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Shiga toxin-producing Escherichia coli (STEC) is a pathogen that causes gastroenteritis and bloody diarrhea but can lead to severe disease, such as hemolytic uremic syndrome (HUS). STEC serotype O78:H(-) is rare among humans, and infections are often asymptomatic. We detected a sorbitol-fermenting STEC O78:H(-):stx(1c):hlyA in blood and fecal samples of a 2-week-old boy who had bacteremia and HUS and in fecal samples of his asymptomatic family members. The phenotypic and genotypic characteristics and the virulence properties of this invasive STEC were investigated. Our findings demonstrate that contrary to earlier suggestions, STEC under certain conditions can invade the human bloodstream. Moreover, this study highlights the need to implement appropriate diagnostic methods for identifying the whole spectrum of STEC strains associated with HUS. [ABSTRACT FROM AUTHOR]

Summary: Objectives: The delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) technique is a method proposed for non-invasive measurement of cartilage glycosaminoglycan (GAG) content. In this method, gadopentetate (Gd-DTPA2−) is assumed to distribute in cartilage in inverse relation to the GAG distribution, thus allowing quantification of the GAG content. For accurate GAG quantification, the kinetics of Gd-DTPA2− in articular cartilage is of critical importance. However, the diffusion of Gd-DTPA2− has not been systematically studied over long time periods using MRI-feasible gadopentetate concentrations. Thus, the present study aims to investigate the diffusion of gadopentetate into cartilage in vitro in intact and enzymatically degraded cartilage. Methods: The diffusion of gadopentetate into bovine articular cartilage was investigated at 9.4T over 18-h time period using repeated T 1 measurements in two models, (1) comparing intact and trypsin-treated tissue and (2) assessing the effect of penetration direction. The diffusion process was further assessed by determining the gadopentetate flux and diffusivity. The results were compared with histological and biochemical reference methods. Results and conclusions: The results revealed that passive diffusion of Gd-DTPA2− was significantly slower than previously assumed, leading to overestimation of the GAG content at equilibrating times of few hours. Moreover, Gd-DTPA2− distribution was found to depend not only on GAG content, but also on collagen content and diffusion direction. Interestingly, the dGEMRIC technique was found to be most sensitive to cartilage degradation in the early stages of diffusion process, suggesting that full equilibrium between gadopentetate and cartilage may not be required in order to detect cartilage degeneration. [ABSTRACT FROM AUTHOR]

Hypotonic oral rehydration salts solutions (ORS) have been proved to be better than isotonic solutions with respect to water absorption. To establish whether a base precursor is essential in the composition of a hypotonic ORS with improved absorption properties, a randomised double blind clinical trial was conducted comparing two formulas of hypotonic ORS, each with an osmolality of 224 mmol/l, with or without citrate, in a group of 107 children admitted to hospital with acute diarrhoea. The two solutions were effective in the correction of dehydration and there was no difference between the treatments in the duration of diarrhoea. The patients receiving the hypotonic ORS with citrate consumed less of the solution, however, and their metabolic acidosis was corrected earlier. It is concluded that citrate is clinically advantageous in a hypotonic ORS, but a hypotonic formula without a base precursor is also effective. [ABSTRACT FROM AUTHOR]

Review: 76 refs. [ABSTRACT FROM AUTHOR]

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ., Competing Interests: Declaration of interests J.-L.C. serves on the scientific advisory boards of ADMA Biologics Inc., Kymera Therapeutics, and Elixiron Immunotherapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cerebrovascular involvement of Kawasaki disease (KD) is poorly studied. White matter hyperintensities (WMH) indicate cerebral small vessel disease and increase the risk for stroke., Purpose: To investigate whether childhood KD is associated with WMHs and other cerebrovascular findings later in adulthood., Materials and Methods: In this case-control study, patients diagnosed with KD (cases) at our tertiary hospital between 1978 and 1995 were invited to brain magnetic resonance (MRI) between 2016 and 2017. Migraine patients (controls) with available brain MRI were matched with cases (ratio 4:1) by age (±2 years) and sex. Two blinded neuroradiologists evaluated independently cerebrovascular findings from the brain MRI scans. Modified Scheltens' visual rating scale was used to evaluate WMH burden and the total WMH volume was measured using manual segmentation., Results: Mean age [years, (SD)] at the time of brain MRI was 33.3 (3.8) and 32.8 (4.0) for cases ( n = 40) and controls ( n = 160), respectively ( P = 0.53). Mean follow-up time for cases was 29.5 years (4.3). Total volume of WMHs (median) was 0.26 cm 3 (IQR 0.34) for cases and 0.065 cm 3 (IQR 0.075) for controls, P = 0.039. Cases had higher total WMH burden ( P = 0.003), deep WMH burden ( P = 0.003), and more periventricular WMHs (prevalence 7.5 vs. 0%, P = 0.008) than controls. Cases had greater risk of having total Scheltens' score ≥2 vs. < 2 (odds ratio, 6.88; 95% CI: 1.84-25.72, P = 0.0041) and ≥3 vs. < 3 (odds ratio, 22.71; 95% CI: 2.57-200.53, P = 0.0049). Diabetes type 1/type 2, hypertension, smoking status or hypercholesterolemia were not risk factors for WMH burden, p > 0.1. Myocarditis at the acute phase of KD increased the risk for periventricular WMHs ( P < 0.05). Three cases (7.5%) and three controls (1.9%) had lacune of presumed vascular origin ( P = 0.0096)., Conclusion: History of KD could be associated with an increased WMH burden. More studies are needed to confirm our results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laukka, Parkkola, Hirvonen, Ylikotila, Vahlberg, Salo, Kivelev, Rinne and Rahi.)

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13., (© 2021. The Author(s).)

Tuberculosis (TB) risk is highest immediately after primary infection, and young children are vulnerable to rapid and severe TB disease. Contact tracing should identify infected children rapidly and simultaneously target resources effectively. We conducted a retrospective review of the paediatric TB contact tracing results in the Hospital District of Helsinki and Uusimaa from 2012 to 2016 and identified risk factors for TB disease or infection. Altogether, 121 index cases had 526 paediatric contacts of whom 34 were diagnosed with TB disease or infection. The maximum delay until first contact investigation visit among the household contacts under 5 years of age with either TB disease or infection was 7 days. The yield for TB disease or infection was 4.6% and 12.8% for household contacts, 0.5% and 0% for contacts exposed in a congregate setting and 1.4% and 5.0% for other contacts, respectively. Contacts born in a TB endemic country (aOR 3.07, 95% CI 1.10-8.57), with household exposure (aOR 2.96, 95% CI 1.33-6.58) or a sputum smear positive index case (aOR 3.96, 95% CI 1.20-13.03) were more likely to have TB disease or infection.Conclusions: Prompt TB investigations and early diagnosis can be achieved with a well-organised contact tracing structure. The risk for TB infection or disease was higher among contacts with household exposure, a sputum smear positive index case or born in a TB endemic country. Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targeted. What is Known: • Vulnerable young children are a high priority in contact tracing and should be evaluated as soon as possible after TB exposure What is New: • Prompt investigations for paediatric TB contacts and early diagnosis of infected children can be achieved with a well-organised contact tracing structure • Large-scale investigations among children exposed in congregate settings can result in a very low yield and should be cautiously targeted.

IntroductionIn 2006, the Bacillus Calmette-Guérin (BCG) vaccination policy in Finland changed from universal to selective.AimWe assessed the impact of the policy change on tuberculosis (TB) morbidity in children under 5 years and epidemiological trends of paediatric TB in Finland.MethodsWe conducted a nationwide, population-based, retrospective registry study of all newly diagnosed active TB cases younger than 15 years in Finland from 1995 to 2015 by linking data from the National Infectious Diseases Register, Finnish Care Register for Health Care, medical patient records and Finnish Population Information System. We compared the TB incidence rate ratio of under 5 year-olds with universal and selective BCG vaccinations with a Poisson log-linear model and analysed incidence trends among those younger than 15 years with a negative binomial model.ResultsWe identified 139 paediatric TB cases: 50 native (including 24 second-generation migrants) and 89 foreign-born children. The TB rate of under 5 year-olds remained stable after changing to selective BCG vaccination (incidence rate ratio (IRR): 1.3; 95% confidence interval (CI): 0.7-2.3). TB rate in the native population under 15 years increased slightly (IRR = 1.06; 95% CI: 1.01-1.11).DiscussionPaediatric TB cases in Finland were concentrated in families with migrant background from high-TB incidence countries. The native TB morbidity in under 5-year-olds did not increase after the BCG policy revision, suggesting that selective vaccinations can prevent TB in the most vulnerable age group in low-incidence settings. Second-generation migrants under 15 years in Finland with high TB risk are probably increasing.

Aim: Bacille Calmette-Guérin (BCG) vaccine (BCG) has been suggested to induce the primary immunity needed for the subsequent Kawasaki disease (KD). We studied the epidemiology of KD before and after the universal BCG vaccination ended in Finland in September 2006., Methods: Kawasaki disease cases were retrieved from national health registries from 1996 to 2016 for annual incidence rates. We then compared 612 433 children born in the BCG vaccination era, from 1 January 1996 to 30 August 2006, to 604 163 born after BCG era, from 1 September 2006 to 31 December 2016., Results: The annual incidence rates did not change after the BCG vaccination stopped. We found 370 first visits for KD by children born in the BCG era and 341 after universal BCG vaccination ended. The mean age at diagnosis increased from 2.6 years to 3.0 years (95% CI-0.64 to -0.012, P = .04) and the proportion of children with Kawasaki disease under 5 years decreased from 87% to 81% (95% CI 1%-12%, P = .02)., Conclusion: Discontinuing the universal BCG vaccination programme did not change the incidence rates of KD. The increased age at diagnosis could suggest that the pathogenesis of KD may be associated with the immunological pathways primed by BCG immunisation., (© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: Cervicofacial lymphadenitis caused by nontuberculous mycobacteria (NTM) is commonly treated with surgery or antimicrobial therapy. The aim of this study was to analyze the utility of our new blood-based diagnostic method and the treatment protocol, surgery or observation alone, in NTM lymphadenitis in children., Methods: All patients under 16 years of age with cervicofacial NTM lymphadenitis diagnosed and treated at Children's Hospital or at the Department of Otorhinolaryngology, Helsinki University Hospital (Helsinki, Finland) in 2007-2017 were retrospectively reviewed., Results: Fifty-two patients, 33 (63%) of whom were girls, were included in the study. The median age at initial presentation of the NTM lymphadenitis was 2.9 years. The novel blood-test had been performed on 49 (94%) of the patients and in all of them it was indicative of NTM infection. A sample for mycobacterial culture was available from 34 patients, and Mycobacterium avium was the most common species detected. Most patients (n = 33, 63%) were treated conservatively with observation alone. Of these, nine patients (27%) did not develop a skin fistula, and the lymphadenitis resolved without drainage., Conclusions: The novel blood test is clinically feasible method for diagnosing childhood cervicofacial NTM lymphadenitis noninvasively. Observation alone is a good alternative to surgery, without the risk of complications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

ATP-sensitive potassium (K ATP ) channels are found in the nervous system and are downstream targets of opioid receptors. K ATP channel activity can effect morphine efficacy and may beneficial for relieving chronic pain in the peripheral and central nervous system. Unfortunately, the K ATP channels exists as a heterooctomers, and the exact subtypes responsible for the contribution to chronic pain and opioid signaling in either dorsal root ganglia (DRG) or the spinal cord are yet unknown. Chronic opioid exposure (15 mg/kg morphine, s.c., twice daily) over 5 days produces significant downregulation of Kir6.2 and SUR1 in the spinal cord and DRG of mice. In vitro studies also conclude potassium flux after K ATP channel agonist stimulation is decreased in neuroblastoma cells treated with morphine for several days. Mice lacking the K ATP channel SUR1 subunit have reduced opioid efficacy in mechanical paw withdrawal behavioral responses compared to wild-type and heterozygous littermates (5 and 15 mg/kg, s.c., morphine). Using either short hairpin RNA (shRNA) or SUR1 cre-lox strategies, downregulation of SUR1 subtype K ATP channels in the spinal cord and DRG of mice potentiated the development of morphine tolerance and withdrawal. Opioid tolerance was attenuated with intraplantar injection of SUR1 agonists, such as diazoxide and NN-414 (100 μM, 10 μL) compared to vehicle treated animals. These studies are an important first step in determining the role of K ATP channel subunits in antinociception, opioid signaling, and the development of opioid tolerance, and shed light on the potential translational ability of K ATP channel targeting pharmaceuticals and their possible future clinical utilization. These data suggest that increasing neuronal K ATP channel activity in the peripheral nervous system may be a viable option to alleviate opioid tolerance and withdrawal., (Copyright © 2019 Fisher, Johnson, Okerman, Jurgenson, Nickell, Salo, Moore, Doucette, Bjork and Klein.)

The ATP-sensitive K + channel (K ATP ) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of K ATP channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different K ATP channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-K ATP channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype K ATP channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.

Objective: Kawasaki disease (KD) is a vasculitis that can cause aneurysm formation in coronary arteries and, more rarely, in peripheral arteries. A possible connection between KD and intracranial aneurysms is unclear. The purpose of this study was to determine if KD is associated with intracranial aneurysms., Methods: In this prospective cohort study, all patients hospitalized and diagnosed with KD in the authors' hospital district area in the period from 1978 to 1995 were identified. Patients with a current age ≥ 25 years and a history of KD in childhood were included in the study, which was conducted between 2016 and 2017. Magnetic resonance angiography (MRA) of the brain was performed in all patients., Results: Forty patients (25 males), whose mean age was 33.5 ± 3.9 years (mean ± standard deviation), were eligible for study inclusion. The mean age at KD diagnosis was 3.9 ± 3.1 years, and the mean follow-up was 29.5 ± 4.3 years. Six patients (15%) had coronary arterial lesions during the acute illness of KD. None of the patients (0%) had intracranial aneurysms on brain MRA, which is significantly under the prevalence of 10% (95% CI 0%-8.8%, p = 0.03) that is the recommended limit for intracranial aneurysm screening., Conclusions: The study results suggest that KD is not associated with an increased prevalence of intracranial aneurysms and that screening for intracranial aneurysms is not warranted in patients with a history of KD.

Background: Epidemiological data on childhood nontuberculous mycobacterial (NTM) disease is scarce and the protective effect of bacille Calmette-Guérin (BCG) vaccination remains debated. In 2006, the BCG policy in Finland changed from universal to selective. We aimed to study the effect of the BCG coverage decrease on the incidence of childhood NTM infections in Finland., Methods: We conducted a nationwide, population-based, retrospective study of NTM notifications recorded to the National Infectious Diseases Register between 1995 and 2016 and identified native-born children aged 0-4 years infected with NTM. Poisson log-linear model was used to estimate the change in the incidence rate of cohorts born during universal or selective BCG policy between 1995 and 2015., Results: We identified 97 native-born children aged <5 years infected with NTM (median age, 27 months; female-to-male ratio, 2:1). The most common species was Mycobacterium avium (n = 69 [71%]). The estimated incidence rates of NTM in universal-BCG and selective-BCG cohorts were 0.2 and 3.9 per 100000 person-years, respectively. The incidence rate ratio of selective-BCG cohorts compared to universal-BCG cohorts was 19.03 (95% confidence interval, 8.82-41.07; P < .001)., Conclusions: After infant BCG coverage in Finland decreased, childhood NTM infections increased drastically. As there is no other apparent cause for the increase, this indicates that BCG offers protection against childhood NTM disease. This observation adds to the understanding of childhood NTM epidemiology and might explain why the disease is emerging in some countries.

Modern environments are full of information, and place high demands on the attention control mechanisms that allow the selection of information from one (focused attention) or multiple (divided attention) sources, react to changes in a given situation (stimulus-driven attention), and allocate effort according to demands (task-positive and task-negative activity). We aimed to reveal how attention deficit hyperactivity disorder (ADHD) affects the brain functions associated with these attention control processes in constantly demanding tasks. Sixteen adults with ADHD and 17 controls performed adaptive visual and auditory discrimination tasks during functional magnetic resonance imaging (fMRI). Overlapping brain activity in frontoparietal saliency and default-mode networks, as well as in the somato-motor, cerebellar, and striatal areas were observed in all participants. In the ADHD participants, we observed exclusive activity enhancement in the brain areas typically considered to be primarily involved in other attention control functions: During auditory-focused attention, we observed higher activation in the sensory cortical areas of irrelevant modality and the default-mode network (DMN). DMN activity also increased during divided attention in the ADHD group, in turn decreasing during a simple button-press task. Adding irrelevant stimulation resulted in enhanced activity in the salience network. Finally, the irrelevant distractors that capture attention in a stimulus-driven manner activated dorsal attention networks and the cerebellum. Our findings suggest that attention control deficits involve the activation of irrelevant sensory modality, problems in regulating the level of attention on demand, and may encumber top-down processing in cases of irrelevant information., (Copyright © 2018 Elsevier B.V. All rights reserved.)