Posterior wall acetabular fracture in a 13-year-old boy treated by open reduction and mini-plate internal fixation: long-term follow-up of 17 years.
Acetabular fractures are uncommon in children and adolescents, mainly because of predominant cartilaginous component and strong surrounding ligaments. Although acetabular fractures at this age can lead to significant disability, there is no consensus regarding management, which continues to be controversial. Particularly, long-term outcome after operative management has not been evaluated. We report a case of a 13-year-old boy skeletally immature who presented with an isolated acetabular fracture involving the posterior wall secondary to a traumatic hip dislocation. A Kocher-Langenbeck approach with a surgical luxation of the hip was used for reduction and mini-plate internal fixation of the fracture. Long-term (17-year) follow-up showed a good clinical outcome and a good congruence of the. The patient has bilateral beginning osteoarthritis due to a cam configuration of both hips CONCLUSION: We describe a case of successful operative management of an acetabulum fracture in a skelettaly immature child with a long-term follow-up. Aggressive management of this rare type of fractures may lead to durable positive outcome.


Long-term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy.
Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated. Compare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride. Seventy-five client-owned IW dogs. Irish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin®), benazepril HCl (Fortekor®), or methyldigoxin (Lanitop®) monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed. Sixty-six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0-5.0 years) and weight, 70.0 kg (63.0-75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl-(997 days; 32.8 months; P = .008) treated dogs. In IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin.


A novel locus in the oxidative stress-related gene ALOX12 moderates the association between PTSD and thickness of the prefrontal cortex.
Oxidative stress has been implicated in many common age-related diseases and is hypothesized to play a role in posttraumatic stress disorder (PTSD)-related neurodegeneration (Miller and Sadeh, 2014). This study examined the influence of the oxidative stress-related genes ALOX 12 and ALOX 15 on the association between PTSD and cortical thickness. Factor analyses were used to identify and compare alternative models of the structure of cortical thickness in a sample of 218 veterans. The best-fitting model was then used for a genetic association analysis in White non-Hispanic participants (n=146) that examined relationships between 33 single nucleotide polymorphisms (SNPs) spanning the two genes, 8 cortical thickness factors, and each SNP×PTSD interaction. Results identified a novel ALOX12 locus (indicated by two SNPs in perfect linkage disequilibrium: rs1042357 and rs10852889) that moderated the association between PTSD and reduced thickness of the right prefrontal cortex. A whole-cortex vertex-wise analysis showed this effect to be localized to clusters spanning the rostral middle frontal gyrus, superior frontal gyrus, rostral anterior cingulate cortex, and medial orbitofrontal cortex. These findings illustrate a novel factor-analytic approach to neuroimaging-genetic analyses and provide new evidence for the possible involvement of oxidative stress in PTSD-related neurodegeneration.


Role of simulated in vitro gastrointestinal digestion on biotransformation and bioactivity of astragalosides from Radix Astragali.
Radix Astragali (RA) is commonly used in Asian herbal therapy or food supply, and astragalosides and flavonoids are its major components with diverse pharmaceutical effects. To provide new information on the potential cardiovascular benefits of RA administered orally, the bioaccessibility of these compounds with relevant in vitro digestion parameters was determined for four digestion phases (oral, gastric, small and large intestines) by ultrahigh-performance liquid chromatography quadrupole time-of-flight-mass spectrometry (UPLC-Q-TOF/MS). Meanwhile, we compared the effects of digestion products on advanced glycation end products (AGEs)-induced intracellular reactive oxygen species (ROS) levels in a human arterial endothelial cells (HAECs) model, and studied the potential of RA against oxidative stress-related cardiovascular disease. The changes of saponins and flavonoids composition and antioxidant activity after digestion in intestines were mainly due to the astragaloside IV (AS-IV) biosynthesis involving saponins acetyl isomerization and deacetylation, and the flavonoid glycosides converted to aglycone by deglycosylation processes. All these results suggest that acetyl biotransformation of RA in small intestine directly influenced the response to oxidative stress, and might provide a reference for elucidation of the multi-component action after oral RA in cardiovascular health care.


When and Where Should Surgery Be Positioned in Pediatric Inflammatory Bowel Disease?
Surgery for children and adolescents with IBD is often thought of as a combination of a failure of medical management and the only option for the severe complications of the disease such as uncontrolled GI bleeding, perforation, fistulae, sepsis, and bowel obstruction. However, in CD, surgery can sometimes be an appropriate option to control disease progression, improve symptoms, allow children to get back on the growth curve, and avoid the toxicities of prolonged use of steroids. In UC, the decision to operate is theoretically curative but the long-term options mandate either intestinal continuity with an ileal pouch or a lifelong ileostomy, both of which can have significant impacts in patients' quality of life.


Angiogenesis and lymphangiogenesis in inflammatory skin disorders.
Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs physiologically in wound healing, during inflammatory diseases, and in tumor growth. Lymphangiogenesis can be activated in inflammation and tumor metastasis. The family of vascular endothelial growth factors (VEGFs) and angiopoietins are essential for angiogenesis and lymphangiogenesis. The angiogenic process is tightly regulated by VEGFs, angiopoietins, and endogenous inhibitors. VEGFs and angiopoietins exert their effects by activating specific receptors present on blood and lymphatic endothelial cells. There is now compelling evidence that cells of innate and adaptive immunity (macrophages, mast cells, neutrophils, eosinophils, lymphocytes) are a major source of angiogenic and lymphangiogenic factors. Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis are characterized by altered angiogenesis, lymphangiogenesis, or both. Also such acute inflammatory skin disorders as urticaria, ultraviolet B-induced damage, and angioedema are associated with changes in angiogenic factors. In systemic sclerosis there is a switch from proangiogenic to antiangiogenic factors that play a role in the defective vascular process of this disorder. As yet, there are no clinical trials showing that canonical VEGF/VEGF receptor-targeted strategies can modulate inflammatory skin diseases. Novel strategies targeting other angiogenic/lymphangiogenic pathways should also be investigated.


Assessing the application of the revised Remane Model to fish species in a fluvially dominated cool-temperate southern African coastal system.
Estuaries are ecologically important areas which support a variety of aquatic species, particularly marine and estuarine fish species. This study represents a case study of the Orange River and Estuary (ORE) to understand patterns in fish assemblages and diversity trends that were compared to the revised Remane Model predictions in an estuary with poor marine fish species richness. A total of 30 species were recorded in the River continuum that comprised 14 freshwater, 10 marine and six estuarine species. Species diversity revealed seasonal variation in fish assemblages during the high-flow and low-flow seasons but not inter-annually. The results revealed that species diversity is lower in higher salinity areas when compared to low salinity areas. These patterns are consistent with the biogeographical trend of decreasing species richness along the South African coast from east to west, however, inconsistent with Remane predictions. The extremely low marine fish richness at its lower end and the extremely large freshwater influx at its upper end are the primary causes of the inconsistency. This may reflects the unsuitability of the Remane model for the Orange Estuary. In comparison to similar river-dominated South African estuaries, the ORE has a low marine species richness. When compared to more conventional South African estuaries, the ORE has a unique biotic environment with low fish species richness of estuarine-associated marine species adjacent to the Benguela upwelling zone and therefore the region does not offer suitable habitat for such species. As a result, the ORE is not a good candidate to test the Remane Model. The data does, however, confirm the left-hand part of the Remane model, which shows a decline in the fish species richness of freshwater fish species as salinity rises towards mesohaline and polyhaline levels.


Anxiolytic profile of pregabalin on elicited hippocampal theta oscillation.
Previous published work with the novel anticonvulsant, analgesic and anti-anxiety medication, pregabalin (Lyrica), has shown that it has anxiolytic-like actions in several animal behavioral models. However, pregabalin is structurally and pharmacologically different from other classes of known anxiolytic drugs, and the mechanisms that alter brain activity to produce anxiolytic-like actions are not well understood. In an effort to determine more about the cellular mechanisms of pregabalin, we studied its effects on hippocampal theta activity of urethane-anesthetized rats that was elicited by electrical stimulation of the nucleus pontis oralis (nPO) in the brainstem. We found that systemic administration of pregabalin significantly reduced the frequency of stimulation-induced hippocampal theta activity similarly to the effects of diazepam. In addition, pregabalin (but not diazepam) significantly altered the stimulus intensity/frequency relationship, and increased slow delta oscillation (<3.0Hz) in spontaneous hippocampal EEG in a dose-dependent manner. Our findings suggest that pregabalin may alter evoked theta frequency activity in the hippocampus by reducing neurotransmitter-mediated activation of either the septal nucleus or the hippocampus, and that its actions are unlikely to be mediated by direct activation of GABA neurotransmitter systems. These observations provide further insight to the action of pregabalin, and support the utilization of stimulation-induced theta model in discovery of novel anxiolytic drugs.


Healing the wounds in the landscape-reclaiming gravel roads in conservation areas.
Reclaiming abandoned and unmaintained roads, built originally for forestry and mineral extraction, is an important part of ecological restoration, because the roads running through natural habitats cause fragmentation. The roads can be reclaimed in a passive way by blocking access to the road, but successful seedling recruitment may require additional management due to the physical constraints present at the road. We established a full factorial study to compare the effects of three road reclaiming measures, namely ripping, creation of safe sites by adding mulch and pine seed addition, on soil processes, recovery of understorey vegetation and seedling recruitment in three conservation areas in eastern Finland. We surveyed soil organic matter, frequency and cover of plant functional types, litter and mineral soil, and number of tree seedlings. The soil organic matter was, on average, 1.3-fold in the 50-cm-deep ripping treatment relative to unripped and 20-cm-deep ripping treatments. The germination and survival of deciduous seedlings and grass establishment were promoted by adding mulch. The addition of pine seeds counteracted the seed limitation and enhanced the regeneration of trees. The treatment combination consisting of ripping, adding mulch and pine seed addition enhanced the vegetation succession and tree-seedling recruitment most: the cover of grasses, herbs and ericaceous dwarf shrubs was 1.3-7.6-fold and the number of coniferous tree seedlings was 3.4-7.1-fold relative to the other treatment combinations. Differences between short-term (1-3 years) and longer-term (6 years) results indicate the need for a sufficient observation period in road reclamation studies.


SNIT: SNP identification for strain typing.
With ever-increasing numbers of microbial genomes being sequenced, efficient tools are needed to perform strain-level identification of any newly sequenced genome. Here, we present the SNP identification for strain typing (SNIT) pipeline, a fast and accurate software system that compares a newly sequenced bacterial genome with other genomes of the same species to identify single nucleotide polymorphisms (SNPs) and small insertions/deletions (indels). Based on this information, the pipeline analyzes the polymorphic loci present in all input genomes to identify the genome that has the fewest differences with the newly sequenced genome. Similarly, for each of the other genomes, SNIT identifies the input genome with the fewest differences. Results from five bacterial species show that the SNIT pipeline identifies the correct closest neighbor with 75% to 100% accuracy. The SNIT pipeline is available for download at http://www.bhsai.org/snit.html.


Energy barriers, pathways, and dynamics during folding of large, multidomain RNAs.
Large, multidomain RNA molecules are generally thought to fold following multiple pathways down rugged landscapes populated with intermediates and traps. A challenge to understanding RNA folding reactions is the complex relationships that exist between the structure of the RNA and its folding landscape. The identification of intermediate species that populate folding landscapes and characterization of elements of their structures are the key components to solving the RNA folding problem. This review explores recent studies that characterize the dominant pathways by which RNA folds, structural and dynamic features of intermediates that populate the folding landscape, and the energy barriers that separate the distinct steps of the folding process.


Self-reported obstructive sleep apnea, simple snoring, and various markers of sleep-disordered breathing as predictors of cardiovascular risk.
Our objective was to investigate whether self-reported obstructive sleep apnea (OSA), simple snoring, and various markers of sleep-disordered breathing (SDB) are associated with cardiovascular risk. We examined a representative nationwide cohort of 5177 Finnish adults aged ≥30 years. The participants underwent measurement of traditional cardiovascular risk factors and answered SDB-related questions derived from the Basic Nordic Sleep Questionnaire, which were used to operationalize self-reported OSA. The primary end point was incidence of a cardiovascular event (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or coronary interventions). During a median follow-up of 11.2 years and 52,910 person-years of follow-up, 634 participants suffered a cardiovascular event. In multivariable-adjusted Cox models, self-reported OSA (hazard ratio [HR] 1.34; 95 % confidence interval [CI] 1.04-1.73; p = 0.03) was an independent predictor of cardiovascular events. Self-reported simple snoring by itself was not associated with future cardiovascular events (HR 0.88 versus non-snorers, 95 % CI 0.75-1.04, p = 0.15). However, among snorers (n = 3152), frequent breathing cessations (HR 2.19, 95 % CI 1.26-3.81, p = 0.006) and very loud and irregular snoring (HR 1.82, 95 % CI 1.31-2.54, p < 0.001) were associated with cardiovascular risk. Self-reported OSA and SDB-related snoring variables are associated with cardiovascular risk, whereas simple snoring is not. In clinical practice and in surveys, questions concerning only habitual snoring should be amended with questions focusing on respiratory pauses and snoring stertorousness, which can be used to estimate the risk of OSA and cardiovascular events.


The regulation of tendon stem cell distribution, morphology, and gene expression by the modulus of microfibers.
The mechanical properties of a stem cell culture substrate significantly impact cell adhesion, survival, migration, proliferation, and differentiation in vitro. A major challenge in engineering artificial stem cell substrate is to properly identify the relevant physical features of native stem cell niches, which are likely different for each stem cell type. The behavior of tendon stem cells has potentially significant implications for tendon repair. Here, microfiber scaffolds with various modulus of elasticity are fabricated by near-field electrospinning, and their regulating effects on the in vitro behavior of tendon stem cells (TSCs) are discussed in this study. The number of pseudopodia shows a biphasic relationship with the modulus of scaffold. The proliferation, polarization ratio and alignment degree along the fibers of the TSCs increase with the increase of fiber modulus. TSCs cultured on the scaffold with moderate modulus (1429 MPa) show the upregulation of tendon-specific genes (Col-I, Tnmd, SCX and TNCF). These microfiber scaffolds provide great opportunities to modulate TSCs behavior at the micrometer scales. In conclusion, this study provides an instructive mechanical microenvironment for TSCs behaviors and may lead to the development of desirable engineered artificial stem cell substrate for tendon healing.


A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coronary syndromes in the UK.
To assess the long-term cost effectiveness of 1 year's treatment with clopidogrel on top of standard therapy (including aspirin; ASA) compared with standard therapy alone, in patients diagnosed with non-ST-segment-elevation acute coronary syndromes (ACS) in the UK. Cost utility analysis using a Markov model, incorporating clinical data from CURE (a multicentre randomised controlled trial, involving 12,562 patients) and data from UK observational studies. Health economic evaluation carried out from the perspective of the UK NHS. A representative cohort of 1000 UK patients aged 66 years, diagnosed with non-ST-segment-elevation ACS. Either a combination of 75 mg/day clopidogrel (300 mg loading dose, within 24 h prior to hospital admission) and standard therapy (including ASA, 75-325 mg/day) for 1 year followed by standard therapy alone for their remaining lifetime, or standard therapy alone (including ASA, 75-325 mg/day) for life. Incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. In the base case, the incremental cost effectiveness of the clopidogrel combination vs standard therapy alone is estimated as pounds 6991 per life-year gained and pounds 7365 per QALY gained. The probability that clopidogrel remains cost effective within the generally accepted pounds 30,000 per QALY threshold is more than 80%. The confidence interval around the relative risk for vascular death was identified as the main parameter affecting the estimated cost effectiveness. One year's treatment with clopidogrel is a cost effective intervention compared with standard therapy that should be considered as a routine treatment for patients with non-ST-segment-elevation ACS.


Retinoic acid causes cell growth arrest and an increase in p27 in F9 wild type but not in F9 retinoic acid receptor beta2 knockout cells.
We have previously shown that an F9 teratocarcinoma retinoic acid receptor beta(2) (RARbeta(2)) knockout cell line exhibits no growth arrest in response to all-trans-retinoic acid (RA), whereas F9 wild type (Wt), F9 RARalpha(-/-), and F9 RARgamma(-/-) cell lines do growth arrest in response to RA. To examine the role of RARbeta(2) in growth inhibition, we analyzed the cell cycle regulatory proteins affected by RA in F9 Wt and F9 RARbeta(2)(-/-) cells. Flow microfluorimetry analyses revealed that RA treatment of F9 Wt cells greatly increased the percentage of cells in the G1/G0 phase of the cell cycle. In contrast, RA did not alter the cell cycle distribution profile of RARbeta(2)(-/-) cells. In F9 Wt cells, cyclin D1, D3, and cyclin E protein levels decreased, while cyclin D2 and p27 levels increased after RA treatment. Compared to the F9 Wt cells, the F9 RARbeta(2)(-/-) cells exhibited lower levels of cyclins D1, D2, D3, and E in the absence of RA, but did not exhibit further changes in the levels of these cell cycle regulators after RA addition. Since RA significantly increased the level of p27 protein (approximately 24-fold) in F9 Wt as compared to the F9 RARbeta(2)(-/-) cells, we chose to study p27 in greater detail. The p27 mRNA level and the rate of p27 protein synthesis were increased in RA-treated F9 Wt cells, but not in F9 RARbeta(2)(-/-) cells. Moreover, RA increased the half-life of p27 protein in F9 Wt cells. Reduced expression of RARbeta(2) is associated with the process of carcinogenesis and RARbeta(2) can mediate the growth arrest induced by RA in a variety of cancer cells. Using both genetic and molecular approaches, we have identified some of the molecular mechanisms, such as the large elevation of p27, through which RARbeta(2) mediates these growth inhibitory effects of RA in F9 cells.


Tryptophan-containing lipopeptide antibiotics derived from polymyxin B with activity against Gram positive and Gram negative bacteria.
Resistance to all known antibiotics is a growing concern worldwide, and has renewed the interest in antimicrobial peptides, a structurally diverse class of amphipathic molecules that essentially act on the bacterial membrane. Propelled by the antimicrobial potential of this compound class, we have designed three new lipopeptides derived from polymyxin B, sp-34, sp-96 and sp-100, with potent antimicrobial activity against both Gram positive and Gram negative bacteria. The three peptides bind with high affinity to lipopolysaccharide as demonstrated by monolayer penetration and dansyl-displacement. The interaction with the cytoplasmic membrane has been elucidated by biophysical experiments with model membranes of POPG or POPE/POPG (6:4), mimicking the Gram positive and Gram negative bacterial membrane. Trp-based fluorescence experiments including steady-state, quenching, anisotropy and FRET, reveal selectivity for anionic phospholipids and deep insertion into the membrane. All three lipopeptides induce membrane fusion and leakage from anionic vesicles, a process that is favored by the presence of POPE. The molecules bind to zwitterionic POPC vesicles, a model of the eukaryotic membrane, but in a different way, with lower affinity, less penetration into the bilayer and no fusion or permeabilization of the membrane. Results in model membranes are consistent with flow cytometry experiments in Escherichia coli and Staphylococcus aureus using a membrane potential sensitive dye (bis-oxonol) and a nucleic acid dye (propidium iodide), suggesting that the mechanism of action is based on membrane binding and collapse of membrane integrity by depolarization and permeabilization.


Intratesticular papillary mucinous cystadenocarcinoma.
The first case of intratesticular papillary mucinous cystadenocarcinoma is described. The tumor was histopathologically different from other types of papillary carcinoma related to the testicle and is believed to have originated from an intratesticular müllerian duct remnant.


An epidemiological re-appraisal of the association between blood pressure and blood lead: a meta-analysis.
Studies on the possible association between blood pressure and blood lead have reached divergent conclusions. In a previous meta-analysis, a doubling of the blood lead concentration was associated with a 1.0/0.6 mm Hg increase in systolic and diastolic blood pressure (BP). This meta-analysis updates the analysis originally performed in 1994. Articles on the association between BP and blood lead were identified from computer searches from January 1980 to February 2001 using the Medical Literature Analysis and Retrieval System. Of the studies reviewed, 31 provided sufficient details to be considered. The meta-analysis included 58518 subjects recruited from the general population in 19 surveys and from occupationally exposed groups in 12 studies. In all but four studies, the results were adjusted for age, and most studies took into account additional confounding factors such as body mass index and the use of alcohol and medication. Weighted joint P-values were calculated using Stouffer's procedure. The association between BP and blood lead was similar in both men and women. In the combined studies, a two-fold increase in blood lead concentration was associated with a 1.0 mm Hg rise in the systolic pressure (95% CI +0.5 to +1.4 mm Hg; P < 0.001) and with a 0.6 mm Hg increase in the diastolic pressure (95% CI +0.4 to +0.8 mm Hg; P < 0.001). On balance, this meta-analysis suggests that there can only be a weak association between BP and blood lead.


The relationship between epilithic periphyton (biofilm) bound metals and metals bound to sediments in freshwater systems.
Surficial sediments and epilithic periphyton (biofilm) were sampled from six sites on the River Churnet and five sites on the River Manifold in Staffordshire and analysed for cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn). The sites demonstrated a wide range of sediment trace metal concentrations determined by inductively coupled plasma optical emission spectrometry (ICP-OES) and atomic absorbtion spectroscopy (AAS). Biofilm was removed from the substrate using physical abrasion and 0.005 M ethylenediaminoethanetetra-acetic acid (EDTA) extractant. The European Standards, Measurements and Testing Programmes (BCR) operationally defined geochemical speciation scheme was used to determine the exchangeable, acid soluble fraction of the sediments. Significant positive correlations were determined between the EDTA extractable biofilm and the exchangeable sediment fraction for Cd, Cu and Zn but not for Pb. Natural epilithic periphyton may be a potential metal biomonitor particularly of Cu, Cd and Zn in aquatic systems and provide supporting information in relation to potential sediment toxicity.


Molecular mechanisms of HPV induced carcinogenesis in head and neck.
A growing subgroup of oropharyngeal cancers is initiated by infection with high-risk human papillomaviruses (HPVs). In parallel to mounting epidemiological evidence, solid experimental data support a causal association between HPV and a subset of oropharyngeal cancers. This Review summarizes the main events of the HPV life cycle, the functions of the viral oncoproteins, and the implications of HPV infection on their hosts, with an emphasis on carcinogenic mechanisms in oropharyngeal cancer. The demonstration that HPVs have a role in head and neck carcinogenesis has fuelled the expectation that HPV-targeted therapeutic strategies may prove curative in these cancers.


Body condition and population regulation by food resources in moose.
In southwestern Québec, non-harvested moose populations stabilize at a density of ≈0.40 animal·km-2. In an attempt to test population regulation by food resources, we investigated moose body condition near this equilibrium density (0.37) and at 2 lower densities (0.22 and 0.17). Annual population growth rates were evaluated at 4, 18, and 24% respectively. We predicted that moose in the high density area would exhibit growth retardation and poorer body condition, compared to moose in the lower density areas. Measurements of head length, cranial breadth, heart weight, and kidney weight were collected from 443 moose killed during the regular autumn harvesting seasons of 1981 and 1982. There was no indication that body condition was poorer at high moose density, and hence no evidence that foraging conditions were deteriorated. We concluded that food limitation was not sufficient to explain the differences in population growth rates. Predation by wolves and/or black bears is presented as an alternative and testable hypothesis.


SIRT1 alleviates senescence of degenerative human intervertebral disc cartilage endo-plate cells via the p53/p21 pathway.
Cartilage end plates (CEP) degeneration plays an integral role in intervertebral disc (IVD) degeneration resulting from nutrient diffusion disorders. Although cell senescence resulting from oxidative stress is known to contribute to degeneration, no studies concerning the role of senescence in CEP degeneration have been conducted. SIRT1 is a longevity gene that plays a pivotal role in many cellular functions, including cell senescence. Therefore, the aim of this study was to investigate whether senescence is more prominent in human degenerative CEP and whether SIRT1-regulated CEP cells senescence in degenerative IVD as well as identify the signaling pathways that control that cell fate decision. In this study, the cell senescence phenotype was found to be more prominent in the CEP cells obtained from disc degenerative disease (DDD) patients than in the CEP cells obtained from age-matched lumbar vertebral fractures (LVF) patients. In addition, the results indicated that p53/p21 pathway plays an important role in the senescence of CEP cells in vivo and vitro. Furthermore, SIRT1 was found to be capable of alleviating the oxidative stress-induced senescence of CEP cells in humans via p53/p21 pathway. Thus, the information presented in this study could be used to further investigate the underlying mechanisms of CEP.


A wearable group-synchronized EEG system for multi-subject brain-computer interfaces.
The multi-subject brain-computer interface (mBCI) is becoming a key tool for the analysis of group behaviors. It is necessary to adopt a neural recording system for collaborative brain signal acquisition, which is usually in the form of a fixed wire. In this study, we designed a wireless group-synchronized neural recording system that supports real-time mBCI and event-related potential (ERP) analysis. This system uses a wireless synchronizer to broadcast events to multiple wearable EEG amplifiers. The simultaneously received broadcast signals are marked in data packets to achieve real-time event correlation analysis of multiple targets in a group. To evaluate the performance of the proposed real-time group-synchronized neural recording system, we conducted collaborative signal sampling on 10 wireless mBCI devices. The average signal correlation reached 99.8%, the amplitude of average noise was 0.87 μV, and the average common mode rejection ratio (CMRR) reached 109.02 dB. The minimum synchronization error is 237 μs. We also tested the system in real-time processing of the steady-state visual-evoked potential (SSVEP) ranging from 8 to 15.8 Hz. Under 40 target stimulators, with 2 s data length, the average information transfer rate (ITR) reached 150 ± 20 bits/min, and the highest reached 260 bits/min, which was comparable to the marketing leading EEG system (the average: 150 ± 15 bits/min; the highest: 280 bits/min). The accuracy of target recognition in 2 s was 98%, similar to that of the Synamps2 (99%), but a higher signal-to-noise ratio (SNR) of 5.08 dB was achieved. We designed a group EEG cognitive experiment; to verify, this system can be used in noisy settings. The evaluation results revealed that the proposed real-time group-synchronized neural recording system is a high-performance tool for real-time mBCI research. It is an enabler for a wide range of future applications in collaborative intelligence, cognitive neurology, and rehabilitation.


[Productive life-span of dairy cows and its economic significance. II. The replacement of dairy cows: an economic model (author's transl)].
A model, initially based on the work of Zeddies (10), is presented , by which the economic aspects of the replacement problem may be studied. First, the principle underlying the replacement decision is discussed. Then, the data to be included in the model are determined. This mainly concerns the elements associated with age, such as milk production, the value of newborn calves, the slaughter of the cows, the feed cost and the cost of a pregnant heifer just before calving. The age-associated probability of culling is also included in the model. A number of questions regarding the economic importance of the duration of herd life have been studied using this model. In the third paper, the results of this application of the model will be presented.


Use of biotinylated probes in serum hepatitis B virus DNA detection.
A dot-blot hybridisation assay for serum HBV DNA is described using a non-radioactive (biotinylated) DNA probe. The assay is both sensitive (1 pg of HBV DNA) and reproducible, and shows several advantages over similar assays which use 32P-labelled probes for the routine detection of infectious virus particles both in blood and in other biological fluids.


Helicobacter pylori and non-malignant diseases.
In recent years, the focus of Helicobacter pylori clinical research has been mainly on gastric malignancy. However, the role of H. pylori in non-malignant diseases, such as peptic ulcer, gastroesophageal reflux disease (GERD) and non-ulcer dyspepsia, as well as non-steroidal anti-inflammatory drug consumption, is still of great interest. A 1- to 2-week course of H. pylori eradication therapy is an effective treatment for H. pylori-positive peptic ulcer disease and a positive CagA status is a predictor for successful eradication of H. pylori. Antral prostaglandin-E2-basal levels appear to be critical for the development of aspirin-induced gastric damage in subjects without H. pylori infection. In clinical practice, among patients treated with proton-pump inhibitors, H. pylori status has no effect on the speed or degree of GERD symptom relief. For the management of dyspepsia in primary care, antisecretory therapy confers a small insignificant benefit compared to strategies based on H. pylori testing while these latter strategies may be cost-effective. H. pylori eradication therapy has a small but statistically significant effect on H. pylori-positive non-ulcer dyspepsia. An economic model suggests that this modest benefit may still be cost-effective but more research is needed.


The Importance of the "Time Factor" for the Evaluation of Inhibition Mechanisms: The Case of Selected HDAC6 Inhibitors.
Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein lysine deacetylase activity in the cytoplasm. The design of specific inhibitors is the focus of a large number of medicinal chemistry programs in the academy and industry because lowering HDAC6 activity has been demonstrated to be beneficial for the treatment of several diseases, including cancer, and neurological and immunological disorders. Here, we show how re-evaluation of the mechanism of action of selected HDAC6 inhibitors, by monitoring the time-dependence of the onset and relief of the inhibition, revealed instances of slow-binding/slow-release inhibition. The same approach, in conjunction with X-ray crystallography, in silico modeling and mass spectrometry, helped to propose a model of inhibition of HDAC6 by a novel difluoromethyloxadiazole-based compound that was found to be a slow-binding substrate analog of HDAC6, giving rise to a tightly bound, long-lived inhibitory derivative.


M13 clones carrying point mutations: identification by solution hybridization.
A solution hybridization procedure for the rapid identification of M13 clones carrying a particular sequence is described. The method, which employs a radiolabeled oligonucleotide probe, can discriminate between sequences which differ by only a single base, and can therefore be used for the identification of mutant sequences created by oligonucleotide-directed mutagenesis. Samples of phage-containing supernatant from cultures of M13-infected Escherichia coli are incubated with radiolabeled probe in the presence of sodium dodecyl sulfate. The mixtures are then subjected to agarose gel electrophoresis to separate hybrid molecules from unbound probe and hybridization is detected by autoradiography. This solution hybridization procedure is quicker and more convenient than membrane hybridization and has the added advantage that more than one probe can be used on a given gel.


Kikuchi disease: An alternative diagnosis in patients with axillary lymphadenopathy.
Kikuchi-Fujimoto disease is a benign, self-limiting lymphohistiocytic disorder. Although this condition is uncommon in Spain, it must be considered in the differential diagnosis of patients with lymphadenopathies. Although the classical presentation of Kikuchi-Fujimoto disease usually involves the cervical lymph nodes, there are also atypical presentations, such as in the case presented here in which the patient had isolated axillary involvement.


[The hippocampus in patients with different forms of senile dementia].
Using cytoarchitectonic and quantitative techniques the hippocampus and dentate fascia of the adult human brain were studied in normal subjects and in patients with senile dementia and Alzheimer's disease. The examination elucidated the peculiarity of the hippocampal structures, identified characteristics of the changes in the structural organization of the hippocampus and dentate fascia and established the severest atrophy in the H2 field of the hippocampus and a dramatic narrowing of the width of the dentate fascia. The data obtained are analyzed.


Contribution of GABAergic cortical circuitry in shaping somatosensory evoked scalp responses: specific changes after single-dose administration of tiagabine.
To determine whether conventional as well as high-frequency somatosensory evoked potentials (SEPs) to upper limb stimulation are influenced by GABAergic intracortical circuitry. We recorded SEPs from 6 healthy volunteers before and after a single-oral administration of tiagabine. Conventional low-frequency SEPs have been obtained after stimulation of the median nerve, as well as after stimulation of the first phalanx of the thumb, which selectively involves cutaneous finger inputs. Median nerve SEPs have been further analyzed after digital narrow-bandpass filtering, to selectively examine high-frequency responses. Lastly, in order to explain scalp SEP distribution before and after tiagabine administration, we performed the brain electrical source analysis (BESA) of raw data. After tiagabine administration, conventional scalp SEPs showed a significant amplitude increase of parietal P24, frontal N24 and central P22 components. Similarly, BESA showed a significant strength increase of the second peak of activation of the first two perirolandic dipoles, which are likely to correspond to the N24/P24 and P22 generators. By contrast, no significant changes of high-frequency SEPs were induced by drug intake. Our findings support the view that both N24/P24 and P22 SEP components are probably generated by deep spiny cell hyperpolarization, which is strongly increased by inhibitory inputs from GABAergic interneurons. By considering the clear influence of inhibitory circuitry in shaping these SEP components, conventional scalp SEP recording could be useful in the functional assessment of the somatosensory cortex in different physiological and pathological conditions. By contrast, intrinsic firing properties of the cell population generating high-frequency SEP responses are unaffected by the increase of recurrent GABAergic inhibition.


Lipidomics to Assess Omega 3 Bioactivity.
How can we resolve the conflict between the strong epidemiological evidence pointing to the usefulness of fish-and, thus, omega 3-consumption with the debacle of supplementation trials? One potential explanation is that the null results obtained thus far are the consequences of ill-contrived investigations that do not allow us to conclude on the effects (or lack thereof) of omega 3 fatty acid supplementation. One potential solution is through the use of lipidomics, which should prove very useful to screen suitable patients and to correlate plasma (or red blood cells, or whole blood, or phospholipid) fatty acid profile with outcomes. This has never been done in omega 3 trials. The wise use of lipidomics should be essential part of future omega 3 trials and would help in untangling this current riddle.


Factors which may influence cardiovascular disease in dialysis and transplant patients--blood pressure (chapter 10).
Many renal units still fail to return blood pressure data to the Renal Registry. In England, Northern Ireland and Wales, the percentage of HD patients achieving the combined blood pressure standard (<140/90 pre-dialysis) averages 43% (inter unit range 16-60%) and post-dialysis (<130/80) average 48% (range 22-66%). On average 27% (range 12-48%) of PD patients achieve the standard of <130/80 and 26% of renal transplant patients (range 16-40%). Over the last 8 years there has been no significant change in systolic or diastolic blood pressure achievement. Better comorbidity data returns are required by the Registry to perform blood pressure survival analyses.


Prognostic significance of N-terminal pro-atrial natriuretic factor (1-98) in acute myocardial infarction: comparison with atrial natriuretic factor (99-126) and clinical evaluation.
To evaluate the prognostic significance of plasma N-terminal pro-atrial natriuretic factor (1-98) concentrations measured in the subacute phase after acute myocardial infarction, and to compare the predictive value of measurement of N-terminal pro-atrial natriuretic factor (1-98) with the measurement of atrial natriuretic factor (99-126) and with clinical assessment of the degree of heart failure. Prospective observational. Norwegian central hospital. 139 patients (mean (SD) age 66.9 (11.1) years, 71.2% males) with acute myocardial infarction. Patients in cardiogenic shock or with severe heart failure (New York Heart Association class IV) were excluded. Cardiovascular death within 12 months. During the follow up period 15 patients died. In a univariate Cox proportional hazards model N-terminal pro-atrial natriuretic factor (1-98) was significantly related to mortality (p = 0.0003). In a multivariate model the prognostic value of N-terminal pro-atrial natriuretic factor (1-98) was better than that of atrial natriuretic factor (99-126) and clinical assessment of heart failure (N-terminal pro-atrial natriuretic factor (1-98), p = 0.0003; atrial natriuretic factor (99-126), p = 0.4513; heart failure, p = 0.0719). The odds ratio estimate of patients in whom plasma concentrations of N-terminal pro-atrial natriuretic factor (1-98) were greater than 2000 pmol/l was 25 (95% confidence interval 2.8-225.0) compared with patients with plasma concentrations less than 1000 pmol/l. These results suggest that determination of plasma N-terminal pro-atrial natriuretic factor (1-98) in the subacute phase of myocardial infarction may provide clinically relevant prognostic information that is superior to that obtained from atrial natriuretic factor (99-126) measurements and clinical evaluation.


Energy dependence of cytosolic enzyme efflux from rat skeletal muscle.
(1) A recirculating isolated superfused skeletal muscle preparation has been developed for the study of rat soleus muscles at physiological temperature using 31P Nuclear Magnetic Resonance (NMR). (2) This system has been used to study intracellular muscle high energy phosphate content and pH during experimental damage to the muscle induced by 2,4-dinitrophenol, deoxycholate and the calcium ionophore, A23187. (3) Results indicate that release of intracellular cytosolic enzymes from damaged skeletal muscle may be induced by phosphocreatine (PCr) and adenosine trisphosphate (ATP) depletion, but under certain circumstances intracellular enzymes can be released from skeletal muscle without any fall in muscle PCr or ATP content.


Modification of chitin with kraft lignin and development of new biosorbents for removal of cadmium(II) and nickel(II) ions.
Novel, functional materials based on chitin of marine origin and lignin were prepared. The synthesized materials were subjected to physicochemical, dispersive-morphological and electrokinetic analysis. The results confirm the effectiveness of the proposed method of synthesis of functional chitin/lignin materials. Mechanism of chitin modification by lignin is based on formation of hydrogen bonds between chitin and lignin. Additionally, the chitin/lignin materials were studied from the perspective of waste water treatment. The synthetic method presented in this work shows an attractive and facile route for producing low-cost chitin/lignin biosorbents with high efficiency of nickel and cadmium adsorption (88.0% and 98.4%, respectively). The discovery of this facile method of synthesis of functional chitin/lignin materials will also have a significant impact on the problematic issue of the utilization of chitinous waste from the seafood industry, as well as lignin by-products from the pulp and paper industry.


Long-range, non-local switching of spin textures in a frustrated antiferromagnet.
Antiferromagnetic spintronics is an emerging area of quantum technologies that leverage the coupling between spin and orbital degrees of freedom in exotic materials. Spin-orbit interactions allow spin or angular momentum to be injected via electrical stimuli to manipulate the spin texture of a material, enabling the storage of information and energy. In general, the physical process is intrinsically local: spin is carried by an electrical current, imparted into the magnetic system, and the spin texture will then rotate in the region of current flow. In this study, we show that spin information can be transported and stored "non-locally" in the material FexNbS2. We propose that collective modes can manipulate the spin texture away from the flowing current, an effect amplified by strong magnetoelastic coupling of the ordered state. This suggests a novel way to store and transport spin information in strongly spin-orbit coupled magnetic systems.


Intermittent selection pressure with zidovudine plus zalcitabine treatment reduces the emergence in vivo of zidovudine resistance HIV mutations.
The development of mutations conferring drug resistance was investigated in 49 antiretroviral-naive asymptomatic HIV-1 subjects with CD4+ cell counts of 250-500/mm3 given intermittent (6-week courses, 6 weeks apart) or continuous treatment with zidovudine (AZT) plus zalcitabine (ddC) over 54 weeks. The concentration of human immunodeficiency virus type 1 RNA in the plasma and the CD4 cell counts were measured every 6 weeks. The rate of decrease of HIV-1 RNA concentration in plasma after a 6-week course of AZT + ddC was similar for each treatment cycle (approximately 1-log reduction). The plasma HIV-1 RNA concentration returned to its initial level at each treatment interruption. The mean CD4 cell counts after 54 weeks in the two treatment groups were similar. Genotype analysis by sequencing the reverse transcriptase coding region from plasma viral RNA on treatment showed a lower frequency of AZT resistance mutations after 54 weeks in patients given intermittent treatment (18%) than in those treated continuously (79 %, P < 0.001). No mutations conferring ddC resistance or multidideoxynucleoside resistance were observed in either group. These findings may have clinical implications for long-term treatment strategies.


Enhancement of radiosensitivity in H1299 cancer cells by actin-associated protein cofilin.
Cofilin is an actin-associated protein that belongs to the actin depolymerization factor/cofilin family and is important for regulation of actin dynamics. Cofilin can import actin monomers into the nucleus under certain stress conditions, however the biological effects of nuclear transport are unclear. In this study, we found that over-expression of cofilin led to increased radiation sensitivity in human non-small lung cancer H1299 cells. Cell survival as determined by colony forming assay showed that cells over-expressing cofilin were more sensitive to ionizing radiation (IR) than normal cells. To determine whether the DNA repair capacity was altered in cofilin over-expressing cells, comet assays were performed on irradiated cells. Repair of DNA damage caused by ionizing radiation was detected in cofilin over-expressing cells after 24 h of recovery. Consistent with this observation, the key components for repair of DNA double-strand breaks, including Rad51, Rad52, and Ku70/Ku80, were down-regulated in cofilin over-expressing cells after IR exposure. These findings suggest that cofilin can influence radiosensitivity by altering DNA repair capacity.


Converting stem cells to dendritic cells by agonist antibodies from unbiased morphogenic selections.
When combinatorial antibody libraries are rendered infectious for eukaryotic cells, the integrated antibody genotype and cellular phenotype become permanently linked and each cell becomes a selection system unto itself. These systems should be ideal for the identification of proteins and pathways that regulate differentiation so long as selection systems can be devised. Here we use a selection system based on the ability of secreted antibodies to alter the morphology of colonies expressing them when grown in soft agar. Importantly, this approach is different from all previous studies in that it used a pure discovery format where unbiased libraries that were not preselected against any known protein were used as probes. As such, the strategy is analogous to classical forward genetic approaches except that it operates directly at the protein level. This approach led to the identification of integrin-binding agonist antibodies that efficiently converted human stem cells to dendritic cells.


Predictors of spontaneous bleeding in Dengue.
To identify the predictive factors for spontaneous bleeding manifestations in Dengue illness in infants and children. 60 cases of Dengue viral infection with spontaneous skin and or mucosal bleed were compared with 72 cases without spontaneous bleed. The protean bleeding manifestations in dengue infection were recorded. Various clinical and laboratory parameters were analyzed using univariate and logistic regression analysis. Prothombin time was abnormal only in cases with spontancous bleed. A combination of (a) biphasic pattern of fever, (b) hemoconcentration, (c) platelet count less than 50,000/mm3 and (d) elevated ALT had a sensitivity of 79.2%, specificity of 64.7% with a positive predictive value of 70% and a negative predictive value of 75% in predicting spontaneous bleeding in dengue.


Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics.
The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.


Evolution of vasopressin levels in the hypothalamo-posthypophysial system of the rat during rehydration following water deprivation. Correlation with ultrastructural aspects in the posterior lobe.
Evolution of the (arginine)-vasopressin (AVP) content of the supraoptic (SON), paraventricular (PVN) and suprachiasmatic nuclei (SchN) and of the posterior lobe of the hypophysis (PLH) has been studied in rats at successive stages of rehydration after 4 days deprivation of drinking water. Particular attention has been focussed on short periods of rehydration. Evolution of the AVP content of the hypothalamo-posthypophysial system (HHS), the blood serum AVP concentration and osmolalities of serum and urine were compared. Variations of the AVP content in the different hypothalamo-hypophysial structures, are parallel. A marked depletion of AVP is observed after 2 and 4 days of dehydration. The AVP content of the PLH and of the hypothalamic nuclei shows two dramatic and short increases 15 min and 3 h after the onset of rehydration; these results are discussed in relation to the known physiological regulation mechanism of the HHS. In the PLH depleted by dehydration, reloading with neurosecretory granules (NSG) begins to be noticeable only after 24 h of rehydration, so that it does not seem to account for elevations of the AVP content occurring earlier. These could be related to a marked increase of the smooth endoplasmic reticulum (SER) network taking place in axons and nerve endings before the NSG reloading.


A Clinical Score for Quantifying Edema in Mechanically Ventilated Children With Congenital Heart Disease in Intensive Care.
Standardized clinical measurements of edema do not exist. To describe a 19-point clinical edema score (CES), investigate its interobserver agreement, and compare changes between such CES and body weight. Prospective observational study in a tertiary PICU of mechanically ventilated children with congenital heart disease. Differences in the median CES between observer groups. We studied 61 children, with a median age of 8.0 days (interquartile range, 1.0-14.0 d). A total of 539 CES were performed by three observer groups (medical 1 [reference], medical 2, and bedside nurse) at 0, 24, and 48 hours from enrollment. Overall, there was close agreement between observer groups in mean, median, and upper quartile of CES scores, with least agreement observed in the lower quartile of scores. Across all quartiles of CES, after adjusting for baseline weight, cardiac surgical risk, duration of cardiopulmonary bypass, or peritoneal dialysis during the study, observer groups returned similar mean scores (medical 2: 25th centile +0.1 [95% CI, -0.2 to 0.5], median +0.6 [95% CI, -0.4 to 1.5], 75th centile +0.1 [95% CI, -1.1 to 1.4] and nurse: 25th centile +0.5 [95% CI, 0.0-0.9], median +0.7 [95% CI, 0.0-1.5], 75th centile -0.2 [95% CI, -1.3 to 1.0]) Within a multivariable mixed-effects linear regression model, including adjustment for baseline CES, each 1 point increase in CES was associated with a 12.1 grams (95% CI, 3.2-21 grams) increase in body weight. In mechanically ventilated children with congenital heart disease, three groups of observers tended to agree when assessing overall edema using an ordinal clinical score assessed in six body regions, with agreement least at low edema scores. An increase in CES was associated with an increase in body weight, suggesting some validity for quantifying edema. Further exploration of the CES as a rapid clinical tool is indicated.


The effect of trauma center designation and trauma volume on outcome in specific severe injuries.
The objective of this study was to investigate the effect of American College of Surgeons (ACS) trauma center designation and trauma volume on outcome in patients with specific severe injuries. Trauma centers are designated by the ACS into different levels on the basis of resources, trauma volume, and educational and research commitment. The criteria for trauma center designation are arbitrary and have never been validated. The National Trauma Data Bank study, which included patients >14 years of age and had injury severity score (ISS) >15, were alive on admission and had at least one of the following severe injuries: aortic, vena cava, iliac vessels, cardiac, grade IV/V liver injuries, quadriplegia, or complex pelvic fractures. Outcomes (mortality, intensive care unit stay, and severe disability at discharge) were compared among level I and II trauma centers and between centers within the same level designation but different volumes of severe trauma (<240 vs > or =240 trauma admissions with ISS >15 per year). The outcomes were adjusted for age (<65 > or =65), gender, mechanism of injury, hypotension on admission, and ISS (< or =25 and >25). A total of 12,254 patients met the inclusion criteria. Overall, level I centers had significantly lower mortality (25.3% vs 29.3%; adjusted odds ratio [OR], 0.81; 95% confidence interval [CI], 0.71-0.94; P = 0.004) and significantly lower severe disability at discharge (20.3% vs 33.8%, adjusted OR, 0.55; 95% CI, 0.44-0.69; P < 0.001) than level II centers. Subgroup analysis showed that cardiovascular injuries (N = 2004) and grades IV-V liver injuries (N = 1415) had a significantly better survival in level I than level II trauma centers (adjusted P = 0.017 and 0.023, respectively). Overall, there was a significantly better functional outcome in level I centers (adjusted P < 0.001). Subgroup analysis showed level I centers had significantly better functional outcomes in complex pelvic fractures (P < 0.001) and a trend toward better outcomes in the rest of the subgroups. The volume of trauma admissions with ISS >15 (<240 vs > or =240 cases per year) had no effect on outcome in either level I or II centers. Level I trauma centers have better outcomes than lower-level centers in patients with specific injuries associated with high mortality and poor functional outcomes. The volume of major trauma admissions does not influence outcome in either level I or II centers. These findings may have significant implications in the planning of trauma systems and the billing of services according to level of accreditation.


Effects of growth hormone and IGF-I on glomerular ultrafiltration in growth hormone-deficient rats.
In growth hormone deficient states glomerular filtration rate (GFR) and renal plasma flow rate (RPF) are both reduced. Studies were performed in growth hormone deficient rats to delineate the physiologic mechanisms by which growth hormone and IGF-I contribute to the regulation of glomerular function. Growth hormone deficient dw/dw rats received, for one week, subcutaneous infusions of vehicle, des(1-3)IGF-I or were injected i.m. with recombinant human growth hormone. Subsequent renal micropuncture and clearance studies revealed a low GFR and single nephron GFR (SNGFR) in vehicle treated growth hormone deficient animals. Glomerular function became normal with growth hormone or IGF-I treatment, respectively. Both treatments raised SNGFR by reducing arteriolar resistance and increasing the glomerular ultrafiltration coefficient. Furthermore, the two treatments also increased the glomerular tuft volume and the kidney weight which may contribute to the rise in SNGFR and GFR. It is concluded that, (1) in growth hormone deficiency glomerular function is reduced secondary to a high renal arteriolar resistance and a low ultrafiltration coefficient. Both result from a lack in IGF-I rather than the growth hormone deficiency state per se. (2) The growth hormone-IGF-I axis may contribute to the maintenance and physiologic regulation of GFR.


Planar cell polarity: A bridge too far?
The mechanisms of planar cell polarity are being revealed by genetic analysis. Recent studies have provided new insights into interactions between three proteins involved in planar cell polarity: Flamingo, Frizzled and Van Gogh.


Can adults with developmental dyslexia apply statistical knowledge to a new context?
We investigated transfer of artificial grammar learning in adults with and without dyslexia in 3 experiments. In Experiment 1, participants implicitly learned an artificial grammar system and were tested on new items that included the same symbols. In Experiment 2, participants were given practice with letter strings and then tested on strings created with a different letter set. In Experiment 3, participants were given practice with shapes and then tested on strings created with different shapes. Results show that in Experiment 1, both groups demonstrated utilization of pre-trained instances in the subsequent grammaticality judgement task, while in Experiments 2 (orthographic) and 3 (nonorthographic), only typically developed participants demonstrated application of knowledge from training to test. A post hoc analysis comparing between the experiments suggests that being trained and tested on an orthographic task leads to better performance than a nonorthographic task among typically developed adults but not among adults with dyslexia. Taken together, it appears that following extensive training, individuals with dyslexia are able to form stable representations from sequential stimuli and use them in a subsequent task that utilizes strings of similar symbols. However, the manipulation of the symbols challenges this ability.


Fabrication and characterization of enhanced hydrazine electrochemical sensor based on gold nanoparticles decorated on the vanadium oxide, ruthenium oxide nanomaterials, and carbon nanotubes composites.
This work describes the synthesis of mixed oxide film of vanadium and ruthenium by pulsed deposition technique on multiwall carbon nanotubes and the decoration of gold nanoparticles on the mixed film. A ternary electrocatalyst has been developed for the electrochemical oxidation of hydrazine by combining two metal oxide mixtures with Au nanoparticles. Surface morphology and chemical composition of the electrode have been examined with SEM, EDX, HRTEM, EIS, and XRD. The peak current of hydrazine increased 9 times at the AuNPs/(VOx-RuOx)/CNT/GCE compared to the bare GCE, and the peak potential shifted to negative 848 mV. Linear sweep voltammetry (LSV) and amperometric techniques revealed that the AuNPs/(VOx-RuOx)/CNT/GCE displays linear concentration range 2.5-10000 µM (LSV) and the concentration range 0.03-100 µM (amperometry). The limit of detection (LOD) is 0.5 μM and 0.1 μM at (S/N = 3) for LSV and amperometric technique, respectively. The results obtained show a good RSD% of 2.1%-3.2% and reasonable recovery of 97%-108% of hydrazine detection.


PreImplantation factor (PIF*) regulates systemic immunity and targets protective regulatory and cytoskeleton proteins.
Secreted by viable embryos, PIF is expressed by the placenta and found in maternal circulation. It promotes implantation and trophoblast invasion, achieving systemic immune homeostasis. Synthetic PIF successfully transposes endogenous PIF features to non-pregnant immune and transplant models. PIF affects innate and activated PBMC cytokines and genes expression. We report that PIF targets similar proteins in CD14+, CD4+ and CD8+ cells instigating integrated immune regulation. PIF-affinity chromatography followed by mass-spectrometry, pathway and heatmap analysis reveals that SET-apoptosis inhibitor, vimentin, myosin-9 and calmodulin are pivotal for immune regulation. PIF acts on macrophages down-stream of LPS (lipopolysaccharide-bacterial antigen) CD14/TLR4/MD2 complex, targeting myosin-9, thymosin-α1 and 14-3-3eta. PIF mainly targets platelet aggregation in CD4+, and skeletal proteins in CD8+ cells. Pathway analysis demonstrates that PIF targets and regulates SET, tubulin, actin-b, and S100 genes expression. PIF targets systemic immunity and has a short circulating half-life. Collectively, PIF targets identified; protective, immune regulatory and cytoskeleton proteins reveal mechanisms involved in the observed efficacy against immune disorders.


In Silico Study of Plant Polyphenols' Interactions with VP24-Ebola Virus Membrane-associated Protein.
The Zaire Ebola viral protein VP24 selectively inhibits nuclear import of STAT1 and as such blocks interferon-induced antiviral responses vital for cell's emergency. Inhibition of VP24 with small molecule inhibitor may neutralize the threatening action of Ebola virus. We performed molecular docking of compounds from a selected small library of plant polyphenols on to VP24. Our research shows that 1,2,3,6-tetragalloyl glucose, epigallocatechin gallate, chlorogenic acic, oleuropein and miquelianin represent promising leads for further studies.


Safe and stable generation of induced pluripotent stem cells using doggybone DNA vectors.
The application of induced pluripotent stem cells (iPSCs) in advanced therapies is increasing at pace, but concerns remain over their clinical safety profile. We report the first-ever application of doggybone DNA (dbDNA) vectors to generate human iPSCs. dbDNA vectors are closed-capped linear double-stranded DNA gene expression cassettes that contain no bacterial DNA and are amplified by a chemically defined, current good manufacturing practice (cGMP)-compliant methodology. We achieved comparable iPSC reprogramming efficiencies using transiently expressing dbDNA vectors with the same iPSC reprogramming coding sequences as the state-of-the-art OriP/EBNA1 episomal vectors but, crucially, in the absence of p53 shRNA repression. Moreover, persistent expression of EBNA1 from bacterially derived episomes resulted in stimulation of the interferon response, elevated DNA damage, and increased spontaneous differentiation. These cellular activities were diminished or absent in dbDNA-iPSCs, resulting in lines with a greater stability and safety potential for cell therapy.


One-time transfers of cash or capital have long-lasting effects on microenterprises in Sri Lanka.
Standard economic theory suggests that one-time business grants can have at most temporary effects, and accordingly, policies to increase incomes of the self-employed in developing countries typically rely on sustained engagement. In contrast, we found long-lasting impacts from one-time grants given in a randomized experiment to subsistence firms. Five years after we gave $100 or $200 to 115 of 197 male and 100 of 190 female Sri Lankan microenterprise owners, we found 10-percentage-point-higher enterprise survival rates, and $8-to-$12-per-month-higher profits for male-owned businesses that received the grants. Female-owned businesses showed no long-term (or short-term) impacts. Our follow-up investigation interviewed 94% of the original sample and collected survivorship data from the remaining 6%, demonstrating that tracking long-term outcomes is both feasible and worthwhile. The results suggest that one-off grants may have lasting impacts on some types of subsistence firms, challenging the view that sustained engagement is always required.


Expression of ETS proto-oncogenes in astrocytes in human cortex.
In order to investigate a possible function of ETS proto-oncogenes in human brain, we incubated a polyclonal antibody raised against the viral region of E26 homologous to ETS1 and ETS2 with human brain frontal cortex sections. Our results show that this antibody decorates astrocytes but not neurons. By using astrocytomas of different grades as a source of astrocytes, we demonstrate the presence of ETS1 and ETS2 messenger RNAs and proteins. This leads to the idea that ETS genes are expressed in cells with dividing potentialities in human cortex and that they could provide a new marker for glial cells. Recently, a microduplication on chromosome 21 including ETS2 locus was described in karyotypically 'normal' Down's syndrome and suspected in Alzheimer's disease; when testing Alzheimer's disease-affected brain cortex sections, no obvious difference was observed with the technique used.


The effect of the wheat Ph1 locus on chromatin organisation and meiotic chromosome pairing analysed by genome painting.
The Ph1 locus in wheat influences homo(eo)logous chromosome pairing. We have analysed its effect on the behaviour and morphology of two 5RL rye telosomes in a wheat background, by genomic in situ hybridisation (GISH), using rye genomic DNA as a probe. Our main objective was to study the effect of different alleles of the Ph1 locus on the morphology and behaviour of the rye telosomes in interphase nuclei of tapetal cells and in pollen mother cells at early stages of meiosis. The telosomes, easily detectable at all stages, showed a brightly fluorescing chromomere in the distal region and a constriction in the proximal part. These diagnostic markers enabled us to define the centromere and telomere regions of the rye telosomes. In the presence of functional copies of Ph1, the rye telosomes associated at pre-leptotene, disjoined and reorganised their shape at leptotene, and became fully homologously paired at zygotene - pachytene. In plants without functional alleles (ph1bph1b), the rye telosomes displayed an aberrant morphology, their premeiotic associations were clearly disturbed and their pairing during zygotene and pachytene was reduced and irregular. The Ph1 locus also influenced the behaviour of rye telosomes in the interphase nuclei of tapetal cells: in Ph1Ph1 plants, the rye telosomes occupied distinct, parallel-oriented domains, whereas in tapetal nuclei of ph1bph1b plants they were intermingled with wheat chromosomes and showed a heavily distorted morphology. The results shed new light on the effect of Ph1, and suggest that this locus is involved in chromosome condensation and/or scaffold organisation. Our explanation might account for various apparently contradictory and pleiotropic effects of this locus on both premeiotic associations of homologues, the regulation of meiotic homo(eo)logous chromosome pairing and synapsis, the resolution of bivalent interlockings and centromere behaviour.


DL-threo-beta-fluoroasparagine inhibits asparagine-linked glycosylation in cell-free lysates.
The effect of beta-fluoroasparagine on N-linked glycosylation was examined in a cell-free translation system in which glycosylation is coupled to protein synthesis. The threo-isomer markedly inhibited glycosylation at a concentration of 1 mM, and this effect was blocked by L-asparagine, indicating that glycosylation was inhibited secondary to incorporation of the asparagine analog into protein. The erythro-isomer, at similar concentrations, was not incorporated into protein and had no effect on glycosylation. threo-beta-Fluoroasparagine is highly toxic to some mammalian cells in culture. Our observations suggest that its toxicity may be due in part to the failure of the fluoroasparagine-containing protein to become glycosylated. The data suggest that this analog will be useful for examining the structural determinants for glycosylation.


CRISPR/Cas9 genome-editing applied to MdPGT1 in apple results in reduced foliar phloridzin without impacting plant growth.
Phloridzin is the most abundant polyphenolic compound in apple (Malus × domestica Borkh.), which results from the action of a key phloretin-specific UDP-2'-O-glucosyltransferase (MdPGT1). Here, we simultaneously assessed the effects of targeting MdPGT1 by conventional transgenesis and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome editing. To this end, we conducted transcriptomic and metabolic analyses of MdPGT1 RNA interference knockdown and genome-edited lines. Knockdown lines exhibited characteristic impairment of plant growth and leaf morphology, whereas genome-edited lines exhibited normal growth despite reduced foliar phloridzin. RNA-sequencing analysis identified a common core of regulated genes, involved in phenylpropanoid and flavonoid pathways. However, we identified genes and processes differentially modulated in stunted and genome-edited lines, including key transcription factors and genes involved in phytohormone signalling. Therefore, we conducted a phytohormone profiling to obtain insight into their role in the phenotypes observed. We found that salicylic and jasmonic acid were increased in dwarf lines, whereas auxin and ABA showed no correlation with the growth phenotype. Furthermore, bioactive brassinosteroids were commonly up-regulated, whereas gibberellin GA4 was distinctively altered, showing a sharp decrease in RNA interference knockdown lines. Expression analysis by reverse transcriptase-quantitative polymerase chain reaction expression analysis further confirmed transcriptional regulation of key factors involved in brassinosteroid and gibberellin interaction. These findings suggest that a differential modulation of phytohormones may be involved in the contrasting effects on growth following phloridzin reduction. The present study also illustrates how CRISPR/Cas9 genome editing can be applied to dissect the contribution of genes involved in phloridzin biosynthesis in apple.


Does microenema administration improve the quality of DWI sequences in rectal MRI?
To determine whether the administration of a microenema immediately prior to rectal magnetic resonance imaging (MRI) decreases the level of gas-related artifacts on diffusion-weighted imaging (DWI) sequences. This retrospective analysis included 492 (183 baseline and 309 post-total neoadjuvant treatment [TNT]) consecutive MRI scans for rectal cancer from January 2019 to January 2020. Scan-related factors were identified including microenema use (yes or no), field of view (FOV) in DWI (b = 800 or b = 1500), and magnet strength (1.5 T or 3 T). Two readers scored DWI studies for gas-related artifacts and T2-weighted sequences for the amount of intraluminal gas on a 5-point scale. Fisher's exact test and the Rao-Scott Chi-squared test were used to examine associations between microenema use and other factors. Generalized estimating equation and multivariable regression models were performed to examine the effect of microenema use in subgroups of scans for each reader. Cohen's κ was used to assess inter-reader agreement. Gas-related artifact levels decreased in scans with microenema overall (P < 0.001) as well as when scans were stratified by FOV (P ≤ 0.003). For both readers, post-TNT scans with microenema showed lower artifact levels overall (P < 0.014 and P < 0.001) and in post-TNT subgroups of axial DWI scans (P ≤ 0.006 and P < 0.001) and scans acquired with a 3 T magnet (P ≤ 0.001 for both FOV). No evidence of decreased artifact level was found for baseline studies. Decreased gas was seen with microenema use (P < 0.001 for both readers). Inter-reader agreement on artifact-level and gas-level assessments ranged from slight to substantial (κ = 0.273-0.685). Microenema use prior to rectal MRI reduces gas-related artifacts on DWI, including both large and small FOV sequences and particularly on post-TNT scans performed at 3 T, and offers a viable solution to improve DWI quality.


Regression of NMU-induced mammary tumors with the combination of melatonin and 9-cis-retinoic acid.
A significant increase in tumor regression was induced in N-nitroso-N-methylurea-induced mammary tumors in rats treated with the combination of melatonin and 9-cis-retinoic acid (9cRA). Treatment groups included: control (ethanolic saline), 9cRA (30 mg/kg chow/day), melatonin 500 microg/day, melatonin 1000 microg/day, melatonin 500 microg/day+9cRA and melatonin 1000 microg/day+9cRA. Rats treated with the lower dose of melatonin 500 microg+9cRA show the greatest degree of tumor regression (78%), with 54% undergoing complete regression and a significant increase in apoptotic cells observed by TUNEL Assay. Furthermore, tumor multiplicity and burden were significantly decreased by the combination of melatonin and 9cRA.


Triage Into the Community for COVID-19 (TICC-19) Patients Pathway - Service evaluation of the virtual monitoring of patients with COVID pneumonia.
COVID-19 pneumonia presented a unique problem for healthcare systems with the potential to overwhelm hospitals and lead to unnecessary morbidity and mortality. Safe triage and follow up systems are required to manage this unprecedented demand. We designed a pathway for the triage and assessment of patients based on their resting oxygen saturations and response to a 30 metre rapid walking test. We admitted patients to a 'Virtual Ward' for remote oximetry monitoring from the Emergency Department, step down from inpatient wards and from the local Primary Care 'Hot Hub'. This allowed the safe and managed readmission of those patients who deteriorated at home. During the first wave of COVID-19 we entered 273 onto the pathway for Virtual Ward follow up. Of these, 31 patients were readmitted to hospital, two were admitted to Intensive Care and one patient died. Median oxygen saturation at presentation was 97 % (IQR 96-98%) and following a 30 metre walk test 96% (IQR 94-97%). Median NEWS-2 score was 2 (IQR 1-3). On feedback 99.5% of patients were likely or extremely likely to recommend the service to their family and friends. There was a cost avoidance of £107,600 per month. It is safe, feasible and cost effective to set up a triage system with remote oximetry monitoring for patients with COVID-19 and overwhelmingly patients find it a positive experience.


A fatal case of amniotic fluid embolism with elevation of serum mast cell tryptase.
A case of a 40-year-old female who died of amniotic fluid embolism is presented. This case showed typical histological findings of this syndrome. Postmortem serum of this case showed an elevated tryptase level (67.2ng/ml, normal levels <10ng/ml). Tryptase is a neutral protease of mast cells, and an important indicator of mast cell activation and degranulation. Thus, mast cell activation, a central feature of anaphylaxis, may have been involved in the pathogenetic mechanism of this case.


Genetic susceptibility to mucosal damage leads to bacterial translocation in a murine burn model.
Since genetic factors may be important in host resistance to infections after thermal injury, we screened the susceptibility of three mouse strains (CD-1, Balb/c, and C57/bl) to thermally induced bacterial translocation from the GI tract. Bacteria translocated to the MLNs of Balb/c but not the CD-1 or C57/bl mice receiving 25% body burns. The increased incidence of bacterial translocation in the burned Balb/c mice appeared to be due to a burn-induced gut mucosal injury, since the intestinal mucosa of the Balb/c but not the CD-1 or C57/bl mice was damaged 24 hr after the thermal injury. The mucosal injury appears to be mediated, at least in part, by xanthine oxidase-generated oxygen-free radicals, since inhibition of xanthine oxidase activity with allopurinol, or inactivation of xanthine oxidase activity by a molybdenum-free tungsten diet, prevented the mucosal injury and reduced the extent of bacterial translocation.


Atypical Manifestation of Direct Low-Flow Carotid-Cavernous Fistula: Case Report and Review of the Literature.
Carotid cavernous fistula (CCF) is a rare type of arteriovenous shunt that develops within the cavernous sinus (CS). Direct CCFs entail a direct communication between the cavernous internal carotid artery and the CS and are typically high-flow lesions. Most CCFs drain into the ophthalmic veins (typical venous drainage pattern), leading to the pathognomic ocular clinical triad associated with a CCF. When an obstruction of the typical venous outflow is present, the arterial pressure generated by the fistula is transmitted into the cerebral venous system via the sphenoparietal sinus, which might lead to intracerebral hemorrhage. We present a rare case of posttraumatic, direct, low-flow CCF associated with cerebral hemorrhage, a typical venous drainage pattern, and without ocular symptoms at presentation. A 76-year-old woman was hospitalized for a posttraumatic frontotemporopolar hemorrhage associated with multiple fractures of the maxillofacial and cranial base skeleton and midline shift >10 mm. On neurologic examination the Glasgow Coma Scale was 8 and right anisocoria was present. Immediate surgical evacuation of the hematoma was performed. Severe arterial bleeding from the anterior third of the middle cranial fossa floor was controlled intraoperatively. Postoperative brain angio-magnetic resonance imaging and digital subtraction angiography showed a direct CCF without theft phenomenon. Ocular symptoms, and ultimately loss of function of the right eye, appeared 2 weeks from surgery. Endovascular treatment of the CCF was attempted attaining partial closure of the shunt using coils. Direct low-flow CCFs are exceedingly rare lesions. Five cases have been described in the literature, 4 of which were associated with spontaneous rupture of a cavernous carotid aneurysm while only 1 case was associated with posttraumatic rupture of a cavernous internal carotid artery pseudoaneurysm. In addition, despite our patient having developed an intraparenchymal hemorrhage most probably correlated to the CCF, the latter was associated with a typical venous drainage via the superior ophthalmic vein, which is uncommonly correlated to intraparenchymal bleeding.


Precision and reproducibility of automated computer-guided Psoriasis Area and Severity Index measurements in comparison with trained physicians.
The Psoriasis Area and Severity Index (PASI) represents the gold standard for psoriasis severity assessments but is limited by its subjectivity and low intra- and inter-rater consistency. To investigate the precision and reproducibility of automated, computer-guided PASI measurements (ACPMs) in comparison with three trained physicians. This was a comparative observational study assessing ACPMs attained by automated total-body imaging and computerized digital image analysis in a cohort of 120 patients affected by plaque psoriasis of various severities. The level of agreement between ACPMs and physicians' PASI measurements was calculated by the intraclass correlation coefficient (ICC). The reproducibility of ACPMs in comparison with physicians' PASI measurements was investigated by performing two successive 'repeat PASI calculations' in the same patients. The agreement between ACPMs and physicians' PASI calculations in 120 fully evaluable patients was high (ICC 0·86, 95% confidence interval 0·80-0·90, mean absolute difference 2·5 PASI points). Repeat ACPMs to measure the reproducibility showed an excellent ICC of 0·99 (95% confidence interval 0·98-0·99) with a mean absolute difference of 0·5 PASI points. The ACPMs thus outperformed the three physicians for intrarater reliability (mean ICC 0·86). The results of this first clinical study investigating ACPMs in 120 patients with psoriasis indicate a similar precision and higher reproducibility in comparison with trained physicians. Limitations arise from poorly observable body sites and from patients unable to attain predefined postures during automated image acquisition.


Adaptations to environmental change: Globin superfamily evolution in Antarctic fishes.
The ancient origins and functional versatility of globins make them ideal subjects for studying physiological adaptation to environmental change. Our goals in this review are to describe the evolution of the vertebrate globin gene superfamily and to explore the structure/function relationships of hemoglobin, myoglobin, neuroglobin and cytoglobin in teleost fishes. We focus on the globins of Antarctic notothenioids, emphasizing their adaptive features as inferred from comparisons with human proteins. We dedicate this review to Guido di Prisco, our co-author, colleague, friend, and husband of C.V. Ever thoughtful, creative, and enthusiastic, Guido spearheaded study of the structure, function, and evolution of the hemoglobins of polar fishes - this review is testimony to his wide-ranging contributions. Throughout his career, Guido inspired younger scientists to embrace polar biological research, and he challenged researchers of all ages to explore evolutionary adaptation in the context of global climate change. Beyond his scientific contributions, we will miss his warmth, his culture, and his great intellect. Guido has left an outstanding legacy, one that will continue to inspire us and our research.


Function of the Yersinia effector YopJ.
The Yersinia virulence factor YopJ inhibits the host immune response and induces apoptosis by blocking multiple signaling pathways, including the MAPK and NFkappaB pathways in the infected cell. YopJ is a cysteine protease that cleaves a reversible post-translational modification in the form of ubiquitin or a ubiquitin-like protein. Homologues of YopJ are expressed in animal and plant pathogens, as well as a plant symbiont, suggesting a universal mechanism of regulating or modulating a variety of signaling pathways. The ability of YopJ to block the innate immune response, its activity as a ubiquitin-like protein protease and its activity with respect to mammalian signalling pathways are discussed in this review.


Differentiation of Neuro-2a neuroblastoma cells by an antibody to GM3 ganglioside.
A monoclonal antibody against GM3 ganglioside (GM3Ab) was found to trigger differentiation of Neuro-2a cells in culture. The differentiation of Neuro-2a cells by GM3Ab was accompanied by increased levels of intracellular serotonin and amino acid neurotransmitters viz. aspartate, glutamate, glutamine, glycine and taurine. Further study indicated that the increase in the serotonin level was not due to a higher rate of serotonin synthesis but rather to a higher rate of active transport of serotonin from the medium. Studies on the cell surface gangliosides revealed that unlike the proliferating cells, the GM3Ab-mediated differentiated cells contained higher gangliosides in addition to GM3 and GM2 gangliosides. Analysis of total cellular proteins indicated the appearance of a 25 kDa protein, pI 5.4, in the GM3Ab-treated cells--a small amount of this protein was observed in dibutyryl cAMP (Bt2cAMP)-treated cells, however, the protein was totally absent in the 5-bromo-2'-deoxyuridine (BrdU)-treated cells. Investigation of the mode of action of GM3Ab indicated that the cellular differentiation was due to increased cAMP accumulation resulting from an increase in the adenylate cyclase activity. Further studies with different agents affecting protein kinase C (PKC) activity and direct assay of PKC ruled out the possibility that GM3Ab mediated its effect via PKC. This GM3Ab-induced differentiation could be inhibited by protein kinase A (PKA) inhibitor, H8, but could not be inhibited by sphingosine, an inhibitor of PKC. Pertussis toxin could mimic the effect of GM3Ab, suggesting that GM3Ab caused the elevation in the adenylate cyclase activity by reducing the Gi-protein inhibition of the adenylate cyclase. The data suggests that GM3Ab, after interaction with cell surface GM3, elevated intracellular cAMP level by withdrawing the inhibitory effect of some undefined factor(s) present in culture medium which normally keeps adenylate cyclase activity low through activation of Gi-protein.


A simple vision-based algorithm for decision making in flying Drosophila.
Animals must quickly recognize objects in their environment and act accordingly. Previous studies indicate that looming visual objects trigger avoidance reflexes in many species [1-5]; however, such reflexes operate over a close range and might not detect a threatening stimulus at a safe distance. We analyzed how fruit flies (Drosophila melanogaster) respond to simple visual stimuli both in free flight and in a tethered-flight simulator. Whereas Drosophila, like many other insects, are attracted toward long vertical objects [6-10], we found that smaller visual stimuli elicit not weak attraction but rather strong repulsion. Because aversion to small spots depends on the vertical size of a moving object, and not on looming, it can function at a much greater distance than expansion-dependent reflexes. The opposing responses to long stripes and small spots reflect a simple but effective object classification system. Attraction toward long stripes would lead flies toward vegetative perches or feeding sites, whereas repulsion from small spots would help them avoid aerial predators or collisions with other insects. The motion of flying Drosophila depends on a balance of these two systems, providing a foundation for studying the neural basis of behavioral choice in a genetic model organism.


Comparing continuation rates and side effects of hormonal contraceptives in East Asian and Caucasian women after abortion.
The purpose of this study was to determine whether East Asian women had more side effects and a higher discontinuation rate than Caucasian women when choosing to use hormonal contraceptives. This was an observational cohort study of usual care using questionnaires for 2 months after being given hormonal contraceptives following an abortion in Vancouver, Canada. In the first month, 73 (64.4%) of the 110 East Asian and 86 (80.4%) of the 107 Caucasian women took any of the sample provided (p=.020). In the second month, 52 (47.3%) of the East Asian and 62 (57%) of the Caucasian women used the prescription to buy and take their hormonal contraception (p=.12). Total side effects were similar, but there was more nausea in the East Asian women (23.3% vs. 8.1%) (p=.03) and more acne in the Caucasian women (8.2% vs. 20.9%) (p=.05). There may be both physiological and cultural differences leading East Asian women to use less hormonal contraception.


The concept of 'mental trauma' and its transcultural application.
Impaired 'traumatic' memory of disaster-affected populations has come to the forefront of humanitarian work. In this article, the application of the notion of 'mental trauma' by psychosocial intervention programmes, relating to the tsunami disaster, will be critically examined. It will be shown in which type of theoretical structure the guidelines' notion of 'mental trauma' is rooted, presenting 'traumatic' experience as a division of the self, which is defined through agency and coherence. It will be argued that this entails a certain subjectivity of representation, which may not have transcultural validity. It is concluded that rehabilitation and development programmes after disasters have to integrate and address multiple levels, including community-level interventions, drawing on local coping strategies and resources.


Effects of cell culture scaffold stiffness on cell membrane damage induced by sonoporation.
As basic studies to realize in vivo sonoporation, rates of cell membrane damage during sonoporation were evaluated using monolayer cells cultured on scaffolds with different degrees of stiffness. Four types of scaffolds, constructed using collagen gel, 10 and 30 % acrylamide gels, and a coverslip, were used for cultivation of monolayer cells. Young's moduli measured using an atomic force microscope were in the range 0.09-8.6 kPa for the gel scaffolds, whereas Young's modulus for living cells was 4.5 kPa. Cells with attached microbubbles were exposed to one-shot pulsed ultrasound of 8.0/-1.3 MPa in peak positive/negative pressures with durations of 3, 100, and 10,000 cycles. Cell membrane damage was visualized by fluorescence microscopy using propidium iodide. The 3-cycle ultrasound pulse had no significant effect; however, the rates of damage caused by 100-cycle and 10,000-cycle pulses showed a strong tendency for higher rates of damage with a higher Young's modulus. The experimental results indicate that the stiffness of the underlying layer of adherent cells should be considered as an essential parameter of the sonoporation condition and that the optimum exposure conditions for in vivo sonoporation should be determined with consideration of the physical properties of underlying tissues.


Peptidoglycan recognition protein LF: a negative regulator of Drosophila immunity.
Peptidoglycan recognition proteins (PGRPs) play important roles in the innate immune defence. Each PGRP detects a distinct subset of peptidoglycans and initiate immune signalling or enzymatic degradation of peptidoglycans. Here we characterize one of the 13 Drosophila PGRPs, PGRP-LF. PGRP-LF is membrane bound and has its two PGRP domains, z and w, localized outside the cell. Our data demonstrate that the z-and w-domain differ in their affinities to peptidoglycan. The z-domain has affinity to several groups of peptidoglycans while the w-domain only recognizes peptidoglycan from Escherichia coli. In addition, we observed that overexpression of PGRP-LF in Drosophila melanogaster Schneider 2 cells (S2 cells) promotes aggregation of cells. Furthermore, following immune stimulation of S2 cells overexpressing PGRP-LF, we noticed a reduced up-regulation of expression of antimicrobial peptide genes, in consonance with an immune suppressive role for PGRP-LF.


In-bag enzymatic splenic digestion: a novel alternative to manual morcellation?
Contained in-bag spleen morcellation is a conventional extraction technique for safe spleen removal during laparoscopic splenectomy. Existing data for the use of in-bag enzymatic splenic digestion as an alternative to morcellation are lacking. This proof-of-concept study sought to evaluate the effectiveness of single and combinatorial enzyme digestion of murine spleens. Murine spleens were digested with collagenase alone or with combinations of commercially available enzymes (collagenase, elastase, hyaluronidase, neutral protease) to determine their degradation effect. The primary end point was the percentage of mass reduction at 15 and 30 min. For collagenase alone (n = 15), the mean reduction in mass was 14 ± 10% (range: 2%-31%) at 15 min and 30 ± 25% (range: 7%-100%) at 30 min. Using combinatorial dissolution with collagenase, hyaluronidase, and elastase (n = 8), the mean reduction in mass was 27 ± 16% (range: 6%-42%) at 15 min and 48 ± 27% (range: 3%-100%) at 30 min. Injecting the enzyme solution into whole spleens (n = 9) yielded a mean reduction in mass of 22 ± 13% (range: 9%-42%) at 15 min and 55 ± 31% (range: 9%-100%) at 30 min; mean reduction was 9 ± 13% (range: 0%-39%) at 15 min and 23 ± 13% (range: 3%-53%) with no injection (n = 12). We provide the first demonstration of successful enzymatic murine spleen digestion as an alternative method for in-bag spleen removal during laparoscopic splenectomy. However, the significant cost and quantities of commercial enzyme required for clinical application dampens the enthusiasm for this novel approach.


Discordance Between Human Papillomavirus Twitter Images and Disparities in Human Papillomavirus Risk and Disease in the United States: Mixed-Methods Analysis.
Racial and ethnic minorities are disproportionately affected by human papillomavirus (HPV)-related cancer, many of which could have been prevented with vaccination. Yet, the initiation and completion rates of HPV vaccination remain low among these populations. Given the importance of social media platforms for health communication, we examined US-based HPV images on Twitter. We explored inconsistencies between the demographics represented in HPV images and the populations that experience the greatest burden of HPV-related disease. The objective of our study was to observe whether HPV images on Twitter reflect the actual burden of disease by select demographics and determine to what extent Twitter accounts utilized images that reflect the burden of disease in their health communication messages. We identified 456 image tweets about HPV that contained faces posted by US users between November 11, 2014 and August 8, 2016. We identified images containing at least one human face and utilized Face++ software to automatically extract the gender, age, and race of each face. We manually annotated the source accounts of these tweets into 3 types as follows: government (38/298, 12.8%), organizations (161/298, 54.0%), and individual (99/298, 33.2%) and topics (news, health, and other) to examine how images varied by message source. Findings reflected the racial demographics of the US population but not the disease burden (795/1219, 65.22% white faces; 140/1219, 11.48% black faces; 71/1219, 5.82% Asian faces; and 213/1219, 17.47% racially ambiguous faces). Gender disparities were evident in the image faces; 71.70% (874/1219) represented female faces, whereas only 27.89% (340/1219) represented male faces. Among the 11-26 years age group recommended to receive HPV vaccine, HPV images contained more female-only faces (214/616, 34.3%) than males (37/616, 6.0%); the remainder of images included both male and female faces (365/616, 59.3%). Gender and racial disparities were present across different image sources. Faces from government sources were more likely to depict females (n=44) compared with males (n=16). Of male faces, 80% (12/15) of youth and 100% (1/1) of adults were white. News organization sources depicted high proportions of white faces (28/38, 97% of female youth and 12/12, 100% of adult males). Face++ identified fewer faces compared with manual annotation because of limitations with detecting multiple, small, or blurry faces. Nonetheless, Face++ achieved a high degree of accuracy with respect to gender, race, and age compared with manual annotation. This study reveals critical differences between the demographics reflected in HPV images and the actual burden of disease. Racial minorities are less likely to appear in HPV images despite higher rates of HPV incidence. Health communication efforts need to represent populations at risk better if we seek to reduce disparities in HPV infection.