Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and ...colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.
Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the ...etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting.
In this retrospective study, all patients who underwent a liver biopsy 1984-2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine.
A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01).
Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.
In this article we describe two separate cases of serious eye injuries that were the result of two teenagers´ attempts to make home-made explosives out of fireworks. They had tampered with the same ...brand of fireworks, Víti, that appears to be popular for this purpose and instructions are available on the internet. One boy got an intraocular glass splinter and underwent vitrectomy for removal. The other boy suffered burns on his corneas that were treated with amniotic membranes. In both cases the outcome was better than expected at first. The objective of this article is to draw attention to the danger of tampering with fireworks and the necessity of preventive measures to minimize the risk of serious eye injuries.
In the ligand channel of the cytochrome c oxidase from Rhodobacter sphaeroides (Rs aa3) W172 and F282 have been proposed to generate a constriction that may slow ligand access to and from the active ...site. To explore this issue, the tryptophan and phenylalanine residues in Rs aa3 were mutated to the less bulky tyrosine and threonine residues, respectively, which occupy these sites in Thermus thermophilus (Tt) ba3 cytochrome oxidase. The CO photolysis and recombination dynamics of the reduced wild‐type Rs aa3 and the W172Y/F282T mutant were investigated using time‐resolved optical absorption spectroscopy. The spectral changes associated with the multiple processes are attributed to different conformers. The major CO recombination process (44 μs) in the W172Y/F282T mutant is ~500 times faster than the predominant CO recombination process in the wild‐type enzyme (~23 ms). Classical dynamic simulations of the wild‐type enzyme and double mutant showed significant structural changes at the active site in the mutant, including movement of the heme a3 ring‐D propionate toward CuB and reduced binuclear center cavity volume. These structural changes effectively close the ligand exit pathway from the binuclear center, providing a basis for the faster CO recombination in the double mutant.
We investigated the effect of mutating the tryptophan and phenylalanine residues that define the narrowing of the ligand channel in Rhodobacter sphaeroides aa3 to the less bulky tyrosine and threonine, respectively. Our time‐resolved optical absorption results show that the major CO recombination process in the mutant (44 μs) is 500 times faster than in the wild type (~23 ms). Classical molecular dynamics simulations of the double mutant show significant changes at the active site that effectively close the ligand exit pathway from the binuclear center, providing a structural basis for the faster CO recombination in the double mutant.
Cytochrome bo 3 ubiquinol oxidase from Escherichia coli catalyzes the reduction of O2 to water by ubiquinol. The reaction mechanism and the role of ubiquinol continue to be a subject of discussion. ...In this study, we report a detailed kinetic scheme of the reaction of cytochrome bo 3 with O2 with steps specific to ubiquinol. The reaction was investigated using the CO flow-flash method, and time-resolved optical absorption difference spectra were collected from 1 μs to 20 ms after photolysis. Singular value decomposition-based global exponential fitting resolved five apparent lifetimes, 22 μs, 30 μs, 42 μs, 470 μs, and 2.0 ms. The reaction mechanism was derived by an algebraic kinetic analysis method using frequency-shifted spectra of known bovine states to identify the bo 3 intermediates. It shows 42 μs O2 binding (3.8 × 107 M–1 s–1), producing compound A, followed by faster (22 μs) heme b oxidation, yielding a mixture of P R and F, and rapid heme b rereduction by ubiquinol (30 μs), producing the F intermediate and semiquinone. In the 470 μs step, the o 3 F state is converted into the o 3 3+ oxidized state, presumably by semiquinone/ubiquinol, without the concomitant oxidation of heme b. The final 2 ms step shows heme b reoxidation and the partial rereduction of the binuclear center and, following O2 binding, the formation of a mixture of P and F during a second turnover cycle. The results show that ubiquinol/semiquinone plays a complex role in the mechanism of O2 reduction by bo 3, displaying kinetic steps that have no analogy in the CuA-containing heme-copper oxidases.
Abstract
In the ligand channel of the cytochrome
c
oxidase from
Rhodobacter sphaeroides
(
Rs aa
3
) W172 and F282 have been proposed to generate a constriction that may slow ligand access to and from ...the active site. To explore this issue, the tryptophan and phenylalanine residues in
Rs aa
3
were mutated to the less bulky tyrosine and threonine residues, respectively, which occupy these sites in
Thermus thermophilus
(
Tt
)
ba
3
cytochrome oxidase. The
CO
photolysis and recombination dynamics of the reduced wild‐type
Rs aa
3
and the W172Y/F282T mutant were investigated using time‐resolved optical absorption spectroscopy. The spectral changes associated with the multiple processes are attributed to different conformers. The major
CO
recombination process (44 μs) in the W172Y/F282T mutant is ~500 times faster than the predominant
CO
recombination process in the wild‐type enzyme (~23 ms). Classical dynamic simulations of the wild‐type enzyme and double mutant showed significant structural changes at the active site in the mutant, including movement of the heme
a
3
ring‐D propionate toward Cu
B
and reduced binuclear center cavity volume. These structural changes effectively close the ligand exit pathway from the binuclear center, providing a basis for the faster
CO
recombination in the double mutant.
Cytochrome bo₃ ubiquinol oxidase from Escherichia coli catalyzes the reduction of O₂ to water by ubiquinol. The reaction mechanism and the role of ubiquinol continue to be a subject of discussion. In ...this study, we report a detailed kinetic scheme of the reaction of cytochrome bo₃ with O₂ with steps specific to ubiquinol. The reaction was investigated using the CO flow-flash method, and time-resolved optical absorption difference spectra were collected from 1 μs to 20 ms after photolysis. Singular value decomposition-based global exponential fitting resolved five apparent lifetimes, 22 μs, 30 μs, 42 μs, 470 μs, and 2.0 ms. The reaction mechanism was derived by an algebraic kinetic analysis method using frequency-shifted spectra of known bovine states to identify the bo3 intermediates. It shows 42 μs O₂ binding (3.8 × 10(7) M(-1) s(-1)), producing compound A, followed by faster (22 μs) heme b oxidation, yielding a mixture of PR and F, and rapid heme b rereduction by ubiquinol (30 μs), producing the F intermediate and semiquinone. In the 470 μs step, the o₃ F state is converted into the o₃(3+) oxidized state, presumably by semiquinone/ubiquinol, without the concomitant oxidation of heme b. The final 2 ms step shows heme b reoxidation and the partial rereduction of the binuclear center and, following O₂ binding, the formation of a mixture of P and F during a second turnover cycle. The results show that ubiquinol/semiquinone plays a complex role in the mechanism of O₂ reduction by bo₃, displaying kinetic steps that have no analogy in the CuA-containing heme-copper oxidases.
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