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Bright lanthanide based probes for optical bioimaging must rely on the antenna principle, where the lanthanide‐centred excited state is formed by a complex sensitization process. Efficient sensitization of lanthanide‐centred emission occurs via triplet states centred on the sensitizing chromophore. Here, the triplet state of thioxanthone chromophores is modulated by extending the π‐system. Three thioxanthone chromophores‐thioxanthone, benzo[c]thioxanthone, and naphtho[2,3‐c]thioxanthone were synthesised and characterised. The triplet state energies and lifetimes is found to change as expected, and two dyes are found to be suitable sensitizers for europium(iii) luminescence. Reactive derivatives of thioxanthone and benzo[c]thioxanthone were prepared and coupled to a 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) lanthanide binding pocket. The photophysics and the performance in optical bioimaging of the resulting europium(iii) complexes were investigated. It is concluded that while the energetics favour efficient sensitization, the solution structure does not. While it was found that the complexes are too lipophilic to be efficient luminescent probes for optical bioimaging, we successfully demonstrated bioimaging using europium(iii) luminescence following 405 nm excitation. [ABSTRACT FROM AUTHOR]

Azaoxatriangulenium dyes with long fluorescence lifetimes offer advantages in fluorescence lifetime imaging (FLIM), time‐gated detection and polarization assays. However, the long excited state lifetimes are also expected to increase sensitivity to photoinduced electron transfer (PET) quenching, potentially increasing the on‐off ratio of PET probes. We report the synthesis and investigation of the optical properties of azaoxatriangulenium salts substituted with phenol substituents for pH sensing. Two series of pH probes with the phenol hydroxy group placed in the ortho, meta, or para positions to azadioxatriangulenium (ADOTA) and diazaoxatriangulenium (DAOTA) chromophores are investigated. All the phenol‐substituted dyes possess pH‐responsive fluorescence signals in the biologically relevant pH window (pH 6–9) due to efficient intramolecular PET from the phenolate form of the pendant arm. While the PET mechanism is partly suppressed in the phenol form of the ADOTA derivatives, it is completely suppressed in the DAOTA derivatives. The long excited state lifetimes of the triangulenium dyes ensure efficient PET quenching leading to very high on‐off ratios of the pH probes. The study clearly demonstrates effects of the position of the phenol/phenolate group relative to the chromophore on both PET quenching rates and pKa values. [ABSTRACT FROM AUTHOR]

Bright lanthanide‐based probes rely on sensitised lanthanide luminescence. The outcome of the excited state energy transfer cascade – from sensitiser chromophore to lanthanide(III) ion – should be the population of the lanthanide excited state with an efficiency equal to unity. This is rarely the case, and this is a particular problem for europium(III) due to the low energy of the Eu(II)/Eu(III) redox couple. Thus, photoinduced electron transfer quenching can be an efficient drain for the excited state energy, reducing the brightness of a probe. Here, the effect of intramolecular PeT in a lanthanide‐based probe is investigated by contrasting intramolecular processes in coumarin‐appended 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetate (DO3A) complexes with intermolecular processes induced through collisional quenching. We find that the excited energy transfer processes involving terbium(III) and europium(III) are slow in the complex when compared to collisional quenching. Further, we show that the quenching event may lead to lanthanide luminescence and suggest that the fate of a PeT quenching event may not be non‐radiative loss of the excitation energy. Bimolecular collisional quenching was used to show that intramolecular excited state energy transfer in lanthanide(III) complexes of a coumarin appended DO3A complex is limited not by slow energy transfer, but by poor access to the conformation that allows energy transfer to occur. [ABSTRACT FROM AUTHOR]

Our understanding of the solution structure of the complexes between a coumarin-appended 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A) ligand and Eu(iii), Gd(iii), Tb(iii) and Y(iii) ions allows us to investigate the excited state energy transfer cascade that result in sensitised lanthanide centred luminescence, and we can do so in unprecedented detail. Spectroscopic data from solutions with ambient oxygen levels, without oxygen and solid solutions at 77 K unequivocally show that the simple model for the antenna principle is not valid. We find that the Tb(iii) complex photophysics is determined by the non-emissive 5D3 state, not the emissive 5D4 state as usually assumed. This scrutiny of the energy transfer cascade in these antenna appended lanthanide complexes, show that detailed knowledge of solution structure and experimental photophysics are needed to rationalise the properties of lanthanide based dyes. [ABSTRACT FROM AUTHOR]

It has been more than 15 years since the last authoritative report on the solution structure of lanthanide complexes made from cylcen derived polydentate ligands. The field has progressed and diversified, and tools have been developed that should enable a step-change in the field in the imminent future. This will only happen if the tools are used, and the results communicated in a form that is consistent within the field and readily accesible to scientists outside the field. In this perspective, the fundamental tools for designing and investigating kinetically inert lanthanide complexes in solution will be covered. The fundamentals of this type of complexes will be laid out. The conformations of lanthanide complexes from cyclen derived ligands and the rate of exchange between conformations will be linked to their 1H NMR and luminescence spectra. The information rich ligand- and metal centred emission spectra will be discussed, and the time-resolved luminescence decay lifetimes are shown to be directly related to the solution structure. The aim is to provide the reader with the information needed to become excited by lanthanide coordination chemistry. [ABSTRACT FROM AUTHOR]

In order to reveal subtle differences between the solution chemistries of trivalent 4f and 5f elements, the physicochemical and photophysical properties of europium(iii), terbium(iii) and curium(iii) complexes formed with a 7-methoxy-coumarin appended 1,4,7,10-tetraazadodecane-1,4,7-triacid (DO3A) ligand were studied. All three complexes were found to be kinetically inert and exhibit stability constants similar to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) equivalents. The Cm(iii) and Eu(iii) complexes feature strong sensitised emission, while the triplet energy of the coumarin prohibits efficient sensitisation of the Tb(iii) analogue. The data presented here indicate significant differences in perturbation of the sensitising chromophore photophysics between the 4f and 5f elements. In contrast, the size of the metal center appears to not be a determining factor for the physicochemical properties of these kinetically inert Eu(iii), Tb(iii), and Cm(iii) complexes. [ABSTRACT FROM AUTHOR]

Lanthanide based dyes and assays exploit the antenna effect, where a sensitiser-chromophore is used as a light harvesting antenna and subsequent excited state energy transfer populates the emitting lanthanide centred excited state. A rudimentary understanding of the design criteria for designing efficient dyes and assays based on the antenna effect is in place. By preparing kinetically inert lanthanide complexes based on the DO3A scaffold, we are able to study the excited state energy transfer from a 7-methoxy-coumarin antenna chromophore to europium(iii) and terbium(iii) centred excited states. By contrasting the photophysical properties of complexes of metal centres with and without accessible excited states, we are able to separate the contributions from the heavy atom effect, photoinduced electron transfer quenching, excited state energy transfer and molecular conformations. Furthermore, by studying the photophysical properties of the antenna chromophore, we can directly monitor the solution structure and are able to conclude that excited state energy transfer from the chromophore singlet state to the lanthanide centre does occur. [ABSTRACT FROM AUTHOR]

Purpose: Severe Combined Immune Deficiency (SCID) is universally fatal unless treated with hematopoietic stem cell transplantation (HSCT). Following the identification of disseminated Bacille Calmette-Guérin (BCG) infections in Canadian First Nations, Métis and Inuit (FNMI) children with unrecognized primary immune deficiencies, a national surveillance study was initiated in order to determine the incidence, diagnosis, treatment and outcome of children with SCID in Canada. Methods: Canadian pediatricians were asked to complete a monthly reporting form if they had seen a suspected SCID case, from 2004 to 2010, through the Canadian Paediatric Surveillance Program (CPSP). If the case met CPSP SCID criteria, more detailed data, including demographics and clinical information about investigations, treatment and outcome was collected. Results: A total of 40 cases of SCID were confirmed for an estimated incidence of SCID in non-FNMI Canadian children of 1.4 per 100,000 live births (95 % CI 1 to 1.9/100,000). The proportion of SCID cases that were FNMI (17.5 %) was almost three times higher than was expected on the basis of proportion of the pediatric population estimated to be FNMI (6.3 %) resulting in an estimated incidence of 4.4 per 100,000 live births (95 % CI 2.1 to 9.2/100,000) in FNMI Canadian children. The mean age at diagnosis for all SCID cases was 4.2 months (range 1–583 days). There were 12 deaths (30 %; 95 % CI 18–46 %); seven died of confirmed or suspected infections before they could receive an HSCT. Conclusions: The frequency of SCID cases in FNMI children is higher than in the general Canadian pediatric population. The high mortality rate, due primarily to infection, suggests that early diagnosis by newborn screening followed by HSCT could significantly benefit children with SCID. [ABSTRACT FROM AUTHOR]

The article discusses the aspects to consider for clinical trials to study the use of cannabinoids for Canadian children with neurologic disorders. Topics mentioned include the need for clinical trials on the use of cannabinoids in pediatric patients to determine its safety and effectiveness and to guide in dosing and the requirements for clinical trial design considerations, such as engagement with families, innovative methods, and multisite collaboration.

Invited for this month's cover are the collaborating groups of Dr. Thomas Just Sørensen at the University of Copenhagen, Denmark and Dr. Robert Pal at Durham University, United Kingdom. The front cover shows the clouds parting for a cell imaged using a thioxanthone‐appended EuIII complex. This work shows that lanthanide luminescence can be used in optical bioimaging with microscopes equipped with the common blue laser line. Read the full text of the article at 10.1002/cplu.201900309. [ABSTRACT FROM AUTHOR]

Front Cover: -Expanded Thioxanthones - Engineering the Triplet Level of Thioxanthone Sensitizers for Lanthanide-Based Luminescent Probes with Visible Excitation (ChemPlusChem 12/2019) Keywords: lanthanides; luminescence; molecular probes; thioxanthones; triplet sensitizers Lanthanides, luminescence, molecular probes, thioxanthones, triplet sensitizers. [Extracted from the article]

The front cover artwork is provided by the Bo W. Laursen group from the University of Copenhagen. The image illustrates the on and off states and the quenching mechanism of a pH‐sensitive phenol‐substituted diazaoxatriangulenium (DAOTA) fluorophore in acidic and basic environments, respectively. Read the full text of the Article at10.1002/cptc.201800266. [ABSTRACT FROM AUTHOR]

InvitedInvited for the cover of this issue are AnneàKathrine Junker and ThomasàJustàSørensen from University of Copenhagen, Denmark. The cover image shows the fireworks of lanthanide luminescence and illustrates that intramolecular excited state energy transfer happens with a rate constant similar to that of the intermolecular process. The main result reported in this article came as a bit of a surprise to us ... ReadRead more about the story behind the cover in the Cover Profile and about the research itself in the Full Paper by A. K. R. Junker and T. J. Sørensen. [ABSTRACT FROM AUTHOR]

The Front Cover shows the fireworks of lanthanide luminescence and lanthanide photophysics. In the paper it is shown that intramolecular excited state energy transfer happens with a rate constant similar to that of the intermolecular process. Exploiting tools from fundamental molecular photophysics, new light was shed on the processes that lead to sensitized lanthanide luminescence. As the cover shows, the energy transfer occurs as efficiently as that between molecules. More information can be found in the Full Paper by A. K. R. Junker and T. J. Sørensen. For more on the story behind the cover research, see the Cover Profile. [ABSTRACT FROM AUTHOR]

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naïve, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB immune deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways. [ABSTRACT FROM AUTHOR]

In this article, the author discusses how health standards for paediatric clinic trials can be improved in Canada. It mentions that the risk of serious side effects in young children should be administered over-the-counter cough and cold medications. It informs that Canada should act with legislative incentives advocated by World Health Organization (WHO), to encourage the conduct of paediatric clinical trials.

The design of bright fluorescent probes based on lanthanide centered emission relies on efficient energy transfer from antenna chromophores to lanthanide centers. Here, we set out to explore the excited state energy migration pathways using collisional quenching of three 1-azathioxanthones by four lanthanide(III) ions. The results show that each combination of lanthanide(III) ion and chromophore must be considered as a unique case, as the rate constants that determine the outcome of the excited state energy migration is modulated differently in each system. For the three dye systems investigated here, the effect of the lanthanide(III) ions is that two dye systems show a strong increase in inter-system crossing leading to increased fluorescence yields and room temperature phosphorescence, while the fluorescence is quenched in the third dye system. Contrasting our results with literature data leads us to conclude that freely diffusing dyes and ions do not shed light on which properties will be found for linked systems. [ABSTRACT FROM AUTHOR]

Background: Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next‐generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers' knowledge regarding which patients to test and barriers to accessing sequencing. Methods: Here, we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014 to 2019. Data were abstracted from a chart review, and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients. Results: We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and had demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow‐up, and prognosis. Conclusion: This paper expands the paucity of literature on genetically confirmed IEIs in North America and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort. [ABSTRACT FROM AUTHOR]

Background: A web-based inventory was developed as a voluntary registry of Canadian pregnancy and birth cohort studies, with the objective to foster collaboration and sharing of research tools among cohort study groups as a means to enrich research in maternal and child health across Canada. Description: Information on existing birth cohort studies conducted in Canada exclusively or as part of broader international initiatives was accessed by searching the literature in PubMed and PsychInfo databases. Additional studies were identified by enquiring about the research activities of researchers at Canadian universities or working in affiliated hospitals or research centres or institutes. Of the fifty-eight birth cohort studies initially identified, forty-six were incorporated into the inventory if they were of a retrospective and/or prospective longitudinal design and with a minimum of two phases of data collection, with the first period having occurred before, during, or shortly after pregnancy and had an initial study sample size of a minimum of 200 participants. Information collected from each study was organized into four main categories: basic information, data source and period of collection, exposures, and outcome measures and was coded and entered into an Excel spreadsheet. The information incorporated into the Excel spreadsheet was double checked, completed when necessary, and verified for completeness and accuracy by contacting the principal investigator or research coordinator. All data collected were then uploaded onto the website of the Institute of Human Development Child and Youth Health of the Canadian Institutes of Health Research. Subsequently, the database was updated and developed as an online searchable inventory on the website of the Maternal, Infant, Child and Youth Research Network. Conclusions: This inventory is unique, as it represents detailed information assembled for the first time on a large number of Canadian birth cohort studies. Such information provides a valuable resource for investigators in the planning stages of cohort studies and identifying current research gaps. [ABSTRACT FROM AUTHOR]

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2-knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to control-transfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects. [ABSTRACT FROM AUTHOR]

Background: Although children have historically been excluded from clinical trials (CTs), many require medicines tested and approved in CTs, forcing health care providers to treat their pediatric patients based on extrapolated data. Unfortunately, traditional randomized CTs can be slow and resource-intensive, and they often require multi-center collaboration. However, an adaptive design (AD) framework for CTs could be used to increase the efficiency of pediatric CTs by incorporating prospectively planned modifications to CT methods without undermining the integrity or validity of the study. There are many possible adaptations, but each will have ethical, logistical, and statistical implications. It remains unclear which adaptations (or combinations thereof) will lead to real-world improvements in pediatric CT efficiency. This study will identify, evaluate, and synthesize the various regulatory, ethical, logistical, and statistical considerations and emerging issues of AD in CTs that could be used to evaluate the use of drugs in children.Methods/design: Following the development of a peer-reviewed search strategy, a systematic review on AD in CTs will be conducted. Data on regulatory, ethical, logistic, and statistical considerations as well as population and trial design characteristics will be synthesized. A mixed-methods study including surveys and focus groups with regulators, research ethics board members, biostatisticians, clinicians, and scientists, as well as representatives from patient groups and the public will evaluate the opportunities and challenges in applying AD in trials enrolling children and propose recommendations on best practices.Discussion: This study will deliver practical recommendations on the use of AD in pediatric CTs. Collaboration and consultation with national and global partners will ensure that our results meet the needs of researchers, regulators, and patients, both locally and globally, and that they remain current and relevant by engaging a wide variety of stakeholders. Overall, this research will enrich the knowledge base regarding if, how, and when AD can be used to answer research questions with fewer resources while still meeting the highest ethical standards and regulatory requirements for CTs. In turn, this will result in increased high-quality clinical research needed by health care providers so they have access to appropriate, population-specific evidence regarding the safe and effective use of medicines in children. [ABSTRACT FROM AUTHOR]

Physical inactivity is increasing among children globally and has been directly linked to the growing problems of overweight and obesity. We aim to assess the impact of a new mobile exergame, MobileKids Monster Manor (MKMM), in a school-based setting. MKMM, developed with input from youth to enhance physical activity, is wirelessly connected to an accelerometer-based activity monitor. Forty-two healthy students (11.3 ± 1.2 years old and 0.28 ± 1.29 body-mass index [BMI] z-score) participated in a randomized 4-week crossover study to evaluate the game intervention. The two study arms consisted of week-long baseline, game intervention/control, washout, and control/game intervention phases. All participants were required to wear an activity monitor at all times to record steps and active minutes for the study duration. MKMM was used during each arm's respective intervention week, during which children were asked to play the game at their convenience. When children were exposed to the game, an increase compared with the control phase of 2,934 steps per day ( p = 0.0004, 95% CI 1,434-4,434) and 46 active minutes per day ( p = 0.001, 95% CI 20-72) from baseline (12,299 steps/day and 190 active minutes/day) was observed. A linear regression model showed that MKMM yielded a greater increase in steps and active minutes per day among children with a higher BMI z-score, showing 10 percent more steps per day and 14 percent more active minutes per day relative to baseline, per unit increase in BMI z-score. In conclusion, MKMM increased steps and active minutes in a school-based environment. This suggests that mobile exergames could be useful tools for schools to promote physical activity and combat obesity in adolescents. [ABSTRACT FROM AUTHOR]

Helicobacter bilis, an unusual cause of chronic infections in patients with X-linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection. [ABSTRACT FROM AUTHOR]

The article presents a case study of a five year old boy who experienced high fever, approximately every 28 days, for five to six days. His fever was treated with Ibuprofen which gave him partial relief. An examination of the child revealed mild erythema of the posterior pharynx without exudate and inflammed lymph nodes in the anterior cervical chain. It is stated that recurring episodes of fever and inflammation are common symptoms of autoinflammatory diseases.

In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4 . The letter also highlights the importance of invasive pneumococcal infection as a critical ‘red flag’ warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency. [ABSTRACT FROM AUTHOR]

Abstract: This FOCIS Centers of Excellence Short Analytical Review is based on the clinical vignette of two boys from the same family with very different outcomes following hematopoietic stem cell transplantation (HSCT) for X-linked severe combined immunodeficiency (SCID). We review the kinetics of immune reconstitution following HSCT in SCID and emphasize the latest information regarding optimizing transplant outcomes for this disorder. The cases illustrate the difficulties and controversies surrounding the optimal strategies for planning SCID transplants. Specifically, we will focus on 3 areas of current debate and investigation: (i) factors involved in donor selection; (ii) the role of pretransplant conditioning; and (iii) benefits of early HSCT for SCID. [Copyright &y& Elsevier]

A novel pigmented dermatosis was observed in four unrelated boys, three of whom had insulin-dependent diabetes. Three patients were the offspring of consanguineous parents. All four boys had pigmented hypertrichotic patches or induration on the upper inner thighs, with variable involvement of the genitalia, trunk, and limbs. Two boys had episcleritis and orbital proptosis with similar facies and musculoskeletal abnormalities including clinodactyly, flat feet, and short stature. One child had paraaortic and inguinal lymphadenopathy and three patients had an enlarged liver and spleen. A large, swollen pancreas was observed on ultrasound imaging in one patient with insulin dependent diabetes who also had echocardiographic evidence of pericardial inflammation. Three boys had elevated laboratory markers of inflammation. Biopsy specimens from the skin and orbit showed a chronic inflammatory cell infiltrate composed of polyclonal lymphocytes, histiocytes, and plasma cells; fibrosis was observed in two patients, one of whom had previously received radiation therapy to the orbit. Two boys responded to treatment with subcutaneous interferon- α, combined with a short course of oral prednisone in the child without diabetes. We believe these inflammatory pigmented skin lesions represent a unique dermatosis associated with diabetes mellitus and systemic disease. The pathogenesis is unknown. The presence of consanguinity in three of four families, and similar dysmorphic features in two boys, suggest a genetic disorder, possibly with autosomal recessive inheritance. [ABSTRACT FROM AUTHOR]

Prenatal ethanol exposure and stress have each been shown to have significant effects on the immune system. This study examined the possible interactive effects of prenatal ethanol exposure and exposure to stress later in life on the immune system. Differential vulnerability to these challenges in female and male offspring was assessed. At 5 to 6 months of age, female and male offspring from prenatal ethanol-exposed (E), pair-fed (PF), and ad libitum-fed control (C) conditions were exposed to 0, 1, or 3 days of cold (4°C). At the end of the cold period, the proliferative response of splenic lymphocytes to the mitogens concanavalin A (Con A) and pokeweed mitogen (PWM) was assessed. The data demonstrate a significant interactive effect between prenatal ethanol exposure and cold stress in female offspring. After 1 day of cold stress, E females had significantly increased PWM-induced lymphocyte proliferation compared with PF and C females, and significantly increased Con A-induced lymphocyte proliferation compared with PF females. There were no differences in PWM or Con A-induced lymphocyte proliferation among E, PF, and C females after 0 or 3 days of cold stress, nor among E, PF, and C males on any test day. Regardless of prenatal treatment, females exposed to 1 or 3 days of cold had significantly greater basal plasma corticosterone levels than females not exposed to cold. In contrast, only E males exposed to 1 or 3 days of cold had significantly increased basal plasma corticosterone levels, compared with E males not exposed to cold; PF and C males showed no significant change in basal corticosterone after cold stress. These data demonstrate that, in response to the challenge of cold stress, changes in lymphocyte proliferation to PWM and Con A may occur selectively in E females. Moreover, the interactive effects of prenatal ethanol and cold stress may result in enhanced rather than suppressed immune responsiveness. [ABSTRACT FROM AUTHOR]

The article discusses the use of research ethics committees (RECs) for data-intensive international research, including in RECs' support for mutual recognition frameworks, the protection of research participants and the role organizations play in verifying secondary research data.

Background/Purpose: To estimate the incidence of periodic fever syndromes in the Canadian paediatric population, to describe the patterns of presentation, and to raise awareness in the medical community. Methods: This study was initiated though the Canadian Pediatric Surveillance Program (CPSP), and is being carried out over a three year period which will conclude in September 2014. The case definition includes patients less than 18 years of age presenting with a newly diagnosed periodic fever syndrome. Conditions under surveillance included Familial Mediterranean fever (FMF), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulin D syndrome (HIDS), Cryopyrin-associated periodic syndromes (CAPS), Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), and Undefined periodic fever syndromes. For each condition the study protocol outlined established clinical and/or genetic criteria for diagnosis. Participating pediatricians and pediatric subspecialists across the country are sent monthly reporting forms. Detailed questionnaires are completed by physicians who report a recent diagnosis. Submissions are screened for accuracy and confirmed cases then entered into a database. Results: During the 20 month period from September 2011 to December 2012 a total of 167 cases were reported. Of these cases, detailed questionnaires were completed on 126, with the remainder pending at the time of this report. 114 cases have been confirmed as meeting the criteria for one of the Periodic Fever Syndromes under surveillance, 55% of which had had genetic testing completed as part of their evaluation. Twelve cases were discarded. Amongst the 114 confirmed cases, PFAPA was most frequent (51%), followed by Undefined Periodic fever syndrome (37%). Also seen were FMF (11%), and one case of HIDS (1%). There were no cases of TRAPS, or CAPS, reported during the study period to date. Amongst the 42 Undefined Periodic Fever syndrome cases the reporting physicians described 11 as being suspected PFAPA, 5 suspected FMF, 3 suspected CAPS, and 1 suspected HIDS. In most cases this was because genetic testing was still pending at the time of reporting. The overall male to female ratio was 1.1:1. Amongst Undefined cases there was a male predominance with a male to female ratio of 1.6:1, whereas the male to female ratio was 0.6:1 for FMF. An equal number of males and females were reported for PFAPA. The most frequent fever associated manifestations for PFAPA included pharyngitis (79%), cervical lymphadenopathy (66%), stomatitis (59%), and fatigue (53%). For FMF most frequent were abdominal pain (69%), arthralgia (54%), pharyngitis (46%), and headache (46%). For Undefined cases most frequent manifestations were fatigue (45%), pharyngitis (38%), abdominal pain (36%), and lymphadenopathy (33%). Conclusion: Although rare periodic fever syndromes are identified across Canada each year. PFAPA, Undefined fever syndromes, and FMF are most frequently seen. We hope to have a more complete picture of the full spectrum and incidence of these autoinflammatory diseases in the Canadian population as genetic test results become available, and additional cases are identified through the end of the study in September 2014. [ABSTRACT FROM AUTHOR]