Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer.
KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C-mutated pancreatic cancer are unknown. We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed. The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation. Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).


Feline panleukopenia virus revisited: molecular characteristics and pathological lesions associated with three recent isolates.
The low incidence of clinical signs or pathological lesions compatible with feline panleukopenia in cats has created the perception among practitioners that the disease has disappeared since the emergence of canine parvovirus type 2 in the late 1970s. Three parvoviruses that were recently isolated from a domestic cat and 2 cheetahs in cell culture or detected by means of the polymerase chain reaction were shown to be typical feline parvoviruses. Phylogenetic comparison with other FPV isolates did not reveal a particular African cluster.


Predictive Modeling for West Nile Virus and Mosquito Surveillance in Lubbock, Texas.
West Nile virus (WNV) was first detected in North America during 1999, and has since spread throughout the contiguous USA. West Nile virus causes West Nile fever and the more severe West Nile neuroinvasive disease. As part of a WNV vector surveillance program, we collected mosquitoes in Lubbock, Texas, using CO2-baited encephalitic vector survey (EVS) traps. During 219 wk from 2009 through 2017, EVS traps were operated for 1,748 trap nights, resulting in more than 101,000 mosquitoes captured. Weekly, selected female mosquito specimens were pooled by species and trap site, and screened for WNV using reverse transcription-polymerase chain reaction assay. Mosquitoes positive for WNV were detected during 16.9% (37/219) of the weeks. Using this information, we constructed a statistical model to predict the probability of detecting an infection within a mosquito pool as a factor of weather variables. The final model indicated that detection of WNV in mosquitoes was negatively associated with the week of year squared and average wind from 3 wk prior to sampling, and was positively associated with week of year, average visibility, average humidity from 2 wk prior to sampling, and average dew point from 4 wk prior to sampling. The model developed in this study may aid public health and vector control programs in swift and effective decision making relative to city-wide mosquito control efforts by predicting when the chances of mosquitoes having WNV are at their greatest.


Endoscopic examination of the nose and results of functional endoscopic sinus surgery in 50 patients.
The concept of and motivation for endoscopic examination of the nose in conjunction with computed tomography of the paranasal sinuses in cases of persistent or chronic recurring sinusitis is discussed. A review of the first 50 cases operated on by the author is given comparing pre- and postoperative symptomatology as well as the most common complications observed.


Surgical anatomy of the musculocutaneous nerve: a photographic essay.
The objective in this study was a microscopic dissection and examination of the musculocutaneous nerve. The origin of the musculocutaneous nerve and its relationship with the surrounding structures, motor and sensory branches, and fascicular structures were studied. The anastomoses between this nerve and other major nerves in the arm and forearm are also described.


[Adaptive reactions of the thyroid system in patients with ischemic heart disease to graded physical exertion].
Data reflecting thyroid response to rationed exercise (bicycle ergometry) in coronary patients are presented with respect to physical stress tolerance and clinical form of coronary disease. The results were compared with those obtained in healthy untrained male subjects. Exercise was carried on until submaximum capacity was reached, or clinical and/or electrocardiographic signs of coronary insufficiency appeared. Radioimmune assays of blood thyrotropin and total triiodothyronine (T3) and thyroxin (T4) were made in the course of exercise. Patients with better functional capacity were shown to develop the relatively-low T3 syndrome. A direct correlation was demonstrated between the T4/T3 index and the threshold effort. Patients with low stress tolerance showed increased T3 secretion and depressed T4/T3 at the peak of exercise.


Facing racism and the moral responsibility of human rights knowledge.
Anthropologists working in arenas of human rights advocacy must be prepared to negotiate dilemmas of human responsibility. Those focusing on racial discrimination as a breach of international human rights conventions must contend with trends in social research that feed into politically consequential claims that neither race nor racism exist as significant social facts. An examination of the global sociocultural and geopolitcal landscape, the human rights system, and models of change reveals that contemporary racism in both its marked and unmarked varieties warrants anthropologists' critical scrutiny and, depending on individual epistemological and political inclination, sociopolitical intervention.


B cell positive selection: road map to the primary repertoire?
Accumulating evidence indicates that positive selection events mediate differentiation, lineage commitment, and longevity of B lymphocytes. The BCR plays a central role, dictating the likelihood that newly formed cells will complete maturation, as well as whether cells persist within mature pools. Competition among B cells for limited, life span-promoting resources, which include self-ligands, lineage-specific cytokines, and innate receptor ligands, underlie these selective processes. Together, these observations suggest that positive selection is a critical feature in the establishment and maintenance of all lymphocyte pools, prompting re-evaluation of the underlying biological rationale for this process.


The lateral port control pharyngeal flap: a versatile approach to velopharyngeal insufficiency.
The surgical therapy for velopharyngeal incompetence has always been a challenging problem. In spite of the surgical choices of palatal pushback, pharyngeal flap, pharyngoplasty, muscle transfers, and pharyngeal wall implants, the reported failure rate has varied from 10% to 50%. A group of ten patients with velopharyngeal insufficiency is presented, two posttonsillectomy and adenoidectomy, three secondary to congenital deficiencies, and five following palatal and pharyngeal paralysis secondary to severe closed head injuries. The technique and experience with the lateral port control pharyngeal flap is discussed.


Epidermis and lymphocyte interactions during an allergic patch test reaction. Increased activity of ETAF/IL-1, epidermal derived lymphocyte chemotactic factor and mixed skin lymphocyte reactivity in persons with type IV allergy.
Recently, we have found an increased activity of epidermal-derived thymocyte-activating factor (ETAF/IL-1) and epidermal lymphocyte chemotactic factor (ELCF) in epidermis overlying a positive tuberculin skin reaction. In the present study, we investigated 20 patients with confirmed or suspected allergic contact dermatitis by using the suction blister technique before and during patch testing. The ETAF/IL-1 was found in epidermis before patch testing. Its presence increased 2.8-fold in epidermis overlying a positive patch test compared with pretesting values. This increase was statistically significant. Interestingly, nontested skin also showed a significant increase of ETAF/IL-1, which was 1.9-fold higher than pretest values. The ETAF/IL-1 activity in patch test areas was significantly correlated with the clinical response. ELCF is not present in epidermis from noneczematous persons. We observed a significant content of ELCF in three of seven patients with eczema prior to patch testing. After patch testing, all patients showed ELCF in epidermis. Nontested skin showed a 1.5-fold higher content of ELCF compared with pretest values, and in the test area ELCF was 1.8-fold higher. The increases were statistically significant. We performed mixed skin lymphocyte reactions in seven patients using epidermal cells from the patch test area. All patients with a positive patch test had an increased mixed skin lymphocyte reactivity compared with epidermis coming from a negative reaction.


Changes in Glucose Fermentation Pathways as a Response to the Free Ammonia Concentration in Microbial Electrolysis Cells.
When a mixed-culture microbial electrolysis cell (MEC) is fed with a fermentable substrate, such as glucose, a significant fraction of the substrate's electrons ends up as methane (CH4) through hydrogenotrophic methanogenesis, an outcome that is undesired. Here, we show that free ammonia-nitrogen (FAN, which is NH3) altered the glucose fermentation pathways in batch MECs, minimizing the production of H2, the "fuel" for hydrogenotrophic methanogens. Consequently, the Coulombic efficiency (CE) increased: 57% for 0.02 g of FAN/L of fed-MEC, compared to 76% for 0.18 g of FAN/L of fed-MECs and 62% for 0.37 g of FAN/L of fed-MECs. Increasing the FAN concentration was associated with the accumulation of higher organic acids (e.g., lactate, iso-butyrate, and propionate), which was accompanied by increasing relative abundances of phylotypes that are most closely related to anode respiration (Geobacteraceae), lactic-acid production (Lactobacillales), and syntrophic acetate oxidation (Clostridiaceae). Thus, the microbial community established syntrophic relationships among glucose fermenters, acetogens, and anode-respiring bacteria (ARB). The archaeal population of the MEC fed 0.02 g FAN/L was dominated by Methanobacterium, but 0.18 and 0.37 g FAN/L led to Methanobrevibacter becoming the most abundant species. Our results provide insight into a way to decrease CH4 production and increase CE using FAN to control the fermentation step, instead of inhibiting methanogens using expensive or toxic chemical inhibitors, such as 2-bromoethanesulfonic acid.


Tumor necrosis factor-alpha and virus expression in the central nervous system of cats infected with feline immunodeficiency virus.
Cytokine disregulation has been implicated in the pathogenesis of lentivirus-induced diseases. In the present study, 18 specific pathogen free (SPF) cats were inoculated with feline immunodeficiency virus (FIV) Petaluma strain and sacrificed at different times post-infection. Five additional SPF cats were used as controls. The cell localization of the cytokine tumor necrosis factor alpha (TNF-alpha) in the central nervous system (CNS) was determined by immunohistochemical and morphometric analyses with a polyclonal rabbit anti-human TNF-alpha antibody. TNF-alpha and FIV RNA were measured using competitive reverse transcriptase polymerase chain reaction (PCR) assays and the number of proviral genomes was estimated by competitive PCR. Portions of frontal cortex were collected from each animal and both formalin-fixed and snap-frozen and stored at -80 degrees C until used. The results showed that TNF-alpha is present mainly in astrocytes and microglial cells. Morphometric analysis showed that areas of TNF-alpha production increased in the early phases of infection. Molecular analyses demonstrated that the kinetics of proviral loads in the CNS were comparable to what observed in lymph nodes and peripheral blood mononuclear cells, with the peaks in the early and late stages of infection. A positive correlation was found between viral parameters and TNF-alpha transcription, the strongest relationship was found between the transcription of the cytokine and viral RNA load. These results confirm that invasion of CNS by FIV occurs soon after virus exposure and that during this phase there is an increase of local viral loads with concomitant up-regulation of TNF-alpha expression. During the asymptomatic phase viral replication remains low in spite of the progression of CNS alterations. The dissociation between the viral load and the lesions observed suggests the importance of an indirect mechanism for the progression of these lesions, even if TNF-alpha seems to play a role particularly in the early phase of infection.


Advanced prostate cancer activates coagulation: a controlled study of activation markers of coagulation in ambulatory patients with localized and advanced prostate cancer.
Cancer and increased age are risk factors for coagulation activation. Patients with advanced prostate cancer, which usually presents in the seventh to eighth decade of life, are likely to be at increased risk for thrombosis. We report results of a controlled study of changes in specific and sensitive markers of coagulation activation in patients with prostate cancer. Complete blood count, prothrombin time, partial thromboplastin time, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT) and quantitative D-dimers (DD) were measured in 30 patients of advanced prostate cancer (androgen ablated), in 30 newly diagnosed localized prostate cancer patients, in 30 healthy age-matched volunteers, and in 20 healthy young volunteers. Plasma F1 + 2 (P < 0.05) and DD (P < 0.05), but not TAT, were significantly elevated in healthy elderly males (mean age, 77 years) when compared with healthy young volunteers (mean age, 35 years). F1 + 2, TAT and DD were significantly elevated in advanced prostate cancer when compared with healthy age-matched controls (P < 0.001). In conclusion, advanced prostate cancer patients have significantly increased levels of sensitive markers of coagulation activation compared with healthy age-matched controls. This data can be used to plan studies to determine the risk of clinically significant coagulopathy and the role of primary prophylaxis in patients with advanced prostate cancer.


Impact of Triggering Events on Outcomes of Acute Heart Failure.
The onset of acute heart failure is known to be associated with increased physical activity and other specific behaviors that can trigger hemodynamic deterioration. This analysis aimed to describe the distribution of triggers in patients hospitalized for acute heart failure, and investigate their effects on in-hospital outcomes. Consecutive patients hospitalized for acute heart failure between 2010 and 2014 were registered in a multicenter data registration system (72 institutions within Tokyo, Japan). Baseline demographics and in-hospital mortality were extracted from 17,473 patients. Patients with a trigger were grouped based on their triggering event: those with onset during (a) physical activity; (b) sleeping; (c) eating or watching television; (d) bathing or excretion (use of restrooms); and (e) engaging in other activities. These patients were compared with patients without identifiable triggers. Multiple imputation was used for missing data. Patients were predominantly men (57.1%), with a mean age of 76.0 ± 13.0 years; a triggering event was present in 49.1%. No significant difference in baseline characteristics was noted between groups except for younger age, higher blood pressure, and prevalence of signs of congestion in the trigger-positive group. In-hospital mortality rate was 7.9%. Presence of triggers was positively associated with a reduced risk of in-hospital mortality (adjusted odds ratio 0.79; 95% confidence interval, 0.70-0.90; P = .0003). In a delta-adjusted pattern mixture model, the effect of a triggering event on in-hospital mortality remained consistently significant. Triggering events for acute heart failure can provide additional information for risk prediction. Efforts to identify the triggers should be made to classify patients according to risk group.


Control of the expression of bacterial genes involved in symbiotic nitrogen fixation.
Several genera of N2-fixing bacteria establish symbiotic associations with plants. Among these, the genus Rhizobium has the most significant contribution, in terms of yield, in many important crop plants. The establishment of the Rhizobium-legume symbiosis is a very complex process involving many genes which need to be co-ordinately regulated. In the first instance, plant signal molecules, known to be flavonoids, trigger the expression of host-specific genes in the bacterial partner through the action of the regulatory NodD protein. In response to these signals, Rhizobium bacteria synthesize lipo-oligosaccharide molecules which in turn cause cell differentiation and nodule development. Once the nodule has formed, Rhizobium cells differentiate into bacteroids and another set of genes is activated. These genes, designated nif and fix, are responsible for N2 fixation. In this system, several regulatory proteins are involved in a complex manner, the most important being NifA and a two component (FixK and FixL) regulatory system. Our knowledge about the establishment of these symbioses has advanced recently, although there are many questions yet to be solved.


[Evaluation of the effect of cardiotropic agents using a mathematical model of electromechanical coupling].
An assessment of the ionic action mechanism of cardiotropic substances with the aid of a mathematical model for excitation-contraction coupling in myocardium is proved to be possible. The technique developed consists in the model parameter identification from the experimental data on electrical and mechanical activity of myocardial strip. The validity of the technique is tested using the known mechanism drugs. An example is given of analysis by the technique suggested of the action mechanism of diltiazem on the rat papillary muscle.


The congenital "magnesium-losing kidney". Report of two patients.
A 39-year-old man with a lifelong history of tetany and hypocalcaemia was found to have hypomagnesaemia (0.29 mmol/l) due to renal magnesium loss. His asymptomatic 29-year-old brother had a similar disorder. Both were infertile and had severe oligospermia but normal endocrine function. They had medullary nephrocalcinosis and glomerular filtration rate was reduced. Renal biopsy showed patchy interstitial fibrosis and some glomerular sclerosis. Electron microscopy showed thickened basement membranes in damaged glomeruli and in tubules in areas of fibrosis. Tests of renal tubule function were normal. Hypocalcaemia and tetany were corrected by oral magnesium supplements which raised the serum magnesium level to around 0.54 mmol/l.


Electrostatic effects and the dynamics of enzyme reactions at the surface of plant cells. 1. A theory of the ionic control of a complex multi-enzyme system.
A theory is proposed to explain the physical bases of the ionic control of the activity of an enzyme system, located on a plant cell surface, and probably involved in cell-wall synthesis and extension. The model, which is based on various previously published experimental results, involves several assumptions: a cell-wall pectin methyl esterase de-esterifies pectins and thus creates the fixed negative charges of the cell wall; various enzymes incorporate uncharged carbohydrates in cell-wall material; cell-wall extension implies the sliding of cellulose microfibrils; the enzymes responsible for carbohydrate incorporation are activated by protons in the pH range 4-8 and have very similar pH dependencies: the cell-wall pectin methyl esterase is inhibited by protons in the same pH range. The mathematical derivation of this model, written in the form of a hypercycle, indicates that it is equivalent to a set of two antagonistic enzyme reactions: an enzyme reaction conditioned by pectin methyl esterase which results in the increase of fixed charge density of the cell wall; a number of 'growth enzymes', which produce extension and building up of the cell wall and therefore a decrease of charge density. The mathematical study of this model shows it may display a very high co-operativity of its response to slight changes of pH. This cooperativity means that the cell wall charge density may dramatically increase or decrease, within a very narrow pH range. The steep response of this system appears to be the direct consequence of different pH sensitivities of pectin methyl esterase and of the other cell-wall enzymes involved in cell growth. Calcium, which tightly binds to the cell wall, may diminish or even suppress this abrupt charge transition. This model suggests a novel theory of the ionic control of cell-wall expansion. The very basis of this theory is the existence of an electrostatic potential difference, delta psi, between the inside and the outside of the cell wall. When this delta psi value is large, the local proton concentration is high. Therefore the enzymes involved in cell wall extension and building up are active, but pectin methyl esterase is not. Therefore, the cell wall extends and the charge density decreases. The delta psi value then declines, as well as the local proton concentration. Under these conditions, the pectin methyl esterase becomes activated, whereas the 'growth enzymes' are not. This activation of pectin methyl esterase restores the initial, or an even higher, electrostatic potential difference, which in turn results in a decrease of local pH.(ABSTRACT TRUNCATED AT 400 WORDS)


An explorative study on energy balance in patients with head and neck cancer.
Background: Involuntary body weight loss in head and neck cancer is common. Fundamental for weight loss is an energy imbalance where total energy expenditure exceeds energy intake.Aim: To map energy intake and parameters of energy expenditure at the start of and after radiotherapy, and their relation to weight change, body mass index, and immune markers in patients with head and neck cancer.Materials and Methods: Data from 20 patients on energy intake (24-hour dietary intake recalls), total energy expenditure (SenseWear Armband Pro3), resting energy expenditure (indirect calorimetry), body weight, body mass index, and immune markers in serum (C-reactive protein and Interleukin-6) were collected at the start of and after radiotherapy (median 8 mo, range 5-13).Results: No statistical significance was shown between the two measurement points for energy intake or for the different parameters of energy expenditure. Median values for energy balance were 0.93 and 0.96 for the start of treatment and follow-up, respectively. Twelve and 13 patients had a negative energy balance at the start of radiotherapy and at follow-up, respectively.Conclusion: A negative energy balance was seen for the majority of patients, which stresses the importance of nutritional treatment at the start of and after radiotherapy.


Users and utilization patterns of over-the-counter acid inhibitors and antacids in The Netherlands.
General practitioners (GPs) are the first-line physicians who are consulted for upper digestive symptoms. Persons with symptoms may, however, prefer to buy acid inhibitors or antacids in drugstores or pharmacies and bypass a GP. The aim of this work was to study users, reasons for use, and utilization patterns of over-the-counter (OTC) acid inhibitors and antacids in The Netherlands. We also studied factors that were associated with the substitution of OTC acid inhibitors or antacid use for consultation with a GP. From July 2005 to January 2006, persons buying OTC acid inhibitors or antacids in 12 pharmacies and 4 drugstores were asked to complete a questionnaire. A total of 82/160 (51%) questionnaires were returned. Heartburn was the main symptom for buying an acid inhibitor or antacid. Seventy-one (87%) participants substituted OTC drug use for a GP consultation. The most commonly reported reason was the belief that symptoms were not serious enough to seek medical care. Exploratory analyses showed that substitution was less common in participants with comorbidity, a history of upper gastrointestinal disorder, use of an acid inhibitor or antacid previously prescribed by a physician, alarm symptoms (such as pain and nausea), and with being symptomatic for >4 days/week. Although the reasons for substitution of OTC acid inhibitor or antacid use for a GP consultation in The Netherlands do not suggest an a priori increased risk of an underlying serious disorder, it may be advisable for staff in drugstores and pharmacies to provide users with information on appropriate use and when to consult a GP.


Lost crops of the Incas: Origins of domestication of the Andean pulse crop tarwi, Lupinus mutabilis.
The Andean highlands are a hotspot of domestication, yet our understanding of the origins of early Andean agriculture remains fragmentary. Key questions of where, when, how many times, and from what progenitors many Andean crops were domesticated remain unanswered. The Andean lupine crop tarwi (Lupinus mutabilis) is a regionally important pulse crop with exceptionally high seed protein and oil content and is the focus of modern breeding efforts, but its origins remain obscure. A large genome-wide DNA polymorphism data set was generated using nextRADseq to infer relationships among more than 200 accessions of Andean Lupinus species, including 24 accessions of L. mutabilis and close relatives. Phylogenetic and demographic analyses were used to identify the likely progenitor of tarwi and elucidate the area and timing of domestication in combination with archaeological evidence. We infer that tarwi was domesticated once in northern Peru, most likely in the Cajamarca region within, or adjacent to the extant distribution of L. piurensis, which is the most likely wild progenitor. Demographic analyses suggest that tarwi split from L. piurensis around 2600 BP and suffered a classical domestication bottleneck. The earliest unequivocal archaeological evidence of domesticated tarwi seeds is from the Mantaro Valley, central Peru ca. 1800 BP. A single origin of tarwi from L. piurensis in northern Peru provides a robust working hypothesis for the domestication of this regionally important crop and is one of the first clear-cut examples of a crop originating in the highlands of northern Peru.


Eligibility, Clinical Outcomes, and Budget Impact of PCSK9 Inhibitor Adoption: The CANHEART PCSK9 Study.
Background The FOURIER (Further Cardiovascular Outcomes Research With PCSK9i [Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors] in Subjects With Elevated Risk) trial found a reduction in cardiovascular events in patients with atherosclerotic cardiovascular disease ( ASCVD ). Our objective was to estimate the eligibility, clinical outcomes, and budget impact of adopting PCSK 9i in a large healthcare system. Methods and Results Ontario, Canada, residents alive in 2011, aged 40 to 85 years, were eligible for inclusion. PCSK 9i eligibility was determined on the basis of FOURIER trial definition. Hazard ratios observed in the FOURIER trial were applied to assess the number of events that could be avoided. Budget impact was calculated as the difference between projected costs of treatment adoption and events avoided if PCSK 9i were used. Of the 2.4 million included individuals, 5.3% had a history of ASCVD . We estimated that 2.7% of the general population and 51.9% of the patients with ASCVD would be eligible for PCSK 9i. Adoption of PCSK 9i in all eligible patients with ASCVD was projected to reduce primary events rates by 1.8% after 3 years. Despite cost reduction of $44 million in events, PCSK 9i adoption would have a net budget impact of $1.5 billion over 3 years. Potential benefits of PCSK 9i varied widely across subgroups, with the largest absolute risk reduction estimated to be 4.3% at 3 years in peripheral artery disease. In this subgroup of 5601 patients, the budget impact of treatment adoption was $116 million. Conclusions We estimated that ≈1 in 2 patients with ASCVD would be eligible for PCSK 9i. The budget impact of adopting PCSK 9i for all patients with ASCVD is substantial. Selective adoption to high-risk patients will lessen the overall budgetary impact of PCSK 9i treatment.


A Review of Relative Pollen Productivity Estimates From Temperate China for Pollen-Based Quantitative Reconstruction of Past Plant Cover.
Model-based quantitative reconstruction of past plant cover in Europe has shown great potential for: (i) testing hypotheses related to Holocene vegetation dynamics, biodiversity, and their relationships with climate and land use; (ii) studying long term interactions between climate and land use. Similar model-based quantitative reconstruction of plant cover in China has been restricted due to the lack of standardized datasets of existing estimates of relative pollen productivity (RPP). This study presents the first synthesis of all RPP values available to date for 39 major plant taxa from temperate China and proposes standardized RPP datasets that can be used for model-based quantitative reconstructions of past plant cover using fossil pollen records for the region. We review 11 RPP studies in temperate China based on modern pollen and related vegetation data around the pollen samples. The study areas include meadow, steppe and desert vegetation, various woodland types, and cultural landscapes. We evaluate the strategies of each study in terms of selection of study areas and distribution of study sites; pollen- and vegetation-data collection in field; vegetation-data collection from satellite images and vegetation maps; and data analysis. We compare all available RPP estimates, select values based on precise rules and calculate mean RPP estimates. We propose two standardized RPP datasets for 31 (Alt1) and 29 (Alt2) plant taxa. The ranking of mean RPPs (Alt-2) relative to Poaceae (= 1) for eight major taxa is: Artemisia (21) > Pinus (18.4) > Betula (12.5) > Castanea (11.5) > Elaeagnaceae (8.8) > Juglans (7.5) > Compositae (4.5) > Amaranthaceae/Chenopodiaceae (4). We conclude that although RPPs are comparable between Europe and China for some genera and families, they can differ very significantly, e.g., Artemisia, Compositae, and Amaranthaceae/Chenopodiaceae. For some taxa, we present the first RPP estimates e.g. Castanea, Elaeagnaceae, and Juglans. The proposed standardized RPP datasets are essential for model-based reconstructions of past plant cover using fossil pollen records from temperate China.


Accelerometer load as a measure of activity profile in different standards of netball match play.
To determine differences in load/min (AU) between standards of netball match play. Load/ min (AU) representing accumulated accelerations measured by triaxial accelerometers was recorded during matches of 2 higher- and 2 lower-standard teams (N = 32 players). Differences in load/min (AU) were compared within and between standards for playing position and periods of play. Differences were considered meaningful if there was >75% likelihood of exceeding a small (0.2) effect size. Mean (± SD) full-match load/min (AU) for the higher and lower standards were 9.96 ± 2.50 and 6.88 ± 1.88, respectively (100% likely lower). The higher standard had greater (mean 97% likely) load/min (AU) values in each position. The difference between 1st and 2nd halves' load/min (AU) was unclear at the higher standard, while lower-grade centers had a lower (-7.7% ± 10.8%, 81% likely) load/min (AU) in the 2nd half and in all quarters compared with the 1st. There was little intrastandard variation in individual vector contributions to load/min (AU); however, higher-standard players accumulated a greater proportion of the total in the vertical plane (mean 93% likely). Higher-standard players produced greater load/min (AU) than their lower-standard counterparts in all positions. Playing standard influenced the pattern of load/min (AU) accumulation across a match, and individual vector analysis suggests that different-standard players have dissimilar movement characteristics. Load/min (AU) appears to be a useful method for assessing activity profile in netball.


Utilization of echocardiography in Intensive Care Units: results of an online survey in Germany.
In patients with hemodynamic instability echocardiography has been recommended as the preferred modality to evaluate the underlying pathophysiology. However, due to the fact that recent scientific data on the utilization of echocardiography in German Intensive Care Units (ICU) are scarce, we sought to investigate current practice. A structured, web-based, anonymized survey was performed from May until July 2015 among members of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) consisting of 14 questions. Descriptive data analysis was performed. One hundred four intensivists participated in the survey. Two-thirds of participants (66%) used echocardiography regularly for hemodynamic monitoring and stated that it changed the therapy in 26-50% of the cases irrespective of the time performed after ordering the examination. Transthoracic (TTE) were more frequently used than transesophageal (TEE) examinations. Twenty-six percent of the participants held an echocardiography certificate with a formal examination, 27% completed a structured training without an examination and almost half of the questioned ICU personnel (47%) did not complete a comprehensive training. The results of this survey demonstrate a widespread utilization of echocardiography as part of routine diagnostic on frequent number of operative ICUs. However, there might be a lack of structured echocardiographic training especially for anesthesiologists.


Dendritic cells from Peyer's patches and mesenteric lymph nodes differ from spleen dendritic cells in their response to commensal gut bacteria.
Commensal gut bacteria have potent effects on the immune system, which are partially mediated by intestinal dendritic cells (DC). Distinct commensals confer different properties to in vitro-generated DC. The aim of the present study was to reveal strain-dependent maturation patterns in primary DC. To this end, we compared the response of mouse Peyer's patch (PP) DC, mesenteric lymph node (MLN) DC and spleen DC to the commensal bacteria, Bifidobacterium longum Q46, Lactobacillus acidophilus X37 and Escherichia coli Nissle 1917. Bacterial maturation of DC occurred independently of tissue origin. Expression of CCR7 and CD103 on the surface of MLN DC, necessary for the induction of gut-homing regulatory T cells, increased with stimulation by Gram-positive commensals. Bacteria-dependent cytokine production (IL-6, IL-10 and TNF-alpha) was similar in spleen and MLN DC, and contaminant cells in these DC preparations produced IFN-gamma in response to L. acidophilus. In contrast, PP DC produced IL-6 only in response to E. coli, little IL-10 and no TNF-alpha, and this low cytokine production was not due to inhibition by IL-10 or TGF-beta. Bifidobacteria downregulate IL-6, TNF-alpha and IL-12 production induced in in vitro-generated DC by L. acidophilus. Similar inhibition was observed in splenic DC, but not in MLN DC. MLN cells responded to bacterial stimulation with higher IFN-gamma production than spleen cells, possibly due to the presence of more responsive natural killer cells. Commensal bacteria therefore play specific roles in the gut immune system distinguishable from the effect they would have if recognized by the systemic immune system.


Visualizing a circadian clock protein: crystal structure of KaiC and functional insights.
Circadian (daily) biological clocks express characteristics that are difficult to explain by known biochemical mechanisms, and will ultimately require characterizing the structures, functions, and interactions of their molecular components. KaiC is an essential circadian protein in cyanobacteria that forms the core of the KaiABC clock protein complex. We report the crystal structure of the KaiC homohexameric complex at 2.8 A resolution. The structure resembles a double doughnut with a central pore that is partially sealed at one end. The crystal structure reveals ATP binding, inter-subunit organization, a scaffold for Kai-protein complex formation, the location of critical KaiC mutations, and evolutionary relationships to other proteins. A key auto-phosphorylation site on KaiC (T432) is identified from the crystal structure, and mutation of this residue abolishes circadian rhythmicity. The crystal structure of KaiC will be essential for understanding this circadian clockwork and for establishing its links to global gene expression.


Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing.
Molecular mechanisms for the establishment of transcriptional memory are poorly understood. 5,6-dichloro-1-D-ribofuranosyl-benzimidazole (DRB) is a P-TEFb kinase inhibitor that artificially induces the poised RNA polymerase II (RNAPII), thereby manifesting intermediate steps for the establishment of transcriptional activation. Here, using genetics and DRB, we show that mammalian Absent, small, or homeotic discs 1-like (Ash1l), a member of the trithorax group proteins, methylates Lys36 of histone H3 to promote the establishment of Hox gene expression by counteracting Polycomb silencing. Importantly, we found that Ash1l-dependent Lys36 di-, tri-methylation of histone H3 in a coding region and exclusion of Polycomb group proteins occur independently of transcriptional elongation in embryonic stem (ES) cells, although both were previously thought to be consequences of transcription. Genome-wide analyses of histone H3 Lys36 methylation under DRB treatment have suggested that binding of the retinoic acid receptor (RAR) to a certain genomic region promotes trimethylation in the RAR-associated gene independent of its ongoing transcription. Moreover, DRB treatment unveils a parallel response between Lys36 methylation of histone H3 and occupancy of either Tip60 or Mof in a region-dependent manner. We also found that Brg1 is another key player involved in the response. Our results uncover a novel regulatory cascade orchestrated by Ash1l with RAR and provide insights into mechanisms underlying the establishment of the transcriptional activation that counteracts Polycomb silencing.


Reaction pH and protein affect the oxidation products of beta-pentagalloyl glucose.
To better understand the biochemical consequences when polymeric polyphenols serve as biological antioxidants, we studied how reaction pH (pH 2.1-7.4) and protein affected the oxidation of pentagalloyl glucose (PGG) by NaIO4 in aqueous solution. PGG oxidation produced an o-semiquinone radical intermediate, which tended to form polymeric products at pH values below 5, and o-quinones at higher pH. The model protein bovine serum albumin promoted the formation of quinone even at low pH. Two other polyphenols, procyanidin (epicatechin16-(4-->8)-catechin) and epigallocatechin gallate, had similar pH-dependent oxidation patterns.


A combined Markov random field and wave-packet transform-based approach for image segmentation.
The author formulates a novel segmentation algorithm which combines the use of Markov random field models for image-modeling with the use of the discrete wavepacket transform for image analysis. Image segmentations are derived and refined at a sequence of resolution levels, using as data selected wave-packet transform images or "channels". The segmentation algorithm is compared with nonmultiresolution Markov random field-based image segmentation algorithms in the context of synthetic image example problems, and found to be both significantly more efficient and effective.


Protein crystal growth with a two-liquid system and stirring solution.
We developed two novel methods for growing large, high-quality protein crystals. A two-liquid system enables the convenient extraction of protein crystals without causing mechanical damage due to growth at the interface between two liquids. Since this system does not require limitations on solution volume, it is also suitable for the seed technique, and for growing large crystals. Another new concept is the mild stirring of the solution using the Floating And Stirring Technique (FAST) and the Micro-stirring technique. When compared to conventional techniques, both techniques result in a reduced number of crystals, as well as the growth of large crystals.


Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel.
A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 μM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.


Cytokine profile of breast cell lines after different radiation doses.
Ionizing radiation (IR) treatment activates inflammatory processes causing the release of a great amount of molecules able to affect the cell survival. The aim of this study was to analyze the cytokine signature of conditioned medium produced by non-tumorigenic mammary epithelial cell line MCF10A, as well as MCF7 and MDA-MB-231 breast cancer cell lines, after single high doses of IR in order to understand their role in high radiation response. We performed a cytokine profile of irradiated conditioned media of MCF10A, MCF7 and MDA-MB-231 cell lines treated with 9 or 23 Gy, by Luminex and ELISA analyses. Overall, our results show that both 9 Gy and 23 Gy of IR induce the release within the first 72 h of cytokines and growth factors potentially able to influence the tumor outcome, with a dose-independent and cell-line dependent signature. Moreover, our results show that the cell-senescence phenomenon does not correlate with the amount of 'senescence-associated secretory phenotype' (SASP) molecules released in media. Thus, additional mechanisms are probably involved in this process. These data open the possibility to evaluate cytokine profile as useful marker in modulating the personalized radiotherapy in breast cancer care.


Sea lice Lepeophtheirus spinifer, Tuxophorus sp. and Caligus sp. infections on wild-caught queenfish Scomberoides commersonnianus from northern Australia.
Studies of ectoparasites of wild-caught queenfish Scomberoides commersonnianus from several areas in northern Australia were reviewed to investigate relationships between parasite burdens, environmental conditions and external lesions. A sample of 27 queenfish captured near a dredge spoil disposal site in Gladstone Harbour, Queensland, Australia, in January 2012 was anomalous, with a high percentage of fish (66.6%) exhibiting grossly visible skin lesions including foci of erythema and petechial haemorrhages, particularly on the pectoral girdle and ventrolateral surfaces. Microscopically, lesions comprised acute epidermal erosion, ulceration and/or perivascular dermatitis with dermal oedema and depigmentation. Skin lesions were associated with high prevalence (100%) and intensity (mean = 21.2 copepods fish-1, range 4-46) of infection by sea lice Lepeophtheirus spinifer. Only queenfish infected with >10 L. spinifer presented with skin lesions. This is the first record of L. spinifer from Australia. In contrast, grossly visible skin lesions were not reported from queenfish (n = 152) sampled from other sites in the Northern Territory and Queensland, where the sampled fish had a much lower prevalence (51.3%) and intensity (mean = 3.54, range 0-26) of copepod (L. spinifer, Caligus spp. and Tuxophorus sp.) infections. Copepods from queenfish in studies undertaken outside Gladstone Harbour exhibited an over-dispersed pattern of infection, with the vast majority (n = 137, or 90.1%) of fish infected with <5 copepods. These data demonstrate that heavy L. spinifer infections, combined with poor water quality and/or direct exposure to contaminated dredge spoil and blooms of the cyanobacterium Lyngbya majuscula, can be associated with cutaneous disease in wild-caught queenfish.


[1st finding of the Ancylostoma braziliense nematode (Gómez de Faria, 1910) in Canis familiaris in Cuba].
According to the results obtained by investigators who have been devoted up to date to the study of dog helminthiases in Cuba dog ancylostomiasis is produced by Ancylostoma caninum. Now, Ancylostoma braziliense (Gómez de Faria, 1910) has been found in two dogs from the Havana province. The knowledge of the invasion extension as well as of the intensity of infestation should wait for the exhaustive study of the collected material.


Nasal challenge test in the diagnosis of allergic respiratory diseases in subjects occupationally exposed to a high molecular allergen (flour).
The objective of this study was the evaluation of the usefulness of the nasal challenge test in the diagnosis of allergic respiratory diseases in subjects occupationally exposed to flour. A single-blind, placebo controlled study was conducted in 100 subjects with occupational atopic asthma with rhinitis. The control groups consisted of 20 atopic subjects not sensitized to investigated allergens and 20 healthy subjects. A 'nasal pool' technique was used to evaluate the changes of the cellular response and protein level in nasal washings after topical provocation with allergen or placebo. The concentrations of eosinophil cationic protein and mast cell-derived tryptase in nasal fluid were evaluated in 60 cases. There were significant increases in eosinophil and basophils number, albumin/total protein ratio, eosinophil cationic protein and tryptase levels in occupationally sensitized patients challenged with specific allergens. There were neither severe bronchial reactions or an increase of bronchial hyperreactivity in occupationally sensitized patients after the nasal provocation with flour. The nasal challenge test appears to be a very useful and safe tool for diagnosing occupational allergy.


Alkene-directed, nickel-catalyzed alkyne coupling reactions.
In alkene-directed, nickel-catalyzed coupling reactions of 1,3-enynes with aldehydes and epoxides, the conjugated alkene dramatically enhances reactivity and uniformly directs regioselectivity, independent of the nature of the other alkyne substituent (aryl, alkyl (1 degrees , 2 degrees , 3 degrees )) or the degree of alkene substitution (mono-, di-, tri-, and tetrasubstituted). These observations are best explained by a temporary interaction between the alkene and the transition metal center during the regioselectivity-determining step. The highly substituted 1,3-diene products are useful in organic synthesis and, in conjunction with a Rh-catalyzed, site-selective hydrogenation, afford allylic and homoallylic alcohols that previously could not be prepared in high regioselectivity (or at all) with related Ni-catalyzed alkyne coupling reactions.


Effect of advanced oxidation processes on the toxicity of municipal landfill leachates.
The aim of the present study was to assess the effect of advanced oxidation processes (AOPs) (oxidation ozone and peroxide/ozone) on the toxicity of leachates from municipal landfill for Warsaw, Poland, using a battery of tests. AOPs used to pre-treat leachates were carried out in laboratory conditions after their coagulation with the use of FeCl3. The effects of the pre-treatment of leachates using the method of coagulation with FeCl3 depended on the concentration of organic compounds and with optimal conditions of the process ranged from 40 to 70%. Further pre-treatment of the leachates after coagulation, involving the use of oxidation with 03 and H2O2/O3, did not cause significant decrease of leachate toxicity. The data of this study demonstrated the usefulness of the battery of tests using Daphnia magna, Artemia franciscana, Scenedesmus quadricauda and Vibrio fischeri for the toxicity evaluation of raw and pre-treated leachates.


Biogeochemical Niche of Magnetotactic Cocci Capable of Sequestering Large Polyphosphate Inclusions in the Anoxic Layer of the Lake Pavin Water Column.
Magnetotactic bacteria (MTB) are microorganisms thriving mostly at oxic-anoxic boundaries of aquatic habitats. MTB are efficient in biomineralising or sequestering diverse elements intracellularly, which makes them potentially important actors in biogeochemical cycles. Lake Pavin is a unique aqueous system populated by a wide diversity of MTB with two communities harbouring the capability to sequester not only iron under the form of magnetosomes but also phosphorus and magnesium under the form of polyphosphates, or calcium carbonates, respectively. MTB thrive in the water column of Lake Pavin over a few metres along strong redox and chemical gradients representing a series of different microenvironments. In this study, we investigate the relative abundance and the vertical stratification of the diverse populations of MTB in relation to environmental parameters, by using a new method coupling a precise sampling for geochemical analyses, MTB morphotype description, and in situ measurement of the physicochemical parameters. We assess the ultrastructure of MTB as a function of depth using light and electron microscopy. We evidence the biogeochemical niche of magnetotactic cocci, capable of sequestering large PolyP inclusions below the oxic-anoxic transition zone. Our results suggest a tight link between the S and P metabolisms of these bacteria and pave the way to better understand the implication of MTB for the P cycle in stratified environmental conditions.


Multiple roles for the Ess1 prolyl isomerase in the RNA polymerase II transcription cycle.
The Ess1 prolyl isomerase in Saccharomyces cerevisiae regulates RNA polymerase II (pol II) by isomerizing peptide bonds within the pol II carboxy-terminal domain (CTD) heptapeptide repeat (YSPTSPS). Ess1 preferentially targets the Ser5-Pro6 bond when Ser5 is phosphorylated. Conformational changes in the CTD induced by Ess1 control the recruitment of essential cofactors to the pol II complex and may facilitate the ordered transition between initiation, elongation, termination, and RNA processing. Here, we show that Ess1 associates with the phospho-Ser5 form of polymerase in vivo, is present along the entire length of coding genes, and is critical for regulating the phosphorylation of Ser7 within the CTD. In addition, Ess1 represses the initiation of cryptic unstable transcripts (CUTs) and is required for efficient termination of mRNA transcription. Analysis using strains lacking nonsense-mediated decay suggests that as many as half of all yeast genes depend on Ess1 for efficient termination. Finally, we show that Ess1 is required for trimethylation of histone H3 lysine 4 (H3K4). Thus, Ess1 has direct effects on RNA polymerase transcription by controlling cofactor binding via conformationally induced changes in the CTD and indirect effects by influencing chromatin modification.


Restriction fragment length polymorphism (RFLP) analysis in wheat. II. Linkage maps of the RFLP sites in common wheat.
Sixty-six F2 plants from the cross, Triticum aestivum cv. Chinese Spring (abbrev. CS) x T. spelta var. duhamelianum (Spelta), exhibiting the greatest number of RFLPs among eight common wheats, were analyzed for their RFLP genotypes using genomic DNA clones of CS as probes. In total, 204 RFLP loci were identified and their linkage relationships established. By nulli-tetrasomic analyses, all linkage groups were assigned to one another of the 21 wheat chromosomes. In addition, the carrier chromosomes of 228 non-RFLP loci were identified. The linkage maps of these RFLP loci have a total size of 1800 cM and exceed those of the classical genes in both size and locus number. Twenty loci show distorted segregation, four of which are clustered on chromosome 4A and three on the 2D chromosome. The CS alleles on 4A exhibit preferential transmission, while those on 2D exhibit depressed transmission, compared with Spelta alleles. This suggests the influence of gametic factors in those regions. RFLP loci are much fewer in the D genome than in the A and B genomes, but the numbers of non-RFLP loci are nearly the same in these three genomes. This suggests that Spelta wheat originated from a hybridization between T. dicoccum (spelt emmer) and T. aestivum.


Electronic Effect Promoted Visible-Light-Driven CO2-to-CO Conversion in a Water-Containing System.
The design of unsaturated nonprecious metal complexes with high catalytic performance for photochemical CO2 reduction is still an important challenge. In this paper, four coordinatively unsaturated Co-salen complexes 1-4 were explored in situ using o-phenylenediamine derivatives and 5-methylsalicylaldehyde as precursors of the ligands in 1-4. It was found that complex 4, bearing a nitro substituent (-NO2) on the aromatic ring of the salen ligand, exhibits the highest photochemical performance for visible-light-driven CO2-to-CO conversion in a water-containing system, with TONCO and CO selectivity values of 5300 and 96%, respectively. DFT calculations and experimental results revealed that the promoted photocatalytic activity of 4 is ascribed to the electron-withdrawing effect of the nitro group in 4 compared to 1-3 (with -CH3, -F, and -H groups, respectively), resulting in a lower reduction potential of active metal centers CoII and lower barriers for CO2 coordination and C-O cleavage steps for 4 than those for catalysts 1-3.


Acceptability and feasibility of early infant male circumcision for HIV prevention in Malawi.
Voluntary medical male circumcision (VMMC) has been successfully implemented in 14 countries as an additional HIV prevention intervention. As VMMC programs mature in most countries, the focus is now on how to sustain the HIV prevention gains realised from VMMC. As part of preparations for the sustainability phase, countries are either piloting or preparing to pilot early infant male circumcision (EIMC). This qualitative study explored the acceptability and feasibility of EIMC in Malawi in order to inform pilot implementation. In 2016, 23 focus group discussions were held across Malawi with participants from several ethnicities and religions/faiths. Additionally, 21 key informant interviews were held with traditional and religious leaders, traditional circumcisers (ngalibas), policy-makers, programme managers and health-care workers. Audio recordings were transcribed, translated into English (where necessary), and thematically coded using NVivo 10. Discussions highlighted the socio-cultural significance of MC in Malawi. Knowledge or experience of EIMC was poor although acceptability was high among most ethnic/religious groups and key informants. Participants identified EIMC's comparative HIV benefits although a few health-care workers expressed scepticism. All participants said EIMC should be offered within a clinical setting. In addition to fathers, maternal uncles and traditional leaders were deemed key decision-makers. Potential barriers to EIMC included concerns about procedure safety as well as cultural considerations. Key informants felt it was feasible to offer EIMC in Malawi. Participants' recommendations, including phased implementation, engagement of traditional leaders, use of external mobilisers and initially reaching out to influential parents, will be taken into account when designing a pilot EIMC program. EIMC is potentially an acceptable and feasible HIV prevention intervention for most ethnic/religious groups in Malawi if wide-ranging, culturally appropriate demand-creation activities are developed, piloted, evaluated and appropriately implemented.


Fluorodeoxyglucose positron emission tomography with computed tomography detects greater metabolic changes that are not represented by plain radiography for patients with osteonecrosis of the jaw.
Imaging is important to identify subclinical changes and for treatment planning in patients with osteonecrosis of the jaw (ONJ) exposed to antiresorptive therapy. The aim of this study was to compare the findings at radiography with those at fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) for patients with ONJ related to antiresorptive therapy. A cross-sectional retrospective analysis of patients with clinically identified ONJ lesions of the mandible was performed. Two imaging modalities were evaluated for each patient: plain radiography (ie, panoramic or periapical) and FDG PET/CT with 1-mm sections. Outcome variables for the radiographic findings were osteolytic and osteosclerotic bone changes. Outcome variables for FDG PET/CT images were localization of FDG uptake. Maximum standard uptake values (SUVmax) of abnormal FDG jaw uptake were recorded, in addition to the mean SUV of the contralateral normal mandible, and used to calculate the target-to-background ratio. Radiographic changes and FDG uptake were classified as local (ie, corresponding to exposed cortical bone) or diffuse (ie, local changes and changes extending beyond the margins of exposed bone) for each imaging technique. Local and diffuse changes detected by each imaging modality were described and the difference in detection was compared with the McNemar test. Twenty-three patients with 25 clinically identified ONJ lesions were analyzed using radiography and FDG PET/CT. Differences were found in how radiography and FDG PET/CT detect local and diffuse changes associated with ONJ. Radiography showed local changes in 17 patients (68%), diffuse changes in 3 patients (12%), and no changes in 5 patients (20%), whereas FDG PET/CT imaging showed local changes in 17 patients (68%) and diffuse changes in 8 patients (32%). The McNemar test indicated that FDG PET/CT imaging was less likely to miss a lesion (P < .001). Mean SUVmax was 6.59, and the mean target-to-background ratio was 5.37. The results of this study show that FDG PET/CT detects local and diffuse metabolic changes that may not be represented by plain radiography for patients with ONJ related to antiresorptive therapy. The target-to-background ratio allowed the discrimination between ONJ lesions and background changes. Future studies are necessary to determine whether FDG PET/CT can determine risk and facilitate management of ONJ.


Mast cells from the human intestinal lamina propria. Isolation, histochemical subtypes, and functional characterization.
With the use of a collagenase dispersion technique, cells were isolated from the lamina propria of the human small and large intestine. The cell suspensions contained 8% mast cells, which on average contained 1 to 2 pg of histamine/cell. With the use of histochemical procedures based upon fixative sensitivity and dye binding, which identify functionally distinct mast cell subtypes in the rat, dispersed human intestinal mast cells contained approximately equal proportions of two histochemical subtypes analogous to those in the rat. Whether these are functionally distinct as in the rat remains to be determined. The histochemically mixed mast cell populations from the human intestinal mucosa secreted histamine in a dose- and energy-dependent manner in response to anti-IgE and A23187, but not 48/80. Theophylline, doxantrazole, quercetin, and salbutamol all significantly inhibited anti-IgE-induced histamine secretion by human intestinal mast cells, but cromolyn sodium and the experimental antisecretory drugs, nedocromil sodium and FPL 52694, did not inhibit histamine secretion by the mast cell mixture to a statistically significant extent. Cromolyn sodium inhibited histamine secretion by 15 to 30%, and whether this reflected inhibition of one of the two histochemical mast cell subtypes to a greater extent than the other or all the cells to a minimal degree remains to be established. Control investigations of the intestinal cell isolation procedure indicated that these qualities did not reflect effects of the cell dispersal procedure. Further characterization and analysis of intestinal mast cells is essential to determine if functionally distinct mast cell subtypes exist in human tissues.


The potential of solanezumab and gantenerumab to prevent Alzheimer's disease in people with inherited mutations that cause its early onset.
The recent failure of several clinical trials on anti-β-amyloid (Aβ) drugs in Alzheimer's disease (AD) suggested earlier intervention in the disease course. Secondary prevention trials have been started in autosomal-dominant AD (ADAD) individuals without cognitive dysfunction and in cognitively healthy subjects at risk of developing sporadic AD (SAD). Herein, the authors discuss prevention trials in ADAD and SAD, with a focus on the anti-Aβ monoclonal antibodies solanezumab and gantenerumab presently in Phase III clinical development. These therapies are also being tested in the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU). Anti-Aβ monoclonal antibodies are being tested in subjects at the preclinical stage of ADAD and even in symptom-free subjects at risk of developing SAD. The subsequent DIAN-TU Adaptive Prevention Trial is a 4-year study that will assess whether such biomarker effects may stop the progress of the AD process, preventing cognitive symptoms. The hope is to interfere in the disease course when it is not too late. A clinical success of these prevention trials would represent the proof of the Aβ hypothesis of AD.


Association of life threat and betrayal with posttraumatic stress disorder symptom severity.
The Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association [APA], 2000) emphasizes life threat as the defining feature of psychological trauma. Recent theoretical and empirical work, however, indicates the need to identify and evaluate other key aspects of trauma. Betrayal has been proposed as a pertinent, distinct, and complementary factor that can explain effects of trauma not accounted for by life threat alone. This study examined the relationship between injury, perceived life threat (PLT), and betrayal with posttraumatic stress disorder (PTSD) symptom severity. Trauma-exposed college students (N = 185) completed self-report measures of trauma exposure and PTSD, as well as items regarding life threat, betrayal, and level of medical care received. In hierarchical regressions incorporating injury, PLT, and betrayal, betrayal was associated with all PTSD symptom clusters and PTSD total severity (f(2) = .08), whereas PLT was associated with hyperarousal (f(2) = .05) and PTSD total (f(2) = .03), and injury had no association with PTSD symptoms. In a revised model with trauma type as an additional variable, betrayal was associated with avoidance (f(2) = .03), numbing (f(2) = .04), and PTSD total (f(2) = .03), whereas PLT was associated with reexperiencing (f(2) = .04), hyperarousal (f(2) = .04), and PTSD total (f(2) = .03), and injury was associated with avoidance (f(2) = .03). These findings support the idea that betrayal is a core dimension of psychological trauma that may play an important role in the etiology of PTSD.


Life-course partnership history and midlife health behaviours in a population-based birth cohort.
Marital and partnership history is strongly associated with health in midlife and later life. However, the role of health behaviours as an explanatory mechanism remains unclear. The aim of this study was to investigate prospective associations between life-course partnership trajectories (taking into account timing, non-marital cohabitation, remarriage and marital transitions) and health behaviours measured in midlife. We analysed data from the British National Child Development Study, a prospective cohort study that includes all people born in 1 week of March 1958 (N=10 226). This study included men and women with prospective data on partnership history from age 23 to 42-44 and health behaviours collected at ages 42-46 (2000-2004). Latent class analysis was used to derive longitudinal trajectories of partnership history. We used multivariable regression models to estimate the association between midlife health behaviours and partnership trajectory, adjusting for various early and young adult characteristics. After adjustment for a range of potential selection factors in childhood and early adulthood, we found that problem drinking, heavy drinking and smoking were more common in men and women who experienced divorce or who had never married or cohabited. Women who married later had a lower prevalence of smoking and were less likely to be overweight than those who married earlier. Overall marriage was associated with a higher body mass index. Individuals who never married or cohabited spent less time exercising. Some aspects of partnership history such as remaining unpartnered and experiencing divorce are associated with more smoking and drinking in midlife, whereas marriage is associated with midlife weight gain. Despite these offsetting influences, differences in health behaviours probably account for much of the association between partnership trajectories and health found in previous studies.


Pumpkin seed oil alleviates oxidative stress and liver damage induced by sodium nitrate in adult rats: biochemical and histological approach.
Nitrate (NO3) is the most common chemical contaminant in the world's ground water aquifer. Oxidative stress has been proposed as a possible mechanism involved in NO3 toxicity on non-target organism. The current study aimed to elucidate the potential protective effect of Telfairia occidentalis (pumpkin seed oil, PSO) against hepatotoxicity induced by sodium nitrate. Wistar rats were exposed either to NaNO3 (200 mg/kg bw) in drinking water in drinking water, or to 4ml PSO/kg bw by gavage or to their combination. Oxidative stress parameters, biochemical biomarkers and liver histopathological examination were determined. Our data showed that the exposure of rats to NaNO3 caused significant changes of some haematological parameters compared to the control. In addition, there was a significant elevation of the levels of biochemical markers as that of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase when compared with the control. Furthermore, exposure of rats to NaNO3 induced liver oxidative stress as indicated by the increase of malondialdehyde, progressive oxidation of protein products and protein carbonyl levels. In addition, a reduction in anti-oxidant status (catalase, glutathione peroxidase, glutathione-S-transferase and superoxide dismutase, reduced glutathione and vitamin C) was observed. Co-administration of PSO to the NaNO3 restored most parameters cited above to near-normal values. Therefore, the present investigation revealed the ability of PSO to attenuate NaNO3-induced oxidative damage.


[Sarcoidosis of the stomach].
The article describes sarcoidosis affected mucous membrane of the stomach. On the basis of literature data and personal observations (2 cases of sarcoidosis affected the mucous membrane of the stomach in 40 sarcoidosis patients examined), the endoscopic characteristics of the mucous membrane of the stomach are given. It is found that the process is frequently localized in the antral portion of the stomach being combined with +pyloric stenosis. Patients with chronic sarcoidosis were examined, unlike foreign authors who surveyed those with first sarcoidosis. The presence of "sarcoid" changes in the mucous membrane of the stomach appears to be one of the signs of the process manifestation and requires hormonal agents to be used. It is necessary to conduct endoscopic examinations of the gastrointestinal tract to detect both the disease and different chronic lesions of the stomach in a specialized hospital where sarcoidosis patients are treated.


[Examination of the orbitomeatal basal line-anthropological basal line crossing angle and acanthiomeatal line-anthropological basal line crossing angle].
Orbitomeatal basal line-anthropological basal line (OML-ABL), and the acanthiomeatal line (AML)-ABL crossing angles were measured using profile pictures. There were 219 volunteers in total: 42 people four years old, 44 people nine years old, 45 people 14 years old, 43 people 19 years old, and 45 people 40 years or older (48±7.4 years). The average OML-ABL crossing angle was 14.3 degrees in the 4-year-old group, while that of the 40-year or older group was 11.1 degrees. The deviation width of the 4-year-old group was 4.8 degrees, and that of the 40-year or older group was 2.4 degrees. The average AML-ABL crossing angle was 12.3 degrees in the 4-year-old group, while that of the 40-year or older group was 15.7 degrees. There were differences between males and females. The deviation width of the 4-year group was 5.4 degrees, and that of the 40-year or older group was 2.7 degrees. The results showed that 14.0 degrees for around 4-year-old, and 12.0 degrees for around 9- to 14-year-olds, could be used as OML-ABL crossing angles as a practical proposition.


A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors.
The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached). The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.


Relating components of pressure-volume area in Suga's formulation of cardiac energetics to components of the stress-time integral.
The concept of pressure-volume area (PVA) in whole heart studies is central to the phenomenological description of cardiac energetics proposed by Suga and colleagues (Physiol Rev 70: 247-277, 1990). PVA consists of two components: an approximately rectangular work loop (W) and an approximately triangular region of potential energy (U). In the case of isovolumic contractions, PVA consists entirely of U. The utility of Suga's description of cardiac energetics is the observation that the oxygen consumption of the heart (Vo(2)) is linearly dependent on PVA. By using isolated ventricular trabeculae, we found a basis on which to correlate the components of stress-length area (SLA; i.e., the 1-D equivalent of PVA) with specific regions of the stress-time integral (STI; i.e., the area under the force-time profile of a single twitch). In each case, proportionality obtains and is robust, independent of the type of twitch contraction (isometric or isotonic), and insensitive to changes of preload or afterload. We apply our results by examining retrospectively the interpretations reached in three independent studies published in the literature.


Frequent gene products and molecular pathways altered in prostate cancer- and metastasis-initiating cells and their progenies and novel promising multitargeted therapies.
Recent gene expression profiling analyses and gain- and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC- and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.


N-3 fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance. Italian Fish Oil Multicenter Study.
A multicenter, randomized, double-blind, place-bo-controlled study evaluated the possible worsening of glycemic control after a moderate daily intake of n-3 fatty acid ethyl esters in patients with hypertriglyceridemia with and without glucose intolerance or diabetes. A total of 935 patients of both sexes in 63 Italian clinical centers were selected; 55% had either impaired glucose tolerance or non-insulin-dependent diabetes mellitus (NIDDM). They received for 2 mo either 1 g n-3 ethyl esters three times a day or a corresponding placebo, followed by 4 mo of either 1 g n-3 ethyl esters twice a day or placebo. In addition to the complete lipid and lipoprotein evaluation, patients with impaired glucose tolerance also underwent an oral-glucose-tolerance test; in patients with NIDDM, serum insulin and glycated hemoglobin (Hb A1c) concentrations were determined. Plasma triacylglycerol concentrations decreased significantly, up to 21.53% at 6 mo compared with baseline (decreased 15% compared with placebo), with a tendency toward a progressive reduction with time. There was no evidence for a different response in patients with either NIDDM or impaired glucose tolerance. Among NIDDM patients, the triacylglycerol reduction was greater in those with high-density-lipoprotein cholesterol < or = 0.91 mmol/L. There was no alteration in the major glycemic indexes: fasting glucose, Hb A1c, insulinemia, and oral glucose tolerance in patients with impaired glucose tolerance or NIDDM after treatment with n-3 ethyl esters. Treatment with a moderate daily dose of n-3 ethyl esters over a prolonged period of time significantly reduced triacylglycerol concentrations without any worsening of glucose tolerance in patients with hypertriglyceridemia with and without impaired glycemic regulation.


A theoretical comparison of electric and magnetic stimulation of the brain.
We present a theoretical comparison of the electric field produced in the brain by three modalities of transcranial stimulation of the cortex: magnetic stimulation, bifocal electric stimulation, and unifocal electric stimulation. The primary focus of this comparison is the focality and direction of the electric fields produced. A three-sphere model is used to represent the scalp, skull, and brain. All electric fields are calculated numerically. For magnetic stimulation we consider only a figure-of-eight coil. We find that magnetic stimulation produces the most focal field, while unifocal electric produces the least. Fields produced during magnetic stimulation are parallel to the head surface, while fields produced during electric stimulation have components both parallel and perpendicular to the head surface. The electric field produced by magnetic stimulation is shown to be insensitive to the skull conductivity, while that produced by electric stimulation is very sensitive to it.


Formation of peptide bonds from metastable versus crystalline phase: implications for the origin of life.
Formation of peptide bonds was attempted by thermal activation of dry amino acids from aqueous solution that simulated prebiotic evaporative environments. The evaporation trend of amino acids solutions shows a bifurcation and can lead to either a crystalline phase (near equilibrium) or a metastable non-crystalline phase (far from equilibrium). Only amino acids in this metastable phase are able to form peptide bonds by thermal activation at temperatures that are generated by solar radiation today. We suggest that this metastable phase is the ideal initial material to trigger amino acid assemblage with protein-like structure because provide the driving force (supersaturation) for an intense interaction between monomers of different amino acids and allows activation of these monomers in plausible prebiotic conditions.


Regulation of Hxt3 and Hxt7 turnover converges on the Vid30 complex and requires inactivation of the Ras/cAMP/PKA pathway in Saccharomyces cerevisiae.
Eukaryotic cells adjust their intracellular protein complement as a mechanism to adapt to changing environmental signals. In Saccharomyces cerevisiae the hexose transporters Hxt3 and Hxt7 are expressed and function on the plasma membrane in high and low glucose abundance, respectively. By contrast, Hxt3 is endocytosed and degraded in the vacuole when cells are starved of glucose and Hxt7 in response to rapamycin treatment or when nitrogen is limiting. Yeast uses several signaling pathways, including the TORC1 and Ras/cAMP/Protein Kinase A (PKA) pathways, to adapt to nutrient changes in the environment. The multi-protein Vid30 complex (Vid30c), an E3 ubiquitin ligase required for the degradation of FBPase, assists in this adaptation process in a mechanism that is poorly understood. Here we show the endocytosis and the subsequent degradation of both Hxt3 and Hxt7, in response to different nutrient signals, is dependent on components of the Vid30c. Additionally, we define the signaling events required for the turnover of Hxt3 and Hxt7 by showing that Hxt3 turnover requires Ras2 and PKA inactivation, whereas Hxt7 turnover requires TORC1 and Ras2 inactivation. Further investigation led us to identify Rim15, a kinase that is inhibited by both the TORC1 and Ras/cAMP/PKA pathways, as a key downstream effector in signaling both turnover events. Finally, we show that the turnover of both Hxt3 and Hxt7 is dependent on the essential E3 ubiquitin ligase, Rsp5, indicating that the role of the Vid30c might be indirect of Hxt ubiquitylation.


[Nature of the effect on RNA and substrate specificity of RNAase of Bacillus amylozyma 9a].
Extracellular RNAase from Bac. amylozyma 9a has endonucleolytic character of the action on RNA, it splits in RNA 5'-phosphodiester bonds of GpXp type (where X is any nucleoside). The hydrolysis proceeds in two steps by the intramolecular transphosphorylation type of reaction to form guanosine-2',3'-phosphates and with the subsequent hydrolysis of cyclic bonds. The enzyme shows a preferable specificity to the single-stranded structure of the polyribonucleotides.


A Mechanistic Reinterpretation of Fast Inactivation in Voltage-Gated Na+ Channels.
The hinged-lid model is long accepted as the canonical model for fast inactivation in Nav channels. It predicts that the hydrophobic IFM motif acts intracellularly as the gating particle that binds and occludes the pore during fast inactivation. However, the observation in recent high-resolution structures that the bound IFM motif locates far from the pore, contradicts this preconception. Here, we provide a mechanistic reinterpretation of fast inactivation based on structural analysis and ionic/gating current measurements. We demonstrate that in Nav1.4 the final inactivation gate is comprised of two hydrophobic rings at the bottom of S6 helices. These rings function in series and close downstream of IFM binding. Reducing the volume of the sidechain in both rings leads to a partially conductive "leaky" inactivated state and decreases the selectivity for Na + ion. Altogether, we present an alternative molecular framework to describe fast inactivation.


Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage.
Articular cartilage is a specialised tissue that has a relatively homogenous endogenous cell population but a diverse extracellular matrix (ECM), with depth-dependent mechanical properties. Repair of this tissue remains an elusive clinical goal, with biological interventions preferred to arthroplasty in younger patients. Osteochondral transplantation (OCT) has emerged for the treatment of cartilage defects and osteoarthritis. Fresh allografts stored at 4 °C have been utilised, though matrix and cell viability loss remains an issue. To address this, several studies have developed media formulations to maintain cartilage explants in vitro. One promising factor for these applications is sprifermin, a human-recombinant fibroblast growth factor-18, which stimulates chondrocyte proliferation and matrix synthesis and is in clinical trials for the treatment of osteoarthritis. The study hypothesis was that addition of sprifermin during storage would maintain the unique depth-dependent mechanical profile of articular cartilage explants, a feature not often evaluated. Explants were maintained for up to 6 weeks with or without a weekly 24 h exposure to sprifermin (100 ng/mL) and the compressive modulus was assessed. Results showed that sprifermin-treated samples maintained their depth-dependent mechanical profile through 3 weeks, whereas untreated samples lost their mechanical integrity over 1 week of culture. Sprifermin also affected ECM balance by maintaining the levels of extracellular collagen and suppressing matrix metalloproteinase production. These findings support the use of sprifermin as a medium additive for OCT allografts during in vitro storage and present a potential mechanism where sprifermin may impact a functional characteristic of articular cartilage in repair strategies.


Linear accelerator-based stereotactic radiosurgery for bilateral vestibular schwannomas in patients with neurofibromatosis type 2.
Patients with neurofibromatosis Type 2 (NF2) patients typically have bilateral vestibular schwannomas (VS) and are at risk for developing bilateral deafness, bilateral trigeminal, and bilateral facial nerve function loss. Previous reports suggested that treatment outcomes in these patients are worse compared with those for patients with sporadic solitary VS. Very few reports, however, have been published on linear accelerator-based radiosurgery (RS) and stereotactic radiation therapy (SRT) in patients with NF2. In particular, in patients with NF2 who already have unilateral hearing loss, avoidance of hearing loss on the opposite side poses a challenge for RS and SRT. We studied our treatment results in patients with NF2 with bilateral VS, treated with linear accelerator-based RS and SRT. In 204 patients with VS treated with RS or SRT in Amsterdam starting from 1992, we identified 25 patients with NF2 who had bilateral tumors. Indications for treatment were either tumor progression on sequential magnetic resonance imaging scans and/or progressive hearing loss. Mean tumor diameter was 2.5 cm. Stereotactic irradiation was administered to all patients using five noncoplanar arcs with a single isocenter to a dose of 10 to 12.5 Gy in a single fraction or 20 to 25 Gy in five fractions in 1 week prescribed to the 80% isodose encompassing the tumor. On the untreated side, all patients showed hearing loss and eight (32%) had ipsilateral deafness. Five patients were followed for less than 1 year. Of the remaining 20 patients, five had ipsilateral deafness before treatment. Consequently, 15 patients were at risk for treatment-related hearing loss. They showed a mean pure tone average (PTA) of 51 dB (8-112 dB) before treatment. After treatment all patients were assessed at yearly intervals including magnetic resonance imaging and pure tone audiometry. Median follow-up time was 51 months (12-109 mo). Local tumor control was obtained in all 20 patients, and no treatment-related trigeminal or facial nerve toxicity was observed. Hearing status was assessed yearly after treatment. This assessment revealed that the mean PTA in the 15 hearing patients dropped from 51 to 77 dB (40-120 dB). In six patients (40%) the additional PTA loss ranged from 0 to 15 dB, in another six (40%) it ranged from 15 to 45 dB, and in three of these patients (20%), it was more than 45 dB. No additional hearing loss was observed beyond 36 months after treatment. In this largest series in the literature of linear accelerator-based RS and SRT for VS NF2 patients, excellent local control rates were found with minimal facial and trigeminal nerve toxicity. Although more than 40% of the patients retained their hearing level or lost less than 15 dB of PTA on the irradiated side, preservation of hearing remains a major concern.


Effect of in feed administration of different butyrate formulations on Salmonella Enteritidis colonization and cecal microbiota in broilers.
Butyrate has been used extensively as a feed additive to improve gut health and to decrease Salmonella colonization in poultry. Salmonella mainly colonizes the ceca so butyrate concentrations should be increased in this gut segment. Discrepancies on the effects of butyrate on Salmonella colonization, described in the scientific literature, could thus be due to butyrate release location effects. In this study, newly developed butyrate formulations were evaluated for their effect on cecal butyrate concentrations and on colonization by Salmonella Enteritidis. In a first trial, broilers were randomly allocated to 7 dietary treatment groups with formulations based on different approaches to modify the butyrate release profile: release from wax matrices based on diffusion/erosion; micropellets supposedly release butyrate around pH 7 in the colon; tributyrin is based on the hydrolysis of esters in the small intestine. Fat-protected butyrate was included as a reference, because of its known effect on reduction of Salmonella colonization. Four days after infection, the number of cfu Salmonella per g cecal content and spleen were determined. Butyrate formulations in a wax matrix significantly reduced the Salmonella colonization in cecal content. In a second trial, wax and fat-protected butyrate treatments were replicated and results from the first trial were confirmed. Compared to the control group a higher proportion of butyrate concentration was observed in ceca for those groups with reduced Salmonella colonization. This was associated with a beneficial shift in the cecal microbiota. In conclusion, formulations that increase cecal butyrate concentrations are superior in protecting against Salmonella Enteritidis colonization.


Risk factors for PTSD and depression in female survivors of rape.
To investigate association of the sociodemographic factors, characteristics of rape and social support to the development of depression and posttraumatic stress disorder at 6 months after the rape. A cross-sectional survey with female survivors of rape was carried out in 3 provinces of South Africa 6 months after the rape. One hundred female survivors s of sexual assault were interviewed. More than half (53%) were from Limpopo, 25% from Western Cape, and 22% from KwaZulu-Natal (KZN). 87% reported high levels of PTSD and 51% moderate to severe depression post rape. The major risk factors for PTSD and depression were the unmarried survivors of rape and those living in KZN. The female survivors of rape in KZN province were 7 times more likely to experience symptoms of depression compared to other provinces, while married/cohabiting female rape survivors were 6 times less likely to report symptoms of depression compared to the unmarried female rape survivors. These findings add support to existing literature on PTSD and depression as common mental health consequence of rape and also provide evidence that survivors' socio- demographics-marital status, employment status-are significant contributors to the development of symptoms of depression and PTSD after rape. The results have research and clinical practice relevance for ensuring that PTSD and trauma treatment focuses on an in-depth understanding of the various aspects of the sociodemographic factors and rape characteristics that contribute to survivors' mental state and how these compound stress and depression symptoms over time post rape victimization. (PsycINFO Database Record


A model for the dynamics of ultrasound contrast agents in vivo.
The Rayleigh-Plesset (RP) equation for a clean gas bubble in an incompressible and infinite liquid has previously been applied to approximately simulate the behavior of ultrasound contrast agents (UCA) in vivo, and extended RP equations have been proposed to account for the effects of the UCA shell or surrounding soft tissue. These models produce results that are consistent with experimental measurements for low acoustic pressure scenarios. For applications of UCAs in therapeutic medicine, the transmitted acoustic pulse can have a peak negative pressure (PNP) up to a few megapascals, resulting in discrepancies between measurements and predictions using these extended RP equations. Here, a model was developed to describe the dynamics of UCAs in vivo while taking account of the effects of liquid compressibility, the shell and the surrounding tissue. Liquid compressibility is approximated to first order and the shell is treated either as a Voigt viscoelastic solid or a Newtonian viscous liquid. Finite deformation of the shell and tissue is derived. Dynamics of UCAs with a shell of lipid, polymer, albumin and liquid are investigated for typical therapeutic ultrasound pulses. The effects of liquid compressibility and shell and tissue parameters are analyzed.


Do Global Cities Enable Global Views? Using Twitter to Quantify the Level of Geographical Awareness of U.S. Cities.
Dynamic social media content, such as Twitter messages, can be used to examine individuals' beliefs and perceptions. By analyzing Twitter messages, this study examines how Twitter users exchanged and recognized toponyms (city names) for different cities in the United States. The frequency and variety of city names found in their online conversations were used to identify the unique spatiotemporal patterns of "geographical awareness" for Twitter users. A new analytic method, Knowledge Discovery in Cyberspace for Geographical Awareness (KDCGA), is introduced to help identify the dynamic spatiotemporal patterns of geographic awareness among social media conversations. Twitter data were collected across 50 U.S. cities. Thousands of city names around the world were extracted from a large volume of Twitter messages (over 5 million tweets) by using the Twitter Application Programming Interface (APIs) and Python language computer programs. The percentages of distant city names (cities located in distant states or other countries far away from the locations of Twitter users) were used to estimate the level of global geographical awareness for Twitter users in each U.S. city. A Global awareness index (GAI) was developed to quantify the level of geographical awareness of Twitter users from within the same city. Our findings are that: (1) the level of geographical awareness varies depending on when and where Twitter messages are posted, yet Twitter users from big cities are more aware of the names of international cities or distant US cities than users from mid-size cities; (2) Twitter users have an increased awareness of other city names far away from their home city during holiday seasons; and (3) Twitter users are more aware of nearby city names than distant city names, and more aware of big city names rather than small city names.


Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders.
People with mental disorders evince excess mortality due to natural and unnatural deaths. The relative life expectancy of people with mental disorders is a proxy measure of effectiveness of social policy and health service provision. To evaluate trends in health outcomes of people with serious mental disorders. We examined nationwide 5-year consecutive cohorts of people admitted to hospital for mental disorders in Denmark, Finland and Sweden in 1987-2006. In each country the risk population was identified from hospital discharge registers and mortality data were retrieved from cause-of-death registers. The main outcome measure was life expectancy at age 15 years. People admitted to hospital for a mental disorder had a two- to threefold higher mortality than the general population in all three countries studied. This gap in life expectancy was more pronounced for men than for women. The gap decreased between 1987 and 2006 in these countries, especially for women. The notable exception was Swedish men with mental disorders. In spite of the positive general trend, men with mental disorders still live 20 years less, and women 15 years less, than the general population. During the era of deinstitutionalisation the life expectancy gap for people with mental disorders has somewhat diminished in the three Nordic countries. Our results support further development of the Nordic welfare state model, i.e. tax-funded community-based public services and social protection. Health promotion actions, improved access to healthcare and prevention of suicides and violence are needed to further reduce the life expectancy gap.