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Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1 , SERPINB8 , GPR87 , and NETO1 -and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.

Increased execution of replication studies contributes to the effort to restore credibility of empirical research. However, a second generation of problems arises: the number of potential replication targets is at a serious mismatch with available resources. Given limited resources, replication target selection should be well-justified, systematic and transparently communicated. At present the discussion on what to consider when selecting a replication target is limited to theoretical discussion, self-reported justifications and a few formalized suggestions. In this Registered Report, we proposed a study involving the scientific community to create a list of considerations for consultation when selecting a replication target in psychology. We employed a modified Delphi approach. First, we constructed a preliminary list of considerations. Second, we surveyed psychologists who previously selected a replication target with regards to their considerations. Third, we incorporated the results into the preliminary list of considerations and sent the updated list to a group of individuals knowledgeable about concerns regarding replication target selection. Over the course of several rounds, we established consensus regarding what to consider when selecting a replication target. The resulting checklist can be used for transparently communicating the rationale for selecting studies for replication., (© 2023 The Authors.)

Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood. Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia. Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated. Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [ n  = 74] or extensive [ n  = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P  < 0.0001). Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.

We endeavored to replicate Mitchell's (2006) finding of 17-year implicit memory priming. Subjects saw word and picture stimuli in 1999-2000 (M age = 18.9) and were retested after 11-14 years (M = 13.2; M age = 32.1). Via the internet, they completed four implicit memory tasks: picture fragment identification, word fragment completion, word stem completion, and category exemplar generation. Relative to control subjects (matched on stimuli, age, and education), longitudinal subjects revealed priming on picture and word fragment identification (perceptual tasks), but no priming on word stem completion or category exemplar generation (conceptual tasks). Four longitudinal subjects who failed to recall participating in the prior laboratory session had priming similar to the 10 subjects who did remember. Thus, we replicated the longevity of perceptual priming for pictures, and extended this to word fragment priming as well., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Family cohesion relates to positive outcomes for both parents and children. Maintaining cohesion may be especially challenging for families of adolescents with developmental disabilities, yet this has been studied infrequently in this group. We investigated cohesion in these families, particularly with respect to partner stress, using the notion of the 'spillover effect' as a model. Adolescents with disabilities and their parents participated. Parents reported on teen adaptive and problem behaviours and on marital satisfaction, parenting stress, and family cohesion. The stress of one partner was tested as a predictor of the quality of family cohesion reported by the other. Adolescent behaviour problems were negative predictors of family cohesion in mothers, and marital satisfaction positively predicted cohesion for both parents. Above other factors, greater partner stress predicted poorer family cohesion for both fathers and mothers. Marital satisfaction acted as a suppressor of this relation. To improve the overall climate of families, care providers should take into consideration individual relationships, including the marital relationship. In addition, the possibility of spillover from one individual to another should be recognized as a factor in family functioning. Family-centred practices are likely to lead to greater feelings of cohesion and overall better individual and family well-being., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Activation of coagulation by expression of tissue factor (TF) in the airspace is a hallmark of acute lung injury (ALI) but the timing of TF activation in relationship to increases in lung permeability and inflammation are unknown., Methods: To test the hypothesis that TF is upregulated early in the course of acute bleomycin lung injury and precedes increased permeability and inflammation we studied the early course of bleomycin-induced ALI in mice. Mice were treated with 0.04U intratracheal bleomycin or vehicle control and bronchoalveolar lavage (BAL) and lung tissue were collected daily for 7 days. Whole lung TF mRNA was determined by QT-PCR. TF protein was assessed by ELISA and immunostaining. BAL procoagulant activity was measured by BAL clot time and thrombin-antithrombin complexes. Inflammation was assessed by BAL cell count, differentials and CXCL1/KC concentration. Lung permeability was assessed by BAL protein and lung wet to dry weight ratio., Results: Expression of CXCL1 occurred by day 1. BAL protein and lung wet-to-dry weight ratio increased significantly by day 3. TF mRNA and BAL procoagulant activity peaked on day 4 while whole lung TF protein peaked on day 6. Changes in permeability and procoagulant activity preceded inflammatory cell influx which was maximal at day 6 while whole lung TF protein peaked along with inflammation., Conclusion: These data demonstrate that cytokine upregulation is the earliest response to bleomycin administration, followed by increased lung permeability, upregulation of TF, and recruitment of inflammatory cells.

Background: Some researchers have proposed an 'advantage' for parents of children with Down syndrome over parents of children with other intellectual disabilities, especially in relation to experiencing less parenting stress. Others have maintained that these differences are an artefact of demographic and related differences. This study extends the investigation of possible differences in dimensions of parenting stress and also examines whether differences exist in maternal and child contingent responsiveness during mother-child interaction in these two groups., Method: Mothers of children with Down syndrome (n = 43) and undifferentiated developmental disabilities (n = 54) completed measures of children's adaptive functioning and behaviour problems, parenting stress and maternal social support. Observers rated the contingent interactions between mothers and children using the Nursing Child Assessment Teaching Scale., Results: Once mother's age, education and social support as well as child adaptive functioning and behaviour problems were considered, neither parent nor child related parenting stress demonstrated an advantage for parents of children with Down syndrome. However, a 'Down syndrome advantage' was apparent for both maternal and child contingent responsiveness after accounting for maternal demographic and contextual variables and child attributes., Conclusions: Children with Down syndrome and their mothers have more positive interactions than children with other developmental disabilities, both in terms of the responsiveness of mothers and of child responses contingent on maternal behaviour. These findings suggest that both children with Down syndrome themselves and their mothers are contributing to a Down syndrome advantage., (© 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families., Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis., Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds., Measurements and Main Results: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function., Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease., Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset., Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects., Measurements and Main Results: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans., Conclusions: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified a kindred with FIP with short telomeres who did not carry a mutation in known FIP genes TERT or hTR . We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred. The proband was a 69 year-old man with dyspnea, restrictive pulmonary function test results, and reticular changes on high-resolution CT scan. An older male sibling had died from IPF. The proband had markedly shortened telomeres in peripheral blood and undetectably short telomeres in alveolar epithelial cells. Polymerase chain reaction-based sequencing of NOP10 , TINF2 , NHP2 , and DKC1 revealed that both affected siblings shared a novel A to G 1213 transition in DKC1 near the hTR binding domain that is predicted to encode a Thr405Ala amino acid substitution. hTR levels were decreased out of proportion to DKC1 expression in the T405A DKC1 proband, suggesting this mutation destabilizes hTR and impairs telomerase function. This DKC1 variant represents the third telomere-related gene identified as a genetic cause of FIP. Further investigation into the mechanism by which dyskerin contributes to the development of lung fibrosis is warranted.

Introduction: The objective of the current study was to compare the outcomes of rigid endoscopic procedures with those of pre-operative flexible nasoendoscopy., Methods: A total of 253 patients who had undergone rigid endoscopic examination under anaesthesia between 6 January 2010 and 31 August 2011 were identified. Their clinical, surgical and histological records were evaluated., Results: A total of 213 patients had a flexible nasoendoscopic procedure performed and recorded pre-operatively, and 82 in this cohort had a specific lesion or area of concern identified. There were 21 confirmed malignant biopsy results, the majority of which were squamous cell carcinoma. No patient with a negative pre-operative endoscopy had a malignant lesion discovered on endoscopic biopsy. The sensitivity and specificity of pre-operative nasoendoscopy were 100 per cent and 66.3 per cent, respectively., Conclusion: Diagnostic rigid endoscopic examination of the upper aerodigestive tract remains an important tool for excluding malignancy in high-risk patients, but is an unnecessary procedure in those low-risk patients with normal pre-operative findings.

Legally blind participants (uncorrected vision of 20/200+) were able to identify a visual stimulus attribute (clock hand position) in the absence of consciously identifying its presence. Specifically, participants--with their corrective lenses removed--correctly guessed the hour-hand position above chance (8%) on a clockface shown on a computer screen. This occurred both when presented in a 1-clockface display (28%), as well as when shown a display containing 4 clockfaces (21%), in which only 1 face contained a hand. Even more striking, hand identification accuracy in the 4-clockface condition was comparable whether the clockface containing the hand was (21%) or was not (20%) correctly identified. That legally blind individuals are capable of identifying stimulus attributes without conscious awareness provides an additional vehicle for exploring implicit perception. Consistent with previous research, the visual system can apparently cope with degraded visual input through information available through a(n unconscious) secondary pathway via the superior colliculi., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is characterized by interstitial lung infiltrates, dyspnea, and progressive respiratory failure. Reports linking telomerase mutations to familial interstitial pneumonia (FIP) suggest that telomerase activity and telomere length maintenance are important in disease pathogenesis. To investigate the role of telomerase in lung fibrotic remodeling, intratracheal bleomycin was administered to mice deficient in telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) and to wild-type controls. TERT-deficient and TERC-deficient mice were interbred to the F6 and F4 generation, respectively, when they developed skin manifestations and infertility. Fibrosis was scored using a semiquantitative scale and total lung collagen was measured using a hydroxyprolinemicroplate assay. Telomere lengths were measured in peripheral blood leukocytes and isolated type II alveolar epithelial cells (AECs). Telomerase activity in type II AECs was measured using a real-time polymerase chain reaction (PCR)-based system. Following bleomycin, TERT-deficient and TERC-deficient mice developed an equivalent inflammatory response and similar lung fibrosis (by scoring of lung sections and total lung collagen content) compared to controls, a pattern seen in both early (F1) and later (F6 TERT and F4 TERC) generations. Telomere lengths were reduced in peripheral blood leukocytes and isolated type II AECs from F6 TERT-deficient and F4 TERC-deficient mice compared to controls. Telomerase deficiency in a murine model leads to telomere shortening, but does not predispose to enhanced bleomycin-induced lung fibrosis. Additional genetic or environmental factors may be necessary for development of fibrosis in the presence of telomerase deficiency.

Objectives: To examine the association of homocysteine with cognitive functioning in very elderly community-dwelling individuals (80 years or older)., Methods: Two hundred twenty-eight nondemented community-dwelling individuals were assessed with a broad neuropsychological battery. Bloods were drawn to measure homocysteine, serum vitamin B12, and folate levels and APOE genotype., Results: Higher homocysteine levels were associated with poorer executive-language functioning scores (r = -0.311). The association persisted when serum B12 and folate levels were controlled for (r = -0.308). Homocysteine levels were not associated with memory score (r = 0.120)., Conclusions: In very elderly, nondemented community dwellers, high homocysteine levels are associated with poorer executive-language functioning but not with memory. This possible differential effect of homocysteine on cognitive functions suggests that it may affect only specific brain regions or mechanisms underlying healthy executive functioning.

Background: Multiplex immunoassays offer many advantages over singleplex assays for the analysis of multiple analytes in a single sample. We sought to validate a specific multiplex cytokine immunoassay (Human 9-plex cytokine array on the Searchlight® platform by Thermoscientific) prior to use in a large clinical study., Methods: We compared spike and recovery of recombinant proteins on the Searchlight® platform to singleplex immunoassays purchased from R&D Systems, measured identical patient samples on the two different platforms, and measured identical patient samples on different days to measure intra- and inter-assay variability., Results: Assays using the Searchlight® platform had inefficient recovery of spiked recombinant proteins compared to R&D Systems singleplex assays. Assaying identical patients samples on different days on the Searchlight platform had acceptable intra-assay variability (intra-assay coefficient of variation (CV%) range for all analytes of 9.1-13.7) but unacceptably high inter-assay variability (CV% range for all analytes 16.7-119.3) suggesting plate-to plate variability. Similar assays for individual cytokines on the R&D platform had an intra-assay CV% range of 1.6-6.4 and an inter-assay CV% range of 3.8-7.1. Some deficiencies in Searchlight® assay performance may be due to irregularities in spotting of capture antibodies during manufacturing., Conclusions: We conclude that the Searchlight® multiplex immunoassay platform would require extensive additional assay optimization prior to widespread clinical research use., (Published by Elsevier B.V.)

Background: The importance of positive parent-adolescent relationships is stressed in research on adolescents, although very little is known about this relationship when a teen has developmental disabilities (DD). We investigated the relationships of adolescents with disabilities with their mothers and their fathers in order to answer a number of questions regarding these relationships. In particular, we asked: are there differences in the relationships of mothers and fathers with their adolescent with DD? Are there early childhood predictors of the parent-teen relationship and are those based on variables that are amenable to intervention? Finally, do these predictors differ for mothers and fathers?, Methods: This study focused on the relationships of 72 mothers and 53 fathers with their 15-year-old teens with DD and their predictors from the early childhood years. Data were collected from parents through interviews and self-administered questionnaires, and from their children with disabilities through structured assessment when children were age 3 years and again at age 15 years., Results: Analyses indicated that both mother-teen and father-teen relationships were predicted by earlier parenting stress. The father-teen relationship was also predicted by early behaviour problems, but this relation was mediated by parenting stress. Socio-economic status, type of disability and the child's level of functioning were not predictive of later relationships between parents and teens. Mothers and fathers did not differ significantly in their reports of perceived positive relationships with their teens., Conclusions: The findings from this study suggest two important points of potential intervention during the early intervention years. First, parenting assistance and support to reduce stress during the early childhood years can benefit both mothers and fathers. Second, helping families and children cope with and diminish problem behaviours is likely to yield multiple advantages for parents and children and deserves emphasis in early intervention and pre-school programmes.

The nature of various memory systems was examined using factor analysis. We reanalyzed data from 11 memory tasks previously reported in Mitchell and Bruss (2003). Four well-defined factors emerged, closely resembling episodic and semantic memory and conceptual and perceptual implicit memory, in line with both memory systems and transfer-appropriate processing accounts. To explore taxonomic issues, we ran separate analyses on the implicit tasks. Using a cross-format manipulation (pictures vs. words), we identified 3 prototypical tasks. Word fragment completion and picture fragment identification tasks were "factor pure," tapping perceptual processes uniquely. Category exemplar generation revealed its conceptual nature, yielding both cross-format priming and a picture superiority effect. In contrast, word stem completion and picture naming were more complex, revealing attributes of both processes.

Patients with acute oesophageal obstruction, either due to a foreign body or food bolus, present to any of the specialties of Otorhinolaryngology, General Surgery, Cardiothoracic Surgery or Gastroenterology. To review current routine management of this condition, we conducted a postal survey of all the consultants in the aforementioned specialties in the South Thames region. The aims of the survey were to assess current practice and to produce a standardized management plan for these patients.

Parents of children with disabilities have been found to be more likely to experience stress and depressive symptoms than parents of typically developing children as a result of the increased challenges inherent in their parenting role. This study investigated the utilization of and satisfaction with adolescent health care services reported by mothers and their relation to maternal well-being. Participants included 73 mothers and their adolescents with developmental disabilities who had been recruited as infants and toddlers from early intervention programs to participate in a longitudinal investigation, the Early Intervention Collaborative Study. Data were collected through parent reports and structured assessments with adolescents. Regression analyses were conducted to test whether utilization and maternal satisfaction with care related to maternal depressive symptoms or parenting stress after controlling for child and family characteristics. The results demonstrated that both utilization and maternal satisfaction with health care added unique variance in predicting lower levels of maternal stress and depressive symptoms.

Individuals who saw pictures for 1 to 3 s in the laboratory were tested 17 years later by mail. Identification rates were significantly higher for fragments from these previously exposed targets than for novel fragments, whereas the same stimuli evoked no differences in control groups that had not been previously exposed to the pictures. Priming--the memorial advantage conferred by prior perceptual experience--was stable over the years (r= .51). Priming was dissociated from episodic memory, in that it was present even in subjects who reported no conscious recollection of their participation in the original laboratory session. These findings suggest that the perceptual representation system is an invulnerable memory system functioning below conscious awareness.

Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.

Cyclooxygenase (COX) inhibition during allergic sensitization and allergen airway challenge results in augmented allergic inflammation. We hypothesized that this increase in allergic inflammation was dependent on increased generation of leukotrienes that results from COX inhibition, as leukotrienes are important proinflammatory mediators of allergic disease. To test this hypothesis, we allergically sensitized and challenged mice deficient in 5-lipoxygenase (5-LO). We found that 5-LO knockout mice that were treated with a COX inhibitor during allergic sensitization and challenge had significantly increased airway hyperresponsiveness (AHR) (p < 0.01) and airway eosinophilia (p < 0.01) compared with 5-LO knockout mice that were treated with vehicle. The proinflammatory cytokines have also been hypothesized to be critical regulators of airway inflammation and AHR. We found that the increase in airway eosinophilia seen with COX inhibition is dependent on IL-5, whereas the increase in AHR is not dependent on this cytokine. In contrast, the COX inhibition-mediated increase in AHR is dependent on IL-13, but airway eosinophilia is not. These results elucidate the pathways by which COX inhibition exerts a critical effect of the pulmonary allergen-induced inflammatory response and confirm that COX products are important regulators of allergic inflammation.

Previous research has shown that children with attention deficit hyperactivity disorder (ADHD) often demonstrate performance deficits on effortful, strategic memory tasks, whereas relatively rote tasks of memory reveal no such deficit. Thus far, research in this domain has focused primarily on explicit memory. This study examined performance on multiple measures of implicit and explicit memory in children aged 7 to 14 years with and without ADHD. Memory for words and pictures was assessed at 15-min and 24-hr intervals. ADHD and non-ADHD groups performed similarly on tests of explicit memory (category-cued recall and recognition) and on perceptual aspects of implicit memory (word stem completion and picture fragment identification) as a function of age, retention interval, and stimulus format (i.e., picture or word). However, there was no evidence of priming on a conceptual implicit memory test (category exemplar generation) for boys with ADHD. This type of conceptual task, which is likely mediated by frontal systems, may indicate a unique memory deficit associated with ADHD.

Nonselective cyclooxygenase (COX) inhibition during the development of allergic disease in a murine model causes an increase in type 2 cytokines and lung eosinophilia; however, the mechanisms responsible for this augmented allergen-induced inflammation have not been examined. Ab depletion of CD4 and CD8 cells revealed that the heightened allergic inflammation caused by COX inhibition was CD4, but not CD8, dependent. Allergen sensitization and airway challenge alone led to undetectable levels of IL-5 and IL-13 in the lungs of IL-4, IL-4Ralpha, and STAT6 knockout (KO) mice, but COX inhibition during the development of allergic inflammation resulted in wild-type levels of IL-5 and IL-13 and heightened airway eosinophilia in each of the three KO mice. These results indicate that the effect of COX inhibition was independent of signaling through IL-4, IL-4Ralpha, and STAT6. However, whereas COX inhibition increased IgE levels in allergic wild-type mice, IgE levels were undetectable in IL-4, IL-4Ralpha, and STAT6 KO mice, suggesting that IL-13 alone is not a switch factor for IgE synthesis in this model. These results illustrate the central role played by products derived from the COX pathway in the regulation of allergic immune responses.

The authors examined age differences in conceptual and perceptual implicit memory via word-fragment completion, word-stem completion, category exemplar generation, picture-fragment identification, and picture naming. Young, middle-aged, and older participants (N = 60) named pictures and words at study. Limited test exposure minimized explicit memory contamination, yielding no reliable age differences and equivalent cross-format effects. In contrast, explicit memory and neuropsychological measures produced significant age differences. In a follow-up experiment, 24 young adults were informed a priori about implicit testing. Their priming was equivalent to the main experiment, showing that test trial time restrictions limit explicit memory strategies. The authors concluded that most implicit memory processes remain stable across adulthood and suggest that explicit contamination be rigorously monitored in aging studies.

Many fear of crime studies have revealed an interesting paradox: Although older adults are less likely to be victims, they report a higher fear of crime than younger adults. In this study, we experimentally manipulated vicarious exposure to crime. Younger (ages 18-29) and older adults (ages 61-78) were randomly assigned to view either a vivid video reenactment of a violent crime or a crime report newscast. Subjects in the violent video condition demonstrated significantly higher fear than did control group participants, but this effect was reliable only for younger adults. The older adults appeared to be unfazed by the violent video, and reported significantly less fear than the younger group. This could not be explained away on the basis of age group differences in neighborhood crime rates, victimization experience, or media exposure. Thus, when greater fear of crime is found in older adults, "old age" per se is not the cause.

Background: Smooth muscle contraction is one of the hallmarks of asthma. A recently developed pyridine derivative, Y-27632, a selective Rho kinase inhibitor, has been reported to inhibit the smooth muscle contraction of human and animal trachea in ex vivo systems but its effect in animal models of airway hyperresponsiveness (AHR) has not been examined. The purpose of this study was to evaluate the effect of Y-27632 in a murine model of allergic and virally induced AHR., Methods: Baseline lung resistance and methacholine induced AHR were measured in mice sensitised to ovalbumin (OVA) and also in mice infected with respiratory syncytial virus (RSV) following ovalbumin sensitisation (OVA/RSV)., Results: Time course and dose ranging experiments indicated that 30 mg/kg Y-27632 given by gavage 2 hours before methacholine challenge significantly reduced baseline lung resistance and prevented AHR in OVA sensitised mice. Y-27632 also suppressed AHR induced by the bronchospastic agent serotonin in OVA sensitised mice and prevented methacholine induced AHR in OVA/RSV mice., Conclusions: These results suggest that the signalling pathway mediated through Rho kinase may have an important role in bronchial smooth muscle tone in allergen induced and virus induced AHR and should be considered as a novel target for asthma treatment.

Nonselective cyclooxygenase (COX) inhibition during allergic sensitization with ovalbumin in a murine model leads to an increase in the Type 2 cytokines interleukin-5 (IL-5) and IL-13; however, the effect of selective COX-1 and COX-2 inhibitors on these cytokines is unknown. We found that COX-1 protein was constitutively expressed in lung tissue. Expression of COX-1 protein did not increase with ovalbumin sensitization, but expression of COX-2 protein did. Ovalbumin-sensitized mice treated with either selective COX-1 inhibitor SC58560 (OVA-COX-1 inhibitor) or selective COX-2 inhibitor SC58236 (OVA-COX-2 inhibitor) had significantly greater airway hyperresponsiveness (p < 0.05) and higher levels of IL-13 (p < 0.05) in lung supernatants than did untreated mice that were ovalbumin sensitized (OVA). Lung mRNA levels for the chemokine receptors CCR1 through CCR5 (expressed on eosinophils, basophils, lymphocytes, and dendritic cells) were increased in the OVA-COX-2 inhibitor and OVA-indomethacin groups. We conclude that in the BALB/c mouse, COX inhibition with either a COX-1 or COX-2 inhibitor during allergen sensitization augments production of IL-13 and increases airway hyperresponsiveness.

Severe respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans have been inconclusive. By use of a well-characterized murine model of RSV infection and allergic sensitization with ovalbumin, the effect of a preceding severe RSV infection on the development of the pulmonary allergic inflammatory response and airway hyperresponsiveness (AHR) was tested. The impact of prior allergic sensitization on RSV-induced illness, as measured by weight loss, also was evaluated. RSV infection before allergic sensitization decreased allergen-induced AHR, production of interleukin-13 in lung tissue, and lung eosinophilia. In contrast, allergic sensitization before RSV infection increased AHR and decreased RSV-related weight loss and lung levels of interferon-gamma but did not alter viral clearance. These data provide evidence that RSV-associated AHR occurs in hosts with allergic responses and that allergic inflammation is diminished when preceded by RSV infection.

We present the ongoing results of the series of 53 consecutive patients who underwent laser-assisted uvulopalatoplasty (LAUP) for snoring at the Kent and Canterbury Hospital. Twenty-nine patients (55 per cent) were completely satisfied with their surgery 18 to 24 months following LAUP when previously questioned via telephone questionnaire. We have followed up the 29 patients with a previously successful result at between 70 and 79 months following surgery. They underwent an average of 1.6 procedures. Twelve patients (22 per cent) continue to be completely satisfied at this late stage, and a further 12 (22 per cent) have some ongoing improvement in their snoring. Only three patients have indicated that a previously successful result has failed since the previous survey. The failure rate of LAUP in the treatment of snoring is seen predominantly in the first two years following surgery, but some long-term subjective recurrence of snoring does occur.

We present a case of malakoplakia presenting as a lesion in the oropharynx of an elderly smoker. In this case a clinical diagnosis of carcinoma of the pharynx was made, biopsy revealed the nature of the lesion and management was radically altered.

The endonasal endoscopic approach to the paranasal sinuses is no longer exclusively practised by a small number of dedicated super-specialists and has gained widespread acceptance in the UK. We have audited the practice of the Consultant members of the BAO-HNS via a confidential postal questionnaire with regards to the consent of their patients prior to surgery, and to the complications they have experienced. The overall rate of complications following endoscopic sinus surgery (ESS) was 0.69%, with the incidence of major complications 0.25% and of minor complications 0.44%. Wide variations in the practice of informed consent were found to exist, and this is discussed with reference to a suggested template for preoperative discussion with the patient.

Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined murine models of allergen-sensitization and RSV infection to explore the interaction of allergic and virus-induced airway inflammation and its impact on airway hyperresponsiveness (AHR). We found that RSV infection during ova-sensitization (OVA/RSV) increased and prolonged AHR compared to mice only RSV-infected (RSV) or ova-sensitized (OVA). AHR is known to be associated with an increase in Type 2 cytokines (IL-4, IL-5, and IL-13) in allergen-sensitized mice. Therefore, we hypothesized that RSV-induced enhancement of AHR was a result of potentiating the Type 2 cytokine profile promoted by ova-sensitization. Surprisingly, we found that Type 2 cytokines induced by ova-sensitization were not increased by RSV infection despite the increase in AHR, and in some cases were diminished. RNAse protection assay revealed no difference in IL-4 and IL-5 mRNA levels between the OVA and OVA/RSV groups, and IL-13 mRNA was significantly decreased in the OVA/RSV mice compared to the OVA group. Flow cytometric analysis of Type 2 cytokines demonstrated the same frequency of IL-4 and IL-5 production in lung-derived T lymphocytes from the OVA/RSV and OVA groups. Direct cytokine ELISA measurements of lung supernatant showed the level of IL-13 was significantly decreased in the OVA/RSV group compared to OVA mice, while there was no difference in either IL-4 or IL-5 between these two groups. These data indicate that the enhanced and prolonged AHR caused by the interaction of allergic airway inflammation and virus-induced immune responses is a complex process that can not be explained simply by augmented production of Type 2 cytokines., (Copyright 2001 Wiley-Liss, Inc.)

We report on three cases of patients whose primary symptoms of myasthenia gravis were related to the upper aerodigestive tract. Symptoms had been present unrecognized in all patients for up to three years, and one patient subsequently developed a myasthenic crisis. We highlight the clinical features of myasthenia gravis to allow its prompt recognition in patients presenting to the ENT surgeon or physician.

Respiratory syncytial virus (RSV)-induced disease is associated with recurrent episodes of wheezing in children, and an effective vaccine currently is not available. The use of 2 immunizations (a formalin-inactivated, alum-precipitated RSV vaccine [FI-RSV] given intramuscularly and live RSV given intranasally [LVIN]), with a control immunization, were compared in a well-characterized model of RSV challenge, with or without concomitant allergic sensitization with ovalbumin. FI-RSV caused a significant increase in airway hyperresponsiveness in mice after RSV infection during allergic sensitization, and this was associated with an increase in type 2 cytokine production. In contrast, immunization with LVIN did not change type 2 cytokine production and protected against RSV-induced airway hyperresponsiveness in the setting of allergic sensitization. This study suggests that immune modulation with RSV vaccination can have profound effects on RSV-induced airway disease and that prevention of airway hyperresponsiveness is an important end point in vaccine development.

The immunomodulatory role of arachidonic acid metabolites in allergic sensitization is undefined. Prostaglandin E(2) (PGE(2)), a product of arachidonic acid metabolism through the cyclooxygenase pathway, has been reported to favor Type 2-like cytokine secretion profiles in murine and human CD4(+) T cells by inhibiting the production of Type 1-associated cytokines. On the basis of these in vitro data, we hypothesized that indomethacin, a nonselective cyclooxygenase inhibitor, would diminish allergen-induced production of Type 2 cytokines in mice, and protect against airway hyperresponsiveness (AHR) to methacholine. We found that ovalbumin-sensitized mice that were treated with indomethacin (OVA-indomethacin mice) had significantly greater AHR (p < 0.05) and higher levels of IL-5 (176 +/- 52 versus 66 +/- 4 pg/ml) and IL-13 (1,226 +/- 279 versus 475 +/- 65 pg/ml) in lung supernatants than mice sensitized with ovalbumin alone (OVA mice), while levels of IL-4 and serum IgE were not different. Lung mRNA expression of the C-C chemokine MCP-1 was increased in OVA-indomethacin mice, while there was no difference between the two groups in lung mRNA expression of eotaxin, MIP-1alpha, MIP-1beta, or MIP-2. Histologic examination revealed greater pulmonary interstitial eosinophilia in OVA-indomethacin mice as well. Contrary to our expectations, we conclude that in the BALB/c mouse, cyclooxygenase inhibition during allergen sensitization increases AHR, production of IL-5 and IL-13, and interstitial eosinophilia.

Objective: To assess the accuracy and utility of magnetic resonance (MR) imaging in the detection and grading of pectoralis major muscle and tendon tears., Design and Patients: A retrospective review was carried out of 10 patients referred for MR imaging for suspected pectoralis muscle injury and possible operative therapy. The pectoralis muscle and tendon were imaged using thin (3-4 mm) axial sections with a variety of sequences combined for anatomical delineation (T1-weighted SE or PD SE) and fluid detection (T2-weighted SE, T2-weighted FSE with fat suppression, or STIR). Surgical correlation was available in six patients. Clinical follow-up was available in four patients treated by nonoperative therapy., Results: MR imaging identified five complete tears, four partial tears and one normal tendon. One complete and one partial tear were at the myotendinous junction. The remaining seven injuries were at the enthesis. Surgical correlation consisted of five complete tears and one partial tear. One complete and one partial tear were at the myotendinous junction with the remaining four complete tears at the enthesis. The MR interpretation and surgical findings were in agreement in all six cases. All four patients treated with nonoperative therapy demonstrated improvement at a clinical follow-up examination, with restoration of function and strength consistent with a healed prior partial injury., Conclusion: MR imaging is accurate and useful in detecting and grading tears involving the pectoralis major muscle and tendon, facilitating the identification of patients with complete tears who are candidates for operative therapy.

T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses.

Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined models of allergen sensitization and RSV infection to begin exploring the immunologic interactions between allergic and virus-induced airway inflammation and its impact on airway hypersensitivity. Airway resistance was measured after methacholine challenge in tracheally intubated mice by whole body plethysmography. Lung inflammation was assessed by bronchoalveolar lavage (BAL) and histopathology. RSV infection alone did not cause significant airway hyperresponsiveness (AHR) to methacholine. Ovalbumin (OVA)-induced AHR lasted only a few days past the discontinuance of OVA aerosol in mice that were ovalbumin sensitized and mock infected. In contrast, OVA-sensitized mice infected with RSV during the OVA aerosol treatments (OVA/RSV) had AHR for more than 2 weeks after infection. However, 2 weeks after either RSV or mock infection, OVA/RSV mice had significantly more lymphocytes found during BAL than OVA mice, whereas the OVA and OVA/RSV groups had the same number of eosinophils. Histopathologic analysis confirmed an increased inflammation in the lungs of OVA/RSV mice compared with OVA mice. In addition, OVA/RSV mice had a more widespread distribution of mucus in their airways with increased amounts of intraluminal mucus pools compared with the other groups. Thus, prolonged AHR in RSV-infected mice during ovalbumin-sensitization correlates with increased numbers of lymphocytes in BAL fluid, increased lung inflammation, and mucus deposition in the airways, but not with airway eosinophilia. A further understanding of the immunologic consequences of combined allergic and virus-induced airway inflammation will impact the management of diseases associated with airway hyperreactivity.

Our ongoing evaluation of the results of laser assisted uvulopalatoplasty (LAUP) for snoring is presented. Follow-up between 18 and 24 months post-treatment completion, of patients with a successful result at six months, reveals that 22 per cent of these patients suffer failure of snoring control between these two evaluation points. This equates to an overall success rate at this time of 55 per cent. LAUP, like other surgical remedies for snoring, has a continued relapse rate. This must be considered when counselling patients.

Phytases (EC 3.1.3.8) belong to the family of histidine acid phosphatases. We have cloned the phytases of the fungi Emericella nidulans and Talaromyces thermophilus. The putative enzyme encoded by the E. nidulans sequence consists of 463 amino acids and has a Mr of 51785. The protein deduced from the T. thermophilus sequence consists of 466 amino acids corresponding to a Mr of 51450. Both predicted amino acid sequences exhibited high identity (48% to 67%) to known phytases. This high level of identity allowed the modelling of all available fungal phytases based on the three-dimensional structure coordinates of the Aspergillus niger phytase. By this approach we identified 21 amino acids which are conserved in fungal phyA phytases and are part of the residues forming the substrate pocket. Furthermore, potential glycosylation sites were identified and compared between the aforementioned phytases and the A. niger phytase.

Young and older adults were first asked to decide if a list of individually presented words were "living" (e.g., "tree") or "nonliving" (e.g., "store"). This was termed the "orienting task." Next, subjects performed a pronunciation task. Semantic priming for young and older adults was indexed by determining if semantic congruence between words in the orienting task and words in the pronunciation task improved performance on the pronunciation task relative to pronounced words from semantic categories not primed in the orienting task. The present data, from two different experiments, revealed that subjects pronounced high-dominance exemplars of the "living" words primed in the orienting task faster than words not primed in the orienting task. These data indicated that semantic priming for relatively long prime-target stimulus onset asynchronies can occur, and that such priming is at least as robust for older adults as for young adults. The results are discussed in terms of four current models of semantic priming.

Phytases catalyse the hydrolysis of phytate (myo-inositol hexakisphosphate) to myo-inositol and inorganic phosphate. In this study genes encoding novel phytases from two different filamentous fungi, Aspergillus terreus strain 9A-1 and Myceliophthora thermophila were isolated. The encoded PhyA phytase proteins show 60% (A. terreus) and 48% (M. thermophila) identity, respectively, to the PhyA of Aspergillus niger and have 21-29% identity compared to other histidine acid phosphatases. All three PhyA proteins, in contrast to the A. niger pH 2.5-optimum acid phosphatase, prefer phytic acid as substrate and show enzyme activity at a broad range of acidic pH values. Based on their enzyme characteristics and protein sequence homology, the phytases form a novel subclass of the histidine acid phosphatase family.

This article describes the changing role of the juvenile court from the perspective of an urban juvenile court judge. The author's experiences as the administrative judge for Baltimore City's juvenile court address typical current juvenile court dilemmas such as lack of funding, physical space that is inadequate for the needs of the court and those it serves, and limited dispositional options for juvenile offenders. Examples of effective judicial advocacy are presented, as are suggestions for positive court reform.

This article presents a set of proposed guidelines for the safety assessment of new pharmaceutical excipients. These guidelines were developed by the Safety Committee of the International Pharmaceutical Excipients Council and represent a new, scientifically based approach to establishing conditions for the safe use of proposed pharmaceutical excipients utilizing various routes of human exposure. They are based upon the best currently available toxicological science and have taken the deliberations of the International Conference on Harmonization into consideration. These guidelines were developed because there are no regulatory agency guidelines currently available which specifically address the toxicological testing of a material intended for use as an excipient in pharmaceutical preparations. Only materials which have been previously permitted for use in a pharmaceutical preparation or which have been permitted for use in foods may be considered safe under current practices. If implemented, these guidelines should expedite the review of a proposed new excipient by regulatory agencies.

Using a picture naming task, we compared the magnitude of repetition priming after one prior study episode (single test priming) versus multiple prior study presentations (multiple test priming). Pictures were repeated either one, two, or three times, and the interval between tests was either several minutes (blocked test) or one week (spaced test). Priming increased with additional prior presentations (beyond one) in the multiple test format. In addition, single test priming decreased within one hour after initial exposure, with little change from one hour to two weeks. Priming was unaffected by a simultaneous recognition task, suggesting that picture naming is an implicit task relatively immune from explicit memory contamination.