Bulky dna adducts in cord blood, maternal fruit-and-vegetable consumption, and birth weight in a European mother-child study (NewGeneris).
Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs. We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy. Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006-2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires. Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p < 0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g). Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective.


Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload.
It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg. Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers; supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.


Analysis by mathematical model of haemodynamic data in the failing Fontan circulation.
Several late complications jeopardize the clinical performance of recipients of the Fontan operation. The underlying causes have been referred to disturbed flow dynamics in the cavopulmonary connections. Presumably, the large pressure drops occurring in the inferior and superior connections play a pivotal role in the pressure level of the entire circulation, especially in the venous. To address this issue, we retrospectively reviewed catheterization data of six patients with failing Fontan circulation and compared them with those of six patients with functioning Fontan circulation. The impact on the systemic and pulmonary pressure of the increase in the cavopulmonary connection resistances was studied through a steady-state mathematical model of the univentricular closed-loop circulation. In the patients with failing Fontan, pressure in the venae cavae was found to be significantly higher, especially at the inferior cava (19.3 +/- 2.2 versus 12.5 +/- 2.3 mmHg) with the pressure drop at the inferior cavopulmonary connection significantly increased (4.7 +/- 3.1 versus 0.33 +/- 0.82 mmHg). The proposed mathematical model permits us to clearly relate the pressure increase in the venae cavae to an increased resistance in the cavopulmonary connections. Therefore, the present analysis confirms that, to avoid possible congestion of venous circulation, the definitive palliation of univentricular heart should not cause pressure drops at the cavopulmonary connections.


Suppressors of the ras2 mutation of Saccharomyces cerevisiae.
Saccharomyces cerevisiae contains two members of the ras gene family. Strains with disruptions of the RAS2 gene fail to grow efficiently on nonfermentable carbon sources. This growth defect can be suppressed by extragenic mutations called sra. We have isolated 79 independent suppressor mutations, 68 of which have been assigned to one of five loci. Eleven additional dominant mutations have not been assigned to a specific locus. Some sra1 and SRA4 and all SRA3 mutations were RAS independent, allowing growth of yeast cells that lack a functional RAS gene. Mutations in sra1, SRA3, SRA4 and sra6 are linked to his6, ino1, met3 and ade6, respectively. Some sra mutants have pleiotropic phenotypes that affect glycogen accumulation, sporulation, viability, respiratory capacity and suppression of two cell-division-cycle mutations, cdc25 and cdc35. The proposed functions of many of the suppressor genes are consistent with the model in which RAS activates adenylate cyclase.


Thermodynamic studies of ionic interactions in aqueous solutions of imidazolium-based ionic liquids [Emim][Br] and [Bmim][Cl].
Experimental measurements of density at different temperatures ranging from 293.15 to 313.15 K, the speed of sound and osmotic coefficients at 298.15 K for aqueous solution of 1-ethyl-3-methylimidazolium bromide ([Emim][Br]), and osmotic coefficients at 298.15 K for aqueous solutions of 1-butyl-3-methylimidazolium chloride ([Bmim][Cl]) in the dilute concentration region are taken. The data are used to obtain compressibilities, expansivity, apparent and limiting molar properties, internal pressure, activity, and activity coefficients for [Emim][Br] in aqueous solutions. Experimental activity coefficient data are compared with that obtained from Debye-Hückel and Pitzer models. The activity data are further used to obtain the hydration number and the osmotic second virial coefficients of ionic liquids. Partial molar entropies of [Bmim][Cl] are also obtained using the free-energy and enthalpy data. The distance of the closest approach of ions is estimated using the activity data for ILs in aqueous solutions and is compared with that of X-ray data analysis in the solid phase. The measured data show that the concentration dependence for aqueous solutions of [Emim][Br] can be accounted for in terms of the hydrophobic hydration of ions and that this IL exhibits Coulombic interactions as well as hydrophobic hydration for both the cations and anions. The small hydration numbers for the studied ILs indicate that the low charge density of cations and their hydrophobic nature is responsible for the formation of the water-structure-enforced ion pairs.


In silico prediction of e-cigarette aerosol particle transport and deposition within the airways.
Electronic cigarettes (ECs) generate aerosols by heating up a liquid ('e-liquid') that typically consists of propylene glycol (PG), vegetable glycerol (VG), nicotine and flavouring agents. These aerosols transport through the airway tree, and lung and deposit non-uniformly in the bronchi and alveoli. Studying the transport of aerosols through lung airways is necessary because it provides information about the concentration and deposition of particles in the upper and lower airways. Here, particle transport and deposition were simulated within an anatomically-realistic airway model, which was constructed from computed tomography imaging. Particle transport was simulated using the advection-diffusion equations. Particle deposition was estimated using three different mechanisms; including sedimentation, impaction and Brownian diffusion. Results show that by increasing the particle size (PS) from 50 nm to 500 nm, the total deposition efficiency decreased from 50% to 10%, and then by increasing the PS to 3 μm, it increased to 60%. In addition, Brownian deposition was the dominant mechanism for nanoparticles (PS≪0.5μm), while the sedimentation deposition mechanism was the dominant one for microparticles (PS≫0.5μm).Clinical relevance-There is an urgent need to understand the risk that ECs pose to human health and to determine the safest methods for using these devices to support smoking cessation whilst also minimising harm. The results of this study will be used to simulate the conditions such as aerosol concentration and flow rate in airways and alveoli to use in in vitro studies.


Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families.
Recent work shows promising associations between schizophrenia and polymorphisms in neuregulin-1 (NRG1) and a large literature also finds strong familial relationships between schizophrenia and cognitive deficits. Given the role of NRG1 in glutamate regulation and glutamate's effect on cognition, we hypothesized that cognitive deficits may be related to variation within NRG1, providing a possible mechanism to increase risk for schizophrenia. This study examined the associations between NRG1, cognition, and schizophrenia using a multigenerational multiplex family sample (total N=419, 40 families), including 58 affected participants (schizophrenia or schizoaffective disorder-depressed type) and their 361 unaffected relatives. Participants were genotyped for 40 NRG1 single nucleotide polymorphisms (SNPs), chosen largely based on previous associations with schizophrenia. All participants completed structured diagnostic interviews and a computerized neurocognitive battery assessing eight cognitive domains. Variance component quantitative trait analyses tested for associations between individual NRG1 SNPs and cognitive performance in the total sample, a subsample of healthy participants with no Diagnostic and Statistical Manual of Mental Disorders diagnosis, and using general intelligence as a covariate. Effect sizes (within-family β coefficients) ranged from 0.08 to 0.73, and 61 of these associations were nominally significant (P≤0.05), with 12 associations at P≤0.01, although none achieved the modified Bonferroni significance threshold of P<0.0003. Attention was the most frequently nominally associated domain and rs10503929, a nonsynonymous SNP, was the most frequently nominally associated SNP. Although not significant experiment-wise, these findings suggest that further study of the associations between variation in NRG1 and cognition may be productive.


Understanding the relationships between health outcomes in generalized anxiety disorder clinical trials.
The Wilson-Cleary health outcomes model is a hypothesized pathway linking traditional clinical variables to health-related quality of life (HRQL). This study tested the application of the Wilson-Cleary model to a patient population with generalized anxiety disorder (GAD) using longitudinal clinical trial data. These secondary analyses pooled data from three similar 8-week, placebo-controlled, double-blind, randomized, multicenter trials of quetiapine XR therapy in GAD. Relevant health assessments for the model concepts included the Clinical Global Impression-Severity of Illness, Hamilton Rating Scale for Anxiety, the Pittsburgh Sleep Quality Index and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form. A lagged path model tested whether the hypothesized relationships at baseline and week 8 between the concepts of the adapted Wilson-Cleary model were consistent with the observed data. The resulting model fit the data (RMSEA = 0.077; CFI = 0.98; NFI = 0.96) and explained 56% of the variance in overall quality of life assessment at baseline and 69% of the variance in this assessment at week 8. Moderate to strong relationships between the adjacent hypothesized concepts support the specified model. This adapted Wilson-Cleary model for health outcomes validated in GAD should improve the understanding and usefulness of health status measurements in this condition and increase the applications of this model to other clinical trial data.


[Prognosis and treatment of patients with systemic lupus erythematosus in different age groups].
The paper is concerned with observation over 470 patients with systemic lupus erythematosus (SLE) admitted to the Institute of Rheumatology, Academy of Medical Sciences of the USSR, since December 1958 to December 1983. Women (453) with a disease onset at 10 to 55 years (355 had associated SLE and nephritis, 155 presented with SLE without nephritis) accounted for the absolute majority of cases. Comparison of the disease clinical picture in 2 groups of patients, who had fallen ill at 14 to 24 years (278 subjects) and at 40 to 55 years (25 subjects) revealed a graver clinical picture in the group of patients, who had fallen ill at a younger and (nephritis in 82% against 56% in the group of older patients) and a considerably less survival as compared to the group of older patients despite more intensive care including pulse-therapy with methyl prednisolone.


Assembling the evidence: patient-focused outcomes research.
Wide variations in medical practice point to the need for better information about the effectiveness of medical interventions derived from well-conducted outcomes studies. The best outcomes research is patient-focused. The example of hysterectomy is used to illustrate the type of information patients need if they are to be active participants in decisions about their care. These decisions are complex, involving the weighing up of a number of potential risks, benefits and uncertainties. Patients as well as doctors need reliable summaries of the evidence to promote shared decision-making and to increase the chance of beneficial health outcomes.


Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure.
Elastin is a major structural component of large elastic arteries and a principal determinant of arterial biomechanical properties. Elastin loss-of-function mutations in humans have been linked to the autosomal-dominant disease supravalvular aortic stenosis, which is characterized by stenotic lesions in both the systemic and pulmonary circulations. To better understand how elastin insufficiency influences the pulmonary circulation, we evaluated pulmonary cardiovascular physiology in a unique set of transgenic and knockout mice with graded vascular elastin dosage (range 45-120% of wild type). The central pulmonary arteries of elastin-insufficient mice had smaller internal diameters (P < 0.0001), thinner walls (P = 0.002), and increased opening angles (P = 0.002) compared with wild-type controls. Pulmonary circulatory pressures, measured by right ventricular catheterization, were significantly elevated in elastin-insufficient mice (P < 0.0001) and showed an inverse correlation with elastin level. Although elastin-insufficient animals exhibited mild to moderate right ventricular hypertrophy (P = 0.0001) and intrapulmonary vascular remodeling, the changes were less than expected, given the high right ventricular pressures, and were attenuated compared with those seen in hypoxia-induced models of pulmonary arterial hypertension. The absence of extensive pathological cardiac remodeling at the high pressures in these animals suggests a developmental adaptation designed to maintain right-sided cardiac output in a vascular system with altered elastin content.


Axonal neuropathy, long limbs and bumpy tongue: think of MEN2B.
Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. A 14-year-old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot-Marie-Tooth syndrome). Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis.


Variation in NICU Admission Rates Without Identifiable Cause.
Admission to the NICU is influenced by physiologic compromise and by hospital care protocols. Providing appropriate care must be balanced with adverse consequences of NICU admission, such as interrupting maternal-infant bonding and unnecessary interventions. This study aims to determine the variation in NICU admissions in term and late preterm infants among 19 hospitals. We used the Consortium on Safe Labor (CSL) database to determine NICU admission rates. This database includes data from 217 442 infants aged 35 to 42 weeks within 19 US maternal delivery hospitals from 2002 to 2008. NICU admission rates were evaluated for absolute factors including, but not limited to, sepsis, asphyxia, respiratory distress, and intracranial hemorrhage, as well as relative factors, such as maternal drug use, chorioamnionitis, and infant birth weight ≤ 2500 g. Percentage of infants 35 to 42 weeks' gestation admitted to the NICU without an identifiable absolute or relative cause for intensive care services ranged from 0% to 59.4% (mean, 10.8%; P < .001). Among infants 35 to 42 weeks' gestation and ≥ 2500 g, infants without absolute or relative identified cause accounted for 9.1% of total NICU days and had lower length of stays (-2.7 days; 95% confidence interval -3.4; -2.1) compared to those with an identified reason. There is significant variation in admission rates among NICUs that cannot be explained by infant health conditions. Further analysis is needed to determine the cause of between-site variation and potential opportunities to refine protocols and optimize use of NICU services.


Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke.
Minocycline provides neurovascular protection reducing acute cerebral injury. However, it is unclear whether minocycline is effective in females. We tested minocycline in both sexes and aged animals using a novel embolic stroke model in mice that closely mimics acute thromboembolic stroke in humans. Five groups of mice were subjected to thromboembolic stroke: adult males, aged males, adult females, aged females, and adult ovariectomized females. They were treated with phosphate saline (vehicle) or minocycline (6 mg/kg) immediately after stroke onset. Behavioral outcomes, infarct volumes and cerebral blood flow were assessed. The effect of minocycline on expression and activity of MMP-9 was analyzed. The model resulted in reproducible infarct in the experimental groups. As expected, adult females were significantly more resistant to cerebral ischemic injury than males. This advantage was abolished by aging and ovariectomy. Minocycline significantly reduced the infarct volume (P < 0.0001) and also improved neurologic score (P < 0.0001) in all groups. Moreover, minocycline treatment significantly reduced mortality at 24 hours post stroke (P = 0.037) for aged mice (25% versus 54%). Stroke up-regulated MMP-9 level in the brain, and acute minocycline treatment reduced its expression in both genders (P < 0.0001). In a thromboembolic stroke model minocycline is neuroprotective irrespective of mouse sex and age.


Antibacterial T6SS effectors with a VRR-Nuc domain are structure-specific nucleases.
The type VI secretion system (T6SS) secretes antibacterial effectors into target competitors. Salmonella spp. encode five phylogenetically distinct T6SSs. Here, we characterize the function of the SPI-22 T6SS of Salmonella bongori showing that it has antibacterial activity and identify a group of antibacterial T6SS effectors (TseV1-4) containing an N-terminal PAAR-like domain and a C-terminal VRR-Nuc domain encoded next to cognate immunity proteins with a DUF3396 domain (TsiV1-4). TseV2 and TseV3 are toxic when expressed in Escherichia coli and bacterial competition assays confirm that TseV2 and TseV3 are secreted by the SPI-22 T6SS. Phylogenetic analysis reveals that TseV1-4 are evolutionarily related to enzymes involved in DNA repair. TseV3 recognizes specific DNA structures and preferentially cleave splayed arms, generating DNA double-strand breaks and inducing the SOS response in target cells. The crystal structure of the TseV3:TsiV3 complex reveals that the immunity protein likely blocks the effector interaction with the DNA substrate. These results expand our knowledge on the function of Salmonella pathogenicity islands, the evolution of toxins used in biological conflicts, and the endogenous mechanisms regulating the activity of these toxins.


Disproving a silicon analog of an alkyne with the aid of topological analyses of the electronic structure and ab initio molecular dynamics calculations.
A silicon compound has recently been synthesized that was claimed to exhibit the first realization of a silicon-silicon triple bond. We debate this classification on the basis of a thorough investigation of the nature of the chemical bond, using the rigorous topological analysis of the electron density as developed in Bader's atoms-in-molecules theory, that of the electron localization function and the related orbital-independent definitions of the bond order. Our results refer both to the ground-state geometry and to nonequilibrium configurations, which are accessed by the system in a room-temperature ab initio molecular dynamics simulation. We also use the reciprocal compliance force constant as an independent chemical descriptor. All the above procedures are in agreement and do not support the classification of the silicon-silicon central bond as triple. The characterization which consistently emerges from the present study is one in which two electron pairs participate in the bonding and the other pair belongs mainly to nonbonding regions.


Intensive care and perioperative management of neonates with functionally univentricular hearts.
Although mortality rates for patients with univentricular hearts continue to fall, the course in the intensive care unit is remarkable for significant morbidity and utilization of significant resources. Preoperative patient management focuses on balancing competing circulations, pulmonary and systemic, which exist in parallel rather than in series, as in the normal circulation. Postoperative patient management focuses on optimizing systemic output, respiratory status, and mitigating the effects of cardiopulmonary bypass. In this article, we review pre- and postoperative intensive care management in neonates with a univentricular heart.


Effect of Ceftaroline, Vancomycin, Gentamicin, Macrolides, and Ciprofloxacin against Methicillin-Resistant Staphylococcus aureus Isolates: An In Vitro Study.
Background: Methicillin-resistant Staphylococcus aureus (MRSA) infection remains a challenging threat because of limited treatment options. Ceftaroline was identified as having potent anti-MRSA activity. Aim: To evaluate the susceptibility of MRSA to gentamicin, macrolides, ciprofloxacin, vancomycin, and ceftaroline and to perform molecular characterization of different resistance genes as aminoglycoside modifying enzyme genes, ermA and ermC, and vanA and vanB genes. Patients and Methods: One hundred non-duplicate MRSA strains were isolated from different samples of hospitalized patients in Cairo University teaching hospitals from November 2015 to August 2016. Determination of antibiotic susceptibility was done using disk diffusion test and minimum inhibitory concentration followed by detection of resistance genes by multiplex polymerase chain reaction (PCR). Results: Of 100 MRSA isolates, 63 (63%) were resistant to gentamicin, erythromycin, clindamycin, and ciprofloxacin, however, all were sensitive to ceftaroline. Fifteen isolates (15%) were vancomycin intermediate resistant and were sensitive to ceftaroline as well. Conclusion: Ceftaroline was potent against MRSA, which was found to be non-susceptible to vancomycin, ciprofloxacin, erythromycin, clindamycin, and gentamicin and it may represent a successful treatment for MRSA infections.


Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B 12 had been excluded.
5-Methyltetrahydrofolate (5-MTHF) is the predominant form of folate and a strong determinant of homocysteine concentrations. There is evidence that suboptimal 5-MTHF availability is a risk factor for cardiovascular disease independent of homocysteine. The analysis of folates remains challenging and is almost exclusively limited to the reporting of "total" folate rather than individual molecular forms. The purpose of this study was to establish the reference intervals of 5-MTHF in plasma and red cells of healthy adults who had been prescreened to exclude biochemical evidence of functional deficiency of folate and/or vitamin B12. Functional folate and vitamin B12 status was assessed by respective plasma measurements of homocysteine and methylmalonic acid in 144 healthy volunteers, aged 19-64 years. After the exclusion of 10 individuals, values for 134 subjects were used to establish the upper reference limits for homocysteine (13 μ mol/L females and 15 μ mol/L males) and methylmalonic acid (430 nmol/L). Subjects with values below these cutoffs were designated as folate and vitamin B12 replete and their plasma and red cell 5-MTHF reference intervals determined, N = 126: 6.6-39.9 nmol/L and 223-1041 nmol/L, respectively. The application of these intervals will assist in the evaluation of folate status and facilitate studies to evaluate the relationship of 5-MTHF to disease.


Traumatic brain injury and age at onset of cognitive impairment in older adults.
There is a deficiency of knowledge regarding how traumatic brain injury (TBI) is associated with age at onset (AAO) of cognitive impairment in older adults. Participants with a TBI history were identified from the Alzheimer's disease neuroimaging initiative (ADNI 1/GO/2) medical history database. Using an analysis of covariance (ANCOVA) model, the AAO was compared between those with and without TBI, and potential confounding factors were controlled. The AAO was also compared between those with mild TBI (mTBI) and moderate or severe TBI (sTBI). Lastly, the effects of mTBI were analyzed on the AAO of participants with clinical diagnoses of either mild cognitive impairment (MCI) or Alzheimer's disease (AD). The AAO for a TBI group was 68.2 ± 1.1 years [95 % confidence interval (CI) 66.2-70.3, n = 62], which was significantly earlier than the AAO for the non-TBI group of 70.9 ± 0.2 years (95 % CI 70.5-71.4, n = 1197) (p = 0.013). Participants with mTBI history showed an AAO of 68.5 ± 1.1 years (n = 56), which was significantly earlier than the AAO for the non-TBI group (p = 0.032). Participants with both MCI and mTBI showed an AAO of 66.5 ± 1.3 years (95 % CI 63.9-69.1, n = 45), compared to 70.6 ± 0.3 years for the non-TBI MCI group (95 % CI 70.1-71.1, n = 935) (p = 0.016). As a conclusion, a history of TBI may accelerate the AAO of cognitive impairment by two or more years. These results were consistent with reports of TBI as a significant risk factor for cognitive decline in older adults, and TBI is associated with an earlier AAO found in patients with MCI or AD.


Phase wavefront aberration modeling using Zernike and pseudo-Zernike polynomials.
Orthogonal polynomials can be used for representing complex surfaces on a specific domain. In optics, Zernike polynomials have widespread applications in testing optical instruments, measuring wavefront distributions, and aberration theory. This orthogonal set on the unit circle has an appropriate matching with the shape of optical system components, such as entrance and exit pupils. The existence of noise in the process of representation estimation of optical surfaces causes a reduction of precision in the process of estimation. Different strategies are developed to manage unwanted noise effects and to preserve the quality of the estimation. This article studies the modeling of phase wavefront aberrations in third-order optics by using a combination of Zernike and pseudo-Zernike polynomials and shows how this combination may increase the robustness of the estimation process of phase wavefront aberration distribution.


Cytopathology of mesenchymal chondrosarcomas: a report and comparison of four patients.
Mesenchymal chondrosarcoma (MC) is an infrequent neoplasm, representing approximately 1% of all chondrosarcomas. Cytologic descriptions of MCs have been confined to rare case reports. In the current report, the authors describe their experience with the cytologic features of four MCs: two primary tumors and two metastatic lesions. Four patients were diagnosed with MC at the authors' institution from 1994 to 2002. Three of four patients underwent fine-needle aspiration (FNA) biopsy as part of their diagnosis; in the fourth patient, imprint cytology was performed. Each tumor also received histologic confirmation. The patients studied included three females and one male. In three patients, the tumor presented initially as a soft tissue mass; whereas, in the remaining patient, the MC presented in the tibia. FNA results demonstrated small, oval-to-spindled cells with high nuclear-to-cytoplasmic ratios. Cells occurred singly and in clumps in a background of basophilic extracellular matrix. Histologic examination of each lesion demonstrated biphasic tumors, including focal areas of relatively mature cartilage formation as well as a small cell population. MC is a rare soft tissue tumor that occurs frequently in extraskeletal locations. FNA of these tumors can be diagnostic if the tumor is sampled appropriately and of critical features, such as the background extracellular matrix, are recognized. Given the propensity of these tumors to metastasize and the poor prognosis of patients with MC, early identification by FNA biopsy may allow earlier, more aggressive interventions.


Association of Body Composition and Intradialytic Hypotension in Hemodialysis Patients.
The relationship between body mass index (BMI) and intradialytic hypotension (IDH) has been inconsistently reported, but no further research has investigated the correlation between body composition and IDH so far. This study aimed to determine whether the lean tissue index (LTI), fat tissue index (FTI), or both derived from body composition monitoring (BCM) is associated with IDH defined as a nadir intradialytic systolic blood pressure of <90 mm Hg and ≥3 episodes hypotension per 10 hemodialysis (HD) treatments in patients undergoing prevalent HD. The observational cohort study comprised 1,463 patients receiving thrice-weekly HD from 13 dialysis centers. LTI and FTI were assessed using a BCM machine, a multifrequency bioimpedance spectroscopy device. Unadjusted and multivariable adjusted logistic regression models were fit to estimate the association of body composition with the odds of developing IDH. One hundred and seven patients (7.3%) were diagnosed as IDH. The difference in dialysis vintage, BMI, FTI, LTI, high-density lipoprotein cholesterol, and C-reactive protein between IDH and non-IDH groups was statistically significant (all p < 0.05). The prevalence of diabetes among IDH patients was slightly higher than among non-IDH patients. In logistic regression models, low LTI and high FTI, but not high BMI were associated with greater odds of IDH ("high" as above median and "low" as below median). When patients were further stratified into 4 distinct body composition groups based on both the LTI and FTI, only the low LTI/high FTI group was connected with a significantly higher odds of IDH (OR 2.686, 95% CI 1.072-6.734; reference: low LTI/low FTI group). The LTI and FTI can provide better correlation of IDH occurrence than the BMI alone in prevalent HD patients. The low LTI/high FTI appears to be most associated with IDH. An optimal body composition for preventing the occurrence of IDH needs to be determined.


[More women in the medical profession--a benefit?].
More than a hundred years have passed since the first woman graduated in medicine in Norway. Today, more than 30% of doctors and 20% of specialists are women. In some specialties there are still few women: in general surgery 5%, in otorhinolaryngology 9%; only in some 10% of the specialties are there a little above 30% female doctors. There are also few women in positions of leadership. A better balance between men and women would be a benefit to the medical profession, to the patients, to the working environment and in the shaping of the politics of healthcare. There is a change going on, but a slow one. At present, 50% of medical students are women. It is to be hoped that they will be able to make their career choices on the basis of their skills and preferences rather than their gender. Women doctors make a positive contribution to a male-dominated profession; indeed, they may contribute to a development and expansion of the doctor's role. This calls for changes in attitudes, good support and role models--and satisfactory working conditions. Project groups within the Norwegian Medical Association as well as its Equal Opportunity Committee will be working for this in the new millennium.


Solar energy powered microbial fuel cell with a reversible bioelectrode.
The solar energy powered microbial fuel cell is an emerging technology for electricity generation via electrochemically active microorganisms fueled by solar energy via in situ photosynthesized metabolites from algae, cyanobacteria, or living higher plants. A general problem with microbial fuel cells is the pH membrane gradient which reduces cell voltage and power output. This problem is caused by acid production at the anode, alkaline production at the cathode, and the nonspecific proton exchange through the membrane. Here we report a solution for a new kind of solar energy powered microbial fuel cell via development of a reversible bioelectrode responsible for both biocatalyzed anodic and cathodic electron transfer. Anodic produced protons were used for the cathodic reduction reaction which held the formation of a pH membrane gradient. The microbial fuel cell continuously generated electricity and repeatedly reversed polarity dependent on aeration or solar energy exposure. Identified organisms within biocatalyzing biofilm of the reversible bioelectrode were algae, (cyano)bacteria and protozoa. These results encourage application of solar energy powered microbial fuel cells.


Programme and policy options for preventing obesity in China.
By 2002, China's prevalence of overweight and obesity among adults was 18.9 and 2.9%, respectively. The replacement of traditional Chinese diet with 'Western diet', major declines in all phases of activity and increased sedentary activity are cited as the main reasons explaining the rapid increase in overweight and obesity, which bring major economic and health costs. The Nutrition Improvement Work Management Approach was released in 2010. Overweight and obesity prevention-related policies were added to national planning for disease prevention and control. The Guidelines for Prevention and Control of Overweight and Obesity of Chinese Adults and the School-age Children and Teenagers Overweight and Obesity Prevention and Control Guidelines in China were promulgated in 2003 and 2007, respectively. Few education programmes have been implemented. Selected academic intervention research projects dominate with a focus on reducing child obesity and promoting healthier diets; increasing physical activity and reducing sedentary time; and facilitating changes in family, school, social and cultural environments. Intervention samples are small and have not addressed the increasing rates of obesity throughout the entire population. Government provision of effective policy measures, multisectoral cooperation and increasing corporate social responsibility are keys to curbing the trend towards overweight and obesity in China.


Magnetic molecularly imprinted polymer for the isolation and detection of biotin and biotinylated biomolecules.
Magnetic separation based on biologically-modified magnetic particles is a preconcentration procedure commonly integrated in magneto actuated platforms for the detection of a huge range of targets. However, the main drawback of this material is the low stability and high cost. In this work, a novel hybrid molecularly-imprinted polymer with magnetic properties is presented with affinity towards biotin and biotinylated biomolecules. During the synthesis of the magneto core-shell particles, biotin was used as a template. The characterization of this material by microscopy techniques including SEM, TEM and confocal microscopy is presented. The application of the magnetic-MIPs for the detection of biotin and biotinylated DNA in magneto-actuated platforms is also described for the first time. The magnetic-MIP showed a significant immobilization capacity of biotinylated molecules, giving rise to a cheaper and a robust method (it is not required to be stored at 4°C) with high binding capacity for the separation and purification under magnetic actuation of a wide range of biotinylated molecules, and their downstream application including determination of their specific targets.


Expression of long non-coding RNA ENSG00000226738 (LncKLHDC7B) is enriched in the immunomodulatory triple-negative breast cancer subtype and its alteration promotes cell migration, invasion, and resistance to cell death.
Triple negative breast cancer (TNBC) represents an aggressive phenotype with poor prognosis compared with ER, PR, and HER2-positive tumors. TNBC is a heterogeneous disease, and gene expression analysis has identified seven molecular subtypes. Accumulating evidence demonstrates that long non-coding RNA (lncRNA) are involved in regulation of gene expression and cancer biology, contributing to essential cancer cell functions. In this study, we analyzed the expression profile of lncRNA in TNBC subtypes from 156 TNBC samples, and then characterized the functional role of LncKLHDC7B (ENSG00000226738). A total of 710 lncRNA were found to be differentially expressed between TNBC subtypes, and a subset of these altered lncRNA were independently validated. We discovered that LncKLHDC7B (ENSG00000226738) acts as a transcriptional modulator of its neighboring coding gene KLHDC7B in the immunomodulatory subtype. Furthermore, LncKLHDC7B knockdown enhanced migration and invasion, and promoted resistance to cellular death. Our findings confirmed the contribution of LncKLHDC7B to induction of apoptosis and inhibition of cell migration and invasion, suggesting that TNBC tumors with enrichment of LncKLHDC7B may exhibit distinct regulatory activity, or that this may be a generalized process in breast cancer. Additionally, in silico analysis confirmed for the first time that the low expression of KLHDC7B and LncKLHDC7B is associated with poor prognosis in patients with breast cancer.


Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy.
This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P = 0. 008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.


[The effect of altitude on insulin binding by erythrocytes in experimental alloxan diabetes].
Alterations in content of glucose, insulin and glucagon in blood as well as binding of insulin with specific erythrocyte receptors were studied in 120 rats with alloxan diabetes and in intact animals. Content of insulin and glucagon was decreased in rat blood within 14 days of maintaining at high altitude, whereas glycemia developed only slightly. Binding of insulin with erythrocytes was increased more distinctly in control rats, which exhibited low index of this function at low altitude. Importance of this mechanism in activation of cellular glycolysis, an increase of 2,3-diphosphate glucose level in erythrocytes as a compensatory response to high altitude hypoxia are discussed.


Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy.
Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids.


The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein.
The multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80-90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein's central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.


Refractory minerals in interplanetary dust.
A newly studied interplanetary dust particle contains a unique set of minerals that closely resembles assemblages in the refractory, calcium- and aluminum-rich inclusions in carbonaceous chondrite meteorites. The set of minerals includes diopside, magnesium- aluminum spinel, anorthite, perovskite, and fassaite. Only fassaite has previously been identified in interplanetary dust particles. Diopside and spinel occur in complex symplectic intergrowths that may have formed by a reaction between condensed melilite and the solar nebula gas. The particle represents a new link between interplanetary dust particles and carbonaceous chondrites; however, the compositions of its two most abundant refractory phases, diopside and spinel, differ in detail from corresponding minerals in calcium- and aluminum-rich inclusions.


Evidence for HTLV-I associated with mycosis fungoides and B-cell chronic lymphocytic leukemia.
Human T-cell lymphotropic virus type I (HTLV-I) is a human retrovirus that can transform T-helper lymphocytes and is etiologically associated with adult T-cell lymphoma/leukemia. Mycosis fungoides represents a primary cutaneous lymphoma of helper T-cell origin, while chronic lymphocytic leukemia is generally considered to be a neoplastic B-lymphocyte disorder. Our patient had HTLV-I with coexistent mycosis fungoides and B-cell chronic lymphocytic leukemia. The concurrent lymphoid proliferations may represent HTLV-I-associated abnormalities of immunoregulation.


Correlations among ocular surface temperature difference value, the tear meniscus height, Schirmer's test and fluorescein tear film break up time.
To report the use of a thermographer for measuring ocular surface temperature, and to evaluate the correlation among the obtained temperature difference values (TDVs) and dry eye parameters (tear meniscus height (TMH); Schirmer's test results; fluorescent tear breakup time (FTBUT)). Forty-three participants (age 40.2±14.7 years; range 21-67 years) from Far Eastern Memorial Hospital, Taiwan were recruited for the study. The surface temperature was measured at the centre of the ocular surface for 4 s after blinking. TDV was defined as the change in corneal surface temperature relative to that of the preceding eye opening, where TDV01, TDV02, TDV03, and TDV04 represent the values obtained 1, 2, 3, and 4 s after blinking, respectively. Anterior segment optical coherence tomography (AS-OCT) was employed to measure the lower TMH. Schirmer's test with topical anaesthetic was conducted to measure the basal tear secretion. The FTBUT was recorded using a digital camera. TDV measurement exhibited high reliability (intraclass correlation coefficient=0.91). TDV03 exhibited the highest significance and strongest positive correlation with the TMH (r=0.52, p=0.0003) and Schirmer's test value (r=0.39, p=0.008), whereas the TDV03-FTBUT correlation was non-significant. Age correlated negatively and significantly with the TDV (r= -0.35, p=0.021), TMH (r= -0.33, p=0.031), and Schirmer's test value (r= -0.31, p=0.044). TDV03 remained significantly correlated with the TMH and Schirmer's test value after adjustment for age. The thermographer was effective in capturing temperature changes in the ocular surface. The temperature difference 3 s after blinking appears to be correlated with lower TMH and Schirmer test values.


Adipose tissue collagen and inflammation in nonobese Asian Indian men.
Obesity is thought to be the driving force for activation of adipose tissue (AT) collagen production and inflammation as well as systemic insulin resistance. The objective of this study was to determine whether these AT abnormalities can be found independent of obesity in the presence of systemic insulin resistance. Thirty-eight normoglycemic men (14 Asian Indians and 24 white) were enrolled in the study and matched for age, body mass index, and total body fat. Subjects underwent anthropometric measurement, total body fat determination by underwater weighing, euglycemic-hyperinsulinemic clamps, and abdominal sc AT biopsy for mRNA extraction and gene expression determination. Fasting blood was collected for adipokine measurements. Both groups were matched for age, body mass index, and percentage of total body fat. Subcutaneous abdominal AT mRNA expression was significantly higher for Col6a3 as well as genes associated with inflammation, CD68, MAC1, and MCP1 in Asian Indians compared with whites. Asian Indian men had significantly lower rates of glucose disposal and lower plasma adiponectin concentration. Plasma high-sensitivity C-reactive protein levels showed a trend towards higher levels in Asian Indian men. Increased col6a3 and macrophage infiltration in AT along with increased systemic insulin resistance is present independent of body fat content in young Asian Indian men, thus suggesting that AT dysfunction associates with systemic insulin resistance regardless of AT mass.


Signatures of optimal control in pairs of schooling zebrafish.
Animals moving in groups coordinate their motion to remain cohesive. A large amount of data and analysis of movement coordination has been obtained in several species, but we are lacking theoretical frameworks that can derive the form of coordination rules. Here, we examine whether optimal control theory can predict the rules underlying social interactions from first principles. We find that a control rule which is designed to minimize the time it would take a pair of schooling fish to form a cohesively moving unit correctly predicts the characteristics of social interactions in fish. Our methodology explains why social attraction is negatively modulated by self-motion velocity and positively modulated by partner motion velocity, and how the biomechanics of fish swimming can shape the form of social forces. Crucially, the values of all parameters in our model can be estimated from independent experiments that need not relate to measurement of social interactions. We test our theory by showing a good match with experimentally observed social interaction rules in zebrafish. In addition to providing a theoretical rationale for observed decision rules, we suggest that this framework opens new questions about tuning problems and learnability of collective behaviours.


Identification of barley and rye varieties using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry with neural networks.
Cereal varieties are normally identified using time-consuming methods such as visual examination of either the intact grain or one-dimensional electrophoretic patterns of the grain storage proteins. A fast method for identification of wheat (Triticum aestivum L.) varieties has previously been developed, which combines analysis of alcohol-soluble wheat proteins (gliadins) using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry with neural networks. Here we have applied the same method for the identification of both barley (Hordeum vulgare L.) and rye (Secale cereale L.) varieties. For barley, 95% of the mass spectra were correctly classified. This is an encouraging result, since in earlier experiments only a grouping into subsets of varieties was possible. However, the method was not useful in the classification of rye, due to the strong similarity between mass spectra of different varieties.


Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models.
The chronic inflammatory bowel disease ulcerative colitis (UC) occurs commonly in the US and other Western countries, but its etiology is unknown. An association between UC and an elevated risk for colorectal cancer is well established. UC-associated colorectal carcinogenesis is probably driven by chronic inflammation, but the mechanism is unclear. The morphological development of UC-associated cancer differs from that of its sporadic counterpart. Similarly, detailed molecular analyses have indicated that whereas many of the genetic alterations observed in sporadic colon cancers also occur in UC-associated neoplasms, the timing and frequency of those changes in the setting of UC are different. These histological and molecular signatures may very well be reflective of an inflammation-driven carcinogenesis process in UC patients. Studies in animal models of UC have helped to shed light on the mechanisms of inflammation-driven colorectal carcinogenesis. The available evidence suggests that DNA damage caused by oxidative stress in the characteristic damage-regeneration cycle is a major contributor to colorectal cancer development in UC patients. Based on this concept, iron over-nutrition is proposed as a risk factor and dietary antioxidants as protective factors for UC and associated carcinogenesis.


Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis.
Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 μM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract.


Pharmacokinetics of erythromycin ethylsuccinate and estolate in infants under 4 months of age.
We studied the pharmacokinetics of erythromycin estolate and ethylsuccinate suspensions in infants under 4 months of age who were being treated for chlamydial infections or pertussis. We conducted our studies after the initial dose of 10 mg/kg and subsequently during steady-state treatment. The estolate preparation resulted in higher peak concentrations in sera, and its absorption and elimination half-lives were longer. Peak concentrations occurred 3 h after a dose with the estolate preparation and 1 h after a dose with the ethylsuccinate preparation. The area under the curve for the estolate preparation was about three times greater than that for the ethylsuccinate preparation. Based on these findings, we recommend that erythromycin estolate suspensions be given to young infants at 8- or 12-h intervals (30 mg/kg per day in three divided doses or 20 mg/kg per day in two divided doses) and that erythromycin ethylsuccinate is best given at 6-h intervals (40 mg/kg per day in four divided doses).


Effect of thyroid hormones on oxidative and nonoxidative glucose metabolism in humans.
The glucoregulatory function of thyroid hormones was investigated in six healthy subjects before and after 14 day 3,5,3',5'-tetraiodothyronine (T4) treatment (300 micrograms/day) using a sequential clamp protocol for 5 h at euglycemia (0-2 h) and hyperglycemia (165 mg/dl, 2-5 h) and different insulin infusion rates (1.0 for 0-3.5 h and 6.5 mU.kg-1.min-1, for 3.5-5 h). T4 treatment increased basal energy expenditure (+8%), glucose disposal (+31%), and oxidation (+87%) but decreased nonoxidative glucose metabolism (-30%) and was without effect on lipid oxidation. During the euglycemic clamp, T4 treatment enhanced insulin-induced glucose disposal (+16%), glucose oxidation (+34%), and inhibition of lipid oxidation (-66 vs. -40%); nonoxidative glucose metabolism was stimulated to a similar extent before and after T4. During hyperglycemia, 3,5,3'-triiodothyronine (T3) did not affect glucose disposal but increased carbohydrate-induced lipogenesis at both insulin infusion rates. We conclude that T4 treatment promotes glucose disposal and oxidation, T3 decreases noninsulin-mediated glucose storage but does not antagonize insulin action.


Assessing the fidelity of the independently getting up off the floor (IGO) technique as part of the ReTrain pilot feasibility randomised controlled trial for stroke survivors.
Hemiparesis and physical deconditioning following stroke lead to an increase in falls, which many individuals cannot get up from. Teaching stroke survivors to independently get off the floor (IGO) might mitigate long-lie complications. IGO was taught as part of a community-based, functional rehabilitation training programme (ReTrain). We explore the feasibility of teaching IGO and assess participant's level of mastery, adherence, and injury risk. Videos of participants (n = 17) performing IGO at early, middle, and late stages of the ReTrain programme were compared to a manualised standard. A visual, qualitative analysis was used to assess technique mastery, adherence, and injury risk. Most participants (64%) achieved independent, safe practice of IGO. A good (73%) level of adherence to IGO and low incidence of risk of injury (6.8%) were observed. Deviations were made to accommodate for non-stroke related comorbidities. IGO was successfully and safely practised by stroke survivors including those with hemiparesis. Trainers should be aware of comorbidities that may impede completion of IGO and modify teaching to accommodate individual need. Further research should assess if IGO can be utilised by individuals who have other disabilities with unilateral impairments and whether IGO has physical, functional and economic benefit.Implications for rehabilitationFalls are common in stroke survivors, and many are unable to get up despite being uninjured, leading to long-lie complications or ambulance call-outs but non-conveyance to hospital.Teaching the independently getting up off the floor (IGO) technique to stroke survivors was possible for those with or without hemiparesis, and remained safe despite modifications to accommodate an individual's needs.Individual assessment is needed to check if a stroke survivor is suitable for learning IGO including, but not limited to, their ability to safely get to the floor and to temporarily stand (without support) at the end of the technique.


A sparse additive model for treatment effect-modifier selection.
Sparse additive modeling is a class of effective methods for performing high-dimensional nonparametric regression. This article develops a sparse additive model focused on estimation of treatment effect modification with simultaneous treatment effect-modifier selection. We propose a version of the sparse additive model uniquely constrained to estimate the interaction effects between treatment and pretreatment covariates, while leaving the main effects of the pretreatment covariates unspecified. The proposed regression model can effectively identify treatment effect-modifiers that exhibit possibly nonlinear interactions with the treatment variable that are relevant for making optimal treatment decisions. A set of simulation experiments and an application to a dataset from a randomized clinical trial are presented to demonstrate the method.


[A rare association of Takayasu's disease and inflammatory bowel disease in Gabon].
Takayasu's disease is a vasculitis affecting large vessels, particularly the aorta and its main branches, for which the role of Mycobacterium tuberculosis has been suggested as a trigger by a hypersensitivity reaction. Inflammatory bowel diseases, which in sub-Saharan Africa can be confused with parasitic diseases, can rarely be found in association with Takayasu's disease. We report an association between both diseases in the Gabonese population.


Authigenic potassium feldspar in cambrian carbonates: evidence of alleghanian brine migration.
The shallow-water limestones and dolostones of the Conococheague Limestone (Upper Cambrian) of western Maryland contain large amounts of authigenic potassium feldspar. The presence of halite daughter crystals in breached fluid inclusions, low whole-rock ratios of chlorine to bromine, and thermochemical data suggest that the potassium feldspar formed at low temperature by the reaction of connate brines with intercalated siliciclastic debris. Analyses of argon age spectra indicate that the authigenic feldspar probably formed during Late Pennsylvanian to Early Permian time. These results may indicate mobilization and migration of connate brines brought about by Alleghanian folding. The widespread occurrence of authigenic potassium feldspar in Cambrian and Ordovician carbonate rocks throughout the Appalachians suggests that this may have occurred throughout the entire basin.


Use of incisional negative pressure wound therapy on closed median sternal incisions after cardiothoracic surgery: clinical evidence and consensus recommendations.
Negative pressure wound therapy is a concept introduced initially to assist in the treatment of chronic open wounds. Recently, there has been growing interest in using the technique on closed incisions after surgery to prevent potentially severe surgical site infections and other wound complications in high-risk patients. Negative pressure wound therapy uses a negative pressure unit and specific dressings that help to hold the incision edges together, redistribute lateral tension, reduce edema, stimulate perfusion, and protect the surgical site from external infectious sources. Randomized, controlled studies of negative pressure wound therapy for closed incisions in orthopedic settings (which also is a clean surgical procedure in absence of an open fracture) have shown the technology can reduce the risk of wound infection, wound dehiscence, and seroma, and there is accumulating evidence that it also improves wound outcomes after cardiothoracic surgery. Identifying at-risk individuals for whom prophylactic use of negative pressure wound therapy would be most cost-effective remains a challenge; however, several risk-stratification systems have been proposed and should be evaluated more fully. The recent availability of a single-use, closed incision management system offers surgeons a convenient and practical means of delivering negative pressure wound therapy to their high-risk patients, with excellent wound outcomes reported to date. Although larger, randomized, controlled studies will help to clarify the precise role and benefits of such a system in cardiothoracic surgery, limited initial evidence from clinical studies and from the authors' own experiences appears promising. In light of the growing interest in this technology among cardiothoracic surgeons, a consensus meeting, which was attended by a group of international experts, was held to review existing evidence for negative pressure wound therapy in the prevention of wound complications after surgery and to provide recommendations on the optimal use of negative pressure wound therapy on closed median sternal incisions after cardiothoracic surgery.


Essential elements of communication in medical encounters: the Kalamazoo consensus statement.
In May 1999, 21 leaders and representatives from major medical education and professional organizations attended an invitational conference jointly sponsored by the Bayer Institute for Health Care Communication and the Fetzer INSTITUTE: The participants focused on delineating a coherent set of essential elements in physician-patient communication to: (1) facilitate the development, implementation, and evaluation of communication-oriented curricula in medical education and (2) inform the development of specific standards in this domain. Since the group included architects and representatives of five currently used models of doctor-patient communication, participants agreed that the goals might best be achieved through review and synthesis of the models. Presentations about the five models encompassed their research base, overarching views of the medical encounter, and current applications. All attendees participated in discussion of the models and common elements. Written proceedings generated during the conference were posted on an electronic listserv for review and comment by the entire group. A three-person writing committee synthesized suggestions, resolved questions, and posted a succession of drafts on a listserv. The current document was circulated to the entire group for final approval before it was submitted for publication. The group identified seven essential sets of communication tasks: (1) build the doctor-patient relationship; (2) open the discussion; (3) gather information; (4) understand the patient's perspective; (5) share information; (6) reach agreement on problems and plans; and (7) provide closure. These broadly supported elements provide a useful framework for communication-oriented curricula and standards.


Seizure types and frequency in patients who "fail" temporal lobectomy for intractable epilepsy.
Temporal lobectomy can lead to favorable seizure outcomes in medically-refractory temporal lobe epilepsy (TLE). Although most studies focus on seizure freedom after temporal lobectomy, less is known about seizure semiology in patients who "fail" surgery. Morbidity differs between seizure types that impair or spare consciousness. Among TLE patients with seizures after surgery, how does temporal lobectomy influence seizure type and frequency? To characterize seizure types and frequencies before and after temporal lobectomy for TLE, including consciousness-sparing or consciousness-impairing seizures. We performed a retrospective longitudinal cohort study examining patients undergoing temporal lobectomy for epilepsy at our institution from January 1995 to August 2010. Among 241 TLE patients who received temporal lobectomy, 174 (72.2%) patients achieved Engel class I outcome (free of disabling seizures), including 141 (58.5%) with complete seizure freedom. Overall seizure frequency in patients with persistent postoperative seizures decreased by 70% (P < .01), with larger reductions in consciousness-impairing seizures. While the number of patients experiencing consciousness-sparing simple partial seizures decreased by only 19% after surgery, the number of individuals having consciousness-impairing complex partial seizures and generalized tonic-clonic seizures diminished by 70% and 68%, respectively (P < .001). Simple partial seizure was the predominant seizure type in 19.1% vs 37.0% of patients preoperatively and postoperatively, respectively (P < .001). Favorable seizure outcome was predicted by a lack of generalized seizures preoperatively (odds ratio 1.74, 95% confidence interval 1.06-2.86, P < .5). Given important clinical and mechanistic differences between seizures with or without impairment of consciousness, seizure type and frequency remain important considerations in epilepsy surgery.


Prevalence of insulin resistance and the metabolic syndrome with alternative definitions of impaired fasting glucose.
We sought to evaluate the effect of the new definition of impaired fasting glucose (IFG = fasting glucose concentration 100-125 mg/dL among people without diabetes) on the ability to identify insulin resistance, as well as the prevalence of the metabolic syndrome in apparently healthy individuals. From the Stanford General Clinical Research Center data-base, we used data from 230 men and 260 women aged 19-79 years who had had an insulin suppression test to measure insulin resistance. From the Third National Health and Nutrition Examination Survey (1988-1994), we used data from 8814 participants aged > or =20 years to estimate the impact of adopting the new IFG criteria on the prevalence of the metabolic syndrome. Among the 490 participants, the prevalence of IFG increased from 5.5% under the old definition of IFG to 20.4% under the new definition. Using the old definition of IFG, the sensitivity, specificity, and positive predictive value (PPV) of IFG of identifying an individual as being insulin resistant were 10%, 97%, and 63%, respectively. Using the new definition, these parameters were 33%, 88%, and 61%, respectively. If the new IFG criteria were adopted, the prevalence of the metabolic syndrome would increase from 21.8% to 26.3%. The new definition of IFG expands the population with insulin resistance by almost four-fold and could expand the population with the metabolic syndrome by about 20%. The clinical and public health implications of the new IFG definition remain to be elucidated.


Validation of the Tunisian version of the Patient Health Questionnaire -9 (PHQ- 9) for Depression screening.
Depression is a major burden for the health-care system worldwide. It is important to use standardized and easily applicable tools for large-scale population screening to improve the early detection of depression. The PHQ-9 has been recommended as the best available screening and case-finding instrument based on its brevity and ability to inform the clinicians on both depression severity and diagnostic criteria. To evaluate the reliability and the validity of the Tunisian version of the PHQ-9 in the general population in Tunisia; the Tunisian version of the Hospital anxiety depression scale (HAD) was used as the gold standard for major depression diagnosis. We undertook a cross-sectional, descriptive and analytical study. A total of 134 participants were enrolled. The PHQ-9 was validated against the HAD reference standard. Test-Retest reliability was determined by intraclass correlation. This scale was stable over 2 weeks (ICC=0,97).The Tunisian version of the PHQ-9 has a good internal reliability (Cronbach's alpha = 0.84). As for criterion validity of the PHQ-9, the Pearson's correlation coefficient between the PHQ-9 and HAD was 0.94 and the Spearman's correlation coefficient was 0,81. A cut-off score of 10 had a sensitivity of 86,2 and a specificity of 83,8. The VPP was 0,6 and the VPN was 0,9. The prevalence of depression in ours ample was 13,4%. There were no statistical difference in gender, education and age for the prevalence of depression. The Tunisan version of the PHQ-9 is a valid and reliable casefinding instrument for detecting depression.


The local management of soft tissue sarcoma.
Soft tissue sarcomas (STS) are rare tumors arising from the connective tissues. STS can arise at any anatomic site, can demonstrate varied behavior and prognosis, and therefore present a formidable challenge in management. The local treatment of STS demands technical complexity in the application of diagnostic tools, including pathology and imaging, as well as treatment approaches, including surgical ablation and reconstruction, radiotherapy, and, in defined cases, chemotherapy. The understanding of the management of these lesions is profoundly dependent on the multidisciplinary setting, where experience has been gained and skills are available to increase the likelihood of a successful result. Several proven options are available for optimal local management, and the choice of approach depends on the prevailing practice and resource profile of the treating center. With modern approaches, the local control rate can be expected to be at least 90% for extremity lesions, which constitute the most common STS. The experience in other anatomic sites is less favorable as a result of a combination of late diagnosis, technically difficult access sites, and possibly less familiarity with these less common presentations. The disappointing results make it all the more important for patients to be referred to a multidisciplinary setting with experience in sarcoma management to maximize the chance of successful local outcome.


The induction of kin genes in cold-acclimating Arabidopsis thaliana. Evidence of a role for calcium.
The involvement of calcium signaling during cold-induction of the kin genes of Arabidopsis thaliana (L.) Heynh. was examined. Treatments with chemicals which either chelate extracellular calcium (EGTA) or block the plasma-membrane calcium channels (La3+, Gd3+) inhibited cold acclimation as well as kin gene expression. Ruthenium red, an inhibitor of calcium release from intracellular stores partially inhibited kin gene expression and development of freezing tolerance. An inhibitor of calcium-dependent protein kinases (CDPKs) and calmodulin prevented cold acclimation as well as the cold induction of kin genes. Using restriction fragment length polymorphism-coupled domain-directed differential display, five CDPK clones were identified which showed differential regulation by cold. The amplified fragments showed homology to known plant CDPKs. The involvement of calcium and calcium-binding proteins in cold acclimation of A. thaliana is discussed.


The business case for better buildings.
Beginning in 2000, a research collaborative of progressive healthcare organizations came together with The Center for Health Design to evaluate the impact of their new buildings on patient outcomes. Those organizations are now engaged in three-year programs of evaluation, using comparative research instruments and outcome measures. Their experiences are synthesized here in a composite 300-bed "Fable Hospital" to present evidence in support of the business case for better buildings as a key component of better, safer, and less wasteful health care.


Novel GM animal technologies and their governance.
Scientific advances in methods of producing genetically modified (GM) animals continue, yet few such animals have reached commercial production. Existing regulations designed for early techniques of genetic modification pose formidable barriers to commercial applications. Radically improved techniques for producing GM animals invite a re-examination of current regulatory regimes. We critically examine current GM animal regulations, with a particular focus on the European Union, through a framework that recognises the importance of interactions among regulatory regimes, innovation outcomes and industry sectors. The current focus on the regulation of risk is necessary but is unable to discriminate among applications and tends to close down broad areas of application rather than facilitate innovation and positive industry interactions. Furthermore, the fields of innovative animal biosciences appear to lack networks of organisations with co-ordinated future oriented actions. Such networks could drive coherent programmes of innovation towards particular visions and contribute actively to the development of regulatory systems for GM animals. The analysis presented makes the case for regulatory consideration of each animal bioscience related innovation on the basis of the nature of the product itself and not the process by which it was developed.


Primordial germ cell migration in the yellowtail kingfish (Seriola lalandi) and identification of stromal cell-derived factor 1.
Primordial germ cells (PGCs) are progenitors of the germ cell lineage, giving rise to either spermatogonia or oogonia after the completion of gonadal differentiation. Currently, there is little information on the mechanism of PGCs migration leading to the formation of the primordial gonad in perciform fish. Yellowtail kingfish (Seriola lalandi) (YTK) (order Perciforms) inhabit tropical and temperate waters in the southern hemisphere. Fundamental details into the molecular basis of larval development in this species can be easily studied in Australia, as they are commercially cultured and readily available. In this study, histological analysis of YTK larvae revealed critical time points for the migration of PGCs to the genital ridge, resulting in the subsequent development of the primordial gonad. In YTK larvae at 3, 5, 7 and 10 days post hatch (DPH), PGCs were not yet enclosed by somatic cells, indicating the primordial gonad had not yet started to form. While at 15, 18 and 20 DPH PGCs had already settled at the genital ridge and started to become enclosed by somatic cells indicating the primordial gonad had started to develop. A higher number of PGCs were observed in the larvae at 15 and 18 DPH indicating PGCs proliferation, which corresponds with them becoming enclosed by the somatic cells. Directional migration of PGCs toward the genital ridge is a critical event in the subsequent development of a gonad. In zebrafish, mouse and chicken, stromal-cell derived factor (SDF1) signalling is one of the key molecules for PGC migration. We subsequently isolated from YTK the SDF1 (Slal-SDF1) gene, which encodes for a 98-residue precursor protein with a signal peptide at the N-terminus. There is spatial conservation between fish species of four cysteine residues at positions C9, C11, C34 and C49, expected to form disulphide bonds and stabilize the SDF structure. In YTK, Slal-SDF1 gene expression analyses shows that this gene is expressed in larvae from 1 to 22 DPH and demonstrates distinct spatial localisation in the larvae at 7 DPH. These results provide a platform for further studies into the molecular machinery of PGC migration in yellowtail kingfish, as well as other perciform fish species.


Floating limb behaviors and self-biting are associated in laboratory monkeys.
Early descriptions of floating limb behaviors in monkeys were associated with isolation rearing, a practice that ended more than two decades ago. The present authors named various forms of behaviors in which a leg is elevated for no apparent reason: "Floating Limb Suite" (FLS). Floating limb behaviors, identified in laboratory monkeys at the Washington National Primate Research Center (WaNPRC), consist of two subcategories distinguished by whether monkeys seem to react to the elevated leg or ignore it. Given the past association of isolation rearing with both self-biting (SB) and floating limb, the investigators predicted that SB and FLS would be associated in monkeys not reared in isolation. The investigators tracked, over a period of 3 years, the presence of FLS and SB in macaques (Macaca nemestrina, M. fascicularis, M. mulatta) and Papio cynocephalus at WaNPRC. SB and both subcategories of FLS occurred in mother-reared and surrogate-peer-nursery-reared monkeys. We analyzed presence of FLS, the two subcategories of FLS, and SB in 1,117 macaques monitored for up to 3 years, and 781 macaques observed for 8 min of structured data collection. The Papio sample size was insufficient for statistical analysis. Both sampling methodologies found FLS and FLS subcategories to be associated with SB. Nearly half the monkeys only engaging in seemingly harmless nonreactive forms of FLS also performed the potentially injurious behavior of self-biting. The positive association between FLS and SB suggests that monkeys exhibiting one of these behaviors are at a heightened risk for developing the other. One impediment to studying floating limb behaviors is lack of consensus on definitions. This study defined seven forms of apparently functionless elevated limb behaviors. Continued research on factors associated with floating limb behaviors across demographic groups and settings may provide insights into the etiology and treatment of self-biting.


Guanine deaminase in rat liver and mouse liver and brain.
1. The guanine deaminase in rat liver supernatant preparations was resolved into two fractions, A and B, on DEAE-cellulose columns. The two differed in electrophoretic mobility and in various properties. The most noteworthy distinction between A and B components was that the enzyme A activity showed a sigmoid dependence on substrate concentration whereas the enzyme B showed classical Michaelis-Menten kinetics. The K(m) value of enzyme A for guanine was 5.3mum and that of enzyme B 20mum. 2. The entire guanine deaminase activity of mouse liver was contained in the 15000g supernatant of iso-osmotic homogenates. 3. A reinvestigation of the behaviour of rat brain 15000g supernatant guanine deaminase isoenzymes revealed that one enzyme had sigmoidal kinetics and the other enzyme showed a hyperbolic response. 4. Of the guanine deaminase in mouse brain iso-osmotic sucrose homogenate 80% was recovered in the 15000g supernatant and the rest from the particles. The supernatant guanine deaminase was resolvable into two fractions on DEAE-cellulose columns. One enzyme showed sigmoidal kinetics whereas the other showed a hyperbolic response to increasing substrate concentration; the K(m) values for the reaction with guanine were respectively 5 and 66mum. 5. The particulate fractions of mouse liver and brain were devoid of any overt inhibitory activity.


Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome.
SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a 'cytokine storm' have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2-specific T cells is limited. Here, we studied 10 COVID-19 patients who required admission to an intensive care unit and detected SARS-CoV-2-specific CD4+ and CD8+ T cells in 10 out of 10 and 8 out of 10 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T cells in 2 out of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with 'common cold' coronaviruses. The strongest T-cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2-specific T cells predominantly produced effector and Th1 cytokines, although Th2 and Th17 cytokines were also detected. Furthermore, we studied T-cell kinetics and showed that SARS-CoV-2-specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T-cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation.


Multiplex microRNA imaging in living cells using DNA-capped-Au assembled hydrogels.
Non-invasively imaging multiplex microRNAs (miRNAs) in living cells is pivotal to understanding their physiological functions and pathological development due to the key regulatory roles of miRNAs in gene expression. However, developing smart delivery systems with large gene loading capacity, biocompatibility and responsiveness remains a significant challenge. Herein, we successfully incorporated DNA-capped Au nanoparticles (NPs) and their complementary fluorescent DNA sequences into a porous 3D hydrogel network (AuDH), in which hairpin-locked DNAzyme strands and active metal ions were loaded (AuDH/M n+/H) for simultaneously imaging multiplex miRNAs in living cells. After transfection into cells, the specific miRNAs trigger the strand-displacement reaction and sequentially activate the DNAzyme-assisted target recycling, leading to a strong increase in the corresponding fluorescence intensity for imaging. This enables simultaneous assessment of the abundance of multiplex cancer-related miRNAs, even if at a very low expression level, in different cells through the different fluorescence intensities due to the dual signal amplification, and the change in abundance of miRNAs induced by siRNA or miRNA mimics in living cells can also be efficiently monitored. The versatile and responsive DNA hydrogel system holds great potential for miRNA biomedical applications.


Analysis of primary fine particle national ambient air quality standard metrics.
In accordance with the Clean Air Act, the U.S. Environmental Protection Agency (EPA) is currently reviewing its National Ambient Air Quality Standards for particulate matter, which are required to provide an adequate margin of safety to populations, including susceptible subgroups. Based on the latest scientific, health, and technical information about particle pollution, EPA staff recommends establishing more protective health-based fine particle standards. Since the last standards review, epidemiologic studies have continued to find associations between short-term and long-term exposure to particulate matter and cardiopulmonary morbidity and mortality at current pollution levels. This study analyzed the spatial and temporal variability of fine particulate (PM2.5) monitoring data for the Northeast and the continental United States to assess the protectiveness of various levels, forms, and combinations of 24-hr and annual health-based standards currently recommended by EPA staff and the Clean Air Scientific Advisory Committee. Recommended standards have the potential for modest or substantial increases in protection in the Northeast, ranging from an additional 13-83% of the population of the region who are living in areas not likely to meet new standards and thereby benefiting from compliance with more protective air pollution controls. Within recommended standard ranges, an optimal 24-hr (98th percentile)/annual standard suite occurs at 30/12 microg/m3, providing short- and long-term health protection for a substantial percentage of both Northeast (84%) and U.S. (78%) populations. In addition, the Northeast region will not benefit as widely as the nation as a whole if less stringent standards are selected. Should the 24-hr (98th percentile) standard be set at 35 microg/m3, Northeast and U.S. populations will receive 16-48% and 7-17% less protection than a 30 microg/m3 standard, respectively, depending on the level of the annual standard. A 30/12 microg/m3 standard suite also provides nearly equivalent 24-hr and annual control of PM2.5 distributions across the United States, thereby ensuring a more uniform and consistent level of protection than unmatched or "controlling" and "backstop" standards. This could occur even within EPA staff's recommended range of standard suites, where 22-43% of the monitors in the country could meet a controlling standard but fail to meet the combined backstop standard, resulting in inconsistent short- and long-term protection across the country. An equivalent standards combination of 30/12 microg/m3 would minimize the wide variation of protectiveness of 24-hr and annual PM2.5 concentrations. Furthermore, given recent associations of subdaily exposures and acute adverse health effects, in the absence of a subdaily averaging metric, a stringent 24-hr standard will more effectively control maximum hourly and multihourly peak concentrations than a weaker standard.


Toll-like receptor 4 mediates induction of the Bcl10-NFkappaB-interleukin-8 inflammatory pathway by carrageenan in human intestinal epithelial cells.
The sulfated polysaccharide carrageenan (CGN) induces activation of NFkappaB and interleukin 8 (IL-8) in human colonic epithelial cells through a pathway of innate immunity mediated by Bcl10 (B-cell CLL/lymphoma 10). In this report, we identify Toll-like receptor 4 (TLR4), a member of the family of innate immune receptors, as the surface membrane receptor for CGN in human colonic epithelial cells. Experiments with fluorescence-tagged CGN demonstrated a marked reduction in binding of CGN to human intestinal epithelial cells and to RAW 264.7 mouse macrophages, following exposure to TLR4 blocking antibody (HTA-125). Binding of CGN to 10ScNCr/23 mouse macrophages, which are deficient in the genetic locus for TLR4, was absent. Additional experiments with TLR4 blocking antibody and TLR4 small interfering RNAs showed 80% reductions in CGN-induced increases in Bcl10 and IL-8. Transfection with dominant-negative MyD88 plasmid demonstrated MyD88 dependence of the CGN-TLR4-triggered increases in Bcl10 and IL-8. Therefore, these results indicate that CGN-induced inflammation in human colonocytes proceeds through a pathway of innate immunity, perhaps related to the unusual alpha-1,3-galactosidic linkage characteristic of CGN, and suggest how dietary CGN intake may contribute to human intestinal inflammation. Because CGN is a commonly used food additive in the Western diet, clarification of its effects and mechanisms of action are vital to issues of food safety.


Focus-on-Teens, sexual risk-reduction intervention for high-school adolescents: impact on knowledge, change of risk-behaviours, and prevalence of sexually transmitted diseases.
A community-based intervention, Focus-on-Kids (FOK) has demonstrated risk-behaviour reduction of urban youth. We modified FOK to Focus-on-Teens (FOT) for high schools. High school adolescents (n=1190) were enrolled over successive school semesters. The small-group sessions were presented during the school-lunch hours. Confidential surveys were conducted at baseline, immediate, six-, and 12-month postintervention for demographics, parental communication/monitoring, sexual risk behaviours and sexually transmitted diseases (STDs)/HIV/condom-usage knowledge. Sexually active participants were encouraged to volunteer for urine-based STDs testing at the School-Based Health Centres. Many (47.4%) students reported having had sexual intercourse at baseline. Overall behaviours changed towards 'safer' sex behaviours (intent-to-use and using condoms, communicating with partner/parents about sex/condoms/STDs) with time (P<0.05). Proportion of students with complete correct knowledge of STDs/HIV increased to 88% at time 4 from 80% at baseline after adjusting for age, gender and sexual activity (P<0.05). High prevalence of STDs was detected in 875 participants who reported for urine testing at time 1: trichomonas, 11.8%; chlamydia, 10.1% and gonorrhoea, 4.1%. Prevalence decreased significantly for 310 participants who re-tested; chlamydia: 27.4% to 6.1% and gonorrhoea: 11.3% to 3.2%. FOT was successfully implemented as an STDs/HIV risk-reduction intervention. Sustained improvements of knowledge about STDs/HIV/condom usage, decreases in sexual risk behaviours supported the effectiveness of this intervention.


Accumulation of intracellular platinum is correlated with intrinsic cisplatin resistance in human bladder cancer cell lines.
We investigated the mechanism of intrinsic resistance to cisplatin in human transitional cell cancer (TCC) using 7 human bladder cancer cell lines, which were derived from untreated TCC of the urinary bladder. The sensitivity to cisplatin was different from cell line to cell line, and a 15-fold difference was observed between the most sensitive line and the most resistant line. No significant correlation was observed between the content of intracellular glutathione and the resistance to cisplatin. In contrast, a positive correlation was seen between intracellular cisplatin accumulation and cisplatin resistance. The expression of drug resistance-related genes including glutathione S-transferase pi, gamma-glutamyl-cysteine synthetase, multidrug resistance-1, multidrug resistance-associated protein, DNA topoisomerase I, topoisomerase II, human canalicular multispecific organic anion transporter, and thioredoxin was not significantly related to cisplatin resistance. These data suggest that intracellular cisplatin may contribute to intrinsic cisplatin resistance and may therefore be a useful biomarker to predict cisplatin sensitivity in human untreated TCC.


Betamethasone-I7, 2I-dipropionate ointment: an effective topical preparation in lichen ruber planus.
A clinical evaluation was carried out in 19 patients with lichen ruber planus to assess the effectiveness of 0.05% betamethasone-17,21-dipropionate ointment in the treatment of patients whose lesions had developed resistance to prolonged treatment with 0.1% betamethasone-17-valerate ointment. The new steroid ointment was substituted for the previous preparation and applied at the same frequency, once or twice daily, for 2 to 3 weeks. The results at the end of the betamethasone-17,21-dipropionate period were classified as better in 14 (73.7%) and equal in the remaining 5 patients.


A Social Marketing Intervention to Prevent Drowning Among Inner-City Youth.
Water-related injuries and fatalities pose serious public health issues, especially to African American youth, a demographic group that drowns at disproportionately high rates. The purpose of this study was to determine if a social marketing intervention targeting the parents and guardians of inner-city youth (U.S. Midwest) could positively influence their perceptions concerning water safety. Researchers employed a quasi-experimental design using matched pairs to evaluate the intervention. Participants consisted of parents who enrolled their children in a six-session survival-swimming course. Guided by the Health Belief Model, the researchers disseminated six prevention messages using six different channels (brochure, e-mail, SMS text message, postcard, Facebook, and window cling). The findings from a two-way analysis of covariance revealed that treatment group participants' knowledge and perceptions of water-related threat all changed favorably. Additionally, all participants planned to reenroll their children in swim lessons. A social marketing campaign using the Health Belief Model improved inner-city parents' knowledge regarding water safety and enhanced their self-efficacy. This study provides practitioners with feasible strategies (prevention messages) to supplement swim lessons, with the ultimate goal of preventing drowning among at-risk youth.


Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway.
The treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, because pro-survival signaling pathways-such as the receptor for advanced glycation end products (RAGE)/signal transducer and activator of transcription 3 (STAT3) pathway-are overexpressed in PDAC cells. Moreover, PDAC cells are highly resistant to chemotherapeutic agents because of autophagy induction. Therefore, autophagy and its modulated signaling pathways are attractive targets for developing novel therapeutic strategies for PDAC. Pterostilbene is a stilbenoid chemically related to resveratrol, and has potential for the treatment of cancers. Accordingly, we investigated whether the autophagy inhibitor chloroquine could potentiate the anticancer effect of pterostilbene in the PDAC cell lines MIA PaCa-2 and BxPC-3, as well as in an orthotopic animal model. The results indicated that pterostilbene combined with chloroquine significantly inhibited autophagy, decreased cell viability, and sensitized the cells to pterostilbene-induced apoptosis via downregulation of the RAGE/STAT3 and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways in PDAC cells. The results of the orthotopic animal model showed that pterostilbene combined with chloroquine significantly inhibited pancreatic cancer growth, delayed tumor quadrupling times, and inhibited autophagy and STAT3 in pancreatic tumors. In summary, the present study suggested the novel therapeutic strategy of pterostilbene combined with chloroquine against the growth of pancreatic ductal adenocarcinoma by inhibiting autophagy and downregulating the RAGE/STAT3 signaling pathways.