Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

2017 French health authority guidelines for neonates at risk of early-onset sepsis: Adherence and barriers in a tertiary hospital.

The objective of this study was to evaluate the adherence to the French Health Authority's 2017 guidelines concerning early-onset sepsis (EOS) in neonates. This 6-month prospective observational study was conducted in 2020 in a tertiary hospital maternity unit. Neonates were classified according to their risk of EOS and the level of appropriate surveillance was analyzed. The risk of EOS was determined for 69.9% of the 1024 included neonates. Of the 123 neonates with a moderate or high risk of EOS, the optimal clinical surveillance was 88%. Even in a tertiary hospital, with training of caregivers, adherence to guidelines was incomplete. Some corrective measures are suggested and should be applied to enhance the adherence.

[Imaging diagnosis of hepatocellular carcinoma. Addendum to hepatocellular carcinoma: diagnosis, staging and treatment strategies]. / Diagnóstico por técnicas de imagen del carcinoma hepatocelular. Addendum de carcinoma hepatocelular: diagnóstico, estadificación y estrategia terapéutica.

This addendum is aimed to review and discuss the updated non-invasive diagnostic algorithm recently published by the American Association for the Study of Liver Diseases (AASLD).

Aminoglycoside prescription: compliance with national guidelines in a pediatric hospital.

OBJECTIVE: Our study aimed to describe the use of aminoglycosides (AGs) in the pediatric population in acute settings and to assess its compliance with the most recent national recommendations. METHODS: A single-center retrospective study conducted over a 5-month period. Pediatric patients who received at least one dose of AGs in emergency or intensive care unit were included. Compliance with the 2011 French recommendations was assessed. RESULTS: A total of 153 AG prescriptions (120 with gentamicin and 33 with amikacin) for 139 patients (median age of patients = 10 months [IQR: 3-36]) were analyzed. Most of the AG prescriptions were initiated in the emergency department (n = 117, 76%) and, overall, compliance with national guidelines was met in half (n = 77) of the prescriptions. In the emergency department, cases of misuse concerned the indication, mostly for patients with pyelonephritis. In the pediatric intensive care unit setting, the misuse concerned underdosing and a low rate of pharmacological monitoring. CONCLUSION: AGs are still misused in pediatric acute settings. In order to limit drug resistance and to be more efficacious, higher doses should be used and monitoring should be performed, in particular in pediatric intensive care units. In the emergency department, more objective criteria should be used to initiate AGs.

Endogenous endophthalmitis as a severe complication following a Streptococcus pyogenes infection.

The diagnosis of endogenous endophthalmitis is challenging. We report a pediatric case of endogenous endophthalmitis due to Streptococcus pyogenes angina. A previously healthy 33-month-old child presented to the emergency department with a history of fever and fatigue related to bacterial angina. On physical examination, an opalescent cornea was noticed and the diagnosis of endogenous endophthalmitis was confirmed by the pediatric ophthalmologist. Streptococcus pyogenes was found in blood culture and in the anterior chamber fluid. There was an adverse outcome with posterior vitrectomy and eye atrophy. Since endogenous endophthalmitis can lead to a poor visual outcome, urgent therapeutic management is necessary.

Splenic infarction associated with transient anti-prothrombin antibodies is a rare manifestation of acute Mycoplasma pneumoniae infection.

We report the first paediatric case of splenic infarction following acute Mycoplasma pneumoniae infection with induction of anti-prothrombin (aPT) antibodies. A 12-year-old boy was admitted to the paediatric emergency department for a left pleuropneumonia and a splenic infarction. aPT antibodies were transitorily detected. The patient recovered fully after antibiotic therapy and a 3-month course of anticoagulation treatment. Antiphospholipid (aPL) antibodies induced by acute infections have already been reported but cases of clinically relevant thrombosis remain rare. The pathogenicity of aPT antibodies is discussed here. We hypothesize that these antibodies were involved in this symptomatic hypercoagulable state.

Evaluating the response to locoregional and systemic treatment for hepatocellular carcinoma. / Evaluación postratamiento locorregional y sistémico del carcinoma hepatocelular.

Evaluating the response to different treatments is a decisive factor in the clinical management of patients with hepatocellular carcinoma because it can determine the efficacy of the treatment and because it can detect the recurrence of treated tumors or the appearance of new lesions that can be candidates for new treatments. When locoregional treatments that induce necrosis or molecular therapies are applied, the treated lesions usually change their behavior on imaging studies. It is important to point out that the size of the lesions does not usually decrease, at least initially, and some lesions can even appear to increase in size. For this reason, it is essential to know the mechanisms of action for each treatment applied and the spectrum of findings that these treatments can cause in the different imaging techniques used to assess the response.

Neonatal fever: A puzzling case.

Toxoplasmosis is a potentially serious fetal infection associated with maternal seroconversion of toxoplasmosis during pregnancy. Follow-up and treatment vary between different countries. We present a case of congenital toxoplasmosis with unusual physiopathology and symptomatology. The mother was immunized before the beginning of pregnancy but immunosuppressive treatments for Crohn disease maintained during the pregnancy could explain toxoplasmosis reactivation in the mother and congenital toxoplasmosis. The baby presented reversible B lymphopenia and hypogammaglobulinemia.

Diagnostic imaging: magnetic resonance imaging, computed tomography, and ultrasound.

The temporomandibular joint (TMJ) is a synovial joint. The TMJ is a freely movable articulation between the condyle of the mandible and the squamous portion of the temporal bone at the base of the skull. The bilateral articulation of the mandible to the cranium implies that the left and right TMJs must act as a single unit. Physical examination alone is inaccurate in determining the status of the joint. The primary rationale for imaging the TMJ lies in the fact that mechanical internal derangement is treated differently from the multiple miscellaneous disorders. It is mandatory to have a correct knowledge of the joint anatomy and normal function that correlates with conventional and cross-sectional imaging studies. The TMJ is illustrated with an overview of imaging strategies and techniques, especially magnetic resonance imaging, computed tomography, and ultrasound.

[Acute epiglottitis due to Haemophilus influenzae b: A severe consequence of increased skepticism about vaccination]. / Épiglottite aiguë à Haemophilus influenzae b : conséquence grave du scepticisme vaccinal.

Acute epiglottis is a life-threatening disease in relation with the occurrence of an acute upper airway obstruction. Its incidence has fallen dramatically since the widespread introduction of Haemophilus influenzae type b (Hib) conjugate vaccine. We report the case of a 26-month-old child who was not fully immunized and presented acute upper airway respiratory distress with fever. The symptoms quickly evolved to a respiratory arrest condition with bradycardia, revealing epiglottitis due to Hib. Despite high immunization coverage with great efficacy and occurrence of herd immunity, this entity still exists because of the French population's skepticism of the routine vaccination schedule.

[Markers of airway remodeling in induced sputum from healthy smokers]. / Marcadores de remodelado bronquial en el esputo inducido de fumadores sanos.

OBJECTIVE: Airway remodeling in chronic obstructive pulmonary disease (COPD) has been linked to the equilibrium between matrix metalloproteinase (MMP) 9 and its inhibitor, tissue inhibitor of metalloproteinase (TIMP) 1. However, that equilibrium has not been analyzed in healthy smokers. The aim of this study was to assess the equilibrium between MMP-9 and TIMP-1 in induced sputum from healthy smokers, healthy nonsmokers (controls), and patients with COPD. PATIENTS AND METHODS: Samples of induced sputum were obtained from 35 individuals: 12 healthy smokers, 12 controls, and 11 patients with COPD. In each sample, a differential cell count was performed and enzyme-linked immunosorbent assays were used to analyze the concentrations of MMP-9 (total and active fraction) and TIMP-1. RESULTS: Compared with controls, healthy smokers were found to have a higher mean (SD) concentration of total MMP-9 (273 [277] ng/mL vs 128 [146] ng/mL) and a higher ratio of total MMP-9 to TIMP-1 (0.16 [0.14] vs 0.08 [0.06]). However, the ratio of active MMP-9 to TIMP-1 was similar in the 2 groups. Samples from patients with COPD had the highest concentrations of total MMP-9 (477 [262] ng/mL) and active MMP-9 (178 [126] ng/mL) and the lowest concentrations of TIMP-1 (1.044 [1.036] microg/mL). When all groups were considered together, there was an inverse relationship between the MMP-9/TIMP-1 ratio and the forced expiratory volume in the first second (FEV1). The relationship between the active MMP-9/TIMP-1 ratio and FEV1 was even stronger, and the relation of both ratios with FEV1 became stronger still when smoking was considered. CONCLUSIONS: Healthy smokers had a higher concentration of total MMP-9 and that concentration was correlated with their exposure to tobacco smoke. Maintenance of the active MMP-9/TIMP-1 ratio in healthy smokers may explain the absence of progressive airway obstruction. Measurement of active MMP-9 concentration could be useful for assessment of airway remodeling.

[Bacillus Calmette-Guérin osteomyelitis. A case report in a former preterm baby]. / Ostéomyélite secondaire à une vaccination par le bacille de Calmette et Guérin : à propos d'un cas chez un ancien prématuré.

Postvaccination osteo-articular mycobacterial infectious disease is a rare and potentially serious complication after Bacillus Calmette-Guérin (BCG) vaccine. We report on a case of a former preterm baby born at 30 weeks of gestation who was vaccinated with BCG Copenhagen strain at 2 months of age. He presented 6 months later with a painful limp, which was found to be a mono-articular osteitis of the right ankle. Histology of the biopsy showed signs of mycobacterial infection and molecular analysis confirmed a BCG infection. Blood tests did not reveal any immunodeficiency associated with the disease (IFN-gamma levels were normal). The course of the disease was favorable with 9 months of antibiotic therapy against mycobacteria. BCG complications should lead to screening for immunodeficiency. The prognosis of BCG osteitis is excellent if the disease is localized. No link between prematurity and BCG complications has been found to date. BCG vaccination of premature infant should be the same as for the general population.

Predicting the development of liver cirrhosis by simple modelling in patients with chronic hepatitis C.

BACKGROUND: Data are scarce on the natural history of chronic hepatitis C (CHC) in patients with mild hepatitis C who did not respond to anti-viral therapy. AIM: To predict the risk of progression to cirrhosis, identifying patients with the more urgent need for therapy with effective anti-virals. METHODS: A cohort of 1289 noncirrhotic CHC patients treated with interferon-based therapy between 1990 and 2004 in two referral hospitals were followed up for a median of 12 years. RESULTS: Overall, SVR was achieved in 46.6% of patients. Data from a randomly split sample (n = 832) was used to estimate a model to predict outcomes. Among nonresponders (n = 444), cirrhosis developed in 123 (28%) patients. In this group, the 3, 5 and 10-year cumulative probabilities of cirrhosis were 4%, 7% and 22%, respectively, compared to <1% in the SVR-group (P < 0.05). Baseline factors independently associated with progression to cirrhosis in nonresponders were: fibrosis ≥F2, age >40 years, AST >100 IU/L, GGT >40 IU/L. Three logistic regression models that combined these simple variables were highly accurate in predicting the individual risk of developing cirrhosis with areas under the receiving operating characteristic curves (AUC) at 5, 7 and 10 years of ~0.80. The reproducibility of the models in the validation cohort (n = 457, nonresponders = 244), was consistently high. CONCLUSIONS: Modelling based on simple laboratory and clinical data can accurately identify the individual risk of progression to cirrhosis in nonresponder patients with chronic hepatitis C, becoming a very helpful tool to prioritise the start of oral anti-viral therapy in clinical practice.

[Extensive swelling reaction after a pentavalent vaccination]. / Réaction locale étendue à un vaccin pentavalent.

Injection site reactions (ISRs) are quite common side effects defined by a local adverse drug reaction directly caused by a vaccine. Twenty-four hours after an intramuscular injection (in the deltoid muscle) of the diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, Haemophilus influenza type b (DTPCa-Hib) combined vaccine, a 3-year-old boy developed fever. A few hours later, local redness and swelling appeared at the injection site, with rapid extension to the entire limb, it was pain-free, and no other clinical anomalies were present. The patient received intravenous antibiotics for suspected cellulitis. The progression was favorable in 12h (apyrexia and decreased limb swelling), allowing the intravenous antibiotic treatment to be discontinued. Since the child was in excellent general health and recovery was fast, an ISR was diagnosed. Extensive limb swelling is frequent, mostly after the fourth dose of DTPCa-Hib. Deltoid muscle injection of DTP vaccine increases the risk of ISR compared to injection in the thigh, before the age of 3 years. The introduction of acellular pertussis vaccine decreased the risk of general side effects but may increase the risk of ISR. These reactions disappear with symptomatic treatment and do not contraindicate the product.

Assessment of the IgA immunosorbent agglutination assay for the diagnosis of congenital toxoplasmosis on a series of 145 toxoplasmic seroconversions.

A retrospective analysis of 145 medical records from our teaching hospital laboratory showed an overall specificity of greater than 97% for the IgA immunosorbent agglutination assay (ISAGA A) performed on the sera of babies to diagnose congenital toxoplasmosis (CT). These actualized data emphasize the ability of this test to confirm a diagnosis of congenital toxoplasmosis.

Utility of pulsed Doppler in the diagnosis and follow-up of acute vascular graft rejection treated with OKT3 monoclonal antibody or antilymphocyte serum.

Fifteen patients with severe acute vascular graft rejection (twelve of them steroid-resistant) treated with OKT3 monoclonal antibody (8) or antilymphocyte serum (7) were sequentially studied with duplex-Doppler ultrasonography (DDUS). Measurements of intrarenal resistance were obtained by means of the resistive index (RI). During rejection episodes, the intrarenal resistance was increased in all patients (RI range: 0.89-1), with absent or reversed diastolic blood flow. Normalization of diastolic blood flow was documented prior to the decrease of serum creatinine level in all patients who recovered from a rejection episode. We conclude that DDUS is a noninvasive technique useful in the diagnosis and monitoring of acute vascular graft rejection. Prediction of graft outcome after rejection treatment could probably be made based on DDUS findings.

Technetium-99m DISIDA hepatobiliary agent in diagnosis of hepatocellular carcinoma: relationship between detectability and tumor differentiation.

The present investigation was aimed to assess the usefulness of biliary agents scintigraphy in the diagnosis of hepatocellular carcinoma (HCC) and to ascertain the relationship between the uptake of these agents and the degree of HCC differentiation. Forty-four patients with this hepatic cancer were included in the study. Liver scans were performed 20 min and 3 hr after the administration of 99mTc diisopropyliminodiacetic acid (DISIDA). DISIDA scintigraphy could not be assessed in six cases. In 16 (42%) out of the remaining 38 patients, the tumor exhibited equal or greater radioactivity uptake than the surrounding liver. In six out of these 16 patients, tumor uptake was apparent in the early and delayed hepatic scans, while in the other ten subjects radioactivity uptake by the HCC could only be detected in the 3-hr delayed scans. In the remaining 22 patients, HCC appeared as a cold area. Tumor location by this technique did not differ from that observed by 99mTc-sulfur colloid scan or ultrasound. DISIDA uptake was significantly related to tumor differentiation: 70% of those well differentiated tumors exhibited DISIDA uptake, whereas it was found in only 30% of those moderately differentiated and in none of those poorly differentiated (p less than 0.05). These results show that DISIDA scintigraphy can be useful in the diagnosis of HCC. Since its sensitivity is related to the degree of tumor differentiation, it may be indicated when aspiration cytology is unable to distinguish between well differentiated HCC and reactive changes due to hepatic cirrhosis.

Detection of Toxoplasma gondii in 94 placentae from infected women by polymerase chain reaction, in vivo, and in vitro cultures.

The biological diagnosis of congenital toxoplasmosis at birth is important to determine the infant's treatment. The aim of this study was to evaluate the placenta results in the congenital toxoplasmosis diagnosis and to compare them with those obtained with other samples collected at birth (cord blood and newborn blood). A total of 94 placentas, of which 33 came from fetuses suspected of or with proven congenital toxoplasmosis (CT+) and 61 from definitely or probably non-infected fetuses (CT-), was analysed by in vitro culture, mouse inoculation and polymerase chain reaction (PCR). The PCR sensitivity was higher (60.9 per cent) than that of cell culture (29.6 per cent) and mouse inoculation (51.5 per cent) but the number of PCR positive results in CT - patients was also higher (9.5 per cent). The presence of Toxoplasma gondii in the placenta tissues was the only argument at birth (IgM and neosynthesized Ig were negative) in three out of the 33 CT+ cases. The detection of IgM by ELISA and ISAGA and the detection of neosynthesized Ig by immunoblotting were more satisfactory to diagnose congenital toxoplasmosis but the placenta analysis was important to improve the sensitivity of the diagnosis at birth, especially when the prenatal diagnosis was negative or not performed.

Monitoring rotavirus environmental contamination in a pediatric unit using polymerase chain reaction.

Rotavirus environmental contamination in a pediatric unit was investigated. Surfaces were swabbed, then viruses eluted, ultracentrifuged, and detected by polymerase chain reaction (PCR) amplification. Of 55 samples, 25 (46%) tested positive. Rotavirus RNA was more prevalent on surfaces in direct contact with children (thermometers and play mats) than on other environmental surfaces (washbasins, door handles, etc). PCR has proved useful for monitoring rotavirus environmental contamination.

Beta 2-microglobulin and immunoglobulins are more useful markers of disease progression in HIV than neopterin and adenosine deaminase.

Reference change values of six biochemical quantities (beta 2-microglobulin, neopterin, adenosine deaminase and immunoglobulins IgA, IgG and IgM) have been established in asymptomatic human immunodeficiency virus (HIV)-infected patients following the method described by Harris and Yasaka in 1983. Patients included in the evaluation were classified as A1, A2 or A3 according to the classification of the Centers for Disease Control (CDC) (January 1993). All patients were followed-up quarterly, with a minimum of four samples each available for statistical analysis. The main objective of this paper was to study whether differences found to be greater than calculated reference change values could predict clinical or immunological worsening in patients' status. Retrospective analysis was made in asymptomatic patients (n = 256) included in an HIV infection protocol carried out in our hospital. Of these patients, 179 showed clinical or immunological worsening during the study period and 77 maintained their clinical and immunological status. Changes in beta 2-microglobulin showed the greatest sensitivity to detect clinical or immunological worsening (43.0%), whereas changes in adenosine deaminase showed the lowest (21.8%). Clinical or immunological worsening in 169 of the 179 patients was detected by one of the six biochemical quantities evaluated. Ten patients showed clinical or immunological worsening, although differences between measurements were lower than the reference change values calculated. Of 77 patients whose clinical state did not deteriorate, there was a change in biochemical analytes greater than the reference value calculated in 29 patients (a period of 12 months had elapsed since detection). In 48 patients, no increases greater than calculated reference change values were detected. The sensitivity obtained using the six analytes was 94.4% and the specificity was 62.3%.