Cryo-EM structures of intermediates suggest an alternative catalytic reaction cycle for cytochrome c oxidase.

Cytochrome c oxidases are among the most important and fundamental enzymes of life. Integrated into membranes they use four electrons from cytochrome c molecules to reduce molecular oxygen (dioxygen) to water. Their catalytic cycle has been considered to start with the oxidized form. Subsequent electron transfers lead to the E-state, the R-state (which binds oxygen), the P-state (with an already split dioxygen bond), the F-state and the O-state again. Here, we determined structures of up to 1.9 Å resolution of these intermediates by single particle cryo-EM. Our results suggest that in the O-state the active site contains a peroxide dianion and in the P-state possibly an intact dioxygen molecule, the F-state may contain a superoxide anion. Thus, the enzyme's catalytic cycle may have to be turned by 180 degrees.

Re-irradiation for recurrent glioblastoma multiforme: a critical comparison of different concepts.

PURPOSE: Purpose of this study was to investigate outcome and toxicity of re-irradiation for recurrent primary glioblastoma (rGBM). We evaluated a group of patients with rGBM and identical primary treatment comprising adjuvant radiotherapy (30â€¯× 2 Gy) with concurrent temozolomide (TMZ). METHODS: In this retrospective study of 46 patients, all received adjuvant or definitive normofractionated radiotherapy to a pretreated area, some with concurrent chemotherapy. Impact of different clinical, histological, or epidemiological factors on survival and radiation toxicity was reviewed. RESULTS: Of 46 patients, 40 completed the intended therapy. Overall survival (OS) was 20 months (range 6-72 months). Overall survival and progression-free survival after re-irradiation (OS2 and PFS2) were 9.5 and 3.4 months (range 2-40 and 0.7-44 months). Simultaneous systemic therapy improved PFS2 and OS2 (4.3 vs. 2.0, p < 0.001 and 12 vs. 4 months, p = 0.13, respectively). Therapy with TMZ or bevacizumab improved PFS2 vs. nitrosureas (6.6 vs. 2.9, p = 0.03 and 5.1 vs. 2.9 months, p = 0.035, respectively). TMZ also improved PFS2 and OS2 vs. all other systemic therapies (6.6 vs. 4, p < 0.001 and 17 vs. 10 months, p = 0.1). In a subgroup analysis for patients with methylation of the MGMT promoter, doses of >36 Gy as well as TMZ vs. no systemic therapy improved PFS2 (p = 0.045 and p = 0.03, respectively). 27.5% of all patients had no acute toxicity. Three patients with acute and four patients with late grade 3 toxicities were reported. CONCLUSION: Normofractionated radiotherapy is a feasible option for rGBM with a good toxicity profile. Simultaneously applied systemic therapy was associated with improved outcome. For MGMT promoter-methylated histology, higher radiation doses improved survival.

[Adherence to Long-term Follow-up in Paediatric Oncology--Results of a Monocentric Analysis]. / Nachsorgeadhärenz in der Pädiatrischen Onkologie - Ergebnisse einer monozentrischen Analyse.

BACKGROUND: Cured paediatric-oncology patients frequently present with health problems even years after treatment. Hence long-term follow-up (LTFU) is essential. This analysis tries to identify factors that influence regular LTFU attendance. STUDY POPULATION: Between 1991 and 2010, 2 153 children and adolescents were treated at Muenster University Department of Paediatric Hematology and Oncology (UKM). 1 708 patients with permanent residence in Germany and completed therapy have been included into this analysis. METHODS: Patients were reviewed for the duration and regularity of LTFU at UKM. Prospective analyses with postponed starting-points have been conducted as well as descriptive analyses to validate correlations. Prospective data were evaluated by Kaplan-Meier-Analyses, the analysis of multivariate correlations by Cox Proportional Hazard Model. RESULTS: 2 years after the end of therapy 83% of the patients were still in LTFU. After 5 and 10 years this percentage decreased to 67 and 42%. Patients diagnosed after the year 2000 and younger patients attended LTFU for a longer period (p<0,005). There were no significant gender differences. Statutory insured patients stayed longer in LTFU than private health insured (p<0,005). The multivariate examination showed only small differences between systemic diseases and solid tumours. The residential distance had no significant influence. CONCLUSIONS: Younger, more recently treated and statutory insured patients showed a significantly longer LTFU.

Gender and racial/ethnic differences in tobacco-dependence treatment: a commentary and research recommendations.

The preparation of the Public Health Service Report, Treating Tobacco Use and Dependence, brought to light a substantial gap in the smoking cessation literature; there is little or no research evidence regarding the success of formal tobacco-dependence treatment specific to gender or racial/ethnic status. Of the 192 articles included in the meta-analyses of the evidence-based PHS Report, none included results based on racial/ethnic group and only four reported results by gender. This commentary identifies tobacco use as a problem that crosses gender and racial/ethnic boundaries, reviews reasons that the different genders or racial/ethnic groups might require different tobacco-dependence treatments, provides suggestive evidence that both gender and racial/ethnic status influence tobacco-dependence treatment efficacy, and recommends changes and directions for future clinical research that will address gender and racial/ethnicity effects.

Helping Wisconsin women quit smoking: a successful collaboration.

The cost of treatments for tobacco dependence frequently presents a financial barrier to their use. To overcome such barriers, the Wisconsin Women's Health Foundation, the Wisconsin Bureau of Public Health, the McNeil Consumer Healthcare, and the University of Wisconsin Center for Tobacco Research and Intervention collaborated in an initiative to distribute nicotine patches to Wisconsin women at no cost. As a result of this collaborative effort, approximately 19,000 women received a 6-week course of Nicotrol Patches. To evaluate the effectiveness of this initiative, a sample of 500 recipients were contacted and surveyed by telephone 6 months after receiving their patches. Approximately 22% of these women reported total abstinence at 6 months, and another 77% reported they had reduced their smoking. At follow-up, women who had successfully quit rated their health status significantly better than women who were still smoking. More than 99% of respondents recommended that the program be repeated. Extrapolating the observed abstinence rate to the 19,000 patch recipients, an estimated 4000 Wisconsin women successfully quit smoking as a result of this program.

[Study on quality assurance in the prevention and therapy of decubitus ulcer by measuring the overlay pressure with test subjects on different prophylaxis systems]. / Studie zur Qualitätssicherung in der Prophylaxe und Therapie des Dekubitus durch Auflagedruckmessungen bei Probanden auf verschiedenen Weichlagerungs- und Wechseldrucksystemen.

The aim of this study on quality assurance in prevention and treatment of bedsores was to analyse the current state of treatment of pressure sores at the University Hospital in Marburg. Measurements of pressure exerted on the skin were taken of six soft storage systems and five alternating pressure systems. In addition, the study aimed to find out whether the applied method of pneumatic pressure measurement could be used with patients in every day nursing and whether reliable and valid data could be generated from patients who have already developed bedsores. In order to answer these questions measurements were taken on 23/19 patients, including patients in lateral position, placing measuring instruments between the mattress/bed system and the body. The soft storage systems results prove a significant pressure reduction at all measuring points (p < 0.05), at the os coccygis even a highly significant pressure reduction (p < 0.01). The alternating pressure systems results show that the average maximum pressure over 12 min lies between 56.39 mmHg and 38.94 mmHg with differing amplitudes (75.47 mmHg-5 mmHg) and alternating frequency (1.5 min-10 min).

Development and validation of the Wisconsin Smoking Withdrawal Scale.

The accurate assessment of nicotine withdrawal is important theoretically and clinically. A 28-item scale, the Wisconsin Smoking Withdrawal Scale, was developed that contains 7 reliable subscales tapping the major symptom elements of the nicotine withdrawal syndrome. Coefficients alpha for the subscales range from .75 to .93. This scale is sensitive to smoking withdrawal, is predictive of smoking cessation outcomes, and yields data that conform to a 7-factor structure. The 7 scales predicted intratreatment smoking, chi2(7, N = 163) = 15.19, p = .034. Moreover, the questionnaire is sufficiently brief so that it can be used in both clinical and research contexts.

Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains.

Glut1 is a specific transporter system that mediates glucose transfer across the blood-brain barrier (BBB). Although the main location of Glut1 is in the capillary endothelium of the brain, its local distribution in different brain regions is not as well defined. In the present investigation, the local pattern of Glut1 distribution was determined in 13 brain structures using an immunoautoradiographic method developed for this purpose. A polyclonal antibody directed against the C-terminal amino acid sequence of Glut1 was applied to cryosections of rat brains. A secondary antibody was added that had been coupled to [35S]. Results show a heterogeneous distribution of Glut1 in the brain with activities of [35S] ranging from 65% below to 15% above the mean. White matter activity was lower than gray matter activity. For comparison, capillary sections were counted in corresponding cryosections by indirect immunofluorescence using fibronectin antibodies. In addition, local cerebral glucose utilization (LCGU) was analyzed in identical brain structures of conscious rats by the quantitative autoradiographic 2-deoxyglucose method. Significant correlations were found between Glut1 density and either LCGU or capillary density. Results indicate a tight coupling of Glut1 transporter density and capillary density to the LCGU of different BBB structures in adult rats.

Antiphospholipid syndrome in pregnancy. Obstetric concerns and treatment.

To be sure, antiphospholipid antibody syndrome is a protean disease with many manifestations, some of which are exacerbated during pregnancy, and some of which even lead to its initial diagnosis during pregnancy. Although the best treatment during pregnancy is uncertain at this point, and some of the treatments are even experimental, there does seem to be a benefit in at least identifying and probably treating those with risk factors. If treatment is not instituted with heparin, aspirin, or other medical management, at least monitoring for the known superimposed disease states, such as intrauterine growth retardation, preeclampsia, and fetal loss, should be judicious, with close antenatal surveillance.

Decline and preservation of reversal learning abilities and acquisition in the course of senescence.

Different types of learning and memory functions decrease at different rates in senescence. The present study examines which types of mental functions show a relatively early decline and which learning abilities are relatively preserved in late senescence by investigating different types of learning abilities in water maze tests. Two groups of senescent male Wistar rats aged 24 months (group W24) and 30 months (group W30), respectively, were compared to adult rats (12 months, group W12). Group W24 represents 'senescent' and group W30 'late-senescent' rats. Whereas acquisition showed a relatively late decline (in group W30), reversal learning was impaired relatively early (group W24).

Regional congruence and divergence of glucose transporters (GLUT1) and capillaries in rat brains.

The association of glucose transporters (GLUT1) and brain capillaries was tested in different brain structures of rats by a direct comparison of the topologies of capillaries and GLUT1 in identical brain sections. Antibody staining of capillaries (fibronectin) and GLUT1 were made visible by fluorescence microscopy. The results showed differences between brain structures containing a tight and a leaky blood-brain barrier. All capillaries of brain structures with a tight blood-brain barrier showed congruent staining of GLUT1 and capillary morphology. The circumventricular organs that are known to have leaky barrier capillaries were stained by fibronectin antibodies but not by GLUT1 antibodies. Ependymal cells showed moderate staining by GLUT1 antibodies both in areas with tight and leaky barriers. The subcommissural organ appeared to be unique showing neither capillary nor GLUT1 stain. It is concluded that glucose transporters (GLUT1) exist in all brain capillaries of blood-brain barrier structures, whereas they are absent in leaky barrier structures. Moderate amounts of glucose transporter (GLUT1) can also be detected in ependymal cells.