A modification of flattening filter free linac for IMRT.
This study investigates the benefits of a modified flattening filter free (FFF) linac over the standard (STD) linac equipped with the flattening filter. Energy and angular spread of the electron beam of the FFF linac were modified. Modification of FFF beam parameters is explored to maximize the monitor unit efficiency and to minimize the head scatter in IMRT delivery for large target volumes or targets lying away from the central axis. The EGSnrc code is used to model FFF and STD linacs and study basic beam properties for both linac types in various beam configurations. Increasing energy of FFF linac results in similar beam attenuation properties and maximized dose rate compared to STD linac. Matching beam attenuation properties allows a more direct exploration of beam flatness of FFF linac in regard to IMRT delivery, especially away from the central axis where the effective dose rate is considerably smaller than the one at the central axis. Flatness of open beam dose profile of FFF linac is improved by increasing the angular spread of the electron beam. The resulting dose rate within the treatment field and outside of the field (peripheral dose) are characterized and compared to the unmodified FFF and STD linacs, In order to match beam penetration properties, the energy of FFF is adjusted from 6.5 to 8.0 MeV for small to medium field sizes and from 6.5 to 8.5 MeV for larger ones. Dose rate of FFF vs STD linac increased by a factor of 1.9 (6.5 MeV) and 3.4-4.1 (8.0-8.5 MeV). Adjusting the mean angular spread of the electron beam from 0 degrees to 5 degrees-10 degrees resulted in complete flattening of photon beam for field sizes between 10 x 10 cm2 and 15 x 15 cm2 and partial flattening for field sizes from 15 x 15 cm2 to 30 x 30 cm2. Values of angular spread > or =14 degrees are not recommended as they exceed the opening of the primary collimator, affecting the area at the edges of the field. FFF fields of sizes smaller than 6 x 6 cm2 are already flat and beam flattening is not necessary. Overall, the angular spread of 5 degrees-10 degrees is sufficient and can satisfactorily flatten open beam dose profiles even for larger field sizes. Increasing the electron beam angular spread amounts to a slight decrease of dose rate of FFF linac. However, for angular spread, 5 degrees-10 degrees dose rate factor of FFF vs STD is still about 1.6-2.6, depending on the field size (and the adjusted energy). Similarly, in case of peripheral dose, a moderate increase in dose can be observed for angular spread of 5 degrees-10 degrees and for field sizes 10 x 10 cm2 to 30 x 30 cm2. Lastly, beam flatness of not modified FFF linac can be conveniently described by an analytical function representing a ratio of STD vs FFF doses: 1 + b|r|(n). A modified FFF beamline with increased energy and electron beam angular spread results in satisfactory flattened beam and high dose rate within the field. Peripheral dose remaining at similar (or smaller) level than that of STD linac for the same delivered dose within the treatment field.


In vitro screening of probiotics and synbiotics according to anti-inflammatory and anti-proliferative effects.
There is emerging evidence of the efficiency of probiotic, prebiotic and synbiotic treatments in inflammatory bowel diseases (IBDs) and one of their long-term complications, colorectal cancer (CRC). In this study, various strains of probiotic lactic acid bacteria, prebiotic glucooligosaccharides (GOS) or a synbiotic combination of the two were screened for anti-inflammatory and anti-proliferative effects in different in vitro models in the context of such diseases. To mimic IBD response to Gram negative bacteria, HT-29 cells were sensitised to inflammatory response to lipopolysaccharide (LPS) by IFNγ which increased expression of TLR4, the LPS biosensor, and were then treated by probiotics, prebiotics and synbiotics. Secreted IL-8 and activated NF-κB were monitored as inflammation biomarkers. A selection of active strains were then subjected to a second inflammatory cell culture model consisting of inflammatory activated transgenic Caco-2 cells transfected by a reporter gene under the control of NF-κB inducible promoter. Quantification of reporter gene expression allowed us to demonstrate some probiotic inhibitory properties or to confirm such characteristics in two different models. Proliferation of cancerous HT-29 cells was monitored by XTT assay. Only three probiotic strains induced a proliferation decrease, but with a lack of reproducibility. Binary or ternary probiotic associations, complemented or not by prebiotic GOS, significantly decreased proliferation, especially with a synbiotic association of Bifidobacterium breve, Lactococcus lactis and oligoalternan, a GOS. This combination was selected for the following experiments. We showed the involvement of both bacterial and carbohydrate compounds of this synbiotic in the observed effect by dose range tests. We demonstrated that this decrease in proliferation may be due to an induction of a differentiated phenotype, as shown by the up-regulation of intestinal alkaline phosphatase, a biomarker of differentiation, monitored by real-time RT-PCR in HT-29 cells treated by the selected synbiotics. Thus, this study demonstrates the ability of probiotics to exert anti-inflammatory effects and shows some anti-proliferative characteristics for a specific synbiotics. These products should be further evaluated in animal models to confirm the in vitro results.


Analysis of Pneumocystis jirovecii DHPS alleles implicated in sulfamethoxazole resistance using an Escherichia coli model system.
Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP). Drug treatment failure has been associated epidemiologically with point mutations in the gene for dihydropteroate synthase which is part of a gene that encodes three covalently linked enzymes involved in folic acid synthesis (FAS). The evaluation of whether mutations found in P. jirovecii FAS lead to sulfa drug resistance is hampered by the lack of a culture system for P. jirovecii as well as the failure of P. jirovecii FAS to complement in a heterologous system. Therefore, we chose to model the P. jirovecii mutations in the Saccharomyces cerevisiae FAS protein (encoded by FOL1) via its expression in Escherichia coli. An optimized drug diffusion assay was used to evaluate the FAS mutants against 15 sulfa drugs. It was established that the single amino acid substitution, P599S, in the (DHPS) domain of FAS led to sulfa drug resistance, whereas the T597A substitution led to increased sensitivity. The presence of both mutations (T597A and P599S) was cooperative and led to increased sulfa drug resistance. Analysis of a novel double mutant, (T597V P599S) was found to have significantly higher sulfa drug resistance than the T597A P599S mutant. These data suggest that further amino acid substitutions may lead to the evolution of higher sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine and sulfathiazole) were identified that had higher inhibitory potential than sulfamethoxazole, which is currently the preferred treatment for PCP.


[Behavior and role of mastocytes and eosinophils in natural and transplantable lymphatic leukemia in mice].
The behavior and role of mast cells and eosinophils, to the spleen cooperations between this cells at the natural and transplantable lymphatic leukaemia L 1210 and P 388 in mice. Mast cells and eosinophils are treated at the differences leukaemia organism in addition to the smearing blood. The growth and the quantity for this cells has been elevated at the beginning of the initial phase of neoplasia and the second decrease is very fast in comparing for the sort of leukaemia (natural, transplantable). The describe for this phenomenon in the bind for the heavy metals part in leukemogenesis.


Ferredoxin reduction by photosystem I from Synechocystis sp. PCC 6803: toward an understanding of the respective roles of subunits PsaD and PsaE in ferredoxin binding.
The process of ferredoxin reduction by photosystem I has been extensively investigated by flash-absorption spectroscopy in psaD and psaE deleted mutants from Synechocystis sp. PCC 6803. In both mutants, the dissociation constant for the photosystem I/ferredoxin complex at pH 8 is considerably increased as compared to the wild type: approximately 25- and 100-fold increases are found for PsaD-less and PsaE-less photosystem I, respectively. However, at high ferredoxin concentrations, submicrosecond and microsecond kinetics of electron transfer similar to that observed in the wild type are present in both mutants. The presence of these fast kinetic components indicates that the relative positions of ferredoxin and of the terminal photosystem I acceptor are not significantly disturbed by the absence of either PsaD or PsaE. The second-order rate constant of ferredoxin reduction is lowered 10- and 2-fold for PsaD-less and PsaE-less photosystem I, respectively. Assuming a simple binding equilibrium between photosystem I and ferredoxin, PsaD appears to be important for the guiding of ferredoxin to its binding site (main effect on the association rate) whereas PsaE seems to control the photosystem I/ferredoxin complex lifetime (main effect on the dissociation rate). The properties of electron transfer from photosystem I to ferredoxin were also studied at pH 5. 8. In the psaE deleted mutant as in the wild type, the change of pH from 8 to 5.8 induces a 10-fold increase in affinity of ferredoxin for photosystem I. In the absence of PsaD, this pH effect is not observed, in favor of this subunit being mostly responsible for the low pH increased affinity.


Possible mechanisms of allogeneic blood transfusion-associated postoperative infection.
Four possible mechanisms have been reported to underlie the apparent association of allogeneic blood transfusion (ABT) with postoperative bacterial infection. These are (1) a transfusion-related immunomodulatory (TRIM) effect of ABT mediated by immunologically active allogeneic white blood cells (WBCs) that downregulate the recipient's immune function, thereby predisposing to infection; (2) a TRIM effect of ABT mediated by soluble biologic response modifiers released in a time-dependent manner from WBC granules or membranes into the supernatant fluid of red blood cells (RBCs) during storage; (3) a TRIM effect of ABT mediated by soluble HLA peptides that circulate in allogeneic plasma; and (4) a related non-TRIM effect of ABT, whereby ABT causes postoperative organ dysfunction that predisposes to infection. The available clinical studies examining the association of ABT with postoperative infection were not designed to specifically test 1 or more of these 4 hypotheses. Thus, it is difficult to make inferences from the published data about the specific mechanism(s) that may underlie the purported association of ABT with infection. To permit such inferences, future studies of the association of ABT with postoperative infection should consider 2 outcomes (ie, postoperative organ dysfunction in addition to postoperative infection), as well as 3 possible exposures (ie, allogeneic WBCs, soluble biologic response modifiers originating in WBC granules or membranes, and/or soluble HLA molecules circulating in allogeneic plasma).


Evidence of vasopressin in adenohypophysis: research into its role in corticotrope activity.
The presence of vasopressin (VP) in pars distalis of rats and pigs was investigated. Using radioimmunoassay and bioassay of VP, a substance with immunological and biological properties of this hormone was found. This substance was not detected in the adenohypophysis of rats with diabetes insipidus. A partial purification of the VP-like peptide showed that it had the chromatographic and electrophoretic properties of VP. It could be identified with arginine vasopressin (AVP) in the case of the rat and lysine-vasopressin (LVP) in the case of the pig. In the Wistar strain, adrenalectomy induced progressively increasing concentrations of adenohypophysial VP. This increase was significant 15 days after surgery. It could be prevented by treatment with dexamethasone. These results indicate that the presence of VP in the anterior pituitary is related to the regulation of ACTH secretion.


In vitro evaluation of the effect of dietary acids and toothbrushing on human root dentin permeability.
The purpose of this in vitro study was to quantify the alterations in human root dentin permeability after exposure to dietary acids and to evaluate the effect of toothbrushing after acid application. Extracted human third molars had their crowns sectioned above the CEJ, pulp tissue removed, and cervical root dentin exposed using a high-speed bur (approximately 1 mm in depth of substance loss). From each root fragment, one specimen was prepared. A total of 25 specimens were used and distributed randomly into five groups. The specimens were attached to a hydraulic pressure apparatus to evaluate the alterations of root dentin permeability after exposure to different acids. Dentin permeability was measured after the following sequential steps: (1) treatment with EDTA for 3 minutes to obtain the maximum permeability; (2) root planing to create a smear layer; (3) exposure to different acidic substances for 5 minutes (vinegar, cola drink, lemon juice, white wine, and orange juice); and (4) brushing for 3 minutes. All acidic substances increased dentin permeability after root planing. Lemon juice produced higher values for permeability when compared to the other substances (P = .009); moreover, orange juice showed similar results (P < .02) except when compared to vinegar (P = .12). Brushing right after acid exposure significantly reduced dentin permeability except in the vinegar group (P = .07). Under the experimental conditions, dietary acids increased root dentin permeability, and immediate brushing reduced permeability levels.


Antimicrobial Resistance, Virulence Profile, and Molecular Characterization of Listeria monocytogenes Isolated from Ready-to-eat Food in China, 2013-2014.
We aimed to investigate the potential pathogenic profile and antibiotic resistance of Listeria monocytogenes isolated from ready-to-eat food in China. Antimicrobial resistance was determined by broth microdilution following the Clinical and Laboratory Standards Institute protocol. Molecular serotyping, virulence, and resistance genes were identified using PCR. Multi-locus sequence typing was performed on resistant strains. A total of 11.53% (113/980) isolates were resistant, from which 82.3% (93/113) harbored all the virulence genes tested. The resistant strains were subtyped into 18 sequence types (STs), from which ST2, ST5, ST8, and ST9 were involved in listeriosis. This study indicated that several L. monocytogenes isolates from ready-to-eat foods in China have pathogenic potential and are resistant to antibiotics, including antibiotics used as medicines by humans for listeriosis treatment.


[Percutaneous revascularization with coronary angioplasty in patients with refractory angina].
Refractory angina, specially when accompanied by electrocardiographic (ECGs) changes, has been associated with a high morbidity and mortality if urgent revascularization is not performed. Percutaneous Transluminal Coronary Angioplasty (PTCA) could be a useful therapeutic alternative in such cases. The aim of this study was to compare the immediate and midterm outcomes of a cohort of high risk patients with refractory angina with or without ECG changes revascularized by PTCA. Of 801 consecutive patients who underwent PTCA, we selected 48 patients (49 procedures, 61 lesions), with unstable angina in spite of treatment with nitroglycerin, calcium channel blockers, beta blockers, heparin and aspirin (refractory angina). Twenty-six patients (27 procedures, 37 lesions) had ECG changes (group A), and 22 patients (22 PTCAs, 24 lesions) did not have changes (group B). Mean age of patients was 65 +/- 11 years. The most frequent ECG changes found in group A were T wave inversion (38%) and ST segment depression (34%). The left anterior descending coronary artery was the most frequent dilated vessel (41%). Some new devices (Stent, Rotablator, etc.) were used in 22% vs 25% of lesions in group A and B respectively. Successful dilatation was achieved in 59 (96%) of attempted lesion without statistical differences between group A and B. One patient in each group developed an acute myocardial infarction. Death occurred in 2 patients from group A (one of non-cardiovascular cause). Follow-up was obtained in 33 (94%) of the 35 patients (minimum follow-up > or = 6 months or less if a major event occurred). Mean follow-up time was 16.7 +/- 6 vs 13.4 +/- 6 months in group A and B. During this time, death occurred in 2 patients (6%) both from group B (one non-cardiac); in 9 (27%) patients a repeat PTCA was performed (26% of patients from group A and 28% from B); CABG was performed in 2 (6%) patients (both from group B), and an AMI occurred in 1 patient in each group. Angiographic follow-up was obtained in 73% of patients in group A vs 91% in group B. The restenosis rate was 47% in group A vs 54% in group B. At the end of the first year of follow-up, 93% of patients were alive and 9/10 patients successfully revascularized were asymptomatic or had less severe angina. At present, PTCA is a safe revascularization method in patients with refractory angina providing a high initial success (95% of cases) and a good mid-term outcome (one year): > 90% survival rate, with improvement in the quality of life in 9/10 patients successfully revascularized, regardless of the presence or absence of ECG changes at the time of PTCA.


Information overload in the teaching of pharmacology.
Medical students are usually drawn from the best of students, but it is not unusual to see these brilliant students fail their exams or even dismissed from medical school because of poor academic performance. Information overload has been recognized as one of the major contributing factors to this problem. The situation is expected to get worse, with the ever-present technology-induced exponential growth in information. In discussing this issue, the authors echo the concerns of several experts regarding the content overload of medical school curricula, particularly in pharmacology. It is the increasing awareness of this problem that led the Association of American Medical Colleges and the General Medical Council of Britain to promote the concept of a core curriculum for each of the principal disciplines in medicine. Several medical schools have adopted the concept and also the problem-based learning approach, which focuses on ameliorating the complex problems associated with information growth in medical education. Based on the authors' experience as medical students, medical practitioners, and pharmacology teachers, they discuss the factors that contribute to information overload, from psychological and nonpsychological perspectives. Issues such as the design and structure of the curriculum, the quality of training and effectiveness of the teachers (clinically qualified vs. nonclinically qualified teachers), and the psychological preparedness of the students are discussed. The authors make suggestions for improvement.


An interview with Peter I. Buerhaus, PhD, RN, FAAN: on hopes and threats for nursing's future.
Peter I. Buerhaus, PhD, RN, FAAN, reflects on several recently published studies examining workforce and nurse survey data and reveals more findings. Dr. Buerhaus identifies several policy and research priorities to accelerate progress and secure a more stable future for nursing. Dr. Buerhaus will be the recipient of the 2007 Nursing Economics/Margaret D. Sovie Writer's Award, for his collective works on nursing workforce issues in the journal, during the Nurse Faculty/Nurse Executive Summit, sponsored by Nursing Economics, in Scottsdale, AZ, November 29-December 1.


CD4-gp120 interactions.
The three-dimensional structure of the binding domain of the CD4 molecule has been determined and extensive mutational analyses of the respective binding sites on gp120 and CD4 have been completed. The consequences of gp120-CD4 binding with respect to secondary changes in the virion, or the cell, that may be required for infection or that may interfere with cellular function are current active areas of investigation.


[Effect of Twist gene on the migration and invasion of gastric carcinoma cells].
To explore the effect of Twist gene on the migration and invasion of human gastric carcinoma cells. MKN28 cells, a human gastric carcinoma cell line, were transfected with PcDNA3.1-Twist plasmid by lipofectamine transfecting technique. The transfected cells were selected with geneticin. Expressions of Twist,ecadherin and vimentin protein were detected by Western blot in cells transfected Twist gene. Matrigel invision chambers were performed to analyse the cell migration and invasion. MKN28 cells transfected with PcDNA3.1-Twist plasmid showed stronger intracellular expression of Twist protein than MKN28 cells transfected with PcDNA3.1 and MKN28 cells without transfection. The expression of ecadherin protein in MKN28 cells transfected with PcDNA3.1-Twist plasmid was significantly decreased compared with that in MKN28 cells transfected with PcDNA3.1 and MKN28 cells without the transfection. However, The expression of vimentin protein in MKN28 cells transfected with PcDNA3.1-Twist plasmid was significantly increased compared with that in MKN28 cells transfected with PcDNA3.1 and MKN28 cells without transfection. The migration and invasion ability of Twist+ - MKN28 cells were stronger than that of MKN28 cells transfected with PcDNA3.1 and MKN28 cells without transfection. Twist gene may promote the migration and invasion ability of gastric carcinoma cells through epithelial mesenchymal transition.


Influence of length of occlusal support on masticatory function of free-end removable partial dentures.
The aim of this study was to determine the influence of occlusal support length (OSL) of free-end removable partial dentures (RPDs) on masticatory function. Twenty-three subjects (mean age: 55.2 ± 8.4 years) who were edentulous in the maxilla and classified as Kennedy Class I in the mandible were selected. Subjects received new maxillary complete dentures and mandibular RPDs. Five OSL conditions were determined by RPD artificial tooth wear: full occlusal support (L1, control), OSL to first molar (L2), OSL to second premolar (L3), OSL to first premolar (L4), and absence of occlusal support (L5). Masticatory performance and efficiency were evaluated using the sieve method. Chewing rate was defined as the number of masticatory cycles per minute. Bolus selection opportunities and bolus breakage function were evaluated using the one-chew method. Qualitative and quantitative measurements of masticatory cycle patterns were recorded kinesiographically. Data were analyzed using repeated-measures analysis of variance and Friedman and Fisher exact tests (α = .05). Masticatory performance and efficiency decreased (P < .05) from L1 (5.46 ± 0.64 mm and 51.21% ± 19.44%, respectively) to L5 (6.24 ± 0.44 mm and 24.50% ± 15.98%, respectively). Chewing rate was higher for L4 than L1 (P < .05). Bolus selection chances and bolus breakage function decreased as OSL was reduced (P < .05); however, there were no differences in masticatory cycle pattern among the OSL conditions (P > .05). Reduction of OSL altered masticatory function, thereby decreasing masticatory performance and efficiency resulting from a lower capacity to select and break down food.


Assessing Trends in Chlamydia Positivity and Gonorrhea Incidence and Their Associations With the Incidence of Pelvic Inflammatory Disease and Ectopic Pregnancy in Washington State, 1988-2010.
Chlamydia and gonorrhea screening for women is beneficial if it prevents serious reproductive sequelae, such as pelvic inflammatory disease (PID) and ectopic pregnancy (EP). We assessed trends in PID and EP among women in Washington and their association with gonorrhea incidence and chlamydia positivity in a screened population of women over a 23 year period. Using data on chlamydia positivity from the Infertility Prevention Project, gonorrhea incidence from state surveillance, and PID and EP hospitalizations from hospital discharge records, we assessed trends in each condition over time. In addition, we estimated total incidence of PID and EP by incorporating information on outpatient-treated cases in alternative populations using a Bayesian approach that accounted for uncertainty in the estimates. We assessed associations between each infection and PID/EP using a linear regression model that accounts for year-to-year correlation in data points. We observed substantial declines in both infections and in each outcome over time. For every 2% decrease in chlamydia positivity, there was a 35.7/100,000 decrease in estimated total PID incidence (P = 0.058) and 184.4/100,000 decrease in estimated total EP (P = 0.149). For every 32/100,000 decline in gonorrhea incidence, there was a 16.5/100,000 decrease in total PID (P = 0.292) and 159.8/100,000 decrease in total EP (P = 0.020). The associations with inpatient PID and EP were highly significant for both chlamydia and gonorrhea. These ecological data note concurrent and substantial declines in chlamydia positivity and gonorrhea incidence, and in PID and EP incidence in Washington from 1988 to 2010 during a time when widespread chlamydia screening was ongoing.


Analysis of the role of bacterial endospore cortex structure in resistance properties and demonstration of its conservation amongst species.
The aim of this work was to compare the chemical structure of the spore cortex of a range of species, and to determine any correlation between cortex structure and spore resistance properties. The fine chemical structure of the cortex of Bacillus subtilis, Bacillus megaterium, Bacillus cereus and Clostridium botulinum was examined by muropeptide analysis using reverse phase HPLC. There is a conserved basic structure between peptidoglycan of these species, with the only difference being the level of de-N-acetylation of an amino sugar. In order to determine if an alteration in cortex structure correlates with heat resistance properties, the peptidoglycan structure and properties of B. subtilis spores prepared under different conditions were compared. Peptidoglycan from spores prepared in Nutrient Broth (NB) showed reduction in single L-alanine substituted muramic acid to only 13.9% compared with 20.6% in CCY-grown spores. NB-prepared spores are also unstable, with 161-fold less heat resistance (60 min, 85 degrees C) and 43 times less Mn(2+) content than CCY-grown spores. Addition of MnCl(2) to NB led to a peptidoglycan profile similar to CCY-grown spores, sevenfold more heat resistance (60 min, 85 degrees C) and an 86-fold increase in Mn(2+) content. Addition of CCY salts to NB led all parameters to be comparable with CCY-grown spore levels. It has been shown that peptidoglycan structure is conserved in four spore-forming bacteria. Also, spore heat resistance is multifactorial and cannot be accounted for by any single parameter. Endospores made by diverse species most likely have common mechanisms of heat resistance. However, the molecular basis for their resistance remains elusive.


[Quality of life in chronic inflammatory bowel diseases. Validation of a questionnaire and first French data].
Inflammatory bowel diseases have an important impact on the daily life of patients. This impact can be measured by the evaluation of the health related quality of life. The aim of this study was to develop and to validate a questionnaire of quality of life in a French population. The questionnaire comprised 70 items and was completed in 15 min. It was made up of a) a general questionnaire of 36 items (SF-36) exploring daily physical and social functioning, mental and general health, body pain and vitality. A sleep module of 6 items was added. b) a specific questionnaire of 28 items (RFIPC), exploring the concerns of the patients. The questionnaire was self-administered to 101 patients with Crohn's disease (57 F. 44 M. mean age: 35 years, acute disease: 28%, inpatients: 27%), 96 patients with ulcerative colitis (38 F. 58 M. mean age: 39 years, acute disease: 53%, inpatients: 21%). Each patient was sex and age matched with a healthy control. The psychometric analysis confirmed the validation of the questionnaire for the item's convergent validity, internal consistency (Cronbach's coefficient being > 0.70), analyses of discrimination. Scores of each scale of SF-36 were worse in patients than in controls. Scores of patients with active disease were worse than those of patients with quiescent disease. Scores were comparable in patients with Crohn's disease and with ulcerative colitis except for score of pain which was worse in acute Crohn's disease. The most important concerns of patients were the uncertain nature of the disease, energy level and having surgery. This study allowed the validation of a questionnaire for the evaluation of the quality of life in French patients with inflammatory bowel disease and provides first indications which need to be confirmed by future epidemiological studies.


Transcriptional and post-transcriptional control of CNS myelination.
The successful transduction of action potentials along vertebrate axons is highly reliant on myelin, the concentric layers of membrane surrounding most large diameter axons. Within the central nervous system myelin is produced by oligodendrocytes. Developmentally, the oligodendrocyte linage arises from subventricular zone progenitors that give rise to oligodendrocyte progenitor cells (OPCs), which divide and migrate throughout the CNS before terminally differentiating to generate mature oligodendrocytes which myelinate receptive axons. Each step of progression along the lineage is under tight transcriptional control, elucidation of this control is vital for understanding developmental myelination and for developing strategies to promote repair in demyelinating diseases. Recent studies have identified a number of new transcriptional regulators and microRNAs as having key roles in CNS myelination.


Levels of Evidence for Foot and Ankle Questions on the Orthopaedic In-Training Examination: 15-Year Trends.
The foot and ankle (FA) content domain is a component of the orthopaedic in-training examination (OITE). Levels of evidence (LoE) have been infrequently studied on the OITE. The purpose of this study is to determine if LoE for primary journal articles referenced for FA questions increased over a 15-year period. We also aim to determine if reference characteristics and question taxonomy have changed during this period. All 132 questions and 261 references in the FA content domain from 1995 to 1997 and from 2010 to 2012 were included. We defined the characteristics of each reference and taxonomy of each question. Every primary journal article was assigned a LoE based on American Academy of Orthopaedic Surgeons (AAOS) guidelines. Foot & Ankle International (FAI) was the most frequently cited journal. The change in the distribution of the Buckwalter classifications was statistically significant (p = 0.0286) with an increase in the number of clinical management questions. There were more level I studies on the 2010 to 2012 OITE (p = 0.0478) 6/54 (11%) of questions on the 2010 to 2012 OITE cited level I or II evidence compared with 3/78 (4%) on the 1995 to 1997 examinations (p = 0.1035). There is a trend toward improved LoE for journal articles within the FA content domain on the OITE over a 15-year period, particularly when analyzing the increase in level I studies. FAI is the most frequently cited journal and questions increasingly test clinical management concepts. Our results can be used to help improve resident self-study and suggest that reviewing recent FAI articles may aid OITE preparation. Basic Science.


Meta-analysis: apples and oranges, or fruitless.
Meta-analysis is an impressive tool for systematic synthesis of health care management and policy research findings. Used wisely, it can impose an appealing order on the chaos of a large body of evidence. Occasionally, it can even contribute to resolution of a clinical controversy. However, the technique is currently in a state of evolution. Until it is further refined and standardized, its consumers must be mindful of its limitations and use meta-analytic reviews with care.


Cervical presentation of thymic cysts.
Sixteen cases of cervical thymic cyst are added to the previously reported fifty-six cases. Seventy-five per cent of the patients were less than twenty years old. Eighty per cent complained of a painless mass preoperatively. The histologic diagnosis of cervical thymic cyst was made if thymic epithelial elements could be found adjacent to the cyst cavity; Hassall's corpuscles were usually present. Cholesterol granulomata could usually be identified. The theories of origin of cervical thymic cyst are discussed.


Echocardiographic findings in pheochromocytoma.
M-mode and 2-dimensional echocardiography were used to study 26 consecutive, unselected patients with pheochromocytoma over a 3-year period. Only 1 patient had congestive heart failure; more than half had no cardiac symptoms or abnormalities. The most common (80% of patients) echocardiographic pattern was normal left ventricular (LV) mass with normal or even increased systolic performance. When LV mass was increased, LV systolic function was either normal or only borderline depressed in most of the patients. Patients with echocardiographic LV hypertrophy had symmetric thickening of ventricular walls; no case of asymmetric septal hypertrophy was found. There was no correlation between 24-hour urinary norepinephrine excretion and any of the echocardiographic variables studied. In some patients, increased LV wall thicknesses did not correlate with increased LV mass as calculated by the Woythaler echocardiographic method. Left atrial enlargement was not seen in any patient, including those with increased LV mass. The electrocardiogram and echocardiogram may be discordant: Electrocardiographic LV hypertrophy was seen in 6 patients, of whom 5 had normal echocardiographic LV mass. In patients with pheochromocytoma who have no cardiac symptoms or other clinical evidence of cardiac involvement, echocardiographic findings are usually normal.


Multifunctional ZrO(2) nanoparticles and ZrO(2)-SiO (2) nanorods for improved MALDI-MS analysis of cyclodextrins, peptides, and phosphoproteins.
Multifunctional ZrO(2) nanoparticles (NPs) and ZrO(2)-SiO(2) nanorods (NRs) have been successfully applied as the matrices for cyclodextrins and as affinity probes for enrichment of peptides (leucine-enkephalin, methionine-enkephalin and thiopeptide), phosphopeptides (from tryptic digestion products of beta-casein) and phosphoproteins from complex samples (urine and milk) in atmospheric pressure matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and MALDI time-of-flight (TOF) MS. The results show that the ZrO(2) NPs and ZrO(2)-SiO(2) NRs can interact with target molecules (cyclodextrins, peptides, and proteins), and the signal intensities of the analytes were significantly improved in MALDI-MS. The maximum signal intensities of the peptides were obtained at pH 4.5 using ZrO(2) NPs and ZrO(2)-SiO(2) NRs as affinity probes. The limits of detection of the peptides were found to be 75-105 fmol for atmospheric pressure MALDI-MS and those of the cyclodextrins and beta-casein were found to be 7.5-20 and 115-125 fmol, respectively, for MALDI-TOF-MS. In addition, these nanomaterials can be applied as the matrices for the analysis of cyclodextrins in urine samples by MALDI-TOF-MS. ZrO(2) NPs and ZrO(2)-SiO(2) NRs efficiently served as electrostatic probes for peptide mixtures and milk proteins because 2-11 times signal enhancement can be achieved compared with use of conventional organic matrices. Moreover, we have successfully demonstrated that the ZrO(2) NPs can be effectively applied for enrichment of phosphopeptides from tryptic digestion of beta-casein. Comparing ZrO(2) NPs with ZrO(2)-SiO(2) NRs, we found that ZrO(2) NPs exhibited better affinity towards phosphopeptides than ZrO(2)-SiO(2) NRs. Furthermore, the ZrO(2) and ZrO(2)-SiO(2) nanomaterials could be used to concentrate trace amounts of peptides/proteins from aqueous solutions without tedious washing procedures. This approach is a simple, straightforward, separation-and washing-free approach for MALDI-MS analysis of cyclodextrins, peptides, proteins, and tryptic digestion products of phosphoproteins.


Determination of testis temperature rhythms and effects of constant light on testicular function in the domestic fowl (Gallus domesticus).
There is a wide range of opinions regarding the operating temperature of the testis in the domestic fowl. We used physiological monitoring techniques to investigate testis and body temperature over daily periods and under various light regimes to elucidate body temperature gradients in the fowl. We confirm that the operating temperature of the adult fowl's testes is equivalent to core body temperature (40-41 degrees C). Long-term continuous temperature monitoring showed that there was no difference between the temperature of the testis, liver, and peritoneum during a 24-h period either in a normal light:dark cycle or under constant light conditions. However, there was a slight decrease in all temperatures at subjective night in each case, a decrease that does not appear to be sufficient to influence spermatogenesis. Birds maintained under constant light throughout two cycles of the seminiferous epithelium (28 days) still exhibited normal testis function and structure, even when "nightly" testis temperature decrease was the lowest. Thus, by undergoing spermatogenesis at an elevated temperature, the domestic fowl system is unique among the homeothermic animal systems studied to date.


An alternate method of radiofrequency neurotomy of the sacroiliac joint: a pilot study of the effect on pain, function, and satisfaction.
The sacroiliac joint (SIJ) can be a source of chronic refractory mechanical spine pain. Few previous studies have described radiofrequency (RF) sensory denervation of the SIJ; results have been inconsistent and technically demanding. This uncontrolled, prospective, cohort study evaluates the effects of an innovative method of RF ablation of the posterior sensory nerves of the SIJ on pain, analgesic use, disability, and satisfaction of patients suffering with chronic mechanical SIJ pain. Nine subjects with SIJ pain, confirmed by a local anesthetic joint block, were studied. Subjects were treated with a series of RF strip lesions performed adjacent to the lateral dorsal foraminal aperture plus conventional monopolar lesioning at the L5 dorsal ramus. Each subject completed a questionnaire twice before and at 1, 3, 6, 9, and 12 months after the procedure. The questionnaire evaluated pain intensity and frequency, analgesic intake, disability, satisfaction (with current pain level and the RF procedure), and procedure complications. Data were analyzed by using linear mixed model analysis. After the procedure, significant reductions of back and leg pain frequency and severity, analgesic intake, and dissatisfaction with their current level of pain occurred. Complications were minimal. Overall, 8 of 9 subjects were satisfied with the procedure. RF sensory ablation of the SIJ using bipolar strip lesions is a technically uncomplicated and low-risk procedure. The resulting effects on pain, disability, and satisfaction are promising. Further evaluation of this technique, including randomized controlled trials, is recommended.


[Endogenous 3-O-methyldopa in man: normal level and effect of an inhibitor of aromatic amino-acid decarboxylase (Benserazid) (author's transl)].
The fasting level of 3-O-methyldopa in human plasma is 120 +/- 18 nmol/1. Four hours after a single dose of 425 mumol benserazid, the level increased to 313 +/- 69 nmol/1.


Roles of light chains in the activity and conformation of smooth muscle myosin.
The 20-kDa regulatory (LC20) and 17-kDa essential (LC17) light chain subunits could be removed from porcine aorta smooth muscle myosin by the use of trifluoperazine and ammonium chloride. The isolated heavy chain rebound both light chains, resulting in the restoration of native properties. Experiments on reconstitution of the isolated heavy chain with LC17 and/or LC20 showed that both light chains were required for folding into the 10 S conformation and thus for the phosphorylation-dependent filament formation of smooth muscle myosin. However, LC17 was not essential for the phosphorylation-dependent regulation of actin-activated ATPase activity and superprecipitation but was required for full regulation. LC17 and phosphorylated LC20 were found to act as activators, and dephosphorylated LC20 was found to act as a repressor of the motor activities of smooth muscle myosin.


HoBi-like is the most prevalent ruminant pestivirus in Northeastern Brazil.
The ruminant pestiviral species BVDV-1, BVDV-2 and BDV, along with the putative species HoBi-like, may cause substantial economic losses in cattle, sheep and goats. Brazil's large size, variable biomes and wide range of ruminant animal production within different geographic regions suggest that the presence and prevalence of ruminant pestivirus may differ by regions within Brazil. This study investigated the genetic diversity of ruminant pestiviruses and determined the frequency of active infections within two states of the Northeast Region of Brazil, Maranhão and Rio Grande do Norte. Serum samples from 16,621 cattle and 2,672 small ruminants from 569 different herds residing in this region were tested by RT-PCR followed by DNA sequencing. Seventeen positive cattle were detected (0.1%) from fifteen different herds (2.64%). All isolates were classified as HoBi-like pestiviruses based on phylogenetic analysis. All small ruminant samples tested negative. The findings presented herein suggest that the Northeast Region of Brazil has a uniquely high prevalence of HoBi-like viruses. The increasing reports of HoBi-like viruses detected in cattle in the field suggest that natural infection with these viruses may be more widespread than previously thought. The identification of HoBi-like viruses as the most prevalent type of ruminant pestivirus circulating in the Northeast Region of Brazil indicates the need for both continued monitoring and determination of the extent of economic losses associated with HoBi-like virus infections. In addition, it must be taken into account in the choice of diagnostic tests and in vaccine formulations.


Glycomics: towards bioinformatic approaches to understanding glycosylation.
Cell surface glycoconjugates control a variety of biological events including cell differentiation, homing to specific tissues, cell adhesion, virus/cell recognition and immunological recognition. The heterogeneity and diversity of these molecules present a challenge to understanding both their functions and how those functions are encoded. Advances in biotechnology have led to new methods for genome and proteome study that allow for the analysis of the entire genetic or protein content of a cell. Efforts towards the systematic study of the variations in cellular glycoconjugates are, in contrast, in their infancy. Recent advances in glycosylation related technology have begun to open up the possibility of exploring both the structure and the functions of the glycome in a systematic manner. This review focuses on the latest mass spectrometry, microarray-based and computational technologies for glycomics.


Lithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway.
Lithium has been reported to inhibit opioid-induced properties. The present study examined the effect of acute and chronic administration of lithium chloride (LiCl) on morphine's biphasic modulation of susceptibility to pentylenetetrazole (PTZ)-induced clonic seizure in mice. We also examined the possible involvement of nitric oxide (NO) pathway in lithium effect. Both acute (0.1 and 1 mg/kg) and chronic (same doses, 21 consecutive days) administration of LiCl completely inhibited the anticonvulsant and proconvulsant effects of morphine (at doses 1 and 30 mg/kg, respectively). A very low and per se noneffective dose of LiCl (0.05 mg/kg) significantly inhibited both phases of morphine effect when administered concomitant with a noneffective low dose of naloxone (0.1 mg/kg). The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) at a per se noneffective dose of 0.3 mg/kg potentiated the inhibitory effects of low doses of LiCl (0.01 and 0.05 mg/kg) on both phases of morphine effect. l-arginine, a NO synthase substrate, at a per se noneffective dose of 30 mg/kg reversed the inhibitory effects of lithium (1 mg/kg). Lithium is capable of antagonizing both modulatory effects of morphine on seizure susceptibility even at relatively low doses. These inhibitory effects of lithium may also involve NO synthesis.


The relative contributions of hostility and depressive symptoms to the income gradient in hospital-based incidence of ischaemic heart disease: 12-Year follow-up findings from the GLOBE study.
There is evidence to support the view that both hostility and depressive symptoms are psychological risk factors for ischaemic heart disease (IHD), additional to the effects of lifestyle and biomedical risk factors. Both are also more common in lower socioeconomic groups. Studies to find out how socioeconomic status (SES) gets under the skin have not yet determined the relative contributions of hostility and depression to the income gradient in IHD. This has been examined in a Dutch prospective population-based cohort study (GLOBE study), with participants aged 15-74 years (n=2374). Self-reported data at baseline (1991) and in 1997 provided detailed information on income and on psychological, lifestyle and biomedical factors, which were linked to hospital admissions due to incident IHD over a period of 12 years since baseline. Cox proportional hazard models were used to study the contributions of hostility and depressive symptoms to the association between income and time to incident IHD. The relative risk of incident IHD was highest in the lowest income group, with a hazard ratio of 2.71. Men on the lowest incomes reported more adverse lifestyles and biomedical factors, which contributed to their higher risk of incident IHD. An unhealthy psychological profile, particularly hostility, contributed to the income differences in incident IHD among women. The low number of IHD incidents in the women however, warrants additional research in larger samples.


Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence.
Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain. Yet, no study has been conducted to determine agomelatine effects on neuropathic pain in animal models. Using 3 rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, we investigated the antihypersensitivity effect of acute and repeated agomelatine administration. We then determined the influence of melatonergic, 5-HT2C, α-2 and β-1/2 adrenergic receptor antagonists in the antihypersensitivity effect of agomelatine. The effect of the combination of agomelatine + gabapentin was evaluated using an isobolographic approach. In STZ and CCI models, single doses of agomelatine significantly and dose dependently reduced mechanical hypersensitivity. After daily administrations for 2 weeks, this effect was confirmed in the CCI model and agomelatine also displayed a marked antihypersensitivity effect in the OXA model. The antihypersensitivity effect of agomelatine involved melatonergic, 5-HT2C, and α-2 adrenergic receptors but not beta adrenoceptors. The isobolographic analysis demonstrated that the combination of agomelatine + gabapentin had additive effects. Agomelatine exerts a clear-cut antihypersensitivity effect in 3 different neuropathic pain models. Its effect is mediated by melatonergic and 5-HT2C receptors and, although agomelatine has no affinity, also by α-2 adrenergic receptors. Finally, agomelatine combined with gabapentin produces an additive antihypersensitivity effect.


[Evaluation of the management of blunt renal trauma and indication for surgery].
Appropriate management of renal trauma is still controversial. Many of the patients have minor injuries and conservative treatment can achieve excellent outcomes without any complications. For major injuries of deep lacerations or ruptures, we have been performing early surgical treatment to salvage the kidney in the selected cases after the precise evaluation of the injury. To obtain the optimal management options, we evaluated the clinical results of our procedures. We conducted a retrospective study, which included 106 cases of blunt renal trauma with evident etiology over the past 22 years and 9 months. The severity of the injury was evaluated mainly by CT scanning. The indication of renal exploration included persistent renal bleeding, large hematoma around the kidney, dislocated fragments, nonviable tissue, massive urinary extravasation and vascular injury. With the patients who required an operation, we first controlled the bleeding by clamping the hilar vessels. Then, the final decision whether to repair or remove the kidney was made based on the direct inspection of the injured kidney after the complete removal of the hematoma. The severity of renal trauma was classified by the classifications found in The Organ Injury Committee of the American Association for the Surgery of Trauma. Sixty-three patients were managed conservatively without any interventions, while 22 surgical repairs and 21 nephrectomies were performed. Of the 63 patients, 35 patients (81.4%) were operated on within 2 days after the injury. Judging from systolic blood pressure, red cell count, blood loss during surgery and transfusion requirements, surgically treated patients were more severely injured than conservatively treated patients. And nephrectomized patients than surgically repaired patients. All the surgically repaired cases were confirmed to have preserved renal functions postoperatively. In all of the 50 patients with Grade I injuries, conservative treatment was successful. Eight out of the 19 Grade II and III cases, who were indicated for kidney exploration because of multiple lacerations or considerable bleeding, were also successfully repaired. Localized hematoma with no urine leakage, even when it was large, settled spontaneously without complication. For the 37 Grade IV and V injuries, including 4 cases with hilar injuries, we implemented conservative procedures on 2 patients, surgical repair on 14 patients and nephrectomy on 21 patients. In the conservatively treated cases, one deep laceration with relatively large, but localized, hematoma, and minimal urine extravasation healed spontaneously. Atrophy of the segment and hypertension developed in the other ruptured kidney with dislocated fragments, large hematoma and urine leakage. This kidney, which also required later surgical exploration, did have good parenchymal blood flow. Hilar injury cases were all resulted in nephrectomy. In most of our cases the indication for surgical exploration or nephrectomy based on our criteria seemed to be properly decided. Several cases, though, might have received overtreatment. Recent advances in evaluations and strategies of renal trauma have decreased the need for surgical exploration. This may have overreached the indication for conservative management. Severely injured kidneys may be managed conservatively because in most cases bleeding settles after the full formation of large hematoma within the Gerota's fascia. In such cases, though, no one can predict whether the injury will heal spontaneously or not, and, moreover, whether a complication will develop or not. We think that the optimal management of the patient requires an accurate evaluation of the injured kidney. Therefore the indication for surgical exploration should be made based on the degree of the injury.


Detection of p53 mutations in gynecologic tumors by means of a simple, nonradioactive minigel method of PCR-SSCP analysis.
We studied 22 gynecological tumors for mutations in exons 5 through 8 of the p53 gene by means of SSCP analysis, using a simplified, nonradioactive technique developed at our laboratory. In order to test the procedure, we carried it out in parallel with the usual radioactive one. Two coincident mutations (in exons 5 and 8) were found by means of both methods. However, an additional one in exon 6 was found by means of our nonradioactive technique. This simplified method for SSCP-analysis of the p53 gene in human tumors is faster, easier and cheaper to perform than the conventional radioactive method, and yields equivalent results. It could be thus an excellent candidate for routine use in the clinical setting.


The influence of dynamic polyelectromyography in formulating a surgical plan in treatment of spastic elbow flexion deformity.
To determine the influence of motor-control analysis with dynamic electromyography on surgical planning in patients with spastic elbow flexion deformity. Prospective observational design. A Traumatic Brain Injury Model Systems-affiliated specialty referral center for the evaluation and treatment of mobility problems associated with neurologic injury and disease. Twenty-one patients with spastic elbow flexion deformity. Two surgeons each formulated a detailed surgical plan for each individual muscle-tendon unit. Patients then underwent motor-control analysis in which kinetic and polyelectromyographic data were collected by using a standard protocol. Each surgeon formulated another surgical plan after independently reviewing the laboratory study. The frequency of change and degree of agreement in the surgical plans after review of the laboratory data were used as measures of the effect of the laboratory studies. Fifty-seven percent of the surgical plans were changed after the motor-control study. The frequency of change did not differ by clinical experience. There was a trend toward higher agreement between surgeons after the study than before. Detailed electromyographic motor-control analysis alters surgical planning for patients with spastic elbow flexion deformity. Clinical assessment alone does not accurately identify the muscles responsible for the deformity or dysfunction. More clinical experience does not result in greater accuracy. Motor-control analysis produces higher agreement between surgeons in planning surgery.


Resistance to the beneficial effects of exercise in type 2 diabetes: are some individuals programmed to fail?
Exercise benefits most, but not all, individuals with type 2 diabetes (T2D). The beneficial effects are well studied, but why some individuals do not respond favorably to exercise training is largely unexplored. It is critical to treatment and prevention strategies to identify individuals with T2D that have a blunted metabolic response to exercise and investigate the underlying mechanisms that might predict this "programmed response to fail." We carried out a systematic review of classic and contemporary primary reports on clinical human and animal exercise studies. We also referenced unpublished data from our previous studies, as well those of collaborators. Genetic and epigenetic components and their associations with the exercise response were also examined. As evidence of the exercise resistance premise, we and others found that supervised exercise training results in substantial response variations in glucose homeostasis, insulin sensitivity, and muscle mitochondrial density, wherein approximately 15-20% of individuals fail to improve their metabolic health with exercise. Classic genetic studies have shown that the extent of the exercise training response is largely heritable, whereas new evidence demonstrates that DNA hypomethylation is linked to the exercise response in skeletal muscle. DNA sequence variation and/or epigenetic modifications may, therefore, dictate the exercise training response. Studies dedicated to uncovering the mechanisms of exercise resistance will advance the field of exercise and T2D, allowing interventions to be targeted to those most likely to benefit and identify novel approaches to treat those who do not experience metabolic improvements after exercise training.


[Analysis of mortality in benign diseases of the organs of the hepato-pancreato-biliary region and the ways of its reduction].
The case records and autopsy protocols of 34 patients, who died from benign diseases of the hepato-pancreato-biliary organs have been analysed. It is concluded that of main importance in the ++thanatogenesis are the following factors: shortcomings in the system of prophylactic medical examination, diagnostic and tactical errors made at prehospital stage of treatment and in a hospital, high incidence of concomitant diseases, late admission to a hospital, elderly and senile age of the majority of patients. A question about importance of the main and competitive causes of death is discussed.


HKI-272 in non small cell lung cancer.
Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene are found in approximately 10% of lung adenocarcinomas sequenced in the United States and in approximately 30% sequenced in Asia. These mutations are associated with sensitivity to the EGFR inhibitors gefitinib and erlotinib. Many patients who initially respond to erlotinib or gefitinib subsequently relapse. Studies have identified EGFR T790M mutations in tumors from patients who initially responded and then relapsed. The T790M mutation, when combined in vitro with treatment-sensitizing EGFR mutations, permits the continued growth of tumor cells in the presence of erlotinib and gefitinib. HKI-272 is an irreversible EGFR/HER/ErbB inhibitor that has been shown to inhibit the growth of T790M mutant cells in vitro in human lung cancer cell lines and in murine cells transfected with sensitizing EGFR mutations. A phase I HKI-272 monotherapy trial in patients with solid tumors is close to completion. Preliminary analyses of the trial, presented at the 2006 annual meeting of American Society of Clinical Oncology, showed that HKI-272 can achieve stable disease control for over 6 months in some patients with non-small cell lung cancer that has progressed after treatment with gefitinib or erlotinib. A phase II trial of HKI-272 in non-small cell lung cancer patients has been initiated. HKI-272 might offer benefits to non-small cell lung cancer patients who have relapsed after an initial response to erlotinib.


An avirulent chimeric Pestivirus with altered cell tropism protects pigs against lethal infection with classical swine fever virus.
A chimeric Pestivirus was constructed using an infectious cDNA clone of bovine viral diarrhea virus (BVDV) [J. Virol. 70 (1996) 8606]. After deletion of the envelope protein E2-encoding region, the respective sequence of classical swine fever virus (CSFV) strain Alfort 187 was inserted in-frame resulting in plasmid pA/CP7_E2alf. After transfection of in vitro-transcribed CP7_E2alf RNA, autonomous replication of chimeric RNA in bovine and porcine cell cultures was observed. Efficient growth of chimeric CP7_E2alf virus, however, could only be demonstrated on porcine cells, and in contrast to the parental BVDV strain CP7, CP7_E2alf only inefficiently infected and propagated in bovine cells. The virulence, immunogenicity, and "marker vaccine" properties of the generated chimeric CP7_E2alf virus were determined in an animal experiment using 27 pigs. After intramuscular inoculation of 1 x 10(7) TCID(50), CP7_E2alf proved to be completely avirulent, and neither viremia nor virus transmission to contact animals was observed; however, CSFV-specific neutralizing antibodies were detected from day 11 after inoculation. In addition, sera from all animals reacted positive in an E2-specific CSFV-antibody ELISA, but were negative for CSFV-E(RNS)-specific antibodies as determined with a CSFV marker ELISA. After challenge infection with highly virulent CSFV strain Eystrup, pigs immunized with CP7_E2alf were fully protected against clinical signs of CSFV infection, viremia, and shedding of challenge virus, and almost all animals scored positive in a CSFV marker ELISA. From our results, we conclude that chimeric CP7_E2alf may not only serve as a tool for a better understanding of Pestivirus attachment, entry, and assembly, but also represents an innocuous and efficacious modified live CSFV "marker vaccine".


Toll-Like Receptors: Ligands, Cell-Based Models, and Readouts for Receptor Action.
This chapter details Toll-like receptors (TLRs) and the tools available to study their biology in vitro. Key parameters to consider before exploring TLR action such as receptor localization, signaling pathways, nature of ligands and cellular expression are introduced. Cellular models (i.e., host cells and readouts) based on the use of cell lines, primary cells, or whole blood are presented. The use of modified TLRs to circumvent some technical problems is also discussed.


Fully automated standard addition method for the quantification of 29 polar pesticide metabolites in different water bodies using LC-MS/MS.
A reliable quantification by LC-ESI-MS/MS as the most suitable analytical method for polar substances in the aquatic environment is usually hampered by matrix effects from co-eluting compounds, which are unavoidably present in environmental samples. The standard addition method (SAM) is the most appropriate method to compensate matrix effects. However, when performed manually, this method is too labour- and time-intensive for routine analysis. In the present work, a fully automated SAM using a multi-purpose sample manager "Open Architecture UPLC®-MS/MS" (ultra-performance liquid chromatography tandem mass spectrometry) was developed for the sensitive and reliable determination of 29 polar pesticide metabolites in environmental samples. A four-point SAM was conducted parallel to direct-injection UPLC-ESI-MS/MS determination that was followed by a work flow to calculate the analyte concentrations including monitoring of required quality criteria. Several parameters regarding the SAM, chromatography and mass spectrometry conditions were optimised in order to obtain a fast as well as reliable analytical method. The matrix effects were examined by comparison of the SAM with an external calibration method. The accuracy of the SAM was investigated by recovery tests in samples of different catchment areas. The method detection limit was estimated to be between 1 and 10 ng/L for all metabolites by direct injection of a 10-μL sample. The relative standard deviation values were between 2 and 10% at the end of calibration range (30 ng/L). About 200 samples from different water bodies were examined with this method in the Rhine and Ruhr region of North Rhine-Westphalia (Germany). Approximately 94% of the analysed samples contained measurable amounts of metabolites. For most metabolites, low concentrations ≤0.10 μg/L were determined. Only for three metabolites were the concentrations in ground water significantly higher (up to 20 μg/L). In none of the examined drinking water samples were the health-related indication values (between 1 and 3 μg/L) for non-relevant metabolites exceeded.


Ultrasonographic assessment of hydronephrosis of pregnancy.
We examined 100 consecutive patients presenting for gestational assessment by ultrasonography for hydronephrosis. Hydronephrosis in these patients was assessed in respect of its incidence, degree, laterality, and its relation to stage of gestation. Hydronephrosis was found to be present in approximately half of our patients particularly in the second and third trimesters. Hydronephrosis was more prevalent on the right than on the left side. We believe that hydronephrosis of pregnancy is physiologic and that both mechanical and hormonal factors contribute to its occurrence.


Nerve conduction velocity varies inversely with height.
Even when all known factors affecting the determination of nerve conduction velocity are controlled, large individual variations persist. In 40 normal controls, we found that peroneal and sural conduction velocities varied inversely with body height (P less than 0.001). This height effect is not due to temperature differences, and it explains almost 50% of the intersubject variability in conduction velocity. We hypothesize that the height influence reflects abrupt, rather than gradual, tapering of axons distally. This mode of tapering may help explain the decrements in conduction velocity from proximal to distal nerve segments and from upper to lower extremities, which have long been observed in clinical electromyography. Clinical recognition of this height effect is important lest one label as abnormal an individual with mildly slowed peripheral nerve conduction velocity solely related to large stature.


Cell instability in basophil leukocytes of patients with chronic obstructive airway disease.
The histamine release from basophils induced by hypo-osmolarity was investigated in 75 healthy persons and in 43 patients with chronic obstructive airway disease. Leukocyte suspensions were diluted with destilled water in cell/water ratio volumen of 1:1, 1:3, and 1:7. Basophils, sequentially treated with increasing amounts of water, show an activation of the release process. A statistically significant age-dependent hypo-osmolar histamine liberation could be demonstrated. Furthermore, a significant higher cell stability was found for the group of patients.


Spinning crystals leads to significant enhancement in 13C spectral resolution in MAS experiments on organic compounds: a new aid in studying phase transitions.
While Andrew [E.R. Andrew, Arch. Sci. (Geneva), 12 (1959) 103; E.R. Andrew, A. Bradbury and R.G. Eades, Nature, 183 (1959) 1802] utilized single crystals in his pioneering magic angle spinning (MAS) experiments, current studies use powders. Our recent MAS measurements on some organic compounds show that single crystals yield significantly narrower peaks than powders, especially for the 13C atoms that are not protonated. In our 13C CP (cross polarization)/MAS measurements on squaric acid (H2C4O4), for example, single crystals yielded a four-fold reduction in line widths as compared to its powder. This additional gain in resolution enabled us to differentiate between the order-disorder versus displasive contributions to the mechanism of the paraelectric-antiferroelectric phase transition of squaric acid at 373 K, which had not been possible with other techniques. Moreover, this gain in resolution appears to increase in proportion to the applied Zeeman field, while retaining the benefit of higher dispersion.


IL-6 stimulates a concentration-dependent increase in MCP-1 in immortalised human brain endothelial cells.
Systemic inflammation is associated with neurodegeneration, with elevated interleukin-6 (IL-6) in particular being correlated with an increased risk of dementia. The brain endothelial cells of the blood brain barrier (BBB) serve as the interface between the systemic circulation and the brain microenvironment and are therefore likely to be a key player in the development of neuropathology associated with systemic inflammation. Endothelial cells are known to require soluble IL-6 receptor (sIL-6R) in order to respond to IL-6, but studies in rat models have shown that this is not the case for brain endothelial cells and studies conducted in human cells are limited. Here we report for the first time that the human cerebral microvascular cell line, hCMVEC, uses the classical mIL-6R signalling pathway in response to IL-6 in a concentration-dependent manner as measured by the production of monocyte chemotactic protein (MCP-1). This novel finding highlights a unique characteristic of human brain endothelial cells and that further investigation into the phenotype of this cell type is needed to elucidate the mechanisms of BBB pathology in inflammatory conditions.


Mediating phosphorylation events in the vanadium-induced respiratory burst of alveolar macrophages.
Occupational exposure by inhalation to vanadium-containing particles such as residual oil fly ash results in respiratory tract inflammation. This inflammation, characterized by abundant neutrophilia, appears to be initiated by alveolar macrophages (AMs) encountering particles and the subsequent release of proinflammatory cytokines. Intracellular signaling events in these cells in response to particles or their components are largely unknown. We investigated two immediate responses of AMs to vanadium exposure in vitro, the production of reactive oxygen intermediates (ROI) or respiratory burst (RB), and the tyrosine phosphorylation of cellular proteins. Macrophages exposed in vitro to 100 microM vanadyl chloride/1 microCi 48V incorporated 8.3% of the metal after 30 min. Exposure of AMs to increasing concentrations of sodium metavanadate resulted in a dose-dependent increase in production of ROI as measured by dichlorofluorescin oxidation. The lowest dose yielding a significant response was 50 microM, whereas 1000 microM increased RB activity by 173%. NADPH oxidase inhibitors deoxy-D-glucose (100 mM) and diphenylene iodonium (25 microM) reduced the metavanadate-induced RB by 62 and 71%, respectively, implicating NADPH oxidase as the primary cellular source of ROI. Enhanced cerium chloride oxidation in response to metavanadate localized to the plasma membrane consistent with increased NADPH oxidase activity. Pretreatment of AMs with the epidermal growth factor receptor inhibitor, tryphostin B50 (10 microM), reduced the metavanadate-induced RB, but did not influence overall tyrosine phosphorylation. Metavanadate and H2O2 exposure greatly increased overall tyrosine phosphorylation, yielding a similar but distinguishable pattern of phosphorylation in these cells. These observations demonstrate that in vitro metavanadate exposure regulates two distinct, yet related intracellular signaling pathways important in initiating inflammatory responses in these cells: (1) activation of the NADPH oxidase complex with subsequent increased ROI synthesis, and (2) enhanced tyrosine phosphorylation of cellular proteins.


Clinical and radiographic evaluation of immediately loaded one-piece implants placed into fresh extraction sockets.
To assess clinical survival and success rates of one-piece implants placed at the time of tooth extraction with immediate provisionalization and to evaluate radiographic peri-implant bone loss around one-piece implants 1 year after functional loading. Forty-six patients (20 men and 26 women) with a mean age of 45.5 years (range, 24 to 74 years) were recruited from four centers for this case series report. Immediately following the extraction of untreatable teeth, all patients received one-piece implants. The implants were immediately restored and placed into function with no occlusal contact. Outcome assessments included clinical and radiographic evaluations. Of the one-piece implants placed after extraction in the maxilla and mandible, 95.7% integrated successfully. The mean marginal bone loss after 1 year was 0.80 mm (SD, 0.53 mm). Overall peri-implant bone loss at maxillary sites was compared with overall bone loss at mandibular sites. At the 1-year follow-up, no statistically significant difference was found. The deeper the implants were placed below the crest, the more marginal bone loss was observed. However, no difference in marginal bone loss was observed as a consequence of the following three variables: implant length (10, 11.5, or 13 mm), implant diameter (3, 3.7, or 4.7 mm); and 3- and 6-month time periods after implant prosthesis placement. Based on data obtained from this sample size study, it can be concluded that one-piece implants can be successfully placed immediately after extraction with minimal peri-implant bone loss.


Provoking factors in bronchial asthma.
Asthmatic patients were identified as having asthma on the basis of lung function studies (76%), objective physical findings of asthma (11%), or a strong history of asthma (13%). Each of the 234 patients so identified was assigned to an asthma subgroup determined by careful clinical assessment of the major provoking factor or factors for his asthmatic episodes; minor provoking factors were also identified. Only 20% of the patients had asthmatic episodes provoked by a single factor. Most asthmatics had at least one major and one or more minor provoking factor(s). Reagin-mediated mechanisms constituted the major provoking factor in 25% of patients and were a minor provoking factor in an additional 20% of the patients. Thus, in only 45% of the patients, were reaginic mechanisms responsible for some part of their asthmatic episodes.


Bombyx adipokinetic hormone receptor activates extracellular signal-regulated kinase 1 and 2 via G protein-dependent PKA and PKC but β-arrestin-independent pathways.
Neuropeptides of the adipokinetic hormone (AKH) family are among the best studied hormone peptides. They play important roles in insect hemolymph sugar homeostasis, larval lipolysis, and storage-fat mobilization. Mechanistic investigations have shown that, upon AKH stimulation, adipokinetic hormone receptor (AKHR) couples to a Gs protein and enhances adenylate cyclase activity, leading to intracellular cAMP accumulation. However, the underlying molecular mechanism by which this signaling pathway connects to extracellular signal-regulated kinase 1/2 (ERK1/2) remains to be elucidated. Using HEK293 cells stably or transiently expressing AKHR, we demonstrated that activation of AKHR elicited transient phosphorylation of ERK1/2. Our investigation indicated that AKHR-mediated activation of ERK1/2 was significantly inhibited by H-89 (protein kinase A inhibitor), Go6983, and GF109203X (protein kinase C inhibitors) but not by U73122 (PLC inhibitor) or FIPI (PLD inhibitor). Moreover, AKHR-induced ERK1/2 phosphorylation was blocked by the calcium chelators EGTA and BAPTA-AM. Furthermore, ERK1/2 activation in both transiently and stably AKHR-expressing HEK293 cells was found to be sensitive to pretreatment of pertussis toxin, whereas AKHR-mediated ERK1/2 activation was insensitive to siRNA-induced knockdown of β-arrestins and to pretreatment of inhibitors of EGFR, Src, and PI3K. On the basis of our data, we propose that activated AKHR signals to ERK1/2 primarily via PKA- and calcium-involved PKC-dependent pathways. Our current study provides the first in-depth study defining the mechanisms of AKH-mediated ERK activation through the Bombyx AKHR.


[The calcium hypothesis of brain aging].
The "calcium hypothesis of brain aging" assumes that a small increase in free intra-cellular calcium concentration ([Ca2+]i) over years or decades finally leads to brain lesions similar to the short [Ca2+]i overload following one acute event (e.g., stroke). Recent data are reviewed that disprove the hypothesis in this rather simple form. Studies on brain cells of experimental animals as well as on animal and human blood cells suggest that [Ca2+]i is reduced rather than elevated in brain aging. However, probably as compensation, aging seems to lead to enhanced sensitivity of the brain (or of calcium-dependent mechanisms in the brain) to changes in [Ca2+]i. Under normal conditions, both alterations seem to compensate each other. However, under situations of additional stress leading to elevated [Ca2+]i (hypoxia, hypoglycemia), aged brain cells might be more vulnerable because of a reduced ability to down-regulate [Ca2+]i. In contrast to these typical changes in the aging, very little evidence exists that [Ca2+]i is also changed in Alzheimer's disease. On the other hand, recent evidence suggests that the modulation of [Ca2+]i by beta-amyloid is specifically altered in this disease, but the pathogenetic significance of this observation is not yet finally understood.


NLRP10 enhances Shigella-induced pro-inflammatory responses.
Members of the NLR family evolved as intracellular sensors for bacterial and viral infection. However, our knowledge on the implication of most of the human NLR proteins in innate immune responses still remains fragmentary. Here we characterized the role of human NLRP10 in bacterial infection. Our data revealed that NLRP10 is a cytoplasmic localized protein that positively contributes to innate immune responses induced by the invasive bacterial pathogen Shigella flexneri. SiRNA-mediated knock-down studies showed that NLRP10 contributes to pro-inflammatory cytokine release triggered by Shigella in epithelial cells and primary dermal fibroblasts, by influencing p38 and NF-κB activation. This effect is dependent on the ATPase activity of NLRP10 and its PYD domain. Mechanistically, NLRP10 interacts with NOD1, a NLR that is pivotally involved in sensing of invasive microbes, and both proteins are recruited to the bacterial entry point at the plasma membrane. Moreover, NLRP10 physically interacts with downstream components of the NOD1 signalling pathway, such as RIP2, TAK1 and NEMO. Taken together, our data revealed a novel role of NLRP10 in innate immune responses towards bacterial infection and suggest that NLRP10 functions as a scaffold for the formation of the NOD1-Nodosome.


DMSO as a mobile phase additive enhances detection of ubiquitination sites by nano-LC-ESI-MS/MS.
Large-scale detection of ubiquitination sites in whole cell proteomes using nano-liquid chromatography coupled to tandem mass spectrometry is a well-established technique that has deepened the understanding of protein degradation processes in eukaryotic cells. Ubiquitination sites are usually identified by detection of Lys-ɛ-Gly-Gly (K-ɛ-GG)-remnant peptides, which are generated by tryptic digestion of proteomes. We show in this application note that dimethyl sulfoxide addition to the liquid chromatography mobile phase enhances identification rates of K-ɛ-GG peptides by more than 100% due to an increase of peptide signal intensities. The gain in the number of ubiquitination site identifications exceeds by far the gain that has been published for other posttranslational modifications, namely, phosphorylation and acetylation.


Pulse compression to subcycle field waveforms with split-dispersion cascaded hollow fibers.
Carefully dispersion- and nonlinearity-managed cascades of gas-filled hollow-core fibers enable, as our theoretical analysis shows, efficient pulse compression with ultrahigh compression ratios. With dispersion and nonlinearity of individual fibers in such cascades optimized toward distinctly different goal functions, millijoule picosecond laser pulses can be compressed to sub-100-GW subcycle field waveforms.


Retrieval of ureteral calculus using a new method of endoscopic assistance in a cat.
A 9-year-old female spayed domestic short-haired cat presented with ureteral obstruction due to a ureteral calculus 4 cm distal to the renal pelvis. Preoperative creatinine was 844 mmol/L. A novel approach to this condition was utilised whereby a flexible endoscope was passed through a hole made in the renal capsule into the renal pelvis and ureter. The calculus was visualised, and the endoscope was removed. A 1.4 mm flexible grasping forceps was introduced into the proximal ureter through the same hole in the renal capsule and the calculus was removed. The creatinine dropped to 282 micromol/L within 2 weeks of surgery. The cat died of apparently unrelated causes several months after surgery.


Predictive assays for the therapy of rectum carcinoma.
Cytofluorometric DNA measurements showed that about 55% of rectum carcinoma (129 patients) had tumours with an abnormal DNA content (DNA aneuploidy). For patients with such a tumour the prognosis was worse than for patients with DNA diploid tumours. From the DNA histograms the number of S-phase cells was calculated. In tumours with the stage pT3, which disseminated to lymph nodes or metastasized, a higher number of S-phase cells was found than in tumours with the staging pT3N0M0. In all untreated tumours cells with micronuclei were found. This demonstrated cell loss. In most tumours this effect was considerable. The ratio:number of S-phase cells/number of cells with micronuclei may allow a rough estimate for cell turnover. In patients with a bad prognosis and in those patients who had a local recurrence after resection of the tumour this ratio was high. In 34 patients the parameters were measured before and after preoperative radiotherapy. In some tumours a rapid increase of S-phase cells occurred after irradiation, this effect might express repopulation. In these patients a local recurrence was frequently found. From the data obtained so far a prediction for local recurrences might be possible from the determination of nuclear protein bound SH-groups. The determination of micronuclei indicated that it can be used as a measure for radiation response in tumours. All parameters show a high variability between individual tumours. A further study is useful whether the measured parameters are suitable as predictors.


[Clearing the doubts of all Wang Bing in the Tang dynasty].
The problem is probed on the clues provided by Si ku ti yao zheng (Analysis on Summary of Books in Four Parts). It is claimed that the Wang bing (*) recommended by Wei Kang and that recommended by Yuwen Rong in Yu Jiaxi's work refer to the same person, both are identical to the time of the author of Su wen. Further, the time of the above 2 Wang Bing(s) and the Wang Bing recorded in lie nu zhuan (Biongraphies of chaste women) as the son of Wang Lin, are also overlapped with the time of the author of Su wen. It is possible that they are the same person. However, the details of the Wang Bing mentioned in Lang guan shi zhu ti ming (inscription for Lang guan Stone Pillar) is unknown. Again, it is unlikely that the Wang Bing (*) is the author of Su wen and can be only a farfetched analogy drawn after Su Fu's poet.


An in situ technique to retrieve an entrapped j-tip guidewire from an inferior vena cava filter.
Entrapment of a guidewire in the vena cava filter during central venous catheter placement is a newly recognized complication. Complex techniques have been described to free the guidewire. We describe a simple in situ technique that may free the guidewire without the application of complex techniques.


Hyperinsulinemia and hyperglucagonemia following pancreatic islet transplantation in diabetic rats.
Fasting blood glucose (FBG), serum immunoreactive insulin (IRI), plasma immunoreactive glucagon (IRG), body weight, and caloric intake were measured in long-term islet-isografted rats eight to 10 months following intraperitoneal islet transplantation in in age-matched, sham-operated, concurrently followed normal and diabetic controls. Islet recipients had normal body weights, but they were significantly polyphagic, hyperinsulinemic, and hyperglucagonemic when compared with normals. Fasting blood glucose levels were reduced by 10 per cent. Several factors may be related to the occurrence of these abnormalities in long-term islet-isografted rats, including (1) the mass of islets transplanted, (2) the age of donor tissue, (3) the heterotopic location of islet grafts, and (4) the lack of normal innervation of transplanted islet cells.


Interaction of marital status and genetic risk for symptoms of depression.
Depression scores (DSSI) were available for 1232 MZ and 751 DZ female twin pairs who completed a mailed questionnaire. Pairs were divided into those concordant for being in a marriage-like state, concordant for having no partners, and those discordant. The pattern of twin correlations differed according to marital status. Our results suggest that having a marriage-like relationship acts as a protective factor in reducing the impact of inherited liability to symptoms of depression in the general population.


Increased Prevalence of Developmental Venous Anomalies in Children with Intracranial Neoplasms.
Developmental venous anomalies are considered variants of venous development that, in and of themselves, are of little clinical import. A possible association between intrinsic brain tumors and developmental venous anomalies has been suggested, but a rigorous investigation has not been performed. The aim of this study was to assess any association between developmental venous anomalies and intrinsic brain neoplasms. A radiology report text search of terms used to describe developmental venous anomalies was performed on a study population of 580 patients with primary intracranial neoplasms and on a control population of 580 patients without neoplasms from the same time period. All positive results were reviewed to confirm that the report was describing a developmental venous anomaly, and the imaging examination was reviewed to confirm the diagnosis. Fifty-nine of the 580 subjects with brain tumors (10.17%) had a developmental venous anomaly identified by report and confirmed on review of the imaging. Thirty-one of the 580 controls (5.34%) had a developmental venous anomaly identified by report and confirmed on review of the imaging (P = .003). No statistically significant difference was noted in the prevalence of developmental venous anomalies among tumor types. No developmental venous anomaly drained the vascular territory of the tumor, and there was no correlation between the location of the developmental venous anomaly and the location of the neoplasm. The prevalence of developmental venous anomalies in this pediatric population with intracranial primary neoplasms is significantly greater than in those without neoplasms, suggesting an association that may be related to shared causative factors or susceptibilities to the development of these 2 separate entities.


Association of proteins.
A review is presented of the various intermolecular forces important in stabilizing protein structure and association. Emphasis is put on entropic as well as enthalpic contributions to the free energy. The factors affecting size and size distribution in protein aggregates are discussed. A theory is presented for the size distribution of casein micelles, taking into account the spherical nature of the micelles and the importance of surface repulsive forces in limiting size.


Lectin binding studies on suspensions of isolated epidermal keratinocytes.
The sugar composition of the surface of isolated human keratinocytes has been investigated using lectins. A method is described in which the FITC-labelled lectin is displaced with competing sugar prior to measurement. This avoids errors due to aspecific binding and utilizes the minimum biological sample. Evidence is presented which indicates that little cell surface glycoconjugate is lost during the preparation of the keratinocyte suspension from human epidermal slices using the technique described here. Values for keratinocytes are similar to those reported for fibroblast lines, being much higher than those found using erythrocytes or lymphocytes.


A case of scapular avulsion with concomitant scapular fracture in a cat.
An 11-year-old cat was referred following vehicular trauma for evaluation and treatment of right thoracic limb lameness which was non-responsive to conservative management. Gait assessment revealed a severe weight-bearing right thoracic limb lameness, soft tissue swelling over the dorsal border of the scapula, crepitus upon direct palpation over the scapula and lateralisation of the scapula upon adduction of the distal limb allowing a diagnosis of scapular avulsion to be made. Computed tomography (CT) demonstrated a comminuted fracture of the right scapula and a tear of the serratus ventralis muscle. The scapular fractures involved the caudal scapular angle and therefore a circumcostal suture was not placed. Stabilisation was achieved through reattachment of the scapula to the serratus ventralis muscle with sutures placed through small holes in the dorsal and cranial borders of the scapula. Follow-up revealed resolution of lameness at 14 weeks postoperatively but non-union of the scapular fractures as evidenced by repeat CT. This case report details the medium-term outcome following this very unusual injury and contributes to the sparse literature regarding the progression of conservatively managed scapular fractures. It demonstrates that full return to function can occur following this injury even when radiographic union of the fracture is not achieved. To our knowledge this is the first report of this specific combination of injuries detailed with medium-term and advanced imaging follow-up.


Results of a cohort of 200 hormone-naïve consecutive patients with prostate cancer treated with iodine 125 permanent interstitial brachytherapy by the same multidisciplinary team.
To report survival and morbidity of a cohort of 200 hormone-naïve consecutive patients with localized prostate cancer, treated by low-dose rate brachytherapy within the frame of multidisciplinary approach. Between 2001 and 2011, 200 patients were treated by the same team with 125 iodine seeds: 167 low-risk and 33 intermediate risk according to the d'Amico classification; eligible patients had clinical stage T1/T2a-b, Gleason score 3+3 or 3+4, baseline prostate-specific antigen level below 15ng/mL, prostate volume less than 60cm(3). The median number of random biopsies was 12 (range 6-32) and the breakdown of positive cores was as follows: 1 (29%), 2 (35%), 3 or more (36%). Acute morbidity was assessed according to the Common Terminology Criteria for Adverse Events and late toxicity according to the EORTC/RTOG scale. Data were prospectively collected. The median follow-up was 69 months (range 16 to 135). The 5- and 10-year biochemical relapse free survivals were 95.6% (95% confidence interval [CI]: 91-98) and 89.7% (95% CI: 79.4-95.0). The 5-year and 10-year overall survival were respectively 96.4% (95% CI: 92-98.4) and 89.7% (95% CI: 80.8-94.6%) and the 10-year disease specific survival, 99.1% (95% CI: 93.0-99.9). The 5- and 10-year grade 3 acute toxicity cumulative rate were respectively 3.3% (95% CI: 1.4-6.6) and 4% (95% CI: 1.4-6.6) and the 5- and 10-year grades 3 cumulative late toxicity 2.5% (95% CI: 2.0-5.9) and 4% (95% CI: 2.0-5.9). Brachytherapy managed within the frame of a multidisciplinary approach - from diagnosis to evaluation - may offer optimized results with a reduced late toxicity rate, while remaining opened to dosimetry and technical improvements.


Central venous pressure monitoring for the critically ill in Zambia.
The safety and value of central venous pressure (CVP) monitoring in 100 critically ill patients in Zambia was studied prospectively. There were six complications related to insertion, the only serious one being a hydrothorax which was recognized and treated. One patient developed catheter-related septicaemia. CVP measurement altered proposed fluid management in 19 cases, determined management in 31 in whom fluid status was uncertain and confirmed fluid therapy in 50. Additional benefits of central venous catheterization were drug infusion in 33 patients and venous access in 53. Technical problems during monitoring occurred in 54 cases and were due to kinking of the catheter, blockage or inadvertent removal. In our circumstances the risks of cannulation of central veins seem justified in selected patients but good nursing supervision of patients is necessary.


Nanoscopic Localization of Surface-Exposed Antigens of Borrelia burgdorferi.
Borrelia burgdorferi sensu lato, the causative agent of Lyme disease, is transmitted to humans through the bite of infected Ixodes spp. ticks. Successful infection of vertebrate hosts necessitates sophisticated means of the pathogen to escape the vertebrates' immune system. One strategy employed by Lyme disease spirochetes to evade adaptive immunity involves a highly coordinated regulation of the expression of outer surface proteins that is vital for infection, dissemination, and persistence. Here we characterized the expression pattern of bacterial surface antigens using different microscopy techniques, from fluorescent wide field to super-resolution and immunogold-scanning electron microscopy. A fluorescent strain of B. burgdorferi spirochetes was labeled with monoclonal antibodies directed against various bacterial surface antigens. Our results indicate that OspA is more evenly distributed over the surface than OspB and OspC that were present as punctate areas.


[Recurrent urinary tract infection in a patient with sacral agenesis and vertebral-lumbar dysraphism. Diagnostic-therapeutic scheme and clinical outcome].
To present and analyze one case of sacral agenesis with distal lumbar vertebral dysraphism, and to highlight the most relevant elements found in a bibliographic search. We describe the clinical characteristics of an adult patient with sacral agenesis, the diagnostic-therapeutic urological management and her outcome over four years of follow-up. A bibliographic search was also performed including review of all articles published over the last 16 years; we briefly include the most relevant elements. Sacral agenesis, as a local regional expression of "caudal regression syndrome" almost invariably produces functional involvement of the bladder and recurrent urinary tract infection, although the evolution may be benign like present case. This does not exempt from the unavoidable need of proper initial morphological-functional diagnosis, periodic follow-up and treatment.


Minimodularity and the perception of layout.
In natural vision, information overspecifies the relative distances between objects and their layout in three dimensions. Directed perception applies (Cutting, 1986), rather than direct or indirect perception, because any single source of information (or cue) might be adequate to reveal relative depth (or local depth order), but many are present and useful to observers. Such overspecification presents the theoretical problem of how perceivers use this multiplicity of information to arrive at a unitary appreciation of distance between objects in the environment. This article examines three models of directed perception: selection, in which only one source of information is used; addition, in which all sources are used in simple combination; and multiplication, in which interactions among sources can occur. To monocular spatial information, using all combinations of the presence or absence of relative size, height in the projection plane, occlusion, and motion parallax. Visual stimuli were computer generated and consisted of three untextured parallel planes arranged in depth. Three tasks were used: one of magnitude estimation of exocentric distance within a stimulus, one of dissimilarity judgment in how a pair of stimuli revealed depth, and one of choice judgment within a pair as to which one revealed depth best. Grouped and individual results of the one direct and two indirect scaling tasks suggest that perceivers use these sources of information in an additive fashion. That is, one source (or cue) is generally substitutable for another, and the more sources that are present, the more depth is revealed. This pattern of results suggests independent use of information by four separate, functional subsystems within the visual system, here called minimodules. Evidence for and advantages of minimodularity are discussed.


Extraosseous osteogenic sarcoma of the breast: mammographic and pathologic findings.
An unusual primary extraosseous osteogenic sarcoma is described. The tumor's mammographic appearance was highly suggestive of the correct histologic diagnosis. This case supports the theory that these tumors originate from a totipotent cell.


Beyond Amyloid - Widening the View on Alzheimer's Disease.
For 25 years, the amyloid cascade hypothesis, based on the finding that mutations in the amyloid precursor protein are closely linked to familial forms of Alzheimer's disease (AD), dominated the research on this disease. Recent failures of clinical anti-amyloidogenic trials, however, substantially support the reasoning (i) that the pathomechanisms that trigger familial AD, namely the generation, aggregation, and deposition of amyloid beta, cannot necessarily be extrapolated to sporadic cases and (ii) that amyloid beta represents a prominent histopathological feature in AD but not its exclusive causative factor. In autumn 2016, the Volkswagen Foundation hosted the Herrenhausen Symposium 'Beyond Amyloid - Widening the View on Alzheimer's Disease' in Hannover, Germany, to bring together current knowledge on cellular and molecular processes that contribute to AD pathogenesis independent of or alongside with the amyloid biochemistry. The following mini review series was authored by key speakers at the meeting, and highlights some of the mechanisms potentially involved in AD etiology that provide alternative viewpoints and mechanisms beyond the amyloid cascade hypothesis. This article is part of the series "Beyond Amyloid".


Effects upon Nitrogen Sorption Analysis in Aerogels.
Nitrogen sorption at 77 K is a standard technique for the characterization of mesoporosity. However, it seemed to be unable to detect the full, theoretically expected pore volume in high-porosity aerogels. Investigating this problem, we found that if only the sample is sufficiently equilibrated upon sorption, the full pore volume is detected regardless of its porosity. As insufficient equilibration also effects the pore size distribution deduced from the isotherm, highly erroneous results can be avoided if complete equilibration upon each sorption step is assured. For compliant aerogels the effect of sample deformation during analysis has to be taken into account. Copyright 2001 Academic Press.