Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrix-associated gene modules.
Recent molecular characterization studies have identified clinically relevant molecular subtypes to coexist within the same histological entities of glioma. Comparative studies between serum-supplemented and serum-free (SF) culture conditions have demonstrated that SF conditions select for glioma stem-like cells, which superiorly conserve genomic alterations. However, neither the representation of molecular subtypes within SF culture assays nor the molecular distinctions between successful and nonsuccessful attempts have been elucidated. A cohort of 261 glioma samples from varying histological grades was documented for SF culture success and clinical outcome. Gene expression and single nucleotide polymorphism arrays were interrogated on a panel of tumors for comparative analysis of SF+ (successful cultures) and SF- (unsuccessful cultures). SF culture outcome was correlated with tumor grade, while no relation was found between SF+ and patient overall survival. Copy number-based hierarchical clustering revealed an absolute separation between SF+ and SF- parental tumors. All SF+ cultures are derived from tumors that are isocitrate dehydrogenase 1 (IDH1) wild type, chromosome 7 amplified, and chromosome 10q deleted. SF- cultures derived from IDH1 mutant tumors demonstrated a fade-out of mutated cells during the first passages. SF+ tumors were enriched for The Cancer Genome Atlas Classical subtype and intrinsic glioma subtype-18. Comparative gene ontology analysis between SF+ and SF- tumors demonstrated enrichment for modules associated with extracellular matrix composition, Hox-gene signaling, and inflammation. SF cultures are derived from a subset of parental tumors with a shared molecular background including enrichment for extracellular matrix-associated gene modules. These results provide leads to develop enhanced culture protocols for glioma samples not propagatable under current SF conditions.


Different interface orientations of pentacene and PTCDA induce different degrees of disorder.
: Organic polymers or crystals are commonly used in manufacturing of today's electronically functional devices (OLEDs, organic solar cells, etc). Understanding their morphology in general and at the interface in particular is of paramount importance. Proper knowledge of molecular orientation at interfaces is essential for predicting optoelectronic properties such as exciton diffusion length, charge carrier mobility, and molecular quadrupole moments. Two promising candidates are pentacene and 3,4:9,10-perylenetetracarboxylic dianhydride (PTCDA). Different orientations of pentacene on PTCDA have been investigated using an atomistic molecular dynamics approach. Here, we show that the degree of disorder at the interface depends largely on the crystal orientation and that more ordered interfaces generally suffer from large vacancy formation.


European Guidelines for Obesity Management in Adults.
Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patient's obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management.


Optimizing the motion of a folding molecular motor in soft matter.
We use molecular dynamics simulations to investigate the displacement of a periodically folding molecular motor in a viscous environment. Our aim is to find significant parameters to optimize the displacement of the motor. We find that the choice of a massy host or of small host molecules significantly increase the motor displacements. While in the same environment, the motor moves with hopping solid-like motions while the host moves with diffusive liquid-like motions, a result that originates from the motor's larger size. Due to hopping motions, there are thresholds on the force necessary for the motor to reach stable positions in the medium. These force thresholds result in a threshold in the size of the motor to induce a significant displacement, that is followed by plateaus in the motor displacement.


Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant Hep G2 cells through a mitochondria-dependent oxidative stress mechanism.
Sorafenib (Nexavar, BAY43-9006), a bi-arylurea, is a newly established anti-cancer drug and its functional attribute of cytotoxicity is based on the multi-kinase inhibitory action. Here, we report yet another novel pathway in which sorafenib can induce apoptotic cell death preferentially and efficaciously on an experimentally proven drug- and radio-resistant human Hep G2 cells via a mitochondria-dependent oxidative stress mechanism. A real time confocal imaging assay revealed that sorafenib could rapidly provoke the production of ROS plethorically, mainly concentrating in the mitochondria, albeit substantial amounts of ROS could also be detected in cytosol and nucleus. The rapid production of ROS could simultaneously induce intracellular glutathione (iGSH) depletion. A nearly 90% of iGSH was found to be depleted in 1h period after the cells received the drug treatment. Besides mitochondria, iGSH depletion could also be detected in other cellular compartment including cytoplasm and nucleus. Interestingly, we also demonstrated that sorafenib could trigger mitochondrial Ca(2+) overload. All these events compoundedly serve as the final arbitrator to initiate lethal apoptotic process through the release of cytochrome c and caspase 3/7 activation. Collectively, we provide first evidence here that sorafenib can provoke an alternative pathway for apoptosis induction of Hep G2 cells through a mitochondria-dependent oxidative stress mechanism which is independent of original kinase inhibitory attribute of the drug action. Most importantly, we also demonstrate that sorafenib can effectively eradicate a highly drug- and radio-resistant HCC cells. Thus, our data can provide the basis for a potential applicability of sorafenib in a combined treatment modality.


Computational modelling for decision-making: where, why, what, who and how.
In order to deal with an increasingly complex world, we need ever more sophisticated computational models that can help us make decisions wisely and understand the potential consequences of choices. But creating a model requires far more than just raw data and technical skills: it requires a close collaboration between model commissioners, developers, users and reviewers. Good modelling requires its users and commissioners to understand more about the whole process, including the different kinds of purpose a model can have and the different technical bases. This paper offers a guide to the process of commissioning, developing and deploying models across a wide range of domains from public policy to science and engineering. It provides two checklists to help potential modellers, commissioners and users ensure they have considered the most significant factors that will determine success. We conclude there is a need to reinforce modelling as a discipline, so that misconstruction is less likely; to increase understanding of modelling in all domains, so that the misuse of models is reduced; and to bring commissioners closer to modelling, so that the results are more useful.


Missing the meaning and provoking resistance; a case of myalgic encephalomyelitis.
The interaction between a clinician and a patient who put his problems down to myalgic encephalomyelitis is described. Despite attempting a patient-centred approach, the doctor acted on his own understanding of the meaning of this diagnosis without gaining proper insight into what it meant for the patient. This failure not only led to damaged rapport, it may have contributed to delayed recovery. The unsatisfactory nature of this encounter led the clinician to consider more effective consulting techniques. A hypothetical interaction is constructed in which the clinician uses reflective listening statements to understand the patient's true meaning of this self-diagnosis. Despite well intentioned attempts to be patient-centered through widening the consultation beyond the biomedical to include personal and contextual factors, clinicians may still end up imposing their own medical meaning on patient's words. Damaged rapport is a signal that another track could be more fruitful and reflective listening is one strategy which enables clinicians to check that they fully understand the patient's meaning. Provoking resistance by following strategies which are not appropriate for the patient might then be avoided.


Introducing random safety audits (RSA) in a neonatal intensive care unit (NICU).
Random safety audits (RSA) have been shown to be effective in improving standards of clinical practice. 19 data collection audits were performed relating to hygiene, safe prescribing, oxygen pulse oximetry monitoring and documentation in keeping with the requirements of the new Medical Practitioners Act (MPA) 2007. Hygiene audits (range from 20/25 to 21/21 80%-100%) and safe prescribing audits (range from 23/25 to 25/25 86%-100%) achieved n=25 100% compliance with unit guidelines over a 3 month period. Compliance with oxygen pulse oximetry monitoring guideline limits improved from 4/27 (15%) to 9/16 (56%). Compliance with requirement and use of Physician IMC registration number in documentation was only 10/18 (56%). RSA's led to improvements in hygiene and prescribing. Compliance with oxygen monitoring guideline limits highlighted the need for greater education. Awareness of legal requirements relating to documentation improved but this has not translated into a change in practice. RSA's can facilitate real time quality improvement in daily clinical practice.


Management of hidradenitis suppurativa in pregnancy.
Hidradenitis suppurativa is a debilitating inflammatory skin disease with a chronic course and often disappointing response to treatment. Though a minority of persons (20%) reports symptom remission during pregnancy, the vast majority experiences no relief (72%), and few experience clinical deterioration (8%). Disease flares are also observed post-partum. The pathophysiological basis for pregnancy-associated fluctuations in clinical status is currently unknown. Because most women with HS require ongoing management throughout pregnancy, it is important to evaluate the suitability and safety of current treatment options for pregnant women. The following review will outline current management strategies for HS and their compatibility with pregnancy and lactation.


Impact of Economic Constraints on Public Health Delivery Systems Structures.
We estimated the effect of economic constraints on public health delivery systems (PHDS) density and centrality during 3 time periods, 1998, 2006, and 2012. We obtained data from the 1998, 2006, and 2012 National Longitudinal Study of Public Health Agencies; the 1993, 1997, 2005, and 2010 National Association for County and City Health Officials Profile Study; and the 1997, 2008, and 2011 Area Resource Files. We used multivariate regression models for panel data to estimate the impact of economic constraints on PHDS density and centrality. Findings indicate that economic constraints did not have a significant impact on PHDS density and centrality over time but population is a significant predictor of PHDS density, and the presence of a board of health (BOH) is a significant predictor of PHDS density and centrality. Specifically, a 1% increase in population results in a significant 1.71% increase in PHDS density. The presence of a BOH is associated with a 10.2% increase in PHDS centrality, after controlling for other factors. These findings suggest that other noneconomic factors influence PHDS density centrality.


Predicting postoperative astigmatism using Scheimpflug keratometry (Pentacam) and automated keratometry (IOLMaster).
To compare keratometry measurements obtained using an automated keratometer (AK, IOLMaster) and a Scheimpflug keratometer (Pentacam) in predicting residual astigmatism after cataract surgery. Preoperative corneal astigmatism was calculated using preoperative refraction, an AK and a Scheimpflug keratometer (anterior corneal power [ACP] and true net power [TNP]) in 155 eyes of 107 Asian subjects. Phacoemulsification cataract removal and nontoric intraocular lens insertion (Akreos(®)MI-60™, Bausch & Lomb, Rochester, NY, USA) were performed through a 2.8 mm temporal clear corneal incision. Six months later, postoperative astigmatism (postA) was calculated using manifest refraction. Error angle (EA) and error magnitude (EM) of above keratometries (AK, ACP, and TNP) in prediction of postA was calculated. The correlation between preoperative astigmatism and postA was analyzed using power vectors (J(0) and J(45)). AK resulted in the lowest EM and ACP resulted in the lowest EA. Preoperative astigmatism (preA) measured using AK, ACP, and TNP showed significant correlation with postA in both J(0) and J(45) components. (AK: rJ(0) = 0.554, rJ(45) = 0.559, ACP: rJ(0) = 0.346, rJ(45) = 0.281, TNP: rJ(0) = 0.409, rJ(45) = 0.231). Preoperative refractive astigmatism showed no significant correlation in any components. PreA determined using AK showed superior performance in prediction of postA than ACP and TNP.


Nanocomposite Furcellaran Films-the Influence of Nanofillers on Functional Properties of Furcellaran Films and Effect on Linseed Oil Preservation.
Nanocomposite films that were based on furcellaran (FUR) and nanofillers (carbon quantum dots (CQDs), maghemite nanoparticles (MAN), and graphene oxide (GO)) were obtained by the casting method. The microstructure, as well as the structural, physical, mechanical, antimicrobial, and antioxidant properties of the films was investigated. The incorporation of MAN and GO remarkably increased the tensile strength of furcellaran films. However, the water content, solubility, and elongation at break were significantly reduced by the addition of the nanofillers. Moreover, furcellaran films containing the nanofillers exhibited potent free radical scavenging ability. FUR films with CQDs showed an inhibitory effect on the growth of Staphylococcus aureus and Escherichia coli. The nanocomposite films were used to cover transparent glass containers to study the potential UV-blocking properties in an oil oxidation test and compare with tinted glass. The samples were irradiated for 30 min. with UV-B and then analyzed for oxidation markers (peroxide value, free fatty acids, malondialdehyde content, and degradation of carotenoids). The test showed that covering the transparent glass with MAN films was as effective in inhibiting the oxidation as the use of tinted glass, while the GO and CQDs films did not inhibit oxidation. It can be concluded that the active nanocomposite films can be used as a desirable material for food packaging.


Distinct substrate specificities of three glycoside hydrolase family 42 β-galactosidases from Bifidobacterium longum subsp. infantis ATCC 15697.
Glycoside hydrolase family 42 (GH42) includes β-galactosidases catalyzing the release of galactose (Gal) from the non-reducing end of different β-d-galactosides. Health-promoting probiotic bifidobacteria, which are important members of the human gastrointestinal tract microbiota, produce GH42 enzymes enabling utilization of β-galactosides exerting prebiotic effects. However, insight into the specificity of individual GH42 enzymes with respect to substrate monosaccharide composition, glycosidic linkage and degree of polymerization is lagging. Kinetic analysis of natural and synthetic substrates resembling various milk and plant galactooligosaccharides distinguishes the three GH42 members, Bga42A, Bga42B and Bga42C, encoded by the probiotic B. longum subsp. infantis ATCC 15697 and revealed the glycosyl residue at subsite +1 and its linkage to the terminal Gal at subsite -1 to be key specificity determinants. Bga42A thus prefers the β1-3-galactosidic linkage from human milk and other β1-3- and β1-6-galactosides with glucose or Gal situated at subsite +1. In contrast, Bga42B very efficiently hydrolyses 4-galactosyllactose (Galβ1-4Galβ1-4Glc) as well as 4-galactobiose (Galβ1-4Gal) and 4-galactotriose (Galβ1-4Galβ1-4Gal). The specificity of Bga42C resembles that of Bga42B, but the activity was one order of magnitude lower. Based on enzyme kinetics, gene organization and phylogenetic analyses, Bga42C is proposed to act in the metabolism of arabinogalactan-derived oligosaccharides. The distinct kinetic signatures of the three GH42 enzymes correlate to unique sequence motifs denoting specific clades in a GH42 phylogenetic tree providing novel insight into GH42 subspecificities. Overall, the data illustrate the metabolic adaptation of bifidobacteria to the β-galactoside-rich gut niche and emphasize the importance and diversity of β-galactoside metabolism in probiotic bifidobacteria.


Age- and strain-related aberrant Ca2+ release is associated with sudden cardiac death in the ACTC E99K mouse model of hypertrophic cardiomyopathy.
Patients with hypertrophic cardiomyopathy, particularly young adults, can die from arrhythmia, but the mechanism underlying abnormal rhythm formation remains unknown. C57Bl6 × CBA/Ca mice carrying a cardiac actin ( ACTC) E99K (Glu99Lys) mutation reproduce many aspects of human hypertrophic cardiomyopathy, including increased myofilament Ca2+ sensitivity and sudden death in a proportion (up to 40%) of young (28-40 day old) animals. We studied the hearts of transgenic (TG; ACTC E99K) mice and their non-TG (NTG) littermates when they were in their vulnerable period (28-40 days old) and when they were adult (8-12 wk old). Ventricular myocytes were isolated from the hearts of TG and NTG mice at these two time points. We also examined the hearts of mice that died suddenly (SCD). SCD animals had approximately four times more collagen compared with age-matched NTG mice, yet myocyte cell size was normal. Young TG mice had double the collagen content of NTG mice. Contraction and Ca2+ transients were greater in cells from young TG mice compared with their NTG littermates but not in cells from adult mice (TG or NTG). Cells from young TG mice had a greater propensity for Ca2+ waves than NTG littermates, and, despite similar sarcoplasmic reticulum Ca2+ content, a proportion of these cells had larger Ca2+ spark mass. We found that the probability of SCD in young TG mice was increased when the mutation was expressed in animals with a CBA/Ca2+ background and almost eliminated in mice bred on a C57Bl6 background. The latter TG mice had normal cellular Ca2+ homeostasis. NEW & NOTEWORTHY Mice with the actin Glu99Lys hypertrophic cardiomyopathy mutation ( ACTC E99K) are prone to sudden cardiac death around 40 days, associated with increased Ca2+ transients, spark mass, and fibrosis. However, adult survivors have normal Ca2+ transients and spark density accompanied by hypertrophy. Penetrance of the sudden cardiac death phenotype depends on the genetic background of the mouse. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/calcium-regulation-in-e99k-mouse-heart/ .


Stretching to prevent or reduce muscle soreness after exercise.
Many people stretch before or after engaging in athletic activity. Usually the purpose is to reduce risk of injury, reduce soreness after exercise, or enhance athletic performance. This is an update of a Cochrane review first published in 2007. The aim of this review was to determine effects of stretching before or after exercise on the development of delayed-onset muscle soreness. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to 10 August 2009), the Cochrane Central Register of Controlled Trials (2010, Issue 1), MEDLINE (1966 to 8th February 2010), EMBASE (1988 to 8th February 2010), CINAHL (1982 to 23rd February 2010), SPORTDiscus (1949 to 8th February 2010), PEDro (to 15th February 2010) and reference lists of articles. Eligible studies were randomised or quasi-randomised studies of any pre-exercise or post-exercise stretching technique designed to prevent or treat delayed-onset muscle soreness (DOMS). For the studies to be included, the stretching had to be conducted soon before or soon after exercise and muscle soreness had to be assessed. Risk of bias was assessed using The Cochrane Collaboration's 'Risk of bias' tool and quality of evidence was assessed using GRADE. Estimates of effects of stretching were converted to a common 100-point scale. Outcomes were pooled in fixed-effect meta-analyses. Twelve studies were included in the review. This update incorporated two new studies. One of the new trials was a large field-based trial that included 2377 participants, 1220 of whom were allocated stretching. All other 11 studies were small, with between 10 and 30 participants receiving the stretch condition. Ten studies were laboratory-based and other two were field-based. All studies were exposed to either a moderate or high risk of bias. The quality of evidence was low to moderate.There was a high degree of consistency of results across studies. The pooled estimate showed that pre-exercise stretching reduced soreness at one day after exercise by, on average, half a point on a 100-point scale (mean difference -0.52, 95% CI -11.30 to 10.26; 3 studies). Post-exercise stretching reduced soreness at one day after exercise by, on average, one point on a 100-point scale (mean difference -1.04, 95% CI -6.88 to 4.79; 4 studies). Similar effects were evident between half a day and three days after exercise. One large study showed that stretching before and after exercise reduced peak soreness over a one week period by, on average, four points on a 100-point scale (mean difference -3.80, 95% CI -5.17 to -2.43). This effect, though statistically significant, is very small. The evidence from randomised studies suggests that muscle stretching, whether conducted before, after, or before and after exercise, does not produce clinically important reductions in delayed-onset muscle soreness in healthy adults.


Electronic self-administered screening for substance use in adult primary care patients: feasibility and acceptability of the tobacco, alcohol, prescription medication, and other substance use (myTAPS) screening tool.
The TAPS Tool is a substance use screening and brief assessment instrument that was developed for use in primary care medical settings. It is one of the first screening instruments to provide rapid assessment of all commonly used substance classes, including illicit and prescription opioids, and is one of the only available screeners designed and validated in an electronic self-administered format (myTAPS). This secondary analysis of data from the TAPS Tool validation study describes the feasibility and acceptability of the myTAPS among primary care patients. Adult patients (N = 2000) from five primary care clinics completed the TAPS Tool on a tablet computer (myTAPS), and in an interviewer-administered format. Requests for assistance and time required were tracked, and participants completed a survey on ease of use, utilization of audio guidance, and format preference. Logistic regression was used to examine outcomes in defined subpopulations, including groups that may have greater difficulty completing an electronic screener, and those that may prefer an electronic self-administered approach. Almost all participants (98.3%) reported that the myTAPS was easy to use. The median time to complete myTAPS screening was 4.0 min (mean 4.48, standard deviation 2.57). More time was required by participants who were older, Hispanic, Black, or reported non-medical prescription drug use, while less time was required by women. Assistance was requested by 25% of participants, and was more frequently requested by those who with lower education (OR = 2.08, 95% CI 1.62-2.67) or age > 65 years (OR = 2.79, 95% CI 1.98-3.93). Audio guidance was utilized by 18.3%, and was more frequently utilized by participants with lower education (OR = 2.01, 95% CI 1.54-2.63), age > 65 years (OR = 1.79, 95% CI 1.22-2.61), or Black race (OR = 1.30, 95% 1.01-1.68). The myTAPS format was preferred by women (OR = 1.29, 95% CI 1.00-1.66) and individuals with drug use (OR = 1.43, 95% CI 1.09-1.88), while participants with lower education preferred the interviewer-administered format (OR = 2.75, 95% CI 2.00-3.78). Overall, myTAPS screening was feasible and well accepted by adult primary care patients. Clinics adopting electronic screening should be prepared to offer assistance to some patients, particularly those who are older or less educated, and should have the capacity to use an interviewer-administered approach when required.


ATR activation and replication fork restart are defective in FANCM-deficient cells.
Fanconi anaemia is a chromosomal instability disorder associated with cancer predisposition and bone marrow failure. Among the 13 identified FA gene products only one, the DNA translocase FANCM, has homologues in lower organisms, suggesting a conserved function in DNA metabolism. However, a precise role for FANCM in DNA repair remains elusive. Here, we show a novel function for FANCM that is distinct from its role in the FA pathway: promoting replication fork restart and simultaneously limiting the accumulation of RPA-ssDNA. We show that in DT40 cells this process is controlled by ATR and PLK1, and that in the absence of FANCM, stalled replication forks are unable to resume DNA synthesis and genome duplication is ensured by excess origin firing. Unexpectedly, we also uncover an early role for FANCM in ATR-mediated checkpoint signalling by promoting chromatin retention of TopBP1. Failure to retain TopBP1 on chromatin impacts on the ability of ATR to phosphorylate downstream molecular targets, including Chk1 and SMC1. Our data therefore indicate a fundamental role for FANCM in the maintenance of genome integrity during S phase.


Analysis of the effect of smoking on the buccal microbiome using next-generation sequencing technology.
This study aimed to investigate the effect of smoking on the buccal microbiome and to analyse the descriptive ability of each of the seven hypervariable regions in their 16S rRNA genes. Microbiome compositions of 40 buccal swab samples collected from smokers (n =20) and non-smokers (n =20) were determined using 16S rRNA sequencing. Seven different 16S rRNA hypervariable regions (V2, V3, V4, V6-7, V8 and V9) in each sample were amplified using the Ion Torrent 16S Metagenomics kit and were sequenced on the Ion S5 instrument. Seven hypervariable regions in the 16S rRNA gene were successfully sequenced for all samples tested. The data obtained with the V2 region was found to be informative but the consensus data generated according to a number of operational taxonomic unit reads gathered from all seven hypervariable regions gave the most accurate result. At the phylum level, no statistically significant difference was found between smokers and non-smokers whereas relative abundances of Veillonella atypica, Streptococcus australis, Prevotella melaninogenica, Prevotella salivae and Rothia mucilaginosa showed significant increases in the smoker group (P-adj=0.05). Alpha diversity results did not show a significant difference between the two groups; however, beta diversity analysis indicated that samples of smoker and non-smoker groups had a tendency to be clustered within themselves. The results of the current study indicate that smoking is a factor influencing buccal microbiome composition. In addition, sequencing of all seven hypervariable regions yielded more accurate results than those with any of the single variable regions.


Soft X-ray-driven femtosecond molecular dynamics.
The direct observation of molecular dynamics initiated by x-rays has been hindered to date by the lack of bright femtosecond sources of short-wavelength light. We used soft x-ray beams generated by high-harmonic upconversion of a femtosecond laser to photoionize a nitrogen molecule, creating highly excited molecular cations. A strong infrared pulse was then used to probe the ultrafast electronic and nuclear dynamics as the molecule exploded. We found that substantial fragmentation occurs through an electron-shakeup process, in which a second electron is simultaneously excited during the soft x-ray photoionization process. During fragmentation, the molecular potential seen by the electron changes rapidly from nearly spherically symmetric to a two-center molecular potential. Our approach can capture in real time and with angstrom resolution the influence of ionizing radiation on a range of molecular systems, probing dynamics that are inaccessible with the use of other techniques.


Recurrent posterior scleritis and orbital myositis as extra-intestinal manifestations of Crohn's disease: Case report and systematic literature review.
Ocular episcleritis and uveitis are well-recognised extra-intestinal manifestations of Crohn's disease. Orbital myositis is rare: to our knowledge it has been associated with Crohn's disease in thirteen cases. Posterior scleritis, orbital myositis and Crohn's disease have been reported as coexisting in only two cases. We describe a third case, that of a 31-year old female with Crohn's colitis for 8 years, complicated by enteropathic arthritis and pyoderma gangrenosum. She presented with intense and intractable periorbital pain, particularly at night and worse on eye movements. B-scan ultrasonography confirmed posterior scleritis and treatment with high dose oral steroids (up to 60 mg prednisolone) was initially effective, but subsequently failed to control the inflammation. There was only a partial response to infliximab. Five months after presentation, diplopia developed, with failure of abduction of the left eye. MRI scan of the orbits confirmed orbital myositis involving the left lateral and medial rectus muscles. Pulsed intravenous methylprednisolone and six cycles of intravenous cyclophosphamide over a three month period resulted in complete resolution of inflammatory symptoms. This case highlights a rare combination of ocular abnormality secondary to Crohn's disease and reports successful resolution with aggressive immunosuppressive therapy.


Polyornithine-based polyplexes to boost effective gene silencing in CNS disorders.
Gene silencing therapies have successfully suppressed the translation of target proteins, a strategy that holds great promise for the treatment of central nervous system (CNS) disorders. Advances in the current knowledge on multimolecular delivery vehicles are concentrated on overcoming the difficulties in delivery of small interfering (si)RNA to target tissues, which include anatomical accessibility, slow diffusion, safety concerns, and the requirement for specific cell uptake within the unique environment of the CNS. The present work addressed these challenges through the implementation of polyornithine derivatives in the construction of polyplexes used as non-viral siRNA delivery vectors. Physicochemical and biological characterization revealed biodegradability and biocompatibility of our polyornithine-based system and the ability to silence gene expression in primary oligodendrocyte progenitor cells (OPCs) effectively. In summary, the well-defined properties and neurological compatibility of this polypeptide-based platform highlight its potential utility in the treatment of CNS disorders.


Pharmacodynamics of Ceftaroline plus Ampicillin against Enterococcus faecalis in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations.
The combination of ampicillin plus ceftaroline has been suggested to be more reliably synergistic against Enterococcus faecalis than ampicillin plus ceftriaxone using time-kill methods. The purpose of this study was to determine if this trend persists in a two-compartment model of simulated endocardial vegetations (SEV) using clinically relevant pharmacokinetic exposures of these antimicrobials. Three clinically derived E. faecalis strains were included in the study. The MICs of study antimicrobials were determined by broth microdilution. Simulations of ampicillin (2 g every 4 h [q4h]; maximum concentration of drug in serum [Cmax], 72.4 mg/liter; half-life [t1/2], 1.9 h), ceftaroline-fosamil (600 mg q8h; Cmax, 21.3 mg/liter; t1/2, 2.66 h), ceftriaxone (Cmax, 257 mg/liter; t1/2, 8 h), and ampicillin plus ceftaroline and ampicillin plus ceftriaxone were evaluated against 3 strains of E. faecalis isolated from patients with endocarditis in an in vitro PK/PD SEV model over 72 h, with a starting inoculum of ∼9 log10 CFU/g. All strains were susceptible to ampicillin (MIC, ≤2 mg/liter). Ceftaroline MICs varied from 2 to 16 mg/liter. All strains had ceftriaxone MICs of 256 mg/liter. W04 and W151 exhibited high-level aminoglycoside resistance but W07 did not. Ampicillin plus ceftaroline resulted in significantly greater reductions in CFU per gram by 72 h than ampicillin for all strains (P ≤ 0.025) than ampicillin plus ceftriaxone for W04 (P = 0.019) but not W07 or W151 (P ≥ 0.15). A 4-fold increase in ampicillin MIC was observed for W07 at 72 h, but this was prevented by the addition of ceftaroline or ceftriaxone. The combination of ampicillin plus ceftaroline appears to be at least as efficacious as ampicillin plus ceftriaxone and may lead to improved activity against some strains of E. faecalis, but these differences may be small and the clinical significance should not be overestimated.


Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis.
In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.


A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation.
Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.


Diagnostic accuracy of MALDI mass spectrometric analysis of unfractionated serum in lung cancer.
There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls. We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training-testing paradigm with application of the model profile defined in a training set to a blinded test cohort. Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A. We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.


The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming.
Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumorigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programmes by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anticancer metabolism therapy development in future.


Functional characteristics of the brain in college students with internet gaming disorder.
Internet gaming disorder (IGD) is a subtype of internet addiction disorder (IAD), but its pathogenesis remains unclear. This study investigated brain function in IGD individuals using task-state functional magnetic resonance imaging (fMRI). It is a prospective study in 19 IGD individuals and 19 matched healthy controls. They all received internet videogame stimuli while a 3.0 T fMRI was used to assess echo planar imaging. Brain activity was analyzed using the Brain Voyager software package. Functional data were spatially smoothed using Gaussian kernel. The threshold level was positioned at 10 pixels, and the activation range threshold was set to 10 voxels. Activated brain regions were compared between the two groups, as well as the amount of activated voxels. The internet videogame stimuli activated brain regions in both groups. Compared with controls, the IGD group showed increased activation in the right superior parietal lobule, right insular lobe, right precuneus, right cingulated gyrus, right superior temporal gyrus, and left brainstem. There was a significant difference in the number of activated voxels between the two groups. An average of 1078 voxels was activated in the IGD group compared with only 232 in the control group. Internet videogame play activates the vision, space, attention, and execution centers located in the occipital, temporal, parietal, and frontal gyri. Abnormal brain function was noted in IGD subjects, with hypofunction of the frontal cortex. IGD subjects showed laterality activation of the right cerebral hemisphere.


An equation to calculate internuclear distances of covalent, ionic and metallic lattices.
This paper briefly describes the many different sets of ionic and covalent radii available. A simple model of ionic and covalent bonding is proposed and an equation to calculate internuclear distances of covalent, ionic and metallic lattices is described. Derivation of covalent radii and the use of a proposed model of metallic structure and bonding to derive ionic radii are discussed. A brief summary of the development of the simple equation for calculating internuclear distances of ionic compounds is provided. Values of internuclear distances calculated from the derived radii are compared to observed values and give good agreement, showing strong evidence that ionic and covalent radii are not additive and electronegativity influences bonding and internuclear distances. Ionic radii derived from the proposed model are applied to calculate lattice energies which agree well with literature values/values calculated by the Born Haber cycle. Work functions of transition metals are shown to be simple inverse functions of the derived radii. Internuclear distances of inter-metallic compounds are calculated and compared with observed values to show good agreement. This work shows that the proposed model of metallic structure complements the band theory and expressions introduced in this work can be used to predict ionic and covalent bond lengths (in different environments) that have not yet been determined as well as being a method for resolving bond type.


Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline.
The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. Participants included expert investigators in the field. Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference. A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism, although a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism but recognized that more data are required before validating this supposition. Finally, the task force recognized, and fully expects, that the definition of this syndrome will evolve over time to incorporate new research findings.


Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum.
Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology.


Transport of tetraethylammonium by rabbit renal brush-border and basolateral membrane vesicles.
Brush-border and basolateral membrane vesicles (BBMV and BLMV, respectively) from rabbit renal cortex were used to study transport of the organic cation, tetraethylammonium (TEA). Outwardly directed proton gradients stimulated uptake of TEA into BBMV and supported concentrative accumulation. Furthermore, an inwardly directed H+ gradient accelerated TEA efflux from BBMV. These data suggest that TEA transport in BBMV involved exchange with H+. The Jmax and Kt for TEA transport into BBMV under pH equilibrium conditions (pH 7.5) were 2.1 nmol.mg-1.min-1 and 0.15 mM, respectively. Under pH gradient conditions (6.0in:7.5out), Jmax increased by 270% with no effect on Kt. Uptake of TEA into BBMV was stimulated by an inside-positive electrical potential difference (PD), although exchange of TEA for H+ appeared to be one for one. In BLMV, H+ gradients had little effect on TEA uptake and were incapable of supporting concentrative transport. The Jmax and Kt for TEA transport in BLMV were 0.33 nmol.mg-1.min-1 and 0.37 mM, respectively. Inside-negative PDs stimulated this uptake, suggesting that it involved an electrically conductive pathway. TEA transport in BBMV and BLMV was inhibited by amiloride and cimetidine, although p-aminohippuric acid was without effect. Thus, secretion of TEA involves carrier-mediated transport steps at both the luminal and peritubular membranes, although an active step is not evident in isolated BLMV.


PRimary Care Opioid Use Disorders treatment (PROUD) trial protocol: a pragmatic, cluster-randomized implementation trial in primary care for opioid use disorder treatment.
Most people with opioid use disorder (OUD) never receive treatment. Medication treatment of OUD in primary care is recommended as an approach to increase access to care. The PRimary Care Opioid Use Disorders treatment (PROUD) trial tests whether implementation of a collaborative care model (Massachusetts Model) using a nurse care manager (NCM) to support medication treatment of OUD in primary care increases OUD treatment and improves outcomes. Specifically, it tests whether implementation of collaborative care, compared to usual primary care, increases the number of days of medication for OUD (implementation objective) and reduces acute health care utilization (effectiveness objective). The protocol for the PROUD trial is presented here. PROUD is a hybrid type III cluster-randomized implementation trial in six health care systems. The intervention consists of three implementation strategies: salary for a full-time NCM, training and technical assistance for the NCM, and requiring that three primary care providers have DEA waivers to prescribe buprenorphine. Within each health system, two primary care clinics are randomized: one to the intervention and one to Usual Primary Care. The sample includes all patients age 16-90 who visited the randomized primary care clinics from 3 years before to 2 years after randomization (anticipated to be > 170,000). Quantitative data are derived from existing health system administrative data, electronic medical records, and/or health insurance claims ("electronic health records," [EHRs]). Anonymous staff surveys, stakeholder debriefs, and observations from site visits, trainings and technical assistance provide qualitative data to assess barriers and facilitators to implementation. The outcome for the implementation objective (primary outcome) is a clinic-level measure of the number of patient days of medication treatment of OUD over the 2 years post-randomization. The patient-level outcome for the effectiveness objective (secondary outcome) is days of acute care utilization [e.g. urgent care, emergency department (ED) and/or hospitalizations] over 2 years post-randomization among patients with documented OUD prior to randomization. The PROUD trial provides information for clinical leaders and policy makers regarding potential benefits for patients and health systems of a collaborative care model for management of OUD in primary care, tested in real-world diverse primary care settings. Trial registration # NCT03407638 (February 28, 2018); CTN-0074 https://clinicaltrials.gov/ct2/show/NCT03407638?term=CTN-0074&draw=2&rank=1.


A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.
The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.


Inhibition of the lipopolysaccharide-induced stimulation of the members of the MAPK family in human monocytes/macrophages by 4-hydroxynonenal, a product of oxidized omega-6 fatty acids.
The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of omega-6-polyunsaturated fatty acids and has been suggested to regulate inflammatory responses because it inhibits tumor necrosis factor (TNF) mRNA production in the human monocytic cell line THP-1. Here we demonstrate that 4-HNE inhibits TNF and interleukin-1beta production in human monocytes in response to lipopolysaccharide. The main action of 4-HNE occurred at the pretranscriptional level; there was no effect on TNF mRNA production or stability when 4-HNE was added after stimulation. The mechanism of action of 4-HNE appears to be downstream of lipopolysaccharide-receptor binding. In the human monocytic MonoMac 6 cell line, 4-HNE caused selective inhibition of the activity of the mitogen-activated protein kinases p38 and ERK1/ERK2, but not JNK. However, in monocytes, the activities of all three kinases were inhibited, suggesting that the effects of 4-HNE were exerted at points upstream of ERK1/ERK2 and JNK as the levels of the phosphorylated kinases were reduced. In contrast, p38 phosphorylation was not inhibited, suggesting that 4-HNE affects kinase activity. 4-HNE also inhibited nuclear factor-kappaB activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-kappaB in inflammation, the data suggest that 4-HNE, at nontoxic concentrations, has anti-inflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.


A human approach to drug development: opportunities and limitations.
The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry's continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more-powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors.


First Report of Zucchini yellow mosaic virus in Watermelon in Serbia.
During a survey of cucurbit viruses in the Gornji Tavankut locality (North Backa District), Serbia in June 2011, field-grown (a surface of 1.8 ha) watermelon plants (Citrullus lanatus [Thunb.] Matsum and Nakai) with mild mosaic symptoms were observed. Large numbers of Aphis gossypii were colonizing the crop. A total of 26 samples, six from plants exhibiting mosaic and 20 from asymptomatic plants, were analyzed by double-antibody sandwich-ELISA using polyclonal antisera virus (Bioreba AG, Reinach, Switzerland) against three cucurbit-infecting viruses known to infect Cucurbita pepo in Serbia: Zucchini yellow mosaic virus (ZYMV), Cucumber mosaic virus, and Watermelon mosaic virus (3). Commercial positive and negative controls were included in ELISA analysis. Only six symptomatic samples tested positive for ZYMV, but no other tested viruses were found. The virus was mechanically transmitted from a representative ELISA-positive watermelon sample (550-11) to five plants of C. pepo 'Ezra F1' and severe mosaic was noticed 10 days after inoculation. For further confirmation of ZYMV infection, total RNA from a naturally infected watermelon plant and symptomatic C. pepo 'Ezra F1' plants were extracted with the RNeasy Plant Mini Kit (Qiagen, Hilden, Germany). Reverse transcription (RT)-PCR was performed with the One-Step RT-PCR Kit (Qiagen) using primer pair ZY-2 and ZY-3 (2). Total RNA obtained from a Serbian isolate of ZYMV from pumpkin (GenBank Accession No. HM072432) and healthy watermelon plants were used as positive and negative controls, respectively. The expected sizes of the RT-PCR products (1,186 bp) were amplified from naturally and mechanically infected symptomatic samples, but not from healthy tissues. The amplified product that derived from isolate 550-11 was purified (QIAquick PCR Purification Kit, Qiagen), sequenced in both directions, deposited in GenBank (Accession No. JN561294), and subjected to sequence analysis using MEGA4 software. Sequence comparisons revealed a high nucleotide identity of 99.9 to 99.8% and 100 to 99.6% amino acid identity for the CP gene with Serbian ZYMV isolates from C. pepo (Accession Nos. JF308188, HM072431, and HM072432). The nucleotide and deduced amino acid sequences of the entire CP gene (837 nt) of the Serbian ZYMV isolate from watermelon shared 99.9 to 93.7% and 100 to 96.8% identity, respectively, with innumerous isolates of ZYMV deposited in the GenBank (e.g., Accession Nos. AJ420012-17 and FJ705262). To our knowledge, this is the first report of ZYMV spreading its host range to watermelon in Serbia. ZYMV infection has been responsible for severe epidemics on cucurbits throughout the world (1). The presence of ZYMV on watermelon could therefore represent a serious threat for this valuable crop in Serbia, especially considering that it is prevalent in other cucurbit crops in the country and the vectors are widespread. References: (1) H. Lecoq et al. Virus Res. 141:190, 2009. (2) K. G. Thomson et al. J. Virol. Methods 55:83, 1995. (3) A. Vučurović et al. Pestic. Phytomed. (Belgrade) 24:85, 2009.


Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells.
Understanding pathways controlling cardiac development may offer insights that are useful for stem cell-based cardiac repair. Developmental studies indicate that the Wnt/beta-catenin pathway negatively regulates cardiac differentiation, whereas studies with pluripotent embryonal carcinoma cells suggest that this pathway promotes cardiogenesis. This apparent contradiction led us to hypothesize that Wnt/beta-catenin signaling acts biphasically, either promoting or inhibiting cardiogenesis depending on timing. We used inducible promoters to activate or repress Wnt/beta-catenin signaling in zebrafish embryos at different times of development. We found that Wnt/beta-catenin signaling before gastrulation promotes cardiac differentiation, whereas signaling during gastrulation inhibits heart formation. Early treatment of differentiating mouse embryonic stem (ES) cells with Wnt-3A stimulates mesoderm induction, activates a feedback loop that subsequently represses the Wnt pathway, and increases cardiac differentiation. Conversely, late activation of beta-catenin signaling reduces cardiac differentiation in ES cells. Finally, constitutive overexpression of the beta-catenin-independent ligand Wnt-11 increases cardiogenesis in differentiating mouse ES cells. Thus, Wnt/beta-catenin signaling promotes cardiac differentiation at early developmental stages and inhibits it later. Control of this pathway may promote derivation of cardiomyocytes for basic research and cell therapy applications.


Entangled in uncertainty: The experience of living with dementia from the perspective of family caregivers.
Too often dementia care is still fragmented and unresponsive to the needs of people living with dementia and their family caregivers. To develop effective health care services, in-depth insight into the experiences of family caregivers is a prerequisite. This Dutch study is a qualitative interview study. The aim was twofold: 1) to develop an in-depth understanding of what it means to live with dementia and 2) to gain insight into what constitutes the art of living with dementia, both from the perspective of family caregivers. Data were gathered through 47 interviews with individuals and 6 focus group interviews. The analysis followed a phenomenologically inspired thematic approach. The findings show that living with dementia can be understood as becoming entangled in uncertainty and isolation. The following themes illustrate this experience in various phases of the disease: a) Before the diagnosis: a growing uneasy feeling that something is amiss; b) The diagnostic disclosure: an uncertain and upsetting relief; c) Dementia at home: entangled in an isolated and exhausting life; d) Capitulation to relocation: torn between relief and grief. In addition, the study shows that the art of living with dementia is associated with: a) The ability to face tragedy; b) The discovery of meaning and dignity in the context of illness; c) Retaining a sense of connection and bond; d) The primacy of attention and recognition by others. Our findings show that dealing with what Boss (2011) called 'ambiguous loss-experiences' is one of the most demanding aspects of living with dementia. Based on the findings, we have developed a model that depicts how people handle contingency and seek balance along the continuum of facing and resisting. Our study shows that resilience in the context of living with dementia should not be understood as merely an individual mental ability, nor as a set of behaviours, but rather as a social-ecological enterprise.


Use of scanning electron microscopy in the evaluation of craniosynostosis.
The cause of craniosynostosis continues to elude researchers. Although several studies have looked at the ultrastructure of normal suture closure, no previous studies have examined the microarchitecture of the synostotic suture. Our goal was to assess the scanning electron microscope (SEM) as a viable and useful tool in examining craniosynostosis. Our hypothesis is that the SEM is a powerful analytical tool that can evaluate nonsynostotic, partial synostotic, and complete synostotic cranial sutures. We analyzed the cranial suture of 3 human infants with nonsyndromic sagittal craniosynostosis. The specimens were separated into three groups, which included regions of partial and complete synostosis and a region of open suture. Histological examination provided cellular and tissue data about craniosynostosis, whereas the SEM provided detailed information regarding the trabecular microarchitecture of the synostosed suture. The SEM produced quality images of complete and partially synostotic sutures and open sutures. At low magnification, the SEM characterized the general bony microarchitecture of cranial sutures in a manner different from, but complementary to, standard histological sections. At higher magnification, the SEM allowed us a look at the cellular population of craniosynostotic sutures in a way that surpasses standard light microscopy. The SEM is an excellent tool for the study of craniosynostosis and has proved invaluable in our ability to evaluate the microarchitecture and cellular population of the fusing suture. We believe we have proven our hypothesis by demonstrating the SEM to be a powerful analytical tool that can evaluate nonsynostotic, partial synostotic, and complete synostotic cranial sutures.


Processes of change in cognitive behavioral therapy for treatment-resistant depression: psychological flexibility, rumination, avoidance, and emotional processing.
Recent clinical research suggests that facilitating psychological flexibility and emotional processing and decreasing rumination and avoidance are important tasks of treatment for disorders characterized by entrenched patterns of psychopathology, such as major depressive disorder. The current study examined these processes as predictors of treatment outcomes in a subsample of depressed adult patients (n = 49) who had not fully responded to antidepressant medication and were randomized to receive cognitive-behavioral therapy (CBT). Target variables were coded from session recordings at baseline and in the vicinity of two therapeutic transition points: a sudden gain (improvement) and a transient spike in depression symptoms, or at similar periods for those without such transitions. Results indicated that psychological flexibility during the pre-sudden gain period predicted less depression at 12-month follow-up, beyond baseline symptoms and other co-occurring processes. Interaction analyses revealed that when flexibility was low during the post-spike period, avoidance and rumination predicted higher depressive symptoms, whereas emotional processing predicted lower symptoms at the 12-month follow-up. When flexibility was high, none of these variables were associated with outcome. Together, these findings highlight psychological flexibility as a key therapeutic target in CBT for treatment-resistant depression and might have implications for relapse prevention.


Changes in expression profiles of genes associated with DNA repair following induction of DNA damage in larval zebrafish Danio rerio.
DNA repair is initiated by transcription of genes in response to specific types of damage. Breaks in DNA strands (single and double) are repaired predominantly through non-homologous end-joining (NHEJ) or homologous recombination (HR), but progression of repair and changes in expression profiles of genes involved are unknown. DNA damage was induced in zebrafish larvae by brief exposure (10min) to hydrogen peroxide (H2O2; 100mM), and induction of DNA strand breaks was assessed by single-cell gel electrophoresis (comet) assay over 24h. H2O2 was selected because it is eliminated rapidly after induction of DNA damage. DNA damage [mean ± standard error of the mean (SEM), % tail DNA] increased significantly immediately after 10-min H2O2 exposure (35.4±3.8; control 17.2±2.0), but damage did not differ from control levels 24h after exposure (9.2±0.4; control 9.9±0.9). At 0-, 1-, 3-, 6-, 12- and 24-h post-exposure, quantitative reverse transcriptase-PCR was conducted to assess expression of selected genes involved in DNA repair including xrcc5, xrcc6 (NHEJ), rad51 (HR) and gadd45a (DNA damage detection). Expression (maximum fold-change ± SEM, triplicate samples of 40 larvae) of each gene increased rapidly (within 6h) after exposure to 100mM of H2O2: 1.8±0.2, rad51; 1.7±0.2, xrcc5 and 1.5±0.1, xrcc6. Acute exposure (200mM of H2O2) caused 10% larval mortality within 2h, upregulated gadd45a (5.0±0.8), but did not change expression of rad51, xrcc5 or xrcc6. Expression profiles (critical exponential model) were similar among genes but differed relative to time and among independent experiments. Results indicate that repair mechanisms are initiated rapidly after DNA damage, that gene expression profiles vary according to potency of H2O2 exposure and that examination of the time course of gene expression changes is necessary to understand the complete gene response over time.


Recent findings and advancements in the detection of designer benzodiazepines: a brief review.
This review article takes a closer look at a new class of psychoactive substances called designer benzodiazepines (DBZs) and the challenges of their detection. These are adinazolam, clonazolam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, phenazepam, and pyrazolam. They are central nervous system depressants and sedatives that can cause psychomotor impairment and increase the overdose risk when combined with other sedatives. DBZs undergo phase I and II metabolism similar to traditional benzodiazepines, but their specific metabolic pathways and the influence of genetic polymorphisms are yet to be clarified. Advances in liquid chromatography-tandem mass spectrometry (LC-MS/MS) have enhanced the method's sensitivity for DBZs and their metabolites in biological samples and coupled with improved blood sampling methods require less blood for drug monitoring. Further research should focus on elucidating their pharmacokinetic properties and metabolism in humans, especially in view of genetic polymorphisms and drug interactions that could inform clinical treatment choices. Even though we have witnessed important advances in DBZ detection and measurement, further refinements are needed to expand the scope of detectable DBZs and their metabolites. All this should help toxicological research to better identify and characterise the risks of chronic and polydrug abuse and facilitate clinical, forensic, and regulatory responses to this growing issue.


Surgery of the primary in stage IV colorectal cancer with unresectable metastases.
Surgery plays an important role in the treatment of patients with limited metastatic disease of colorectal cancer (CRC). Long term survival and cure is reported in 20-50% of highly selected patients with oligometastatic disease who underwent surgery. This paper describes the role of surgery of the primary tumour in patients with unresectable stage IV colorectal cancer. Owing to the increased efficacy of chemotherapeutic regimens in stage IV colorectal cancer, complications from unresected primary tumours are relatively infrequent. The risk of emergency surgical intervention is less than 15% in patients with synchronous metastatic disease who are treated with chemotherapy. Therefore, there is a tendency among surgeons not to resect the primary tumour in case of unresectable metastases. However, it is suggested that resection of the primary tumour in case of unresectable metastatic disease might influence overall survival. All studies described in the literature (n = 24) are non-randomised and the majority is single-centre and retrospective of nature. Most studies are in favour of resection of the primary tumour in patients with symptomatic lesions. In asymptomatic patients the results are less clear, although median overall survival seems to be improved in resected patients in the majority of studies. The major drawback of all these studies is that primarily patients with a better performance status and better prognosis (less metastatic sites involved) are being operated on. Another limitation of these studies is that few if any data on the use of systemic therapy are presented, which makes it difficult to assess the relative contribution of resection on outcome. Prospective studies on this topic are warranted, and are currently being planned. Surgery of the primary tumour in patients with synchronous metastasised CRC is controversial, although data from the literature suggest that resection might be a positive prognostic factor for survival. Therefore prospective studies on the value of resection in this setting are required.


The impact of social phobia on quality of life.
Although social phobia is a prevalent mental disorder in the general population, it has only recently received clinical and public attention and very few and rather general data are currently available on the general and disease-specific impairments, disabilities, handicaps and economic burdens associated with social phobia. This report summarizes findings from a case-control study in which quality of life and other indices of impairment in 65 subjects with social phobia but without significant comorbidity of other psychiatric disorders (pure social phobia) were compared to those in a matched control group of 65 subjects with a history of herpes infection. On the basis of the standardized Composite International Diagnostic Interview (CIDI, core version 1.1), the subjects with social phobia had been chronically impaired clinically for more than two decades, with an average duration of 22.9 years and an onset predominantly in childhood or adolescence. As assessed by the Social Functioning (SF-36) questionnaire, these subjects had a significantly lower quality of life, particularly in the scales measuring vitality, general health, mental health, role limitations due to emotional health and social functioning. Standardized summed scores for mental health components of the SF-36 showed that 23.1% of all the subjects with social phobia were severely impaired and 24.6% were significantly impaired compared to only 4.5% of control subjects impaired. Work productivity in the week before the study day, assessed by the Work Productivity And Impairment (WPAI) questionnaire, was significantly diminished in the subjects with social phobia, as indicated by (1) a threefold higher rate of unemployed cases, (2) a significantly elevated rate of mean work hours missed due to social phobia problems and (3) a significantly higher number of subjects reporting significant impairments in work performance. Slightly elevated rates of current (past 4 weeks) treatment by mental health specialists were found (9.2%) in the subjects with social phobia, and higher rates of lifetime psychotropic medication use (24.6%). Overall, these findings emphasize that social phobia is a chronic, impairing anxiety disorder, which results in considerable subjective suffering and has a long-term negative impact on work performance and social relationships. Current disabilities and impairments are usually less pronounced than in the past, presumably due to adaptive behaviors in the lifestyle of the respondents. Our data also suggest that social phobia is poorly recognized and treated by the health care and mental health system.


Learning from the crowd while mapping to LOINC.
To describe the perspectives of Regenstrief LOINC Mapping Assistant (RELMA) users before and after the deployment of Community Mapping features, characterize the usage of these new features, and analyze the quality of mappings submitted to the community mapping repository. We evaluated Logical Observation Identifiers Names and Codes (LOINC) community members' perceptions about new "wisdom of the crowd" information and how they used the new RELMA features. We conducted a pre-launch survey to capture users' perceptions of the proposed functionality of these new features; monitored how the new features and data available via those features were accessed; conducted a follow-up survey about the use of RELMA with the Community Mapping features; and analyzed community mappings using automated methods to detect potential errors. Despite general satisfaction with RELMA, nearly 80% of 155 respondents to our pre-launch survey indicated that having information on how often other users had mapped to a particular LOINC term would be helpful. During the study period, 200 participants logged into the RELMA Community Mapping features an average of 610 times per month and viewed the mapping detail pages a total of 6686 times. Fifty respondents (25%) completed our post-launch survey, and those who accessed the Community Mapping features unanimously indicated that they were useful. Overall, 95.3% of the submitted mappings passed our automated validation checks. When information about other institutions' mappings was made available, study participants who accessed it agreed that it was useful and informed their mapping choices. Our findings suggest that a crowd-sourced repository of mappings is valuable to users who are mapping local terms to LOINC terms.


Usability of an Immersive Augmented Reality Based Telerehabilitation System with Haptics (ARTESH) for Synchronous Remote Musculoskeletal Examination.
This study describes the features and utility of a novel augmented reality based telemedicine system with haptics that allows the sense of touch and direct physical examination during a synchronous immersive telemedicine consultation and physical examination. The system employs novel engineering features: (a) a new force enhancement algorithm to improve force rendering and overcoming the "just-noticeable-difference" limitation; (b) an improved force compensation method to reduce the delay in force rendering; (c) use of the "haptic interface point" to reduce disparity between the visual and haptic data; and (d) implementation of efficient algorithms to process, compress, decompress, transmit and render 3-D tele-immersion data. A qualitative pilot study (n=20) evaluated the usability of the system. Users rated the system on a 26-question survey using a seven-point Likert scale, with percent agreement calculated from the total users who agreed with a given statement. Survey questions fell into three main categories: (1) ease and simplicity of use, (2) quality of experience, and (3) comparison to in-person evaluation. Average percent agreements between the telemedicine and in-person evaluation were highest for ease and simplicity of use (86%) and quality of experience (85%), followed by comparison to in-person evaluation (58%). Eighty-nine percent (89%) of respondents expressed satisfaction with the overall quality of experience. Results suggest that the system was effective at conveying audio-visual and touch data in real-time across 20.3 miles, and warrants further development.


Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study.
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.


The evolution of ovule number and flower size in wind-pollinated plants.
In angiosperms, ovules are "packaged" within individual flowers, and an optimal strategy should occur depending on pollination and resource conditions. In animal-pollinated species, wide variation in ovule number per flower occurs, and this contrasts with wind-pollinated plants, where most species possess uniovulate flowers. This pattern is usually explained as an adaptive response to low pollen receipt in wind-pollinated species. Here, we develop a phenotypic model for the evolution of ovule number per flower that incorporates the aerodynamics of pollen capture and a fixed resource pool for provisioning of flowers, ovules, and seeds. Our results challenge the prevailing explanation for the association between uniovulate flowers and wind pollination. We demonstrate that when flowers are small and inexpensive, as they are in wind-pollinated species, ovule number should be minimized and lower than the average number of pollen tubes per style, even under stochastic pollination and fertilization regimes. The model predicts that plants benefit from producing many small inexpensive flowers, even though some flowers capture too few pollen grains to fertilize their ovules. Wind-pollinated plants with numerous flowers distributed throughout the inflorescence, each with a single ovule or a few ovules, sample more of the airstream, and this should maximize pollen capture and seed production.


Patients report improvement in quality of life and satisfaction after hip resurfacing arthroplasty.
A number of reconstructive procedures are available for the management of hip osteoarthritis. Hip resurfacing arthroplasty is now an accepted procedure, with implant survivorship comparable to THA at up to 10 years' followup in certain series. Most reports focus on implant survivorship, surgeon-derived results, or complications. Fewer data pertain to patient-reported results, including validated measures of quality of life (QoL) and satisfaction and baseline measures from which to determine magnitude of improvement. Validated patient-reported results are essential to guide patients and surgeons in the current era of informed and shared decision making. We determined whether patients reported improvement in disease-specific, joint-specific, and generic QoL after hip resurfacing arthroplasty; whether patients were satisfied with the results of the procedure; and latest activity level and return to sport. We retrospectively reviewed 127 patients (100 men, 27 women) who underwent 143 hip resurfacing procedures between 2002 and 2006. Mean patient age was 52 years. Patients completed the WOMAC, Oxford Hip Score, and SF-12 at baseline and again at minimum 2-year followup (mean, 2.5 years; range, 2-6 years). At latest followup, patients completed a validated satisfaction questionnaire and UCLA activity score. All QoL scores improved (normalized to a 0-100 scale, where 100 = best health state). WOMAC improved from 46 to 95, Oxford Hip Score from 42 to 95, SF-12 (physical) from 34 to 54, and SF-12 (mental) from 46 to 56. Patient satisfaction score was 96. UCLA activity score was 8. The majority of patients reported improvement in QoL, were very satisfied with their outcome, and returned to a high level of activity after hip resurfacing arthroplasty. Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


A comparison between a white LED confocal imaging system and a conventional flash fundus camera using chromaticity analysis.
Conventional flash fundus cameras capture color images that are oversaturated in the red channel and washed out in the green and blue channels, resulting in a retinal picture that often looks flat and reddish. A white LED confocal device was recently introduced to provide a high-quality retinal image with enhanced color fidelity. In this study, we aimed to evaluate the color rendering properties of the white LED confocal system and compare them to those of a conventional flash fundus camera through chromaticity analysis. A white LED confocal device (Eidon, Centervue, Padova, Italy) and a traditional flash fundus camera (TRC-NW8, Topcon Corporation, Tokyo, Japan) were used to capture fundus images. Color images were evaluated with respect to chromaticity. Analysis was performed according to the image color signature. The color signature of an image was defined as the distribution of its pixels in the rgb chromaticity space. The descriptors used for the analysis are the average and variability of the barycenter positions, the average of the variability and the number of unique colors (NUC) of all signatures. Two hundred thirty-three color photographs were acquired with each retinal camera. The images acquired by the confocal white LED device demonstrated an average barycenter position (rgb = [0.448, 0.328, 0.224]) closer to the center of the chromaticity space, while the conventional fundus camera provides images with a clear shift toward red at the expense of the blue and green channels (rgb = [0.574, 0.278, 0.148] (p < 0.001). The variability of the barycenter positions was higher in the white LED confocal system than in the conventional fundus camera. The average variability of the distributions was higher (0.003 ± 0.007, p < 0.001) in the Eidon images compared to the Topcon camera, indicating a greater richness of color. The NUC percentage was higher for the white LED confocal device than for the conventional flash fundus camera (0.071% versus 0.025%, p < 0.001). Eidon provides more-balanced color images, with a wider richness of color content, compared to a conventional flash fundus camera. The overall higher chromaticity of Eidon may provide benefits in terms of discriminative power and diagnostic accuracy.


Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor.
Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A2A receptor (A2AAR). Multiple 500-1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A2AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A2AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A2AAR.


Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice.
Ginsenoside Rg3, a saponin extracted from ginseng, inhibits angiogenesis. The combination of low-dose chemotherapy and anti-angiogenic inhibitors suppresses growth of experimental tumors more effectively than conventional therapy or anti-angiogenic agent alone. The present study was designed to evaluate the efficacy of low-dose gemcitabine combined with ginsenoside Rg3 on angiogenesis and growth of established Lewis lung carcinoma in mice. C57L/6 mice implanted with Lewis lung carcinoma were randomized into the control, ginsenoside Rg3, gemcitabine and combination group. The quality of life and survival of mice were recorded. Tumor volume, inhibitive rate and necrosis rate were estimated. Necrosis of tumor and signals of blood flow as well as dynamic parameters of arterial blood flow in tumors such as peak systolic velocity (PSV) and resistive index (RI) were detected by color Doppler ultrasound. In addition, expression of vascular endothelial cell growth factor (VEGF) and CD31 were observed by immunohistochemstry, and microvessel density (MVD) of the tumor tissues was assessed by CD31 immunohistochemical analysis. Quality of life of mice in the ginsenoside Rg3 and combination group were better than in the control and gemcitabine group. Combined therapy with ginsenoside Rg3 and gemcitabine not only enhanced efficacy on suppression of tumor growth and prolongation of the survival, but also increased necrosis rate of tumor significantly. In addition, the combination treatment could obviously decrease VEGF expression and MVD as well as signals of blood flow and PSV in tumors. Ginsenoside Rg3 combined with gemcitabine may significantly inhibit angiogenesis and growth of lung cancer and improve survival and quality of life of tumor-bearing mice. The combination of chemotherapy and anti-angiogenic drugs may be an innovative and promising therapeutic strategy in the experimental treatment of human lung cancer.


Factors influencing family physicians to enter rural practice: does rural or urban background make a difference?
To examine where rural physicians grew up, when during their training they became interested in rural medicine, factors influencing their decision to practise rural medicine, and differences in these measures according to rural or urban upbringing. Mailed survey. Rural Canada. Rural family physicians who graduated between 1991 and 2000 from a Canadian medical school. Backgrounds of recently graduated rural physicians, when physicians first became interested in rural practice during training, and most influential factors in decisions to practise rural medicine. Response rate was 59% (382/651). About 33% of rural physicians grew up in communities of less than 10 000 people, 44% in cities of 10 000 to 499 999 people, and 23% in cities of more than 500 000 people. Physicians raised in rural areas were more likely than those raised in urban areas to have some interest in rural family practice at the start and end of medical school (90% vs 67% at the start, 98% vs 91% at the end, respectively, P < .0001). Physicians raised in urban areas were more likely to state that rural medical training was the most influential factor in their choice of rural practice (19% vs 9%, P = .015). Other factors cited as influential were the challenge of rural practice (24% for both urban and rural upbringing), rural lifestyle (14% for urban and 18% for rural upbringing) and, for physicians raised in rural areas, having grown up or spent time in a rural area (27% for rural and 4.1% for urban upbringing, P < .001). Financial incentives were least frequently cited as the most influential factor (7.5% for urban and 4.9% for rural upbringing, P = .35). Although other studies have suggested that physicians with a rural upbringing are more likely to practise rural medicine and policy makers might still wish to target students raised in rural areas as candidates for rural medicine, this study shows that physicians raised in urban areas remain the main source of human resources for rural communities. They account for two thirds of new physicians in rural areas. Education in rural medicine during medical training has a stronger influence on physicians raised in urban areas than on physicians raised in rural areas. Undergraduate and postgraduate training periods, therefore, offer an important opportunity for recruiting physicians raised in urban areas to rural practice.


Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men.
We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of second-generation Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that approximately 56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only approximately 13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that approximately 20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and approximately 36% have IGT.


The diagnostic utility of maspin in the distinction between malignant mesothelioma and pulmonary adenocarcinoma.
Immunohistochemistry is frequently employed to differentiate between malignant mesothelioma (MM) and pulmonary adenocarcinoma (AC) infiltrating the pleura, but there is uncertainty as to which antibodies are most useful. The present study investigated the presence of the serine protease, maspin, in epithelioid MMs and evaluated the diagnostic utility of maspin for the differential diagnosis between epithelioid MM and pulmonary AC with pleural involvement. The results showed more frequent maspin immunostaining among AC cases compared with MM cases. Maspin positivity was significantly higher among AC cases with respect to both the extent and intensity of staining. A significant difference also existed between the two tumour types with respect to the overall maspin score. Despite these findings, the sensitivity and specificity of maspin positivity to detect AC were only 59% and 73%, respectively, indicating that detection of maspin is of no value for the differential diagnosis of AC and MM.


de Morton Mobility Index Is Feasible, Reliable, and Valid in Patients With Critical Illness.
Intensive care unit (ICU) stays often lead to reduced physical functioning. Change in physical functioning in patients in the ICU is inadequately assessed through available instruments. The de Morton Mobility Index (DEMMI), developed to assess mobility in elderly hospitalized patients, is promising for use in patients who are critically ill. The aim of this study was to evaluate the clinimetric properties of the DEMMI for patients in the ICU. A prospective, observational reliability and validity study was conducted. To evaluate interrater and intrarater reliability (intraclass correlation coefficients), patients admitted to the ICU were assessed with the DEMMI during and after ICU stay. Validity was evaluated by correlating the DEMMI with the Barthel Index (BI), the Katz Index of Independence in Activities of Daily Living (Katz ADL), and manual muscle testing (MMT). Feasibility was evaluated based on the percentage of participants in which the DEMMI could be assessed, the floor and ceiling effects, and the number of adverse events. One hundred fifteen participants were included (Acute Physiology and Chronic Health Evaluation II [APACHE II] mean score=15.2 and Sepsis-related Organ Failure Assessment [SOFA] mean score=7). Interrater reliability was .93 in the ICU and .97 on the wards, whereas intrarater reliability during the ICU stay was .68. Validity (Spearman rho coefficient) during the ICU stay was .56, -.45, and .57 for the BI, Katz ADL, and MMT, respectively. The DEMMI showed low floor and ceiling effects (2.6%) during and after ICU discharge. There were no major adverse events. Rapid changes in participants' health status may have led to underestimation of intrarater reliability. The DEMMI was found to be clinically feasible, reliable, and valid for measuring mobility in an ICU population. Therefore, the DEMMI should be considered a preferred instrument for measuring mobility in patients during and after their ICU stay.