Skull base chordoma treated with proton therapy: A systematic review.
Chordoma located in the skull base is usually a challenging surgical condition. It is often not possible to achieve gross total resection. Residual tumors have been treated with adjuvant focal radiation therapy employing high-energy particles most commonly through proton beam. In this review, we systematically analyzed indications and outcomes of this treatment with respect to local control rates of the lesion and factors determining recurrence of skull base chordomas. In addition, we collected data on treatment-associated radiation-induced side effects. In line with the PRISMA guidelines, the authors performed a literature search algorithm for relevant articles using three databases: PubMed, Embase, and Cochrane. Inclusion and exclusion criteria were applied to evaluate all identified studies published between 1980 and 2018. Our review included 11 studies for analysis (n = 511 patients). The mean age of the study population was 47.3 ± 5.8 years. The mean dose of postsurgical irradiation at the time of initial treatment was 71.1 ± 3.1 Gy. The mean follow-up duration was 45.0 ± 17.5 months. Within this follow-up duration, recurrence occurred in 26.8% of the patients. The mean time to recurrence was 34.5 ± 15.2 months. A significant number of patients experienced side effects varying from Grade 1 (mild dermatitis) to Grade 4 (temporal lobe necrosis and visual disorders). Despite advances in proton therapy, recurrence rates in skull base chordoma remain high. The toxicity of proton therapy may be more prevalent than generally thought. Unfortunately, there is substantial variation in the methods of data reporting.


A Review on Fucoidan Structure, Extraction Techniques, and Its Role as an Immunomodulatory Agent.
Functional ingredients for human health have recently become the focus of research. One such potentially versatile therapeutic component is fucose-containing sulfated polysaccharides (FCSPs), referred to as fucoidans. The exploitation of marine brown algae provides a rich source of FCSPs because of their role as a structural component of the cell wall. Fucoidans are characterized by a sulfated fucose backbone. However, the structural characterization of FCSPs is impeded by their structural diversity, molecular weight, and complexity. The extraction and purification conditions significantly influence the yield and structural alterations. Inflammation is the preliminary response to potentially injurious inducements, and it is of the utmost importance for modulation in the proper direction. Improper manipulation and/or continuous stimuli could have detrimental effects in the long run. The web of immune responses mediated through multiple modulatory/cell signaling components can be addressed through functional ingredients, benefiting patients with no side effects. In this review, we attempted to address the involvement of FCSPs in the stimulation/downregulation of immune response cell signaling. The structural complexity and its foremost influential factor, extraction techniques, have also attracted attention, with concise details on the structural implications of bioactivity.


Assessing the Quality of Educational Services of Iranian Universities of Medical Sciences Based on the SERVQUAL Evaluation Model: A Systematic Review and Meta-Analysis.
Determining the gap in the quality of educational services, followed by the adoption of appropriate strategies for eliminating or reducing the existing obstacles, is considered the first basic step in developing quality improvement programs for universities. Therefore, this study was conducted to evaluate the quality of educational services of Iranian medical universities. This study was a systematic review and a meta-analysis based on the SERVQUAL evaluation pattern, and data collection was done through accessing published articles in reputable academic websites inside and outside Iran including and searching 4 keywords "the quality of educational services, SERVQUAL Evaluation Model, educational service gap, and Iran" without time and language restrictions. The CMA software, version 2.2.064, was used for data analysis. There was a negative gap in all 5 dimensions. The average gap in all the dimensions was -1.335 out of the maximum 5 (responsiveness=-1.463, assurance=-1.367, tangibility=-1.364, empathy=-1.297, and reliability=-1.091). Based on the results of this study, it can be claimed that students are not satisfied with the current state of the quality of the educational services provided, and we are far away from achieving the ideal state and wining their full satisfaction. The differences observed among the 5 dimensions of the quality of educational services can be used as a guide for planning and allocating resources. Iranian medical science universities should try to pay their most attention to the dimensions that have the widest gaps and place them at the top of their priorities.


Socioeconomic and Geographic Disparities in Idiopathic Intracranial Hypertension.
To identify relationships between idiopathic intracranial hypertension (IIH) and socioeconomic determinants of health, such as low-income status and proximity to healthy food. This retrospective case-control study of adult female neuro-ophthalmology patients from one institution identified 223 women with and 4,783 women without IIH. Street addresses were geocoded and merged with US census data to obtain census tract-level information on income and food access. Choropleth maps visualized IIH clusters within certain neighborhoods. Logistic regression compared the proportion of patients with IIH from racial and ethnic minority backgrounds, low-income census tracts, and food deserts and swamps to controls without IIH. In our cohort, when adjusted for age, women with IIH were more likely to be Black (odds ratio [OR] 3.96, 95% confidence interval [CI] 2.98-5.25), Hispanic (OR 2.23, 95% CI 1.14-4.36), and live in low-income tracts (OR 2.24, 95% CI 1.71-2.95) or food swamps (OR 1.54, 95% CI 1.15-2.07). Patients with IIH were less likely to live in food deserts than controls (OR 0.61, 95% CI 0.45-0.83). The association between Black race and IIH remained significant even after adjusting for other variables. IIH is more common among Black and Hispanic women than expected even when accounting for the demographics of a metropolitan city. Some of this relationship is driven by the association of obesity and IIH incidence with low income and proximity to unhealthy foods.


Analgesic Effect of Duloxetine on an Animal Model of Monosodium Iodoacetate-Induced Hip Osteoarthritis.
We investigated the efficacy of duloxetine on hyperalgesia, histopathological and radiographic findings, pain-related sensory innervation of dorsal-root ganglia (DRG), and spinal changes in a rat model of induced hip osteoarthritis (OA). The right hip joints of male Sprague-Dawley rats (n = 6 rats/group) in the Sham group were injected with 25 μl of sterile saline and 25 μl of sterile saline with 2 mg of monosodium iodoacetate (MIA) were injected to the MIA + Vehicle and MIA + Duloxetine groups. We injected duloxetine 20 mg/kg intraperitoneally in the MIA + Duloxetine group 28 days after injection, whereas rats in the MIA + Vehicle group were injected with 0.5 ml of 20% dimethyl sulfoxide. We assessed hyperalgesia, histopathological changes, immunoreactive (-ir) neurons for calcitonin gene-related peptide and activating transcription factor 3 in DRG, and immunoreactive neurons for ionized-calcium-binding adaptor molecule 1 (Iba1) in the dorsal horn of the spinal cord. MIA administration into the hip joint let to mechanical hyperalgesia of the ipsilateral hind paw (p < 0.05). A single injection of duloxetine significantly attenuated it in induced hip OA (p < 0.05) and suppressed the number of Iba1-ir microglia of the ipsilateral dorsal horn (p < 0.05). These results suggest that a single injection of duloxetine suppressed mechanical hyperalgesia and may influence the expression of Iba1 in the microglia of the ipsilateral dorsal horn in the MIA-induced hip OA. This finding implies the inhibitory effects of duloxetine against neuropathic pain, which may lead to a change of microglial activities. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:422-430, 2020.


Numerical determination of the interfacial energy and nucleation barrier of curved solid-liquid interfaces in binary systems.
The phase-field crystal (PFC) technique is a widely used approach for modeling crystal growth phenomena with atomistic resolution on mesoscopic time scales. We use a two-dimensional PFC model for a binary system based on the work of Elder et al. [Phys. Rev. B 75, 064107 (2007)PRBMDO1098-012110.1103/PhysRevB.75.064107] to study the effect of the curved, diffuse solid-liquid interface on the interfacial energy as well as the nucleation barrier. The calculation of the interfacial energy and the nucleation barrier certainly depends on the proper definition of the solid-liquid dividing surface and the corresponding nucleus size. We define the position of the sharp interface at which the interfacial energy is to be evaluated by using the concept of equimolar dividing surface (r^{e}) and the minimization of the interfacial energy (r^{s}). The comparison of the results based on both radii shows that the difference r^{e}-r^{s} is always positive and has a limit for large cluster sizes which is comparable to the Tolman length. Furthermore, we found the real nucleation barrier for small cluster sizes, which is defined as a function of the radius r^{s}, and compared it with the classical nucleation theory. The simulation results also show that the extracted interfacial energy as function of both radii is independent of system size, and this dependence can be reasonably described by the nonclassical Tolman formula with a positive Tolman length.


p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation.
In this work, we analyzed the role of the PI3K-p70 S6 kinase (S6K) signaling cascade in the stimulation of endothelial cell proliferation. We found that inhibitors of the p42/p44 MAPK pathway (PD98059) and the PI3K-p70 S6K pathway (wortmannin, Ly294002, and rapamycin) all block thymidine incorporation stimulated by fetal calf serum in the resting mouse endothelial cell line 1G11. The action of rapamycin can be generalized, since it completely inhibits the mitogenic effect of fetal calf serum in primary endothelial cell cultures (human umbilical vein endothelial cells) and another established capillary endothelial cell line (LIBE cells). The inhibitory effect of rapamycin is only observed when the inhibitor is added at the early stages of G(0)-G(1) progression, suggesting an inhibitory action early in G(1). Rapamycin completely inhibits growth factor stimulation of protein synthesis, which perfectly correlates with the inhibition of cell proliferation. In accordance with its inhibitory action on protein synthesis, activation of cyclin D1 and p21 proteins by growth factors is also blocked by preincubation with rapamycin. Expression of a p70 S6K mutant partially resistant to rapamycin reverses the inhibitory effect of the drug on DNA synthesis, indicating that rapamycin action is via p70 S6K. Thus, in vascular endothelial cells, activation of protein synthesis via p70 S6K is an essential step for cell cycle progression in response to growth factors.


Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex.
The input conductance of cells in the cat primary visual cortex (V1) has been shown recently to grow substantially during visual stimulation. Because increasing conductance can have a divisive effect on the synaptic input, theoretical proposals have ascribed to it specific functions. According to the veto model, conductance increases would serve to sharpen orientation tuning by increasing most at off-optimal orientations. According to the normalization model, conductance increases would control the cell's gain, by being independent of stimulus orientation and by growing with stimulus contrast. We set out to test these proposals and to determine the visual properties and possible synaptic origin of the conductance increases. We recorded the membrane potential of cat V1 cells while injecting steady currents and presenting drifting grating patterns of varying contrast and orientation. Input conductance grew with stimulus contrast by 20-300%, generally more in simple cells (40-300%) than in complex cells (20-120%), and in simple cells was strongly modulated in time. Conductance was invariably maximal for stimuli of the preferred orientation. Thus conductance changes contribute to a gain control mechanism, but the strength of this gain control does not depend uniquely on contrast. By assuming that the conductance changes are entirely synaptic, we further derived the excitatory and inhibitory synaptic conductances underlying the visual responses. In simple cells, these conductances were often arranged in push-pull: excitation increased when inhibition decreased and vice versa. Excitation and inhibition had similar preferred orientations and did not appear to differ in tuning width, suggesting that the intracortical synaptic inputs to simple cells of cat V1 originate from cells with similar orientation tuning. This finding is at odds with models where orientation tuning in simple cells is achieved by inhibition at off-optimal orientations or sharpened by inhibition that is more broadly tuned than excitation.


Let's Get Real About Health Care Reform.
In light of the ongoing debate about health care policy in the United States, including efforts to repeal and replace the Affordable Care Act, it will be critically important for the academic community to engage in the dialogue. Developing a viable approach to health care reform requires an understanding of the interaction and interdependence between choice, cost, and coverage in a competitive and functional market-based system. Some institutions have implemented models that indicate the feasibility of providing high-quality, efficient patient care while working within fixed budgets. The academic community must stay engaged in these conversations because of its moral commitment to equitable access to health care for all. Academic medical centers will also have to define and protect their roles in an evolving health care delivery system in the United States.


Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase.
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m(2)). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min(-1).m(-2).), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.


New [ONOO]-type amine bis(phenolate) ytterbium(II) and -(III) complexes: synthesis, structure, and catalysis for highly heteroselective polymerization of rac-lactide.
Two divalent ytterbium (Yb(II)) complexes, 1 and 2, supported by new [ONOO]-type amine bis(phenolate) ligands L(a,b) were synthesized in good yield by an amine elimination reaction of Yb(II)(N(SiMe3)2)2(TMEDA) (TMEDA = tetramethylethylenediamine) with one equivalent of the ligand precursor. X-ray structural determination showed complexes 1 and 2 both have a monomeric structure. Each adopts distorted octahedral coordination geometry around the six-coordinate Yb(II) ion. Two new trivalent ytterbium (Yb(III)) aryloxide complexes, 4 and 5, bearing [ONOO]-type amine bis(phenolate) ligands L(c) and L(d) were prepared by double-protonation reaction of Yb(C5H5)3THF with one equivalent of the ligand precursor, then one equivalent of phenol. Complex 4 has a symmetric dimeric structure with a Yb2O2 core bridging through the oxygen atoms of the OC6H4-4-CH3 groups. Complex 5 is a THF-solvated monomer. Each six-coordinated Yb(III) ion in both complexes adopts a distorted octahedron. All the complexes synthesized together with the known Yb(II) complex 3 were evaluated in the ring-opening polymerization (ROP) of rac-lactide (rac-LA). Complexes 1 and 4 were found to be extremely active for controlled ROP of rac-LA, as judged by narrow molar mass distributions (Mw/Mn: 1.07-1.16 for complex 1 and 1.07-1.10 for complex 4) and experimental molar mass Mn,exp values in good agreement with theoretic Mn,calcd values calculated on a single PLA chain produced per metal center of initiator. Complex 5 is less controlled. Complexes 1, 4, and 5 exhibited the same high stereoselectivity to give heterotactic polylactide with a Pr (probability of racemic enchainment of monomer units) ranging from 0.97 to 0.99. Dramatic decreases in activity and stereoselectivity were found for complexes 2 (Pr = 0.82) and 3 (Pr = 0.67), indicating the framework of L in the unit of [YbL] is crucial for determining activity and stereoselectivity of either Yb(II) or Yb(III) complexes.


Mobile Health Intervention to Close the Guidelines-To-Practice Gap in Hypertension Treatment: Protocol for the mGlide Randomized Controlled Trial.
Suboptimal treatment of hypertension remains a widespread problem, particularly among minorities and socioeconomically disadvantaged groups. We present a health system-based intervention with diverse patient populations using readily available smartphone technology. This intervention is designed to empower patients and create partnerships between patients and their provider team to promote hypertension control. The mGlide randomized controlled trial is a National Institutes of Health-funded study, evaluating whether a mobile health (mHealth)-based intervention that is an active partnership between interprofessional health care teams and patients results in better hypertension control rates than a state-of-clinical care comparison. We are recruiting 450 participants including stroke survivors and primary care patients with elevated cardiovascular disease risk from diverse health systems. These systems include an acute stroke service (n=100), an academic medical center (n=150), and community medical centers including Federally Qualified Health Centers serving low-income and minority (Latino, Hmong, African American, Somali) patients (n=200). The primary aim tests the clinical effectiveness of the 6-month mHealth intervention versus standard of care. Secondary aims evaluate sustained hypertension control rates at 12 months; describe provider experiences of system usability and satisfaction; examine patient experiences, including medication adherence and medication use self-efficacy, self-rated health and quality of life, and adverse event rates; and complete a cost-effectiveness analysis. To date, we have randomized 107 participants (54 intervention, 53 control). This study will provide evidence for whether a readily available mHealth care model is better than state-of-clinical care for bridging the guideline-to-practice gap in hypertension treatment in health systems serving diverse patient populations. Clinicaltrials.gov NCT03612271; https://clinicaltrials.gov/ct2/show/NCT03612271. DERR1-10.2196/25424.


Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice.
Activation of C5L2, a G-protein-coupled receptor, by acylation-stimulating protein/complement C3adesArg (ASP/C3adesArg) has been shown to stimulate triglyceride (TG) synthesis in both mature adipocytes and preadipocytes. ASP is an adipocyte-derived hormone that acts by increasing diacylglycerol acyltransferase activity and glucose transport. ASP-deficient mice (C3KO, precursor protein) are lean, display delayed postprandial TG clearance, increased food intake, and increased energy expenditure. The present study shows that C5L2KO mice on a low fat diet are hyperphagic (~60% increase in total food intake) yet maintain the same body weight and adipose tissue mass as wild-type (WT) controls. However, on a high fat diet, average adipocyte size and adipose tissue TG/DNA content were significantly reduced and postprandial TG clearance was delayed in C5L2KO. Adipose tissue TG synthesis (WT: 47.2 +/- 5.6 versus C5L2KO: 7.8 +/- 1.8 pmol/microg protein, P < 0.001), TG lipolysis (WT: 227.6 +/- 36.4 versus C5L2KO: 45.8 +/- 5.0 nmol/microg protein, P < 0.001), and fatty acid re-esterification (WT: 85.3 +/- 2.4% versus C5L2KO: 59.5 +/- 6.8%, P < 0.001) were significantly reduced in C5L2KO mice. Indirect calorimetry measurements revealed C5L2KO mice have unchanged oxygen consumption levels yet reduced respiratory quotient value, suggesting preferential fatty acid utilization over carbohydrate. In agreement, fatty acid oxidation was elevated in heart and skeletal muscle tissue in C5L2KO mice and skeletal muscle levels of uncoupling protein 3 (425.5 +/- 86.3%, P < 0.0001), CD36 (277.6 +/- 49.5%, P < 0.05), cytochrome c (252.6 +/- 33.9%, P < 0.05), and phospho-acetyl CoA carboxylase (118.4 +/- 9.3%, P < 0.05) were significantly increased in C5L2KO mice versus WT (100%). The study shows that in response to reduced TG storage in white adipose tissue, C5L2KO mice have developed a compensatory mechanism of increased muscle fat oxidation.


Some observations on the circulation of influenzaviruses in domestic and wild birds.
Four viruses isolated from poultry in the USSR and Poland were identified as influenza A strains. One strain was closely related to fowl plague virus, the second showed an antigenic relationship to A/chicken/Scotland/59 (Hav5N1), and two others were antigenically related to A/duck/Ukraine/1/63 (Hav7Neq2) and A/duck/England/56 (Hav3Nav1). Antibodies to different strains of influenzavirus were detected in sera collected from poultry and from wild birds in the northern area of the USSR. More of the sera collected from migratory sea birds in the autumn gave HI reactions than did those collected in the spring. HI reactions were of higher titre when recent locally isolated viruses were used than with reference strains of influenzavirus. Sera collected in the autumn of 1969 from wild sea birds (mostly herring gulls, ducks, arctic loons, and long-tailed ducks) frequently showed HI activity not only with avian influenzavirus but also with A/equine/Miami/1/63 (Heq2 Neq2) and A/Hong Kong/1/68 (H3N2). The significance of these findings is discussed.


[Pathophysiology and treatment of fatigue in multiple sclerosis].
Patients suffering from multiple sclerosis (MS) frequently complain of fatigue (53 to 92 percent depending on studies). Fatigue can be one of the most disabling symptoms of MS and presents as physical or mental fatigue in daily living activities. Besides this permanent feeling of exhaustion, MS patients can suffer from an abnormal tiredness and lack of energy after a given motor or mental task, which defines fatigability. A number of studies explored the origins of fatigue and fatigability by means of subjective and objective tools. The implication of central nervous system dysfunctions has been established in several studies; however the contribution of peripheral nervous system factors and systemic abnormalities associated with inflammatory and immunological parameters was also suggested. The aim of this review is to present the different types of fatigue and fatigability occurring in MS patients, their origins, the investigation tools which allow the quantification of fatigue and fatigability and characterization of their mechanisms. The currently available therapeutic strategies that have been proposed to relieve this disabling symptom are presented.


Nanoscale rippling on polymer surfaces induced by AFM manipulation.
Nanoscale rippling induced by an atomic force microscope (AFM) tip can be observed after performing one or many scans over the same area on a range of materials, namely ionic salts, metals, and semiconductors. However, it is for the case of polymer films that this phenomenon has been widely explored and studied. Due to the possibility of varying and controlling various parameters, this phenomenon has recently gained a great interest for some technological applications. The advent of AFM cantilevers with integrated heaters has promoted further advances in the field. An alternative method to heating up the tip is based on solvent-assisted viscoplastic deformations, where the ripples develop upon the application of a relatively low force to a solvent-rich film. An ensemble of AFM-based procedures can thus produce nanoripples on polymeric surfaces quickly, efficiently, and with an unprecedented order and control. However, even if nanorippling has been observed in various distinct modes and many theoretical models have been since proposed, a full understanding of this phenomenon is still far from being achieved. This review aims at summarizing the current state of the art in the perspective of achieving control over the rippling process on polymers at a nanoscale level.


Measurement of the -3 keV resonance in the reaction 13C(α,n)16O of importance in the s-process.
The (13)C(α,n)(16)O reaction is the neutron source for the main component of the s-process, responsible for the production of most nuclei in the mass range 90</~A</~204. It is active inside the helium-burning shell in asymptotic giant branch stars, at temperatures </~10(8) K, corresponding to an energy interval where the (13)C(α,n)(16)O is effective from 140 to 230 keV. In this region, the astrophysical S(E)-factor is dominated by the -3 keV subthreshold resonance due to the 6.356 MeV level in (17)O, giving rise to a steep increase of the S(E)-factor. Notwithstanding that it plays a crucial role in astrophysics, no direct measurements exist inside the s-process energy window. The magnitude of its contribution is still controversial as extrapolations, e.g., through the R matrix and indirect techniques, such as the asymptotic normalization coefficient (ANC), yield inconsistent results. The discrepancy amounts to a factor of 3 or more right at astrophysical energies. Therefore, we have applied the Trojan horse method to the (13)C((6)Li,n(16)O)d quasifree reaction to achieve an experimental estimate of such contribution. For the first time, the ANC for the 6.356 MeV level has been deduced through the Trojan horse method as well as the n-partial width, allowing to attain an unprecedented accuracy in the (13)C(α,n)(16)O study. Though a larger ANC for the 6.356 MeV level is measured, our experimental S(E)-factor agrees with the most recent extrapolation in the literature in the 140-230 keV energy interval, the accuracy being greatly enhanced thanks to this innovative approach.


The scale-of-choice effect and how estimates of assortative mating in the wild can be biased due to heterogeneous samples.
The mode in which sexual organisms choose mates is a key evolutionary process, as it can have a profound impact on fitness and speciation. One way to study mate choice in the wild is by measuring trait correlation between mates. Positive assortative mating is inferred when individuals of a mating pair display traits that are more similar than those expected under random mating while negative assortative mating is the opposite. A recent review of 1134 trait correlations found that positive estimates of assortative mating were more frequent and larger in magnitude than negative estimates. Here, we describe the scale-of-choice effect (SCE), which occurs when mate choice exists at a smaller scale than that of the investigator's sampling, while simultaneously the trait is heterogeneously distributed at the true scale-of-choice. We demonstrate the SCE by Monte Carlo simulations and estimate it in two organisms showing positive (Littorina saxatilis) and negative (L. fabalis) assortative mating. Our results show that both positive and negative estimates are biased by the SCE by different magnitudes, typically toward positive values. Therefore, the low frequency of negative assortative mating observed in the literature may be due to the SCE's impact on correlation estimates, which demands new experimental evaluation.


RAF1 amplification: an exemplar of MAPK pathway activation in urothelial carcinoma.
Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.


Simultaneous quantification method for multiple antiviral drugs in serum using isotope dilution liquid chromatography-tandem mass spectrometry.
We describe the simultaneous quantification of six antiviral drugs in serum based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The target drugs-hydroxychloroquine, chloroquine, favipiravir, umifenovir, ritonavir, and lopinavir-were extracted and purified from serum with 75 % v/v methanol as the precipitant reagent. The six analytes were clearly separated within 15 min using gradient elution and mixed-mode stationary phase. The measurement accuracy and precision were assured by adopting isotopes as internal standards. The optimized measurement procedure was strictly validated in linearity, sensitivity, accuracy, and precision. To confirm the robustness of the method in matrix, the method was additionally applied to various types of serum, namely hyperlipidemic and hyperglycemic serum. The method was then applied to assess the stability of the drugs in serum in order to set sample handling and storage guides for laboratory testing. Lastly, the method was implemented in different LC-MS systems to confirm its applicability across similar equipment commonly used in clinical testing laboratories. The overall results show that the optimized protocol is suitable for the accurate, simultaneous quantification of the six antiviral drugs in serum, and it is anticipated to satisfactorily serve as a reference protocol for the analysis of a wide range of other antiviral drugs for drug monitoring with various purposes.


Nutrition and the etiology of cancer.
There is a growing body of scientific evidence that diet and nutrients play a causative role in the formation of cancer and that these factors may be amenable to active methods of prevention. It has been estimated that up to 35 per cent of cancers may be preventable by dietary manipulation. A theoretical basis for this are the direct-acting carcinogens ingested or produced in the diet, but these are not a major factor in the United States. Altered intake, metabolism, and excretion of cholesterol and bile acids by bacterial flora may be an important mechanism related to several commonly occurring cancers. Fiber and other constituents of vegetables may act as important protectors against the development of cancer. Dietary components related to cancer include dietary fat, fiber, fruits and vegetables, protein, alcohol, vitamins, and minerals. Practical advice for the primary care physician is given regarding two common food additives, saccharin and nitrites.


Acute facial paralysis: a virological study.
A serological study using the complement fixation reaction for herpes zoster virus (HZV) and herpes simplex virus (HSV) was carried out on 120 patients with Bell's palsy and 5 with Ramsay-Hunt syndrome. Three Bell's palsy patients (2.5%) showed a significant HZV antibody titre rise. In no case was a rise of HSV antibody titre observed. Two Ramsay-Hunt patients showed a significant rise of HZV antibody titre. Rise of HSV antibody titre was not observed in this group either. The Monosticon test to exclude infectious mononucleosis, proved to be negative in all cases of Bell's palsy. In 2 cases of Bell's palsy, a biopsy specimen for virus isolation was obtained during a decompression operation. No virus could be cultured from the epineurium of the first patient. That of the second patient was found to contain HSV type I. There was no serological evidence of a HSV antibody titre rise.


Differential diagnosis of chest pain in an emergency department: the value of homocysteinemia as a diagnostic marker.
Only 20 to 45% of patients (pts) admitted to an emergency department (ED) with chest pain (CP) have a cardiac ischemic CP (ICP). Apart from the need for a rapid detection of ICP cases, it is important to avoid discharging patients with false negative ICP. We studied the capability of plasma homocysteine (Hcy) values to improve the differential diagnosis (DD) in patients admitted to an ED with CP. 125 patients, 80 males, mean age 61 yrs (25-96 yrs), 75 (60%) without prior atherosclerotic cardiovascular disease (ACVD), consecutively admitted to the ED with CP which was not immediately clear. Definitive diagnosis: ICP-58 patients (46%); non-ischemic (non-ICP)--64 patients (54%). Hcy was measured on admittance (fasting state not required), by means of a fluorescence polarization enzyme immunoassay (IMx, Abbott); at real conditions, the results were obtained within 2 hours (but not displayed). 1) Hcy (mumol/L) = 10.9 +/- 5.4 (non ICP without prior CDAV); 13.9 +/- 7.7 (ICP). 2) Hcy > or = 15.0 mumol/L in patients without prior ACVD: 5 patients (9%) with non ICP, 8 patients (38%) with ICP--p < 0.01; RR = 2.9 (95% CI = 1.2-7.1); positive value = 62%; negative predictive value = 79%. In patients without ACVD, Hcy may contribute to improve DD of equivocal CP, namely: 1) before a normal or non-diagnostic ECG and negative ischemia markers, Hcy > or = 15.0 mumol/L will imply additional cardiological investigation in the ED; 2) Hcy < 15.0 increases the liability of a non-ICP diagnosis.


Healthy Skin, Healthy Mepla: A skin health promotional event for children in the Torres Strait.
Skin infections such as impetigo and scabies are common in Aboriginal Australian and Torres Strait Islander children living in rural and remote settings. Effective health promotion is a key element when addressing health literacy aimed at reducing the burden of skin disease. Community-driven health promotion provides a potentially effective and sustainable model for improved health outcomes. A one-day community-driven skin health promotional event was conducted on Waiben [Thursday Island] with the aim of improving local Torres Strait Islander children's appreciation of the importance of skin health through art, music and creation of a video. Participants completed written pre- and post-questionnaires to determine their response. Fifty-two children participated in the event; median (range) age was 11 (9-12) years and all identified as Torres Strait Islander. Overall, 34 of 50 children (68%) felt that participating in this workshop improved their skin health knowledge. Skin health promotion can be successful achieved through a locally conceived, locally driven and locally owned approach. SO WHAT?: This skin health promotional event could be a model for other health promotion activities in the Torres Strait.


Highly selective and non-conventional sorbents for the determination of biomarkers in urine by liquid chromatography.
Urine is one of the most extensively analysed biological fluids in clinical and toxicological investigations owing to its high availability and non-invasive collection. The chemical nature of the analytes involved (polarity and thermal instability) makes liquid chromatography the separation technique of choice for compound determination. Moreover, sample treatment based on solid-phase extraction is usually carried out owing to its flexibility and the availability of new sorbent materials with increased selectivity and versatility towards the target compounds. Taking into account these three fundamental points, this review focuses on recent developments in urine pretreatment using highly selective and non-conventional sorbents in solid-phase extraction such as affinity sorbents (immunosorbents and molecularly imprinted polymers), restricted access materials and carbon nanotubes, with emphasis on the new synthesis methods. Their main advantages and shortcomings are presented, together with representative examples in this context.


Human purified protein derivative-specific CD4+ T cells use both CD95-dependent and CD95-independent cytolytic mechanisms.
CTL, both CD4+ and CD8+, are essential in the eradication of intracellular pathogens. Data generated using murine T cells have suggested a critical role for CD95 (Fas, Apo-1) in CD4+ T cell-induced apoptosis of target cells. In contrast, CD8+ CTL predominantly use the perforin/granzyme lytic pathway. At present little is known about the mechanism of CD4+ CTL lytic function during intracellular infection in humans. We have used human CD4+ T cells specific for purified protein derivative (PPD) of Mycobacterium tuberculosis to explore whether CD95 is the dominant cytolytic mechanism. PPD-reactive CD4+ clones efficiently lysed Ag-pulsed autologous monocytes, adherent macrophages, and EBV-transformed B cells. Addition of an antagonistic CD95 Ab had a minimal effect on cytolysis, whereas addition of MgEGTA to block perforin/granzyme resulted in complete inhibition of killing. In contrast, lysis of activated peripheral blood B cells could be partially blocked with the antagonistic CD95 Ab. Supporting these observations, monocytes, macrophages, and EBV-transformed B cells were not lysed by an agonistic CD95 Ab. Activated B cells were readily lysed by the agonistic CD95 Ab. T cell clones triggered through the TCR with anti-CD3 were capable of lysing the CD95-sensitive Jurkat T cell line in a CD95-dependent manner, but were also able to release granzymes. We conclude that human CD4+ T cells are capable of lysing PPD-pulsed targets using both perforin/granzyme and CD95 pathways. The contribution of CD95 is strictly dependent on target cell susceptibility to CD95-mediated killing.


HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer.
EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.


Serum metalloproteinase 9 levels in patients with coronary artery disease: a novel marker of inflammation.
The finding that expression of metalloproteinases (MMPs) is induced in atherosclerotic plaques prone to rupture suggests the possibility that patients with atherosclerotic diseases would show enhanced blood levels of MMPs and that MMPs might represent a potential inflammatory risk factor for atherosclerosis. Therefore, the present study was aimed at verifying whether MMPs may represent sensitive markers of inflammation in patients with coronary artery disease. MMP-2, MMP-9, interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen levels were measured in blood samples obtained from 66 cases with previous acute myocardial infarction and 66 control subjects similar for age, sex, and major atherosclerotic risk factors but without history or evidence of atherothrombotic diseases. Biohumoral markers of inflammation and MMP-9 levels were significantly elevated in cases compared with controls (median values 40.6 versus 9.8 ng/mL; p < .0001), whereas MMP-2 levels did not differ between the two groups (median values 839 versus 873 ng/mL; p = .53). A direct correlation was found among MMP-9, CRP, IL-6, and fibrinogen levels. Conditional logistic regression analysis showed that MMP-9 is related to myocardial infarction (p = .006) even after adjusting for cardiovascular medications and CRP. These findings suggest that measurement of serum MMP-9 levels may represent a novel marker of inflammation in patients with known coronary artery disease and might provide an index of plaque activity in this clinical setting.


Accumulation and DNA damage in fathead minnows (Pimephales promelas) exposed to 2 brominated flame-retardant mixtures, Firemaster 550 and Firemaster BZ-54.
Firemaster 550 and Firemaster BZ-54 are two brominated formulations that are in use as replacements for polybrominated diphenyl ether (PBDE) flame retardants. Two major components of these mixtures are 2,3,4,5-tetrabromo-ethylhexylbenzoate (TBB) and 2,3,4,5-tetrabromo-bis(2-ethylhexyl) phthalate (TBPH). Both have been measured in environmental matrices; however, scant toxicological information exists. The present study aimed to determine if these brominated flame-retardant formulations are bioavailable and adversely affect DNA integrity in fish. Fathead minnows (Pimephales promelas) were orally exposed to either FM 550, FM BZ54, or the nonbrominated form of TBPH, di-(2-ethylhexyl) phthalate (DEHP) for 56 d and depurated (e.g., fed clean food) for 22 d. At several time points, liver and blood cells were collected and assessed for DNA damage. Homogenized fish tissues were extracted and analyzed on day 0 and day 56 to determine the residue of TBB and TBPH and the appearance of any metabolites using gas chromatography-electron-capture negative ion mass spectrometry (GC/ECNI-MS). Significant increases (p < 0.05) in DNA strand breaks from liver cells (but not blood cells) were observed during the exposure period compared with controls, although during depuration these levels returned to control. Both parent compounds, TBB and TBPH, were detected in tissues at approximately 1% of daily dosage along with brominated metabolites. The present study provides evidence for accumulation, metabolism, and genotoxicity of these new formulation flame retardants in fish and highlights the potential adverse effects of TBB- and TBPH-formulated fire retardants to aquatic species.


The effect of body mass index and wound irrigation on outcome after bilateral breast reduction.
Thirty patients undergoing bilateral breast reduction by inferior pedicle technique were entered into a prospective, randomized study to determine the effect of unilateral saline wound irrigation and body mass index (BMI) on outcome. Each patient was assessed at 1, 4, and 8 weeks after surgery for wound dehiscence, infection, fat necrosis, and breast comfort by means of a visual analog pain score. The mean patient age was 33 years; mean weight, 67.7 kg; mean BMI, 26.3; and mean weight of breast tissue excised per patient, 1270 g. In 60 breasts there were 13 cases of minor wound breakdown, all of which had healed by 8 weeks postoperatively. Wound irrigation had no significant effect on the rate of T-junction breakdown or on postoperative pain. BMI was associated significantly with wound breakdown (BMI > 26.3, 33% wound breakdown rate; BMI < 26.3, 10% wound breakdown rate; P < 0.05, chi2 test). Patients with a high BMI are more likely to have delayed healing after breast reduction.


Blend Sign on Computed Tomography: Novel and Reliable Predictor for Early Hematoma Growth in Patients With Intracerebral Hemorrhage.
Early hematoma growth is not uncommon in patients with intracerebral hemorrhage and is an independent predictor of poor functional outcome. The purpose of our study was to report and validate the use of our newly identified computed tomographic (CT) blend sign in predicting early hematoma growth. Patients with intracerebral hemorrhage who underwent baseline CT scan within 6 hours after onset of symptoms were included. The follow-up CT scan was performed within 24 hours after the baseline CT scan. Significant hematoma growth was defined as an increase in hematoma volume of >33% or an absolute increase of hematoma volume of >12.5 mL. The blend sign on admission nonenhanced CT was defined as blending of hypoattenuating area and hyperattenuating region with a well-defined margin. Univariate and multivariable logistic regression analyses were performed to assess the relationship between the presence of the blend sign on nonenhanced admission CT and early hematoma growth. A total of 172 patients were included in our study. Blend sign was observed in 29 of 172 (16.9%) patients with intracerebral hemorrhage on baseline nonenhanced CT scan. Of the 61 patients with hematoma growth, 24 (39.3%) had blend sign on admission CT scan. Interobserver agreement for identifying blend sign was excellent between the 2 readers (κ=0.957). The multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and presence of blend sign on baseline CT scan to be independent predictors of early hematoma growth. The sensitivity, specificity, positive and negative predictive values of blend sign for predicting hematoma growth were 39.3%, 95.5%, 82.7%, and 74.1%, respectively. The CT blend sign could be easily identified on regular nonenhanced CT and is highly specific for predicting hematoma growth.


Deformability in the cleavage site of primary microRNA is not sensed by the double-stranded RNA binding domains in the microprocessor component DGCR8.
The prevalence of double-stranded RNA (dsRNA) in eukaryotic cells has only recently been appreciated. Of interest here, RNA silencing begins with dsRNA substrates that are bound by the dsRNA-binding domains (dsRBDs) of their processing proteins. Specifically, processing of microRNA (miRNA) in the nucleus minimally requires the enzyme Drosha and its dsRBD-containing cofactor protein, DGCR8. The smallest recombinant construct of DGCR8 that is sufficient for in vitro dsRNA binding, referred to as DGCR8-Core, consists of its two dsRBDs and a C-terminal tail. As dsRBDs rarely recognize the nucleotide sequence of dsRNA, it is reasonable to hypothesize that DGCR8 function is dependent on the recognition of specific structural features in the miRNA precursor. Previously, we demonstrated that noncanonical structural elements that promote RNA flexibility within the stem of miRNA precursors are necessary for efficient in vitro cleavage by reconstituted Microprocessor complexes. Here, we combine gel shift assays with in vitro processing assays to demonstrate that neither the N-terminal dsRBD of DGCR8 in isolation nor the DGCR8-Core construct is sensitive to the presence of noncanonical structural elements within the stem of miRNA precursors, or to single-stranded segments flanking the stem. Extending DGCR8-Core to include an N-terminal heme-binding region does not change our conclusions. Thus, our data suggest that although the DGCR8-Core region is necessary for dsRNA binding and recruitment to the Microprocessor, it is not sufficient to establish the previously observed connection between RNA flexibility and processing efficiency.


An uncommon cause of diffuse alveolar hemorrhage in a young male.
It is uncommon for Systemic lupus erythematosus (SLE) to present with diffuse alveolar hemorrhage (DAH) as the initial presentation. To diagnose this in a young male with no renal involvement is further uncommon. We report a case of a 16-year-old boy, who presented with hemoptysis and was eventually diagnosed as DAH with underlying SLE. Treatment with steroids and immunosuppressant helped in rapid recovery from this potentially life-threatening condition. This case highlights the need of defining diagnostic criteria for SLE in patients presenting as DAH and formulating guidelines for treatment of the same, especially in absence of co-existing lupus nephritis.


Endovascular repair of the ruptured abdominal aortic aneurysm.
The present knowledge on endovascular repair of ruptured abdominal aortic aneurysms (rAAA) prevents firm conclusions when to use this method in comparison to open repair. This review article briefly summarizes results from case series, and discusses how to achieve reliable information despite the absence of randomized controlled trials. At present a careful conclusion might be that dedicated centers with an adequate organization and reasonably high volume of abdominal aortic aneurysm (AAA) should use detailed registry protocols to achieve experience and data to create an as reliable basis as possible for future recommendations.


Lycium barbarum polysaccharide alleviates DSS-induced chronic ulcerative colitis by restoring intestinal barrier function and modulating gut microbiota.
This study examined the protective effects and mechanism of Lycium barbarum polysaccharides (LBP) in the context of intestinal barrier function and intestinal microbiota in mice with dextran sulfate sodium (DSS)-induced chronic ulcerative colitis (UC). C57BL/6J male mice were assigned to a standard normal diet without DSS (control group), a normal diet with DSS (DSS group, 2% DSS given discontinuously for 3 weeks) or a normal diet supplemented with LBP (1% dry feed weight, LBP group, 2% DSS given discontinuously for 3 weeks) for a total of 8 weeks, at which point colonic tissues and caecal contents were collected. LBP exerted a significant effect against colitis by increasing body weight, colon length, DAI and histopathological scores. LBP inhibited proinflammatory cytokines (IL-1β, IL-6, iNOS and TNF-α) expression, improved anti-inflammatory cytokine (IL-10) expression, promoted the expression of tight junction proteins (Occludin and ZO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and decreased Claudin-2 expression to maintain the intestinal mucosal barrier. In addition, the abundances of some probiotics (Ruminococcaceae, Lactobacillus, Butyricicoccus, and Akkermansia) were decreased with DSS treatment but increased obviously with LBP treatment. And LBP reduced the abundance of conditional pathogens associated with UC (Mucispirillum and Sutterella). Furthermore, LBP improved the production of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid and isobutyric acid. LBP can alleviate DSS-induced UC by regulating inflammatory cytokines and tight junction proteins. Moreover, LBP promotes probiotics, suppresses conditional pathogens and increases SCFAs production, showing a strong prebiotic effect.


Evaluation of cytotoxicity of new trans-palladium(II) complex in human cells in vitro.
Studies of cytotoxicity allow to elucidate the mechanisms by which chemical compounds influence cells and tissues. On the basis of the structural analogy between platinum(II) and palladium(II) complexes, a variety of studies on palladium(II) compounds as potential anticancer drugs have been carried out (1, 2). The cytotoxicity was evaluated by MTT assay. Abilities of trans-palladium(II) complex containing diethyl (pyridin-2-ylmethyl)phosphates as non-leaving ligands (trans-[PdCl2(2-pmOpe 2)]) to induce apoptosis and necrosis in normal lymphocytes, A549 cells and HT29 cell lines were performed by use of fluorochrome staining. The obtained results revealed, that the new trans-palladium(II) complex was more cytotoxic against A549 and HT29 tumor cells than on the normal lymphocytes in vitro. The novel complex induces apoptosis in all tested cells, but in lymphocytes to a lesser degree. The compound tested also induced significant amounts of necrotic cells, which exceeded the level of apoptotic cell fractions. The results demonstrate that the trans-Pd(II) complex showed substantial cytotoxic activity against A549 and HT29 tumor cells and indicate that the new trans-palladium(II) complex effectively inhibited cancer cells growth.


Heparin inhibits proliferation of myometrial and leiomyomal smooth muscle cells through the induction of alpha-smooth muscle actin, calponin h1 and p27.
Mast cells are widely distributed in human tissues, including the human uterus. However, the function of mast cells in uterine smooth muscle has not been clearly established. Mast cells possess secretory granules containing such substances as heparin, serotonin, histamine and many cytokines. To help establish the role of mast cells in the human myometrium, the action of heparin was investigated using smooth muscle cells (SMC) from normal myometrium and from leiomyoma. The proliferation of cultured myometrial and leiomyomal SMC was inhibited by heparin treatment. Flow cytometric analysis showed that the population in the G1 phase of the cell cycle increased under heparin treatment. Western blotting analysis showed that markers of SMC differentiation such as alpha-smooth muscle actin (alpha-SMA), calponin h1 and cyclin-dependent kinase inhibitor p27 were induced by heparin, whereas cell-cycle-related gene products from the G1 phase of the cell cycle, such as cyclin E and cdk2, were not changed. Taken together, these results indicate that heparin inhibits the proliferation of myometrial and leiomyomal SMC through the induction of alpha-SMA, calponin h1 and p27. We suggest that heparin from mast cells may induce differentiation in uterine SMC and may influence tissue remodelling and reconstruction during physiological and pathophysiological events.


Survivors of Chronic Stroke Experience Continued Impairment of Dexterity But Not Strength in the Nonparetic Upper Limb.
To investigate the performance of the less affected upper limb in people with stroke compared with normative values. To examine less affected upper limb function in those whose prestroke dominant limb became paretic and those whose prestroke nondominant limb became paretic. Cohort study of survivors of chronic stroke (7.2±6.7y post incident). The study was performed at a freestanding academic rehabilitation hospital. Survivors of chronic stroke (N=40) with severe hand impairment (Chedoke-McMaster Stroke Assessment rating of 2-3 on Stage of Hand) participated in the study. In 20 participants the prestroke dominant hand (DH) was tested (nondominant hand [NH] affected by stroke), and in 20 participants the prestroke NH was tested (DH affected by stroke). Not applicable. Jebsen-Taylor Hand Function Test. Data from survivors of stroke were compared with normative age- and sex-matched data from neurologically intact individuals. When combined, DH and NH groups performed significantly worse on fine motor tasks with their nonparetic hand relative to normative data (P<.007 for all measures). Even the participants who continued to use their prestroke DH as their primary hand after the stroke demonstrated reduced fine motor skills compared with normative data. In contrast, grip strength was not significantly affected in either group of survivors of stroke (P>.140). Survivors of stroke with severe impairment of the paretic limb continue to present significant upper extremity impairment in their nominally nonparetic limb even years after stroke. This phenomenon was observed regardless of whether the DH or NH hand was primarily affected. Because this group of survivors of stroke is especially dependent on the nonparetic limb for performing functional tasks, our results suggest that the nonparetic upper limb should be targeted for rehabilitation.


MLAOS: a multi-point linear array of optical sensors for coniferous foliage clumping index measurement.
The canopy foliage clumping effect is primarily caused by the non-random distribution of canopy foliage. Currently, measurements of clumping index (CI) by handheld instruments is typically time- and labor-intensive. We propose a low-cost and low-power automatic measurement system called Multi-point Linear Array of Optical Sensors (MLAOS), which consists of three above-canopy and nine below-canopy optical sensors that capture plant transmittance at different times of the day. Data communication between the MLAOS node is facilitated by using a ZigBee network, and the data are transmitted from the field MLAOS to a remote data server using the Internet. The choice of the electronic element and design of the MLAOS software is aimed at reducing costs and power consumption. A power consumption test showed that, when a 4000 mAH Li-ion battery is used, a maximum of 8-10 months of work can be achieved. A field experiment on a coniferous forest revealed that the CI of MLAOS may reveal a clumping effect that occurs within the canopy. In further work, measurement of the multi-scale clumping effect can be achieved by utilizing a greater number of MLAOS devices to capture the heterogeneity of the plant canopy.


Polymorphism of the GLIS3 gene in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia.
Earlier, GLIS3 gene polymorphisms have been shown to be associated with the development of maturity onset diabetes of the young (MODY). We screened GLIS3 gene sequences among patients with MODY to identify probably pathogenic variants by whole-exome sequencing. We estimated frequency of rare single-nucleotide variants in the coding region of GLIS3 in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. We identified 15 single-nucleotide variants in GLIS3. Three rare variants (minor allele frequency < 1%) rs806052, rs143051164, and rs149840771 were genotyped in 126 cases of MODY, in 188 patients with type 2 diabetes mellitus (DM2), and 564 randomly selected Caucasian individuals in Russia. A heterozygous rs806052 variant was identified in one patient with DM2; c.1270T frequency was 0.003. Prevalence of rs143051164 c.844G was 0.003 in the control population and 0.004 and 0.003 in MODY and DM2 samples, respectively. Prevalence of rs149840771 c.2096A was 0.003 and 0.004 in the control population and among MODY patients, respectively. In DM2 patients, rs149840771 c.2096A was not identified. We did not detect any associations of rs806052, rs143051164, and rs149840771 with carbohydrate metabolism disorders among patients with MODY and DM2 in Russia.


Histiocytosis: a review focusing on neuroimaging findings.
Histiocytosis is a systemic disease that usually affects the central nervous system. The aim of this study is to discuss the neuroimaging characteristics of Langerhans cell histiocytosis (LCH), the most common of these diseases; and the non-Langerhans cells histiocytosis (NLCH), which includes entities such as hemophagocytic syndrome, Erdheim-Chester and Rosai-Dorfman diseases. Literature review and illustrative cases with pathologic confirmation. In LCH, the most common findings are 1) osseous lesions in the craniofacial bones and/or skull base; 2) intracranial, extra-axial changes; 3) intra-axial parenchymal changes (white and gray matter); 4) atrophy. Among the NLCH, diagnosis usually requires correlation with clinical and laboratory criteria. The spectrum of presentation includes intraparenchymal involvement, meningeal lesions, orbits and paranasal sinus involvement. It is important the recognition of the most common imaging patterns, in order to include LCH and NLCH in the differential diagnosis, whenever pertinent.


Does neighbourhood composition modify the association between acculturation and unhealthy dietary behaviours?
Studies have shown that immigrants' acculturation is associated with numerous unhealthy behaviours. Yet, the role of environmental factors in modifying the effect of acculturation on health behaviours has received little attention. This study aims to create a more nuanced understanding of the health effects of acculturation by examining how neighbourhood immigrant composition modifies the association between individuals' eating patterns and acculturation. Cross-sectional Data from Los Angeles County Health Survey 2007 adult sample were linked to data on retail food establishments and US Census 2000 neighbourhood characteristics. Acculturation was measured by language spoken at home and years stayed in the US. Eating fast food more than once per week and eating zero serving of fruit or vegetables during the previous day were used as proxy indicators for unhealthy dietary behaviour. Multilevel logistic regression models were performed in the full sample and in the sample with only Latino adults. Immigrants' lack of acculturation and living in a neighbourhood with a high percentage immigrants were associated with healthier dietary behaviour. We also identified that lack of acculturation conveyed a significantly stronger protective effect on regular fast-food consumption for immigrants living in neighbourhoods with higher percentage immigrants (OR: 0.34, 95% CI: 0.12 to 0.93). Among immigrants in Los Angeles County, living in a neighbourhood with a high density of other immigrants attenuates the negative effects of acculturation on healthy eating behaviours. Healthy eating promotion efforts should build on this protective effect in outreach to acculturating immigrant communities.


Polymer microfiber rings for high-sensitivity optical humidity sensing.
We demonstrate microrings assembled with polyacrylamide (PAM) microfibers for high-sensitivity relative humidity (RH) sensing. When exposed to moisture, the PAM microfiber absorbs water molecules and inflates monotonically with the increasing humidity, resulting in evident spectral shifts of the resonance peaks of the microring. By measuring the spectral shifts, the microring shows sensitivity as high as 490 pm/%RH and a response time of about 120 ms, within a dynamic range from 5% to 71% RH.


Topics on maternal, fetal and neonatal immunology of dogs and cats.
Birth and the first few weeks of age are critical periods of developing the immune system of puppies and kittens and adapting to an environment containing a variety of infectious agents. The survival rate during these periods depends mainly on the newborn's immune capacity to prevent and combat infections. Although most components of innate and adaptive immunity are present at birth, responses are slow and immature compared to adults. Due to immunological immaturity and the endotheliochorial placental structure, circulating concentrations of immunoglobulins in dogs and cats at birth are quite low. Thus, newborns need a prompt and immediate immune response, which is essentially provided by defense cells and maternal antibodies via colostrum. Failure to ingest colostrum is correlated with high mortality rates in the neonatal period. Concurrently, factors related to pregnant, such as pregnancy physiological immunosuppression and nutritional and health states, can directly influence newborn immunity and health. Therefore, understanding the maternal and neonatal immunological aspects, importance of colostrum, risk factors for failure to transfer passive immunity and colostrum substitute strategies are essential to ensure the survival of the litter.


Nesidioblastosis and persistent neonatal hyperinsulinism.
Neonatal hyperinsulinism is characterized by severe hypoglycaemia which can cause serious neurologic effects. Pancreatic morphological abnormalities involve either focal or diffuse lesions. The former can be cured by resection, whereas the latter, of uncertain pathogenesis, often require subtotal pancreatectomy. We investigated various hypotheses in an effort to explain the origin of this latter form of hyperinsulinism. We determined that nesidioblastosis, long considered to be the basic structural lesion of the diffuse form of hyperinsulinism, is not specific and does not correspond to a continuous proliferation of endocrine cells. We found that an increase in beta-cell mass can be excluded since the volume density of beta cells is not systematically higher in hyperinsulinemic infants than in controls. The hypothesis of a decrease in D cells is attractive but should be considered with due caution since the decrease of the D-cell volume density observed in hypoglycaemic infants is inconstant. Finally, the notion of beta-cell functional abnormality seems the most likely explanation since a higher quantity of proinsulin was detected within the Golgi area by a specific antibody and abnormal nuclei with abundant cytoplasm were observed in some cells. These histological abnormalities can be observed during intraoperative morphological examination. Functional activity might also be evaluated by studying the messenger RNA of proinsulin.


Glycosylphosphatidylinositol-anchor intermediates associate with triton-insoluble membranes in subcellular compartments that include the endoplasmic reticulum.
Glycosylphosphatidylinositol (GPI)-anchored proteins are resistant to solubilization with Triton X-100 at 4 degrees C, and they can be recovered in Triton-insoluble membranes (TIMs) that float to a characteristic buoyant density. Because the GPI structure itself has been shown to target GPI-anchored proteins to TIMs, we investigated the association of GPI-anchor intermediates with TIMs. GPI-anchor biosynthesis involves a pathway of some 10 steps that take place in the endoplasmic reticulum (ER). These intermediates include glucosaminyl-acylphosphatidylinositol [GlcN-(acyl)PI] and later mannosylated GPIs, denoted H6, H7 and H8, that are present not only in the ER but also in other cell compartments, including the plasma membrane. At least two-thirds of the GlcN-(acyl)PI in HeLa D cells and mannosylated GPIs in K562 cells were found in TIMs. Although previous reports have considered TIMs to be derived primarily from the plasma membrane, we recovered TIMs from subcellular fractions enriched in ER membranes. The ER marker calnexin and GPI-anchored proteins as well as N-acetylglucosaminyl-phosphatidylinositol and mannosylated GPIs were present in ER-TIMs. Interestingly, GlcN-PI and H7 were less enriched in ER-TIM than the other GPIs, suggesting that ER-TIMs might reflect a compartmentalization of the GPI-anchor biosynthetic pathway in the ER.


Silencing of mutant p53 by siRNA induces cell cycle arrest and apoptosis in human bladder cancer cells.
p53 is the most frequently mutated tumor-suppressor gene in human cancers. It has been reported that mutations in p53 result not only in the loss of its ability as a tumor suppressor, but also in the gain of novel cancer-related functions that contribute to oncogenesis. The present study evaluated the potential of silencing of mutant p53 by small interfering RNA in the treatment of bladder cancer cells in vitro. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability and flow cytometry to detect cell cycle alterations and apoptosis. The related molecular mechanisms were assessed by western blotting. We also used the MTT assay and flow cytometry to investigate if silencing of mutant p53 by knockdown with small interfering (si)RNA would change the sensitivity to cisplatin treatment. Using 5637 and T24 human bladder cancer cell lines characterized by mutations in p53, we found that silencing of the mutant p53 by RNA interference induced evident inhibition of cell proliferation and viability, which was related to the induction of G2 phase cell cycle arrest and apoptosis. Moreover, our study also showed that the p53-targeting siRNA cooperated with cisplatin in the inhibition of bladder cancer cells. These findings suggest that RNA interference targeting mutant p53 may be a promising therapeutic strategy for the treatment of bladder cancer.


[Which follow-up of the second generation antipsychotic in adolescents?].
Since the introduction of so called second generation antipsychotic (SGA), the prescription of these drugs has been relatively frequent in adolescence. This article gives a synopsis of the potential side effects and contra-indications, and proposes a practical guideline for the follow-up of these SGAs in adolescent and young adults. The main secondary side effects are in metabolic, endocrine, neurologic, cardiovascular systems and also on the hematological and liver functions. Thus, a strict follow-up should start before the introduction of a SGA treatment and should be continued during the time of administration. Since there is no common consent for a follow-up in SGA use in adolescents for Europe, this article may give a practical guideline for general practitioners and pediatricians, including a clinical exam and biological parameters to be controlled.


Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia.
The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.


Natural and socioeconomic determinants of the embodied human appropriation of net primary production and its relation to other resource use indicators.
Indicators of resource use such as material and energy flow accounts, emission data and the ecological footprint inform societies about their performance by evaluating resource use efficiency and the effectiveness of sustainability policies. The human appropriation of net primary production (HANPP) is an indicator of land-use intensity on each nation's territory used in research as well as in environmental reports. 'Embodied HANPP' (eHANPP) measures the HANPP anywhere on earth resulting from a nation's domestic biomass consumption. The objectives of this article are (i) to study the relation between eHANPP and other resource use indicators and (ii) to analyse socioeconomic and natural determinants of global eHANPP patterns in the year 2000. We discuss a statistical analysis of >140 countries aiming to better understand these relationships. We found that indicators of material and energy throughput, fossil-energy related CO2 emissions as well as the ecological footprint are highly correlated with each other as well as with GDP, while eHANPP is neither correlated with other resource use indicators nor with GDP, despite a strong correlation between final biomass consumption and GDP. This can be explained by improvements in agricultural efficiency associated with GDP growth. Only about half of the variation in eHANPP can be explained by differences in national land-use systems, suggesting a considerable influence of trade on eHANPP patterns. eHANPP related with biomass trade can largely be explained by differences in natural endowment, in particular the availability of productive area. We conclude that eHANPP can deliver important complimentary information to indicators that primarily monitor socioeconomic metabolism.


Influences of oxytocin and respiratory sinus arrhythmia on emotions and social behavior in daily life.
The literature concerning biological influences on positive social behavior shows that, in nonthreatening contexts, tonic oxytocin (OT) and respiratory sinus arrhythmia (RSA) each predict positive, affiliative behaviors toward certain others and are associated with positive health outcomes. The purpose of this investigation was to determine the degree to which the positive affiliative correlates of OT and RSA can be distinguished when observed at the level of everyday life events. A sample of midlife adults (N = 73) provided tonic indices of these biological characteristics, as well as perceptions of a variety of common life events alongside reports of their emotions during those events. OT and RSA each independently moderated the link between perceived event sociality and positive emotions, whereas only RSA predicted the probability of being with other people during an event. These findings suggest that OT and RSA may each be linked to positive social experiences in complementary yet distinct ways. (PsycINFO Database Record


Inverse association between yoghurt intake and upper aerodigestive tract cancer risk in a Japanese population.
Although the combination of tobacco smoking and alcohol drinking account for approximately 80% of upper aerodigestive tract (UADT) cancer risk, the role of dietary factors, including dairy products, in the risk of these cancers remains controversial. We aimed to evaluate the association between dairy product intake and UADT cancer risk in a Japanese population. We conducted a case-control study in 959 patients with UADT cancer and 2877 sex- and age-matched noncancer control subjects who visited the Aichi Cancer Center in Nagoya, Japan. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Associations were assessed by multivariate logistic regression models that considered potential confounders. We found a significant inverse association between yoghurt intake and UADT cancer risk with multivariate-adjusted odds ratios and 95% confidence intervals for <1 time/week, ≥ 1 time/week and <1 time/day, and ≥ 1 time/day consumption of yoghurt of 0.70 (95% confidence interval: 0.54-0.91), 0.67 (0.54-0.84), and 0.73 (0.55-0.95) relative to nonconsumers (P trend=0.005). When stratified by primary tumor site, this association was significant among patients with hypopharyngeal, laryngeal, and esophageal cancer. However, we saw no significant association between milk or butter intake and UADT cancer risk. In this study, we found that a high intake of yoghurt may lower the risk of developing UADT cancer in a Japanese population. Further investigation of this association is warranted.


Efficient ER exit and vacuole targeting of yeast Sna2p require two tyrosine-based sorting motifs.
SNA (Sensitive to Na(+)) proteins form a membrane protein family, which, in the yeast Saccharomyces cerevisiae, is composed of four members: Sna1p/Pmp3p, Sna2p, Sna3p and Sna4p. In this study, we focused on the 79 residue Sna2p protein. We found that Sna2p is localized in the vacuolar membrane. Directed mutagenesis showed that two functional tyrosine motifs YXXØ are present in the C-terminal region. Each of these is involved in a different Golgi-to-vacuole targeting pathway: the tyrosine 65 motif is involved in adaptor protein (AP-1)-dependent targeting, whereas the tyrosine 75 motif is involved in AP-3-dependent targeting. Moreover, our data suggest that these motifs also play a crucial role in the exit of Sna2p from the endoplasmic reticulum (ER). Directed mutagenesis of these tyrosines led to a partial redirection of Sna2p to lipid bodies, probably because of a decrease in ER exit efficiency. Sna2p is the first yeast protein in which two YXXØ motifs have been identified and both were shown to be functional at two different steps of the secretory pathway, ER exit and Golgi-to-vacuole transport.


Neurofibromatosis: part 2--clinical management.
Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.


Open-loop analysis on sympathetically mediated arterial pressure and urine output responses in rats: effect of renal denervation.
Primary acute sympathetic activation (PASA) can increase arterial pressure (AP). Under this situation, the kidneys may receive mutually opposing influences from sympathetic activation: a direct anti-diuretic effect via the renal innervation and pressure diuresis. We examined whether PASA would reduce urine output regardless of the AP elevation. We also examined the impact of renal denervation (RDN) on urine output during PASA. The experiment was performed on rats 3 to 9 days after unilateral RDN (n = 10). Under anesthesia, systemic sympathetic nerve activity (SNA) was varied over a wide range via the carotid sinus baroreflex. The slope of urine flow versus SNA was positive (0.252 ± 0.052 μL·min-1·kg-1· %-1) on the intact side, and it was greater on the denervated side (0.331 ± 0.069 μL·min-1·kg-1· %-1, P < 0.05). In conclusion, urine output change was an effect of elevated AP during PASA. Nevertheless, RDN was able to augment pressure diuresis during PASA.


Risk of hepatitis C virus transmission from an infected gynecologist to patients: results of a 7-year retrospective investigation.
Currently, it is not known how often hepatitis C virus (HCV) is transmitted from infected health care workers to patients during medical care. In the present investigation, we tried to determine the rate of provider-to-patient transmission of HCV among former patients of an HCV-positive gynecologist after it was proven that he infected one of his patients with HCV during a cesarean section. All 2907 women who had been operated on by the HCV-positive gynecologist between July 1993 and March 2000 were notified about potential exposure and were offered free counseling and testing. The crucial differentiation between HCV transmissions caused by the gynecologist and infections contracted from other sources was achieved by epidemiological investigations, nucleotide sequencing, and phylogenetic analysis. Of the 2907 women affected, 78.6% could be screened for markers of HCV infection. Seven of these former patients were found to have HCV. Phylogenetic analysis of HCV sequences from the gynecologist and the women did not indicate that the virus strains were linked. Therefore, no further iatrogenic HCV infections caused by the gynecologist could be detected. The resulting overall HCV transmission rate was 0.04% (1 per 2286; 95% confidence interval, 0.008%-0.25%). To our knowledge, this is the largest retrospective investigation of the risk of provider-to-patient transmission of HCV conducted so far. Our findings support the notion that such transmissions are relatively rare events and might provide a basis for future recommendations on the management of HCV-infected health care workers.


Greater self-efficacy, psychological readiness and return to sport amongst paediatric patients compared with adolescents and young adults, 8 and 12 months after ACL reconstruction.
The purpose of this study was to evaluate differences in rehabilitation-specific outcomes between paediatric patients, adolescents and young adults within the first 2 years after anterior cruciate ligament (ACL) reconstruction. A further aim was to determine whether patient age was associated with an increased risk of not achieving symmetrical muscle function within the first 2 years after ACL reconstruction. The patient data in the present study were extracted from the rehabilitation outcome registry, Project ACL. Patients aged 11-25 years registered for primary ACL reconstruction with a hamstring tendon autograft between April 1, 2013 and November 23, 2020 were included. A total of 691 patients met the inclusion criteria and were included in the study; 41 paediatric patients (females 11-13, males 11-15 years), 347 adolescents (females 14-19, males 16-19 years) and 303 young adults (females 20-25, males 20-25 years). The comparison between groups revealed that 70% of paediatric patients, 39% of adolescents and 35% of young adults had returned to knee-strenuous sport at 8 months and that 90% of paediatric patients, 71% of adolescents and 62% of young adults had returned to sport at 12 months. Paediatric patients also reported higher scores compared with both the other patient groups on the Knee Self-Efficacy Scale (K-SES) and the Anterior Cruciate Ligament Return to Sport after Injury scale (ACL-RSI) at 8 and 12 months. A larger proportion of paediatric patients had returned to sport compared with adolescents and young adults 8 and 12 months after ACL reconstruction. Paediatric patients also reported higher self-efficacy and greater psychological readiness to return to sport at 8 and 12 months than the other two groups. No differences in terms of muscle function tests when comparing paediatric patients, adolescents and young adults were found. II.


[Baroreflexes originated in vertebral artery zones upon peripheral vein tonus, systemic arterial blood pressure, and external respiration].
The investigation was intended to study the role ofbaroreceptors ofhemodynamically isolated zone of vertebral arteries in regulation of peripheral veins tonus, arterial pressure and external respiration. Pressure decrease in this vascular reflexogenic zone led to reflex responses of increase in femoral vein tonus, elevation of blood pressure level and stimulation of external respiration. The opposite reflex responses of cardio-respiratory functional system to initial pressure activation of vertebral arteries baroreceptors are observed. Basing on generalization of our own findings and similar physiological and morphological researches of other authors, it is established that afferentation from the vertebral artery zone is a reflexogenic factor of somatic muscles' veins tonus regulation. These reflexes of capacity vessels tonic activity changes are part of cardio-respiratory responses of maintaining the tissue gaseous exchange.


Compatibility of tissue conditioners and dental stones: effect on surface roughness.
Although the primary use of tissue conditioners is to treat abused mucosa, these materials are also frequently used as functional impression materials. No information was identified on the effect that these materials may have on the surface of the resultant dental stone cast. This study evaluated the compatibility of 3 tissue conditioners with dental stones and changes in surface conditions over time. Three tissue conditioners (COE-comfort, Soft-conditioner, and Visco-gel) and 4 dental stones (Capstone DF, New Plastone, Die Stone, and New Fujirock) were evaluated. One impression material (Examixfine) was used as a control. Tissue conditioner disks were made by pouring freshly mixed material into a polypropylene container, pressing the material down with a glass plate, and then removing the plate 2 hours later. The disks were then stored in distilled water for 0 or 24 hours, or 3, 7, or 14 days. Subsequently, each dental stone was mixed and poured over the top of each disk and allowed to remain for 60 minutes. Twenty-five disk-shaped specimens, 18 x 2 mm, for each tissue conditioner/stone cast combination were prepared. Mean surface roughness (Ra) values of the dental stone casts made from the tissue conditioners were determined using a profilometer. Five measurements for each specimen were made. Data were analyzed with 1- and 3-way analysis of variance and the Student-Newman-Keuls test (alpha=.05). Detail reproduction was also determined using a ruled test block, as specified in ISO specification 4823. Contribution ratios determined by 3-way analysis of variance indicated that the surface roughness values were significantly more influenced by the time of immersion in water ( P <.0005, contribution ratio rho=37%), than the type of tissue conditioner ( P <.0005, rho=19%) or dental stone used ( P <.0005, rho=1%). The best surface quality was obtained with a New Fujirock cast (0.81 +/- 0.06 microm), followed by New Plastone (0.83 +/- 0.12 microm) and Die Stone (0.85 +/- 0.05 microm) casts, in combination with Visco-gel without immersion in water, and those were nearly equivalent in surface roughness to a Die stone cast from Examixfine. The surface roughness values of all specimens, especially the COE-comfort/stone cast combinations, significantly increased with tissue conditioner immersion time ( P <.0005). Visco-gel tended to produce a better surface quality during the test periods than the other materials. All stone casts made from the tissue conditioners not immersed in water reproduced 20-microm or 50-microm lines, while the detail diminished over time with immersion. The type of tissue conditioner, and especially immersion time, had a significant effect on the surface quality of dental stone casts. The type of dental stone used is less important.


[Structural review of chemical agents that can induce parkinsonism].
To identify similar structural elements in the largest number possible of chemical agents which can induce Parkinsonism and study their relation with the main chemical changes seen in Parkinsonism. We studied the chemical structure and structural relations of the chemical agents reported in the literature because of their ability to induce Parkinsonism. We observed the structural similarity of the majority of chemical agents and the structural discrepancy of the rest. The structural element identified as common had three clearly differentiated parts: a cyclic fragment, bridge fragment and nitrogen atom fragment. We studied the diversity of the parts of each fragment. We studied the relation of the common structural element with other biochemical components which are altered in Parkinsonism, and also the possible mechanism of action of the structural element in the process of induction of Parkinsonism. There is a structural grouping close to the molecule of the dopamine neurotransmitter in most of the organic compounds which can induce Parkinsonism. Therefore, we suggest that the origin of certain Parkinsonian conditions may be due to changes in the natural equilibrium of dopamine due to the action of chemical agents with a suitable chemical substructure similar to that of dopamine.


Drosophila MAGI interacts with RASSF8 to regulate E-Cadherin-based adherens junctions in the developing eye.
Morphogenesis is crucial during development to generate organs and tissues of the correct size and shape. During Drosophila late eye development, interommatidial cells (IOCs) rearrange to generate the highly organized pupal lattice, in which hexagonal ommatidial units pack tightly. This process involves the fine regulation of adherens junctions (AJs) and of adhesive E-Cadherin (E-Cad) complexes. Localized accumulation of Bazooka (Baz), the Drosophila PAR3 homolog, has emerged as a critical step to specify where new E-Cad complexes should be deposited during junction remodeling. However, the mechanisms controlling the correct localization of Baz are still only partly understood. We show here that Drosophila Magi, the sole fly homolog of the mammalian MAGI scaffolds, is an upstream regulator of E-Cad-based AJs during cell rearrangements, and that Magi mutant IOCs fail to reach their correct position. We uncover a direct physical interaction between Magi and the Ras association domain protein RASSF8 through a WW domain-PPxY motif binding, and show that apical Magi recruits the RASSF8-ASPP complex during AJ remodeling in IOCs. We further show that this Magi complex is required for the cortical recruitment of Baz and of the E-Cad-associated proteins α- and β-catenin. We propose that, by controlling the proper localization of Baz to remodeling junctions, Magi and the RASSF8-ASPP complex promote the recruitment or stabilization of E-Cad complexes at junction sites.


Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells.
Hypoxia plays an important role in vascular development through hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation and downstream pathway activation. We sought to explore the in vitro response of cultures of human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human endothelial progenitor cells (hEPCs), and human umbilical cord vein endothelial cells (HUVECs) to normoxic and hypoxic oxygen tensions. We first measured dissolved oxygen (DO) in the media of adherent cultures in atmospheric (21% O(2)), physiological (5% O(2)), and hypoxic oxygen conditions (1% O(2)). In cultures of both hEPCs and HUVECs, lower oxygen consumption was observed when cultured in 1% O(2). At each oxygen tension, feeder-free cultured hESCs and iPSCs were found to consume comparable amounts of oxygen. Transport analysis revealed that the oxygen uptake rate (OUR) of hESCs and iPSCs decreased distinctly as DO availability decreased, whereas the OUR of all cell types was found to be low when cultured in 1% O(2), demonstrating cell adaptation to lower oxygen tensions by limiting oxygen consumption. Next, we examined HIF-1alpha accumulation and the expression of target genes, including VEGF and angiopoietins (ANGPT; angiogenic response), GLUT-1 (glucose transport), BNIP3, and BNIP3L (autophagy and apoptosis). Accumulations of HIF-1alpha were detected in all four cell lines cultured in 1% O(2). Corresponding upregulation of VEGF, ANGPT2, and GLUT-1 was observed in response to HIF-1alpha accumulation, whereas upregulation of ANGPT1 was detected only in hESCs and iPSCs. Upregulation of BNIP3 and BNIP3L was detected in all cells after 24-h culture in hypoxic conditions, whereas apoptosis was not detectable using flow cytometry analysis, suggesting that BNIP3 and BNIP3L can lead to cell autophagy rather than apoptosis. These results demonstrate adaptation of all cell types to hypoxia but different cellular responses, suggesting that continuous measurements and control over oxygen environments will enable us to guide cellular responses.


CENTRAL, PEDro, PubMed, and EMBASE are the most comprehensive databases indexing randomized controlled trials of physical therapy interventions.
Many bibliographic databases index research studies evaluating the effects of health care interventions. One study has concluded that the Physiotherapy Evidence Database (PEDro) has the most complete indexing of reports of randomized controlled trials of physical therapy interventions, but the design of that study may have exaggerated estimates of the completeness of indexing by PEDro. The purpose of this study was to compare the completeness of indexing of reports of randomized controlled trials of physical therapy interventions by 8 bibliographic databases. This study was an audit of bibliographic databases. Prespecified criteria were used to identify 400 reports of randomized controlled trials from the reference lists of systematic reviews published in 2008 that evaluated physical therapy interventions. Eight databases (AMED, CENTRAL, CINAHL, EMBASE, Hooked on Evidence, PEDro, PsycINFO, and PubMed) were searched for each trial report. The proportion of the 400 trial reports indexed by each database was calculated. The proportions of the 400 trial reports indexed by the databases were as follows: CENTRAL, 95%; PEDro, 92%; PubMed, 89%; EMBASE, 88%; CINAHL, 53%; AMED, 50%; Hooked on Evidence, 45%; and PsycINFO, 6%. Almost all of the trial reports (99%) were found in at least 1 database, and 88% were indexed by 4 or more databases. Four trial reports were uniquely indexed by a single database only (2 in CENTRAL and 1 each in PEDro and PubMed). The results are only applicable to searching for English-language published reports of randomized controlled trials evaluating physical therapy interventions. The 4 most comprehensive databases of trial reports evaluating physical therapy interventions were CENTRAL, PEDro, PubMed, and EMBASE. Clinicians seeking quick answers to clinical questions could search any of these databases knowing that all are reasonably comprehensive. PEDro, unlike the other 3 most complete databases, is specific to physical therapy, so studies not relevant to physical therapy are less likely to be retrieved. Researchers could use CENTRAL, PEDro, PubMed, and EMBASE in combination to conduct exhaustive searches for randomized trials in physical therapy.


MAJIQ-SPEL: web-tool to interrogate classical and complex splicing variations from RNA-Seq data.
Analysis of RNA sequencing (RNA-Seq) data have highlighted the fact that most genes undergo alternative splicing (AS) and that these patterns are tightly regulated. Many of these events are complex, resulting in numerous possible isoforms that quickly become difficult to visualize, interpret and experimentally validate. To address these challenges we developed MAJIQ-SPEL, a web-tool that takes as input local splicing variations (LSVs) quantified from RNA-Seq data and provides users with visualization and quantification of gene isoforms associated with those. Importantly, MAJIQ-SPEL is able to handle both classical (binary) and complex, non-binary, splicing variations. Using a matching primer design algorithm it also suggests to users possible primers for experimental validation by RT-PCR and displays those, along with the matching protein domains affected by the LSV, on UCSC Genome Browser for further downstream analysis. Program and code will be available at http://majiq.biociphers.org/majiq-spel. Supplementary data are available at Bioinformatics online.


Development of an instrument to measure cancer screening knowledge, attitudes and behaviours.
The development of a comprehensive survey instrument to measure the knowledge, attitudes and behaviours of the general public with regard to cancer screening was the goal of this project. A thorough review of the literature was undertaken, and existing survey instruments were identified and organized according to type of cancer screening behaviour being measured; question foci (predisposing, enabling and reinforcing factors); and survey implementation protocol. A comprehensive survey instrument was developed with the intention that, if feasible, the survey of cancer screening behaviours could be implemented nationally by telephone. Separate survey instruments were developed according to sex. Focus groups were held across Canada to determine the comprehensiveness of the survey items; ease of understanding and ability to respond; feasibility with respect to possible sensitivity of some of the question items; and general implementation issues (e.g. length, sex of interviewer). This paper reports on the qualitative portion of the project. Our study supports the use of qualitative methodology for instrument development and implementation.


Upregulation of Th1 cytokine profile in bronchoalveolar lavage fluid of patients with hypersensitivity pneumonitis.
The aim was to find out how the IL-12 and IL-18 levels in the bronchoalveolar lavage fluid (BALF) correspond to the inflammatory activity of the hypersensitivity pneumonitis (HP). We studied 12 patients with HP and 13 normal subjects. IL-12 and IL-18 levels were measured using ELISA kits. We found a significantly higher plasma angiotensin-converting enzyme (ACE) concentration (55 vs. 34 U/L, P=0.0016), lymphocyte percentage (57 vs. 14%, P<0.001), CD8+ cells (32 vs. 17%, P<0.001) and a lower CD4/CD8 ratio (1.2 vs. 2.0, P<0.0001). The IL-12 and IL-18 levels in BALF were significantly higher in HP patients than in healthy subjects (3.9 vs. 3.2 pg/ml, P=0.003 and 14.2 vs. 6.15 pg/ml, P% 0.0001, respectively). We found a strong positive correlation between IL-12 and the percentage of lymphocytes (r=0.68, P=0.015) and a negative one between IL-12 and the percentage of macrophages in BALF (r=-0.64, P=0.024). We conclude that upregulation of the Th1 cell cytokine profile may play a significant role in the pathogenesis of HP.