The CARDIA dietary history: development, implementation, and evaluation.
To meet the objectives for dietary assessment in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective study, we developed a dietary history to provide accurate and reliable quantitative data on habitual individual nutrient intakes at baseline. The CARDIA dietary history was an interviewer-administered method that included a short questionnaire regarding general dietary practices followed by a comprehensive food frequency questionnaire about typical intake of foods using the previous month as a reference for recall. For each broad category of foods, participants were questioned in detail about specific foods only if they indicated that they consumed foods from that category. Follow-up questions for selected foods concerned serving size, frequency of consumption, and common additions to these foods. Provision was made for reporting foods not found in the food frequency list. The interview took approximately 45 minutes. Cue cards prompted responses and plastic food models assisted in estimating usual amounts consumed. A precoded format standardized coding for reported items and established the detail needed for recall during the interview. Baseline nutrient analyses from the CARDIA dietary history provided estimates that agreed reasonably well with expected caloric intake for body mass index according to the age- and sex-specific Recommended Dietary Allowances, but were higher than those reported from 24-hour recalls for comparable age, sex, and race groups in the second National Health and Nutrition Examination Survey. The CARDIA dietary history is a comprehensive assessment tool that can provide a dietitian with detailed information regarding habitual eating patterns and nutrient intakes among adults.


Preventing malnutrition in prison.
Vulnerable patient groups are at increased risk of malnutrition. This article focuses on the importance of ensuring that the nutritional needs of those in institutional settings, in particular prisons, are met. Offenders often present with a number of health and social factors which can lead to a high risk of malnutrition. The consequences of malnutrition are significant, ranging from delayed recovery to increased mortality. The treatment of malnutrition is discussed in this article from detection through to management and monitoring. Adequate nutrition is a basic human right and those in prison should be provided with healthy food choices to optimise health.


Predictors of parent-child communication among a nationally representative sample in Nigeria.
This study explores what constructs are associated with parent-adolescent communication about AIDS/sexually transmitted infections (STIs) and sexual relationships in Nigeria. The analyses use data from the 2007 National HIV/AIDS and Reproductive Health Survey on 2593 men and women who had at least one child over the age of 12 years. The respondents were classified as low, medium, or high communicators. Low communicators were parents who did not talk to their child about either AIDS/STIs or sexual relationships. Medium communicators were parents who discussed only one topic with at least one child. High communicators were parents who discussed both topics with at least one child. Logistic regression was used to compare high communicators with low/medium communicators. There are commonalities and differences among men and women in the factors associated with parent-adolescent communication. Age, religion, and knowing where to obtain information about HIV/AIDS were associated with the extent of communication, regardless of the parent's gender. Perceived social support was an important correlate for fathers, while knowledge of female STI symptoms showed a significant association only for mothers. Programmatic and communication implications of the findings include addressing men and women differently, developing strategies to specifically reach younger parents and Muslims, and increasing general awareness of HIV/AIDS information resources. Further research is needed to understand the context, content, and timing of parent-adolescent conversations about AIDS/STIs and sexual relationships and how these factors affect the sexual behaviors of adolescents.


Targeting Unoccupied Surfaces on Protein-Protein Interfaces.
The use of peptidomimetic scaffolds to target protein-protein interfaces is a promising strategy for inhibitor design. The strategy relies on mimicry of protein motifs that exhibit a concentration of native hot spot residues. To address this constraint, we present a pocket-centric computational design strategy guided by AlphaSpace to identify high-quality pockets near the peptidomimetic motif that are both targetable and unoccupied. Alpha-clusters serve as a spatial representation of pocket space and are used to guide the selection of natural and non-natural amino acid mutations to design inhibitors that optimize pocket occupation across the interface. We tested the strategy against a challenging protein-protein interaction target, KIX/MLL, by optimizing a single helical motif within MLL to compete against the full-length wild-type MLL sequence. Molecular dynamics simulation and experimental fluorescence polarization assays are used to verify the efficacy of the optimized peptide sequence.


Mechanisms related to carbon nanotubes genotoxicity in human cell lines of respiratory origin.
Potential genotoxicity and carcinogenicity of carbon nanotubes (CNT), as well as the underlying mechanisms, remains a pressing topic. The study aimed to evaluate and compare the genotoxic effect and mechanisms of DNA damage under exposure to different types of CNT. Immortalized human cell lines of respiratory origin BEAS-2B, A549, MRC5-SV40 were exposed to three types of CNT: MWCNT Taunit-M, pristine and purified SWCNT TUBALL™ at concentrations in the range of 0.0006-200 μg/ml. Data on the CNT content in the workplace air were used to calculate the lower concentration limit. The genotoxic potential of CNTs was investigated at non-cytotoxic concentrations using a DNA comet assay. We explored reactive oxygen species (ROS) formation, direct genetic material damage, and expression of a profibrotic factor TGFB1as mechanisms related to genotoxicity upon CNT exposure. An increase in the number of unstable DNA regions was observed at a subtoxic concentration of CNT (20 μg/ml), with no genotoxic effects at concentrations corresponding to industrial exposures being found. While the three test articles of CNTs exhibited comparable genotoxic potential, their mechanisms appeared to differ. MWCNTs were found to penetrate the nucleus of respiratory cells, potentially interacting directly with genetic material, as well as to enhance ROS production and TGFB1 gene expression. For A549 and MRC5-SV40, genotoxicity depended mainly on MWCNT concentration, while for BEAS-2B - on ROS production. Mechanisms of SWCNT genotoxicity were not so obvious. Oxidative stress and increased expression of profibrotic factors could not fully explain DNA damage under SWCNT exposure, and other mechanisms might be involved.


MedDigital trends and tactics to lead into the future.
Physician executives need to harness appropriate digital technology by understanding key trends and implementing best tactics. Being and doing MedDigital means taking back control and improving care--and, at the same time, improving efficiencies and the bottom line. This article presents seven e-trends that are shaping health care: (1) Consumers and patients are pushing doctors to go digital; (2) from Web health information to MedDigital decision support; (3) beyond managed care to custom health; (4) wireless is the way of the new world; (5) Passive web portals yield to digital destinations; (6) e-commerce means lower transaction cost; and (7) develop e-health care ROI methodologies and track results. The authors provide myriad examples of new technology that will revolutionize health care and provide both physicians and consumers with valuable interactive tools to enhance health, treatment, and decision-making.


[Thermal and salinity tolerance of eurybiotic freshwater shrimp Gmelinoides fasciatus (Stebbing) under different acclimation conditions].
Critical thermal maximum and critical salinity maximum in their dependence on the water temperature and salinity were studied in the freshwater shrimps, Gmelinoides fasciatus, during their acclimation. Nine combinations of temperature (12.7-14.7, 16.3-21.3, 22.0-25.6 degrees C) and salinity (0.2, 2.5 per thousand) were studied. The shrimps were shown to be largest CTM in the fresh water at 22-26 degrees C and to be smallest CTM at 12-14 degrees C. The thermal effect on the thermal stability was similar in the brackish water (2 per thousand), while its effect on the salinity stability was reverse, that is, the shrimps' endurance to the high salinity decreased with the temperature growth. During acclimation, viability reached 50 to 100 per cent at 5 per thousand, the individuals adapted to the lower temperature (12-14 degrees C) appearing to be most endurant. Thermal stability was revealed to increase with the body length growth reaching the stable level at the body length of 7-8 mm. Salinity stability of the shrimps acclimated in the brackish water at 22-26 degrees C tend to increase with the body length growth, while it did not depend on the body length at other temperature regimes reaching about the same level in both fresh and brackish waters. The data obtained indicate that the temperature below 22 degrees C would be optimal for the shrimps acclimation in the brackish water.


Characterization of beta-adrenoreceptors of rainbow trout (Oncorhynchus mykiss) erythrocytes.
Although many studies have characterized these receptors according to pharmacological criteria, this work represents only the second direct characterization of the rainbow trout beta-adrenergic receptors. Radioligand binding assays using (+/-)-4-(3-t-butylamino-2-hydroxy-propoxy)-[5,7-3H]benzimidazol-2- one ([3H]CGP 12177) and 1-[4,6-propyl 3H]dihydroalprenolol ([3H]DHA) were conducted to determine equilibrium binding times, ligand-receptor dissociation constants (KD) and binding capacities (Bmax). Furthermore, we assessed the influence of erythrocyte handling, suspension medium and endogenous catecholamines on Bmax and KD. Maximal binding was obtained when erythrocytes were handled minimally and maintained suspended in plasma rather than physiological saline. Washing and resuspending the erythrocytes, as well as the transfer of the erythrocytes into saline, significantly impaired apparent radioligand affinity and receptor density. Endogenous catecholamines, at levels considered normal for non-stressed animals, did not interfere with the radioligand binding assays, and thus eliminated the need to wash and resuspend erythrocytes. Based on the binding characteristics after intentional lysis of erythrocytes, it is shown that the total receptor population of trout erythrocytes can be estimated by propranolol-displaceable DHA binding, the density of high-affinity surface receptors can best be determined by isoproterenol-displaceable CGP binding, and the number of receptors located within the erythrocytes can be calculated from the difference between the total receptor density and the number of isoproterenol-displacable DHA binding sites. Each of these components must be considered when performing radioreceptor assays using these radioligands and this has significant implications for the interpretation of erythrocyte beta-adrenorecptor localization and mobilization.


Alteration of the cytoplasmic domain of the membrane-spanning glycoprotein p62 of Semliki Forest virus does not affect its polar distribution in established lines of Madin-Darby canine kidney cells.
Expression of the Semliki Forest virus p62/E2 protein was studied in the polarized epithelial cell line Madin-Darby canine kidney (MDCK). After infection this transmembrane protein, together with the other spike subunit E1, accumulates at the basolateral surface of MDCK cells (Fuller, S. D., C.-H. von Bonsdorff, and K. Simons, 1985, EMBO (Eur. Mol. Biol. Organ.) J., 4:2475-2485). The cDNAs encoding truncated forms of the protein were used to stably transform MDCK cells to examine the role of subunit oligomerization (E1-E2) and the cytoplasmic domain of p62/E2 in directed transport to the basolateral surface. The biochemical characteristics and polarity of the expressed proteins were studied using cell monolayers grown on nitrocellulose filters. A wild-type form of p62/E2, in the absence of E1, and two forms having either 15 or 3 of the wild-type 31-amino acid carboxyl cytoplasmic domain were all localized to the basolateral surface. These results indicate that the cytoplasmic domain of E2 does not contain the information essential for directed transport to the plasma membrane, and imply that this information resides in either the lumenal and/or membrane-spanning segments of this transmembrane protein.


Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients.
Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.


Validation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) and Its Association with Functional Impairment in Brazilian Gamers.
Despite the growing recognition of gaming disorder as a mental disorder, there is still debate about how it should be best screened for. This is especially relevant in countries where prevalence studies that could support evidence-based policymaking are still to be conducted. This study aims to evaluate the psychometric properties of the Brazilian Portuguese version of the Ten-Item Internet Gaming Disorder Test (IGDT-10) and to explore its association with functional impairment. An online convenience sample of 805 Brazilian adults who reported playing games completed the adapted version of IGDT-10 and World Health Organization Disability Assessment Schedule 2.0, as well as the Problematic Internet Use Questionnaire, the Center for Epidemiologic Studies-Depression Scale, the Rosenberg Self Esteem Scale and socio-demographic questions. The Brazilian Portuguese version of IGDT-10 demonstrated a unidimensional structure in both confirmatory and exploratory factor analysis, with satisfactory internal consistency and adequate temporal stability. Participants who scored five or more on IGDT-10 presented higher levels of functional impairment compared to those who scored positive for four symptoms or less. The difference between the two groups was statistically significant and showed a moderate effect size. Network analysis showed a direct connection between IGDT-10 and functional impairment, and identified "negative consequences" as the most relevant item connecting these variables. The IGDT-10 is a brief, easy-to-understand, valid, and reliable instrument, proving to be a suitable candidate for screening gaming disorder in future epidemiological studies.


Preparation and characterization of a molecularly imprinted polymer by grafting on silica supports: a selective sorbent for patulin toxin.
A new molecularly imprinted polymer (MIP) has been prepared on silica beads using the radical "grafting from" polymerization method for selective extraction of minor contaminant mycotoxin of patulin (PTL). After the introduction of amino groups onto the silica surface with 3-aminopropyltriethoxysilane, azo initiator onto the silica surface was achieved by the reaction of surface amino groups with 4,4'-azobis(4-cyanopentanoic acid). The scale-up synthesis of MIP was then carried out in the presence of 6-hydroxynicotinic acid as template substitute, functional, and cross-linking monomers. The prepared sorbent was characterized using FT-IR spectroscopy, scanning electron microscopy, elemental analysis, and the adsorption-desorption selectivity, and the capacity characteristic of the polymer was investigated by a conventional batch adsorption test and Scatchard plot analysis. The results indicated that coated polymers had specific adsorption to PTL as compared with its co-occurring 5-hydroxymethyl-2-furaldehyde (hydroxymethylfurfural (HMF)), at the same bulk concentration for solution of PTL and HMF, the maximum absorbance in the solid-phase extraction (SPE) method to PTL were 93.97% or 0.654 μg/mg while to HMF they were 76.89% or 0.496 μg/mg. Scatchard analysis revealed that two classes of binding sites were formed in PTL-MIP with dissociation constants of 3.2 × 10(-2) and 5.0 × 10(-3) mg/mL and the affinity binding sites of 8.029 and 1.364 mg/g, respectively. The recoveries of PTL were more than 90% for the developed MISPE and around 75% for the traditional liquid-liquid extraction in spiked apple juice samples. It was concluded that the method is suitable for the scale-up synthesis of PTL-MIP grafted on silica, and the polymer can be effectively applied as SPE coupled with high-performance liquid chromatography (HPLC) for the determination of PTL in apple juice or other related products.


Histometry of high-grade cervical intraepithelial neoplasia and LEEP excision margin in HIV-infected and uninfected women.
To investigate whether the size of the lesion correlates with the completeness of excision, and whether human immunodeficiency virus (HIV) infection was a risk factor for incompleteness of excision. We investigated the size of high-grade cervical intraepithelial lesions of loop electrosurgical excision procedure (LEEP) specimens to assess its effect on the status of the excision margins. Because of the possible negative effect of HIV infection on the completeness of excision, we compared HIV-positive with HIV-negative cases. Cross-sectional study of 226 consecutive LEEP specimens with cervical intraepithelial neoplasia (CIN). There were 126 CINs > or = 2; 59 (46.8%) were HIV positive. We measured the linear surface, the number of involved crypts, and the number of step sections involved by CIN > or = 2. The excision margins were involved in 65.1%. The measurable linear extent and the average number of involved crypts and sections were significantly higher with incomplete excision (p < 0.0001, p = 0.001, and p = 0.02, respectively). The endocervical excision margin was involved in 52.4% of incomplete excisions. The excision was incomplete in 43.9% of HIV-infected and 56.1% of HIV-uninfected cases (chi2 = 0.03, p = 0.88). It appears that instead of the linear surface involvement, it is rather the location in the endocervix and the extension inside the crypts that affects the excision margin status. HIV infection did not affect the completeness of excision.


[Ultrasonography findings in a case with infantile herpes encephalitis].
We present the case of an eleven months old infant, who suffered from herpes simplex type I encephalitis. Cerebral ultrasound examination showed on 5th day of disease signs of focal echodensity. At that time CT showed a focal meningeal enhancement and CSF findings were normal. Suspicions changes were also obtained by MR-Imaging and EEG on the same day. Herpes simplex virus was identified in the CSF with Polymerase chain reaction days later. There are no typical clinical signs for herpes encephalitis, CT, NMR, EEG findings as well as antigen and antibody-tests do naturally take their time. Cerebral sonography in infants offers to be the best bed-side method for early suspicion of herpes encephalitis, which may support diagnostic workup and can help to start a specific therapy (Acyclovir) as soon as possible.


Everyday stress response targets in the science of behavior change.
Stress is an established risk factor for negative health outcomes, and responses to everyday stress can interfere with health behaviors such as exercise and sleep. In accordance with the Science of Behavior Change (SOBC) program, we apply an experimental medicine approach to identifying stress response targets, developing stress response assays, intervening upon these targets, and testing intervention effectiveness. We evaluate an ecologically valid, within-person approach to measuring the deleterious effects of everyday stress on physical activity and sleep patterns, examining multiple stress response components (i.e., stress reactivity, stress recovery, and stress pile-up) as indexed by two key response indicators (negative affect and perseverative cognition). Our everyday stress response assay thus measures multiple malleable stress response targets that putatively shape daily health behaviors (physical activity and sleep). We hypothesize that larger reactivity, incomplete recovery, and more frequent stress responses (pile-up) will negatively impact health behavior enactment in daily life. We will identify stress-related reactivity, recovery, and response in the indicators using coordinated analyses across multiple naturalistic studies. These results are the basis for developing a new stress assay and replicating the initial findings in a new sample. This approach will advance our understanding of how specific aspects of everyday stress responses influence health behaviors, and can be used to develop and test an innovative ambulatory intervention for stress reduction in daily life to enhance health behaviors.


Systematic screening of hepatoprotective components from traditional Chinese medicine: Zuojin Pill as an example.
Zuojin Pill (ZJP), composed of Coptis chinensis Franch. and Euodia ruticarpa (A. Juss.) Benth. in a mass ratio of 6:1, is a famous traditional Chinese medicine (TCM) formula recorded in "Danxi's Experiential Therapy", an ancient medical book from the Ming Dynasty of China. It is used to treat liver fire invading the stomach, which is caused by liver stagnation transforming into fire and disharmony between the liver and stomach. To develop a systematic strategy to screen hepatoprotective components from TCMs using ZJP as a model sample. A CCl4-induced mouse model of acute liver injury was used for the verification of the hepatoprotective effects of ZJP. UPLC-Q-Exactive Plus Orbitrap MS/MS was used for the identification of the components in mouse serum after intragastric administration of ZJP. The hepatoprotective activities of the components found in mouse serum were tested in primary cultured mouse hepatocytes induced by CCl4. Nine components with significant hepatoprotective activity including berberine, epiberberine, coptisine, palmatine, jateorhizine, rutaecarpin, dehydroevodiamine, evocarpine and chlorogenic acid were successfully screened out. Our developed strategy has the advantages of high efficiency and low cost, and would provide a powerful tool for screening potential hepatoprotective components from TCM.


Characteristics Of Difficult-To-Treat Psoriatic Arthritis: A Comparative Analysis.
The EULAR task force recently published the difficult-to-treat rheumatoid arthritis (D2T RA) criteria, however, a definition of D2T patients in psoriatic arthritis (PsA) is still lacking. To date, we have little data concerning D2T PsA, especially in real-world. One of the limitations of the D2T RA EULAR definition is the absence of a temporal criterion. The primary endpoint of this work was to study the characteristics of D2T PsA patients using the EULAR definition. The second objective was to study a sub-group of patients with a predefined more stringent definition including a temporal criterion. A retrospective study was performed in a tertiary center. D2T PsA was defined as failure of ≥ 2 b/tsDMARDs with different mechanism of action. Very D2T PsA was defined as failure of ≥ 2 b/tsDMARDs in less than 2 years of follow-up. D2T and Very D2T PsA patients were compared to nD2T PsA patients using statistical tests. 150 PsA patients were included (from 2004 to 2015): 49 D2T PsA and 101 nD2T PsA. D2T PsA was associated with a higher prevalence of axial involvement (p=0.030), axial and/or peripheral structural damage (p=0.007) at baseline and more bDMARDs discontinuation due to poor dermatological control (p=0.005). There was no significant difference regarding comorbidities such as obesity, smoking status, fibromyalgia or depression. In multivariate analysis, peripheral structural damage at baseline was found to be a predictive factor for D2T PsA with an OR of 2.57 (1.16 to 5.69; p=0.020). 17 PsA (11.3%) patients were categorized as Very D2T PsA. When compared to nD2T group, proportion of obesity was higher (p=0.015) and axial involvement was more prevalent in the Very D2T group (p=0.020). D2T PsA patients had a higher prevalence of axial involvement, peripheral structural damage and therapeutic discontinuation due to poor dermatological control whereas Very D2T PsA patients were more likely obese with axial involvement. Very D2T PsA represent a minim proportion among patients when applying a more stringent definition. Pending the PsA D2T definition by the European and American societies, this study highlights some characteristics that may help practitioners better identify D2T patients.


Linezolid cerebrospinal fluid concentration in central nervous system infection.
We report two cases of central nervous system infection due to methicillin-resistant Staphylococcus epidermidis treated with linezolid. The first case was a 72-year old woman with ventriculitis in the presence of intraventricular catheter: therapeutic effectiveness was documented clinically and microbiologically; serum and cerebrospinal fluid levels were measured after the first and fourth doses: trough linezolid concentrations in cerebrospinal fluid were 1.44 and 2.9 mg/L respectively, higher than the minimum inhibitory concentration (MIC). The second case was a 27-year old man with post-traumatic cerebral abscess; during 5 days linezolid was not found in his cerebrospinal fluid despite very high serum level peak, and the drug was not detectable in cerebral tissue surgically removed after 14 days of therapy. Linezolid may not reach therapeutic concentrations in cerebrospinal fluid, and, when possible, we suggest that drug levels be monitored.


Commercially Available Apps to Support Healthy Family Meals: User Testing of App Utility, Acceptability, and Engagement.
Parents juggling caregiving and paid employment encounter a range of barriers in providing healthy food to their families. Mobile apps have the potential to help parents in planning, purchasing, and preparing healthy family food. The utility and acceptability of apps for supporting parents are unknown. User perspectives of existing technology, such as commercially available apps, can guide the development of evidence-based apps in the future. This study aims to determine the feasibility of existing commercially available apps for supporting the healthy food provision practices of working parents. Working parents (N=133) were recruited via the web and completed a 10-item Capability, Opportunity, Motivation, and Behavior (COM-B) self-evaluation survey assessing their needs in relation to the provision of healthy family meals. A total of 5 apps were selected for testing, including a meal planning app, recipe app, recipe manager app, family organizer app, and barcode scanning app. Survey items were mapped to app features, with a subsample of parents (67/133, 50.4%) allocated 2 apps each to trial simultaneously over 4 weeks. A semistructured interview exploring app utility and acceptability and a web-based survey, including the System Usability Scale and the user version of the Mobile App Rating Scale, followed app testing. The interview data were analyzed using a theoretical thematic approach. Survey participants (N=133; mean age 34 years, SD 4 years) were mainly mothers (130/133, 97.7%) and partnered (122/133, 91.7%). Participants identified a need for healthy recipes (109/133, 82% agreed or strongly agreed) and time for food provision processes (107/133, 80.5%). Engagement quality was the lowest rated domain of the user version of the Mobile App Rating Scale across all 5 apps (mean score per app ranging from 3.0 to 3.7 out of a maximum of 5). The family organizer, requiring a high level of user input, was rated the lowest for usability (median 48, IQR 34-73). In the interviews, participants weighed the benefits of the apps (ie, time saving) against the effort involved in using them in determining their acceptability. Organization was a subtheme emerging from interviews, associated with the use of meal planners and shopping lists. Meal planners and shopping lists were used in time, while behavior was occurring. Meal planning apps and features promoting organization present feasible, time-saving solutions to support healthy food provision practices. Attention must be paid to enhancing app automation and integration, as well as recipe and nutrition content, to ensure that apps do not add to the time burden of food provision and are supportive of healthy food provision behavior in time.


[Computer-assisted planning and corrective osteotomy in distal radius malunion].
Corrective osteotomy of the malunited distal radius following fracture was performed in six patients using virtual planning and computer-assisted surgery. Radius joint angles and ulnar variance were assessed by CT scan and compared with the uninvolved wrist. Dorsal tilt was improved by 6 degrees, radial inclination by 3 degrees, radius rotation by 7 degrees and ulnar variance by 4.6 mm. Results were almost equivalent to the noninvolved radius. Corrective osteotomy in extraarticular malunited distal radius fracture was optimized by computer-assisted planning and surgery.


Fermi pockets and quantum oscillations of the Hall coefficient in high-temperature superconductors.
Recent quantum oscillation measurements in high-temperature superconductors in high magnetic fields and low temperatures have ushered in a new era. These experiments explore the normal state from which superconductivity arises and provide evidence of a reconstructed Fermi surface consisting of electron and hole pockets in a regime in which such a possibility was previously considered to be remote. More specifically, the Hall coefficient has been found to oscillate according to the Onsager quantization condition, involving only fundamental constants and the areas of the pockets, but with a sign that is negative. Here, we explain the observations with the theory that the alleged normal state exhibits a hidden order, the d-density wave, which breaks symmetries signifying time reversal, translation by a lattice spacing, and a rotation by an angle pi/2, while the product of any two symmetry operations is preserved. The success of our analysis underscores the importance of spontaneous breaking of symmetries, Fermi surface reconstruction, and conventional quasiparticles. We primarily focus on the version of the order that is commensurate with the underlying crystalline lattice, but we also touch on the consequences if the order were to incommensurate. It is shown that whereas commensurate order results in two independent oscillation frequencies as a function of the inverse of the applied magnetic field, incommensurate order leads to three independent frequencies. The oscillation amplitudes, however, are determined by the mobilities of the charge carriers comprising the Fermi pockets.


An analysis of population-based prenatal screening for overt hypothyroidism.
The purpose of the study was to evaluate pregnancy outcomes of hypothyroidism that were identified in a population-based prenatal screening program. This is a secondary analysis of a prospective prenatal population-based study in which serum thyroid analytes were obtained from November 2000 to April 2003. Initial screening thresholds were intentionally inclusive (thyroid-stimulating hormone [TSH], >3.0 mU/L; free thyroxine, <0.9 ng/dL); those who screened positive were referred for confirmatory testing in a hospital-based laboratory. Hypothyroidism was identified and treated if TSH level was >4.5 mU/L and if fT4 level was <0.76 ng/dL. Perinatal outcomes in these women and those who screened positive but unconfirmed to have hypothyroidism were compared with women with euthyroidism. Outcomes were then analyzed according to initial TSH levels. A total of 26,518 women completed initial screening: 24,584 women (93%) were euthyroid, and 284 women (1%) had abnormal initial values that suggested hypothyroidism. Of those referred, 232 women (82%) underwent repeat testing, and 47 women (0.2% initially screened) were confirmed to have hypothyroidism. Perinatal outcomes of women with treated overt hypothyroidism were similar to women with euthyroidism. Higher rates of pregnancy-related hypertension were identified in the 182 women with unconfirmed hypothyroidism when compared with women with euthyroidism (P < .001); however, this association was seen only in women with initial TSH >4.5 mU/L (adjusted odds ratio, 2.53; 95% confidence interval, 1.4-4.5). The identification and treatment of overt hypothyroidism results in pregnancy outcomes similar to women with euthyroidism. Unconfirmed screening results suggestive of hypothyroidism portend pregnancy risks similar to women with subclinical hypothyroidism, specifically preeclampsia; however, this increased risk was seen only in women with initial TSH levels of >4.5 mU/L and suggests that this is a more clinically relevant threshold than 3.0 mU/L.


A new species of Herpomyces (Laboulbeniomycetes: Herpomycetales) on Periplaneta fuliginosa (Blattodea: Blattidae) from Argentina.
We are becoming increasingly aware of the dazzling diversity of fungi-new taxa are being discovered from poorly sampled habitats and integrative approaches point at (near-)cryptic species in many groups. The class Laboulbeniomycetes, which is composed of three orders (Herpomycetales, Laboulbeniales, Pyxidiophorales), is no exception. However, still, in the orders Herpomycetales and Laboulbeniales, species are predominantly described based on morphology alone. Here, we present a new species of Herpomyces from Argentina parasitic on Periplaneta fuliginosa, the smokybrown cockroach. Herpomyces spegazzinii, sp. nov., is characterized based on morphology and molecular data. Phylogenetic inference based on internal transcribed spacer (ITS, consisting of ITS1-5.8S-ITS2) barcode region supports the status of this fungus as a separate species, sister to the recently described H. shelfordellae.


A Fast k Nearest Neighbor Finding Algorithm Based on the Ordered Partition.
We propose a fast nearest neighbor finding algorithm, named tentatively an ordered partition, based on the ordered lists of the training samples of each projection axis. The ordered partition contains two properties, one is ordering¿to bound the search region, and the other is partitioning¿to reject the unwanted samples without actual distance computations. It is proved that the proposed algorithm can find k nearest neighbors in a constant expected time. Simulations show that the algorithm is rather distribution free, and only 4.6 distance calculations, on the average, were required to find a nearest neighbor among 10 000 samples drawn from a bivariate normal distribution.


Coprophagy in iron-deficient rats: II. 2 novel methods of prevention.
2 novel methods of coprophagy prevention were used in iron-deficient rats to measure their effect on haemoglobin regeneration during the feeding of ferrous sulphate or several soya proteins. Neck collars produced considerable weight loss and depression in food intake compared to aluminium anal cups which were tolerated well. Both methods of coprophagy prevention reduced iron availability from a range of soya proteins and ferrous sulphate and it is suggested that the practice of coprophagy in iron-deficient and possibly iron-replete rats may overestimate iron (and possibly other mineral) absorption (retention) studies.


Isolation of peptides from phage-displayed random peptide libraries that interact with the talin-binding domain of vinculin.
Peptides isolated from combinatorial libraries typically interact with, and thus help to characterize, biologically relevant binding domains of target proteins. To characterize the binding domains of the focal adhesion protein vinculin, vinculin-binding peptides were isolated from two phage-displayed random peptide libraries. Altogether, five non-similar vinculin-binding peptides were identified. Despite the lack of obvious sequence similarity between the peptides, binding and competition studies indicated that all five interact with the talin-binding domain of vinculin and do not disrupt the binding of alpha-actinin or paxillin to vinculin. The identified peptides and talin bind to vinculin in a comparable manner; both bind to immobilized vinculin, but neither binds to soluble vinculin unless the C-terminus of vinculin has been deleted. An analysis of amino acid variants of one of the peptides has revealed three non-contiguous motifs that also occur in the region of talin previously demonstrated to bind vinculin. Amino acid substitutions within a 127-residue segment of talin capable of binding vinculin confirmed the importance of two of the motifs and suggest that residues critical for binding are within a 16-residue region. This study demonstrates that the vinculin-binding peptides interact with vinculin in a biologically relevant manner and represent an excellent tool for further study of the biochemistry of vinculin.


Opposing parallel connections through crayfish local nonspiking interneurons.
Unilateral local nonspiking interneurons in the terminal (sixth) abdominal ganglion of crayfish (Procambarus clarkii Girard) can be classified into two major groups of PL and AL types by their gross morphology and somatic position. These premotor interneurons are the neural components of uropod motor pattern formation. They receive sensory input from the exopodite of the contralateral side as well as that of the ipsilateral side. Small fluctuations in their membrane potentials cause sustained change in activity of the motoneurons innervating the uropod muscles. PL interneurons, which make noninverting connections to an identified closer, the reductor motoneuron No. 1, mainly receive excitatory input from the afferents of the contralateral exopodite, whereas inverting PL interneurons receive inhibitory input. AL interneurons receive distinctly different input from the afferents. Noninverting AL interneurons mainly receive inhibitory input, whereas inverting AL interneurons receive excitatory input. The rate of discharge of the reductor motoneurons is increased by sensory stimulation. The PL interneurons form either excitatory or disinhibitory pathways, which are relevant in function to the observed increase of the motoneuron. Conversely, the AL interneurons form either inhibitory or disfacilitatory pathways. Thus, the PL and the AL interneurons are fractionated in function and distinguishable in terms of their physiology by their input and output correlations. Functional meaning of the presence of these two types of unilateral local nonspiking interneurons of opposing connections in the uropod motor control system is discussed.


A Comparison of Self-Selected Walking Speeds and Walking Speed Variability When Data Are Collected During Repeated Discrete Trials and During Continuous Walking.
A typical gait analysis data collection consists of a series of discrete trials, where a participant initiates gait, walks through a motion capture volume, and then terminates gait. This is not a normal 'everyday' gait pattern, yet measurements are considered representative of normal walking. However, walking speed, a global descriptor of gait quality that can affect joint kinematics and kinetics, may be different during discrete trials, compared to continuous walking. Therefore, the purpose of this study was to investigate the effect of continuous walking versus discrete trials on walking speed and walking speed variability. Data were collected for 25 healthy young adults performing 2 walking tasks. The first task represented a typical gait data collection session, where subjects completed repeated trials, beginning from a standstill and walking along a 12-m walkway. The second task was continuous walking along a "figure-of-8" circuit, with 1 section containing the same 12-m walkway. Walking speed was significantly higher during the discrete trials compared to the continuous trials (p < .001), but there were no significant differences in walking speed variability between the conditions. The results suggest that choice of gait protocol may affect results where variables are sensitive to walking speed.


Hip flexor muscle dysfunction during walking at self-selected and fast speed in patients with aortoiliac peripheral arterial disease.
Intermittent claudication aggravates physical function and is associated with an increased risk of death in patients with peripheral arterial disease (PAD). Previous studies on kinetic parameters (joint moment and power) of lower limbs in these patients have largely focused on the decline in the ankle plantar flexor moment and power at self-selected (SS) walking speed, which may not be an optimal condition to induce claudication pain. In the present study, we investigated the abnormalities in joint kinetic parameters in patients with PAD at both SS and at fast walking speeds. We recruited 16 patients with aortoiliac PAD (4 unilateral and 12 bilateral) and 10 healthy controls. The participants were instructed to walk at SS and fast speeds along a 7-meter walkway embedded with a force plate. Spatiotemporal parameters and joint kinetic parameters of the lower limbs during the stance phase were recorded using a three-dimensional motion analysis device. Compared with the controls, patients with PAD showed a significant reduction in their walking speed, step length, stride length, and cadence. Further, a reduction in peak hip flexor moment at fast walking speed and in peak hip flexor generation power was observed in both modes of walking. However, no significant between-group differences were observed for the peak ankle plantar flexor moment or power at either walking speed. Multiple regression analysis showed peak hip flexor generation power was a strong contributor to reduction at both SS and fast walking speeds in patients with PAD. Patients with aortoiliac PAD walk slowly and show reduced kinetic parameters of the hip joint at both SS and fast walking speeds. Our results suggest that hip flexor muscles may be a useful target for exercise training in patients with aortoiliac PAD.


Characterization of malignant brain tumor using elastic light scattering spectroscopy.
We report a pilot study designed to test elastic light-scattering (ELS) spectroscopy for characterizing normal, tumor, and tumor-infiltrated brain tissues. ELS spectra were measured from 393 sites on 36 ex vivo tissue specimen obtained from 29 patients. We employed and compared the performances of three methods of spectral classification for tissue characterization, including spectral slope analysis, principle component analysis (PCA), and artificial neural network (ANN) classification. The ANN classifier yielded the best correlation between spectral pattern and histopathological diagnosis, with a typical sensitivity of 80% and specificity of 93% for differentiating tumor from normal brain tissues. We also demonstrate that all three classification methods discriminate between tumor and normal tissue and have the potential to identify and quantitatively characterize tumor-infiltrated brain tissues.


Monitoring decay of black gum wood (Nyssa sylvatica) during growth of the shiitake mushroom (Lentinula edodes) using diffuse reflectance infrared spectroscopy.
Abstract diffuse reflectance infrared spectroscopy (DRIFT) and elemental analysis were employed to monitor biodegradation of black gum wood (Nyssa sylvatica) during growth of the shiitake mushroom (Lentinula edodes). Black gum was decayed for up to 4.3 years by L. edodes, during which time it was sampled at 19, 31, and 52 months. Biodegraded woods displayed increased % O (w/w) and decreased % C (w/w) relative to the undecayed control. The DRIFT spectra of decayed black gum showed a decrease in relative intensity of absorption bands at 1735 cm(-1) assigned to carboxyl functional groups from xylans and an increase in the absorption band at 1640 cm(-1) assigned to conjugated carbonyl groups originating from lignin. Xylan decay was rapid initially but slowed after 19 months; however, oxidative decay of the lignin side chains occurred throughout the 52-month decay period. Overall elemental and DRIFT data show that both polysaccharides and lignin were decayed during cultivation of the edible white-rot fungus.


Premotor neurons encode torsional eye velocity during smooth-pursuit eye movements.
Responses to horizontal and vertical ocular pursuit and head and body rotation in multiple planes were recorded in eye movement-sensitive neurons in the rostral vestibular nuclei (VN) of two rhesus monkeys. When tested during pursuit through primary eye position, the majority of the cells preferred either horizontal or vertical target motion. During pursuit of targets that moved horizontally at different vertical eccentricities or vertically at different horizontal eccentricities, eye angular velocity has been shown to include a torsional component the amplitude of which is proportional to half the gaze angle ("half-angle rule" of Listing's law). Approximately half of the neurons, the majority of which were characterized as "vertical" during pursuit through primary position, exhibited significant changes in their response gain and/or phase as a function of gaze eccentricity during pursuit, as if they were also sensitive to torsional eye velocity. Multiple linear regression analysis revealed a significant contribution of torsional eye movement sensitivity to the responsiveness of the cells. These findings suggest that many VN neurons encode three-dimensional angular velocity, rather than the two-dimensional derivative of eye position, during smooth-pursuit eye movements. Although no clear clustering of pursuit preferred-direction vectors along the semicircular canal axes was observed, the sensitivity of VN neurons to torsional eye movements might reflect a preservation of similar premotor coding of visual and vestibular-driven slow eye movements for both lateral-eyed and foveate species.


LC-MS/MS bioanalysis of loratadine (Claritin) in dried blood spot (DBS) samples collected by subjects in a clinical research study.
A high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the quantitative analysis of loratadine, an H1 histamine antagonist, in human dried blood spot (DBS) samples following a single self-administered 10 or 20mg oral dose. The samples were produced by spotting approximately 30μl of whole blood onto PE-226 cards. Two 3-mm discs were cut from the DBS samples and extracted using aqueous methanol containing the internal standard. After transfer and drying of the resulting sample extract, the reconstituted residues were chromatographed using a Waters XSelect C18 column and isocratic elution for MS/MS detection. The possible impact due to hematocrit, volume of blood sample spotted, storage temperature, and humidity, on the accuracy of measured DBS results were investigated. The results showed that only spotted blood volume might have an impact; a small volume (10μl) tended to give a larger negative bias in the measured value than the large volume ones (≥20μl). The current method was fully validated over a dynamic range of 0.200-20.0ng/ml with correlation coefficients (r(2)) for three validation batches equal to or better than 0.990. The intra-day accuracy and precision at the LLOQ were -11.5 to 0.0% bias and 6.4 to 8.9% CV, respectively. For the other QC samples (0.600, 3.00, 10.0 and 15.0ng/ml), the precision ranged from 4.2 to 9.8% CV and from 6.3 to 8.1% CV, respectively, in the intra-day and inter-day evaluations; the accuracy ranged from -1.7 to 10.0% and 2.7 to 5.3% bias, respectively, in the intra-day and inter-day batches. Loratadine is stable in the DBS samples for at least 271 days at ambient temperature in a desiccator, for at least 24h at 60°C and under 80% relative humidity, followed by re-conditioning at ambient temperature in a desiccator. The current methodology has been applied to determine the loratadine levels in DBS samples collected by subjects in a clinical research study to evaluate pharmacokinetic sampling in point-of-care setting.


Complete Genome Sequencing of Protease-Producing Novel Arthrobacter sp. Strain IHBB 11108 Using PacBio Single-Molecule Real-Time Sequencing Technology.
A previously uncharacterized species of the genus Arthrobacter, strain IHBB 11108 (MCC 2780), is a Gram-positive, strictly aerobic, nonmotile, cold-adapted, and protease-producing alkaliphilic actinobacterium, isolated from shallow undersurface water from Chandra Tal Lake, Lahaul-Spiti, India. The complete genome of the strain is 3.6 Mb in size with an average 58.97% G+C content.


Blood pressure during nocturnal sleep in headache.
Interactions between blood pressure control, sleep and headache have been largely studied, although not well understood. We designed a study trying to simultaneously evaluate all three aspects in the same subjects. We particularly concentrated on the observation of physiological blood pressure circadian rhythm, and the presence of cutaneous allodynia correlated to headache. Objective of the study was to investigate blood pressure during nocturnal sleep in patients that underwent a blood pressure 24 hours monitoring, and at the same time the presence of headache and of sleep behavioural alterations. Blood pressure 24 hours monitoring was performed by an ambulatory blood pressure (ABP) monitor (Space Labs) with its ad hoc software. Headache diagnosis was made according to ICHD-II criteria. Presence of allodynia and sleep behavior were evaluated through semi-structured ad hoc questionnaires. A total of 195 subjects were included, of which 122 without headache (mean age 60.4±11.6 years, 78 men and 44 women) and 73 with history of headache, (mean age 54.2±12.5 years, 18 men and 55 women). Fifty-one headache patients had migraine (mean age 52.6±11.7 years, 11 men and 40 women) and 22 tension type headache (TTH - mean age 58.0±13.5 years, 7 men and 15 women). Allodynia was found in 30 out of 73 headache patients: 23 out of 51 in the migraine group and in 7 out of 22 in the tension-type one. The physiological reduction of blood pressure during night (dipping) was more conserved among headache patients (34 dippers out of 73 subjects, 46,6%) with respect to subjects without headache (40 dippers out of 122, 32,8%) and that this border-line difference was more strongly significant comparing allodynic subjects (19 dippers out of 30, 63.3%) with both non-headache (40 dippers out of 122, 32.8%, P<0.001) and non-allodynic (15 out of 43, 34.9%, P<0.05) ones. No significant difference was observed between headache patients and subjects without headache in terms of mean systolic and diastolic pressure, neither between migraine and TTH. Allodynic headache patients seem to maintain a more physiologic pressure circadian rhythm. While considering the possibility of selection bias, the hypothesis of an allostatic function of headache and allodynia in patients with unbalanced blood pressure could be made.


Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases: a mutational analysis of the functionally important sites in the S2+ and S2- splice variants.
Inositol 1,4,5-trisphosphate receptors (InsP3R) are the major route of intracellular calcium release in eukaryotic cells and as such are pivotal for stimulation of Ca2+-dependent effectors important for numerous physiological processes. Modulation of this release has important consequences for defining the particular spatio-temporal characteristics of Ca2+ signals. In this study, regulation of Ca2+ release by phosphorylation of type-1 InsP3R (InsP3R-1) by cAMP (PKA)- and cGMP (PKG)-dependent protein kinases was investigated in the two major splice variants of InsP3R-1. InsP3R-1 was expressed in DT-40 cells devoid of endogenous InsP3R. In cells expressing the neuronal, S2+ splice variant of the InsP3R-1, Ca2+ release was markedly enhanced when either PKA or PKG was activated. The sites of phosphorylation were investigated by mutation of serine residues present in two canonical phosphorylation sites present in the protein. Potentiated Ca2+ release was abolished when serine 1755 was mutated to alanine (S1755A) but was unaffected by a similar mutation of serine 1589 (S1589A). These data demonstrate that Ser-1755 is the functionally important residue for phosphoregulation by PKA and PKG in the neuronal variant of the InsP3R-1. Activation of PKA also resulted in potentiated Ca2+ release in cells expressing the non-neuronal, S2- splice variant of the InsP3R-1. However, the PKA-induced potentiation was still evident in S1589A or S1755A InsP3R-1 mutants. The effect was abolished in the double (S1589A/S1755A) mutant, indicating both sites are phosphorylated and contribute to the functional effect. Activation of PKG had no effect on Ca2+ release in cells expressing the S2- variant of InsP3R-1. Collectively, these data indicate that phosphoregulation of InsP3R-1 has dramatic effects on Ca2+ release and defines the molecular sites phosphorylated in the major variants expressed in neuronal and peripheral tissues.


Evolution of genomic imprinting as a coordinator of coadapted gene expression.
Genomic imprinting is an epigenetic phenomenon in which the expression of a gene copy inherited from the mother differs from that of the copy inherited from the father. Many imprinted genes appear to be highly interconnected through interactions mediated by proteins, RNA, and DNA. These kinds of interactions often favor the evolution of genetic coadaptation, where beneficially interacting alleles evolve to become coinherited. Here I demonstrate theoretically that the presence of gene interactions that favor coadaptation can also favor the evolution of genomic imprinting. Selection favors genomic imprinting because it coordinates the coexpression of positively interacting alleles at different loci. Evolution is expected to proceed through a scenario where selection builds associations between beneficial combinations of alleles and, if one locus evolves to become imprinted, it leads to selection for its interacting partners to match its pattern of imprinting. This process should favor the evolution of physical linkage between interacting genes and therefore may help explain why imprinted genes tend to be found in clusters. The model suggests that, whereas some genes are expected to evolve their imprinting status because selection directly favors a specific pattern of parent-of-origin-dependent expression, other genes may evolve imprinting as a coevolutionary response to match the expression pattern of their interacting partners. As a result, some genes will show phenotypic effects consistent with the predictions of models for the evolution of genomic imprinting (e.g., conflict models), but other genes may not, having simply evolved imprinting to follow the lead of their interacting partners.


The petrous bone--a new sampling site for identifying early dietary patterns in stable isotopic studies.
Intraskeletal variation in the composition of carbon (delta(13)C) and nitrogen (delta(15)N) stable isotopes measured in collagen is tested from various human bones and dentine. Samples were taken from the femur, rib, and petrous part of the temporal bone from well-preserved skeletons of both adults (n = 34) and subadults (n = 24). Additional samples of dentine from the root of 1st molars were taken from 16 individuals. The skeletal material is from a medieval cemetery (AD 1200-1573) in Holbaek, Denmark. Our results indicate that the petrous bone has an isotopic signal that differs significantly from that of femur and rib within the single skeleton (P < 0.001 and P < 0.001, respectively), with only minor variation seen between femur and rib. On the other hand, there was no significant difference between the petrous bone and the 1st molar. The intraskeletal variation may reflect differences in turnover rate among skeletal elements. The inner periosteal layer of the petrous bone is formed in uterus and does not undergo any further remodelling after the age of 2 years, whereas the rib and femur have a continuous turnover rate of approximately 5 and 10-20 years, respectively. From the results of this study it is believed the petrous bone may be a new useful bone element and a supplement or a proxy for teeth in the analysis of early dietary patterns as it may reflect diet in fetal stages and early years of life.


Oxidised cellulose powder for haemostasis following sinus surgery: a pilot randomised trial.
Haemorrhage is the most common major complication of endoscopic sinus surgery. Post-operative absorbable or non-absorbable nasal packing can cause pain and blockage. Haemostatic powders or gels may prevent this problem. However, when based on factors in the clotting cascade, they induce an inflammatory reaction and can cause post-operative synechiae. Oxidised cellulose powder produces haemostasis without inducing synechiae formation, but has not been trialled for sinus surgery. A randomised clinical trial was performed to compare cellulose powder to non-absorbable packing following sinus surgery. Participants were 50 consecutive patients undergoing sinus surgery, 47 of whom completed the study. The main outcome measures were post-operative bleeding, pain scores and synechiae formation. Cellulose powder was effective at stopping bleeding, and was associated with less pain than nasal packing, with no evidence of increased synechiae formation. Cellulose powder appears to be a good haemostatic agent following sinus surgery. A larger trial would allow more accurate quantification of its effectiveness.


Study of various immunological parameters in the diagnosis of allergy to penicillin G and its derivatives.
The objective of this paper was to draw up an efficient and safe study protocol to diagnose allergy to beta-lactam antibiotics. Seven hundred and fifty patients with clinical histories suggesting penicillin allergy were studied. RAST to penicilloyl G/V, skin tests with PPL, MDM, penicillin G and ampicillin, epicutaneous tests with differed type reactions and a provocation test (in case of the negative results of the other tests) were performed on the patients. The incidence of this pathology is very low (6.5%) and atopic patients do not present greater predisposition to suffer from it than the general population. By carrying out RAST and skin tests with PPL, MDM, penicillin G and ampicillin we arrived at the diagnosis, in the anaphylactic type charts, in 97.5% of the cases. In reactions of a differed type, by performing patch tests we arrived at the diagnosis in 50% of the cases.


Anisotropic 2H NMR spin-lattice relaxation in L alpha-phase cerebroside bilayers.
A series of 2H NMR inversion recovery experiments in the L alpha phase of the cerebroside N-palmitoylgalactosylsphingosine (NPGS) have been performed. In these liquid crystalline lipid bilayers we have observed substantial anisotropy in the spin-lattice relaxation of the CD2 groups in the acyl chains. The form and magnitude of the anisotropy varies with position in the chain, being positive in the upper region, decreasing to zero at the 4-position, and reversing sign at the lower chain positions. It is also shown that addition of cholesterol to the bilayer results in profound changes in the anisotropy. These observations are accounted for by a simple motional model of discrete hops among nine sites, which result from the coupling of two modes of motion--long-axis rotational diffusion and gauche-trans isomerization. This model is employed in quantitative simulations of the spectral line shapes and permits determination of site populations and motional rates. These results, plus preliminary results in sphingomyelin and lecithin bilayers, illustrate the utility of T1 anisotropy measurements as a probe of dynamics in L alpha-phase bilayers.


Lack of local anaesthetic efficacy of Sarapin in the abaxial sesamoid block model.
Sarapin is a distillate of the pitcher plant that has long been used in human and veterinary medicine for 'regional analgesia'. The mechanism of the reported analgesic response is unknown; however, the agent is purported to provide more effective analgesia for slow, chronic pain than for sharp, acute pain. Reportedly, Sarapin is also widely used as an analgesic agent in the horse, generally in combination with corticosteroids and other agents. To determine its local anaesthetic efficacy in the horse, we tested Sarapin in a unilateral abaxial sesamoid block model at two dose levels, 2 mL and 10 mL per site, respectively. Cutaneous pain was induced with a light/heat lamp, and analgesia was assessed by measuring the hoof-withdrawal reflex latency period. Neither dose of Sarapin altered hoof-withdrawal reflex latency in this experimental model tested over a two-week period. Based on the demonstrated efficacy of this local anaesthetic model, it seems clear that Sarapin has no significant classical local anaesthetic actions in the horse, and probably not in other species either.


Do residential care and low social capital negatively influence oral health-related quality of life (OHRQoL) among older adults? A cross-sectional study.
To compare oral health status, OHRQoL and social capital between dependent older adults living in a residential care setting (RC) and community dwellers living independently (CD) and to assess the possible role of social capital and residential status as independent predictors of OHRQoL in a sample of older adults in the Udupi region of Karnataka, South India. As the global population ages, a greater number of older adults are now living in residential care settings than ever before. This study provides insights into the role of residential care and social capital in influencing the oral health-related quality of life (OHRQoL) among older adults. A total of 296 older adults, comprising 148 dependent older adults living in residential care (RC) and 148 community dwelling older adults living independently (CD), completed the General Oral Health Assessment Index (GOHAI) and a Social Capital Scale after undergoing clinical oral examination for dentition and periodontal status. The caries experience in both the residential care group (RC) and the community dwelling group (CD) was high with mean DMF scores of 21.6 (SD = 9.6) and 20.1 (SD = 10.7) respectively. The Mean Social Capital score was significantly higher (P = .01) among the RC group (33.2, SD = 5.1) than the CD group (31.5, SD = 5.7), whereas the mean GOHAI score was significantly higher (P = .02) among the CD (61.5, SD = 6.8) than the RC group (59.5, SD = 7.9). Linear regression showed lower DMFT scores (β: -0.26, P ˂ .001), being a community dweller (β: 0.14, P = .01) and having higher social capital (β: 0.11, P = .04) were associated with better OHRQoL (higher GOHAI scores) after adjusting for possible confounders. Dependent older adults living in residential care had higher social capital but poorer OHRQoL. Caries experience, residential status and social capital were independently associated with OHRQoL.


Use of gene marking technologies in oncology.
Investigation of the mechanism of relapse in patients receiving stem cell rescue as therapy for malignant disease has been facilitated by gene marking studies. These studies have shown the marker gene to be present in malignant cells in the patient at the time of relapse, indicating that infused stem cells can contribute to disease recurrence. As normal progenitor cells are also marked and can be tracked in vivo, these studies have also helped us learn how haemopoietic stem cells respond to manipulation, for example with growth factors. Second generation studies with multiple, modified vectors are beginning to provide information about a wider variety of clinical and biological issues, including the efficacy of purging. Although marker studies have been useful for haematological malignancy and for neuroblastoma, they are hampered by the low efficiency of marking achieved by retroviral vectors. For many malignancies, marking efficiencies are insufficient for useful information to be obtained. This problem may be overcome by the introduction of vectors that, unlike retroviruses, can stably integrate in cells that are not in cycle at the time of vector exposure. Other improvements will focus on the marker genes themselves, using marker elements that are simpler to track and will not produce any modification of the cells' behaviour. Finally, marker studies have proved safe so far, but follow-up of the treated patients continues.


Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms.
The recently identified small molecule, 3-amino-5-chloro-6-methoxy-4-methylthieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (LY2033298), is the first selective allosteric modulator of the muscarinic acetylcholine receptors (mAChRs) that mediates both receptor activation and positive modulation of the endogenous agonist, acetylcholine (ACh), via the same allosteric site on the M(4) mAChR. We thus utilized this novel chemical tool, as well as ACh, the bitopic (orthosteric/allosteric) agonist, McN-A-343, and the clinically efficacious M(1)/M(4) mAChR-preferring agonist, xanomeline, in conjunction with site-directed mutagenesis of four different regions of the M(4) mAChR (extracellular loops 1, 2, and 3, and transmembrane domain 7), to identify regions that govern ligand-specific modes of binding, signaling, and allosteric modulation. In the first extracellular loop (E1), we identified Ile(93) and Lys(95) as key residues that specifically govern the signaling efficacy of LY2033298 and its binding cooperativity with ACh, whereas Phe(186) in the E2 loop was identified as a key contributor to the binding affinity of the modulator for the allosteric site, and Asp(432) in the E3 loop appears to be involved in the functional (activation) cooperativity between the modulator and the endogenous agonist. In contrast, the highly conserved transmembrane domain 7 residues, Tyr(439) and Tyr(443), were identified as contributing to a key activation switch utilized by all classes of agonists. These results provide new insights into the existence of multiple activation switches in G protein-coupled receptors (GPCRs), some of which can be selectively exploited by allosteric agonists, whereas others represent global activation mechanisms for all classes of ligand.


Antibacterial effect of the red sea soft coral Sarcophyton trocheliophorum.
The marine soft corals Sarcophyton trocheliophorum crude extracts possessed antimicrobial activity towards pathogenic bacterial strains, i.e. Bacillus cereus, Salmonella typhi, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Bioassay-guided fractionation indicated that the antimicrobial effect was due to the presence of terpenoid bioactive derivatives. Further biological assays of the n-hexane fractions were carried out using turbidity assay, inhibition zone assay and minimum inhibitory concentration for investigating the growth-inhibition effect towards the Gram-positive and Gram-negative bacteria. The fractions were screened and the structure of the isolated compound was justified by interpretation of the spectroscopic data, mainly mass spectrometry (GC-MS). The structure was assigned as (5S)-3-[(3E,5S)-5-hydroxy-3-hepten-6-yn-1-yl]-5-methyl-2(5H)-furanone and was effective at concentrations as low as 0.20 mg/mL. The above findings, in the course of our ongoing research on marine products, may implicate that the profound anti-microbial activity of the S. trocheliophorum soft corals, inhabiting the red sea reefs, is attributed to the presence of growth-inhibiting secondary metabolites mainly terpenoids.


Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy.
The risk of intrauterine transmission of cytomegalovirus (CMV) during pregnancy is much greater for women who contract primary CMV infection after conception than for women with evidence of infection (circulating CMV antibodies) before conception. Thus, laboratory tests that aid in the identification of recent primary CMV infection are important tools for managing the care of pregnant women suspected of having been exposed to CMV. CMV IgM detection is a sensitive marker of primary CMV infection, but its specificity is poor because CMV IgM is also produced during viral reactivation and persists following primary infection in some individuals. Studies conducted over the last 20 years convincingly demonstrate that measurement of CMV IgG avidity is both a sensitive and a specific method for identifying pregnant women with recent primary CMV infection and thus at increased risk for vertical CMV transmission. IgG avidity is defined as the strength with which IgG binds to antigenic epitopes expressed by a given protein; it matures gradually during the 6 months following primary infection. Low CMV IgG avidity is an accurate indicator of primary infection within the preceding 3 to 4 months, whereas high avidity excludes primary infection within the preceding 3 months. In this minireview, we summarize published data demonstrating the clinical utility of CMV IgG avidity results for estimating time since primary infection in pregnant women, describe commercially available CMV IgG avidity assays, and discuss some of the issues and controversies surrounding CMV IgG avidity testing during pregnancy.


Identification of a novel metastasis inducing lncRNA which suppresses the KAI1/CD82 metastasis suppressor gene and is upregulated in triple-negative breast cancer.
Inactivation of tumor/metastasis suppressor genes via epigenetic silencing is a frequent event in human cancers. KAI1/CD82 is a metastasis suppressor gene whose normal protecting activity is deficient in twelve different solid malignancies. Here we have identified and characterized a primarily nuclear non-polyadenylated, antisense (as)-lncRNA, initiating upstream of the KAI1 human metastasis suppressor gene transcription start site; and elongating in the opposite direction to KAI1 mRNA. We show that the KAI1 promoter is bi-directional giving rise to KAI1 mRNA and its as-lncRNA. Moreover, expression of this lncRNA transcript emerges to be inversely related to the KAI1 mRNA expression, and in direct relationship to the invasiveness level of human breast cancer derived cell lines. Importantly, knockdown of the KAI1 as-lncRNA in the triple-negative breast cancer cell line MDA-MB-231 have led to increased KAI1 mRNA and protein expression, manifested in stronger adhesion to fibronectin, retardation of cell migration and reduced cell invasion in vitro. Accordingly we have named this lncRNA, SKAI1BC, standing for "Suppressor of KAI1 in Breast Cancer". These results uncover a potential way to harness tumor metastasis via targeting SKAI1BC in human breast cancer, and perhaps also in other KAI1-deficient human malignancies.


Cognitive impairment in multiple sclerosis.
Cognitive impairment (CI) is a serious complication of multiple sclerosis (MS), and the domains affected are well established, but new affected domains such as theory of mind are still being identified. The evidence that disease-modifying therapies (DMTs) improve and prevent the development of CI in MS is not solid. Recent studies on the prevalence of CI in MS among people treated with DMT, although not as solid as studies completed prior to DMT introduction, suggest that CI remains a problem even among people on DMTs and that CI occurs frequently even at the very earliest stages of MS. Functional MRI studies and studies using diffusion tractography show that the impact of lesions on cognition depends on the particular cortical networks affected and their plasticity. Cognitive rehabilitation and L-amphetamine appear promising symptomatic treatments for CI in MS, while, cholinesterase inhibitors and memantine have failed, and data on Ginkgo and exercise are limited. We need more work to understand better CI in MS and develop treatments for this serious complication of MS.


Pulmonary Alveolar Proteinosis in Setting of Inhaled Toxin Exposure and Chronic Substance Abuse.
Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which defects in alveolar macrophage maturation or function lead to the accumulation of proteinaceous surfactant in alveolar space, resulting in impaired gas exchange and hypoxemia. PAP is categorized into three types: hereditary, autoimmune, and secondary. We report a case of secondary PAP in a 47-year-old man, whose risk factors include occupational exposure to inhaled toxins, especially aluminum dust, the use of anabolic steroids, and alcohol abuse, which in mice leads to alveolar macrophage dysfunction through a zinc-dependent mechanism that inhibits granulocyte macrophage-colony stimulating factor (GM-CSF) receptor signalling. Although the rarity and vague clinical presentation of PAP can pose diagnostic challenges, clinician awareness of PAP risk factors may facilitate the diagnostic process and lead to more prompt treatment.


A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication.
DEAD-box proteins are enzymes endowed with nucleic acid-dependent ATPase, RNA translocase and unwinding activities. The human DEAD-box protein DDX3 has been shown to play important roles in tumor proliferation and viral infections. In particular, DDX3 has been identified as an essential cofactor for HIV-1 replication. Here we characterized a set of DDX3 mutants biochemically with respect to nucleic acid binding, ATPase and helicase activity. In particular, we addressed the functional role of a unique insertion between motifs I and Ia of DDX3 and provide evidence for its implication in nucleic acid binding and HIV-1 replication. We show that human DDX3 lacking this domain binds HIV-1 RNA with lower affinity. Furthermore, a specific peptide ligand for this insertion selected by phage display interferes with HIV-1 replication after transduction into HelaP4 cells. Besides broadening our understanding of the structure-function relationships of this important protein, our results identify a specific domain of DDX3 which may be suited as target for antiviral drugs designed to inhibit cellular cofactors for HIV-1 replication.


The contribution of maternal effects to selection response: an empirical test of competing models.
Maternal effects can dramatically influence the evolutionary process, in some cases facilitating and in others hindering adaptive evolution. Maternal effects have been incorporated into quantitative genetic models using two theoretical frameworks: the variance-components approach, which partitions variance into direct and maternal components, and the trait-based approach, which assumes that maternal effects are mediated by specific maternal traits. Here, we demonstrate parallels between these models and test their ability to predict evolutionary change. First, we show that the two approaches predict equivalent responses to selection in the absence of maternal effects mediated by traits that are themselves maternally influenced. We also introduce a correction factor that may be applied when such cascading maternal effects are present. Second, we use several maternal effect models, as well as the standard breeder's equation, to predict evolution in response to artificial selection on flowering time in American bellflower, Campanulastrum americanum. Models that included maternal effects made much more accurate predictions of selection response than the breeder's equation. Maternal effect models differed somewhat in their fit, with a version of the trait-based model providing the best fit. We recommend fitting such trait-based models when possible and appropriate to make the most accurate evolutionary predictions.


Facial Edema Associated with Dasatinib: Case Report with Successful Treatment.
Tyrosine kinase inhibitors (TKI) are an effective treatment option for chronic myeloid leukemia (CML). The most common associated adverse effects of TKI include thrombocytopenia, neutropenia, nausea, vomiting, and diarrhea. Facial edema is a rare adverse reaction that may cause significant psychological burden. Treatment is life-long in many cases therefore it is vital to have options available to manage these adverse effects. We present a 70-year-old female with a medical history of CML, diabetes, hypertension, and hypercholesterolemia who presented to our dermatology clinic for chief complaint of worsening edematous facial rash beginning after initiation of dasatinib. We were able to achieve significant improvement with a regimen that allowed her to remain on dasatinib. We treated the patient with a novel, unreported regimen of topical metronidazole 1% gel to be applied every morning and topical tacrolimus 0.1% ointment to be applied twice daily. She had significant improvement with the treatment and was continued on this topical regimen indefinitely. Previous reports of treatment options available for TKI-associated facial edema include topical and systemic corticosteroids, which can cause long-term side effects int the context of long-term TKI use. Our patient achieved an acceptable reduction in facial edema and rash with our combination regimen of metronidazole gel and tacrolimus ointment. We present the only such case of successful treatment of facial edema associated with a tyrosine kinase inhibitor. We encourage future studies on the efficacy and safety of this regimen to treat this adverse effect.


Most personal exposure to house dust mite aeroallergen occurs during the day.
The bed is commonly regarded as the main site of house dust mite exposure; however this has not been directly established by continuous measurements. The objective of this study was to determine the pattern of personal exposure to mite aeroallergen over 24 hours. 12 adults each collected 9 sequential samples (8 during the day, mean 115 mins, and one overnight, mean 514 mins) over 24 hours using a portable air-pump (2L/min) connected to an IOM filter located on the shoulder during the day and on the bed head overnight. Samples were analysed for mite allergen Der p 1 by ELISA. Location and activity were recorded. A mixed model analysis was performed to determine exposure as a function of 14 categories of activity. Personal aeroallergen exposure differed widely over time, both within and between subjects. The highest average exposure (1117 pg/m(3), 95% CI: 289-4314) occurred on public transport and the lowest overnight in bed (45 pg/m(3), 95% CI: 17-17), which contributed only 9.8% (95% CI: 4.4%-15.1%) of total daily exposure. Aeroallergens were not related to bed reservoirs. The study challenges the current paradigm that the bed is the main site of HDM exposure and instead suggests most exposure occurs in association with domestic activity and proximity to other people. Effective mite interventions, designed to improve asthma outcomes, need to first identify and then address the multiple sources of aeroallergen exposure.


The "Culture OSCE"--introducing a formative assessment into a postgraduate program.
There is a growing need for appropriate training models in the area of cultural competence. An Objective Structured Clinical Exam (OSCE) format is ideal for this endeavor, since it allows for skills practice and feedback. As a result, we designed the first formative Culture OSCE at Maimonides Medical Center and have been implementing it since 1999. An interdisciplinary committee developed the OSCE as a formative assessment. Stations were designed based on a review of the literature and real situations experienced in the hospital. A two-hour workshop introducing the concept of cultural competence precedes the OSCE. The emphasis is on skills that are generalizable to encounters with any culture. Standardized patients are recruited from the relevant cultural groups or are trained to understand specific cultural issues. Costumes and props are utilized to enhance the authenticity of the encounter. Faculty, recruited and trained to observe encounters, gives constructive feedback, thus enhancing faculty development in this area as well. A rating scale was developed which incorporates communication and cultural skills as two separate dimensions of the encounter. Written feedback is obtained from residents, the trained faculty observers and the standardized patients. Resident feedback has demonstrated good face validity. A post-OSCE debriefing session allows residents an opportunity to consolidate learning and give oral feedback. The Maimonides Medical Center Pediatrics Department designed the first Culture OSCE. This is deemed to be a valuable training tool, and serves to highlight the importance of cultural competence within the Department.


Successful downstaging by S-1-based chemotherapy followed by surgical resections for gastric carcinoma with extensive distant lymph node metastasis - report of two cases and a review of cases with surgical resection after downstaging by S-1-based chemotherapy.
We report two cases of gastric carcinoma with successful downstaging using S-1-based chemotherapy followed by surgical resection, which enabled us to confirm the histological effect of chemotherapy. These patients were associated with extensive distant lymph node metastases for which curative resections were unlikely to be performed. We performed anticancer chemotherapy using S-1 with or without concomitant administration of cisplatin in a neoadjuvant setting. After the successful downstaging of these metastatic gastric carcinomas evaluated by imaging analyses, the patients underwent surgical resections. Effect of the chemotherapy was confirmed by the histological analyses. These cases provide further evidence, suggesting that S-1-based chemotherapy enabled downstaging of stage IV gastric carcinoma associated with distant extensive lymph node metastasis and consequently the following possible curative resections. The review of 16 cases of S-1-based chemotherapy followed by surgical resections indicated that, although downstaging may not be expected when N3 lymph node metastases are evident, the S-1-based chemotherapeutic regimens were effective in short cycles for patients in whom potential curative resection is expected. Survival benefit of downstaging followed by surgical resection, however, remains to be further elucidated.


Assessing sedentary behavior with the GENEActiv: introducing the sedentary sphere.
The Sedentary Sphere is a method for the analysis, identification, and visual presentation of sedentary behaviors from a wrist-worn triaxial accelerometer. This study aimed to introduce the concept of the Sedentary Sphere and to determine the accuracy of posture classification from wrist accelerometer data. Three samples were used: 1) free living (n = 13, ages 20-60 yr); 2) laboratory based (n = 25, ages 30-65 yr); and 3) hospital inpatients (n = 10, ages 60-90 yr). All participants wore a GENEActiv on their wrist and activPAL on their thigh. The free-living sample wore an additional GENEActiv on the thigh and completed the Multimedia Activity Recall for Children and Adults. The laboratory-based sample wore the monitors while seated at a desk for 7 h, punctuated by 2 min of walking every 20 min. The free-living and inpatient samples wore the monitors for 24 h. Posture was classified from wrist-worn accelerometry using the Sedentary Sphere concept. Sitting time did not differ between the wrist GENEActiv and the activPAL in the free-living sample and was correlated in the three samples combined (rho = 0.9, P < 0.001), free-living and inpatient samples (r ≃ 0.8, P < 0.01). Mean intraindividual agreement was 85% ± 7%. In the laboratory-based and inpatient samples, sitting time was underestimated by the wrist GENEActiv by 30 min and 2 h relative to the activPAL, respectively (P < 0.05). Posture classification disagreed during reading while standing, cooking while standing, and brief periods during driving. Posture allocation validity was excellent when the GENEActiv was worn on the thigh, evidenced by the near-perfect agreement with the activPAL (96% ± 3%). The Sedentary Sphere enables determination of the most likely posture from the wrist-worn GENEActiv. Visualizing behaviors on the sphere displays the pattern of wrist movement and positions within that behavior.


Development of a Machine Learning-Based Prognostic Model for Hormone Receptor-Positive Breast Cancer Using Nine-Gene Expression Signature.
Determining the prognosis of hormone receptor positive (HR+) breast cancer (BC), which accounts for 80% of all BCs, is critical in improving survival outcomes. Stratifying individuals at high risk of BC-related mortality and improving prognosis has been the focus of research for over a decade. However, these tools are not universal as they are limited to clinical factors. We hypothesized that a new framework for predicting prognosis in HR+ BC patients can develop using artificial intelligence. A total of 2,338 HR+ human epidermal growth factor receptor 2 negative (HER2-) BC cases were analyzed from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) cohorts. Groups were then divided into high- and low-risk categories utilizing a recurrence prediction model (RPM). An RPM was created by extracting nine prognosis-related genes from over 18,000 genes using a logistic progression model. Risk classification by RPM was significantly stratified in both the discovery cohort and validation cohort. In the time-dependent area under the curve analysis, there was some variation depending on the cohort, but accuracy was found to decline significantly after about 10 years. Cell cycle related gene sets, MYC, and PI3K-AKT-mTOR signaling were enriched in high-risk tumors by the Gene Set Enrichment Analysis. High-risk tumors were associated with high levels of immune cells from the lymphoid and myeloid lineage and immune cytolytic activity, as well as low levels of stem cells and stromal cells. High-risk tumors were also associated with poor therapeutic effects of chemotherapy and endocrine therapy. This model was able to stratify prognosis in multiple cohorts. This is because the model reflects major BC therapeutic target pathways and tumor immune microenvironment and, further is supported by the therapeutic effect of chemotherapy and endocrine therapy.


Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose study of gefitinib.
The goals of this investigation were to illustrate the use of pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategies in drug development based on a multiple-dose study of gefitinib in a preclinical tumor model. Mice bearing s.c. LN229-wild-type epidermal growth factor receptor or LN229-EGFRvIII mutant (a sensitizing mutation) tumors were administered gefitinib at oral doses of either 55 mg/kg/d p.o. x 15 days or 30 mg/kg/d p.o. x 15 days, respectively, as dictated by the equivalent PK/PD dosing strategy. In each tumor group, gefitinib plasma and tumor concentrations were quantitated, as well as the tumoral amounts of phosphorylated-extracellular signal-regulated kinase 1/2 (pERK), a selected PD end point, and tumor size. The resultant data provided the basis to develop hybrid physiologically based PK/PD/tumor growth models for each tumor type. It was found that the 1.83-fold dose difference administered to the two tumor groups resulted in analogous pERK profiles on both days 1 and 15, and further induced similar antitumor efficacy based on tumor size. In addition, using brain tumor patient PK data linked to the pERK PD model, simulations were conducted to illustrate potential applications of a target tumor model to patients. The simulations provided insight on the relationships between blood-brain barrier penetration, brain tumor gefitinib concentrations, and the extent of inhibition of pERK. The implementation of the PK/PD equivalent dosing strategy offers a new approach to drug development.


Novel Imaging-Based Biomarkers for Identifying Carotid Plaque Vulnerability.
Carotid artery disease has traditionally been assessed based on the degree of luminal narrowing. However, this approach, which solely relies on carotid stenosis, is currently being questioned with regard to modern risk stratification approaches. Recent guidelines have introduced the concept of the "vulnerable plaque," emphasizing specific features such as thin fibrous caps, large lipid cores, intraplaque hemorrhage, plaque rupture, macrophage infiltration, and neovascularization. In this context, imaging-based biomarkers have emerged as valuable tools for identifying higher-risk patients. Non-invasive imaging modalities and intravascular techniques, including ultrasound, computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, have played pivotal roles in characterizing and detecting unstable carotid plaques. The aim of this review is to provide an overview of the evolving understanding of carotid artery disease and highlight the significance of imaging techniques in assessing plaque vulnerability and informing clinical decision-making.


Quinacrine-induced psychiatric disturbances.
We have described three patients who illustrate the broad clinical spectrum of quinacrine-associated neuropsychiatric disturbances. The toxic manifestations range from subtle changes of restlessness, insomnia, hyperirritability to frank psychosis and seizures. These symptoms may follow only a few doses of the drug, or they may occur well after the drug has been discontinued. Our patients reemphasize the importance of recognizing the variability of quinacrine-induced toxic reactions.


Influence of the position of the double bond in steroid substrates on the efficiency of the proton-transfer reaction by Pseudomonas testosteroni 3-oxo-steroid delta 4-delta 5-isomerase.
Studies of the proton-transfer reaction by Pseudomonas testosteroni 3-oxo steroid Delta(4)-Delta(5)-isomerase with Delta(5(6))- and Delta(5(10))-steroid substrates demonstrate the importance of the position of the double bond for the efficiency of the isomerization process. Thus 3-oxo-Delta(5(6))-substrates have markedly high k(cat.) values, whereas those of 3-oxo-Delta(5(10))-substrates are very low and their apparent K(m) values approach equilibrium dissociation constants. The first step in the isomerization process is: [Formula: see text] which is governed by the k(-1)/k(+1) ratio and is shown to be very similar for the two classes of substrates (3-oxo-Delta(5(6))- and -Delta(5(10))-steroids). They therefore differ in the steps distal to the initial formation of the Michaelis-Menten complex. The use of the deuterated androst-5(6)-ene-3,17-dione substrate enabled us to calculate individual rate constants k(+1) and k(-1) as well as to determine the apparent rate-limiting step in the isomerization process. With the deuterated oestr-5(10)-ene-3,17-dione substrate, no significant isotope effect was observed suggesting that a different rate-limiting step may be operative in this isomerization process. Data are presented that indicate that under optimal concentrations of the efficient androst-5(6)-ene-3,17-dione substrate, the forward reaction for ES complex formation (as defined by k(+1)) is limited only by diffusion and the apparent K(m) does not approach the equilibrium constant, suggesting that the evolution of this enzyme has proceeded close to ;catalytic perfection'.


The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.
The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.


Differences in nucleotide specificity and catalytic mechanism between Vibrio harveyi aldehyde dehydrogenase and other members of the aldehyde dehydrogenase superfamily.
The fatty aldehyde dehydrogenase (Vh-ALDH) isolated from the luminescent bacterium, Vibrio harveyi, differs from other aldehyde dehydrogenases in its high affinity for NADP(+). The binding of NADP(+) appears to arise from the interaction of the 2'-phosphate of the adenosine moiety of NADP(+) with a threonine (T175) in the nucleotide recognition site just after the beta(B) strand as well as with an arginine (R210) that pi stacks over the adenosine moiety. The active site of Vh-ALDH contains the usual suspects of a cysteine (C289), two glutamates (E253 and E377) and an asparagine (N147) involved in the aldehyde dehydrogenase mechanism. However, Vh-ALDH has one polar residue in the active site that distinguishes it from other ALDHs; a histidine (H450) is in close contact with the cysteine nucleophile. As a glutamate has been implicated in promoting the nucleophilicity of the active site cysteine residue in ALDHs, the close contact of a histidine with the cysteine nucleophile in Vh-ALDH raises the possibility of alternate routes to increase the reactivity of the cysteine nucleophile. The effects of mutation of these residues on the different functions catalyzed by Vh-ALDH including acylation, (thio)esterase, reductase and dehydrogenase activities should help define the specific roles of the residues in the active site of ALDHs.


Family psychology: Past and future reflections on the field.
Prominent issues in the field of family psychology during my term as editor (1998-2003) of this journal were briefly noted, including a focus on marital issues, divorce, remarriage and family conflict. Parenting, attachment and parent-child relationships were also significant topics in this period. Special sections of the journal focused on cultural variations, families and the law, families and religion, and family routines and rituals. Several neglected issues that need more attention in the future were noted. These include the need to recognize the embeddedness of families in socioecological contexts, the importance of monitoring the impact of secular changes on families, and the value and limitations of viewing family psychology as a separate field. Other topics for a future agenda include the challenge of defining "family" in the midst of changing family forms, the effects of technological change on families, and the challenges of integrating biological research into the family psychology agenda. A multilevel bio-social approach to family research was recommended. (PsycINFO Database Record