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Showing papers by "Dalhousie University published in 2007"


Journal ArticleDOI
TL;DR: Although based on a simple count, the frailty index shows several interesting properties, including a characteristic rate of accumulation, a submaximal limit, and characteristic changes with age in its distribution.
Abstract: This review article summarizes how frailty can be considered in relation to deficit accumulation. Recalling that frailty is an age-associated, nonspecific vulnerability, we consider symptoms, signs, diseases, and disabilities as deficits, which are combined in a frailty index. An individual's frailty index score reflects the proportion of potential deficits present in that person, and indicates the likelihood that frailty is present. Although based on a simple count, the frailty index shows several interesting properties, including a characteristic rate of accumulation, a submaximal limit, and characteristic changes with age in its distribution. The frailty index, as a state variable, is able to quantitatively summarize vulnerability. Future studies include the application of network analyses and stochastic analytical techniques to the evaluation of the frailty index and the description of other state variables in relation to frailty.

1,998 citations


Journal ArticleDOI
TL;DR: The authors developed an 18-item measure, the ASI-3, which assesses the 3 factors best replicated in previous research: Physical, Cognitive, and Social Concerns and displayed generally good performance on other indices of reliability and validity, along with evidence of improved psychometric properties over the original ASI.
Abstract: Accumulating evidence suggests that anxiety sensitivity (fear of arousal-related sensations) plays an important role in many clinical conditions, particularly anxiety disorders. Research has increasingly focused on how the basic dimensions of anxiety sensitivity are related to various forms of psychopathology. Such work has been hampered because the original measure--the Anxiety Sensitivity Index (ASI)--was not designed to be multidimensional. Subsequently developed multidimensional measures have unstable factor structures or measure only a subset of the most widely replicated factors. Therefore, the authors developed, via factor analysis of responses from U.S. and Canadian nonclinical participants (n=2,361), an 18-item measure, the ASI-3, which assesses the 3 factors best replicated in previous research: Physical, Cognitive, and Social Concerns. Factorial validity of the ASI-3 was supported by confirmatory factor analyses of 6 replication samples, including nonclinical samples from the United States and Canada, France, Mexico, the Netherlands, and Spain (n=4,494) and a clinical sample from the United States and Canada (n=390). The ASI-3 displayed generally good performance on other indices of reliability and validity, along with evidence of improved psychometric properties over the original ASI.

1,461 citations


Journal ArticleDOI
Peter Szatmari1, Andrew D. Paterson2, Lonnie Zwaigenbaum1, Wendy Roberts2, Jessica Brian2, Xiao-Qing Liu2, John B. Vincent2, Jennifer Skaug2, Ann P. Thompson1, Lili Senman2, Lars Feuk2, Cheng Qian2, Susan E. Bryson3, Marshall B. Jones4, Christian R. Marshall2, Stephen W. Scherer2, Veronica J. Vieland5, Christopher W. Bartlett5, La Vonne Mangin5, Rhinda Goedken6, Alberto M. Segre6, Margaret A. Pericak-Vance7, Michael L. Cuccaro7, John R. Gilbert7, Harry H. Wright8, Ruth K. Abramson8, Catalina Betancur9, Thomas Bourgeron10, Christopher Gillberg11, Marion Leboyer9, Joseph D. Buxbaum12, Kenneth L. Davis12, Eric Hollander12, Jeremy M. Silverman12, Joachim Hallmayer13, Linda Lotspeich13, James S. Sutcliffe14, Jonathan L. Haines14, Susan E. Folstein15, Joseph Piven16, Thomas H. Wassink6, Val C. Sheffield6, Daniel H. Geschwind17, Maja Bucan18, W. Ted Brown, Rita M. Cantor17, John N. Constantino19, T. Conrad Gilliam20, Martha R. Herbert21, Clara Lajonchere17, David H. Ledbetter22, Christa Lese-Martin22, Janet Miller17, Stan F. Nelson17, Carol A. Samango-Sprouse23, Sarah J. Spence17, Matthew W. State24, Rudolph E. Tanzi21, Hilary Coon25, Geraldine Dawson26, Bernie Devlin27, Annette Estes26, Pamela Flodman28, Lambertus Klei27, William M. McMahon25, Nancy J. Minshew27, Jeff Munson26, Elena Korvatska29, Elena Korvatska26, Patricia M. Rodier30, Gerard D. Schellenberg26, Gerard D. Schellenberg29, Moyra Smith28, M. Anne Spence28, Christopher J. Stodgell30, Ping Guo Tepper, Ellen M. Wijsman26, Chang En Yu26, Chang En Yu29, Bernadette Rogé31, Carine Mantoulan31, Kerstin Wittemeyer31, Annemarie Poustka32, Bärbel Felder32, Sabine M. Klauck32, Claudia Schuster32, Fritz Poustka33, Sven Bölte33, Sabine Feineis-Matthews33, Evelyn Herbrecht33, Gabi Schmötzer33, John Tsiantis34, Katerina Papanikolaou34, Elena Maestrini35, Elena Bacchelli35, Francesca Blasi35, Simona Carone35, Claudio Toma35, Herman van Engeland36, Maretha de Jonge36, Chantal Kemner36, Frederike Koop36, Marjolijn Langemeijer36, Channa Hijimans36, Wouter G. Staal36, Gillian Baird37, Patrick Bolton38, Michael Rutter38, Emma Weisblatt39, Jonathan Green40, Catherine Aldred40, Julie Anne Wilkinson40, Andrew Pickles40, Ann Le Couteur41, Tom Berney41, Helen McConachie41, Anthony J. Bailey42, Kostas Francis42, Gemma Honeyman42, Aislinn Hutchinson42, Jeremy R. Parr42, Simon Wallace42, Anthony P. Monaco42, Gabrielle Barnby42, Kazuhiro Kobayashi42, Janine A. Lamb42, Inês Sousa42, Nuala Sykes42, Edwin H. Cook43, Stephen J. Guter43, Bennett L. Leventhal43, Jeff Salt43, Catherine Lord44, Christina Corsello44, Vanessa Hus44, Daniel E. Weeks27, Fred R. Volkmar24, Maïté Tauber45, Eric Fombonne46, Andy Shih47 
TL;DR: Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
Abstract: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

1,338 citations


Journal ArticleDOI
02 Feb 2007-Science
TL;DR: The findings of these 12 FeAXs reveal that iron supply exerts controls on the dynamics of plankton blooms, which in turn affect the biogeochemical cycles of carbon, nitrogen, silicon, and sulfur and ultimately influence the Earth climate system.
Abstract: Since the mid-1980s, our understanding of nutrient limitation of oceanic primary production has radically changed. Mesoscale iron addition experiments (FeAXs) have unequivocally shown that iron supply limits production in one-third of the world ocean, where surface macronutrient concentrations are perennially high. The findings of these 12 FeAXs also reveal that iron supply exerts controls on the dynamics of plankton blooms, which in turn affect the biogeochemical cycles of carbon, nitrogen, silicon, and sulfur and ultimately influence the Earth climate system. However, extrapolation of the key results of FeAXs to regional and seasonal scales in some cases is limited because of differing modes of iron supply in FeAXs and in the modern and paleo-oceans. New research directions include quantification of the coupling of oceanic iron and carbon biogeochemistry.

1,269 citations


Journal ArticleDOI
30 Mar 2007-Science
TL;DR: For example, this paper found that the abundance of all 11 great sharks that consume other elasmobranchs (rays, skates, and small sharks) fell over the past 35 years, while 12 of 14 of these prey species increased in coastal northwest Atlantic ecosystems.
Abstract: Impacts of chronic overfishing are evident in population depletions worldwide, yet indirect ecosystem effects induced by predator removal from oceanic food webs remain unpredictable. As abundances of all 11 great sharks that consume other elasmobranchs (rays, skates, and small sharks) fell over the past 35 years, 12 of 14 of these prey species increased in coastal northwest Atlantic ecosystems. Effects of this community restructuring have cascaded downward from the cownose ray, whose enhanced predation on its bay scallop prey was sufficient to terminate a century-long scallop fishery. Analogous top-down effects may be a predictable consequence of eliminating entire functional groups of predators.

1,093 citations


Journal ArticleDOI
TL;DR: Patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolIZumab Pegol treatment than with a switch to placebo.
Abstract: Background Certolizumab pegol is a pegylated humanized Fab′ fragment with a high binding affinity for tumor necrosis factor α that does not induce apoptosis of T cells or monocytes. Methods In our randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate-to-severe Crohn's disease. As induction therapy, 400 mg of certolizumab pegol was administered subcutaneously at weeks 0, 2, and 4. Patients with a clinical response (defined as reduction of at least 100 from the baseline score on the Crohn's Disease Activity Index [CDAI]) at week 6 were stratified according to their baseline C-reactive protein level and were randomly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24, with follow-up through week 26. Results Among patients with a response to induction therapy at week 6 (428 of 668 [64%]), the response was maintained through week 26 in 62% of patients with a baseline C-reactive prote...

977 citations


Journal ArticleDOI
01 Sep 2007-Gut
TL;DR: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn’s disease naive to anti-TNF treatment in a follow-on randomised controlled trial.
Abstract: Background: Adalimumab induced clinical remission after four weeks in patients with active Crohn’s disease in the CLASSIC I trial. Objective: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn’s disease in a follow-on randomised controlled trial (CLASSIC II). Methods: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn’s disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI Results: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p Conclusions: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn’s disease naive to anti-TNF treatment.

926 citations


Journal ArticleDOI
TL;DR: The rigorously developed Pediatric Ulcerative Colitis Activity Index is a noninvasive, valid, highly reliable, and responsive index with which to assess disease activity in pediatric ulcerative colitis.

843 citations


Journal ArticleDOI
TL;DR: In this article, the phase changes and regions of phase stability that occur during the lithiation and delithiation of the Si electrode were investigated using in situ X-ray diffraction (XRD) techniques.
Abstract: The electrochemical reaction of lithium with a crystalline Si composite electrode at room temperature was investigated using in situ X-ray diffraction (XRD) techniques. The study confirmed that crystalline Si becomes amorphous during the first lithiation. The range of the coexistence region between crystalline Si and amorphous lithiated Si is 3350 ± 200 mAh/g. The highly lithiated amorphous Li x Si phase was found to crystallize into Li 15 Si 4 rapidly at about 60 mV (vs Li/Li + ) and this Li 15 Si 4 phase exists over a relatively narrow range of capacity. During delithiation, the Li 15 Si 4 phase coexists with amorphous Li z Si with z = 2.0 +0 -1 . Once all the Li 15 Si 4 phase disappears, the amorphous phase persists as the remaining Li is extracted. The formation of the Li 15 Si 4 phase can be avoided if the potential of the Si electrode is controlled above 70 mV during cycling. Based on the electrochemical and XRD data, a "phase diagram" was constructed to show the phase changes and regions of phase stability that occur during the lithiation and delithiation of the Si electrode.

787 citations


Journal ArticleDOI
TL;DR: This double-blind, placebo-controlled trial demonstrates the therapeutic efficacy of an interleukin-12/23 monoclonal antibody in psoriasis and provides further evidence of a role of the interleUKin- 12/23 p40 cytokines in the pathophysiology of Psoriasis.
Abstract: Background Skin-infiltrating lymphocytes expressing type 1 cytokines have been linked to the pathophysiology of psoriasis. We evaluated the safety and efficacy of a human interleukin-12/23 monoclonal antibody in treating psoriasis. Methods In this double-blind, placebo-controlled trial, 320 patients with moderate-to-severe plaque psoriasis underwent randomization to treatment with the interleukin-12/23 monoclonal antibody (one 45-mg dose, one 90-mg dose, four weekly 45-mg doses, or four weekly 90-mg doses) or placebo; 64 patients were randomly assigned to each group. Patients assigned to the interleukin-12/23 monoclonal antibody received one additional dose at week 16 if needed. Patients assigned to placebo crossed over to receive one 90-mg dose of interleukin-12/23 monoclonal antibody at week 20. Results There was at least 75% improvement in the psoriasis area-and-severity index at week 12 (the primary end point) in 52% of patients who received 45 mg of the interleukin-12/23 monoclonal antibody, in 59% o...

784 citations


Journal ArticleDOI
TL;DR: It is concluded that chemerin is a novel adipose-derived signaling molecule that regulates adipogenesis and adipocyte metabolism and has a role in adaptive and innate immunity.

Journal ArticleDOI
TL;DR: Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada, and the decrease was greatest in areas in which the baseline rate was high.
Abstract: Results A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively). Conclusions Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.

Journal ArticleDOI
TL;DR: This data indicates that once-weekly dosing with adalimumab is a safe and effective treatment for moderate to severe chronic plaque psoriasis in women with atypical immune response to chemotherapy.
Abstract: BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P<0.001 vs. adalimumab) and 18.9% for placebo (P<0.001 vs. adalimumab). Statistically significantly more adalimumab-treated patients (16.7%) than methotrexate-treated patients (7.3%) or placebo-treated patients (1.9%) achieved complete clearance of disease. The response to adalimumab was rapid, with a 57% improvement in mean PASI observed at week 4. Adverse events were similar across treatment groups. Adverse events leading to study discontinuation were greatest in the methotrexate group, primarily because of hepatic-related adverse events. CONCLUSIONS: After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.

Journal ArticleDOI
TL;DR: In this paper, the performance of negative electrodes based on commercially available crystalline Si powder and sodium carboxymethyl cellulose (CMC) binder was investigated, and a high specific capacity of about 1100 mAh/g for 70 cycles was achieved with a lower cutoff potential of 0.170 V vs Li/Li +.
Abstract: The electrochemical performance of negative electrodes based on commercially available crystalline Si powder and sodium carboxymethyl cellulose (CMC) binder was investigated. Compared to the conventional binder, polyvinylidene fluoride, Si electrodes using CMC binder show vastly improved cycling performance. A high specific capacity of about 1100 mAh/g for 70 cycles has been achieved with a lower cutoff potential of 0.170 V vs Li/Li + . Si electrodes made using CMC binder have better capacity retention than those using a binder consisting of CMC and styrene butadiene rubber. CMC is an extremely stiff and brittle polymer, so it is surprising that it functions well as a binder in electrodes where the volume change of the active material particles is about 100%.

Journal ArticleDOI
Judith Lipp1
TL;DR: In this paper, Denmark, Germany and the United Kingdom stand out as lead countries based on their experiences with the feed-in tariff (FIT) and RPS and provide important lessons for other nations.


Journal ArticleDOI
TL;DR: A meta-analysis of trials randomizing patients with colon cancer to laparoscopically assisted or open colectomy to enhance the power in determining whether laparoscopic coLECTomy for cancer is oncologically safe was performed.
Abstract: OBJECTIVE: To perform a meta-analysis of trials randomizing patients with colon cancer to laparoscopically assisted or open colectomy to enhance the power in determining whether laparoscopic colect ...

Journal ArticleDOI
TL;DR: This work presents a graphical language for dagger compact closed categories, and sketches a proof of its completeness for equational reasoning, and gives a general construction, the CPM construction, which associates to each Dagger compact closed category its ''category of completely positive maps'', and shows that the resulting category is again dagger compactclosed.

Journal Article
TL;DR: Qualitative findings from interviews with 89 youth support a culturally embedded understanding of positive youth development that better accounts for young people's resilience in western and non-western countries.
Abstract: An international mixed methods study of resilience of 14 sites in eleven countries identified seven tensions that youth resolve in culturally specific ways Resolution of these tensions is foundational to experiences of resilience This paper reports on the qualitative findings from interviews with 89 youth Results support a culturally embedded understanding of positive youth development that better accounts for young people's resilience in western and non-western countries Specifically, the seven tensions identified include: access to material resources, relationships, identity, cohesion, power and control, social justice, and cultural adherence Findings show that no one pattern in the resolution of these tensions predicts resilience better than another A case study of a Palestinian boy demonstrates the intersection of the seven tensions and the uniqueness of their resolution The implications of this work for interventions is discussed

Journal ArticleDOI
19 Dec 2007-JAMA
TL;DR: In this study, CTPA was not inferior to V(dot)Q(dot scanning in ruling out pulmonary embolism, however, significantly more patients were diagnosed with pulmonary emblism using the CTPA approach.
Abstract: ContextVentilation-perfusion (/) lung scanning and computed tomographic pulmonary angiography (CTPA) are widely used imaging procedures for the evaluation of patients with suspected pulmonary embolism. Ventilation-perfusion scanning has been largely replaced by CTPA in many centers despite limited comparative formal evaluations and concerns about CTPA's low sensitivity (ie, chance of missing clinically important pulmonary embuli).ObjectivesTo determine whether CTPA may be relied upon as a safe alternative to / scanning as the initial pulmonary imaging procedure for excluding the diagnosis of pulmonary embolism in acutely symptomatic patients.Design, Setting, and ParticipantsRandomized, single-blinded noninferiority clinical trial performed at 4 Canadian and 1 US tertiary care centers between May 2001 and April 2005 and involving 1417 patients considered likely to have acute pulmonary embolism based on a Wells clinical model score of 4.5 or greater or a positive D-dimer assay result.InterventionPatients were randomized to undergo either / scanning or CTPA. Patients in whom pulmonary embolism was considered excluded did not receive antithrombotic therapy and were followed up for a 3-month period.Main Outcome MeasureThe primary outcome was the subsequent development of symptomatic pulmonary embolism or proximal deep vein thrombosis in patients in whom pulmonary embolism had initially been excluded.ResultsSeven hundred one patients were randomized to CTPA and 716 to / scanning. Of these, 133 patients (19.2%) in the CTPA group vs 101 (14.2%) in the / scan group were diagnosed as having pulmonary embolism in the initial evaluation period (difference, 5.0%; 95% confidence interval [CI], 1.1% to 8.9%) and were treated with anticoagulant therapy. Of those in whom pulmonary embolism was considered excluded, 2 of 561 patients (0.4%) randomized to CTPA vs 6 of 611 patients (1.0%) undergoing / scanning developed venous thromboembolism in follow-up (difference, −0.6%; 95% CI, −1.6% to 0.3%) including one patient with fatal pulmonary embolism in the / group.ConclusionsIn this study, CTPA was not inferior to / scanning in ruling out pulmonary embolism. However, significantly more patients were diagnosed with pulmonary embolism using the CTPA approach. Further research is required to determine whether all pulmonary emboli detected by CTPA should be managed with anticoagulant therapy.Trial Registrationisrctn.org Identifier: ISRCTN65486961

Journal ArticleDOI
TL;DR: In this article, a set of guidelines for designing high energy-density alloy anode materials is proposed for designing alloys with the maximum possible energy density for a given electrode-coating performance.
Abstract: A set of guidelines is proposed for designing high-energy-density alloy anode materials It is first shown that the molar volume of lithium is about 9 mL/mol in a wide variety of lithium alloys and is independent of lithium content Using this property of lithium alloys, simple relationships between the volumetric energy density and the volumetric expansion of an alloy are derived These relationships are extremely powerful for designing alloys with the maximum possible energy density for a given electrode-coating performance

Journal ArticleDOI
TL;DR: Solid evidence is provided that among infants for whom a source case was identified, household members were responsible for 76%–83% of transmission of Bordetella pertussis to this high-risk group.
Abstract: BACKGROUND: Pertussis vaccination has reduced the number of notified cases in industrialized countries from peak years by more than 95%. The effect of recently recommended adult and adolescent vaccination strategies on infant pertussis depends, in part, on the proportion of infants infected by adults and adolescents. This proportion, however, remains unclear, because studies have not been able to determine the source case for 47%-60% of infant cases. METHODS: A prospective international multicenter study was conducted of laboratory confirmed infant pertussis cases (aged

Journal ArticleDOI
TL;DR: A much more satisfying derivation founded on second-order perturbation theory in the closure approximation and a semiclassical evaluation of the relevant interaction integrals is presented.
Abstract: We have recently introduced a model of the dispersion interaction based on the position-dependent dipole moment of the exchange hole [J. Chem. Phys. 122, 154104 (2005)]. The original derivation, involving simple dipole-induced-dipole electrostatics, was somewhat heuristic, however, and lacking in rigor. Here we present a much more satisfying derivation founded on second-order perturbation theory in the closure approximation and a semiclassical evaluation of the relevant interaction integrals. Expressions for C6, C8, and C10 dispersion coefficients are obtained in a remarkably straightforward manner. Their values agree very well with ab initio reference data on dispersion coefficients between the atoms H, He, Ne, Ar, Kr, and Xe. We also highlight the importance of the exchange-hole contribution to the dispersion coefficients, especially to C6.

Journal ArticleDOI
TL;DR: Pattern pluralism (the recognition that different evolutionary models and representations of relationships will be appropriate, and true, for different taxa or at different scales or for different purposes) is an attractive alternative to the quixotic pursuit of a single true TOL.
Abstract: Darwin claimed that a unique inclusively hierarchical pattern of relationships between all organisms based on their similarities and differences [the Tree of Life (TOL)] was a fact of nature, for which evolution, and in particular a branching process of descent with modification, was the explanation. However, there is no independent evidence that the natural order is an inclusive hierarchy, and incorporation of prokaryotes into the TOL is especially problematic. The only data sets from which we might construct a universal hierarchy including prokaryotes, the sequences of genes, often disagree and can seldom be proven to agree. Hierarchical structure can always be imposed on or extracted from such data sets by algorithms designed to do so, but at its base the universal TOL rests on an unproven assumption about pattern that, given what we know about process, is unlikely to be broadly true. This is not to say that similarities and differences between organisms are not to be accounted for by evolutionary mechanisms, but descent with modification is only one of these mechanisms, and a single tree-like pattern is not the necessary (or expected) result of their collective operation. Pattern pluralism (the recognition that different evolutionary models and representations of relationships will be appropriate, and true, for different taxa or at different scales or for different purposes) is an attractive alternative to the quixotic pursuit of a single true TOL.

Journal ArticleDOI
TL;DR: In all nine children, early impairment in social-communicative development coexisted with atypical sensory and/or motor behaviors, as did a temperamental profile marked by irritability/distress and dysregulated state.
Abstract: The present paper documents the development of autism/autistic spectrum disorder in a consecutive series of nine high-risk infants followed prospectively from 6 months of age. Evidence is provided for two broadly defined subgroups: the first subgroup (n = 6) showed a decrease in IQ between 12 and 24 or 36 months (from average/near average to severe cognitive impairment), whereas the second subgroup (n = 3) continued to obtain average or near average IQs. Signs of autism emerged and/or were more striking earlier in the first subgroup. In all nine children, early impairment in social-communicative development coexisted with atypical sensory and/or motor behaviors, as did a temperamental profile marked by irritability/distress and dysregulated state. Discussion focuses on issues raised by the pattern of findings.

Journal ArticleDOI
TL;DR: This study compared the gait of 50 patients with end-stage knee osteoarthritis to a group of 63 age-matched asymptomatic control subjects to determine gait pattern differences between the OA and the control groups.

Journal ArticleDOI
TL;DR: A central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored and an attempt is made to address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.
Abstract: Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Journal ArticleDOI
TL;DR: The IRAK-4–dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae, and appear to play a redundant role in protective immunity to most infections.
Abstract: Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.

Journal ArticleDOI
TL;DR: The Modified DMQ-R scores showed good to excellent test-retest reliability in a sample of undergraduates who were relatively frequent drinkers, and drinking motives prospectively predicted number of drinks consumed per week and alcohol-related problems, over and above demographics and initial alcohol use.

Journal ArticleDOI
TL;DR: It is argued that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity, and the potential for the use of the gene signatures described in this study to better assess the immunopathology and clinical management of severe viral infections.
Abstract: It is not understood how immune inflammation influences the pathogenesis of severe acute respiratory syndrome (SARS). One area of strong controversy is the role of interferon (IFN) responses in the natural history of SARS. The fact that the majority of SARS patients recover after relatively moderate illness suggests that the prevailing notion of deficient type I IFN-mediated immunity, with hypercytokinemia driving a poor clinical course, is oversimplified. We used proteomic and genomic technology to systematically analyze host innate and adaptive immune responses of 40 clinically well-described patients with SARS during discrete phases of illness from the onset of symptoms to discharge or a fatal outcome. A novel signature of high IFN-alpha, IFN-gamma, and IFN-stimulated chemokine levels, plus robust antiviral IFN-stimulated gene (ISG) expression, accompanied early SARS sequelae. As acute illness progressed, SARS patients entered a crisis phase linked to oxygen saturation profiles. The majority of SARS patients resolved IFN responses at crisis and expressed adaptive immune genes. In contrast, patients with poor outcomes showed deviated ISG and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. We contend that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity. The potential for the use of the gene signatures we describe in this study to better assess the immunopathology and clinical management of severe viral infections, such as SARS and avian influenza (H5N1), is therefore worth careful examination.