Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome

Velo-cardio-facial syndrome/DiGeorge syndrome results from unequal crossing-over events between two 240-kb low-copy repeats termed LCR22 (LCR22-2 and LCR22-4) on Chromosome 22q11.2, comprised of modules, each of which are >99% identical in sequence. To delineate regions in the LCR22s that might contain hotspots for 22q11.2 rearrangements, we scanned the interval for increased rates of recombination with the hypothesis that these regions might be more prone to breakage. We generated an algorithm to detect sites of altered recombination by searching for single nucleotide polymorphic positions in BAC clones from different libraries mapped to LCR22-2 and LCR22-4. This method distinguishes single nucleotide polymorphisms from paralogous sequence variants and complex polymorphic positions. Sites of shared polymorphism are considered potential sites of gene conversion or double cross-over between the two LCR22s. We found an inverse correlation between regions of paralogous sequence variants that are unique to a given position within one LCR22 and clusters of shared polymorphic sites, suggesting that these clusters depict altered recombination and not remnants of ancestral single nucleotide polymorphisms. We postulate that most shared polymorphic sites are products of past transfers of DNA information between the LCR22s, suggesting that frequent traffic of genetic material may induce genomic instability in the two LCR22s. We also found that gaps up to 1.5 kb long can be transferred between LCR22s.     

Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27

Genetic linkage studies indicate that germline variations in a gene or genes on chromosome Xq27-28 are implicated in prostate carcinogenesis. The linkage peak of prostate cancer overlies a region of approximately 750 kb containing five SPANX genes (SPANX-A1, -A2, -B, -C, and -D) encoding sperm proteins associated with the nucleus; their expression was also detected in a variety of cancers. SPANX genes are >95% identical and reside within large segmental duplications (SDs) with a high level of similarity, which confounds mutational analysis of this gene family by routine PCR methods. In this work, we applied transformation-associated recombination cloning (TAR) in yeast to characterize individual SPANX genes from prostate cancer patients showing linkage to Xq27-28 and unaffected controls. Analysis of genomic TAR clones revealed a dynamic nature of the replicated region of linkage. Both frequent gene deletion/duplication and homology-based sequence transfer events were identified within the region and were presumably caused by recombinational interactions between SDs harboring the SPANX genes. These interactions contribute to diversity of the SPANX coding regions in humans. We speculate that the predisposition to prostate cancer in X-linked families is an example of a genomic disease caused by a specific architecture of the SPANX gene cluster.     

Increase in IL-6, TNF-α, and MMP-9, but not sICAM-1, concentrations depends on exercise duration

It has been suggested that exercise intensity is of importance in the regulation of increase in pro-inflammatory molecules, but there is still a debate about the effect of duration on these molecules. Therefore, the effect of exercise duration on the serum concentrations of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), soluble form of intercellular adhesion molecule-1 (sICAM-1), and matrix metalloproteinase-9 (MMP-9) was studied in 22 half-marathon (HM) and 18 marathon (M) male amateur runners who completed their exercise task in 1.8 ± 0.2 (mean ± standard deviation) and 3.6 ± 0.4 h, respectively (thus, average speed was 11.7 ± 1.5 and 11.9 ± 1.8 km h^?1, respectively). Blood was sampled 2 days before, 15 min after, and 28 h after the race. IL-6, TNF-α, and MMP-9 always increased immediately after exercise, but the increase was larger (P < 0.05) in M versus HM (?IL-6: 31 ± 24 vs. 5 ± 4 pg ml^?1; ?TNF-α: 1.7 ± 1.9 vs. 0.5 ± 0.8 pg ml^?1; MMP-9: 288 ± 216 vs. 145 ± 128 ng ml^?1, respectively). sICAM-1 also increased with exercise, but similarly in M and HM (20 ± 40 vs. 23 ± 32 ng ml^?1, respectively). Only sICAM-1 remained elevated 28 h post-exercise in both HM and M, while IL-6, TNF-α, and MMP-9 returned to pre-exercise levels. Competitive HM and M races induce significant increases in IL-6, TNF-α, sICAM-1, and MMP-9 concentrations. As HM and M runners performed the competition with similar absolute intensity, the difference in response between the groups suggests that exercise duration is of importance in the regulation of IL-6, TNF-α, and MMP-9, but not sICAM-1 concentrations in response to prolonged running.     

Evolutionary dynamics of transposable elements in the short-tailed opossum Monodelphis domestica

The genome of the gray short-tailed opossum Monodelphis domestica is notable for its large size ( approximately 3.6 Gb). We characterized nearly 500 families of interspersed repeats from the Monodelphis. They cover approximately 52% of the genome, higher than in any other amniotic lineage studied to date, and may account for the unusually large genome size. In comparison to other mammals, Monodelphis is significantly rich in non-LTR retrotransposons from the LINE-1, CR1, and RTE families, with >29% of the genome sequence comprised of copies of these elements. Monodelphis has at least four families of RTE, and we report support for horizontal transfer of this non-LTR retrotransposon. In addition to short interspersed elements (SINEs) mobilized by L1, we found several families of SINEs that appear to use RTE elements for mobilization. In contrast to L1-mobilized SINEs, the RTE-mobilized SINEs in Monodelphis appear to shift from G+C-rich to G+C-low regions with time. Endogenous retroviruses have colonized approximately 10% of the opossum genome. We found that their density is enhanced in centromeric and/or telomeric regions of most Monodelphis chromosomes. We identified 83 new families of ancient repeats that are highly conserved across amniotic lineages, including 14 LINE-derived repeats; and a novel SINE element, MER131, that may have been exapted as a highly conserved functional noncoding RNA, and whose emergence dates back to approximately 300 million years ago. Many of these conserved repeats are also present in human, and are highly over-represented in predicted cis-regulatory modules. Seventy-six of the 83 families are present in chicken in addition to mammals.     

MLST of housekeeping genes captures geographic population structure and suggests a European origin of Borrelia burgdorferi

Lyme borreliosis, caused by the tick-borne bacterium Borrelia burgdorferi, has become the most common vector-borne disease in North America over the last three decades. To understand the dynamics of the epizootic spread and to predict the evolutionary trajectories of B. burgdorferi, accurate information on the population structure and the evolutionary relationships of the pathogen is crucial. We, therefore, developed a multilocus sequence typing (MLST) scheme for B. burgdorferi based on eight chromosomal housekeeping genes. We validated the MLST scheme on B. burgdorferi specimens from North America and Europe, comprising both cultured isolates and infected ticks. These data were compared with sequences for the commonly used genetic markers rrs-rrlA intergenic spacer (IGS) and the gene encoding the outer surface protein C (ospC). The study demonstrates that the concatenated sequences of the housekeeping genes of B. burgdorferi provide highly resolved phylogenetic signals and that the housekeeping genes evolve differently compared with the IGS locus and ospC. Using sequence data, the study reveals that North American and European populations of B. burgdorferi correspond to genetically distinct populations. Importantly, the MLST data suggest that B. burgdorferi originated in Europe rather than in North America as proposed previously.     

Intertrochanteric valgus lengthening osteotomy in adults with coxa vara

Surgical Principles Intertrochanteric open wedge valgus osteotomy with lateral femoral displacement to gain limb length. Internal fixation with a 95° condylar plate. Revised Version from: Operat. Orthop. Traumatol. 2 (1990), 193–202 (German Edition).     

A fundamental division in the Alu family of repeated sequences.

The Alu family of repeated sequences from the human genome contains two distinct subfamilies. This division is based on different base preferences in a number of diagnostic sequence positions. One subfamily of the sequences, referred to as the Alu-J subfamily, is very similar to 7SL DNA in these positions. The other subfamily, Alu-S, can be divided further into well-defined branches of sequences. These findings revise the previous picture of the Alu family and expose their complex evolutionary dynamics. They reveal sequence variations of potential importance for the proliferation of Alu repeats and relate them to their structural features. In addition, they open the possibility of using different types of Alu sequences as natural markers for studying genetic rearrangements in the genome.     

Haemodynamic variables and functional outcome in hypothermic patients following out-of-hospital cardiac arrest

Aim of the study

To evaluate the association between haemodynamic variables during the first 24 h after intensive care unit (ICU) admission and neurological outcome in out-of-hospital cardiac arrest (OHCA) victims undergoing therapeutic hypothermia.

Methods

In a multi-disciplinary ICU, records were reviewed for comatose OHCA patients undergoing therapeutic hypothermia. The hourly variable time integral of haemodynamic variables during the first 24 h after admission was calculated. Neurologic outcome was assessed at day 28 and graded as favourable or adverse based on the Cerebral Performance Category of 1–2 and 3–5. Bi- and multivariate regression models adjusted for confounding variables were used to evaluate the association between haemodynamic variables and functional outcome.

Results

67/134 patients (50%) were classified as having favourable outcome. Patients with adverse outcome had a higher mean heart rate (73 [62–86] vs. 66 [60–78] bpm; p = 0.04) and received noradrenaline more frequently (n = 17 [25.4%] vs. n = 9 [6%]; p = 0.02) and at a higher dosage (128 [56–1004] vs. 13 [2–162] μg h⁻¹; p = 0.03) than patients with favourable outcome. The mean perfusion pressure (mean arterial blood pressure minus central venous blood pressure) (OR = 1.001, 95% CI  = 1–1.003; p = 0.04) and cardiac index time integral (OR = 1.055, 95% CI = 1.003–1.109; p = 0.04) were independently associated with adverse outcome at day 28.

Conclusion

Mean perfusion pressure and cardiac index during the first 24 h after ICU admission were weakly associated with neurological outcome in an OHCA population undergoing therapeutic hypothermia. Further studies need to elucidate whether norepinephrine-induced increases in perfusion pressure and cardiac index may contribute to adverse neurologic outcome following OHCA.