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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.
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Interferón gamma , Janus Quinasa 2 , Infecciones por Mycobacterium , Humanos , Masculino , Proteínas de Ciclo Celular/metabolismo , Interferón gamma/inmunología , Interleucina-12 , Interleucina-23 , Janus Quinasa 2/metabolismo , Mycobacterium/fisiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Proteínas Oncogénicas/metabolismoRESUMEN
BackgroundNeonatal early-onset disease caused by group B Streptococcus (GBS) is a leading cause of infant morbidity. Intrapartum antibiotic prophylaxis (IAP) is effective in preventing early-onset GBS disease, but there is no agreement on the optimal strategy for identifying the pregnant women requiring this treatment, and both risk-based prophylaxis (RBP) and GBS screening-based prophylaxis (SBP) are used.AimThe aim of this study was to evaluate the effect of SBP as a public health intervention on the epidemiology of early-onset GBS infections.MethodsIn 2012, Finland started the universal SBP, while Denmark, Iceland, Norway and Sweden continued with RBP. We conducted an interrupted time series analysis taking 2012 as the intervention point to evaluate the impact of this intervention. The incidences of early- and late-onset GBS infections during Period I (1995-2011) and Period II (2012-2019) were collected from each national register, covering 6,605,564 live births.ResultsIn Finland, a reduction of 58% in the incidence of early-onset GBS disease, corresponding to an incidence rate ratio (IRR) of 0.42 (95%â¯CI: 0.34-0.52), was observed after 2012. At the same time, the pooled IRR of other Nordic countries was 0.89 (95%â¯CI: 0.80-1.0), specifically 0.89 (95%â¯CI: 0.70-1.5) in Denmark, 0.34 (95%â¯CI: 0.15-0.81) in Iceland, 0.72 (95%â¯CI: 0.59-0.88) in Norway and 0.97 (95% CI: 0.85-1.1) in Sweden.ConclusionsIn this ecological study of five Nordic countries, early-onset GBS infections were approximately halved following introduction of the SBP approach as compared with RBP.
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Complicaciones Infecciosas del Embarazo , Infecciones Estreptocócicas , Lactante , Embarazo , Humanos , Femenino , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/prevención & control , Profilaxis Antibiótica , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/prevención & control , Tamizaje Masivo , Países Escandinavos y Nórdicos/epidemiología , Streptococcus agalactiae , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Antibacterianos/uso terapéuticoRESUMEN
PURPOSE: Congenital cytomegalovirus infection (cCMV) is the most frequent nonhereditary cause for sensorineural hearing loss (SNHL) in children. Data on vestibular function in children with cCMV are, however, scarce, although some evidence for cCMV-associated vestibular dysfunction exists. In this prospective cohort study, we evaluated long-term vestibular function and hearing outcomes in a cohort of children with cCMV. METHODS: Participants were 6-7-year-old children with cCMV from a large population-based screening study. Controls were age and gender matched healthy children, who were CMV-negative at birth. Hearing was examined with pure tone audiometry. Definition of hearing loss was pure-tone average > 20 dB. Vestibular function was assessed using the video head impulse test that provides a measure of semicircular canal function. Definition of vestibular dysfunction was lateral semicircular canal gain < 0.75. RESULTS: Vestibular dysfunction occurred in 7/36 (19.4%) of children with cCMV and in 1/31 (3.2%) of controls (p = 0.060). SNHL was recorded in 4/38 (10.5%) of children with cCMV and in 0/33 of controls (p = 0.118). Hearing loss was unilateral in all cases. In cCMV group, the two children with bilateral vestibular dysfunction also had SNHL, whereas those with unilateral vestibular dysfunction (n = 5) had normal hearing. CONCLUSIONS: In this cohort of children with cCMV identified using newborn screening, vestibular dysfunction was more common than SNHL at 6 years of age. Vestibular dysfunction occurred both in children with and without SNHL. Based on these data, inclusion of vestibular tests in follow-up protocol of cCMV should be considered.
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Infecciones por Citomegalovirus , Sordera , Pérdida Auditiva Sensorineural , Recién Nacido , Humanos , Niño , Lactante , Estudios Prospectivos , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/congénito , Audición , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/congénito , Audiometría de Tonos PurosRESUMEN
BACKGROUND: The fusion (F) glycoprotein of respiratory syncytial virus (RSV) represents the major neutralizing antigen, and antibodies against the pre-F conformation have the most potent neutralizing activity. This study aimed to assess the correlation between maternal antibody titers against the pre-F, post-F, and G glycoproteins and the child's risk of developing severe RSV bronchiolitis early in infancy. METHODS: We identified previously healthy term infants <3 months of age hospitalized with RSV bronchiolitis from December 2015 to March 2016. We measured IgG antibody titers to pre-F, post-F, and G proteins in maternal sera obtained at 9-12 weeks of pregnancy of these hospitalized infants' mothers (nâ =â 94) and compared them with serum antibody titers of control pregnant mothers (nâ =â 130) whose children were not hospitalized. RESULTS: All maternal samples (nâ =â 224) had detectable pre-F antibodies. Pre-F antibody titers were significantly lower in mothers whose infants were hospitalized with RSV bronchiolitis compared with those mothers whose infants were not hospitalized (23.9 [range (or antibody titer range), 1.4-273.7] µg/L vs 30.6 [XXX, 3.4-220.0] µg/L; Pâ =â .0026). There were no significant differences in maternal post-F and G antibody titers between hospitalized and nonhospitalized infants. CONCLUSIONS: Our findings indicate that maternal pre-F antibodies are fundamental for providing immune protection to the infant.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Niño , Femenino , Hospitalización , Humanos , Lactante , Embarazo , Mujeres Embarazadas , Proteínas Virales de FusiónRESUMEN
AIM: We investigated whether the ongoing COVID-19 pandemic was associated with the occurrence of Kawasaki disease or with multi-inflammatory syndrome in children (MIS-C). METHODS: This national Finnish register-based study was based on laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, MIS-C and Kawasaki disease cases. We performed a time series analysis on the occurrence of Kawasaki disease in 2016-2020. RESULTS: In 2020, there were 5170 laboratory-confirmed COVID-19 cases in children under 18 years of age and five fulfilled the MIS-C case definition. The occurrence of MIS-C was 0.97 per 1000 (95% confidence interval: 0.31-2.26) laboratory-confirmed SARS-CoV-2 infections in children. Our time series analysis showed that Kawasaki disease cases decreased during the COVID-19 pandemic. The seasonally adjusted incidence rate ratio was 0.49 (95% confidence interval: 0.32-0.74) when it was compared to pre-pandemic levels. This coincided with a reduced occurrence of respiratory infections, due to social distancing in the population. CONCLUSION: This nationwide register-based study found that MIS-C was a rare complication of the SARS-CoV-2 infection. The occurrence of Kawasaki disease and respiratory infections decreased during the pandemic. This suggests that transmissible microbes may play an important role in Kawasaki disease and social distancing may have a protective effect.
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COVID-19 , Síndrome Mucocutáneo Linfonodular , Adolescente , COVID-19/complicaciones , COVID-19/epidemiología , Niño , Finlandia/epidemiología , Humanos , Síndrome Mucocutáneo Linfonodular/epidemiología , Pandemias , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
BACKGROUND: The effects of antibiotics on infant gut microbiota are unclear. We hypothesized that the use of common antibiotics results in long-term aberration in gut microbiota. METHODS: Antibiotic-naive infants were prospectively recruited when hospitalized because of a respiratory syncytial virus infection. Composition of fecal microbiota was compared between those receiving antibiotics during follow-up (prescribed at clinicians' discretion because of complications such as otitis media) and those with no antibiotic exposure. Fecal sampling started on day 1, then continued at 2-day intervals during the hospital stay, and at 1, 3 and 6 months at home. RESULTS: One hundred and sixty-three fecal samples from 40 patients (median age 2.3 months at baseline; 22 exposed to antibiotics) were available for microbiota analyses. A single course of amoxicillin or macrolide resulted in aberration of infant microbiota characterized by variation in the abundance of bifidobacteria, enterobacteria and clostridia, lasting for several months. Recovery from the antibiotics was associated with an increase in clostridia. Occasionally, antibiotic use resulted in microbiota profiles associated with inflammatory conditions. CONCLUSIONS: Antibiotic use in infants modifies especially bifidobacterial levels. Further studies are warranted whether administration of bifidobacteria will provide health benefits by normalizing the microbiota in infants receiving antibiotics.
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Antibacterianos/uso terapéutico , Microbioma Gastrointestinal , Infecciones por Virus Sincitial Respiratorio/microbiología , Infecciones por Virus Sincitial Respiratorio/virología , Amoxicilina/uso terapéutico , Bifidobacterium/efectos de los fármacos , Clostridium/efectos de los fármacos , Enterobacteriaceae/efectos de los fármacos , Heces , Femenino , Biblioteca de Genes , Hospitalización , Humanos , Lactante , Recién Nacido , Inflamación , Estudios Longitudinales , Macrólidos/uso terapéutico , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. METHODS: The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. RESULTS: Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 109/L, and need for dialysis were predictive factors for poor renal outcome. CONCLUSIONS: Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.
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Síndrome Hemolítico-Urémico/epidemiología , Adolescente , Factores de Edad , Niño , Preescolar , Creatinina/sangre , Femenino , Síndrome Hemolítico-Urémico/microbiología , Síndrome Hemolítico-Urémico/terapia , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Diálisis Renal/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Escherichia coli Shiga-Toxigénica/aislamiento & purificaciónRESUMEN
This study characterizes a large Mycoplasma pneumoniae outbreak observed in Kymenlaakso in Southeastern Finland during August 2017-January 2018. The first part of the investigation included 327 patients, who sought healthcare consultation at local GPs or hospitals due to clinical symptoms, and were tested for M. pneumoniae antibodies (Patient cohort). The second part of the investigation, conducted approximately 4 weeks after the peak of the outbreak, consisted of school screening of pupils (N = 239) in three different school buildings by PCR on respiratory specimens and questionnaires (Screening cohort). PCR positive respiratory specimens were subsequently utilized for molecular typing. The outbreak peaked in late October 2017. Of the Patient cohort, 9/106 (8.5%) respiratory specimens were PCR positive. In contrast, 3/182 (1.6%) of the Screening cohort were PCR positive. Asymptomatic carriage was observed. Multiple-locus variable-number tandem-repeat analysis (MLVA) identified two distinct MLVA types. All typed M. pneumoniae strains belonged to P1 type 1. No mutations leading to macrolide resistance were observed. In total, 61/327 (19%) of the Patient cohort had a serological indication of recent infection. The IgM test reactivity at the time of a negative PCR test result varied from a completely non-reactive value up to very strong reactivity, highlighting the difficulty in a single specimen serodiagnosis.
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Anticuerpos Antibacterianos/sangre , Técnicas de Laboratorio Clínico/métodos , Brotes de Enfermedades , Epidemiología Molecular , Mycoplasma pneumoniae/aislamiento & purificación , Neumonía por Mycoplasma/epidemiología , Adolescente , Adulto , Niño , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Humanos , Inmunoensayo , Inmunoglobulina M/sangre , Masculino , Tipificación Molecular , Mycoplasma pneumoniae/clasificación , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/inmunología , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable [AQ4] other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies.
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Encefalopatías/genética , Dermatitis Exfoliativa/genética , Desmoplaquinas/genética , Insuficiencia de Crecimiento/genética , Variación Genética , Herpes Simple/genética , Ictiosis/genética , Encefalopatías/diagnóstico por imagen , Preescolar , Dermatitis Exfoliativa/diagnóstico , Dermatitis Exfoliativa/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Insuficiencia de Crecimiento/diagnóstico , Predisposición Genética a la Enfermedad , Herpes Simple/diagnóstico , Herpes Simple/virología , Humanos , Ictiosis/diagnóstico , Ictiosis/tratamiento farmacológico , Lactante , Recién Nacido , Masculino , Fenotipo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ustekinumab/uso terapéuticoRESUMEN
PURPOSE: Off-label (OL) use of drugs for hospitalized children is very common. OL use occurs especially in the youngest patients, neonates. This study focused on the OL use of antimicrobials in neonates. To our knowledge, only few studies have focused on the prevalence of OL use of antimicrobials in neonates. METHODS: We investigated the OL use of antimicrobials in neonates in a tertiary children's hospital. First, we investigated what were the most consumed OL antimicrobials in defined daily doses according to hospital's registry data from neonatal intensive care unit (NICU) during 2009-2014. Second, we conducted a targeted retrospective study of premature neonates (400-2000 g) with blood culture-positive infections and receiving antimicrobial therapy between 2005 and 2014 (N = 282). The data were obtained from the electronic patient records and from the hospital's electronic infection registry. Statistical analysis was conducted by using a univariate logistic regression model fitted for OL usage. RESULTS: In NICU, 35% (7/20) of antimicrobials used were OL. Eighteen percent (51/282) of premature neonates with blood culture-positive infections received at least one antimicrobial OL. The most commonly used OL antimicrobials in neonates were meropenem 88% (45/51), rifampicin 18% (9/51), and ciprofloxacin 8% (4/51). The odds for OL use were significantly higher the smaller the neonate birth weight was. An increase in birth weight was found to statistically significantly decrease the probability of OL usage (odds ratio = 0.85 for 100 g increase in birth weight, p value <0.001). CONCLUSION: More studies in neonates on especially dosing and pharmacokinetics of antimicrobials are urgently needed.
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Antiinfecciosos/uso terapéutico , Hospitales Pediátricos , Humanos , Recién Nacido , Centros de Atención TerciariaRESUMEN
The study group consisted of 180 patients who had 186 community-acquired blood-culture positive infections during 2007-June 2013. Three of them died of meningitis caused by S. pneumoniae or N. meningitidis. A ten-valent conjugated pneumococcal vaccine was introduced in the Finnish National Vaccine Program in 2010. After that the incidence of invasive pneumococcal infections decreased markedly. The numbers of resistant S. pneumoniae appeared to decrease slightly, as did also hospitalization due to pneumonia in age group 0 to 2 years. No evidence for serotype replacement was found. The situation requires constant monitoring as the time passes, since the introduction of vaccination is quite recent.
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Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/uso terapéutico , Adolescente , Niño , Preescolar , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/prevención & control , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Intestinal botulism is primarily reported in small babies as a condition known as infant botulism. The condition results from the ingestion of environmental or foodborne spores of botulinum neurotoxin (BoNT) producing Clostridia, usually Clostridium botulinum, and subsequent spore germination into active botulinum neurotoxinogenic cultures in the gut. It is generally considered that small babies are susceptible to C. botulinum colonization because of their immature gut microbiota. Yet, it is poorly understood which host factors contribute to the clinical outcome of intestinal botulism. We previously reported a case of infant botulism where the infant recovered clinically in six weeks but continued to secrete C. botulinum cells and/or BoNT in the feces for seven months. CASE PRESENTATION: To further understand the microbial ecology behind this exceptionally long-lasting botulinum neurotoxinogenic colonization, we characterized the infant fecal microbiota using 16S rRNA gene amplicon sequencing over the course of disease and recovery. C. botulinum could be detected in the infant fecal samples at low levels through the acute phase of the disease and three months after recovery. Overall, we observed a temporal delay in the maturation of the infant fecal microbiota associated with a persistently high-level bifidobacterial population and a low level of Lachnospiraceae, Bacteroidaceae and Ruminococcaceae compared to healthy infants over time. CONCLUSION: This study brings novel insights into the infant fecal composition associated with intestinal botulism and provides a basis for a more systematic analysis of the gut microbiota of infants diagnosed with botulism. A better understanding of the gut microbial ecology associated with infant botulism may support the development of prophylactic strategies against this life-threatening disease in small babies.
RESUMEN
There is limited information on vaccine responses in children with congenital cytomegalovirus infection (cCMV). We studied diphtheria, tetanus, measles, mumps and rubella vaccine responses in 6-year-old children with cCMV and controls. Protective antibody levels and geometric mean concentrations did not differ significantly between the study groups. Therefore, immunizations for children with cCMV should be administrated according to established national schedules.
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Infecciones por Citomegalovirus , Sarampión , Rubéola (Sarampión Alemán) , Niño , Humanos , Lactante , Vacuna contra el Sarampión-Parotiditis-Rubéola , Vacuna contra Difteria, Tétanos y Tos Ferina , Sarampión/prevención & control , Inmunización , Infecciones por Citomegalovirus/prevención & control , Anticuerpos Antivirales , Rubéola (Sarampión Alemán)/prevención & control , Vacuna AntisarampiónRESUMEN
Shiga toxin (Stx)-producing Escherichia coli (STEC) infections cause outbreaks of severe disease in children ranging from bloody diarrhea to hemolytic uremic syndrome (HUS). The adherent factor intimin, encoded by eae, can facilitate the colonization process of strains and is frequently associated with severe disease. The purpose of this study was to examine and analyze the prevalence and polymorphisms of eae in clinical STEC strains from pediatric patients under 17 years old with and without HUS, and to assess the pathogenic risk of different eae subtypes. We studied 240 STEC strains isolated from pediatric patients in Finland with whole genome sequencing. The gene eae was present in 209 (87.1%) strains, among which 49 (23.4%) were from patients with HUS, and 160 (76.6%) were from patients without HUS. O157:H7 (126, 60.3%) was the most predominant serotype among eae-positive STEC strains. Twenty-three different eae genotypes were identified, which were categorized into five eae subtypes, i.e., γ1, ß3, ε1, θ and ζ3. The subtype eae-γ1 was significantly overrepresented in strains from patients aged 5-17 years, while ß3 and ε1 were more commonly found in strains from patients under 5 years. All O157:H7 strains carried eae-γ1; among non-O157 strains, strains of each serotype harbored one eae subtype. No association was observed between the presence of eae/its subtypes and HUS. However, the combination of eae-γ1+stx2a was significantly associated with HUS. In conclusion, this study demonstrated a high occurrence and genetic variety of eae in clinical STEC from pediatric patients under 17 years old in Finland, and that eae is not essential for STEC-associated HUS. However, the combination of certain eae subtypes with stx subtypes, i.e., eae-γ1+stx2a, may be used as risk predictors for the development of severe disease in children.
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Adhesinas Bacterianas , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Síndrome Hemolítico-Urémico , Escherichia coli Shiga-Toxigénica , Adolescente , Niño , Humanos , Adhesinas Bacterianas/genética , Infecciones por Escherichia coli/epidemiología , Escherichia coli O157/genética , Proteínas de Escherichia coli/genética , Finlandia/epidemiología , Síndrome Hemolítico-Urémico/epidemiología , Síndrome Hemolítico-Urémico/genética , Serotipificación , Escherichia coli Shiga-Toxigénica/genética , Pueblos Nórdicos y EscandinávicosRESUMEN
OBJECTIVES: Cytomegalovirus (CMV) is the most common congenital infection affecting about 0.6% of all newborns in developed countries. Vertical transmission to fetus can take place either after maternal primary or non-primary CMV infection during pregnancy. It is the most common infectious agent for sensorineural hearing loss (SNHL) in young children. The hearing loss after congenital CMV (cCMV) may be present at birth, or may develop after months or even years. In this study, we evaluated hearing outcome at 3-4 years of age in children (n 32) with cCMV identified in universal saliva CMV-PCR-based screening. METHODS: Study population consisted of mainly asymptomatic children (median age 3.1 years) with cCMV identified in newborn CMV screening. The type of maternal CMV infection (primary or non-primary) was determined by analyzing CMV antibodies (IgM, IgG and IgG avidity) from preserved maternal serum samples drawn in the end of first trimester of pregnancy. Hearing was evaluated with pure tone audiometry (PTA), or transient-evoked otoacoustic emission (TEOAE) and sound field audiometry (SF). RESULTS: Unilateral hearing loss occurred in 5/32 (16%) of the children with cCMV. None of the subjects in our cohort had bilateral hearing loss. Hearing loss occurred in 3/15 (20%) of children who were born to mothers with non-primary CMV infection during pregnancy, and in 2/10 (20%) of children whose mother had had a primary CMV infection during the 2-3 trimester. None of the additional 6 children, whose mother had primary infection in the first trimester, had hearing loss by age of 3-4 years. Two children with normal hearing at 1 years age had developed unilateral hearing loss by the age of three. CONCLUSIONS: Unilateral hearing loss was relatively common among the mainly asymptomatic children with cCMV identified in screening. Long-term follow up of children with cCMV is essential to identify the children with late-onset hearing loss.
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Infecciones por Citomegalovirus , Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva Unilateral , Audiometría de Tonos Puros , Niño , Preescolar , Citomegalovirus , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/epidemiología , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Audición , Pérdida Auditiva Sensorineural/congénito , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/epidemiología , Humanos , Inmunoglobulina G , Lactante , Recién Nacido , EmbarazoRESUMEN
Shiga toxin-producing Escherichia coli (STEC) infection can cause mild to severe illness, such as nonbloody or bloody diarrhea, and the fatal hemolytic uremic syndrome (HUS). The molecular mechanism underlying the variable pathogenicity of STEC infection is not fully defined so far. Here, we performed a comparative genomics study on a large collection of clinical STEC strains collected from STEC-infected pediatric patients with and without HUS in Finland over a 16-year period, aiming to identify the bacterial genetic factors that can predict the risk to cause HUS and poor renal outcome. Of 240 STEC strains included in this study, 52 (21.7%) were from pediatric patients with HUS. Serotype O157:H7 was the main cause of HUS, and Shiga toxin gene subtype stx2a was significantly associated with HUS. Comparative genomics and pangenome-wide association studies identified a number of virulence and accessory genes overrepresented in HUS-associated STEC compared to non-HUS STEC strains, including genes encoding cytolethal distending toxins, type III secretion system effectors, adherence factors, etc. No virulence or accessory gene was significantly associated with risk factors for poor renal outcome among HUS patients assessed in this study, including need for and duration of dialysis, presence and duration of anuria, and leukocyte counts. Whole-genome phylogeny and multiple-correspondence analysis of pangenomes could not separate HUS STEC from non-HUS STEC strains, suggesting that STEC strains with diverse genetic backgrounds may independently acquire genetic elements that determine their varied pathogenicity. Our findings indicate that nonbacterial factors, i.e., characteristics of the host immunity, might affect STEC virulence and clinical outcomes. IMPORTANCE Shiga toxin-producing Escherichia coli (STEC) is a serious public health burden worldwide which causes outbreaks of gastrointestinal diseases and the fatal hemolytic uremic syndrome (HUS) characterized by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute renal failure. Understanding the mechanism underlying the disease severity and patient outcome is of high importance. Using comparative genomics on a large collection of clinical STEC strains from STEC-infected patients with and without HUS, our study provides a reference of STEC genetic factors/variants that can be used as predictors of the development of HUS, which will aid risk assessment at the early stage of STEC infection. Additionally, our findings suggest that nonbacterial factors may play a primary role in the renal outcome in STEC-infected patients with HUS; further studies are needed to validate this.
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Infecciones por Escherichia coli , Síndrome Hemolítico-Urémico , Escherichia coli Shiga-Toxigénica , Niño , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Finlandia/epidemiología , Genómica , Síndrome Hemolítico-Urémico/epidemiología , Síndrome Hemolítico-Urémico/microbiología , Humanos , Toxina Shiga , Escherichia coli Shiga-Toxigénica/genéticaRESUMEN
In early life, the immature human gut microbiota is prone to colonization by pathogens that are usually outcompeted by mature microbiota in the adult gut. Colonization and neurotoxin production by a vegetative Clostridium botulinum culture in the gut of an infant can lead to flaccid paralysis, resulting in a clinical outcome known as infant botulism, a potentially life-threatening condition. Beside host factors, little is known of the ecology, colonization, and adaptation of C. botulinum to the gut environment. In our previous report, an infant with intestinal botulism was shown to be colonized by neurotoxigenic C. botulinum culture for 7 months. In an effort to gain ecological and evolutionary insights into this unusually long gut colonization by C. botulinum, we analyzed and compared the genomes of C. botulinum isolates recovered from the infant feces during the course of intoxication and isolates from the infant household dust. A number of observed mutations and genomic alterations pinpointed at phenotypic traits that may have promoted colonization and adaptation to the gut environment and to the host. These traits include motility, quorum-sensing, sporulation, and carbohydrate metabolism. We provide novel perspectives and suggest a tentative model of the pathogenesis of C. botulinum in infant botulism. IMPORTANCE While the clinical aspects of infant botulism and the mode of action of BoNT have been thoroughly investigated, little is known on the pathogenesis and adaptive mechanisms of C. botulinum in the gut. Here, we provide for the first time a comprehensive view on the genomic dynamics and plasticity of C. botulinum over time in a case of infant botulism. The genomic and phenotypic analysis of C. botulinum isolates collected during the disease course offers an unprecedented view of C. botulinum ecology, evolution, and pathogenesis and may be instrumental in developing novel strategies for prevention and treatment of toxicoinfectious botulism.
Asunto(s)
Botulismo , Clostridium botulinum , Microbioma Gastrointestinal , Botulismo/etiología , Clostridium botulinum/genética , Heces , Genómica , Humanos , LactanteRESUMEN
Expression of the alcohol dehydrogenase gene ADH1, which converts ethanol into carcinogenic acetaldehyde, significantly inversely correlated with the expression of CDR1 and CDR2, genes linked to azole resistance in Candida albicans isolated from chronic oral candidosis in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED, APS-I) patients. This is a novel link between candidal two-carbon metabolism genes and azole resistance.
Asunto(s)
Alcohol Deshidrogenasa/biosíntesis , Candida albicans/genética , Candida albicans/metabolismo , Candidiasis Bucal/microbiología , Proteínas Fúngicas/biosíntesis , Regulación Fúngica de la Expresión Génica , Poliendocrinopatías Autoinmunes/microbiología , Acetaldehído/metabolismo , Alcoholes/metabolismo , Antifúngicos/metabolismo , Azoles/metabolismo , Candida albicans/aislamiento & purificación , Carcinógenos/metabolismo , Enfermedad Crónica , HumanosRESUMEN
OBJECTIVES: Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) suffer from chronic candidosis caused mainly by Candida albicans, and repeated courses of azole antifungals have led to the development of resistance in the APECED patient population in Finland. The aim of our study was to address whether the patients are persistently colonized with the same or genetically closely related strains, whether epidemic strains are present and which molecular mechanisms account for azole resistance. METHODS: Sets of C. albicans (nâ=â19) isolates from nine APECED patients reported with decreased susceptibility to fluconazole isolated up to 9 years apart were included. The strains were typed by multilocus sequence typing. CDR1/2, MDR1 and ERG11 mRNA expression was analysed by northern blotting and Cdr1, Cdr2 and Mdr1 protein expression by western blotting, and TAC1 and ERG11 genes were sequenced. RESULTS: All seven patients with multiple C. albicans isolates analysed were persistently colonized with the same or a genetically closely related strain for a mean of 5 years. All patients were colonized with different strains and no epidemic strains were found. The major molecular mechanisms behind the azole resistance were mutations in TAC1 contributing to overexpression of CDR1 and CDR2. Six new TAC1 mutations were found, one of which (N740S) is likely to be a gain-of-function mutation. Most isolates were found to have gained multiple TAC1 and ERG11 point mutations. CONCLUSIONS: Despite clinically successful treatment leading to relief of symptoms, colonization by C. albicans strains is persistent within APECED patients. Microevolution and point mutations occur within strains, leading to the development of azole-resistant isolates.