condições edafoclimáticas da região. Os teores de triptofano e lisina na proteína, na média dos três ciclos de seleção foram de 0,88% e 3,91%, respectivamente, o que confere alta qualidade protéica à população CMS-453.