Effect of Tibial Component Misalignment on the Lower Limb Joint Kinematics During Squat.
The component orientation of the total knee replacement is critical to surgical outcomes. There have been many studies focused on knee movement for different component rotations. However, the effect of component misalignment on a dynamic movement, especially which requires high knee flexion, is not widely studied. The aim of this study is to investigate the effect of tibial component misalignment on a squat motion by predictive simulation. Squat motions with different replacement component alignments were predicted by formulating an optimal control problem. The result indicates that component misalignment on coronal and horizontal planes reduces peak joint flexion angles and the external rotation on the horizontal plane has the most negative impact. Misalignment in external rotation resulted in the greatest reduction of peak joint flexion angles. The simulation was validated by comparison with experimental data, which showed a high level of correlation with the predicted motion.Clinical relevance- The predictive simulation presented in this study can predict the dynamic post-surgery movement of TKR. It has the potential to help surgeons and clinicians at the preoperative planning stage.


Epidemiological factors involved in the development of bronchopulmonary dysplasia in very low birth-weight preterm infants.
In spite of the advances made in perinatal medicine, the incidence of bronchopulmonary dysplasia (BPD) has not decreased and the aetiopathogenesis of the "new" BPD is still a matter for debate. The objectives of the present study were to analyse the epidemiological factors and morbidity associated with the development of BPD in a cohort of very low birth-weight (VLBW) preterm infants. This retrospective observational study included all the preterm infants with birth weight ≤1500 g who were admitted to a tertiary-level hospital NICU from 2008 to 2011. A neurological follow-up was also carried out during the first two years of life. A total of 140 VLBW infants were analyzed: 28.4% presented oxygen dependence at 28 days, and 17.2% at 36 weeks adjusted gestational age. Predictive factors for the development of BPD were gestational age, birth weight, number of days of parenteral nutrition, number of days to achieve full enteral feeding, number of transfusions, duration of respiratory support and insulin administration, vasoactive drugs, diuretics, sedoanalgesia and postnatal corticosteroids. The neonatal morbidity associated with the development of BPD was late neonatal sepsis, patent ductus arteriosus, retinopathy of prematurity (ROP) and intraventricular hemorrhage. Non-significant associations with neurodevelopmental impairment were observed. Predictive factors for the development of BPD were respiratory support, feeding and different types of medication. Moreover, patients with BPD had a higher associated morbidity than those who did not develop BPD.


Cutaneous lymphoma of the tarsus in cats: 23 cases (2000-2012).
To determine features of lymphoma of the tarsus in cats. Multi-institutional retrospective study. 23 cats with cutaneous lymphoma of the tarsus. Veterinary oncologists were requested to submit cases fitting the following criteria: histologically or cytologically confirmed lymphoma with a location at or near the tarsus and described as subcutaneous or mass-like. Data regarding breed, sex, age, FeLV and FIV status, and reason for evaluation were collected. Results of staging tests, location of the tumor, immunophenotype, and histopathologic description were recorded. Type of treatments, outcome, survival time, presence or absence of progressive disease, and cause of death or reason for euthanasia were also recorded. Most cats were older, with a median age of 12 years (range, 7 to 18 years). No association with positive retroviral status was found. Popliteal lymph node involvement at diagnosis was reported in 5 cats, and a suspicion of lymphoma at a different site on the basis of results of abdominal ultrasonography was reported in 4 cats. Treatments were variable and included corticosteroids alone (n = 2), chemotherapy (9), radiation and chemotherapy (7), or surgery with or without chemotherapy (5). Thirteen cats were reported to have lymphoma at a different site at the time of last follow-up, death, or euthanasia. Median survival time for all cats in the study was 190 days (range, 17 to 1,011 days). Results suggested that tarsal lymphoma is an uncommon manifestation of lymphoma in cats, and in this study was most commonly nonepitheliotropic and of high grade as determined on histologic evaluation. Systemic involvement was identified; therefore, thorough staging is recommended prior to initiating treatment. Future studies are warranted to evaluate effective treatment protocols.


Chemical composition of bioactive pressurized extracts of Romanian aromatic plants.
In this contribution, pressurized liquid extraction (PLE) has been employed to isolate bioactive compounds from three native Romanian plants, oregano (Origanum vulgare), tarragon (Artemisia dracunculus) and wild thyme (Thymus serpyllum). Different PLE conditions have been tested including extraction with water, ethanol and their mixtures in a wide range of extraction temperatures (50-200°C), and the antioxidant capacity of the extracts was measured using different assays (DPPH radical scavenging, TEAC assay and Folin-Ciocalteau assay to measure total phenols). Moreover, a complete chemical characterization by using LC-MS/MS was carried out to be able to correlate the bioactivity with the particular chemical composition of each extract and plant. The use of PLE with water as a solvent at the highest temperature tested (200°C) always provided the highest extraction yields for the three studied plants, being maximum for oregano (>60%). Besides, oregano's pressurized water extracts at lower temperatures (50°C) presented the highest content on total phenols (184.9 mg gallic acid/g extract) and the best antioxidant activities (EC(50) 6.98 μg/ml). In general, oregano extracts were the most active, followed by wild thyme extracts. The antioxidant capacity measured by DPPH assay was highly correlated with the amount of total phenols. Moreover, the use of a LC-MS/MS method allowed the identification of 30 different phenolic compounds in the different extracts, including phenolic acids, flavones, flavanones and flavonols, which have an important influence on the total antioxidant capacity of the different extracts.


CRISPR/Cas9-mediated grna gene knockout leads to neurodevelopmental defects and motor behavior changes in zebrafish.
Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions in early embryogenesis, anti-inflammation, and neurodegeneration. A good model for the functional study of PGRN is the zebrafish with knockdown or knockout of grn, the gene encoding PGRN. Morpholino oligonucleotides (MOs) and zinc finger nucleases have been used to generate zebrafish grn models, yet they have shown inconsistent phenotypes due to either the neurotoxicity of the MOs or possible genetic compensation responses during gene editing. In this study, we generated stable grna (one of the major grn homologues of zebrafish) knockout zebrafish by using CRISPR/Cas9-mediated genome editing. A grna sgRNA was designed to target the similar repeated sequence shared by exon 13, exon 15, and exon 19 in zebrafish. The F1 generation with the frameshift mutation of + 4 bp (the addition of 4 bp to exon15), which causes a premature termination, was obtained and subjected to morphological and behavioral evaluation. The grna knockout zebrafish showed neurodevelopmental defects, including spinal motor neurons with shorter axons, decreased sensory hair cells, thinning of the outer nuclear layer and thickening of the inner nuclear layer of the retina, decreased expression of rhodopsin in the cone cells, and motor behavior changes. Moreover, the phenotypes of grna knockout zebrafish could be rescued with the Tol2 system carrying the grna gene. The grna knockout zebrafish model generated in this study provides a useful tool to study PGRN function and has potential for high-throughput drug screening for disease therapy.


The equine periodic paralysis Na+ channel mutation alters molecular transitions between the open and inactivated states.
1. The Na+ channel mutation associated with equine hyperkalaemic periodic paralysis (HPP) affects a highly conserved phenylalanine residue in an unexplored region of the alpha-subunit. This mutation was introduced into the rat skeletal muscle Na+ channel gene at the corresponding location (i.e. F1412L) for functional expression and characterization in Xenopus oocytes. 2. In comparison with wild-type (WT) channels, equine HPP channels showed clear evidence for disruption of inactivation: increased time-to-peak current, slowed rates of whole-cell current decay, significant increases in sustained current, rightward shifts in the steady-state inactivation curve by 9.5 mV, a 6-fold acceleration in the rate of recovery from inactivation at -80 mV, decreased number of blank single-channel sweeps, repetitive opening of single channels throughout depolarizing steps, increased open probability per sweep, and an increased mean open time. 3. The observed disruption of inactivation in HPP occurred without measurable changes in steady-state activation and first latency kinetics of channel opening. 4. Kinetic modelling demonstrates that the equine HPP phenotype can be simulated by altering the rate constants for transitions entering and leaving the inactivated states resulting from an energetic destabilization of the inactivated state. 5. These results suggest that the highly conserved cytoplasmic end of the third transmembrane segment (S3) in the fourth internal repeat domain (domain IV) plays a critical role in Na+ channel inactivation.


Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible.
The structural requirements for the inhibition of ferrochelatase by N-alkylated porphyrins were investigated and experiments carried out to explore the mechanism of enzyme inhibition. Three dicarboxylic porphyrins, all substrates of the enzyme, are strongly inhibitory when N-alkylated; in contrast, uroporphyrin and coproporphyrin (which are not substrates) do not inhibit after N-alkylation. Free carboxylic acid functions are required for inhibition, as the methyl ester derivatives are not themselves inhibitory. Porphyrins bearing the alkyl group on the pyrrole nitrogen of rings C and D are less effective inhibitors, particularly when zinc is chelated in the centre of the tetrapyrrole or the N-alkyl group is relatively large in size. The substituents at the 2- and 4-positions of the porphyrin system may also affect the inhibitory activity, particularly for the isomers with ring C and D alkylated. The zinc chelates of several N-alkylprotoporphyrins are inhibitory towards haem oxygenase, another haem-binding enzyme, and also in this case increasing the size of the alkyl group decreased the inhibitory activity, particularly for isomers with ring C or D alkylated. The inhibition could be reversed by prolonged incubation with excess porphyrin substrate, but dealkylation of the N-alkylporphyrin during enzyme inhibition could not be demonstrated. It is concluded (a) that N-alkylated dicarboxylic porphyrins compete reversibly with the porphyrin substrate for the enzyme active site and (b) that the structural and steric factors discussed above affect the inhibitory activity by modifying the affinity of the N-alkylporphyrin inhibitor for the enzyme.


Basolateral amiloride-sensitive Na+ transport pathway in rat tongue epithelium.
1. Experiments were conducted to test for the presence of basolateral Na+ channels in the rat lingual epithelium. Researchers have proposed a model in which some lingual taste cells have Na+ channels in the basolateral membrane. That model is designed to account for the portion of the neural taste response and the portion of the transepithelial short-circuit current (Isc) in vitro that are insensitive to mucosal amiloride; some Na+ would diffuse across the tight junction into the cell via this lateral pathway, and would be transported out of the cell by Na+ pumps in the basal membrane. The model could also account for the differential effect of mucosal amiloride on Na+ salts of various anions, in which the neural taste responses to Na+ salts with anions larger than Cl- are more sensitive to mucosal amiloride than is the taste response to NaCl. 2. Voltage-clamp data were obtained from an in vitro preparation of the anterior-dorsal rat tongue epithelium in which the connective tissue was removed by enzyme digestion. Isc in a modified Ussing chamber was reduced by amiloride in the submucosal solution. 3. The pattern of sensitivity to submucosal amiloride differed in several respects from the pattern for mucosal amiloride. The inhibition constant (Ki) was 52 microM amiloride concentration, higher than for the apical amiloride-sensitive Na+ channel. The selectivity for Na+ over K+ was much less than for the response to mucosal amiloride; with 0.5 M NaCl or KCl on the mucosal side, the ratio of inhibition for the NaCl response to inhibition for the KCl response varied between 1 and 3. 4. As the concentration of NaCl in the mucosal solution was varied, submucosal amiloride caused little inhibition of Isc for mucosal NaCl below isosmotic concentration, with the percent inhibition increasing as mucosal salt concentration increased. With 0.5 M sodium gluconate in the mucosal solution, there was very little inhibition due to submucosal amiloride. 5. The results support the presence of amiloride-sensitive Na+ channels in the basolateral membranes of the dorsal tongue epithelium in rat, and are consistent with the proposed model in which these channels are present in taste cells.


Can SHED or DPSCs be used to repair/regenerate non-dental tissues? A systematic review of in vivo studies.
Dental pulp has been identified as a novel and promising stem cell source. The following systematic review presents and summarises in vivo studies that have used stem cells from the dental pulp of permanent and deciduous teeth to repair or regenerate non-dental tissues. An electronic customised search was performed using 4 different databases (Entrez PubMed, Cab Abstracts, Scopus and Web of Science). Only full-text research manuscripts published in English between the years of 2000 and 2012 were included. The manuscripts were retrieved based on the following keywords and/or abbreviations: [Stem Cells from Human Exfoliated Deciduous teeth (SHED)] AND/OR [Dental Pulp Stem Cells (DPSC)] AND [tissue regeneration] AND [tissue repair]. Only manuscripts involving in vivo applications of SHED or DPSC for the repair and/or regeneration of non-dental tissues were included. The search strategy produced 2309 papers, from which 14 were eligible according to the predetermined inclusion and exclusion criteria. Although human tissue was the source of cells in half of the studies included in our review, all of the studies involved transplantation into animals of other species, such as pigs, rats and mice. Most of the manuscripts reported the successful use of DPSCs or SHED for non-dental tissue repair or regeneration. While these cell populations represent promising alternative sources of stem cells for tissue engineering and cell-based regenerative medicine therapies, it is not yet possible to guarantee the appropriate clinical management of this technique.


Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients.
Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney-pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.


The effect of vitamin D supplementation on serum total 25(OH) levels and biochemical markers of skeletal muscles in runners.
The beneficial adaptation of skeletal muscle function to strenuous exercise is partially attributable to the improvement of vitamin D status. The present study aimed to evaluate the effects of a 3-week vitamin D supplementation on serum 25(OH)D levels and skeletal muscle biomarkers (i.e. troponin, myoglobin, creatine kinase and lactic dehydrogenase) of endurance runners. A double-blind placebo-controlled study design was used and vitamin D supplementation was compared to a non-treatment control group. Twenty-four runners, competitors of the ultra-marathons held during the National Running Championships, were randomly assigned into two groups supplemented with the dose of 2000 IU vitamin D or placebo for three weeks. All subjects participated in three exercise protocols: (a) incremental exercise test (to determine the maximum oxygen uptake and the intensity of eccentric exercise), (b) eccentric exercise before and (c) after two dietary protocols. Venous blood samples were drawn at rest, immediately after the exercise and after 1 h and 24 h of recovery in order to estimate serum 25(OH)D levels, skeletal muscle biomarkers, proinflammatory cytokines and tumor necrosis factor-alpha (TNF-α) levels. A two-way ANOVA was used to test main effects and their interactions and Pearson correlation coefficients were analyzed to determine the effects of inter-variable relationships. Significant differences between pre- and post-intervention in baseline 25(OH)D levels were observed (34.9 ± 4.7 versus 40.3 ± 4.9 ng/ml, p = 0.02) in supplemented group. A higher post intervention 25(OH)D level was observed after vitamin D diet compared to placebo (40.3 ± 4.9 versus 31.8 ± 4.2 ng/mL, respectively; p < 0.05). The vitamin D supplementation decreased post-exercise (TN max) and 1 h post-exercise troponin (p = 0.004, p = 0.03, respectively), 1 h post-exercise myoglobin concentration (p = 0.01) and TNF-α levels(p < 0.03). 24 h post exercise creatine kinase activity was significantly lower in supplemented group compared to placebo (p < 0.05). A negative correlation was observed between post exercise 25(OH)D levels and myoglobin levels (r = - 0.57; p = 0.05), and 25(OH)D levels and TNFα (r = - 0.58; p = 0.05) in vitamin D supplemented group. Three weeks of vitamin D supplementation had a positive effect on serum 25(OH)D levels in endurance trained runners and it caused a marked decrease in post-exercise biomarkers levels. We concluded that vitamin D supplementation might play an important role in prevention of skeletal muscle injuries following exercise with eccentric muscle contraction in athletes.


Transcription-driven twin supercoiling of a DNA loop: a Brownian dynamics study.
The torque generated by RNA polymerase as it tracks along double-stranded DNA can potentially induce long-range structural deformations integral to mechanisms of biological significance in both prokaryotes and eukaryotes. In this paper, we introduce a dynamic computer model for investigating this phenomenon. Duplex DNA is represented as a chain of hydrodynamic beads interacting through potentials of linearly elastic stretching, bending, and twisting, as well as excluded volume. The chain, linear when relaxed, is looped to form two open but topologically constrained subdomains. This permits the dynamic introduction of torsional stress via a centrally applied torque. We simulate by Brownian dynamics the 100 micros response of a 477-base pair B-DNA template to the localized torque generated by the prokaryotic transcription ensemble. Following a sharp rise at early times, the distributed twist assumes a nearly constant value in both subdomains, and a succession of supercoiling deformations occurs as superhelical stress is increasingly partitioned to writhe. The magnitude of writhe surpasses that of twist before also leveling off when the structure reaches mechanical equilibrium with the torsional load. Superhelicity is simultaneously right handed in one subdomain and left handed in the other, as predicted by the "transcription-induced twin-supercoiled-domain" model [L. F. Liu and J. C. Wang, Proc. Natl. Acad. Sci. U.S.A. 84, 7024 (1987)]. The properties of the chain at the onset of writhing agree well with predictions from theory, and the generated stress is ample for driving secondary structural transitions in physiological DNA.


Papillomavirus infection of the cervix. III: Relationship of the presence of viral structural proteins to the expression of involucrin.
Forty-two cervical biopsies with cervical intraepithelial neoplasia were compared with respect to the expression of human papillomavirus (HPV) structural proteins and the expression of the cellular structural protein involucrin, a marker of suprabasal squamous differentiation. HPV structural protein and involucrin expression displayed an inverse correlation with the severity of dysplasia. Both of these proteins were detected in 11 of 28 cases (39%) of mild and moderate dysplasia, but in only two of 14 (14%) cases of severe dysplasia. This difference was statistically significant (p less than 0.001). The presence of HPV was also associated with expression of involucrin in the full thickness of the epithelium, including the basal layer, and an altered staining pattern in the more superficial cells, particularly the koilocytotic cells. These findings support the hypothesis that squamous differentiation is required for the expression of viral structural proteins and that HPV infection begins in the basal epithelium. The study also demonstrates the utility of involucrin staining in differentiating virus-induced cytologic atypia from true neoplasia.


Ultrafast assessment of left ventricular dyssynchrony from nuclear myocardial perfusion imaging on a new high-speed gamma camera.
To validate the ultrafast assessment of left ventricular (LV) dyssynchrony by phase analysis using high-speed nuclear myocardial perfusion imaging (MPI) on a new gamma camera with cadmium-zinc-telluride (CZT) solid-state detector technology. In 46 patients rest MPI with 960 MBq (99m)Tc-tetrofosmin was acquired on a dual-head detector SPECT camera (Ventri, GE Healthcare) and an ultrafast CZT camera (Discovery NM 530c, GE Healthcare) with acquisition times of 15 and 5 min, respectively. LV dyssynchrony was assessed using the Emory Cardiac Toolbox with established values for histogram bandwidth (male <62.4°; female <49.7°) and standard deviations (male <24.4°; female <22.1°) as the gold standard. Evaluating CZT scan times of 0.5, 1, 2, 3 and 5 min (list mode) in 16 patients revealed the preferred scan time to be 5 min, which was then applied in all 46 patients. Intraclass correlation and the level of agreement in dyssynchrony detection between the CZT and Ventri cameras were assessed. In LV dyssynchrony the mean histogram bandwidths with the CZT camera (n = 8) and the Ventri camera (n = 9) were 123.3 ± 50.6° and 130.2 ± 43.2° (p not significant) and 42.4 ± 13.6° vs. 43.2 ± 12.7° (p not significant). Normal bandwidths and SD obtained with the CZT camera (35.9 ± 7.7°, 12.6 ± 3.5°) and the Ventri camera (34.8 ± 6.6°, 11.1 ± 2.1°, both p not significant) excluded dyssynchrony in 38 and 37 patients, respectively. Intraclass correlation and the level of agreement between the CZT camera with a 5-min scan time and the Ventri camera were 0.94 (p < 0.001, SEE 14.4) and 96% for histogram bandwidth and 0.96 (p < 0.001, SEE 3.9) and 98% for SD. This ultrafast CZT camera allows accurate assessment of LV dyssynchrony with a scan time of only 5 min, facilitating repeat measurements which would potentially be helpful for parameter optimization for cardiac resynchronization therapy.


Haemagglutinins and adhesion of Escherichia coli to HEp2 epithelial cells.
Strains of Escherichia coli producing type-1 fimbriae, associated with mannose-sensitive haemagglutinin (MSHA), or three antigenically different kinds of 'MRE' fimbriae, associated with mannose-resistant and eluting haemagglutinins (MREHAs), adhered poorly to HEp2 epithelial cells in an in-vitro adhesion model previously used to demonstrate the importance of motility and type-1 fimbriae for the attachment of strains of Salmonella typhimurium to HEp2 cells. Strains of E. coli producing narrow-spectrum MREHA, agglutinating human erythrocytes only of 14 red-cell species tested, adhered well to HEp2 cells, particularly so when bacteria produced MSHA (and type-1 fimbriae) along with the narrow-spectrum 'man-only' MREHA. These findings are discussed with regard to recent observations suggesting that narrow-spectrum 'man-only' MREHA in E. coli may be associated with fine, fibrillar appendages 2-nm wide.


Dental Stigmata of Congenital Syphilis: A Historic Review With Present Day Relevance.
Syphilis was the first sexually transmitted disease to be diagnosed in childhood. Most developed countries controlled syphilis effectively after the 1950s and congenital syphilis became rare. Since the late 1990s there has been a resurgence of syphilis in developed and developing countries and the WHO estimates that at least half a million infants die of congenital syphilis every year. The earliest reference to the dental manifestations of congenital syphilis was by Sir Jonathan Hutchinson, Assistant Surgeon at The London Hospital in 1861. Three main dental defects are described in congenital syphilis; Hutchinson's incisors, Moon's molars or bud molars, and Fournier's molars or mulberry molars. Although many physicians, dentists, and pathologists in developed countries will be aware of the dental features of syphilis, most will never have seen a case or made the diagnosis. The purpose of this article is to review some of the history of congenital syphilis, remind healthcare professionals of the features, and bring to their attention that the changes are still prevalent and that milder cases can be mistaken for other causes of hypoplasia.


Differential effects of fresh frozen plasma and normal saline on secondary brain damage in a large animal model of polytrauma, hemorrhage and traumatic brain injury.
We have previously shown that the extent of traumatic brain injury (TBI) in large animal models can be reduced with early infusion of fresh frozen plasma (FFP), but the precise mechanisms remain unclear. In this study, we investigated whether resuscitation with FFP or normal saline differed in their effects on cerebral metabolism and excitotoxic secondary brain injury in a model of polytrauma, TBI, and hemorrhagic shock. Yorkshire swine (n = 10) underwent Grade III liver injury, rib fracture, standardized TBI, and volume-controlled hemorrhage, (40% ± 5%) and were randomly resuscitated with either FFP or normal saline. Hemodynamic parameters and brain oxygenation were continuously monitored, while microdialysis was used to measure the brain concentrations of pyruvate, lactate, glutamate, and glycerol at baseline; 1 hour and 2 hours after shock; immediate postresuscitation (PR); as well as 2, 4, and 6 hours PR. Cells from the injured hemisphere were separated into mitochondrial and cytosolic fractions and analyzed for activity of the pyruvate dehydrogenase complex (PDH). There were no baseline differences in cerebral perfusion pressure, brain oxygenation, as well as concentrations of pyruvate, lactate, glutamate, and glycerol between the groups. At 2 hours and 4 hours PR, the FFP group had significantly higher cerebral perfusion pressures (52 [5] mm Hg vs. 43 [2] mm Hg, p = 0.016; and 50 [7] mm Hg vs. 37 [1] mm Hg, p = 0.008, respectively). There was a sustained and significant (p < 0.05) drop in the glutamate and glycerol levels in the FFP group, implying a decrease in excitotoxicity and brain damage, respectively. Mitochondrial PDH activity was significantly higher (2,666.2 [638.2] adjusted volume INT × mm vs. 1,293.4 [88.8] adjusted volume INT × mm, p = 0.008), and cytosolic PDH activity was correspondingly lower (671.4 [209.2] adjusted volume INT × mm vs. 3070.7 [484.3] adjusted volume INT × mm, p < 0.001) in the FFP group, suggesting an attenuation of mitochondrial dysfunction and permeability. In this model of TBI, polytrauma, and hemorrhage, FFP resuscitation confers neuroprotection by improving cerebral perfusion, diminishing glutamate-mediated excitotoxic secondary brain injury and reducing mitochondrial dysfunction.


Contraception with long acting subdermal implants: I. An effective and acceptable modality in international clinical trials.
This paper presents results of a double blind, multi-centered and multi-national study of two progestin only subdermal implants used for contraception. A regimen of six capsules of levonorgestrel (Ng) used by 492 women had a net cumulative 12-month pregnancy rate of 0.6 percent and a continuation rate of 74.6 percent. 498 women used six capsules of norgestrienone (R2010) and experienced a net cumulative 12-month pregnancy rate of 3.5 percent and a continuation rate of 79.4 percent. The difference in the pregnancy rate was significant at P less than 0.01, while there was no significant difference in the continuation rates. Menstrual problems were the principal reason for termination of the levonorgestrel regimen, accounting for approximately half of all terminations. There were significantly fewer menstrual problems among users of the norgestrienone (R2010) capsules; the net cumulative 12-month termination rate for this reason was 4.3 percent. Results are compared with continuation and termination rates for acceptors of the Copper T 200 at the same clinics. The low pregnancy rate and reasonably high continuation rate of the norgestrel implants coupled with the fact that the expected effective lifetime of a set of capsules is of the order of 3-5 years appears to warrant further development of this contraceptive regimen.


Ultrafine PtCuRh nanowire catalysts with alleviated poisoning effect for efficient ethanol oxidation.
As a green power source, direct ethanol fuel cells (DEFCs) have broad application prospects. However, most catalysts of DEFCs still exhibit defects, such as the difficulty of C-C bond cleavage, serious CO poisoning and limited catalytic activity. Here, we report ultrafine PtCuRh nanowires (NWs) with outstanding anti-CO-poisoning properties and enhanced activity. The average diameter of the ultrafine PtCuRh NWs is about 1.49 nm, effectively improving the atomic utilization efficiency (UE) of platinum. Owing to the combination of an ultrafine nanostructure, good electronic interaction and the high UE of Pt atoms, the optimized ultrafine PtCuRh NWs/C display superior electrocatalytic activity and stability compared with commercial Pt/C for the ethanol oxidation reaction (EOR). More importantly, further electrochemical results demonstrate that the incorporation of Rh is beneficial for enhancing the antipoisoning capability for some CO-like intermediates. Meanwhile, the synthetic method in this report is robust and universal, and can also be applied to the synthesis of ultrafine trimetallic PtCuPd and PtCuIr nanowires.


Augmented limb blood flow during neurovascular stress in physically fit women.
The study examined whether cardiorespiratory fitness modifies cardiovascular responses by normotensive men and women during the Stroop color-word interference test. Independent of age and an estimate of body fatness, fitness level was positively related (R² = .39 and .51) to increases in limb blood flow and vascular conductance, coherent with cardiac-vagal withdrawal and a decrease in heart period, among women but not men. Fitness was unrelated to changes in systolic and diastolic blood pressures and muscle sympathetic nerve activity. The augmented hemodynamic responses among fitter women were not consistent with passive vasodilation via withdrawal of sympathetic neural tone. The results encourage further gender comparisons testing whether fitness augments limb blood flow during mental stress by neurohumoral and flow-mediated vasodilatory mechanisms or by increased cardiac output.


Cell-Based Therapy Restores Olfactory Function in an Inducible Model of Hyposmia.
Stem cell-based therapies have been proposed as a strategy to replace damaged tissues, especially in the nervous system. A primary sensory modality, olfaction, is impaired in 12% of the US population, but lacks treatment options. We report here the development of a novel mouse model of inducible hyposmia and demonstrate that purified tissue-specific stem cells delivered intranasally engraft to produce olfactory neurons, achieving recovery of function. Adult mice were rendered hyposmic by conditional deletion of the ciliopathy-related IFT88 gene in the olfactory sensory neuron lineage and following experimentally induced olfactory injury, received either vehicle or stem cell infusion intranasally. Engraftment-derived olfactory neurons were identified histologically, and functional improvements were measured via electrophysiology and behavioral assay. We further explored mechanisms in culture that promote expansion of engraftment-competent adult olfactory basal progenitor cells. These findings provide a basis for translational research on propagating adult tissue-specific sensory progenitor cells and testing their therapeutic potential.


RIFM fragrance ingredient safety assessment, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)-, CAS Registry Number 499-44-5.
The existing information supports the use of this material as described in this safety assessment. This material has not been fully evaluated for photoallergenic potential. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. Based on data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is a photoirritant but is not a concern under the current declared use levels. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was not evaluated for photoallergenicity. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.


The needs of siblings of children with cancer: a nursing perspective.
Findings from research studies on the needs of siblings of children with cancer have highlighted the imperative that these siblings be supported and involved in the plan of care when a diagnosis of cancer is made. However, few studies have included the perspective of the nurse when evaluating sibling needs or identifying interventions used to meet the needs. This qualitative descriptive study used a combination of individual interviews and a focus group to capture perspectives from 13 pediatric oncology nurses employed at a leading Children's Hospital located in the northeast. Transcripts were analyzed for content and theme in relation to the 2 research questions. Needs identified included getting attention, wanting to know, having fears/worries, feeling at fault, wanting to help, and wanting a normal routine, whereas interventions identified included recognizing their needs, getting siblings involved, sharing appropriate information, being a resource, giving support, and bending the rules. Findings support previous studies that document the variety of needs experienced by siblings of children with cancer and offer examples of nursing interventions to meet these needs.


ISOdb: A Comprehensive Database of Full-Length Isoforms Generated by Iso-Seq.
The accurate landscape of transcript isoforms plays an important role in the understanding of gene function and gene regulation. However, building complete transcripts is very challenging for short reads generated using next-generation sequencing. Fortunately, isoform sequencing (Iso-Seq) using single-molecule sequencing technologies, such as PacBio SMRT, provides long reads spanning entire transcript isoforms which do not require assembly. Therefore, we have developed ISOdb, a comprehensive resource database for hosting and carrying out an in-depth analysis of Iso-Seq datasets and visualising the full-length transcript isoforms. The current version of ISOdb has collected 93 publicly available Iso-Seq samples from eight species and presents the samples in two levels: (1) sample level, including metainformation, long read distribution, isoform numbers, and alternative splicing (AS) events of each sample; (2) gene level, including the total isoforms, novel isoform number, novel AS number, and isoform visualisation of each gene. In addition, ISOdb provides a user interface in the website for uploading sample information to facilitate the collection and analysis of researchers' datasets. Currently, ISOdb is the first repository that offers comprehensive resources and convenient public access for hosting, analysing, and visualising Iso-Seq data, which is freely available.


Non-atherosclerotic acute cardiac syndromes: spontaneous coronary artery dissection and Takotsubo syndrome. Comparison of long-term clinical outcomes.
Spontaneous coronary artery dissection (SCAD) and Takotsubo syndrome (TTS) constitute two common causes of nonatherosclerotic acute cardiac syndrome particularly frequent in women. Currently, there is no information comparing long-term clinical outcomes in unselected patients with these conditions. We compared the baseline characteristics, in-hospital outcomes, and the 12-month and long-term clinical outcomes of two large prospective registries on SCAD and TTS. A total of 289 SCAD and 150 TTS patients were included; 89% were women. TTS patients were older with a higher prevalence of cardiovascular risk factors. Precipitating triggers were more frequent in TTS patients, while emotional triggers and depressive disorders were more common in the SCAD group. Left ventricular ejection fraction was lower in TTS patients, but SCAD patients showed higher cardiac biomarkers. In-hospital events (43.3% vs. 5.2%, P <0.01) occurred more frequently in TTS patients. TTS patients also presented more frequent major adverse events at 12-month (14.7% vs. 7.1%, HR 5.3, 95% CI: 2.4-11.7, P <0.01) and long-term (median 36 vs. 31 months, P =0.41) follow-up (25.8% vs. 9.6%, HR 4.5, 95% CI: 2.5-8.2, P <0.01). Atrial fibrillation was also more frequent in TTS patients. Moreover, TTS patients presented a higher 12-month and long-term mortality (5.6% vs. 0.7%, P =0.01; and 12.6% vs. 0.7%, P <0.01) mainly driven by noncardiovascular deaths. Compared to SCAD, TTS patients are older and present more cardiovascular risk factors but less frequent depressive disorder or emotional triggers. TTS patients have a worse in-hospital, mid-term, and long-term prognosis with higher noncardiac mortality than SCAD patients.


Release of Applied Mechanical Loading Stimulates Intercellular Calcium Waves in Drosophila Wing Discs.
Mechanical forces are critical but poorly understood inputs for organogenesis and wound healing. Calcium ions (Ca2+) are critical second messengers in cells for integrating environmental and mechanical cues, but the regulation of Ca2+ signaling is poorly understood in developing epithelial tissues. Here we report a chip-based regulated environment for microorgans that enables systematic investigations of the crosstalk between an organ's mechanical stress environment and biochemical signaling under genetic and chemical perturbations. This method enabled us to define the essential conditions for generating organ-scale intercellular Ca2+ waves in Drosophila wing discs that are also observed in vivo during organ development. We discovered that mechanically induced intercellular Ca2+ waves require fly extract growth serum as a chemical stimulus. Using the chip-based regulated environment for microorgans, we demonstrate that not the initial application but instead the release of mechanical loading is sufficient, but not necessary, to initiate intercellular Ca2+ waves. The Ca2+ response depends on the prestress intercellular Ca2+ activity and not on the magnitude or duration of the mechanical stimulation applied. Mechanically induced intercellular Ca2+ waves rely on IP3R-mediated Ca2+-induced Ca2+ release and propagation through gap junctions. Thus, intercellular Ca2+ waves in developing epithelia may be a consequence of stress dissipation during organ growth.


Adaptive Transfer of Graph Neural Networks for Few-Shot Molecular Property Prediction.
Few-Shot Molecular Property Prediction (FSMPP) is an improtant task on drug discovery, which aims to learn transferable knowledge from base property prediction tasks with sufficient data for predicting novel properties with few labeled molecules. Its key challenge is how to alleviate the data scarcity issue of novel properties. Pretrained Graph Neural Network (GNN) based FSMPP methods effectively address the challenge by pre-training a GNN from large-scale self-supervised tasks and then finetuning it on base property prediction tasks to perform novel property prediction. However, in this paper, we find that the GNN finetuning step is not always effective, which even degrades the performance of pretrained GNN on some novel properties. This is because these molecule-property relationships among molecules change across different properties, which results in the finetuned GNN overfits to base properties and harms the transferability performance of pretrained GNN on novel properties. To address this issue, in this paper, we propose a novel Adaptive Transfer framework of GNN for FSMPP, called ATGNN, which transfers the knowledge of pretrained and finetuned GNNs in a task-adaptive manner to adapt novel properties. Specifically, we first regard the pretrained and finetuned GNNs as model priors of target-property GNN. Then, a task-adaptive weight prediction network is designed to leverage these priors to predict target GNN weights for novel properties. Finally, we combine our ATGNN framework with existing FSMPP methods for FSMPP. Extensive experiments on four real-world datasets, i.e., Tox21, SIDER, MUV, and ToxCast, show the effectiveness of our ATGNN framework.


The coming of age of artificial intelligence in medicine.
This paper is based on a panel discussion held at the Artificial Intelligence in Medicine Europe (AIME) conference in Amsterdam, The Netherlands, in July 2007. It had been more than 15 years since Edward Shortliffe gave a talk at AIME in which he characterized artificial intelligence (AI) in medicine as being in its "adolescence" (Shortliffe EH. The adolescence of AI in medicine: will the field come of age in the '90s? Artificial Intelligence in Medicine 1993;5:93-106). In this article, the discussants reflect on medical AI research during the subsequent years and characterize the maturity and influence that has been achieved to date. Participants focus on their personal areas of expertise, ranging from clinical decision-making, reasoning under uncertainty, and knowledge representation to systems integration, translational bioinformatics, and cognitive issues in both the modeling of expertise and the creation of acceptable systems.


Post-ischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia-inducible, neuroprotective protein that also stimulates proliferation of neuronal precursor cells. Accordingly, HB-EGF may contribute to recovery from cerebral injury through direct neuroprotective effects, by enhancing neurogenesis, or both. When administered by the intracerebroventricular route 1-3 days after focal cerebral ischemia in adult rats, HB-EGF decreased the volume of the resulting infarcts and reduced post-ischemic neurological deficits. HB-EGF also increased the incorporation of bromodeoxyuridine into cells expressing the immature neuronal marker protein TUC-4 in the dentate subgranular and rostral subventricular zones, consistent with increased proliferation of neuronal precursors. However, HB-EGF decreased the number of newborn neurons that migrated into the ischemic striatum, perhaps partly because reduction of infarct size by HB-EGF also reduced the stimulus to migration. To determine if HB-EGF might also directly inhibit migration of neuronal precursors, we co-cultured subventricular zone (SVZ) explants treated with HB-EGF or vehicle together with hypoxic cerebral cortical explants, and measured cell migration from the former toward the latter. HB-EGF reduced directed migration of SVZ cells toward the cortical explants, possibly due to a local chemoattractant effect on neuronal precursor cells, which may be mediated through the HB-EGF-specific receptor, N-arginine dibasic convertase. The delayed neuroprotective effect of HB-EGF may have implications for efforts to prolong the therapeutic window for intervention in stroke.


(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function.
Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor. The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.


pQCT study on diffusion and equilibrium distribution of iodinated anionic contrast agent in human articular cartilage--associations to matrix composition and integrity.
X-ray imaging of articular cartilage using anionic contrast agents has been introduced for quantification of tissue glycosaminoglycan (GAG) concentration. In this in vitro study we investigated diffusion and equilibrium distribution of an anionic contrast agent in human articular cartilage and related the results to tissue composition and integrity. Osteochondral cylinders (d=4.0mm, n=24) were prepared from femoral medial condyles (FMCs, cartilage thickness 2.13+/-0.54 mm, mean+/-standard deviation [SD]), and tibial medial plateaus ([TMPs]1.99+/-0.38 mm) of human cadaver knees. Samples were immersed for 24h at room temperature in 21 mM concentration of anionic contrast agent Hexabrix. The X-ray absorption maps and profiles were measured before immersion, and after every 2h of immersion using clinical peripheral quantitative computed tomography (pQCT). An increase in X-ray attenuation along cartilage depth, indicating a characteristic density profile increasing from superficial to deep tissue, could be seen in pQCT images acquired without contrast agent. The complete diffusion of the contrast agent into cartilage took more than 12h. However, the uronic acid concentration correlated with the contrast agent concentration in femoral cartilage (r=-0.76, n=12, P=0.004) as early as after 2h of immersion, and the linear correlation was virtually unchanged during the remaining 22 h. Similarly, the histological tissue integrity (Mankin score) correlated positively with the contrast agent concentration in tibial cartilage (r=+0.75, P=0.005) after 2h of immersion. The X-ray absorption profiles before immersion, i.e., without the contrast agent, and after 24h of immersion were significantly correlated (r=-0.76+/-0.34, mean+/-SD). Although the complete contrast agent diffusion into human articular cartilage in vitro took more than 12h, significant apparent correlations were revealed between the spatial proteoglycan (PG) and contrast agent distributions already after 2h of immersion. At the stage of incomplete penetration, however, the spatial contrast agent concentration distribution cannot directly reflect the true PG distribution as the Donnan equilibrium has not been reached. However, in degenerated cartilage the diffusion rate increases. Obviously, this can lead to the reported correlation between the bulk PG content and the bulk contrast agent concentration already at the early stages of diffusion.


Fabrication of hydrophilic composites by bridging the secondary structures between rice proteins and pea proteins toward enhanced nutritional properties.
Protein structures combining designable nutritional and functional properties are attracting great attention in the food industry. In this study, novel protein composites with shared internal structures were fabricated by co-dissolving rice proteins (RPs) and pea proteins (PPs) at pH 12 prior to a one-step neutralization. Structural and morphological characterization revealed that both unfolded protein molecules reacted at pH 12 via their secondary structures, driven by hydrophobic forces. The co-assembled structures therefore obtained considerable resistance against acid-induced refolding, affording the formation of nanoscale (∼100 nm), water-dispersible composites at pH 7. Eventually, the drawbacks of either proteins, such as the insolubility of RPs or slow digestion of PPs, were overcome due to structural alterations. Moreover, the strategy raised the level of Lys which was limiting in RPs in the same way as the level of those that were limiting in PPs such as Met and Cys-s. Based on the above results, the study would enrich the techniques of processing protein ingredients toward tailored structures and on-demand nutritional properties.


Genotypes and genetic characters of Mycobacterium tuberculosis from Myanmar using three typing methods.
Knowledge on basic characteristics of Mycobacterium tuberculosis (MTB) is helpful to understand the disease epidemiology and support the prediction of clinical outcome of the disease. The aim of this study was to detect the genotypes and genotypic characters of clinical Mycobacterium tuberculosis (MTB) isolates from new and retreatment rifampicin-resistant patients using three different genotyping methods. Mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU-VNTR) typing was used to determine the diversity of 222 clinical isolates. Spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing were also used to investigate the genetic characters of 105 MTB strains. Among the 15 genotypes detected by MIRU-VNTR, Beijing strains were the most prevalent of all strains (54.8%); new cases (40.5%) and retreatment cases (69.4%), followed by EAI strain. Spoligotyping categorized the strains into 11 lineages and 13 orphans whereas 96 different IS6110 patterns were identified using RFLP method. The mode number of IS6110 was 18 and 20. Higher band numbers were found in Beijing genotype (p < 0.001). Clustering rates by spoligotyping, MIRU-VNTR and IS6110-RFLP typing were 0.714, 0.004 and 0.085, respectively. Discriminatory powers of spoligotyping, MIRU-VNTR typing and IS6110-RFLP typing were 0.637, 1.000 and 0.997, respectively. Dominant Beijing genotype in both new and retreatment cases denoting that prevailing tuberculosis in Myanmar changed from EAI to Beijing lineage.


1064 nm laser-induced defects in pure SiO₂ fibers.
We investigate evidence of the formation of nonbridging oxygen hole centers in pure silica photonic crystal fibers from 5 ps 1064 nm pulses. The formation of the defects is attributed to the breaking of stressed silicon-oxygen bonds in the glass matrix through a many-photon process. We compare the photodarkening induced by the 1064 nm pump with photodarkening induced by short wavelength light in a 1064 nm pumped supercontinuum extending to 400 nm. It is shown that the higher peak power at the pump wavelength makes it a more significant cause of photodarkening when compared to the shorter wavelength light generated in the fiber.


Scapinin-induced inhibition of axon elongation is attenuated by phosphorylation and translocation to the cytoplasm.
Scapinin is an actin- and PP1-binding protein that is exclusively expressed in the brain; however, its function in neurons has not been investigated. Here we show that expression of scapinin in primary rat cortical neurons inhibits axon elongation without affecting axon branching, dendritic outgrowth, or polarity. This inhibitory effect was dependent on its ability to bind actin because a mutant form that does not bind actin had no effect on axon elongation. Immunofluorescence analysis showed that scapinin is predominantly located in the distal axon shaft, cell body, and nucleus of neurons and displays a reciprocal staining pattern to phalloidin, consistent with previous reports that it binds actin monomers to inhibit polymerization. We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon. Because its expression is highest in relatively plastic regions of the adult brain (cortex, hippocampus), scapinin is a new regulator of neurite outgrowth and neuroplasticity in the brain.


Eight-channel transceiver RF coil array tailored for ¹H/¹⁹F MR of the human knee and fluorinated drugs at 7.0 T.
The purpose of this study was to evaluate the feasibility of an eight-channel dual-tuned transceiver surface RF coil array for combined (1)H/(19)F MR of the human knee at 7.0 T following application of (19)F-containing drugs. The (1)H/(19)F RF coil array includes a posterior module with two (1)H loop elements and two anterior modules, each consisting of one (1)H and two (19)F elements. The decoupling of neighbor elements is achieved by a shared capacitor. Electromagnetic field simulations were performed to afford uniform transmission fields and to be in accordance with RF safety guidelines. Localized (19)F MRS was conducted with 47 and 101 mmol/L of flufenamic acid (FA) – a (19)F-containing non-steroidal anti-inflammatory drug – to determine T1 and T2 and to study the (19)F signal-to-dose relationship. The suitability of the proposed approach for (1)H/(19)F MR was examined in healthy subjects. Reflection coefficients of each channel were less than -17 dB and coupling between channels was less than -11 dB. Q(L)/Q(U) was less than 0.5 for all elements. MRS results demonstrated signal stability with 1% variation. T1 and T2 relaxation times changed with concentration of FA: T1 /T2 = 673/31 ms at 101 mmol/L and T1 /T2 = 616/26 ms at 47 mmol/L. A uniform signal and contrast across the patella could be observed in proton imaging. The sensitivity of the RF coil enabled localization of FA ointment administrated to the knee with an in-plane spatial resolution of (1.5 × 1.5) mm(2) achieved in a total scan time of approximately three minutes, which is well suited for translational human studies. This study shows the feasibility of combined (1)H/(19)F MRI of the knee at 7.0 T and proposes T1 and T2 mapping methods for quantifying fluorinated drugs in vivo. Further technological developments are necessary to promote real-time bioavailability studies and quantification of (19)F-containing medicinal compounds in vivo.


Effect of a somatostatin analogue on gastric motor and sensory functions in healthy humans.
Pharmacological approaches to alter satiation may have an impact on functional upper gastrointestinal disorders and potentially change food intake in obesity. Our aim was to compare the effects of two doses of octreotide and placebo on postprandial symptoms, gastric accommodation, and gastric emptying using validated non-invasive techniques. In a randomised, parallel group, two dose, double blind, placebo controlled study, 39 healthy participants (13 per group) were randomised to 30 or 100 micro g octreotide or placebo, administered subcutaneously, 30 minutes before each study. Studies were performed on three separate days and included scintigraphic gastric emptying of solids and liquids, (99m)Tc SPECT imaging to measure fasting stomach volume and gastric accommodation following a 300 ml Ensure meal, and a standardised nutrient drink test to measure maximum tolerated volume and postprandial symptoms. Relative to placebo, both doses of octreotide delayed gastric emptying of solids (not liquids), increased fasting gastric volume, reduced the change in gastric volume post meal, and decreased the sensation of fullness after a satiating meal. The somatostatin analogue octreotide significantly alters human gastric functions, including inhibition of the normal reflex responses of gastric volume increase and emptying of the meal. These pharmacological effects suggest studies of the medication in disorders of satiation, including obesity and dyspepsia, are warranted.


Mechanics of finger-tip electronics.
Tactile sensors and electrotactile stimulators can provide important links between humans and virtual environments, through the sensation of touch. Soft materials, such as low modulus silicones, are attractive as platforms and support matrices for arrays sensors and actuators that laminate directly onto the fingertips. Analytic models for the mechanics of three dimensional, form-fitting finger cuffs based on such designs are presented here, along with quantitative validation using the finite element method. The results indicate that the maximum strains in the silicone and the embedded devices are inversely proportional to the square root of radius of curvature of the cuff. These and other findings can be useful in formulating designs for these and related classes of body-worn, three dimensional devices.


Mothers' and fathers' depressive symptoms and conflict-resolution strategies in the marriage and children's externalizing and internalizing behaviors.
The authors examined mothers' and fathers' avoidance and attacking conflict-resolution strategies in the marriage and their depressive symptoms as they related to children's externalizing and internalizing behaviors. A nonclinical community sample of 51 families and their children's 1st-grade teachers (N = 41) participated. Both mothers and teachers completed a behavior-problem checklist in order to evaluate the incidence of internalizing and externalizing behaviors in the children. Correlational statistics revealed significant associations between parents' avoidance and attacking strategies and their depressive symptoms. Also, parents' use of avoidance was related to more internalizing behaviors in the children. When hierarchical regression analyses were used to examine the contributions of the parents' attributes to children's externalizing and internalizing behaviors, mothers' avoidance and an interaction between mothers' and fathers' avoidance were identified as significant predictors of children's internalizing behaviors.


Open Questions of Chemically Powered Nano- and Micromotors.
Chemically powered nano- and micromotors are microscopic devices that convert chemical energy into motion. Interest in these motors has grown over the past 20 years because they exhibit interesting collective behaviors and have found potential uses in biomedical and environmental applications. Understanding how these motors operate both individually and collectively and how environments affect their operation is of both fundamental and applied significance. However, there are still significant gaps in our knowledge. This Perspective highlights several open questions regarding the propulsion mechanisms of, interactions among, and impact of confinements on nano- and micromotors driven by self-generated chemical gradients. These questions are based on my own experience as an experimentalist. For each open question, I describe the problem and its significance, analyze the status-quo, identify the bottleneck problem, and propose potential solutions. An underlying theme for these questions is the interplay among reaction kinetics, physicochemical distributions, and fluid flows. Unraveling this interplay requires careful measurements as well as a close collaboration between experimentalists and theoreticians/numerical experts. The interdisciplinary nature of these challenges suggests that their solutions could bring new revelations and opportunities across disciplines such as colloidal sciences, material sciences, soft matter physics, robotics, and beyond.


[Update on chronic obstructive pulmonary disease].
Chronic obstructive pulmonary disease (COPD), mainly caused by smoking, is predicted to be the third most frequent cause of death in the world by 2020. It is a multicomponent, progressive, disabling condition that ultimately ends in respiratory failure and death. There is evidence that systemic inflammation and extra pulmonary effects are also common in COPD, although the association between systemic inflammation and systemic manifestations of COPD is still not entirely clear. COPD is not only preventable but also treatable and the past decade has witnessed great progress in COPD research. New drugs have been developed and tested and a growing base of scientific evidence now documents the efficacy of several therapies for symptoms and exacerbations. It is clear that many patients with the disease can benefit from an aggressive management, with a decrease in the frequency of hospitalizations and improvements in symptoms and quality of life. Moreover, basic and clinical scientists have now identified cells, mechanisms, and molecules that play key roles in its pathogenesis. The advent of newer and more effective therapies will lead to a decline in the contribution of this disease to worldwide disease burden. COPD is now viewed under a new paradigm as preventable and treatable.


Effects of a synthetic analog of polycavernoside A on human neuroblastoma cells.
Polycavernoside A is a glycosidic marine toxin first extracted from the red alga Polycavernosa tsudai in 1991 when 3 people died after the ingestion of this food. Polycavernoside A is an interesting molecule because of its complex macrolide structure and strong bioactivity. However, the target site of this toxin has not been characterized. We studied the effects of a synthethic analog of polycavernoside A on human neuroblastoma cells by measuring changes in membrane potential with bis-oxonol and variations in intracellular calcium levels with fura-2. Fluorescent phalloidin was utilized for assaying activity on actin cytoskeleton. Data showed that this polycavernoside A analog induced a membrane depolarization and an increase in cytosolic calcium levels. These results provide the first insight into the mode of action of polycavernoside A, suggesting that: i) this toxin triggers an initial extracellular calcium entry neither produced across L-type voltage-gated calcium channels nor activation of muscarinic receptors ii) there is a depolarization induced by the toxin and due to the extracellular calcium entry.


Calibration and data elaboration procedure for sky irradiance measurements.
The problems encountered in the elaboration of measurements of direct and sky diffuse solar irradiance are the following: (1) to carry out the calibration for the direct irradiance, which consists in determining the direct irradiance at the upper limit of the atmosphere; (2) to carry out the calibration for the diffuse irradiance, which consists in determining the solid viewing angle of the sky radiometer; (3) to determine the input parameters, namely, ground albedo, real and imaginary parts of the aerosol refractive index, and aerosol radius range; and (4) to determine from the optical data the columnar aerosol optical depth and volume radius distribution. With experimental data and numerical simulations a procedure is shown that enables one to carry out the two calibrations needed for the sky radiometer, to determine a best estimate of the input parameters, and, finally, to obtain the average features of the atmospheric aerosols. An interesting finding is that inversion of only data of diffuse irradiance yields the same accuracy of result as data of both diffuse and direct irradiance; in this case, only calibration of the solid viewing angle of the sky radiometer is needed, thus shortening the elaboration procedure. Measurements were carried out in the Western Mediterranean Sea (Italy), in Tokyo (Japan), and in Ushuaia (Tierra del Fuego, Argentina); data were elaborated with a new software package, the Skyrad code, based on an efficient radiative transfer scheme.


Role of Lymphatic Deficiency in the Pathogenesis and Progression of Inflammatory Bowel Disease to Colorectal Cancer in an Experimental Mouse Model.
Inflammatory bowel disease (IBD) is characterized by chronic inflammation, which can progress to colorectal cancer, with duration of disease being the most important risk factor. Although many factors are involved, the pathogenic link between inflammation and cancer and the role played by the lymphatic system have not been fully investigated. This project uses lymphatic-deficient mice (Angiopoietin-2 [Ang2] knockout) to examine the lymphatic system in the progression of IBD to colorectal cancer. Angiopoietin-2 wild-type, heterozygote, and knockout mice received a single injection of the procarcinogen azoxymethane and had an IBD-promoting chemical irritant (dextran sodium sulfate) added to their drinking water over a 7-week period. We measured disease activity (weight loss, stool consistency, fecal occult blood) during the study and at sacrifice, collected blood for cytokine/biomarker (Ang2, interleukin [IL] 1-β, IL-6, tumor necrosis factor α [TNFα], and VEGF-C) enzyme-linked immunosorbent assay analysis, measured colon length, and assessed tumor burden. Ang2 knockout (KO) mice exhibited reduced (55%) survival vs wild-type (100%) and heterozygotes (91%; P < 0.01 and P < 0.0001, respectively). Most (>89%) mice developed tumors, and the incidence of colorectal cancer did not differ among the genotypes (P = 0.32). The tumor area was significantly increased in KO mice (P = 0.004). Of the biomarkers measured in the serum, Ang2 and TNF-α concentrations were significantly different among the genotypes (P = 3.35e-08 and P = 0.003 respectively). Disease activity was significantly increased in KO mice compared with wild-type and heterozygote mice (P = 0.033). Lymphatic deficiency, defective lymphangiogenesis, and impaired lymphatic-generated inflammation did not protect against clinical IBD or progression to colorectal cancer in this experimental model.


How OBRA admission rules affect nursing facilities.
Because of disclosure requirements contained in the Omnibus Budget Reconciliation Act of 1987, nursing facilities should review their admission agreement documents. The new rules become effective on Oct. 1 and cover resident rights, rules of conduct, and other expectations during a nursing home stay. Information contained in admission agreements, along with any changes, must be given to residents orally and in writing.


Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures.
It is uncertain whether or how rapidly elderly women continue to lose bone with advancing age. To determine rates of change in bone mass at the hip and at the calcaneus in elderly women and to compare these rates of change among estrogen users and nonusers, we prospectively measured rates of change in bone mineral density (BMD) at the total hip and its four subregions (mean +/- SD, 3.55 +/- 0.29 years between examinations) and at the calcaneus (mean +/- SD, 5.69 +/- 0.33 years between examinations) in 5689 community-dwelling white women aged 65 years or older at the baseline examination. The rate of decline in total hip BMD steadily increased from 2.5 mg/cm 2/year (95% confidence interval 2.0 to 2.9) in women 67-69 years old to 10.4 mg/cm 2/year in those aged 85 or older (95% confidence interval 8.4 to 12.4). The rate of bone loss also increased with aging at all subregions of the hip and at the calcaneus. The average loss of bone from the total hip is sufficient to increase the risk of hip fracture by 21% per 5 years in women aged 80 years or older. Compared with nonusers, current estrogen users had a 33% lower age-adjusted mean rate of loss at the total hip (2.9 vs 4.3 mg/cm 2/year, p < or = 0.0001) and a 35% lower age-adjusted mean rate of loss at the calcaneus (3.9 vs 6.0 mg/cm 2/year, p < or = 0.0001). The rate of bone loss in the hip and calcaneus steadily increases with advancing age in older women. Estrogen therapy may significantly decrease this loss. Efforts to understand and prevent bone loss should include elderly women.


Vitamin B 12 and the macromolecular composition of Euglena. II. Recovery from unbalanced growth induced by Vitamin B 12 deficiency.
When vitamin B(12) is added to B(12)-deficient cultures of Euglena gracilis, the cells undergo two relatively synchronous cell divisions within a shorter than usual period of time, apparently as a result of a transitory shortening of the cell cycle. The first cell division pulse, occurring 4.5 h after addition of B(12), is preceded by the completion of DNA duplication, but appears to involve no net synthesis of RNA or protein. Before the second round of cell division at about 11 h, a significant amount of DNA synthesis is observed. This time it is accompanied by a minor increase in the RNA and protein content of the culture. The cellular contents of RNA and protein were observed to decrease steadily after the resumption of cell division in B(12)-depleted cultures receiving the vitamin. Ultimately all three macromolecules returned to their nondeficient, plateau stage levels; by this time, cell division had ceased.


Effects of vitamin E on the blastogenic response of splenocytes and lipofuscin contents in the hearts and brains of aged mice.
Semipurified diets containing 30 or 500 ppm of dl-alpha-tocopherol (VE) were fed for 12 weeks to young (3-month-old) and old (20-month-old) Swiss mice. We measured the blastogenic response of splenocytes, the serum VE, and the lipofuscin levels in brains and hearts. We found that old mice fed with 500 ppm VE diet had a significantly higher serum VE level and blastogenic response of splenocytes to concanavalin-A (ConA) and lipopolysaccharide (LPS) than those fed with 30 ppm VE diet (p < 0.01). However, the lipofuscin level in the brains and hearts of aged mice declined substantially with the VE supplementation (heart: p < 0.001, brain: p < 0.05). Furthermore, the effects of dietary VE on the serum VE and tissue lipofuscin content in aged mice were much more obvious than in the young animals.


RAS-MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma.
Mutations affecting the RAS-MAPK pathway frequently occur in relapsed neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis, we generated several model systems to define a neuroblastoma RAS-MAPK pathway signature. Activation of this pathway in primary tumors indeed correlated with poor survival and was associated with known activating mutations in ALK and other RAS-MAPK pathway genes. Integrative analysis showed that mutations in PHOX2B, CIC, and DMD were also associated with an activated RAS-MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induced activation of the RAS-MAPK pathway. This activation was independent of phosphorylated ERK in CIC knockout systems. Furthermore, deletion of CIC caused a significant increase in tumor growth in vivo These results show that the RAS-MAPK pathway is involved in tumor progression and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.Significance: This work identifies CIC as a powerful tumor suppressor affecting the RAS-MAPK pathway in neuroblastoma and reinforces the importance of mutation-driven activation of this pathway in cancer. Cancer Res; 78(21); 6297-307. ©2018 AACR.


Systematic detection of polygenic cis-regulatory evolution.
The idea that most morphological adaptations can be attributed to changes in the cis-regulation of gene expression levels has been gaining increasing acceptance, despite the fact that only a handful of such cases have so far been demonstrated. Moreover, because each of these cases involves only one gene, we lack any understanding of how natural selection may act on cis-regulation across entire pathways or networks. Here we apply a genome-wide test for selection on cis-regulation to two subspecies of the mouse Mus musculus. We find evidence for lineage-specific selection at over 100 genes involved in diverse processes such as growth, locomotion, and memory. These gene sets implicate candidate genes that are supported by both quantitative trait loci and a validated causality-testing framework, and they predict a number of phenotypic differences, which we confirm in all four cases tested. Our results suggest that gene expression adaptation is widespread and that these adaptations can be highly polygenic, involving cis-regulatory changes at numerous functionally related genes. These coordinated adaptations may contribute to divergence in a wide range of morphological, physiological, and behavioral phenotypes.


Irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis.
Renal failure is a rare complication of neuroblastoma or its therapy. To our knowledge, no reports describe treatment of children with neuroblastoma with chemotherapy in the setting of renal failure and maintenance hemodialysis. We report a 6-year-old child with high-risk neuroblastoma who developed renal failure requiring long-term hemodialysis. She was subsequently treated with 13 cycles of intravenous irinotecan 20 mg/m(2)/day and oral temozolomide 100 mg/m(2)/day for 5 days before disease progression without any dose adjustments, transfusions, febrile neutropenia or diarrhea. This case demonstrates that irinotecan and temozolomide can be safely administered in children with renal failure requiring hemodialysis.


Platelet-rich therapy in the treatment of patients with hip fractures: a single centre, parallel group, participant-blinded, randomised controlled trial.
To quantify and draw inferences on the clinical effectiveness of platelet-rich therapy in the management of patients with a typical osteoporotic fracture of the hip. Single centre, parallel group, participant-blinded, randomised controlled trial. UK Major Trauma Centre. 200 of 315 eligible patients aged 65 years and over with any type of intracapsular fracture of the proximal femur. Patients were excluded if their fracture precluded internal fixation. Participants underwent internal fixation of the fracture with cannulated screws and were randomly allocated to receive an injection of platelet-rich plasma into the fracture site or not. Failure of fixation within 12 months, defined as any revision surgery. Primary outcome data were available for 82 of 101 and 78 of 99 participants allocated to test and control groups, respectively; the remainder died prior to final follow-up. There was an absolute risk reduction of 5.6% (95% CI -10.6% to 21.8%) favouring treatment with platelet-rich therapy (χ(2) test, p=0.569). An adjusted effect estimate from a logistic regression model was similar (OR=0.71, 95% CI 0.36 to 1.40, z test; p=0.325). There were no significant differences in any of the secondary outcome measures excepting length of stay favouring treatment with platelet-rich therapy (median difference 8 days, Mann-Whitney U test; p=0.03). The number and distribution of adverse events were similar. Estimated cumulative incidence functions for the competing events of death and revision demonstrated no evidence of a significant treatment effect (HR 0.895, 95% CI 0.533 to 1.504; p=0.680 in favour of platelet-rich therapy). No evidence of a difference in the risk of revision surgery within 1 year in participants treated with platelet-rich therapy compared with those not treated. However, we cannot definitively exclude a clinically meaningful difference. Current Controlled Trials, ISRCTN49197425, http://www.controlled-trials.com/ISRCTN49197425.


Toxins and secretion systems of Photorhabdus luminescens.
Photorhabdus luminescens is a nematode-symbiotic, gram negative, bioluminescent bacterium, belonging to the family of Enterobacteriaceae. Recent studies show the importance of this bacterium as an alternative source of insecticides, as well as an emerging human pathogen. Various toxins have been identified and characterized in this bacterium. These toxins are classified into four major groups: the toxin complexes (Tcs), the Photorhabdus insect related (Pir) proteins, the "makes caterpillars floppy" (Mcf) toxins and the Photorhabdus virulence cassettes (PVC); the mechanisms however of toxin secretion are not fully elucidated. Using bioinformatics analysis and comparison against the components of known secretion systems, multiple copies of components of all known secretion systems, except the ones composing a type IV secretion system, were identified throughout the entire genome of the bacterium. This indicates that Photorhabdus luminescens has all the necessary means for the secretion of virulence factors, thus it is capable of establishing a microbial infection.


Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei.
Based on crystal structures of Trypanosoma brucei methionyl-tRNA synthetase (TbMetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel TbMetRS inhibitors targeting this parasite enzyme. One series has a 1,3-dihydro-imidazol-2-one containing linker, the other has a rigid fused aromatic ring in the linker. For both series of compounds, potent inhibition of parasite growth was achieved with EC50 < 10 nM and most compounds exhibited low general toxicity to mammalian cells with CC50s > 20 000 nM. Selectivity over human mitochondrial methionyl tRNA synthetase was also evaluated, using a cell-based mitochondrial protein synthesis assay, and selectivity in a range of 20-200-fold was achieved. The inhibitors exhibited poor permeability across the blood brain barrier, necessitating future efforts to optimize the compounds for use in late stage human African trypanosomiasis.


Impact of the olefin structure on the catalytic cycle and decomposition rates of Hoveyda-Grubbs metathesis catalysts.
A relatively fast degradation of ruthenium catalysts in the presence of selected olefins, and ethylene in particular, is one of the bottlenecks in their use in metathesis reactions. Here we explore the structure-activity relationships between the rate of degradation of Hoveyda-Grubbs catalysts and the structure of olefins by means of DFT calculations. We show that (Z)-1,2-dichloroethene can't form stable complexes with a 14-electron active complex due to a strong inductive electron withdrawal effect. Hoveyda-Grubbs catalysts can be, however, used to convert (Z)-1,2-dichloroethene to (E)-1,2-dichloroethene due to differences in crucial barriers in the catalytic cycle for E/Z isomers. Hoveyda-Grubbs catalysts in the presence of both isomers of 1,2-dimethoxyethene and 1,2-dichloroethene are predicted to be very stable in the unproductive metathesis, while for monosubstituted olefins the methoxyethene presence gives relatively low barriers for crucial degradation transition states and can readily undergo decomposition.


Ultrafast and Broad-Band Graphene Heterojunction Photodetectors with High Gain.
Graphene possesses an exotic band structure that spans a wide range of important technological wavelength regimes for photodetection, all within a single material. Conventional methods aimed at enhancing detection efficiency often suffer from an extended response time when the light is switched off. The task of achieving ultrafast broad-band photodetection with a high gain remains challenging. Here, we propose a devised architecture that combines graphene with a photosensitizer composed of an alternating strip superstructure of WS2-WSe2. Upon illumination, n+-WS2 and p+-WSe2 strips create alternating electron- and hole-conduction channels in graphene, effectively overcoming the tradeoff between the responsivity and switch time. This configuration allows for achieving a responsivity of 1.7 × 107 mA/W, with an extrinsic response time of 3-4 μs. The inclusion of the superstructure booster enables photodetection across a wide range from the near-ultraviolet to mid-infrared regime and offers a distinctive photogating route for high responsivity and fast temporal response in the pursuit of broad-band detection.


Interaction of related Tn916-like transposons: analysis of excision events promoted by Tn916 and Tn5386 integrases.
In recent work, we described the excision of a large genomic region from Enterococcus faecium D344R in which the sequence from "joint" regions suggested that excision resulted from the interaction of conjugative transposon Tn916 and the related mobile element Tn5386. In the present study, we examined the ability of integrases and integrase-excisase combinations from Tn916 and Tn5386 to promote the excision of constructs consisting of the termini of Tn916, Tn5386, and the VanB mobile element Tn5382. Integrases alone from either Tn916 or Tn5386 promoted the circularization of constructs from the three different transposons, even when the different termini used in the constructs were discordant in their transposon of origin. The termini of Tn916 and Tn5382 found in all joints were consistent with previously identified Tn916 and Tn5382 termini. Substantial variation was seen in the integrase terminus of Tn5386 used to form joints, regardless of the integrase that was responsible for circularization. Variability was observed in joints formed from Tn5386 constructs, in contrast to joints observed with the termini of Tn916 or Tn5382. The coexpression of excisase yielded some variability in the joint regions observed. These data confirm that integrases from some Tn916-like elements can promote circularization with termini derived from heterologous transposons and, as such, could promote excision of large genomic regions flanked by such elements. These findings also raise interesting questions about the sequence specificities of the C terminals of Tn916-like integrases, which bind to the ends and facilitate strand exchange.


An archaeal origin for the actin cytoskeleton: Implications for eukaryogenesis.
A hallmark of the eukaryotic cell is the actin cytoskeleton, involved in a wide array of processes ranging from shape determination and phagocytosis to intracellular transport and cytokinesis. Recently, we reported the discovery of an actin-based cytoskeleton also in Archaea. The archaeal actin ortholog, Crenactin, was shown to belong to a conserved operon, Arcade (actin-related cytoskeleton in Archaea involved in shape determination), encoding an additional set of cytoskeleton-associated proteins. Here, we elaborate on the implications of these findings for the evolutionary relation between archaea and eukaryotes, with particular focus on the possibility that eukaryotic actin and actin-related proteins have evolved from an ancestral archaeal actin gene. Archaeal actin could thus have played an important role in cellular processes essential for the origin and early evolution of the eukaryotic lineage. Further exploration of uncharacterized archaeal lineages is necessary to find additional missing pieces in the evolutionary trajectory that ultimately gave rise to present-day organisms.


Effect of prehospital advanced life support on outcomes of major trauma patients.
Determine whether prehospital advanced life support (ALS) improves the survival of major trauma patients and whether it is associated with longer on-scene times. A 36-month retrospective study of all major trauma patients who received either prehospital bag-valve-mask (BVM) or endotracheal intubation (ETI) and were transported by paramedics to our Level I trauma center. Logistic regression analysis determined the association of prehospital ALS with patient survival. Of 9,451 major trauma patients, 496 (5.3%) had either BVM or ETI. Eighty-one percent received BVM, with a mean Injury Severity Score of 29 and a mortality rate of 67%; 93 patients (19%) underwent successful ETI, with a mean Injury Severity Score of 35 and a mortality rate of 93%. Adjusted survival for patients who had BVM was 5.3 times more likely than for patients who had ETI (95% confidence interval, 2.3-14.2, p = 0.00). Survival among patients who received intravenous fluids was 3.9 times more likely than those who did not (p = not significant). Average on-scene times for patients who had ETI or intravenous fluids were not significantly longer than those who had BVM or no intravenous fluids. ALS procedures can be performed by paramedics on major trauma patients without prolonging on-scene time, but they do not seem to improve survival.


Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.
Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses. The purpose of this work was to investigate structural analogues of Pyr to improve its in vitro and cellular activity. A series of 36 Pyr analogues were synthesized and tested in a sequence of in vitro and cell-based assays to monitor their DHFR inhibitory activity, cellular target engagement, and impact on breast cancer cell viability. Ten top compounds were identified, two of which stood out as potential lead candidates, 32 and 34. These functionalized Pyr analogues potently engaged DHFR in cells, at concentrations as low as 1 nM and represent promising DHFR inhibitors that could be further explored as potential anti-cancer agents.


Music training enhances the automatic neural processing of foreign speech sounds.
Growing evidence shows that music and language experience affect the neural processing of speech sounds throughout the auditory system. Recent work mainly focused on the benefits induced by musical practice on the processing of native language or tonal foreign language, which rely on pitch processing. The aim of the present study was to take this research a step further by investigating the effect of music training on processing English sounds by foreign listeners. We recorded subcortical electrophysiological responses to an English syllable in three groups of participants: native speakers, non-native nonmusicians, and non-native musicians. Native speakers had enhanced neural processing of the formant frequencies of speech, compared to non-native nonmusicians, suggesting that automatic encoding of these relevant speech cues are sensitive to language experience. Most strikingly, in non-native musicians, neural responses to the formant frequencies did not differ from those of native speakers, suggesting that musical training may compensate for the lack of language experience by strengthening the neural encoding of important acoustic information. Language and music experience seem to induce a selective sensory gain along acoustic dimensions that are functionally-relevant-here, formant frequencies that are crucial for phoneme discrimination.


Salmonella typhimurium mutagenicity tester strains that overexpress oxygen-insensitive nitroreductases nfsA and nfsB.
We have designed and constructed a series of plasmids that contain the major and/or minor Escherichia coli nitroreductase genes, nfsA and nfsB, in different combinations with R plasmid mucA/B genes and the Salmonella typhimurium OAT gene. The plasmid encoded gene products are necessary for both the metabolic activation of a range of structurally diverse nitrosubstituted compounds, and for mutagenic translation bypass. Introduction of these plasmids into S. typhimurium TA1538 and TA1535 has created several new tester strains which exhibit an extremely high mutagenic sensitivity and a broad substrate specificity towards a battery of nitrosubstituted test compounds that included 4-nitroquinoline-1-oxide (4-NQO), nitrofurazone (NF), 1-nitropyrene (1-NP), 2-nitronaphthalene (2-NN), 2-nitrofluorene (2-NF), and 1,6-dinitropyrene (1,6-DNP). Our studies show that the nfsA gene encodes a product that is extremely effective in the metabolic activation of a range of structurally diverse nitrosubstituted compounds. Several of the new tester strains are more than two orders of magnitude more sensitive to nitrosubstituted compounds than the Ames tester strains TA100 or TA98. In addition to enhancing mutagenic sensitivity, plasmids encoding both metabolic and mutagenesis functions on a single plasmid provide considerable flexibility for future mechanistic studies or tester strain development, in which it may be necessary to introduce additional plasmids containing different antibiotic resistance markers.


Investigation outcomes of tuberculosis suspects in the health centers of Addis Ababa, Ethiopia.
Little is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia. In the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have > = 2 weeks symptoms of TB such as cough, fever and weight loss. Diagnosis of TB and HIV was based on the national guidelines. Information concerning socio-demographic variables and knowledge of the respondents about TB was collected using pretested questionnaire. Of the 545 TB suspects, 506 (92.7%) of them participated in the study. The prevalence of both pulmonary and extra pulmonary TB was 46.0% (233/506). The smear positivity rate among pulmonary TB suspect was 21.3%. Of the TB suspects, 298 (58.9%) of them were tested for HIV and 27.2% (81/298) were HIV seropositive. Fifty percent of the HIV positive TB suspects had TB. TB suspects who had a contact history with a TB patient in the family were 9 times more likely to have TB than those who did not have a contact history, [OR = 9.1, (95%CI:4.0, 20.5)]. Individuals who had poor [OR = 5.2, (95%CI: 2.3, 11.2)] and fair knowledge [OR = 3.7, (95%CI: 1.3, 10.4)] about TB were more likely to have TB than individuals who had good knowledge. In conclusion, the prevalence of TB among TB suspects with duration of 2 or more weeks is high. Fifty percent of the HIV positive TB suspects had TB. Case finding among TB suspects with duration of 2 or more weeks should be intensified particularly among those who have a contact history with a TB patient.


Impact of community health workers on improving identification and primary care of hypertension among the urban poor - findings from Chhattisgarh state of India.
Hypertension is a major health problem globally and in India. Around 60% of people with hypertension in India are not aware that they have the condition. Less than 30% of individuals with hypertension are on treatment. Existing studies have indicated that community health workers (CHWs) can play a useful role in expanding the care for hypertension. Evaluations are needed to study the impact when an intervention is implemented by the government in its existing large-scale CHW programme to improve the identification, regular follow-up and medication adherence for hypertension. Chhattisgarh state implemented a pilot intervention to improve screening and follow-up for hypertension by equipping Mitanin-CHWs to measure blood pressure (BP). The study design involved an intervention-group and a comparison-group of urban slum population. The survey covered 5974 individuals (30-79 years age) in intervention-group and 5131 in comparison-group. Multivariate analysis was conducted to find out the effect of intervention on the desired outcomes. In intervention-group, 80.2% of the individuals (30-79 years age) had been screened for hypertension whereas the proportion was 37.9% in comparison-group. For 47.0% of individuals in intervention-group, Mitanin CHW was the provider who measured BP for the first time. Around 16.3% of individuals in intervention-group and 9.5% in comparison-group had been diagnosed with hypertension. Around 85.9% of hypertension cases in intervention-group and 77.0% in comparison-group were on treatment. BP had been measured in preceding 30 days for 81.8% of hypertension-cases in intervention-group and 64.3% in comparison-group. Around 70.3% of hypertension-cases in intervention-group and 55.1% in comparison-group had taken their complete medication for last seven days. Multivariate analysis showed that CHW intervention was associated significantly with improvements in all the desired outcomes. Equipping the CHWs to measure BP was effective in increasing the screening and identification of hypertension, regular measurement of BP of individuals with hypertension and the adherence to medication. This shows the potential if the one-million strong work-force of Accredited-Social-Health-Activists (ASHA) CHWs in India gets equipped for this role. Governments need to provide a stronger policy push to get this materialised.


Increased brain serotonin synthesis in migraine.
To measure brain serotonin synthesis with PET using the tracer alpha-[11C]methyl-L-tryptophan in migraine patients. Although the cause of migraine remains poorly understood, there is considerable evidence to support a role of the neurotransmitter serotonin in the pathophysiology of migraine. We studied 11 women (aged 33+/-7.7 years) with a diagnosis of migraine according to International Headache Society criteria and 8 healthy women (aged 29+/-9.2 years). Five patients were studied before and after chronic treatment with propranolol or nadolol. Serotonin synthesis capacity (K-complex) values in migraine patients were higher than those measured in controls throughout the brain (p = 0.016); mean K-complex for whole brain was 0.0077 + 0.0020 mL/g/min in patients with migraine and 0.0054+/-0.0003 mL/g/min in controls. The regional pattern did not differ between the two groups. However, the K-complex for whole brain in the subgroup of migraine patients with aura (n = 3) did not differ from that of the control group (p = 0.32). In the five patients studied twice (before and after treatment), we found a trend of increased whole-brain K-complex after drug treatment (p = 0.06). Our findings indicating increased brain serotonin synthesis capacity in migraine patients are consistent with previous reports of systemic alteration of serotonin metabolism in patients without aura. Our results also suggest that the mechanism of action of beta-adrenergic antagonists for migraine prophylaxis may involve regulation of serotonin synthesis.