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Background: Muscle disease associated with different etiologies has been shown to produce localized accumulations of amyloid and oxidative stress-related proteins that are more commonly associated with neurodegeneration in the brain. In this study we examined changes in muscle tissue in a classic model of diabetes and hyperglycemia in wild-type rabbits to determine if similar dysregulation of Alzheimer Abeta peptides, the prion protein (PrP), and Superoxide dismutase 1 (SOD1), as well as Nitric oxide synthases is produced in muscle in diabetic animals. This wild-type rabbit model includes systemic physiological expression of human-like Alzheimer precursor proteins and Abeta peptides that are considered key in Alzheimer protein studies. Results: Diabetes was produced in otherwise normal rabbits by injection of the toxic glucose analogue alloxan, which selectively enters pancreatic beta cells and irreversibly decreases insulin production, similar to streptozotocin. Quadriceps muscle from rabbits 16 wks after onset of diabetes and hyperglycemia were analyzed with biochemical and in situ methods. Immunoblots of whole muscle protein samples demonstrated increased PrP, SOD1, as well as neuronal and inducible Nitric oxide synthases (NOS1 and NOS2) in diabetic muscle. In contrast, we detected little or no change in Alzheimer precursor protein (APP) levels. However, Abeta peptides measured by ELISA increased several fold in diabetic muscle, suggesting a key role for Abeta cleavage in muscle similar to Alzheimer neurodegeneration in this diabetes model. Histological changes in diabetic muscle included localized accumulations of PrP, Abeta, NOS1 and 2, and SOD1, and evidence of increased central nuclei and cell infiltration. Conclusions: The present study provides evidence that several classic amyloid and oxidative stress-related disease proteins coordinately increase in overall expression and form localized accumulations in diabetic muscle. The present study highlights the capacity of this wild-type animal model to produce an array of hallmark pathological features that have been also been described in other muscle diseases.

Background: Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months.Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective. Methods: In the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E.Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety.DiscussionThe Cleopatra Trial is the first study to evaluate the effect of carbon ion radiotherapy within multimodality treatment of primary glioblastoma in a randomized trial comparing this innovative treatment of the treatment standard, consisitng of photon radiotherapy in combination with temozolomide.Trial Registration:ISRCTN37428883 and NCT01165671

Background: Because of the implant-related problems with pedicle screw-based spinal instrumentations, other types of fixation have been tried in spinal arthrodesis. One such technique is the direct trans-pedicular, trans-discal screw fixation, pioneered by Grob for spondylolisthesis. The newly developed GO-LIF procedure expands the scope of the Grob technique in several important ways and adds security by means of robotic-assisted navigation. This is the first clinical trial on the GO-LIF procedure and it will assess safety and efficacy.Methods / Design: Multicentric prospective study with n=40 patients to undergo single level instrumented spinal arthrodesis of the lumbar or the lumbosacral spine, based on a diagnosis of: painful disc degeneration, painful erosive osteochondrosis, segmental instability, recurrent disc herniation, spinal canal stenosis or foraminal stenosis. The primary target criteria with regards to safety are: The number, severity and cause of intra- and perioperative complications. The number of significant penetrations of the cortical layer of the vertebral body by the implant as recognized on postoperative CT. The primary target parameters with regards to feasibility are: Performance of the procedure according to the preoperative plan. The planned follow-up is 12 months and the following scores will be evaluated as secondary target parameters with regards to clinical improvement: VAS back pain, VAS leg pain, Oswestry Disability Index, short form - 12 health questionnaire and the Swiss spinal stenosis questionnaire for patients with spinal claudication. The secondary parameters with regards to construct stability are visible fusion or lack thereof and signs of implant loosening, implant migration or pseudarthrosis on plain and functional radiographs.DiscussionThis trial will for the first time assess the safety and efficacy of guided oblique lumbar interbody fusion. There is no control group, but the results, the outcome and the rate of any complications will be analyzed on the background of the literature on instrumented spinal fusion. Despite its limitations, we expect that this study will serve as the key step in deciding whether a direct comparative trial with another fusion technique is warranted.Trial Registration: Clinical Trials NCT00810433

Background: Meiotic prophase is a critical stage in sexual reproduction. Aberrant chromosome recombination during this stage is a leading cause of human miscarriages and birth defects. However, due to the experimental intractability of mammalian gonads, only a very limited number of meiotic genes have been characterized. Here we aim to identify novel meiotic genes important in human reproduction through computational mining of cross-species and cross-sex time-series expression data from budding yeast, mouse postnatal testis, mouse embryonic ovary, and human fetal ovary. Results: Orthologous gene pairs were ranked by order statistics according to their co-expression profiles across species, allowing us to infer conserved meiotic genes despite obvious differences in cellular synchronicity and composition in organisms. We demonstrated that conserved co-expression networks could successfully recover known meiotic genes, including homologous recombination genes, chromatin cohesion genes, and genes regulating meiotic entry. We also showed that conserved co-expression pairs exhibit functional connections, as evidenced by the annotation similarity in Gene Ontology and overlap with physical interactions. More importantly, we predicted six new meiotic genes through their co-expression linkages with known meiotic genes, and subsequently used the genetically more amenable yeast system for experimental validation. The deletion mutants of all six genes showed sporulation defects, equivalent to a 100% validation rate. Conclusions: We identified evolutionarily conserved gene modules in meiotic prophase by integrating cross-species and cross-sex expression profiles from budding yeast, mouse, and human. Our co-expression linkage analyses confirmed known meiotic genes and identified several novel genes that might be critical players in meiosis in multiple species. These results demonstrate that our approach is highly efficient to discover evolutionarily conserved novel meiotic genes, and yeast can serve as a valuable model system for investigating mammalian meiotic prophase.

Background: Epidemiological studies on the association between maternal exposure to persistent organic pollutants (POPs) and fetal growth alteration report inconsistent findings which weights in favor of additional studies. Methods: Blood samples were collected from interviewed pregnant women in Greenland (572), Kharkiv (611) and Warsaw (258) and were analyzed for CB-153 and p,p'-DDE by gas chromatography-mass spectrometry. Data on birth weight, gestational age and preterm birth were obtained for 1322 singleton live births. We examined the association between natural log-transformed serum POPs concentration and birth weight and gestational age using multiple linear regression and the association with prematurity using logistic regression controlling for potential confounding factors. Results: The median serum concentrations of CB-153 and p,p'-DDE were for Inuit mothers 105.6 and 298.9, for Kharkiv mothers 27.0 and 645.4 and for Warsaw mothers 10.7 and 365.2 ng/g lipids, respectively. Increase in CB-153 concentration by one unit on the log scale in Inuit mothers serum was associated with significant decrease in infant birth weight of -59 g and gestational age by -0.2 week. Decreases observed in the cohorts in Kharkiv (-10 g and -0.1 week) and in Warsaw (-49 g and -0.2 week) were not statistically significant. Increase in p,p'-DDE concentration by one unit on the log scale was associated with a statistically significant decrease in infant birth weight of -39.4g and -104.3 g and shortening of gestational age of -0.2 week and -0.6 week in the Inuit and Warsaw cohorts, respectively. In the Kharkiv cohort decrease in birth weight (-30.5 g) was not significant, however a shortening of gestational age of -0.2 week per increase in p,p'-DDE concentration by one unit on the log scale was of the borderline significance. There was no significant association between CB-153 and p,p'-DDE concentrations and risk of preterm birth however, in all cohorts the odds ratio was above 1. Conclusions: In utero exposure to POPs may reduce birth weight and gestational age of newborns however, new insights as to why results vary across studies were not apparent.

Background: Imprisonment may lead to the development of mental illness, especially depression. This study examines the clinical and sociodemographic profiles of imprisoned women, identifies indicative signs of depression, and relates these indicators to other variables. Methods: This study took the form of descriptive exploratory research with a psychometric evaluation. A total of 100 of 300 women in a female penitentiary were interviewed. A questionnaire with sociodemographic, clinical and penal situation information was used, along with the Beck Depression Inventory. The authors performed bivariate and multivariate analysis regarding depression. Results: In all, 82 women presented signs of depression (light = 33, mild = 29 and severe = 20). Comorbidities, lack of religious practice, absence of visitors and presence of eating disorders were risk factors for depression (P = 0.03, 0.03, 0.02, 0.04, and 0.01). Being older was a protection factor against severe depression; for women over 30, the risk of depression was multiplied by 0.12. The rate of depression among women prisoners was high. Conclusions: Comorbidities, the lack of religious practice, not having visitors and eating disorders are significant risk factors for depression, while age is a protective factor, among incarcerated women.

Background: Although injuries due to circular saws are very common all over the world, there is surprisingly little information available about their functional outcomes. As the socioeconomic impact of these injuries is immense and determined by the casualties' disability and impairment, it is the objective of this study to present data on the functional outcome, disability, and impairment of hand injuries due to electric circular saws. Methods: Patients treated from 1999 through 2007 for circular saw-related hand injuries were contacted and asked for clinical follow-up assessment. The clinical follow-up protocol consisted of a physical examination and an assessment of static muscle power (grip and pinch strength). For assessment of the subjective experience of the patients regarding their injury-related disability and impairment, the DASH follow-up questionnaire was used. The occupational impact of these injuries was measured by number of lost working days. Finally, safety-related behaviour of the patients was investigated. Results: 114 Patients were followed-up on average 52 months after the injury. Average in-house treatment was 8.8 days. Average time lost from work was 14.8 weeks. A significant reduction of static muscle testing parameters compared with the uninjured hand was revealed for grip strength, tip pinch, key pinch, and palmar pinch. Average DASH score was 17.4 (DASH work 15.8, DASH sports/music 17.7). Most patients had more than ten years experience in using these power tools. Conclusion: The everyday occurrence of circular saw-related hand injuries followed by relatively short periods of in-house treatment might distort the real dimension of the patients' remaining disability and impairment. While the trauma surgeon's view is generally confined to the patients' clinical course, the outcome parameters in this follow-up investigation, with loss of working time as the key factor, confirm that the whole socioeconomic burden is much greater than the direct cost of treatment.

Background: To implement an Insecticide Resistance Management (IRM) strategy through a randomized controlled trial (phase III), 28 villages were selected in southern Benin. No recent entomological data being available in these villages, entomological surveys were performed between October 2007 and May 2008, before vector control strategies implementation, to establish baseline data. Methods: Mosquitoes were sampled by human landing collection (16 person-nights per village per survey per village) during 5 surveys. Mosquitoes were identified morphologically and by molecular methods. The Plasmodium falciparum circumsporozoite indexes were measured by ELISA, and the entomological inoculation rates (EIRs) were calculated. Molecular detection of pyrethroid knock down resistance (Kdr) and of insensitive acetylcholinesterase were performed. Results: 44,693 mosquitoes belonging to 28 different species were caught from October 2007 to May 2008. Among mosquitoes caught, 318 were An. gambiae s.s., 2 were An. nili, 568 were An. funestus s.s., and one individual was An. leesoni. EIR was 2.05+/-1.28 infective bites per human per 100 nights on average, of which 0.67+/-0.60 were from An. funestus and 1.38+/-0.94 infective bites were from An. gambiae. Important variations were noted between villages considering mosquito density and malaria transmission indicating a spatial heterogeneity in the study area. The kdr allelic frequency was 28.86% in An. gambiae s.s. on average and significantly increases from October 2007 (10.26%) to May 2008 (33.87%) in M molecular form of An. gambiae s.s. Ace 1 mutation was found in S molecular of An. gambiae s.s at a low frequency (<1%). Conclusion: This study updates information on mosquito diversity and malaria risk in rural villages from south Benin. It showed a high spatial heterogeneity in mosquito distribution and malaria transmission and underlines the need of further investigations of biological, ecological, and behavioral traits of malaria vectors species and forms. This study is a necessary prerequisite to cartography malaria risk and to improve vector control operations in southern Benin.

IntroductionGravimetric validation of single-indicator extravascular lung water (EVLW) and normal EVLW values have not been well studied in humans thus far. The aims of this study were (1) to validate the accuracy of EVLW measurement by single transpulmonary thermodilution with postmortem lung weight measurement in humans and (2) to define the statistically normal EVLW values. Methods: We evaluated the correlation between pre-mortem EVLW value by single transpulmonary thermodilution and post-mortem lung weight from 30 consecutive autopsies completed within 48 hours following the final thermodilution measurement. A linear regression equation for the correlation was calculated. In order to clarify the normal lung weight value by statistical analysis, we conducted a literature search and obtained the normal reference ranges for post-mortem lung weight. These values were substituted into the equation for the correlation between EVLW and lung weight to estimate the normal EVLW values. Results: EVLW determined using transpulmonary single thermodilution correlated closely with post-mortem lung weight (r = 0.904, P < 0.001). A linear regression equation was calculated: EVLW (mL) = 0.56 lung weight (g) 58.0. The normal EVLW values indexed by predicted body weight were approximately 7.4 +/- 3.3 mL/kg (7.5 +/- 3.3 mL/kg for males and 7.3 +/- 3.3 mL/kg for females). Conclusions: A definite correlation exists between EVLW measured by the single-indicator transpulmonary thermodilution technique and post-mortem lung weight in humans. The normal EVLW value is approximately 7.4 +/- 3.3 mL/kg.Trial Registration: UMIN000002780.

Background: The results of an in vivo study on the "ratio method" used in electronic foramen locators (EFL) are presented. EFLs are becoming widely used in the determination of the working length (WL) during the root canal treatment. The WL is the distance from a coronal reference point to the point at which canal preparation and filling should terminate. The "ratio method" was assessed by many clinicians with the aim of determining its ability to locate the apical foramen (AF). Nevertheless, in vivo studies to assess the method itself and to explain why the "ratio method" is able to locate the apical foramen and is unable to determine intermediate distances were not published so far. Methods: A developed apparatus applies an electrical current signal with constant amplitude of 10uARMS through the endodontic file within the root canal. The applied current signal is composed by summing six sine waves, from 250 Hz to 8 kHz. Data were acquired with the endodontic file tip at 7 different positions within root canals. In the frequency domain the quotients between the amplitude of a reference frequency and the amplitudes of the other frequencies components were calculated. Twenty one root canals were analyzed in vivo, during the endodontic treatment of twelve teeth of different patients, with age between 20 to 55 years. Results: For the range of frequencies used in the commercial EFLs and for distances ranging from -3 mm to -1 mm of the AF, the impedance of the root canal is mainly resistive. However, when the file tip gets closer to AF, the root canal electrical impedance starts to change from a mainly resistive to a complex impedance. This change in the measured root canal impedance starts when the file tip is near -1.0 mm from the AF, getting stronger as the file tip gets closer to the AF. This change in the impedance behavior affects the ratio (quotient) of the impedance measured at different frequencies. Through graphic analysis it is demonstrated why EFLs based on the ratio method are unable to accurately measure any distances between -3.0 and -0.5 mm from the apical foramen. The only reliable measurement is the 0 mm distance, which is when the file tip is at the AF. Conclusions: The electrical impedance values of 21 root canals were in vivo studied. The results confirm the ability of EFLs that are based on the ratio method to accurately locate the AF position and explain why they are unable to determine the file tip position along the root canal.