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This Practice Parameter is a revision of a previous Parameter addressing reactive attachment disorder that was published in 2005. It reviews the current status of reactive attachment disorder (RAD) and disinhibited social engagement disorder (DESD) with regard to assessment and treatment. Attachment is a central component of social and emotional development in early childhood, and disordered attachment is defined by specific patterns of abnormal social behavior in the context of "insufficient care" or social neglect. Assessment requires direct observation of the child in the context of his or her relationships with primary caregivers. Treatment requires establishing an attachment relationship for the child when none exists and ameliorating disturbed social relatedness with non-caregivers when evident.

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$0.759 \pm 0.003$ \end{document}0.759±0.003, and the median DBC is (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$0.87 \pm 0.01$ \end{document}0.87±0.01) mm. An intra-observer comparison for the same scans gives a median CI of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$0.820 \pm 0.002$ \end{document}0.820±0.002 and a DBC of (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$0.64 \pm 0.01$ \end{document}0.64±0.01) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

The aim of this study was to investigate the occurrence of tissue hypoxia and apoptosis at different stages of tendinopathy and tears of the rotator cuff. We studied tissue from 24 patients with eight graded stages of either impingement (mild, moderate and severe) or tears of the rotator cuff (partial, small, medium, large and massive) and three controls. Biopsies were analysed using three immunohistochemical techniques, namely antibodies against HIF-1α (a transcription factor produced in a hypoxic environment), BNip3 (a HIF-1α regulated pro-apoptotic protein) and TUNEL (detecting DNA fragmentation in apoptosis). The HIF-1α expression was greatest in mild impingement and in partial, small, medium and large tears. BNip3 expression increased significantly in partial, small, medium and large tears but was reduced in massive tears. Apoptosis was increased in small, medium, large and massive tears but not in partial tears. These findings reveal evidence of hypoxic damage throughout the spectrum of pathology of the rotator cuff which may contribute to loss of cells by apoptosis. This provides a novel insight into the causes of degeneration of the rotator cuff and highlights possible options for treatment.

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S420 756 THE NEUROHISTOLOGY OFPAINFUL AND PAIN-FREE ROTATOR CUFF TENDONS: A CASE CONTROL STUDY B.J. Dean, S.L. Franklin, R.J. Murphy, R. Benson, K. Javaid, A.J. Carr. Univ. of Oxford, Oxford, United Kingdom Purpose:Our main purpose was to compare the tendon neurohistology in two groups of patients; one with significant pain prior to undergoing SAD and one with resolved pain over 6 years post SAD. Methods: Supraspinatus tendon specimens were obtained using an ultrasound guided biopsy technique from 9 patients with painful RCT resistant to conservative management (painful group) and 9 pain-free patients at over 6 years (median 6 years 11 months) following SAD (pain-free group). Pain symptoms were measured using the validated Oxford Shoulder Score (OSS). Structural tendon integrity was assessed ultrasonographically. The tendon tissue was analysed using basic histological techniques (Haematoxylin and Eosin, and Alcian Blue) and Immunohistochemistry. Image analysis was performed by two blinded observers using Image-J to quantify the amount of 3,3’-diaminobenzidine staining present. Isotype controls were also processed. Mann-Whitney U tests were carried out using SPSS with significance levels set at a minimum of p < 0.05. Results: The groups were similar in terms of age, sex and structural tendon abnormality. The painful group consisted of 7 males and 2 females, the pain-free group of 6 males and 3 females. The mean age of the painful group was 50 years (range 38 to 61) and that of the pain-free group was 53 years (range 39 to 65). The median OSS in the painful group was 32 (range 23 to 34) and this was significantly lower (p 1⁄4 0.0002) than the median OSS in the pain-free group (all 48). There were two partial thickness tears in both groups and no full thickness tears. The modified Bonar scores in the painful and the pain-free groups were comparable. There were no significant differences between groups in terms of cellularity, vascularity, proliferation and hypoxia induciblefactor 1a expression. The leucocyte count (CD45 positive cells) and macrophage count (CD68 positive cells) were increased in the painful group versus pain-free (p 1⁄4 0.01 and 0.05 respectively). The expression of the metabotropic glutamate receptor 7 (mGluR7) was reduced in the painful group versus pain-free (p 1⁄4 0.008 and 0.002 respectively). PGP 9.5 (a nerve marker) expression was increased in the painful group versus pain-free (p 1⁄4 0.008). There were no significant differences in glutamate, the inotropic glutamate receptor (NMDAR1) and the metabotropic glutamate receptors (mGluR1, 2 and 5) between groups. Conclusions: This study has shown that specific characteristics of tendon histology are associated with a resolution of shoulder pain over six years following SAD. This provides strong evidence that the rotator cuff tendon is of key importance in the symptomatology of RCT. The mechanism behind these tendon differences remains unclear. These findings are novel and improve our understanding of pain in RCT, and may help provide novel therapeutic targets. 757 NEGATIVE CORRELATION BETWEEN THE POPULATION OF CD105 POSITIVE SUBSET OF MONOCYTES/MACROPHAGES IN SYNOVIAL FLUID AND THE SEVERITY OF JOINT PAIN AFTER ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION SURGERY K. Nakamura y, K. Tsuji z, H. Katagiri y, M. Inoue x, K. Abula y, I. Sekiya k, T. Muneta y. yDept. of Joint Surgery and Sports Med., Tokyo Med. and Dental Univ., Tokyo, Japan; zDept. of Cartilage Regeneration, Tokyo Med. and Dental Univ., Tokyo, Japan; xDept. of Plastic Reconstructive and Aesthetic Surgery, Tokyo Med. and Dental Univ., Tokyo, Japan; kCtr. for Stem Cell and Regenerative Med., Tokyo Med. and Dental Univ., Tokyo

As the national economy has worsened, a large cadre of tenured senior faculty is graying and staying at their institutions. This has left an older set of full professors who began their careers in ...

This Parameter addresses the key concepts that differentiate the forensic evaluation of children and adolescents from a clinical assessment. There are ethical issues unique to the forensic evaluation, because the forensic evaluator's duty is to the person, court, or agency requesting the evaluation, rather than to the patient. The forensic evaluator clarifies the legal questions to be answered and structures the evaluation to address those issues. The forensic examination may include a review of collateral information, interviews and other assessments of the child or adolescent, and interviews with other relevant informants. The principles in this Parameter suggest the general approach to the forensic evaluation of children and adolescents and are relevant to delinquency, child custody, child maltreatment, personal injury, and other court-ordered and noncourt-ordered evaluations.

We assessed the predictive value of the macroscopic and detailed microscopic appearance of the coracoacromial ligament, subacromial bursa and rotator-cuff tendon in 20 patients undergoing subacromial decompression for impingement in the absence of full-thickness tears of the rotator cuff. Histologically, all specimens had features of degenerative change and oedema in the extracellular matrix. Inflammatory cells were seen, but there was no evidence of chronic inflammation. However, the outcome was not related to cell counts. At three months the mean Oxford shoulder score had improved from 29.2 (20 to 40) to 39.4 (28 to 48) (p < 0.0001) and at six months to 45.5 (36 to 48) (p < 0.0001). At six months, although all patients had improved, the seven patients with a hooked acromion had done so to a less extent than those with a flat or curved acromion judged by their mean Oxford shoulder scores of 43.5 and 46.5 respectively (p = 0.046). All five patients with partial-thickness tears were within this group and demonstrated less improvement than the patients with no tear (mean Oxford shoulder scores 43.2 and 46.4, respectively, p = 0.04). These findings imply that in the presence of a partial-thickness tear subacromial decompression may require additional specific treatment to the rotator cuff if the outcome is to be improved further.

This practice parameter describes the epidemiology, clinical picture, differential diagnosis, course, risk factors, and pharmacological and psychotherapy treatments of children and adolescents with major depressive or dysthymic disorders. Side effects of the antidepressants, particularly the risk of suicidal ideation and behaviors are discussed. Recommendations regarding the assessment and the acute, continuation, and maintenance treatment of these disorders are based on the existent scientific evidence as well as the current clinical practice. J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503Y1526. Key Words: major depressive disorder, dysthymic disorder, evaluation, treatment, antidepressants, selective serotonin reuptake inhibitors, psychotherapy, practice parameter. Depressive disorders are often familial recurrent illnesses associated with increased psychosocial morbidity and mortality. Early identification and effective treatment may reduce the impact of depression on the family, social, and academic functioning in youths and may reduce the risk of suicide, substance abuse, and persistence of depressive disorders into adulthood. Evidencesupported treatment interventions have emerged in psychotherapy and medication treatment of childhood depressive disorders that can guide clinicians to improve outcomes in this population.

This paper presents preliminary observations and calculations obtained for the reflux condensation of a water–methanol vapor mixture in a plain tube and a tube fitted with inserts. It is an attempt to present findings that resolve the reflux condenser controllability and operability, which has always been a major issue in the industry. A modification to the experimental apparatus has improved pressure measurement and aided in determining mass and heat balance information, thus giving greater confidence in the operation of the reflux condenser. Tube inserts are installed in the condenser tube in two different arrangements. The tube inserts are called HiTRAN® and are manufactured by Cal Gavin Ltd. (UK). This work describes some of the behaviors observed in the reflux condenser both with and without tube inserts. The dynamic temperature and pressure trends are notable. The inserts threshold length is the length where the reflux condensation process avoids flooding and has a recovery of heavier and lighter co...

This prospective study assesses the roles of illness beliefs, emotion regulation factors, and sociodemographic characteristics in decisions to participate in a group support program for women recently diagnosed with breast cancer.Women recruited during clinic visits 2 to 4 weeks after diagnosis completed measures of affective and cognitive factors identified by Leventhal's Common-Sense Model of illness self-regulation: cancer-related distress, avoidance tendencies, beliefs that the breast cancer was caused by stress and altered immunity, and personal control beliefs. Measures of general anxiety and depression, social support, and demographic characteristics were also completed; prognostic status information was obtained from medical records. All women were encouraged to participate in a free, 12-week program offering coping skills training and group support. Participation was recorded by program staff.Of the 110 women, 54 (49%) participated in the group support program and 56 (51%) did not. Logistic regression analyses revealed that participation was predicted by stronger beliefs that the cancer was caused by altered immunity, higher cancer-related distress, lower avoidance tendencies, and younger age.Participation in the group psychosocial support program appeared to be guided by cognitive and affective factors identified by the Common-Sense Model. Psychosocial support programs and informational materials promoting their use may attract more participants if they are tailored to focus on resolving cancer-related distress rather than on general anxiety or depression, appeal to those with high avoidance tendencies, address the role of immune function in cancer progression, and meet the needs of older participants.

1-Deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr) is a key enzyme in a biosynthetic pathway for isoprenoids that is unique to eubacteria and plants. Dxr catalyzes the rearrangement and NADPH-dependent reduction of 1-deoxy-D-xylulose 5-phosphate to 2-C-methyl-D-erythritol 4-phosphate. The authors have purified Escherichia coli Dxr and devised a high-throughput screen (HTS) for compounds that bind to this enzyme at a functional site. Evidence is presented that the surrogate ligand directly binds or allosterically affects both the D-1-deoxyxylulose 5-phosphate (DXP) and NADPH binding sites. Compounds that bind at either or both sites that compete for binding with the surrogate ligand register as hits. The time-resolved fluorescence-based assay represents an improvement over the Dxr enzyme assay that relies on relatively insensitive measurements of NADPH oxidation. Screening 32,000 compounds from a diverse historical library, the authors obtained 89 potent inhibitors in the surrogate ligand competition assay. The results presented here suggest that peptide surrogate ligands may be useful in formatting HTS for proteins with difficult biochemical assays or targets of unknown function.

We present a description of and results from our ongoing development of miniature time-of-flight mass spectrometers (TOF-MS) for future landed planetary missions. A new, flexible TOF-MS instrument has been developed to permit the analysis of elemental, isotopic, and molecular composition in solid samples. The new instrument incorporates normal-incidence ultraviolet pulsed laser desorption, a gridless ion source, and a novel curved-field reflectron to maximize sensitivity and resolution over wide abundance and mass ranges. Results with unprepared sample materials are compared with previous work based on infrared laser ablation. Flight instruments based on these technologies can potentially be as small as a soda can without sacrificing their ability to detect low levels of atomic and organic species at grain scales.

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed-salts amphetamine, and pemoline. It carries FDA indications for treatment of attention-deficit/hyperactivity disorder and narcolepsy.

This parameter reviews the current state of the prevention and management of child and adolescent aggressive behavior in psychiatric institutions, with particular reference to the indications and use of seclusion and restraint. It also presents guidelines that have been developed in response to professional, regulatory, and public concern about the use of restrictive interventions with aggressive patients with regard to personal safety and patient rights. The literature on the use of seclusion, physical restraint, mechanical restraint, and chemical restraint is reviewed, and procedures for carrying out each of these interventions are described. Clinical and regulatory agency perspectives on these interventions are presented. Effectiveness, indications, contraindications, complications, and adverse effects of seclusion and restraint procedures are addressed. Interventions are presented to provide more opportunities to promote patient independence and satisfaction with treatment while diminishing the necessity of using restrictive procedures.

Background. A reduction in acute rejection may reduce graft losses from chronic rejection, benefiting the recipient and helping ease the huge donor organ shortfall in the UK. The prediction of recipients at greater risk of acute rejection might justify the administration to them of more potent immunosuppression, but defining this group on clinical parameters has been largely unsuccessful. Events impacting on the kidney by the time of donation may, if detectable histologically, predict those kidneys more likely to undergo rejection. Methods. A prospective immunohistochemical analysis was undertaken to detect P-Selectin (PS), E-Selectin (ES), platelets, leukocyte common antigen, macrophages, T cells, and neutrophils in the pretransplant biopsies of 77 adult renal transplant recipients. Twenty-nine (38%) of this group rejected. Results. A significantly increased number of recipients rejected if the donor biopsy was PS positive (63 vs. 24%, P=0.0007), contained five or more leukocytes/ glomerulus (48 vs. 21%, P=0.03), contained >9.3 leukocytes/high power field (46.5 vs. 10.5%, P=0.006) or was both PS positive and contained >9.3 leukocytes/high power field (61.9 vs. 0.0%, P=0.0001). The PS was mostly of platelet origin and the majority of leukocytes were macrophages. Only previous CMV or any current infection in the donor correlated with the immunohistochemical changes. Conclusions. These immuno-histochemical changes are present before transplantation, which allows the prediction of recipients at both a higher and a lower risk of acute rejection, enabling the administration of recipient tailored immunosuppression, and supports the use of additional therapeutic intervention to reduce the injury response both within the recipient and the donor.

Increasing bacterial drug resistance and hard-to-eradicate opportunistic infections have created a need for new antibiotics. Sequencing of microbial genomes has yielded many new potential targets for antibacterial drug discovery. However, little is known about the biochemical activities of many of these targets, making it difficult to develop HTS assays for them. Peptides isolated by phage display can be used as 'surrogate ligands' in competition assays for screening of targets of unknown function with small-molecule libraries. These screening assays can be adapted into a variety of high-throughput formats, including those based on radioactive, luminescence or fluorescence detection.

In this paper, an analysis is provided for the steering of a long, warped web that is transported between two rollers. The web is modeled using the Timoshenko beam theory, which admits small amounts of elastic bending and transverse shearing. Closed-form solutions are obtained for three commonly encountered forms of in-plane imperfection: (1) a splice, (2) a sinusoidal warpage, and (3) a cambered web with a constant radius-of-curvature. The fact that partial wrinkling in the web can affect the lateral dynamics is demonstrated in a simple example. This analysis reveals information on the phenomenon of weave regeneration and will be useful to designers of transport systems who wish to control the lateral tracking of webs with geometrical flaws.

A new immunoaffinity fluorometric biosensor has been developed for detecting and quantifying aflatoxins, a family of potent fungi-produced carcinogens that are commonly found in a variety of agriculture products. They have also been cited as a biological agent under weapons development. The handheld, self-contained biosensor is fully automatic, highly sensitive, quick, quantitative, and requires no special storage. Approximately 100 measurements can be made before refurbishment is required, and concentrations from 0.1 parts per billion (ppb) to 50 ppb can be determined in

A nonlinear analysis is presented to describe the static equilibrium of a long elastic tape wrapped onto a rigid drum. Closed-form results are obtained for the case when the tape can be modeled as an inextensional beam with finite bending rigidity. Strains are assumed to be small, but rotations of the beam may be arbitrarily large. The tape’s stiffness in bending requires the abandonment of a common modeling assumption—that the tape approaches the drum along a perfectly straight tangent. After calculating the actual shape of the elastica, a number of changes are seen to occur in the loading and geometry of the system. Among these are a lower tape tension at the point of tape/drum contact, an increased torque on the drum, and the introduction of an elastic compliance between the drum and distant locations in the tape.

This summary provides an overview of the assessment and treatment recommendations contained in the Practice Parameters for the Assessment and Treatment of Children and Adolescents With Depressive Disorders. Depressive disorders in children and adolescents are marked by core symptoms similar to those seen in adults, although symptom expression varies greatly with developmental stage. These disorders are common, chronic, and recurrent, and they are associated with comorbid psychiatric conditions and poor outcome that can be alleviated by early identification and treatment. Opinions differ regarding treatment planning and duration of treatment required. Development of a treatment relationship with the patient and family is crucial for a successful outcome. Psychotherapy is an appropriate treatment for all children and adolescents with depressive disorders. Antidepressants may prove useful in some cases and are especially recommended for patients with psychosis, bipolar depression, and severe depression. Continuation treatment is necessary in all patients after the acute phase; long-term maintenance is required in some. Early detection and intervention is effective in ameliorating the poor psychosocial outcome.

An automated on-line method for the quantitative detection of fumonisins B1, B2, and B3 and hydrolyzed fumonisin B1 in corn-based feed was developed using a combination of immunoaffinity capture (IAC)/cleanup, coupled with reversed phase liquid chromatography and electrospray ionization mass spectrometry. Blocking the C2 amine of fumonisin B1 with 9-fluorenylmethylchloroformate allowed coupling to keyhole limpet hemocyanin through the tricarballylic end, leaving the amino terminus exposed on the immunogenic conjugate after removal of the blocking group. Antiserum had specificity for the C1−C10 fumonisin domain and was used for ELISA and to prepare immunoaffinity columns. The quantitation limit (s/n = 10) for fumonisin B1 standard was 250 pg using the protonated molecule signal (m/z 722). Similar sensitivity was observed for fumonisins B2 and B3 (m/z 706) and hydrolyzed fumonisin B1 (m/z 406). The on-line IAC/LC/ESI-MS method provided a linear response from the detection limit to 5 ng for fumonisin B1 and ...

The nuclear import of proteins bearing a basic nuclear localization signal (NLS) is dependent on karyopherin alpha/importin alpha, which acts as the NLS receptor, and karyopherin beta1/importin beta, which binds karyopherin alpha and mediates the nuclear import of the resultant ternary complex. Recently, a second nuclear import pathway that allows the rapid reentry into the nucleus of proteins that participate in the nuclear export of mature mRNAs has been identified. In mammalian cells, a single NLS specific for this alternate pathway, the M9 NLS of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), has been described. The M9 NLS binds a transport factor related to karyopherin beta1, termed karyopherin beta2 or transportin, and does not require a karyopherin alpha-like adapter protein. A yeast homolog of karyopherin beta2, termed Kap104p, has also been described and proposed to play a role in the nuclear import of a yeast hnRNP-like protein termed Nab2p. Here, we define a Nab2p sequence that binds to Kap104p and that functions as an NLS in both human and yeast cells despite lacking any evident similarity to basic or M9 NLSs. Using an in vitro nuclear import assay, we demonstrate that Kap104p can direct the import into isolated human cell nuclei of a substrate containing a wild-type, but not a defective mutant, Nab2p NLS. In contrast, other NLSs, including the M9 NLS, could not function as substrates for Kap104p. Surprisingly, this in vitro assay also revealed that human karyopherin beta1, but not the Kap104p homolog karyopherin beta2, could direct the efficient nuclear import of a Nab2p NLS substrate in vitro in the absence of karyopherin alpha. These data therefore identify a novel NLS sequence, active in both yeast and mammalian cells, that is functionally distinct from both basic and M9 NLS sequences.

A theoretical analysis of the fluid mechanics of the air cushion of the air reversers used in web-handling systems is presented. A two-dimensional model of the air flow is derived by averaging the equations of conservation of mass and momentum over the clearance between the web and the reverser. The resulting equations are Euler’s equations with nonlinear source terms representing the air supply holes in the surface of the reverser. The equations are solved analytically for the one-dimensional case and numerically for the two-dimensional case. Results are compared with an empirical formula and the one-dimensional airjet theory developed for hovercraft. Conditions that maximize the air pressure supporting the web are analyzed and design guidelines are deduced.

Expedited site characterization (ESC) is an environmental investigation approach that focuses on using nonintrusive and minimally intrusive investigative techniques synergistically to efficiently and thoroughly characterize hazardous waste sites. Unlike traditional approaches, ESC uses a dynamic (i.e., flexible) work plan with an on-site decision making team of senior-level technical staff. Another key feature of the ESC process is the emphasis on understanding site geology and hydrogeology at a high level of detail before searching for the contaminants. Geophysical techniques were successfully incorporated into an ESC project at an oil seepage basin site on the U.S. Department of Energy’s Savannah River site to define the limits of buried wastes, to detect and map an inorganic plume emanating from the waste trenches, and to define the approximate depth and lateral continuity of major stratigraphic units across the site. The geophysical techniques, integrated with minimally intrusive direct push technologies, provided the framework for the development of the conceptual site model. The refined conceptual site model was then successfully used to guide ground water contaminant sampling to define the spatial extent of the inorganic and organic plume emanating from the waste trenches.

Urethane (ethyl carbamate) is a carcinogen that has been detected as a contaminant in certain foods and alcoholic beverages. The carcinogenicity of urethane appears to be mediated through a metabolic pathway involving sequential cytochrome P-450-catalyzed oxidation to vinyl carbamate and vinyl carbamate epoxide, the latter of which reacts with DNA to yield etheno-type DNA adducts. The interactions of ethanol on urethane metabolism and carcinogenicity are varied and complex. Urethane is oxidized by cytochrome P-450 IIE1, an isoform induced by ethanol, which suggests that chronic ethanol consumption could increase the oxidation of urethane to its epoxide derivative. On the other hand, ethanol coadministration is known to inhibit the elimination and hydrolysis of urethane. Ethanol has decreased the tumorigenicity of urethane in two bioassays, but did not have an effect in a third. While the results to date suggest that ethanol will decrease the metabolic activation of urethane, with a resultant decrease in tumorigenicity, additional studies are clearly necessary to elucidate the mechanisms by which ethanol influences the carcinogenicity of urethane.

Heterogeneous nuclear ribonucleoprotein A1 contains a sequence, termed M9, that functions as a potent nuclear localization signal (NLS) yet bears no similarity to the well-defined basic class of NLSs. Here, we report the identification of a novel human protein, termed MIP, that binds M9 specifically both in vivo and in vitro yet fails to interact with non-functional M9 point mutants. Of note, the 101 kDa MIP protein bears significant homology to human karyopherin/importin-beta, a protein known to mediate the function of basic NLSs. The in vitro nuclear import of a protein substrate containing the M9 NLS was found to be dependent on provision of the MIP protein in trans. Cytoplasmic microinjection of a truncated form of MIP that retains the M9 binding site blocked the in vivo nuclear import of a substrate containing the M9 NLS yet failed to affect the import of a similar substrate bearing a basic NLS. These data indicate that nuclear import of hnRNP A1 is mediated by a novel cellular import pathway that is distinct from, yet evolutionarily related to, the pathway utilized by basic NLS sequences.

Objectives To determine the level of demand from general dental practitioners (GDPs) for specialist restorative dental services in the Yorkshire region. To investigate barriers and promoters to referral and GDPs' perceptions of restorative mono-specialists. Methods A postal questionnaire was sent to 301 randomly selected GDPs (stratified for location) registered in the six Family Health Service Units in Yorkshire. Questionnaires were piloted prior to release; reminders were sent to non-respondents. Results A response rate of 72% (n=217) was achieved, of these 195 questionnaires were useable (65% useable response rate). Results showed a large demand for restorative specialist services. Main promoters for National Health Service (NHS) referral were dentolegal issues (77% GDPs ranked this as a top three promoter) and for private referral increasing patient expectations (78%). The top barriers against referral were length of waiting lists for NHS patients (79% GDPs ranked this as a top three barrier) and high cost of treatment for private patients (88%). Excessive distance to specialist centre was the greatest barrier common to both NHS and private referrals. Fifty-eight per cent of GDPs would prefer to refer private patients to mono-specialists, compared with 5% who would prefer restorative specialists. Conclusions There is a strong demand for specialist restorative services which may increase in the future. Results indicate a high regard for mono-specialists. Overall demand is for a prompt, locally based, low cost referral service.

Fragile X syndrome results from lack of expression of a functional form of Fragile X mental retardation protein (FMRP), a cytoplasmic RNA-binding protein of uncertain function. Here, we report that FMRP contains a nuclear export signal (NES) that is similar to the NES recently identified in the Rev regulatory protein of human immunodeficiency virus type 1 (HIV-1). Mutation of this FMRP NES results in mis-localization of FMRP to the cell nucleus. The FMRP NES is encoded within exon 14 of the FMR1 gene, thus explaining the aberrant nuclear localization of a natural isoform of FMRP that lacks this exon. The NES of FMRP can substitute fully for the Rev NES in mediating Rev-dependent nuclear RNA export and specifically binds a nucleoporin-like cellular cofactor that has been shown to mediate Rev NES function. Together, these findings demonstrate that the normal function of FMRP involves entry into the nucleus followed by export via a pathway that is identical to the one utilized by HIV-1 Rev. In addition, these data raise the possibility that FMRP could play a role in mediating the nuclear export of its currently undefined cellular RNA target(s).

The Rex protein of human T-cell leukemia virus type 1, like the functionally equivalent Rev protein of human immunodeficiency virus type 1, contains a leucine-rich activation domain that specifically interacts with the human nucleoporin-like Rab/hRIP cofactor. Here, this Rex sequence is shown to function also as a protein nuclear export signal (NES). Rex sequence libraries containing randomized forms of the activation domain/NES were screened for retention of the ability to bind Rab/hRIP by using the yeast two-hybrid assay. While the selected sequences differed widely in primary sequence, all were functional as Rex activation domains. In contrast, randomized sequences that failed to bind Rab/hRIP lacked Rex activity. The selected sequences included one with homology to the Rev activation domain/NES and a second that was similar to the NES found in the cellular protein kinase inhibitor alpha. A highly variant, yet fully active, activation domain sequence selected on the basis of Rab/hRIP binding retained full NES function even though this sequence preserved only a single leucine residue. In contrast, nonfunctional activation domain mutants that were unable to bind Rab/hRIP had also lost NES function. These data demonstrate that NES activity is a defining characteristic of the activation domains found in the Rev/Rex class of retroviral regulatory proteins and strongly support the hypothesis that the Rab/hRIP cofactor plays a critical role in mediating the biological activity of these NESs. In addition, these data suggest a consensus sequence for NESs of the Rev/Rex class.

Chronic acetaminophen (APAP) toxicity poses a difficult diagnostic challenge to the clinician. Signs and symptoms are nonspecific and no currently available laboratory study can confirm APAP as the causative agent of hepatic injury. In this study an antigenic biomarker for APAP toxicity was used to confirm the diagnosis of APAP-induced hepatic failure in two children with chronic APAP toxicity. APAP that has been metabolized to N-acetyl-benzoquinone imine (NAPQI) reacts with cellular proteins to form 3-(cystein-S-yl)-APAP protein adducts (3-Cys-A). Serum from both patients was submitted for quantitation of 3-Cys-A by a competitive inhibition enzyme-linked immunosorbent assay (ELISA). Concentrations of 3-Cys-A in the two patients were 1.97 and 2.77 nmol/mg protein, which are similar to concentrations found in adults with hepatic injury secondary to an overdose of APAP. Individuals with no exposure to APAP have no detectable 3-Cys-A in serum. It was concluded that 3-Cys-A is a useful marker of APAP intoxication after long-term ingestion of APAP when total dose and time course of ingestion are uncertain, and may prove to be a useful clinical and investigative tool in the study of APAP intoxication.

The relative importance of expression and symbolic content in acoustic communication of cetaceans has been debated. These topics may be examined by observing how general rates of vocalizations change with excitatory state and how specific vocalizations vary independently of state and depend upon content. In this study, whistles (0.32 to 22 kHz) of two captive bottlenose dolphins (Tursiops truncatus) were recorded underwater before, during, and after six swim sessions in which the behavior of the dolphins and four human swimmers was controlled by a trainer on the dock. Sonograms of 205 min of recorded whistles were analyzed. Variation of whistle‐type and rate was observed relative to the three contexts. The contours of distinguishable whistles (n=591) revealed 32 types. Ten types were observed during one context only; during the swim sessions. Almost half of the whistle types (15 to 32) were more likely to occur prior to swim sessions and the others were more likely during swim sessions. None were more frequent after swims. Rate of whistles was significantly higher than expected during the swim sessions (z=7.21) and lower than expected after the swim sessions (z=−0.03).

The foil bearing problem, common to magnetic tape recording, is modeled through numerical simulation. The emphasis is on the effects of cross-width changes in the system parameters. Air lubrication is modeled using the Reynolds equation including the first-order slip correction terms and compressibility. A segmented structural model is introduced for the tape displacements where the tape is modeled as a cylindrical shell in the wrap zone and as a plate in the straight segments between the guide pins and the tangency points. Tape inertia and transport effects are included by using the material time derivative of the displacements. An explicit time integration method is used for the tape equation in order to obtain a faster transient coupling algorithm. The Reynolds equation is solved with the alternating direction implicit (ADI) integration method. The effects of axial tape tension, guide shape variations and the tape width on the steady-state tape-guide separation are investigated. It is shown that small axial variations on the parameters mentioned can lead to important and unintended variations in tape-guide separation.

To promote healing of many orthopedic injuries, tissue engineering approaches are being developed that combine growth factors such as Bone Morphogenetic Proteins (BMP) with biomaterial carriers. Although these technologies have shown great promise, they still face limitations. We describe a generalized approach to create target-specific modular peptides that bind growth factors to implantable biomaterials. These bifunctional peptide coatings provide a novel way to modulate biology on the surface of an implant. Using phage display techniques, we have identified peptides that bind with high affinity to BMP-2. The peptides that bind to BMP-2 fall into two different sequence clusters. The first cluster of peptide sequences contains the motif W-X-X-F-X-X-L (where X can be any amino acid) and the second cluster contains the motif F-P-L-K-G. We have synthesized bifunctional peptide linkers that contain BMP-2 and collagen-binding domains. Using a rat ectopic bone formation model, we have injected rhBMP-2 into a collagen matrix with or without a bifunctional BMP-2: collagen peptide (BC-1). The presence of BC-1 significantly increased osteogenic cellular activity, the area of bone formed, and bone maturity at the site of injection. Our results suggest that bifunctional peptides that can simultaneously bind to a growth factor and an implantable biomaterial can be used to control the delivery and release of growth factors at the site of implantation.

A new model is developed for predicting the internal loads in a wound roll. The principal contribution is the ability to account for large deformation. This is important for applications that require tightly packed rolls with large interlayer pressure and web compression. A nonlinear, orthotropic, plane-strain, pseudoelastic constitutive law is used. Arguments are made as to why the “material symmetry condition” does not apply to the wound roll. An efficient numerical solution scheme is developed, and a good correlation is achieved with interlayer pressure measurements available in the literature.

An analysis is presented to describe how a sliding sheet might entrain air that lubricates the interface. Closed-form results are obtained for a wide, slightly curled, elastic sheet sliding on an incompressible layer of air. Example results are calculated for a paper sheet typically used in copiers, and an approximate model for mixed lubrication is developed.