Jordi Pou

Hyperlactatemia in Human Immunodeficiency Virus–Uninfected Infants Who Are Exposed to Antiretrovirals

Objective. Exposure to nucleoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) measurements have been used to monitor nucleoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals. Methods. We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury. Results. Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia. Conclusions. In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue–induced toxicity affected neurologic development.

Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment.

Background. Hyperlactatemia and lactic acidosis occur in HIV-infected adults receiving antiretroviral treatment. Our objective was to determine the incidence, course and risk factors for hyperlactatemia in our HIV-infected pediatric patients. Design. A prospective observational study of venous lactate concentrations during a 28-month period in 80 HIV-infected children, most of whom were receiving antiretrovirals. Methods. Venous blood lactate concentrations were measured every 6 months under optimal sample-obtaining conditions. Alanine values from the same blood sample were performed when lactate concentrations were elevated. Hyperalaninemia is observed only when mitochondrial oxidative phosphorylation is chronically disturbed. Results. Twenty-three patients (29%) were identified with hyperlactatemia, in 9 of the cases with normal alaninemia, probably caused by difficult venous punctures. The other 14 children (17%) had pathologic alanine concentrations with a mean lactate peak of 2.67 mmol/l (range, 2.05 to 4.9 mmol/l); none of them showed metabolic acidosis, and they were all symptom-free. Treatment was continued in all cases, and lactate has progressed spontaneously to normal values in 5 patients. Conclusions. Symptom-free hyperlactatemia was observed in HIV-infected children receiving nucleoside analog reverse transcriptase inhibitors. In our study, only a younger age at the beginning of antiretroviral treatment was a statistically significant risk factor for hyperlactatemia. Random measurements of blood lactate concentrations should be included in the clinical follow-up of those HIV-infected children <3 years of age who are treated with nucleoside analog reverse transcriptase inhibitors, symptomatic or not.

Diagnostic approach to inborn errors of metabolism in an emergency unit

Objectives Our aim was to review the patients with a final diagnosis of inborn error of metabolism (IEM) who had previously required clinical attention at the emergency unit of our hospital over the last 9 years. Methods From the 184 patients with IEM, we selected 53 patients who required clinical attention at the EU as a prior step that led to a definitive diagnosis. We analyzed the frequency of the various IEM, their clinical presentations, and basic biochemical abnormalities in decompensation. Results We detected a predominance of neurologic signs (in 85% of our patients), followed by digestive symptoms (58.5%). Both were associated in 51% of patients. Vomiting and other digestive signs were observed in the same proportion as described in other series, but dehydration was only seen in three of our patients, probably because of early attention and fluid correction. Conclusions 1) the diagnosis of an IEM has often been made after the first consultation at the EU, leading to hospitalization; 2) we should suspect an IEM in patients with neurologic abnormalities (eg, developmental delay, hypotonus or feeding difficulties), especially in those patients with multisystem involvement who appear with acute symptoms; 3) it is of the greatest importance that the appropriate sample collection be made before starting any treatment, because abnormal biochemical data can yield a first approach and allow the definitive diagnosis; and 4) the diagnosis of a patient with an IEM is not based on a single clinical or biochemical data but rather on all abnormal features taken together.

Acute overdose due to benzydamine

Benzydamine is a nonsteroidal anti-inflammatory drug, currently available as mouthwash, aerosol, dermal cream, vaginal douche preparation, pills and otic drops. Up to now no cases of poisoning due to this drug have been reported. A 6-year-old girl with an accidental poisoning with benzydamine is described. The episode consisted of hallucinosis without other symptoms and resolved spontaneously in 17 h.

Do retinal haemorrhages occur in infants with convulsions

Aim: To determine the prevalence of retinal haemorrhages in infants presenting with convulsions and admitted to hospital, and to consider whether this finding indicates shaken baby syndrome. Methods: Prospective study of children aged 15 days to 2 years admitted with a diagnosis of first convulsion over a 2-year period (May 2004–May 2006). All infants were examined by an experienced ophthalmologist using indirect ophthalmoscopy within 72 h of admission. Results: 182 of 389 children seen in the accident and emergency department were admitted and two were found to have retinal haemorrhages. Both children were eventually diagnosed as being abused. Conclusions: Convulsions alone are unlikely to cause retinal haemorrhages in children under 2 years of age.

Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions

Type II interleukin-1 receptor (IL-1R2) is a non-signaling decoy receptor that negatively regulates the activity of interleukin-1 (IL-1), a pro-inflammatory cytokine involved in atherogenesis. In this article we assessed the relevance of IL-1R2 in atherosclerosis by studying its expression in monocytes from hyperlipidemic patients, in THP-1 macrophages exposed to lipoproteins and in human atherosclerotic lesions. Our results showed that the mRNA and protein expression of IL-1R2 was reduced in monocytes from patients with familial combined hyperlipidemia (-30%, p<0.05). THP-1 macrophages incubated with increasing concentrations of acetylated low density (ac-LDL) and very low density (VLDL) lipoproteins also exhibit a decrease in IL-1R2 mRNA and protein levels. Pre-incubation with agents that block intracellular accumulation of lipids prevents the decrease in IL-1R2 mRNA caused by lipoproteins. Lipoproteins also prevented the increase in IL-1R1 and IL-1R2 caused by a 4-h stimulation with LPS and reduced protein expression of total and phosphorylated IL-1 receptor-associated kinase-1. Finally, IL-1R2 expression in human atherosclerotic vessels was markedly lower than in non-atherosclerotic arteries (-80%, p<0.0005). Overall, our results suggest that under atherogenic conditions, there is a decrease in IL-1R2 expression in monocytes/macrophages and in the vascular wall that may facilitate IL-1 signaling.

Subdural Haematomas and Physical Abuse in the First Two Years of Life

Objective: To analyze our institution’s work-up for patients with a diagnosis of subdural haematoma (SDH) in order to determine how many of them are secondary to child abuse, as well as to examine their final functional outcome. Methods: Retrospective review of children under 2 years of age diagnosed as having SDH between 1995 and 2005. Results: A total of 35 cases were identified. Fifteen patients that had underlying conditions that predispose them to bleed were excluded. Among the remaining 20 patients, seizures and head trauma were the main causes for consultation. All patients had a coagulation study and a head computed tomography carried out, 11 of these had a magnetic resonance imaging and 1 had a post-mortem examination. Bilateral SDHs in different stages of evolution was the most common pattern of intracranial haemorrhage. Fourteen infants had a skeletal survey, 4 had a bone scintigraphy and 19 had an ophthalmoscopic examination. Fractures were diagnosed in 7 patients and retinal haemorrhages in 11. The final diagnoses were: 10 shaken baby syndromes, 4 idiopathic SDH, 3 strokes, 2 coagulopathies and 1 accidental head injury. Upon follow-up, 1 patient had died and 9 had sustained permanent disabilities. Conclusions: Cases of infantile SDH are usually thoroughly investigated. In spite of this, sometimes it is not possible to determine the SDH aetiology. Nonetheless, shaken baby syndrome remains the most frequent cause of SDH in infants, and it carries a poor prognosis.

Minor head trauma and linear skull fracture in infants: cranial ultrasound or computed tomography?

Objective To determine the clinical evolution of children with skull fractures as a result of a minor head trauma from a witnessed accidental fall that have been studied by transfontanellar ultrasound (TFUS). Methods Observational study for 2 years (2004–2006) of children up to 1 year of age who suffered a skull fracture after minor head trauma and for whom a TFUS was carried out as the first neuroimaging test to rule out intracranial injuries. Results One hundred and twenty-three children were evaluated. The mean age was 5.7 months (SD 2.9) and the most common mechanism of injury was rolling off the bed. In seven (5.7%) patients, a computed tomography (CT) was eventually performed after TFUS; in two of these patients, this was because of the detection of possible intracranial alterations and in the others, it was because of a small fontanelle. Both patients with abnormal TFUS had a small epidural haematoma on the CT scan that did not need surgery. The clinical course for all patients was uneventful. Conclusion TFUS is a valid and reliable alternative to CT for minor head trauma in infants with skull fractures. Its innocuousness and cost-effectiveness in comparison with CT makes it a good choice in this situation.

Monocyte gene-expression profile in men with familial combined hyperlipidemia and its modification by atorvastatin treatment

AIM The genetic origin of familial combined hyperlipidemia (FCH) is not well understood. We used microarray profiling of peripheral blood monocytes to search novel genes and pathways involved in FCH. METHODS Fasting plasma for determination of lipid profiles, inflammatory molecules and adipokines was obtained and peripheral blood monocytes were isolated from male FCH patients basally and after 4 weeks of atorvastatin treatment. Sex-, age- and adiposity-matched controls were also studied. Gene-expression profiles were analyzed using Affymetrix Human Genome U133A 2.0 GeneChip arrays. RESULTS Analysis of gene expression by cDNA microarrays showed that 82 genes were differentially expressed in FCH monocytes compared with controls. Atorvastatin treatment modified the expression of 86 genes. Pathway analysis revealed the over-representation of the complement and coagulation cascades, the hematopoietic cell lineage and the arachidonic acid metabolism pathways. Changes in the expression of some genes, confirmed by real-time RT-PCR, (CD36, leucine-rich repeats and immunoglobulin-like domains-1, tissue factor pathway inhibitor 2, myeloid cell nuclear differentiation antigen, tumor necrosis factor receptor superfamily, member 25, CD96 and lipoprotein lipase), may be related to a proinflammatory environment in FCH monocytes, which is partially reversed by atorvastatin. Higher plasma levels of triglycerides and free fatty acids and lower levels of adiponectin in FCH patients could also trigger changes in gene expression that atorvastatin cannot modify. CONCLUSION Our results show clear differences in gene expression in FCH monocytes compared with those of matched healthy controls, some of which are influenced by atorvastatin treatment.

Tissue factor pathway inhibitor 2 is induced by thrombin in human macrophages

Tissue factor pathway inhibitor 2 (TFPI2) is a serine protease inhibitor critical for the regulation of extracellular matrix remodeling and atherosclerotic plaque stability. Previously, we demonstrated that TFPI2 expression is increased in monocytes from patients with familial combined hyperlipidemia (FCH). To gain insight into the molecular mechanisms responsible for this upregulation, we examined TFPI2 expression in THP-1 macrophages exposed to lipoproteins and thrombin. Our results showed that TFPI2 expression was not affected by treatment with very low density lipoproteins (VLDL), but was induced by thrombin (10 U/ml) in THP-1 (1.9-fold increase, p<0.001) and human monocyte-derived macrophages (2.3-fold increase, p<0.005). The specificity of the inductive effect was demonstrated by preincubation with the thrombin inhibitors hirudin and PPACK, which ablated thrombin effects. TFPI2 induction was prevented by pre-incubation with MEK1/2 and JNK inhibitors, but not by the EGF receptor antagonist AG1478. In the presence of parthenolide, an inhibitor of NFκB, but not of SR-11302, a selective AP-1 inhibitor, thrombin-mediated TFPI2 induction was blunted. Our results also show that thrombin treatment increased ERK1/2, JNK and IκBα phosphorylation. Finally, we ruled out the possibility that TFPI2 induction by thrombin was mediated by COX-2, as preincubation with a selective COX-2 inhibitor did not prevent the inductive effect. In conclusion, thrombin induces TFPI2 expression by a mechanism involving ERK1/2 and JNK phosphorylation, leading finally to NFkB activation. In the context of atherosclerosis, thrombin-induced macrophage TFPI2 expression could represent a means of avoiding excessive activation of matrix metalloproteases at sites of inflammation.